Deciphering AIDS Vaccines — a a — Vaccines AIDS Deciphering Deciphering AIDS Vaccines

deciphering AIDS vaccines — a a — vaccines AIDS deciphering Deciphering AIDS Vaccines

an anthology of VAX and IAVI Report articles explaining

key concepts in aids vaccine research and clinical trials VAX

and and IAVI Report IAVI anthology

For free subscriptions to IAVI Report and VAX, please visit www.iavireport.org or email [email protected]

Deciphering AIDS Vaccines

fter 25 years of battling the AIDS pandemic New technologies to prevent HIV transmission Athat has already claimed the lives of more remain an imperative and an AIDS vaccine offers than 25 million people, the need for an AIDS vac- the greatest hope of all for reversing the pandemic. cine has never been greater. Last year marked the There are still many scientific obstacles to the culmination of the most ambitious global pro- development of an effective vaccine, but impor- gram to date aimed at providing antiretrovirals tant advancements have been made. Researchers (ARVs) to people with AIDS in developing coun- now have a clearer understanding of the earliest tries. Although the World Health Organization’s immunologic events in HIV infection and are ‘3 by 5’ program fell short of its target to place 3 actively studying long-term nonprogressors to million HIV-infected people on these life-saving understand the mechanisms that allow some indi- medications by the end of 2005, the funding viduals to effectively control their HIV infection from this program and others—including the without ARVs. They are also gathering new Global Fund to Fight AIDS, Tuberculosis and insights on how to manipulate animal models to Malaria and the President’s Emergency Plan for enhance the pre-clinical evaluation of vaccine can- AIDS Relief (PEPFAR)—have helped provide didates. These advancements, as well as the results ARVs to 20% of individuals in need in low- and from around 30 ongoing clinical trials of preven- middle-income countries. tive AIDS vaccine candidates in more than a This is a significant accomplishment and the dozen countries around the world, will provide momentum it has created is helping to bring researchers with important clues on how to reach hope to many communities devastated by the ultimate goal—an effective AIDS vaccine. HIV/AIDS. Importantly, these programs are also The articles in Deciphering AIDS Vaccines encouraging more and more people to be tested originally appeared in VAX and IAVI Report, the for HIV infection. But the pandemic shows little only comprehensive publications on the AIDS sign of abating. There are now about 40 million vaccine field. We hope that you enjoy and learn people infected with HIV around the globe, and from the articles in this anthology and that you 4 million of them were infected just last year. The will be intrigued to find out more. Visit soaring costs of treatment may soon make it www.iavireport.org for more information. unfeasible, perhaps impossible, to provide treatment to all in need. The IAVI Report Team Imagine a world without AIDS Editor Simon Noble, PhD FREE SUBSCRIPTIONS: To obtain a FREE subscription to IAVI Report and VAX, or for reprint Science Writer permission, please send a request, including full postal address, to Kristen Jill Kresge [email protected]. If you would like to receive multiple print copies of IAVI Report and VAX to distribute and/or use in your programs, please Production Manager send your request, including number of copies and postal address, to Nicole Sender [email protected].

The International AIDS Vaccine Initiative (IAVI) is a global not-for-profit organization whose mission is to ensure the development of safe, effective, accessible, preventive HIV vaccines for use throughout the world. Founded in 1996 and operational in 23 countries, IAVI and its network of collaborators research and develop vaccine candidates. IAVI’s financial and in-kind supporters include the Alfred P. Sloan Foundation, the Bill & Melinda Gates Foundation, The John D. Evans Foundation, The New York Community Trust, The Rockefeller Foundation, The Starr Foundation; the Governments of the Basque Country, Canada, Denmark, European Union, Ireland, The Netherlands, Norway, Sweden, United Kingdom, and United States; multilateral organizations such as The World Bank; corporate donors including BD (Becton, Dickinson & Co.), Continental Airlines, Google Inc., Merck & Co., Inc. and Pfizer Inc; leading AIDS charities such as Broadway Cares/Equity Fights AIDS, Crusaid, Deutsche AIDS-Stiftung, and Until There’s A Cure Foundation; other private donors such as The Haas Trusts; and many generous individuals from around the world. For more information, see www.iavi.org. www.iavireport.org Table of contents

Understanding… the science of AIDS vaccines …the early stages of HIV infection ...... 5 …mucosal immunity ...... 8 …AIDS vaccine pre-clinical development ...... 10 …pre-existing immunity ...... 12 …long-term nonprogressors ...... 14 …HIV clades ...... 16

An interview with… José Esparza ...... 18 Understanding… AIDS vaccine clinical trials …the benefits and risks of participating in clinical research ...... 23 …community advisory boards ...... 25 …capacity building at vaccine trial sites ...... 27 …informed consent ...... 29 …research voluntary counseling and testing ...... 31 …couples voluntary counseling and testing ...... 33 …home-based voluntary counseling and testing ...... 35 …test of concept trials ...... 37 AIDS vaccines for adolescents ...... 39

An interview with… Zackie Achmat ...... 43 Understanding… other HIV prevention strategies Cutting HIV transmission ...... 47 Treatment as prevention ...... 52 Capping infection ...... 56 HIV prevention in a pill? ...... 61

An interview with… Stephen Lewis ...... 65 Understanding… other vaccines Cervical cancer vaccines ...... 70 Malaria vaccines: Renewed promise ...... 73 Rotavirus: Vaccines enter battle against an intestinal virus ...... 77

www.iavireport.org Understanding… the science of AIDS vaccines

…the early stages of HIV infection How can studying what happens immediately following HIV infection help researchers design an AIDS vaccine? By Kristen Jill Kresge

here are many reasons why HIV is such a the CD4+ T-cell count is dangerously low, the Tdifficult virus to combat (Figure 1). One is immune system is incapable of defending the that HIV directly attacks the human immune body from attack by other pathogens and a per- system, the body’s defense against pathogens son also becomes susceptible to many oppor- like viruses and bacteria. The primary target of tunistic infections, which can be deadly. HIV is the CD4+ T cells, an important immune Measuring the number of CD4+ T cells in the cell that directs the body’s response to an infec- blood is a convenient way for researchers to esti- tion. During HIV infection huge numbers of mate the damage HIV is doing to the immune these cells are infected and killed each day, but system, since blood samples are easily obtained. new ones take their place. But the majority of the body’s CD4+ T cells Doctors or nurses can monitor the progres- aren’t in the blood. Rather they are found in the sion of HIV disease by CD4+ T-cell counts, mucosal tissues, such as those lining the respira- which are a measure of the number of CD4+ T tory, gastrointestinal, and genital tracts. Looking cells circulating in the blood. For many years only at the blood may paint an inaccurate picture after initial infection the quantity of these of what is really happening during HIV infec- important immune cells can stay the same or tion, so researchers have recently focused on drop only slightly, but in most people the virus studying the immune responses occurring specif- will eventually take over and the total number of ically at these mucosal sites. CD4+ T cells will start to dwindle. A typical defini- tion of AIDS is when the total number of CD4+ T cells in an HIV- infected person dips below 200 in a milliliter of blood (in people with healthy immune systems there are between +

600-1200 CD4 T s e g a

cells in this same m I y t t amount of blood) e G / x u

or when a person o b i G

develops one of sev- c r a M eral AIDS-associ- - n a e ated illnesses. Once J

www.iavireport.org 5 6 ASSEMBLY AND RELEASE Viral RNA and proteins are then assembled into viral 1 BINDING particles. The virus then The GP120 protein THE VIRUS buds out of the cell. on the surface of the virus binds to GP120 the CD4 receptor RNA on the host cell and undergoes a Core conformational Reverse change. It then transcriptase binds to a second receptor, CCR5 Integrase or CXCR4, and initiates fusion. CD4

CCR5 CD4 5 TRANSLATION CD4 Provirus is transcribed to viral RNA and viral proteins are produced THE prior to packaging into new HIV particles. Reverse HOST transcriptase CELL

RNA S RNA EU L C U

N DNA Viral DNA 2 FUSION Integrase The viral envelope 4 INTEGRATION fuses with the cell The HIV integrase allows membrane, and the 3 TRANSCRIPTION integration of viral DNA into viral RNA and Cell The HIV reverse transcriptase the host chromosome as a enzymes enter the DNA provirus. This integration cytoplasm. allows the single-stranded RNA of the virus to be copied and double- provides the latency that stranded DNA to be generated. enables the virus to evade host responses so effectively.

Figure 1. The HIV replication cycle. The virus first enters a human cell where it reverse transcribes its genetic material (RNA) into DNA that is then integrated into the cellular chromosomes. Once integration occurs the cell is permanently infected and throughout its lifespan it can produce new virus particles.

Looking at the gut toms or develops AIDS, and often even before an When researchers looked at mucosal tissues individual knows they are infected with HIV. they found something very interesting. In both The bulk of CD4+ T-cell death in these tissues animal models and humans, researchers observed actually occurs within a few weeks after a person a massive killing of CD4+ T cells at mucosal sur- contracts the virus, during a period referred to as faces in the intestine, or gut, very early in the acute infection. Although the number of CD4+ course of HIV infection. For many years scien- T cells in the blood also decreases during this ini- tists were more concerned with the dynamics of tial stage of HIV infection, researchers found that the human immune system much later in HIV the greatest depletion is seen in the mucosal tis- infection when it begins to fail. But research now sues of the gut. suggests that a critical destruction of immune Researchers have also found that the immune cells occurs long before a person exhibits symp- system has trouble repairing damage in these

6 www.iavireport.org mucosal tissues. CD4+ T-cell counts often type of epidemiological study with recently rebound quickly in the blood once an individual HIV-infected volunteers at several centers in starts taking antiretrovirals (ARVs), but the Africa. CD4+ T cells in the gut are restored much more Other research organizations are working with slowly than in blood, even in HIV-infected indi- collaborators to identify and follow newly- viduals who have been receiving treatment with infected individuals at sites in many countries ARVs for several years. This may mean that the loss of CD4+ T cells at the mucosal surfaces is a better predictor of Research now suggests that disease progression than monitoring their quan- a critical destruction of tity in the blood. immune cells occurs long But it would be difficult to monitor HIV- infected individuals by repeatedly measuring before a person exhibits CD4+ T-cell counts at mucosal sites. Testing symptoms or develops AIDS, these tissues requires a procedure known as a and often even before an biopsy, which is a more invasive process than collecting a blood sample. Researchers are now look- individual knows they are ing for ways to analyze subtle differences between infected with HIV. CD4+ T cells in the blood in order to more easily determine and predict what is happening in the gut. around the world. Information collected from these studies may offer clues to help better define Implications for vaccines the target for a preventive vaccine. This research has many implications for AIDS Another important implication from this vaccine design and research. If the critical battle research is the need for AIDS vaccine candidates between HIV and the immune system takes place that induce strong immune responses at mucosal in the earliest stages of HIV infection, as this tissues, especially those lining the intestine. research suggests, it is important to closely study Several researchers think this will be necessary for the virus that is transmitted and to characterize a preventive vaccine to be effective and many the nature of the immune responses in the first methods are now being explored to enhance the weeks and months of infection. mucosal immunity induced by existing AIDS Many organizations involved in developing vaccine candidates (see Understanding mucosal AIDS vaccine candidates are therefore inter- immunity, page 8). ested in studying recently HIV-infected individuals. IAVI is one group conducting this Originally published in the April 2006 edition of VAX.

www.iavireport.org 7 …mucosal immunity How could the need to assess mucosal immunity affect AIDS vaccine trials? By Kristen Jill Kresge

he most common way that HIV can be for a vaccine candidate to induce strong mucosal Ttransmitted from person to person is immune responses. through sexual contact with an HIV-infected So in recent years there has been an increased partner. Researchers estimate that about 85% of interest among researchers in developing vaccines HIV infections are caused by sexual transmission that stimulate mucosal immunity. But there is of the virus. HIV can enter the body during still relatively little known about the events lead- vaginal or anal sex, and also very rarely during ing up to the sexual transmission of HIV or the oral sex, through the surface tissues (mucosae) of immune responses necessary to prevent infection. the genitals. Researchers are now beginning to study the mucosal immune responses induced by AIDS vaccine candidates in animal models and are also Since an effective preventive looking at ways to improve and optimize these AIDS vaccine will primarily responses. have to protect an individual Vaccines to induce mucosal immunity from sexual transmission One factor that affects the level of immune of HIV, researchers think responses at the mucosal tissues is the route of vaccine administration. Most of the AIDS vac- it will probably be cine candidates that are currently in clinical tri- important for a vaccine als around the world are delivered by intramus- candidate to induce strong cular or intradermal injection. This route of administration can produce antibodies and cell- mucosal immune responses. based immune responses in the blood (systemic immunity), but does not guarantee a robust immune response at the mucosal surfaces. The human immune system can be divided Scientists think that mucosally-administered into several parts. One of these, referred to as the vaccines, including those by oral or nasal admin- mucosal immune system, relies on immune cells istration, will be more effective at producing and a specific class of antibody to prevent responses in these tissues. pathogens such as viruses or bacteria from pene- But the immune responses generated by trating and then replicating at mucosal surfaces- mucosally-administered vaccines may vary including those of the genital, intestinal, and res- greatly between the different mucosal surfaces in piratory tracts. the body. Vaccines that are taken orally tend to For sexually-transmitted viruses like HIV that produce the greatest immune responses at the enter the body through the genital mucosae, the mucosae of the intestinal tract, but are not very mucosal immune responses are the first line of efficient at producing a specific class of antibody defense and play an important role in fending off known as immunoglobulin A (IgA) at the vagi- a possible infection. Since an effective preventive nal mucosae, which could be necessary for pro- AIDS vaccine will primarily have to protect an tection against infections that can be sexually individual from sexual transmission of HIV, transmitted. Oral vaccines however are effective researchers think it will probably be important at preventing infections that primarily target

8 www.iavireport.org intestinal tissues. There are a few licensed vac- candidate in clinical trials. In the future they cines that are administered orally, including one may need to actually measure in people the for polio and two for cholera, which is a diar- level of antibody or cellular immune responses rheal disease caused by bacteria that mainly at the mucosae during an AIDS vaccine trial. infect the intestine. While systemic immunity can be measured by a Recent research suggests that vaccines that are simple blood test, measuring mucosal immu- administered to humans as sprays into the nasal nity will involve more invasive procedures that passages can give rise to substantial IgA produc- would need to be done repeatedly throughout tion in the mucosal tissues of the vagina, making the course of the trial. this type of immunization appealing to AIDS vaccine researchers. However there are also possible safety issues with nasal immunization that While systemic immunity will need to be fully explored before they are eval- can be measured by a uated in human clinical trials. Another way that mucosal immune responses simple blood test, can be optimized is by the choice of delivery sys- measuring mucosal tem for the vaccine components. Several bacter- immunity will involve ial and viral vaccine vectors are currently being developed as AIDS vaccine candidates and some more invasive procedures of these are known to generate strong mucosal that would need to be done immune responses, depending on how they are repeatedly throughout the administered. Researchers are also studying how course of the trial. some factors, such as cholera toxin, which are known to be potent inducers of mucosal immunity, can be altered to make them safe for human administration. This could make AIDS vaccine trials more Scientists are also looking at how substances complex because it will involve fully and clearly called adjuvants delivered along with the vac- explaining these procedures to all potential trial cine candidate can be used to improve the volunteers as part of the informed consent mucosal immune responses induced. Adjuvants process. It would also require training the site are already used with several licensed vaccines staff on how to take mucosal samples and provid- for other diseases to boost the level of immune ing the trial sites with the equipment required to responses and their duration. Now several assess the level of mucosal immunity from the research groups are looking at novel substances small quantity of cells obtained through such that can specifically increase the production of sampling. antibodies and immune cells at mucosal sur- It will be important that mucosal immune faces. responses are measured in diverse populations of people during clinical trials because differences in Measuring mucosal immune responses nutrition, intestinal environment, and previous Researchers are studying how AIDS vaccine infections have been shown to affect the efficacy candidates induce mucosal immunity in ani- of mucosal vaccines. mals, but they are not sure how these responses will differ in humans who receive the vaccine Originally published in the December 2005 edition of VAX.

www.iavireport.org 9 …AIDS vaccine pre-clinical development How are AIDS vaccine candidates tested for safety and immunogenicity before they enter clinical trials? By Kristen Jill Kresge

linical trials are a stepwise process to determine to generate a well-informed hypothesis about the Cthe safety and immunogenicity of AIDS vac- types of immune responses the vaccine candidate cine candidates in human volunteers. The earliest might induce in humans. trials (Phase I and II) are designed primarily to evaluate safety, while the later stage trials (Phase IIb Other pre-clinical evaluations and III) are when researchers determine if the vac- Even with a strong hypothesis, laboratory cine candidate is effective. Each Phase involves a studies can only give researchers a vague idea of progressively larger number of volunteers and con- how the vaccine will work in the complex envi- ducting clinical trials is a time-consuming and ronment within the human body. expensive process. The conduct of these trials is To try to gauge the safety and immunogenicity of closely monitored by regulatory agencies, like the a vaccine candidate, therefore, scientists have to con- US Food and Drug Administration or the duct research in animal models. Usually the vaccine European Union’s European Agency for the candidate will first be tested in mice and then in Evaluation of Medicinal Products, to ensure that a non-human primates, most often rhesus macaques. vaccine candidate meets necessary safety standards. Researchers start by administering the vaccine Prior to testing in humans, vaccine candidates are candidate to macaques and then characterizing developed and tested extensively by researchers in the immune response it induces. This includes a the laboratory and then in different animal models. detailed analysis of the cellular responses, espe- Data from these pre-clinical studies give researchers cially in T cells, and measuring the level and type important information about how vaccine candi- of antibody responses. Based on these results dates might work in people and are carefully researchers can alter the vaccine candidate to try reviewed by regulators when they are granting to enhance its immunogenicity and then re-test it approval to an organization or company to proceed in macaques. Working with animal models allows with a Phase I clinical trial. researchers to obtain extensive data that would be impossible to collect from human volunteers. Vaccine development Next researchers usually use challenge studies to Before a vaccine candidate is tested using animal evaluate vaccine candidates. In these studies the vac- models, researchers fully characterize the engi- cine candidate is administered to macaques that are neered vaccine in the laboratory—whether it is a later infected with simian immunodeficiency virus viral vector, protein subunit, or DNA-based vac- (SIV), which naturally infects many species of non- cine that will be used to present HIV protein to the human primates. Challenge studies are only con- immune system (Figure 2). For candidates that use ducted in animal models, never in human volun- viral vectors (see VAX September 2004 Primer on teers. In this type of study researchers can determine Understanding viral vectors), scientists will already how many macaques are protected by the vaccine have an extensive body of knowledge about how candidate from becoming infected with SIV. They the naturally-occurring virus acts both biologically can also determine how long this protection lasts by and immunologically so that they have an idea of challenging the macaques again later. Challenge how it will act in humans. This allows researchers studies may also provide clues on what type of

10 www.iavireport.org VACCINES FROM HIV GENES The vaccine uses HIV gene(s) as an immunogen. When taken up by human cells, these genes make HIV protein(s) that cannot cause disease but stimulate immune defenses.

Naked DNA The vaccine consists of HIV gene(s).

Viral vectors The vaccine consists of a weakened virus unrelated to HIV, into which HIV gene(s) are inserted. The virus delivers HIV gene(s) to human cells.

Bacterial vectors HIV gene(s) are delivered via weakened bacteria.

Figure 2. Different types of AIDS vaccine designs VACCINES FROM HIV PROTEINS immune responses (specific types of antibodies or Proteins The vaccine uses HIV proteins (e.g., gp120 cellular responses) are responsible for this protec- on HIV’s surface) as an immunogen. tion, an idea referred to as correlates of protection. This data gives researchers critical information Peptides about the vaccine candidate and helps them The vaccine uses small pieces of HIV determine if it is safe and immunogenic enough protein(s) as an immunogen. to move into clinical trials involving human volunteers. Many of the vaccine candidates that are clinical evaluation more difficult. This is just one evaluated in pre-clinical studies never actually of the many complications researchers face in advance into clinical trials because they are not developing an effective AIDS vaccine. immunogenic enough to explore further. For many years, therefore, researchers have sought ways to improve their ability to evaluate can- Limitations didates in pre-clinical studies and find a better ani- One important limitation with these animal mal model for HIV infection. Recently researchers studies is that the vaccine is not being tested against have developed an engineered mouse model where an HIV challenge. Researchers must evaluate the human cells are transplanted into mice that have vaccine candidate’s immunogenicity against SIV, their own immune systems depleted. This allows which is a closely-related but different virus, because mice to grow human immune cells that can be HIV does not infect non-human primates. To more infected by HIV. With refinement this type of closely mimic HIV infection in humans, researchers model may be useful to researchers as an initial have tried running challenge studies with an engi- screen for AIDS vaccine candidates to help deter- neered virus that contains both SIV and HIV mine if a candidate is immunogenic enough to pur- genes—known as SHIV—but this is generally seen sue in human clinical trials. as an even less satisfactory model than SIV for pre- Scientists are also studying the genetic factors dicting how a vaccine will work in humans. that allow non-human primates to fend off HIV Another limitation is that researchers have to infection. This research might one day enable sci- also modify the vaccine candidate to carry SIV entists to engineer an HIV strain that can pro- genes, rather than HIV genes, to match the virus ductively infect an animal model and therefore being used in the challenge studies. Using a dif- more closely mimic human infection. ferent challenge virus and a different vaccine candidate in a different animal species makes pre- Originally published in the October 2006 edition of VAX.

www.iavireport.org 11 …pre-existing immunity What is pre-existing immunity to a vaccine vector? By Kristen Jill Kresge

hen a person is infected with any disease- First, the immune system must ‘see’ the vac- Wcausing agent (or pathogen, such as a cine. Many current AIDS vaccine candidates virus) the immune system makes antibodies and use a vector as a carrier to get to the immune immune cells that recognize the pathogen and system. The vector is a weakened virus (or bac- control the infection. Many of these antibodies terium) that is safe for use in humans. and immune cells disappear after the infection Sometimes the vector is developed from a vac- is over. But a group of immune cells remain that cine against another disease. Scientists are work- are called memory cells. These cells stay inactive ing with a number of different vectors for AIDS in the body until the person is exposed to that vaccines (see VAX September 2004 Primer on same virus again. The memory cells can then Understanding viral vectors). Vectors made from quickly recognize the virus and make more anti- other viruses are called viral vectors. bodies or immune cells to limit and clear out When a common virus or vaccine is used as a the infection. vector, some people will have been previously exposed to this virus either naturally or through immunization. Some people will have an immu- Researchers are trying to nity to the vector; this is called pre-existing design a vaccine so that the immunity. When someone has pre-existing immunity to a protein of HIV will cause an virus or to a harmless vector, they have immune immune response strong memory cells or antibodies specific to that enough to protect people if pathogen or vector stored in their body. If the they are later exposed to HIV. vaccinated person’s immune response is directed towards the vector, it might limit the immune response to the HIV immunogens. This could make the vaccine less effective. So for each vector A vaccine tries to get your immune system to it is important to figure out whether preexisting produce the same immune response as in a natu- immunity to it could prevent the vaccine from ral infection by using immunogens (pieces of working. viral protein). These small pieces of virus generate memory cells that can rapidly respond if the Current vectors person is later exposed to that virus. Several promising AIDS vaccine candidates In order to generate an immune response are using a modified human adenovirus called against HIV, an AIDS vaccine will have to con- Ad5 as a vector. Human adenoviruses naturally tain some immunogens that are copies of pieces cause severe colds. After the infection is cleared of the genetic material of HIV. Because only a the infected person has memory cells and anti- part of the HIV genetic material is used, this type bodies specific to that adenovirus. There are of vaccine cannot cause HIV infection. about 40 different groups (called serotypes) of Researchers are trying to design a vaccine so that human adenoviruses. About 35% of people in the protein of HIV will cause an immune Europe and the US, and as many as 90% of peo- response strong enough to protect people if they ple in some countries (South Africa, Zambia, are later exposed to HIV. Botswana, and Thailand), have previously been

12 www.iavireport.org infected with Ad5. So pre-existing immunity to this vector is common. An important AIDS vaccine trial is now ongoing with Merck’s Ad5 vector, called MRKAd5. This trial will test the ability of the vaccine to s e either prevent infection g a m I y with HIV or control dis- t t e G / ease progression in peo- x u o b i

ple who do later become G c r infected with HIV. a M - n a

Researchers hope that e J the vaccine will stimu- A researcher examines an ELISPOT assay and compares it with an late the immune system automated readout on the computer screen. to produce killer T cells that can kill HIV-infected cells. This is called a Researchers are yet to determine whether pre- cellular immune response. existing immunity will be a problem for the dif- This vaccine is being tested in 1500 volun- ferent vectors being developed as AIDS vaccine teers in eight countries. Only people with a candidates. low level of pre-existing immunity to Ad5 are The Modified Vaccinia Ankara (MVA) vector enrolling in this trial. Without the problem of is one example where pre-existing immunity pre-existing immunity, researchers can fairly does not seem to be a problem. This vector is assess how effective the vaccine candidate is part of several ongoing trials, including one against HIV. But the results of this trial are not that began in January. MVA is similar enough due for about four years. In the meantime to the virus used for smallpox immunizations researchers are exploring different approaches that pre-existing immunity to the smallpox vac- to improve the adenovirus vector. Some of cine could possibly affect the efficacy of an these approaches include using higher doses of MVA-based AIDS vaccine candidate. But this vaccine or using more than one vaccination vector may have less trouble with pre-existing (what is called a prime-boost strategy). immunity because smallpox vaccinations ended Another approach would be to use a different in most countries in the mid-1970s. People serotype of adenovirus for which there is less enrolling in vaccine trials are typically aged 25- pre-existing immunity, like Ad11 and Ad35. 40 and therefore pre-existing immunity will be These serotypes are currently being developed unlikely. It is also no longer a naturally-circu- as vectors for AIDS vaccines and could be used lating virus because of the successful worldwide to get around the problem of pre-existing immunization campaign. So far no effect of immunity to Ad5 if the current trial shows pre-existing immunity has been seen for MVA promise. vectors but more information is needed. Other viral vectors now being used or devel- Until researchers have more data on pre- oped for preventive AIDS vaccines may also existing immunity this is just one of the many face the problem of pre-existing immunity considerations that vaccine developers must (such as measles or polio vaccine viruses) but face. each new vector must be studied to determine the importance of pre-existing immunity. Originally published in the February 2005 edition of VAX.

www.iavireport.org 13 …long-term nonprogressors What can AIDS vaccine researchers learn from studying people who are HIV infected but progress more slowly to AIDS? By Kristen Jill Kresge

t takes, on average, about a decade for an that can suppress the virus. Typically a person’s IHIV-infected individual to develop AIDS. CD4+ T cell count begins to rebound soon after This progression occurs gradually as the virus starting ARV therapy and their viral load drops attacks and destroys CD4+ T cells, a subset of dramatically, often falling below the limit immune cells that are an essential component detectable by routine tests. of the body’s immune response to pathogens But some HIV-infected individuals are able such as viruses and bacteria. Other mecha- to control the virus for much longer than a nisms are also implicated in the gradual decade without ever taking ARVs. Researchers depletion of these cells. Many CD4+ T cells have even identified people who have been are initially replenished by the immune sys- HIV infected for as long as 28 years and have tem and as a result most HIV-infected indi- never progressed to AIDS. These individuals viduals remain healthy with few, if any, symp- are known as long-term nonprogressors, and they maintain very low viral loads and either don’t progress to AIDS or do so much more AIDS vaccine researchers are slowly. Researchers estimate that 1% of all peo- particularly interested in ple who are HIV infected are long-term non- determining the type of progressors. Just what makes these individuals able to immune responses that are control HIV for longer than others is still responsible for slowing something of a mystery, and it is further com- disease progression because plicated because it could be due to different mimicking these responses factors in different people. Several characteristics of the virus or the individual’s genetic might be the key to producing makeup could be partly responsible for this dif- an effective vaccine. ference and researchers are actively studying long-term nonprogressors to determine exactly what enables them to control their HIV infec- toms for several years. But eventually the tion. AIDS vaccine researchers are particularly immune system begins to fail and the number interested in determining the type of immune of CD4+ T cells slowly declines. This is often responses that are responsible for slowing dis- accompanied by an increase in the HIV viral ease progression because mimicking these load, which physicians measure by quantify- responses might be the key to producing an ing the number of copies of virus in a sample effective vaccine. of blood. This could be especially true for a partially- A person with a healthy immune system has effective vaccine, one that would most likely between 600-1200 CD4+ T cells in a milliliter of not prevent HIV infection entirely but could blood. When the number of CD4+ T cells falls lower viral load in people who do become below 200, a person is clinically defined as hav- infected. This lowered viral load would reduce ing AIDS. At this point it is recommended that the risk of them transmitting the virus to oth- individuals begin taking antiretrovirals (ARVs) ers, so a partially-effective vaccine could signif-

14 www.iavireport.org icantly reduce the number of new HIV infec- tant in controlling HIV infection, a team of sci- tions. Long-term nonprogressors may hold entists are now collaborating on a project to important clues about what type of immune study specific subsets of long-term nonprogres- responses an AIDS vaccine would have to sors known as elite or viremic controllers. Elite induce to keep HIV viral load under control. controllers are HIV-infected individuals not taking ARVs who maintain viral loads that are con- Possible explanations sidered undetectable (<50 copies of virus per ml Researchers began studying long-term non- of blood). About 1 in every 300 HIV-infected progressors more than 15 years ago and they people is considered an elite controller. Viremic have identified several possible explanations for controllers are infected people not taking ARVs why some people have the ability to control whose viral load remains below 2000 copies/ml HIV more effectively than others. One is that of blood. the virus that these individuals are infected with is weaker and therefore less able to infect and kill CD4+ T cells. Some people are Long-term nonprogressors infected with a strain of HIV that is missing a may hold important clues key viral protein, known as Vpr, which limits about what type of immune its ability to infect cells. responses an AIDS vaccine Another possible explanation is that people have CD4+ T cells that are resistant to HIV would have to induce to keep infection. Individuals have been identified who HIV viral load under control. lack a receptor on the surface of these immune cells that is normally used by HIV to gain entry into and subsequently infect the cell. Researchers Bruce Walker and colleagues at the Harvard think there are probably also other genetic prop- Medical School are now working with other erties that allow a person’s immune cells to target AIDS vaccine researchers to identify a group of and kill HIV more effectively. 1000 elite and viremic controllers around the But there are also many individuals who are world—they estimate there are about 2000 in long-term nonprogressors who are not infected the US alone, most of whom don’t know it. with a weakened version of HIV or who do not They plan to analyze the immunologic and have any of the known genetic properties that genetic characteristics of these individuals uti- bolster their resistance to the virus. Researchers lizing the information collected by the Human have studied these individuals to see if their Genome Project that successfully mapped the immune systems are somehow able to mount thousands of human genes. By comparing this more effective immune responses against HIV. information across a larger cohort of con- So far none of the immune responses they’ve trollers, researchers are hopeful that they will studied in long-term nonprogressors are any dif- be able to identify the specific genes or ferent than in people who progress to AIDS immune responses that allow some people to more quickly. control their HIV infection. Hopefully this will yield important clues for the future design Elite controllers of AIDS vaccines. To try to solve this puzzle and identify the particular immune response that might be impor- Originally published in the September 2006 edition of VAX.

www.iavireport.org 15 …HIV clades How does the genetic diversity of HIV affect AIDS vaccine design? By Renata Rutman

key concern for AIDS vaccine researchers is But there are still many unanswered ques- Athe tremendous genetic diversity of HIV. tions about the significance of viral diversity The majority of global HIV infections are caused for AIDS vaccine design. Scientists do not yet by a single group of virus, which is divided into know whether immune responses induced by a nine different subtypes, or clades, designated by preventive AIDS vaccine would be able to pro- the letters A through K. Further complicating tect against only one particular HIV clade or matters are the viral recombinants that occur against several. Most clinical trials of AIDS when viruses from different clades combine seg- vaccine candidates have occurred in communi- ments of their genome, forming a hybrid. These ties where the antigen in the vaccine comes occur in several regions of the world where more from the same HIV clade as the one circulating than one HIV clade is circulating. in the region, a concept known as clade or genetic matching. The key for an effective The advent of clades AIDS vaccine is to elicit the kind of immune The diversity of HIV and the development response that would be effective against the of clades stems from the ability of HIV to pro- circulating virus in the region, but this is not duce billions of viral particles daily (Figure 3). well predicted by clade alone. Clade classifica- The enzyme involved in viral replication, tion refers to the different protein sequences reverse transcriptase, is not precise and some- that distinguish the circulating viruses and not times incorporates mistakes into the viral the way the human immune system recognizes genome, resulting in genetic mutations. The or reacts to HIV, so the importance of such more HIV replicates, the more likely it is to matching is still in question. Scientists are also make mistakes, increasing the potential for still trying to determine the type and magni- genetic variation. tude of immune response required for protec- Each of HIV’s genes develops mutations at a tion, so clinical trials to determine the different rate. The genetic sequence of the enve- immunogenicity of vaccine candidates in rele- lope gene (env), for example, which encodes the vant populations remain critical. HIV surface protein that attaches the virus to human cells, can vary by as much as 35% in virus Implications for vaccine design samples from different clades. Others, such as the When the first AIDS vaccine trials were initi- gag gene that encodes the internal core of the ated, vaccine development efforts focused mostly virus, remain more conserved, varying by less on candidates from isolates of HIV clade B, than 10% from one clade to another. Overall, the found in North America, parts of South America, genetic makeup between all clades deviates by Western Europe, and Australia, and currently approximately 30%. responsible for approximately 12% of global HIV clades also vary in prevalence throughout infections. Later, candidates with antigens from the world. For example, HIV clade B is found clades A and D, both common in parts of Africa, mostly throughout North America and Europe, were brought to clinical trials. Several others were while the epidemic in South Africa and India is also developed based on clade C, the subtype cir- due to HIV clade C. Researchers are therefore culating in Southern Africa, India, and China, trying to develop an AIDS vaccine candidate that which is responsible for over 50% of all HIV offers the broadest possible protection. infections worldwide.

16 www.iavireport.org High Mutation Rate Recombination Rapid Replication Approximately 1 substitution Approximately 7-30 crossovers Approximately 10.3 x 109 per genome per round per genome per round virions per day

HIV-1 variation tree

Reverse transcriptase

Transcription error The phylogenetic tree depicts relationships based on complete HIV-1 genomes from nine genetic subtypes, two of which are divided into sub-subtypes, and from 16 of the circulating recombinant forms (CRF). Many other inter-subtype recombinant forms, termed URF for “Unique recombinant forms,” are circulating at low levels, particularly Recombinant in regional epidemics where two or virus more subtypes co-circulate.

Tree source: From the laboratory of Francine Figure 3. Causes of HIV variability and impact on the circulating virus McCutchan, Henry M. Jackson Foundation

As more candidates entered clinical testing dif- novirus serotype 5 (Ad5) vaccine candidate, ferent approaches to vaccine development have known as MRKAd5. The candidate is currently emerged to tackle HIV diversity. One strategy being evaluated in another Phase IIb trial in aimed at eliciting cellular immune responses North America, South America, the Caribbean, involves the use of the most conserved regions of and Australia. The addition of a South African HIV or widely recognized protein pieces from trial marks the first time this candidate will be different parts of HIV to develop an AIDS vac- evaluated in a population where the circulating cine candidate. clade of HIV, clade C, does not match that in the A different vaccine strategy that aims to elicit vaccine. broadly-neutralizing antibodies against several In 2003 the African AIDS Vaccine Programme clades uses a combination vaccine with env genes came out strongly in favor of planning trials to from several clades. A third approach, which is give clear answers about protection across differ- not yet in clinical trials, compares the sequences ent clades as long as there is evidence that the of HIV genomes from different clades to create a vaccine candidate induces immune responses computer-generated sequence that best matches against the most commonly circulating virus, the highest number of strains, with the hope that regardless of clade classification. Preclinical data any protective immune response that the vaccine for MRKAd5 show reactivity between the vac- elicits would confer protection against infection cine antigens and the predominant virus found by different HIV clades. in South Africa. The Merck trial therefore offers an opportunity to test this in a “proof of concept” Informing the field trial that may provide preliminary answers about Merck and the HIV Vaccine Trials Network a vaccine’s efficacy while answering crucial ques- (HVTN) are now completing site preparations in tions for vaccine design. South Africa for a second Phase IIb “test of concept” trial with the company’s clade B-based ade- Originally published in the July 2006 edition of VAX.

www.iavireport.org 17 An Interview with… José Esparza HIV vaccine developments

José Esparza MD, PhD has been a leader in the international HIV arena for almost two decades and for much of that time has been a consistent champion for AIDS vaccines, particularly for developing countries. He currently wears two hats, one as Senior Advisor on HIV Vaccines at the Bill & Melinda Gates Foundation, as well as head of the interim secretariat for the Global HIV Vaccine Enterprise. Esparza began his research career at the Venezuelan Institute of Scientific Research in Caracas, Venezuela, where he rose from graduate student to full professor. During that time he completed his PhD at Baylor College of Medicine, Houston, Texas, and managed a two-year spell as a visiting professor at Duke University, North Carolina. His research interests have encompassed epidemiology to molecular biology in human virology, including herpes simplex viruses, Venezuelan equine encephalitis virus, and rotaviruses. In 1986 he joined the World Health Organization (WHO) in Geneva, and soon became a leader in that organization’s HIV/AIDS programs, with an emphasis on vaccines. Esparza then moved in 1996 to the Joint United Nations Programme on HIV/AIDS (UNAIDS) to lead their HIV vaccine programs. In 2004 he joined the Bill & Melinda Gates Foundation and has been an important figure in establishing the nascent Vaccine Enterprise.

IAVI Report Editor Simon Noble spoke to Esparza in December 2005 about the Gates Foundation, the Vaccine Enterprise, and recent developments in the field of AIDS vaccines.

The Gates Foundation is now a leading health—the emphasis is to develop interventions global health organization. Consequently it that can be used in developing countries—takes now has a very wide scope of activities—in about 60% of our funding at this time. comparison to other diseases, what empha- When AIDS appeared 25 years ago, it not only sis does the Foundation place on HIV? created major inequities but also helped to iden- The Gates Foundation is a family foundation tify existing major inequities, including inequities and our mission—which reflects the vision of Bill to do with access to education that helped prevent and Melinda Gates—is to help address fundamen- many people in the North from becoming tal inequities in the world, something that Bill has infected but that wasn’t widely available in the referred to as the random geography of birth: A South. And that inequity between the haves and child born in the US or Europe has a totally differ- the have-nots was then increased when antiretro- ent perspective in relation to access to health, edu- viral drugs were developed. cation, housing, the future in general, when com- I hope that once an HIV vaccine is developed it pared to a child who is born in, say, the middle of will not contribute to further increasing the gap Africa. They have identified that two of the major between the North and the South. If the vaccine that factors of this inequity has to do with lack of access is developed is not appropriate for developing coun- to education and healthcare. Because of that, global tries because of the cost, because of the regimen for

18 www.iavireport.org administration, because of the sub-type specificity, in industrialized and developing countries. A key or for some reason it’s not available in developing strategic decision was when the end point to meas- countries, then that would be the ultimate tragedy. ure vaccine efficacy was changed from prevention About $1.1 billion of the $6 billion in global of infection to prevention of disease, which is a health grants to date have gone towards HIV. current discussion in the HIV vaccine community, This proportion may change as we find where the although there are important differences. strategic opportunity arises, so we can move there In rotavirus, there is not natural immunity after and make a difference. infection, children who are infected with rotavirus can be re-infected and re-infected. Conventional How much emphasis is placed on HIV pre- wisdom will tell you that if there is no post-infection vention versus treatment? immunity, forget about a vaccine. The eureka Today, in 2006, we don’t see a dichotomy moment came when Al Kapikian at the US National between prevention and treatment. Both are impor- Institutes of Health (NIH) and others realized that tant components of our response to AIDS, they the primary infection was the more pathogenic, and have to go hand in hand. But 10 years ago, there when a child was re-infected the disease was gener- was confrontation between prevention and treat- ally very mild. That actually led to a change in the ment. When I was at the WHO I remember mak- paradigm: A vaccine may not be able to prevent ing the point that an organization that focuses on infection, but let’s measure instead the severity of dis- prevention can’t disregard those who are infected. ease. And voila—there was a clear difference. We’re very encouraged by the recent progress on There are other parallels with HIV vaccines. treatment, but there’s still a long way to go on pre- There are many rotavirus types—although the vention. We are developing a broad prevention problem of rapid mutation does not apply—and portfolio, including microbicides, vaccines, pre- one vaccine is based on one type, and the other vac- exposure prophylaxis, behavioral components like cine on four types. How much cross-protection the Avahan initiative in India to empower disen- between types exists? With correlates of protection, franchised populations, and others. We work with the rotavirus vaccine protection seems to be better other partners to ensure that the response to the than the level of circulating and mucosal antibod- epidemic is not skewed in any direction but ies would predict. So the immune correlates of pro- remains comprehensive, rational, and durable. tection are not very clear. Also, the rotavirus vac- There have been major efforts in the last three cine was developed without a good animal model. years, like the President’s Emergency Plan for The other lesson for HIV vaccines of course is AIDS Relief (PEPFAR) and the ‘3 by 5’ program, the need to conduct multiple, multiple Phase III to increase access to therapy. That’s wonderful, trials. To some extent, it was an empirically-devel- and it has facilitated the work of organizations oped vaccine. It wasn’t this approach that scientists like IAVI that focus on prevention. tend to have, that you do a trial or an experiment to prove that your hypothesis was correct. It was You used to work on rotavirus, it must be actually a very exploratory, empirical approach to exciting to finally see an effective vaccine vaccines that they learned by doing. Overall, the come to market. Does this example have rotavirus vaccine gives us some good lessons for lessons for AIDS vaccine development? HIV, including the need to maintain a balance Yes, I started working with rotavirus soon after between rational development and empirical test- it was discovered, in 1974. The ultimate goal was ing. There is no substitute for clinical trials. the development of a vaccine, and I am thrilled that now we have one, or maybe even two. I often Do you think that within the AIDS vac- use rotavirus as a paradigm for HIV vaccines. The cine field people are seeing that preven- development of the vaccine took over 30 years of tion of infection, sterilizing immunity, is hard work, with multiple efficacy trials conducted such an elevated goal that perhaps we

www.iavireport.org 19 have to lower the bar and go for preven- developing countries to justify using a vaccine tion of disease? Do you think that’s being that was found not to be safe enough for the US. tacitly agreed upon? I’ve seen all the calculations of how many lives I don’t think so, or at least for me it’s not clear. I will be saved, because intussusception, as you say, think that the intermediate goal of a vaccine may be is a very rare phenomenon, but from the very prevention of disease rather than infection. But we beginning I knew that it would be too much to don’t have the information to conclude that this ask for decision-makers in developing countries should be the ultimate goal of a vaccine. Experience to accept a vaccine that had been found unsafe. is that people who become infected will, sooner or Now, had the rotavirus vaccine been simultane- later, progress to disease. And accepting this inter- ously tested and introduced into industrialized and mediate goal too early could actually prevent the developing countries, I think the discussion would research that is needed to see if we can develop a have been different. Developing countries may vaccine that confers sterilizing immunity. There are have different risk-benefit decisions than industri- many, many opinions in this field and I think we alized countries. A risk-benefit analysis takes into need more than opinions; we need facts. Science is account burden of disease, the cost of the product, not what you believe but what you know. its ease of use, and many other factors that typically I think that debate is still ongoing. I would differ from country to country. But the value of life caution against premature agreement in the sci- is the same anywhere in the world, and if the per- entific community that the goal should be a vac- ception is that you are proposing a substandard cine that just prevents disease. This is work in vaccine in developing countries, that will not fly. progress; we don’t yet know the limitations. So that’s a lesson to learn for HIV vaccines: Simultaneous testing and simultaneous introduc- An effective rotavirus vaccine was intro- tion of the vaccine in developing countries, and duced into the US in 1999 but was subse- allowing developing countries to make their own quently associated with intussusception (a risk-benefit analysis. A major priority for the folding of the intestine) in fewer than Foundation is helping to ensure that health prod- 1:10,000 children given the vaccine, leading ucts that could save lives reach the people who to its withdrawal. In industrialized coun- need them the most as quickly as possible. tries rotavirus is a fairly innocuous infection but in developing countries almost half Given those provisos, do you think there is a million children die each year from dehy- a global perception now that HIV/AIDS dration caused by rotaviral diarrhea. Do you within developing countries has become think this has any relevance for AIDS vac- such a crisis that perhaps these conversa- cines, that perhaps we have to look at the tions can now be broached again? risk-benefit analysis of a vaccine in the con- Yes, I think so, and the reason is that there is text of a particular country? far greater research literacy in developing coun- I’m very familiar with the intussusception story, tries today than ten or 15 years ago. Then it was and we lost an opportunity there. The strategy for very difficult because basically you went to devel- introducing most vaccines, still in use today, is intro- oping countries to ask them ‘Please trust me. duction first in industrialized countries to try to Trust the NIH. Trust the WHO.’ It’s very diffi- recoup some of the development costs and then cult to have a rational and pragmatic discussion move it to developing countries. The conversation when you’re asking people to trust you. Today, I about rotavirus vaccine took place after the intussus- think that thanks to the work of many people, ception issue was identified in the US, when the vac- IAVI included, vaccine literacy is much higher. cine was not actually in use in developing countries. There is a very, very heavy political component What do you think sets apart the to this. It’s very difficult for decision-makers in Enterprise’s way of doing business? What

20 www.iavireport.org does it offer above and beyond the collab- their contribution, then I like the industrial model. orative efforts already underway? A number of people believe there is a strategic I have been observing the field of HIV vaccines gap in the field of HIV vaccines. We can divide for many years, and I saw a major strategic shift after the vaccine development process, from an idea to the results from the recent Phase III trials. On one injection into the arms of people, through four hand, the research community realized that devel- phases. The first is the discovery phase, creation oping an HIV vaccine was one of the major scien- of new knowledge, and the NIH is the driving tific challenges we were confronting and that a force. Most NIH-funded scientists stop at that much more intense and rational effort was needed level, publication is basically their goal. The sec- to complement the more or less empirical approach ond is the translational or, as I like to call it, mat- taken up till then. The other shift was what I call uration phase. The third phase is the manufactur- from the “solitary hunting approach” to “pack hunting phase, the typical industrial approach, the ing,” as prehistoric man did when he shifted from engineering phase. And the fourth phase is the hunting small animals to mammoths. If we want to delivery of the vaccine; we have a vaccine, how do succeed on this hunt, we need to reorganize our- we make it available to people around the world? selves in a more purposeful and targeted way, as that My feeling is that we have a strategic gap in the proposed by the Enterprise. Collaborative efforts second phase, and that is one of the areas where should expand beyond exchanging reagents and the Enterprise can make a major contribution talking in meetings, to a more structured and and help mature ideas so that they become inter- accountable way—perhaps we should look at how esting leads for industry to follow, and then work collaboration is structured in industry. together with industry as real partners, because But I want to clarify that the Enterprise does we need industry for their process development not propose to replace the creativity of individual and manufacturing expertise. investigators, which we consider essential. The Enterprise proposes to supplement that creativity What are your initial impressions of how the with systems and structures that provide the crit- Center for HIV-AIDS Vaccine Immunology ical mass, a clear blueprint for research that may (CHAVI) is developing? lead to discovery and product development, I think that the success of CHAVI is related to access to information and resources, a supportive the success of the Enterprise: We need to improve political and community environment, and the the way scientists interact with each other and financial resources to achieve success. CHAVI represents a new model for increased col- I recently had a conversation with Rino laboration. CHAVI and the NIH decided to first Rappuoli, who for me is the quintessential, practi- identify the core leaders and then asked those lead- cal vaccinologist, and he thinks the industrial ers to develop the network. The foundation is tak- model is very much an engineering approach. If ing a similar approach, although we first identified you want to put a man on the moon, you know the the members of the network, and now we are work- laws of physics that will govern how a rocket will fly ing with them to establish a collaborative group. from the earth to the moon, so it’s an engineering What I see from CHAVI is that they are making problem, an industrial problem. The problem we a very serious effort to do two things. One is to bring have with HIV vaccines is that we are to some new partners to the field. Now, of course many of extent in a pre-industrial stage, because we don’t the leaders are veterans of the HIV vaccine effort, have a solution, and we have to explore many because you have to go to those people who have the avenues, we have to build many small space probes knowledge that we need to tap. The trick is getting rather than one big spaceship. However, if the the same players to play a different game, a more industrial model means a more targeted effort with cooperative game. But CHAVI is also making an clear milestones, with clear go-no go decisions, in effort to bring in new players, and in their list of col- which the different partners are accountable for laborators you see more people from developing

www.iavireport.org 21 countries, more strategic alliances being created with a new paradigm, you’re trying to jump with ideas people who are actually newcomers to the field. that are not supported by data, because they are The second is to bring new money to the field, new. Most of the time those new ideas outside of and the NIH has pledged up to US$350 million the paradigm are wrong. So jumping to a new for CHAVI. That is additive money, and hopefully paradigm will require taking risks to a level that it’ll create a culture of more collaborative work most organizations cannot accept. than the typical NIH R01 grants. We are eager to Although the solution for an HIV vaccine may see CHAVI’s progress: I’m very optimistic that come out from the current paradigm we need to CHAVI is a critical contribution to the Enterprise. be constantly looking at innovative research, how to bring really new science, not only theoretical It seems that the Enterprise’s strategic knowledge but also even instrumentation and scientific plan has been quite a step for- bioengineering tools. ward, and that at least the broad scientific questions, have been agreed upon. What do you see as the next big step in the I’m going to say something you may not be Vaccine Enterprise? expecting: While the plan is important, in fact what’s A year ago the Gates Foundation issued a more important is the process that led to the devel- Request for Proposals, inviting the scientific opment of the plan. That’s a process of bringing peo- community to submit innovative ideas and ple together and challenging them to identify the approaches to accelerate HIV vaccine develop- key questions and potential ways to address those ment focusing on vaccine discovery, both anti- questions, and I think that discussion between 150 body and T-cell inducing vaccines, and labora- scientists from around the world was very helpful. tory standardization. We’re planning to make an The plan was agreed upon by everybody. Why? announcement within the next few months. Because it basically represents what we would call We’re structuring these projects as an interactive the current paradigm. I wrote an article and collaborative network that shares informa- (International Microbiology 8, 93, 2005) on the tion, reagents, and ideas, not only among them- Enterprise where I address the issue of group think selves but with other key partners of the versus individual thinking, and I refer to one of my Enterprise, including CHAVI, IAVI, and others. favorite philosophers, Thomas Kuhn, who said that Our major priority is expanding the research in the scientific community knowledge moves not agenda to implement the scientific priorities iden- by gradual increment but by scientific revolutions. tified in the Enterprise plan. Also, the Enterprise Thinking within the scientific community is is almost ready to appoint its first Chief Executive defined by the current paradigm because the indi- and to establish its permanent secretariat. In the vidual thinking that the scientific community val- short term, our other priorities are to update the ues so much is constrained by preexisting data and current scientific plan and establish approaches to available tools, but also by the ability of getting monitor its implementation by the Enterprise grants or getting published, by the peer review sys- partners, start the implementation of activities in tem in general. If you are a very innovative, cre- the areas of clinical trials capacity, have a reality ative person, maybe you will not get the grants and check on our approaches to working with indus- your papers will not be published. So the scientific try in areas of process development and future plan that we have today is mostly a current para- manufacturing, fine-tune our investment digm plan, but still have to explore harder how to menu—a list of financial needs to implement the bring in new paradigms, real innovative ideas. priorities identified in the scientific plan—and Kuhn proposed that when the current para- use it to raise the necessary funds for the digm doesn’t provide a solution to a scientific Enterprise partners and for the secretariat. problem, then the scientific community jumps to a new paradigm. Now, when you try to jump to Originally published in the January/February 2006 edition of IAVI Report.

22 www.iavireport.org Understanding… AIDS vaccine clinical trials

…the benefits and risks of participating in clinical research What are the major considerations influencing the decision to volunteer for an AIDS vaccine trial? By Kristen Jill Kresge

aking the decision to participate in an AIDS There are also several possible benefits for Mvaccine clinical trial is a complex and per- those who decide to participate in an AIDS vac- sonal process and it is important that all potential cine clinical trial. They include the VCT serv- volunteers fully understand what is involved in ices and risk-reduction counseling that the vol- the trial when making this choice. Researchers unteers will receive regularly throughout the and staff conducting AIDS vaccine trials take sev- course of the trial (see VAX August 2005 Primer eral measures to ensure that, to the best of their on Understanding risk-reduction counseling). ability, any possible benefits and risks of trial par- Volunteers will also have continuous access to ticipation are identified. These are then reviewed the best available prevention measures in their before the trial begins by local and independent community, including male and female con- groups known as ethical review committees (ERC) or institutional review boards (IRB) and sponsors to ensure the list is complete. The ERC There are several ways that is committed to ensuring that the trials are run to clinical research, including the highest safety and ethical standards. All of the AIDS vaccine trials, can possible benefits and risks are also explained carefully to each interested volunteer during the benefit the countries and informed consent process (see Understanding communities in which the informed consent, page 29). trials take place even if the Benefits vaccine candidate being There are several ways that clinical research, tested is eventually found including AIDS vaccine trials, can benefit the coun- to be not effective. tries and communities in which the trials take place even if the vaccine candidate being tested is eventually found to be not effective. Before AIDS vaccine doms. Participants in AIDS vaccine trials also trials are conducted, educational campaigns take benefit from the rewarding feeling of being place to raise awareness within the community involved in medical research that may benefit about HIV transmission and prevention and these others. Altruism, or concern for the welfare of can benefit all community members, not just those others, is one of the most common reasons trial who choose to volunteer for the trial. Many of these volunteers give for their participation. outreach programs also promote voluntary counsel- Other possible benefits include the basic med- ing and testing (VCT) for community members to ical care that volunteers receive during the trial. find out if they are HIV infected, which can influ- People interested in volunteering for AIDS vac- ence future decisions about their health and help cine trials who are found to have malaria or reduce the stigma associated with HIV testing. tuberculosis can receive referrals to treatment

www.iavireport.org 23 programs in their community, therefore improv- studying how to ensure that adolescents fully ing their overall health. This is also true for peo- understand the risks and benefits of participa- ple who are found to be HIV infected or who tion in medical research before agreeing to become HIV infected during the course of the enroll. This may be an important issue in the trial through exposure in their community. These future as researchers consider the possibility of individuals can be referred to treatment pro- testing AIDS vaccine candidates in this age grams, as well as to support groups. group. Volunteers in AIDS vaccine trials might also receive reimbursement for transportation to Risks and from the trial site or for food if they are It is equally important that all volunteers expected to be at the site during a mealtime. A understand the potential risks of participating in reasonable amount is determined, with input AIDS vaccine clinical trials. All vaccine candi- from the community advisory board, before the dates are tested extensively before they enter trial begins and is reviewed and approved by human clinical trials, but there is still the possi- the ERC. bility that there will be side effects or adverse reactions caused by the vaccine candidate. Often these are mild and can include headaches, fever, Researchers and trials staff and inflammation at the injection site, but these are dedicated to making sure effects should be explained to all volunteers clearly during the informed consent process. that AIDS vaccine trials are However, researchers can’t predict each individ- run safely and ethically and ual’s response to the vaccine. that these trials contribute It is also critical for volunteers to understand to the overall health and that there is a possibility that the vaccine candidate will not be effective or that they will be welfare of the communities randomly selected at the start of the trial to that participate in AIDS receive an inactive substance known as a vaccine research. placebo. Either way, the volunteers won’t be protected against HIV infection by participating in the trial, emphasizing the need to practice risk-reduction behaviors. Researchers and the ethics committees take Other potential risks include the possibility these considerations seriously because they don’t of receiving a false-positive HIV test result in want the compensation or the health care pro- the future (see VAX November 2005 Primer on vided at the trial sites to be the reason that peo- Understanding HIV testing), being unable to ple join the study. All trial organizers and donate blood after participation in the trial, approval bodies work carefully to avoid undue and social risks such as facing possible stigma or inducement. To prevent this, some trial sites may discrimination. strive to provide a level of care that is consistent Despite these inherent risks, researchers and with what is available in the broader community. trial staff are dedicated to making sure that Other sites try to extend some basic healthcare AIDS vaccine trials are run safely and ethically services as much as possible to the wider commu- and that these trials contribute to the overall nity, which can be difficult at urban sites. health and welfare of the communities that par- Volunteers should not feel pressured by the ticipate in AIDS vaccine research, especially in trial staff into enrolling in a trial but should developing countries. make a decision only after weighing all of the potential benefits and risks. Ethicists are also Originally published in the February 2006 edition of VAX.

24 www.iavireport.org …community advisory boards What role do community advisory boards have in vaccine trials? By Kristen Jill Kresge

n important part of preparing for clinical tri- began on the continent. The goal of CABs is to Aals of preventive AIDS vaccine candidates is build a strong relationship between the engaging policymakers, government leaders, researchers running vaccine trials and the local non-governmental organizations (NGOs), and community where the vaccine candidates are members of the community where the trial is tak- being tested to ensure that the community has ing place. Each of these groups has a role in input into the process. ensuring that trials are run ethically and that the entire community benefits from having access to Who attends CAB meetings? information about AIDS vaccines and other pre- Participation in CABs is voluntary but in vention strategies. some communities members are asked to The involvement of members of the local com- remain committed to the group for a set munity is vital to a successful trial because they amount of time. The CABs for vaccine trials are the people who will be volunteering. usually include community leaders like nurses, Community advisory boards (CABs) are one way for members of the community to be closely involved in the process of planning and running The goal of CABs is to vaccine trials. build a strong relationship CABs became part of the clinical trials process in the US and Europe in the early between the researchers 1980s when AIDS activists urged researchers running vaccine trials and and regulatory groups, including the US Food the local community where and Drug Administration (FDA), to quickly find and approve treatments for HIV infection. the vaccine candidates are Many community activists educated themselves being tested to ensure that about HIV and demanded that they be the community has input involved in the design of treatment trials. The into the process. community activists were successful in chang- ing the drug approval process in the US so that essential drugs could be approved faster. Activists were also part of CABs that met with teachers, members of the media, or NGO staff. pharmaceutical companies and the FDA to Many may also involve local religious leaders. review how trials were being run. The CAB CABs try to be as diverse as the local popula- members then shared this information with tions they represent so that all members of the others, making them the liaison between the community can benefit. The members of a researchers and the community. CAB will have different educational back- CABs were also part of the first AIDS vaccine grounds and concerns. Some members may trials that took place in the US and Europe and understand medical or scientific issues while are now an important part of trials that are run others may just be interested in HIV preven- throughout developing countries. Uganda tion. The early CABs in the US included formed one of the first CABs in Africa in the late mostly people who were HIV infected because 1990s, a year before the first AIDS vaccine trial the trials were testing HIV treatments. For vac-

www.iavireport.org 25 become infected with HIV from the vaccine candidate, which may ease some of the worries people have about participating in a trial. CABs are also asked to share their questions and concerns about the s e g

a informed consent process m I y t that all volunteers must t e G / x participate in before join- u o b i

G ing a trial. This process c r a includes a description of M - n a e the trial, details of what J Many public health campaigns, like this one in Nairobi, Kenya, focus participation in the trial on vaccination. entails, and explains the possible side effects of the cine trials, CABs may include people who are vaccine candidate. Informed consent is one area current or past volunteers in a trial and want to where CABs can have a direct influence on trial help improve the process in the future. protocols. CABs can advise the trial coordina- There are typically around 20 members in each tors about what information to include in the CAB who meet regularly to discuss the trial process to ensure that volunteers understand the process. A researcher or investigator from the trial aim of the trial. They can also help researchers site will often attend the meetings to provide understand how to explain the process of updates on trials that are in progress or to explain informed consent to volunteers in a way that is those that are starting soon. culturally acceptable. Other issues a CAB may address include the compensation for volunteers What does the CAB discuss? in vaccine trials, the community’s fears about CAB members are often asked to provide participating in research, the stigma involved comments on the way trials are designed, includ- with HIV research, and understanding the ing how volunteers are recruited for the trial. results of vaccine trials. Members of the CAB can help recruiters by giv- The CAB meeting is a place where the ing them culturally-specific advice on how to members can ask questions and comment on reach local populations that are important to any part of the trial process and where there is include as trial volunteers. This may include an exchange of information between the com- where the best locations are to recruit volunteers munity and the research staff. This creates a or how the trial staff can use gender-specific supportive environment for vaccine trials approaches to encourage women to enroll in vac- because CAB members can be certain that cine trials. The CAB also encourages other mem- researchers are considering the perspective of bers of the community to volunteer by giving the participants. them information about the trial. For example, CAB members can explain that you cannot Originally published in the May 2005 edition of VAX.

26 www.iavireport.org …capacity building at vaccine trial sites How can AIDS vaccine trials help build infrastructure and capacity in developing countries? By Kristen Jill Kresge

n order to determine whether an AIDS vaccine ties for healthcare workers that can serve the com- Icandidate is effective it must be tested in the munity long after the trial ends or by attracting other populations that are most affected by the disease. medical services to the area, such as HIV treatment Clinical trials have to take place in communities programs (see Understanding the benefits and risks of where there is a high enough incidence of HIV participating in clinical research, page 23). infection for researchers to determine positive benefits from the vaccine. This often requires Infrastructure running trials in developing countries, where The first step in building an AIDS vaccine clini- there is the highest HIV/AIDS burden. It is also cal trial site involves constructing the actual build- essential that vaccines be evaluated in the com- ings that will serve as clinics and laboratories or munities that need them the most. modifying those that already exist. These facilities are Many organizations involved in AIDS vaccine then equipped with the instruments necessary to research, including the Global HIV Vaccine process laboratory samples obtained from volunteers Enterprise and the European & Developing during the trial and preparing these specimens for Countries Clinical Trials Partnership (EDCTP), storage or shipment. Some sites may even develop have recently published reports emphasizing the sophisticated HIV immunology and virology labo- importance of developing both the physical infra- ratories that can analyze samples and process the data structure and the human resources at clinical trial from the trial in the country where it takes place. sites in developing countries. This is the strategy India recently started an AIDS vaccine trial used by organizations like Walter Reed Army sponsored by IAVI in partnership with the Institute of Research, the US Centers for Disease Control and Prevention, and IAVI that have been running vaccine trials in Africa and Asia. The idea of building trial site capacity involves both establishing clinics and laboratories and training medical profession- s e g als. Both of these steps help a m I

y t ensure that the research site t e G / is sustainable over the long x u o b i G

term and can be used for c r a

future clinical trials. M - n a e

Developing these sites also J benefits the community by James Onyango in a Kenya AIDS Vaccine Initiative (KAVI) laboratory providing career opportuni- in Nairobi, Kenya.

www.iavireport.org 27 Indian Council of Medical Research and the specialized training on enrolling women in AIDS National AIDS Control Organization at the vaccine trials and other gender-related issues. Tuberculosis Research Center (TRC) in Chennai. For the staff working in the laboratories the The TRC, a newly-established center of excel- training includes how to handle and process the lence for the clinical evaluation of vaccines in the laboratory samples and the procedures for data country, features a safety and immunology labo- management. All tests run in the laboratories are ratory where all laboratory tests will be run. verified by quality control processes to ensure that the results of the trial are meaningful. Human capacity The process of site development continues Once the clinics and laboratories are established even after the trial has started. Many organiza- it is also important to build human capacity at tions continue working to enhance the site’s abil- AIDS vaccine trial sites. Sponsor organizations ity to deliver HIV prevention and treatment serv- spend significant amounts of time hiring and train- ices and to provide referrals to other clinics in the ing medical professionals in developing countries community. This can involve additional training to handle the activities associated with the trial. sessions or meetings arranged with the staff from other AIDS vaccine clinical trial sites in order to learn from shared experiences. Developing these sites also Providing the site staff with such extensive benefits the community by training helps strengthen the human resources in that community. Once the trial is complete, these providing career opportunities medical professionals can work in many other for healthcare workers that areas, including research, nursing, or in conduct- can serve the community long ing other clinical trials. after the trial ends or Sustainable trial sites by attracting other medical Developing both the physical infrastructure services to the area, such as and human capacity at a site are necessary steps for conducting an AIDS vaccine clinical trial in HIV treatment programs. developing countries, but once established these sites can continue to function well beyond the end of the current trial. The staff’s expertise in This occurs through a series of instructional HIV could make the site suitable for other types workshops that cover all aspects of the clinical of HIV prevention trials, including trials of trial process, from screening and enrolling volun- microbicides, or for clinical research studies that teers to collecting and analyzing data, and are contribute to the understanding of the based on a set of work practices developed specif- HIV/AIDS epidemic in that country. These sites ically for each site. All trials are certified accord- may also attract HIV treatment programs or ing to a set of international guidelines, known as other healthcare services that can continue Good Clinical Practice (GCP). Compliance with adding benefit to the community. Keeping these GCP guidelines ensures that the trial is run prop- sites active is also of great interest to organiza- erly, that the rights and needs of the volunteers tions sponsoring AIDS vaccine trials, since many are protected, and that the data collected during vaccine candidates will need to be evaluated in the trial is of high quality. the future and these trials will require experi- Counselors and nurses are trained to work with enced sites and surrounding communities that potential volunteers and to administer the informed have successfully conducted past trials. consent process (see Understanding informed consent, page 29). These individuals may also receive Originally published in the March 2006 edition of VAX.

28 www.iavireport.org …informed consent How does the informed consent process work in vaccine trials? By Kristen Jill Kresge

IDS vaccine candidates must be tested in document, must receive approval from a local Ahuman volunteers to evaluate their safety and ethics committee and national regulatory authority efficacy. A vaccine trial can only be successful if before that trial can begin. people in the community are willing to volunteer for the trial, receive the vaccination, and return to Information the trial site for follow-up visits. An essential part Community outreach is the first step of the of running ethical research is assuring that the informed consent process and aims to prepare a rights of these volunteers are protected. community for a vaccine trial. All the educational To ensure that the volunteer enrollment in vac- materials about HIV and AIDS vaccines are a cine trials meets high ethical standards there is a necessary first step in getting people informed process known as informed consent. During this and interested in participating in a trial. This process trial investigators must fully explain the general information includes what HIV is, how it details of the trial and the vaccine candidate that is transmitted, and how an AIDS vaccine might will be tested, make sure that the volunteer work. When members of the community who understands the information, and allow the may be interested in volunteering come to the potential volunteer to freely decide if they wish to trial site, they are educated about the trial and the participate. The informed consent process must vaccine candidate being tested. be completed for each person before he or she The nurse or counselor at the trial site begins by can enter the screening process for the trial. explaining any general background information During the screening process all volunteers about HIV and then explains why the vaccine can- undergo research voluntary counseling and test- didate is being tested, what participation in the trial ing (see Understanding research voluntary counsel- involves, and how the trial is being conducted. For ing and testing, page 31) for HIV infection example in some trials, not every person in the trial because only people who are not infected with will receive the vaccine candidate. Some volunteers HIV can enroll in a preventive vaccine trial. will receive an inactive substance known as At the end of the informed consent process, placebo, so that the researchers can compare the everyone who chooses to join the trial is asked to vaccine being tested to something they know will sign the informed consent document that has all have no effect. In most trials, neither the volunteers this information in writing. The document shows nor the researchers will know who receives the vac- that they want to participate in the trial, but cine candidate or placebo until the end of the trial informed consent involves much more than simply (this is called a double-blinded study). The nurse or signing a paper. The United Nations Joint counselor explains that the person can’t be infected Programme on HIV/AIDS (UNAIDS) established with HIV from the vaccine candidate and also a set of guidelines that recommends cooperation emphasizes that the vaccine being tested may not between researchers, community representatives in provide any protection against HIV infection and the form of Community Advisory Boards (see so all volunteers must avoid risk behaviors. Understanding community advisory boards, page The information provided also includes 25), and regulatory bodies to design and imple- specifics about the trial process, including the ment the informed consent process at AIDS vac- length of the trial, the number of visit to the site, cine trial sites throughout the world. The protocol and what medical tests (such as the collection of for a vaccine trial, including the informed consent blood samples) will be required. Potential volun-

www.iavireport.org 29 teers will also be informed about the type of gen- tions to the best of their ability. This is an impor- eral healthcare they will receive during the trial, tant part of obtaining “true” informed consent. any reimbursement they will receive for traveling Researchers must be able to explain complicated to the site, and most importantly, their right to terms to potential volunteers in a way that is rel- leave the trial at any time. evant to the community and can easily be under- The way this information is provided varies stood, sometimes even in languages that have no based on the trial site, but informed consent doc- translations for these words. uments used in developing and developed coun- The local ethics board as well as Community tries are very similar. At some sites the informed Advisory Boards have input into the informed consent process can extend over several visits, consent process before the trial protocol is allowing the volunteers to take the information implemented and can therefore influence this home and discuss it with their family. Once the process. Leaders in the community can provide trial site staff are trained, it is their responsibility the investigators with culturally-specific ways to carry out informed consent process according to explain key concepts. But it is still very to international and local standards. important that researchers uphold the standards of the informed consent process, while trying to make it more sensitive to the beliefs of When members of the the community. community who may be Understanding interested in volunteering The final step of the informed consent come to the trial site, process involves ensuring that each individual they are educated about fully understands the information provided. At the trial and the vaccine some sites investigators may use written tests to verify their understanding. The investigators candidate being tested. also try to ensure that each person’s decision to participate is truly voluntary. The potential volunteer must not be pressured into enrolling by Researchers may use videos or flip charts to anyone at the trial site, or anyone in their fam- explain complex issues like the benefits and risks ily or community. This can be difficult in some of participation in the trial. The possible benefits cultures where, for example, women are unable include the medical attention that volunteers to make decisions without consulting their hus- receive, as well as the rewarding feeling of partic- bands or community leaders. The nurses our ipating in research that will benefit the commu- counselors at the trial site should do their best nity. Potential risks of participating in a vaccine to find out if each person’s decision was made trial include the possibility of side effects of the independently. vaccine candidate or the possibility of temporar- After they are certain the choice was made ily having a false positive HIV test in the future, independently and based on a firm understand- even though they are not HIV infected. A false ing of the trial, the informed consent document positive can occur because the vaccine may cause can be signed. If the volunteer cannot write, he the person’s immune system to make antibodies or she may be identified in another way, such as to HIV, which is what the standard tests measure. a thumbprint. Volunteers that complete this step can enter the screening process, where they are Cultural considerations examined and tested to see if they are eligible for Investigators at the site do their best to explain the trial. terms in a way that is easy for the individual to understand and should try to answer all ques- Originally published in the June 2005 edition of VAX.

30 www.iavireport.org …research voluntary counseling and testing How is voluntary counseling and testing provided to volunteers in clinical research or vaccine trials? By Kristen Jill Kresge

efore a clinical trial of an AIDS vaccine candi- this process researchers ensure that volunteers Bdate or a clinical research study takes place in understand what is involved in the trial before a community, the essential components of a enrolling and that their participation is voluntary. research and healthcare system must be in place. Different models are used to recruit people These components include infrastructure for a into RVCT programs where they can find out study site, training researchers and healthcare their HIV status and learn about how studies are workers at study sites to counsel and test people conducted. Several methods of recruitment may for HIV, and a place to refer those in need for be used from general community awareness, proper treatment. This is sometimes referred to as focus group discussions, and one-on-one interac- the three Ts (Training, Testing, and Treatment); tions. All approaches involve strong community without these there can be no trial. participation through community advisory Eligibility for enrollment in a vaccine trial or a boards—groups of people in the community that clinical research study will hinge upon whether a are familiar with the trial or study. potential volunteer is infected with HIV, so everyone must have an HIV test. For AIDS vaccine tri- Pre-test counseling als potential volunteers can not be HIV-infected, All volunteers meet with a trained counselor but for other types of clinical research studies only before having an HIV test. In this session the HIV-infected individuals can enroll. HIV testing counselor provides each volunteer with basic prior to joining a study is voluntary and the process information about HIV/AIDS and asks ques- is referred to as research voluntary counseling and tions to determine the understanding of how testing (RVCT). These programs serve as the gate- HIV is transmitted and what methods of protec- way to enrollment in studies. Other types of com- tion are available. An important part of RVCT is munity-based VCT programs involve similar pro- also explaining what type of research is being cedures but do not share the goal of enrolling conducted at the specific site and informing the people in a trial. The primary aim of community volunteer that they may be able to participate. VCT programs is getting people to know their During pre-test counseling background infor- HIV status and undergo risk-reduction counseling mation is discussed with each volunteer. so that they can protect themselves and their part- Information is collected about the volunteer’s risk ners against HIV infection or be referred for care behaviors including sexual behavior, condom use, and treatment. history of sexually-transmitted diseases, and use Like VCT, RVCT is confidential and seeks to of injection drugs. Based on the information pro- help the volunteers understand the risk behaviors vided, the counselor will give explanations and associated with HIV infection, the implications of recommendations on how to avoid and reduce the test results, and how they can reduce their the risk of HIV infection. If the volunteer joins future risk. RVCT also involves explaining what the study this information may also be used to participation in a trial involves and getting the determine how his/her risk behavior may change potential volunteer’s informed consent to partici- over time. This will be analyzed by researchers at pate in a clinical research or vaccine trial. During the site.

www.iavireport.org 31 test results so they can receive the post-test counseling and be referred to healthcare facilities for HIV care and treatment should they be HIV-infected. For AIDS vaccine trials, more sophisticated HIV tests may be used in addition to s e g

a the classic rapid tests to m I y t

t ensure accuracy. e G / x u o b i

G Post-test counseling c r a

M Once the results are - n a e

J available the counselor Vials of blood that are being collected for HIV testing. Samples are bar will inform each person coded to protect the anonymity of those being tested. whether or not they are HIV infected and help For volunteers considering joining an AIDS vac- them to understand the results. If the volunteer is cine trial, the counseling session also covers the not HIV infected the counselor will explain that study procedures. These include regular HIV test- there is a period of time (called a window period) ing, use of contraceptive methods, duration of the between when a person gets infected and when trial, and the necessity of making all scheduled the body makes antibodies against HIV. Though study visits. In an RVCT session the counselor will they usually appear in three weeks, it can take up explain that some volunteers in the trial will receive to three to six months for these antibodies to reg- an inactive substance, called a placebo, instead of ister on the test. If the volunteer reports risk the candidate vaccine. Most vaccine trials are dou- behaviors in this window period then they may be ble-blinded, which means that neither the doctor asked to return for a repeat test. nor the volunteer knows who is receiving vaccine Counselors will review ways for volunteers to or placebo. RVCT counselors will also emphasize reduce risk behaviors in the future, regardless of the that the researchers do not know whether the vac- test results. For volunteers who are HIV infected cine candidate is protective or not, and that until the post-test counseling will provide the volunteer Phase III efficacy trials show otherwise the vaccine with the opportunity to discuss their concerns. The candidate should be considered as not protective. counselor will help the volunteer set a plan of A volunteer may choose not to be tested for action, including notifying their partners or fami- HIV after receiving pre-test counseling. lies finding ways to stay healthy, and referral for care and treatment available in the community. Testing RVCT has many benefits for communities. The type of HIV testing that is used may vary by Research studies have shown that HIV incidence site. Many sites now use the rapid HIV tests that often declines in areas where extensive testing and require only a finger prick to collect a blood sample public health campaigns promoting HIV educa- and test for the presence of antibodies against HIV. tion take place. People who know their HIV status Results from these tests are available in just 15 min- are also likely to encourage other members of their utes. Some trial sites will do two rapid tests at the community to be tested. This helps support enroll- same time so they can be more assured of the results. ment in vaccine trials or clinical research studies. At sites where rapid tests are not available it is very important to ensure that volunteers return for their Originally published in the April 2005 edition of VAX.

32 www.iavireport.org …couples voluntary counseling and testing Why is voluntary counseling and testing for couples an important process for recruiting women into vaccine trials? By Kristen Jill Kresge

oluntary counseling and testing (VCT) is the HIV infection can involve others outside of Vprocess used by community-based clinics and their relationship. trial sites to offer HIV testing, education, and A couple will go through the entire process counseling to individuals who want to know together, including completing the consent doc- whether they are HIV infected or not. The VCT uments (see Understanding informed consent, page process involves learning about how HIV is 29), pre-test counseling, HIV testing, and post- transmitted and what behaviors put a person at test counseling. The consent for participation in risk for infection, in addition to the meaning and CVCT requires that the partners agree to receive implications of the individual’s test results. their HIV test results together, but these results There are several different types of VCT remain confidential outside of the couple. depending on whether the service is administered Dependent on their test results, the nurse or at a community clinic, as an initial screening for counselor will work with the couple during the participation in an AIDS vaccine trial, or before post-test counseling to help them make a plan for joining a research study (see Understanding research voluntary counseling and testing, page 31). There are also different types of VCT used to tar- Counselors can work closely get specific populations. One involves testing and with discordant couples to counseling couples that are married or living together, rather than individuals, and is therefore create an atmosphere referred to as couples VCT (CVCT). where the partners support each other, both What is different about a CVCT session? During a traditional VCT session a person is through this process and given information on what can put them at risk in the future, while limiting for HIV infection. In a couples session the the uninfected partner’s risk counselor works with the couple to find out how their behaviors work together to influence of becoming HIV infected. their risk. This involves opening a dialogue between partners about their sexual activities and empowering them to communicate their the future. In testing and counseling couples there shared risks, which can be complicated in coun- are three scenarios: both partners are HIV tries where such discussion may be taboo. Nurse infected, both are uninfected, or one is infected counselors encourage each person to take and the other is uninfected. This last case is what responsibility for their behaviors and inform researchers refer to as a discordant couple. them about ways the can limit their risk, such as Counselors can work closely with discordant cou- using condoms. CVCT is a complex process ples to create an atmosphere where the partners because counselors are working with the needs support each other, both through this process and and emotions of two people whose risks for in the future, while limiting the uninfected part-

www.iavireport.org 33 How can CVCT be used to recruit women for vaccine trials? CVCT is an important way for researchers to reach out to more women about accessing counseling and testing services as well as possibly joining a vac- s e g

a cine trial. In recent years m I y t the number of people uti- t e G / x lizing VCT services in u o b i

G some areas of sub-Saharan c r a Africa has increased dra- M - n a e matically, mainly because J Entrance to a medical center in Ggaba, Uganda, where IAVI is working of new treatment pro- with the Uganda Virus Research Institute (UVRI) on research studies in grams that offer people preparation for future vaccine trials. life-saving drugs if they are found to be HIV infected. ner’s risk of becoming HIV infected. Despite being more vulnerable to infection, Working with couples rather than individuals women remain underrepresented at many VCT has been shown to have many positive effects, sites. including increased condom use and a lower rate Counseling and testing partners together can of new HIV infections between partners. empower women to access VCT services, while avoiding discrimination or even possible vio- Why is CVCT an important recruitment lence from their husbands or communities. At tool for AIDS vaccine trials? some sites counselors will invite couples who To find out if an AIDS vaccine candidate is have received CVCT to come for focus groups to effective at blocking HIV transmission, see how they feel about possibly enrolling in a researchers must administer the vaccine candidate trial. Couples can learn about the vaccine candi- to groups or cohorts of people who are at high risk date being tested and find out what it is like to of becoming infected with HIV. This requires volunteer for an AIDS vaccine trial. testing the vaccine in countries or communities One of the earliest centers to implement where there is a high prevalence of infection. In CVCT was a clinic in Kigali, Rwanda run by Africa, couples are at the highest risk for HIV Projet San Francisco and Susan Allen, a infection and researchers estimate that between researcher from Emory University who has 60-70% of HIV transmission occurs within cou- established one of the largest couples counsel- ples that are married or living together. ing centers in Africa. This site started screen- African couples are therefore an important ing couples because women requested that cohort for evaluating the efficacy of AIDS vaccine their husbands also be tested. Of the original candidates and CVCT is one way to enroll volun- 1500 women that were seen at the Kigali cen- teers that are at high risk of HIV infection from ter, 1000 were able to convince their husbands heterosexual transmission. This may not be true or partners to join them. The nurse counselors on other continents like Asia, where HIV trans- are now preparing for the site’s first AIDS vac- mission is still mainly occurring in the more tra- cine trial. ditional high-risk groups such as sex workers or injection drug users. Originally published in the October 2005 edition of VAX.

34 www.iavireport.org …home-based voluntary counseling and testing How can home-based or mobile services for HIV counseling and testing improve community responses? By Kristen Jill Kresge

oluntary counseling and testing (VCT) serv- The process Vices are a key component of HIV prevention, The VCT services administered in people’s treatment, and care programs. Individuals learn homes are conducted similarly to those in clinics. about behaviors that put them at risk of HIV Community healthcare workers are trained to pro- infection and how they can reduce this risk vide HIV counseling and testing and must obtain through the counseling process, and this infor- consent from all individuals before administering mation can be a catalyst for people to alter their VCT. The only difference is that these healthcare behaviors. workers go door-to-door offering these services. Individuals who undergo VCT also find out whether or not they are HIV infected (see VAX November 2005 Primer on Understanding HIV Since VCT is such a powerful testing). VCT services, therefore, are often the tool in getting people primary entry point for infected individuals into information on HIV and treatment and care programs. These important outcomes make VCT programs a critical part of access to treatment if needed, the community’s response to HIV/AIDS. researchers have looked for There are various types of VCT services, ways to maximize the number of including those given before enrollment in a vaccine trial or research study or sessions specifically people utilizing these services. tailored for couples (see Understanding research voluntary counseling and testing, page 31, and Understanding couples voluntary counseling and Some organizations, such as The AIDS Support testing, page 33). These almost always occur at Organization (TASO) in Mbale, Uganda, couple community health clinics or clinical trial sites, their home-based VCT services with at-home care but the stigma associated with HIV in many programs. So when field officers deliver antiretro- communities, as well as the distance people are virals (ARVs) directly to the homes of infected required to travel to clinics in rural areas, can individuals they also offer VCT services to other prevent people from seeking these services on family members in the household. their own. Since VCT is such a powerful tool in Others, like the AIDS Information Centre (AIC) getting people information on HIV and access in Uganda, have implemented a stand alone home- to treatment if needed, researchers have looked based VCT program in an effort to increase the for ways to maximize the number of people uti- number of people being tested for HIV. National lizing these services. One of these approaches is surveys in the country reported that although 70% taking VCT services directly to people in their of people want to be tested for HIV infection, only homes or neighborhoods. Such home-based or about 10% have actually participated in VCT. mobile VCT services, while limited, have been A pilot project, funded by the US Centers for successful in getting more people to be tested for Disease Control and Prevention (CDC) was started HIV infection. by AIC in 2004 in the districts of Tororo and Busia

www.iavireport.org 35 much less of an influence on a person’s decision to undergo HIV testing when VCT services are administered in the home, instead of in clinics. Home-based VCT services could also be a promising strategy for reaching dis- s e g a empowered individuals, m I y t t

e especially women. G / x u Another option is provid- o b i G

c ing just the test results and r a M

- post-test counseling at n a e J home. In settings where A housing community in Uganda. Organizations like TASO are rapid tests are unavailable, implementing home-based VCT programs in the country. people sometimes do not in Uganda in an attempt to reach as many people as return to the clinic to find out the results of their HIV possible in these districts and offer them home- test. In a study conducted by the Medical Research based VCT services. Trained outreach teams visited Council in Entebbe, Uganda, researchers found that each home and offered all family members informa- offering test results in a person’s home was an effec- tion so they could decide if they wished to partici- tive way to ensure that people received them. pate. Adults in the household were given the choice to receive these services individually, or as couples. Mobile units Anyone who was found to be HIV infected during Another method for bringing VCT services this process received referrals to treatment and care directly to communities is to utilize mobile VCT programs in their community. units. The Foundation Agency for Rural Development, a non-governmental organization in Judging success Nairobi, Kenya, uses bicycles to bring VCT to local Many organizations have found that offering communities. Four mobile sites are set up in differ- home-based VCT programs is an effective way to ent areas throughout the city and each week several increase access to treatment and prevention serv- individuals undergo VCT. Like home-based services. The AIC program lasted for one year and ices, these mobile units can reach people who may during this time over 5000 individuals received be unable to travel to a clinic to receive VCT. VCT services in their homes, which was more than double the study’s target. The outreach teams From community to country visited more than 2000 homes in these two dis- The most ambitious home-based VCT program tricts of Uganda and in 65% of them at least one is currently taking place in Lesotho, where on World household member agreed to participate in VCT. AIDS Day last year the president announced plans The results of this program were presented at to take VCT services door-to-door in an effort to the International AIDS Society meeting on HIV reach every household in the country by 2007. To Pathogenesis and Treatment, which took place meet this challenge the government trained 6500 last year in Rio de Janeiro, Brazil, and the CDC healthcare workers to provide VCT services. Prior to plans to use this program to create guidelines that this universal HIV testing initiative, it was estimated will allow additional home-based VCT programs that only 1% of the population had accessed VCT. to be started in Uganda. The AIC concluded that stigma seemed to be Originally published in the June 2006 edition of VAX.

36 www.iavireport.org …test of concept trials Why are Phase IIb trials an important step in evaluating AIDS vaccine candidates? By Kristen Jill Kresge

IDS vaccine candidates are evaluated in a response generated by the vaccine that cause it to Astepwise manner in a series of clinical trials be effective. This can often be difficult to do in known as Phase I, II, and III. Phase I and II tri- large Phase III trials. als generally involve a small number of volunteers However because Phase IIb trials are run in and provide researchers with critical information smaller populations, the precision of the trial is about the safety and immunogenicity of the vac- less. Therefore a vaccine can not be licensed cine. It isn’t until Phase III trials that the efficacy based on the results of Phase IIb testing. If the of the vaccine is assessed. These trials test the results of a Phase IIb trial indicate that this ability of the candidate to prevent infection approach is promising, a Phase III efficacy trial and/or slow progression of disease. These trials will be required before licensing and use of the require large numbers of volunteers, are vaccine. This means that the decision to run a extremely expensive (can cost more than a hundred million dollars), and take a long time to set up and complete. Phase III efficacy trials are the A test of concept trial is not final step before a vaccine can get approval for designed to establish the licensure from a regulatory body like the Food efficacy of a particular and Drug Administration in the US or the Agency for the Evaluation of Medicinal Products candidate but rather to help in Europe. researchers decide if this candidate is worth testing What is a test of concept trial? As the name implies, a test of concept trial in larger Phase III trials. is about finding out if the vaccine concept or the type of vaccine being tested will be effective. A test of concept trial is not designed to Phase IIb trial will extend the total amount of establish the efficacy of a particular candidate time it takes to complete the clinical trials but rather to help researchers decide if this process. Phase IIb trials are an important screen- candidate is worth testing in larger Phase III ing step for different vaccine candidates and help trials. These intermediate studies are also organizations determine which ones to move for- referred to as “proof of concept” or Phase IIb ward into Phase III trials, without expending trials. more time and money. The number of volunteers required for such The idea of using Phase IIb studies is more trials is smaller, only around 2000-5000 volun- than a decade old but the first one involving an teers as compared to over 10,000 for Phase III AIDS vaccine candidate began just last year. Test trials. Phase IIb trials are therefore much easier to of concept trials have already been done for other design and manage, and are less costly. Since vaccines as well as for other preventive technolo- fewer doses of vaccine are required, these trials gies. US-based Merck and GlaxoSmithKline are also much faster to implement because the Biologicals in Europe tested their respective vac- manufacturing process is limited. Very impor- cine candidates for human papilloma virus in tantly, they may also provide researchers with the Phase IIb trials. These candidates are now both immune correlates of protection, or the immune being tested in Phase III efficacy trials. The HIV

www.iavireport.org 37 find out if this strategy will be able to prevent HIV infection or to slow the progression of disease in people who do become infected through exposure in their community. The results of this trial will influence the company’s s e g decision to go ahead with a a m I y

t Phase III trial and will pro- t e G /

x vide the entire AIDS vac- u o b i cine field with critical G c r a information about the M - n a e importance of cell-medi- J A researcher prepares to analyze polymerase chain reaction samples ated immune responses in on a gel. vaccine efficacy. Another advantage of a Prevention Trials Network is also testing a micro- Phase IIb trial is that it allows researchers to eval- bicide candidate known as Buffergel PRO2000 uate a candidate in a more confined study popu- in an ongoing Phase IIb trial to see if this agent lation. The MRKAd5 candidate is based on a can block transmission of HIV. particular strain of a human virus that naturally causes the common cold (adenovirus serotype 5). Why are test of concept trials especially This candidate may not work as well in people useful for AIDS vaccines? who have already developed immunity to this Because the challenge of developing an effec- strain of natural adenovirus, due to what is called tive AIDS vaccine has proven so difficult and pre-existing immunity (see Understanding pre- the need remains so great, researchers must eval- existing immunity, page 12). Initially Merck’s uate several candidates as quickly as possible. Phase IIb trial was designed to include only peo- This requires testing several candidates at the ple who had low levels of pre-existing immunity, same time. so that they could find out if the vaccine concept Researchers are also using new approaches to try was even feasible under optimal conditions. The to find an effective AIDS vaccine. Test of concept trial has since been amended to include a more studies are one way to find out quickly if these new diverse population of volunteers. candidates can be successful. An example of this is The use of test of concept studies to evaluate the first Phase IIb trial of an AIDS vaccine candi- AIDS vaccine candidates is also being considered date, which is being conducted by Merck and the by other organizations and more may be con- HIV Vaccine Trials Network. This ongoing study is ducted in the future. For trial volunteers, com- testing the company’s lead vaccine candidate munities, and health policymakers it is important known as MRKAd5 in approximately 3000 volun- to understand that a vaccine will not be approved teers. The MRKAd5 candidate primarily generates based on the results of these studies even if the a cellular immune response, but scientists are investigators are able to draw preliminary conclu- unsure if this type of vaccine will be sufficient to sions about its efficacy. protect people from HIV infection. Merck decided to test this type of vaccine in a Phase IIb trial to Originally published in the September 2005 edition of VAX.

38 www.iavireport.org AIDS vaccines for adolescents

By Kristen Jill Kresge

s HIV continues to infect millions of people An adolescent epidemic Athroughout the world, more and more of the In the US, 40% of all new HIV infections are newly infected are between the ages of 15 and now occurring in individuals younger than 25. 24. Young people in this age group now account Although the risk facing teenagers varies greatly for almost half of all new HIV infections, with from place to place, in many countries, espe- nearly three million becoming HIV infected cially in Africa, the situation facing young each year. Despite these startling statistics, AIDS women is particularly dire. Young women in vaccines have so far not been tested in adolescent South Africa continue to be at very high risk of volunteers. HIV infection, with studies showing that HIV “The epidemic is becoming more youth- prevalence rates approach 16% among girls driven,” says Linda-Gail Bekker of the between age 15 and 24, four times the infection Desmond Tutu HIV Centre in Cape Town, rates seen in boys of the same age. In Botswana who is preparing for AIDS vaccine trials nearly 25% of girls between the ages of 15 and involving adolescents in South Africa. 19 are already HIV infected. Research shows that despite increased efforts to reach adolescents and provide them with information about HIV prevention, young people “…when you look at the in many communities are having sex and pur- epidemic in Africa, adolescents suing injection drug use at an earlier age. This makes the optimal age for vaccination even are the highest incidence younger, since adolescents should ideally group and if you’re going to receive a preventive AIDS vaccine before they make headway in dealing with become sexually active. “That’s our big motiva- tion,” adds Bekker. the epidemic you But before AIDS vaccine trials with promis- need to involve them.” ing candidates can be initiated in adolescents, – Michael Robertson researchers must tackle potentially thorny legal, ethical, and regulatory issues, and make sure they adequately address the concerns of parents about their children participating in research. Statistics like these are helping to fuel dis- Many organizations are currently working to cussions amongst researchers, sponsoring develop guidelines and protocols that will organizations, and regulatory agencies about enable future trials to be conducted successfully how and when to test AIDS vaccine candidates with adolescent volunteers. Progress in these in younger volunteers. “Everyone has been areas will help guarantee that an effective AIDS cautious about moving into adolescents with vaccine, when available, will reach both adult AIDS vaccines,” says Michael Robertson, a and adolescent populations as quickly as possi- lead investigator on Merck’s Phase IIb AIDS ble, offering the greatest chance for curbing the vaccine trial. “But when you look at the epi- pandemic. “I think we need to keep the pres- demic in Africa, adolescents are the highest sure on,” says Bekker. “As we move closer to incidence group and if you’re going to make more promising candidates, we don’t want to headway in dealing with the epidemic you be caught short.” need to involve them.”

www.iavireport.org 39 Researchers were given some guidance cally reduced mortality rates. recently on adolescent trials by the US Food and But there is much less of a precedent for Drug Administration (FDA). In a document adolescent vaccination. A vaccine against hep- issued in May 2006 (Development of Preventive atitis B virus (HBV) was the only one to tar- HIV Vaccines for Use in Pediatric Populations, get this age group until a vaccine for human www.fda.gov/cber/guidelines.htm) the agency papillomavirus (HPV) was recently licensed provided vaccine trial sponsors with direction by the FDA for girls aged 9 to 26 (see Cervical on the requirements for licensure in adolescent cancer vaccines, page 70). The large efficacy populations. Most regulatory agencies like the trials for the HPV vaccine involved thousands FDA that oversee the approval and licensure of of adolescent (age 12-18) and pre-adolescent medicines and vaccines require that experimen- girls, and many researchers are closely moni- tal products are tested in the population in toring the acceptance and inclusion of this which they will be used. For most vaccines this new vaccine into immunization programs to is in infants, who are susceptible to many dis- help gauge the response to vaccines still in eases that they would normally catch during development that aim to prevent other sexu- early childhood. Infants are also at greatest risk ally-transmitted infections, including HIV of developing life-threatening symptoms from and herpes simplex virus type 2. “It’s an excel- viral infections because their immune systems lent model for AIDS vaccine researchers,” says haven’t fully developed. Extensive childhood Jeffrey Safrit of the Elizabeth Glaser Pediatric immunization programs have been imple- AIDS Foundation. mented in many countries where sufficient Results from HPV and HBV vaccine trials healthcare infrastructure exists, and have drasti- also give researchers good reason to be opti- s e g a m I y t t e G / x u o b i G c r a M - n a e J A group of young people gather at a health clinic in Cape Town, South Africa.

40 www.iavireport.org mistic that adolescents may respond even better Program (AAVP) also sponsored a meeting ear- to vaccination than adults. Clinical trials with lier this year in Gaborone, Botswana, to both vaccines induced stronger immune address some of the challenges of including responses in younger volunteers. The primary adolescent volunteers in AIDS vaccine trials. concern will be establishing safety data in these And Merck is now considering testing its lead populations rather than immunogenicity, says vaccine candidate in adolescents in South Robertson. Africa as part of a Phase IIb trial that will start The guidance document issued by the FDA there later this year in cooperation with the US suggested that strong safety and immuno- National Institutes of Health and the HVTN. genicity data for AIDS vaccine candidates “The plans are very much in the discussion should be collected in adults before adolescent phase,” says Robertson. “We’ve discussed trials begin. The agency also emphasized that expanding the planned trial and amending the efficacy data collected in adults could only be age cutoff to include adolescents, or adding extrapolated to adolescents if researchers another small safety and immunogenicity trial could successfully identify the immune there just for adolescents.” responses that are predictive of protection, also known as correlates of protection. Key challenges Establishing which immune responses corre- But before an actual trial begins these groups late with protection is not a simple task and are working to overcome some of the key chal- for both HPV and rotavirus vaccines (see lenges that are unique to adolescent trials. Rotavirus: Vaccines enter battle against an intes- Chief among these is the need to obtain tinal virus, page 77) correlates of protection have not been identified even after large Phase III efficacy trials. Involving adolescent For AIDS vaccine candidates it may there- organizations and fore be necessary to run large efficacy trials in community advisory adolescents. It is unlikely that these can only be done in the US since HIV incidence rates boards that can offer peer there are generally too low among adolescents support to volunteers to support a conclusive Phase III trial, says could greatly improve the Audrey Smith Rogers, an epidemiologist at the experience of adolescent US National Institute of Child Health and Human Development. The guidance docu- volunteers. ment by the FDA recommends that trials sponsors discuss AIDS vaccine efficacy trials planned in other countries to ensure that this informed consent from both the adolescent data can be applied to adolescent approval in and their parent or guardian prior to enroll- the US. ment (see Understanding informed consent, Researchers in South Africa and Botswana page 29). US and South African law both are leading the charge due to the high preva- require that parental consent be provided for lence of HIV infection among adolescents in any trial involving minors where the vaccine these countries. The South African AIDS isn’t guaranteed to provide some benefit, and Vaccine Initiative (SAAVI) is currently collab- Bekker predicts that many parents may be ret- orating with the HIV Vaccine Trials Network icent, at least initially, to allow their children (HVTN) to prepare a protocol for an adoles- to participate, necessitating education and cent trial. The World Health Organization counseling for both adolescents and parents. (WHO) and the African AIDS Vaccine “Once you give them the statistics, you can

www.iavireport.org 41 easily change people’s perception,” she says. the potential that volunteers in AIDS vaccine “Parents are very aware that their children are trials may test positive on HIV tests without in danger.” actually being HIV infected (see VAX Parental consent also requires striking a bal- November 2005 Primer on Understanding HIV ance between involving parents and protecting testing). And researchers will also face obstacles, the confidentiality and privacy of the volunteer. including the retention of adolescent volun- Adolescents may be uncomfortable disclosing teers who tend to be more mobile than adults. their potential risk behaviors to a parent or “I don’t think these are insurmountable prob- guardian. This may become even more compli- lems,” says Rogers. cated in efficacy trials, where enrollment is For these trials to be successful, expertise dependent on the volunteer being sexually active must come from outside the vaccine field. and therefore at some risk of HIV infection, says Involving adolescent organizations and com- Rogers. munity advisory boards that can offer peer support to volunteers could greatly improve the experience of adolescent volunteers. “My take Including adolescents in has always been that this can be done, but it can’t be done by everyone,” says Bekker. “You trials is viewed as a necessary have to have groups who are used to working step in making an eventual with adolescents.” AIDS vaccine available to Preliminary research indicates that many this population. adolescents are eager to participate in AIDS vaccine research. Results from a feasibility study conducted by Bekker in South Africa indicate that 53% of 256 adolescents (age 11- This raises legal and ethical issues about 19) were willing to participate in a trial. involving adolescents in trials before they have However the most common reason given for reached the legal age for sexual consent, which participation was the perception that it would varies from country to country. “The implica- offer them protection from HIV infection. tion is that you’re saying the age of consent isn’t This raises the concern of behavioral disinhi- applicable,” says Bekker. “I’m a bit squeamish bition in trials, where volunteers feel a false about that, even though I’ve been a great pro- sense of protection from a vaccine candidate tagonist.” A possible solution to this dilemma is that hasn’t yet proven effective. As a result including in efficacy trials only adolescents over they may continue or increase behaviors that the age of sexual consent and reserving Phase I put them at higher risk of HIV infection. and II trials for younger volunteers. Disinhibition is an important consideration in Regardless of these sexual consent issues, trial any prevention trial, but may be even more protocols are being developed to protect these critical for adolescents. “It’s a valid concern adolescent volunteers by tailoring the informed but I don’t know that there’s data out there to consent process and counseling sessions to specif- support it,” says Bekker. ically address their concerns, as well as those of Including adolescents in trials is viewed as a their parents. “These are the same issues we faced necessary step in making an eventual AIDS vac- with our HPV program,” says Robertson. The cine available to this population, but the need to experiences in running these efficacy trials are protect this vulnerable group from stigma and helping the company plan future AIDS vaccine other social harms is imperative during the con- trials in teenagers. duct of the trials. Another concern for parents when making the decision to allow their child to participate is Originally published in the August 2006 edition of VAX.

42 www.iavireport.org An Interview with… Zackie Achmat Facing a prevention crisis

Zackie Achmat is one of the best known and most important AIDS activists in the world. He co-founded the Treatment Action Campaign (TAC) in 1998, which is now one of South Africa’s preeminent AIDS organizations as well as one of the most influential activist groups anywhere. Since their inception TAC has been a critical proponent for affordable generic antiretrovirals (ARVs) and has challenged the South African government in and out of the courtroom over their slow response in making these medicines available. For several years Achmat refused to take ARVs to treat his own HIV infection in protest of the government’s failure to provide treatment to all citizens in need. His candor about his own struggles with the disease—he is most often seen in a tee shirt that reads “HIV Positive”—has helped create an open and supportive movement for the country’s more than five million HIV-infected individuals. Achmat was an activist long before turning his attention to HIV/AIDS. He was born in Johannesburg in 1962 and by the late 1970s he was leading student protests against apartheid. Later he began advocating for gay rights and eventually founded the National Coalition for Gay and Lesbian Equality.

In 2003 he was awarded both the Nelson Mandela Award for Health and Human Rights and the Jonathan Mann Award for Global Health and Human Rights. The following year he was nominated for the Nobel Peace Prize. Achmat remains a persistent and spirited champion for the rights of people infected with HIV, but as the epidemic in his country continues to grow—there were 500,000 newly-infected individuals last year alone with a prevalence rate among adults now around 25%—he is now also turning his focus to HIV prevention efforts. TAC is organizing a prevention march for early 2006 in Cape Town during the biannual international Microbicides conference. Achmat hopes it will create the same momentum for prevention as the treatment protest held at the 2000 International AIDS Conference in Durban, which is often referred to as a turning point in the battle for ARV access in developing countries. VAX and IAVI Report Science Writer Kristen Jill Kresge spoke with Achmat in November 2005 about HIV prevention advocacy and how activists can ensure that communities understand the research and development of new prevention technologies like vaccines and microbicides.

What are the key challenges you still face establish second- and third-line regimens for peo- as a treatment activist in your country? ple who fail their initial treatments and provide Unfortunately there are still many challenges access to ARV treatment for children. in South Africa regarding treatment. In our All of these problems are worsened by some country about 800,000 people currently need serious mixed messages from our government, treatment and fewer than 110,000 are receiving including denial by some of the science of HIV it. Of these, fewer than 70,000 are in the public infection. This political and scientific denial really sector. That’s quite sad. There is also the need to reinforces very deep, personal denial for many

www.iavireport.org 43 South Africans. The government isn’t utilizing the HIV work and all we worried about was giving strong and open HIV-positive movement, which out condoms. We never said how the condom doesn’t exist in many other countries, to create prevented transmission of the virus and it’s a further progress and that makes all of our tasks as tragedy that it took politicians and the Catholic activists much bigger. It’s particularly difficult for Church to make us explain exactly how these the individual who discovers they have HIV and tools work and get us to think about the science then doesn’t have access to a doctor or nurse who of prevention in a way we didn’t before. understands what the issues are. There are numerous prevention service organizations with people who talk about condoms or What is the situation with HIV prevention voluntary counseling and testing, but I am yet to efforts in South Africa? come across someone in those programs who actu- We don’t simply have a crisis of treatment; we ally understands the science. It’s just a simplistic also have a critical crisis of prevention. Our coun- ABC message, which is why these messages are so try had 500,000 new HIV infections last year counterproductive because they actually stop peo- and it’s critical that we act on that. It’s critical ple from thinking. Our first job as activists in that we look at why the ABC [abstinence, be South Africa was actually on the prevention of faithful, use a condom] message has failed. You mother-to-child transmission and many of us who cannot reduce prevention of HIV to a simple slo- started TAC actually began in HIV prevention and gan. It is a caricature of what needs to be a com- human rights work. Now it’s sort of coming full prehensive prevention program that is linked to circle as we are trying to make sure that what we serious treatment and care issues. learned in treatment goes back into prevention. I think all of us know that prevention is the key to ending the epidemic and that means we According to the latest report from have to find new tools, like vaccines and micro- UNAIDS and WHO on the status of the bicides. But there isn’t a magic bullet and there’s global epidemic, the HIV prevalence rates not going to be one for a long time so we have to among pregnant women in Kwazu-Natal, use the array of tools that we have at the one of the hardest hit provinces in South moment, whether it is barrier methods like male Africa, is around 40%. Is there still and female condoms or programs to prevent the debate about the use of single-dose nevi- mother-to-child transmission of HIV. We have rapine as a way to prevent mother-to-child some decent programs on prevention, but cur- transmission? rently we’re not doing enough to scale them up or I have never believed in having one standard to encourage openness about their use. for the north and another for the south, but you have a situation in many countries where there Why haven’t activists done more preven- are no antenatal services for poor women and so tion advocacy? single-dose nevirapine is a first step. It provides For many activists their inhibition is discussing an entry point for building the antenatal and basic science. Unfortunately all of us that have treatment services that are needed. To automati- worked in prevention haven’t developed the scien- cally say that this regimen is third class and you tific literacy that needs to go along with a serious either have to have the best or nothing at all is understanding of the social problems and inequal- not practical. Even single-dose nevirapine is ity that inhibit behavior change. There is now reaching less than 10% of people who need it. some understanding of how gender and economic That frustrates me. We’re still delaying both pre- inequality hamper prevention efforts and put peo- vention and treatment significantly. ple at risk, but there isn’t a scientific understanding of prevention tools and how they can be used. Presumably it’s even more difficult to I remember when we were first starting to do explain the basic science involved in the

44 www.iavireport.org research and development of vaccines and It’s really critical that there be a global and microbicides. How can this be accom- urgent summit to discuss an appropriate way to plished? respond to this. If the reduction is valid, then it South Africa is one of the few countries where will be an important intervention and it should be there is a relatively good understanding of microbi- offered to every man who wishes to do it, along cides among activists and increasingly within civil with condoms and other means of protection. society because there are some really good researchers in the country. And all of us who are Many African countries face problems activists, whether in prevention or treatment, now with infrastructure and lack of medical have a much clearer understanding of what we centers or trained physicians. Is this a need to do to ensure that there is access to informa- problem in South Africa? tion about microbicide and vaccine development. It’s not South Africa’s major problem but there is It’s difficult to explain the science of microbicides a problem with human resources. I was just looking and vaccines, but no more difficult than treatment. at some research that said 12,000-16,000 of our HIV treatment has allowed us to become engaged nurses and doctors work outside South Africa. There in science and it’s time that we became a lot more are also 55,000 trained nurses inside the country scientifically literate about HIV prevention. who are working outside the healthcare system. So We need to find a way to reach out to a there’s a huge potential pool of people who just need broader community and find people who love to better pay, improved conditions, and minor retrain- talk about basic science and then bring them into ing to be brought back into the system. the HIV movement so that we get to the point where the conversation about HIV vaccines, You were in New York City recently to microbicides, and new medicines is an informed attend a Global Health Summit sponsored scientific conversation. There has to be a certain by TIME magazine. Do you think it is level of scientific literacy within communities important for the international media to because otherwise they can be exploited by either keep global health issues in the news? quacks or people who wish to misuse science for I think it is a major step forward that the US commercial or political ends. media in particular is talking about global health I also believe it’s important that we as activists problems and raising it as an issue to inform don’t try to undermine the outcomes of science. Americans. Now this needs to be matched with Whether it’s favorable to what we believe or not, the mobilization of civil society in the US on we have to support the integrity of the scientific health, both locally and globally. It’s very impor- process. tant to raise the issue of global public health and not just in terms of economic consequences or Recently there has also been a great deal cost-effective strategies, but on what Helene of discussion about male circumcision to Gayle [director of AIDS programs at the Bill & prevent HIV infection in men based on the Melinda Gates Foundation] referred to as the results of a study in South Africa. How do policy of being a good neighbor and if my neigh- you think the international community bor is sick then I should do something about it. should react to this? In that sense we still have a long way to go. We As soon as there’s a scientific consensus we have to create a consensus that everyone has the need to move with rapidity. But first we have to right to life and everyone has the right to health be aware of and prepared for every single pitfall. care. And that includes understanding that the You have to consider situations where young men right to life is about a life with dignity. will go and get circumcised in a bush with unclean implements, without having been tested What role has the South African media for HIV. had in covering the country’s epidemic?

www.iavireport.org 45 The media in South Africa has played a critical olds. Is there any momentum building for role in discussing HIV. They raised awareness on this type of trial? the government’s delay on providing treatment There’s no momentum for it and there’s not and on a range of other issues. There’s still a lot enough talk about the young people. I think more the media can do, but it’s much better than that’s certainly an area where we need to do some almost anywhere else that I’ve seen. They’ve been work. There’s obviously a range of consent and dealing with the issues in a non-sensationalist possible infection issues involved, but the fact is and non-judgmental way and clearly laying out clear that if you stand at least a 1 in 10 chance of what still needs to be done. getting infected then there’s a duty to prevent that. And just as we try to advocate for condoms South Africa is now hosting a Phase II in school, we should advocate for very good trial vaccine trial and a Phase III microbicide practices for adolescent volunteers. trial. Do vaccine and microbicide trials in general receive much attention in the What advice would you give to the activist South African media? community? Microbicides and vaccines get coverage, but TAC is regarded as one of the strongest move- the problem with the publicity has been with ments in the country and as one of the strongest talking about them as magic bullets. This causes movements of people living with HIV in the a degree of skepticism, both in the public and the world, yet I don’t believe we reach 1 in 100 peo- activist community, about the potential for ple in our country, maybe a little more or a little microbicides and vaccines. Skepticism is good for less. But there are 46 million people in our coun- most things, but I think we need to eliminate this try. And in any other country the burden of deal- type of skepticism because it can paralyze us from ing with such a public health crisis would not fall taking action or wanting more information about on organizations like ours, it would fall on the these important strategies. There’s no way we can state, so we have to reach more people. We have proceed with an infection of this nature that con- the capacity. In our organization more than half tinues to infect millions of people across the of our activists are under 25. I’m really one of the globe, and at least half a million people a year in oldest and I think these young people are essen- our country alone, without educating ourselves. tial. But we don’t have the resources to reach as We need to ensure that we understand the many people as we want. range of measures that need to be taken to end Still we all must continue to educate ourselves, the AIDS epidemic. We can end the epidemic spread the message, and ensure that there’s but there are at least two things we have to do: money available. But then also start looking find a vaccine for tuberculosis (TB) and HIV. So three, five, even ten years ahead. What happens I would like to see organizations like IAVI work when a vaccine or microbicide becomes available? closely with AIDS and TB activists. We have to Do we have the systems ready for it? How do we end the solo approach to treatment and preven- make sure that access is once again not going to tion and look at the broader impact and use of be limited? Discussion about vaccines allows us HIV as a way to promote really good medical to talk about issues with intellectual property that care for everyone’s benefit. rewards research and development and allows companies who want to make a profit to do so, As the AIDS vaccine community begins while at the same time ensuring the widest possi- discussing the possibility of testing vac- ble access everywhere. Every person has the right cine candidates in adolescent volunteers to decent health care whether it’s in the US, there will undoubtedly be discussion China, India, or South Africa. about South Africa since there is such a high prevalence rate among 15-24 year Originally published in the Nov./Dec. 2005 edition of IAVI Report.

46 www.iavireport.org Understanding… other HIV prevention strategies

Cutting HIV transmission Male circumcision as a potential HIV prevention strategy By Sheri Fink, MD, PhD

hile the ultimate hope for stopping the transmission and acquisition,” says Godfrey WAIDS epidemic, a vaccine, remains years Kigozi, a co-principal investigator with the away there may already be a way to effectively Rakai Health Sciences Program in southwest- cut the sexual transmission of HIV—male cir- ern Uganda, a body established in 1988 as the cumcision. Scientists in eastern and southern Rakai Project. “During sexual intercourse the Africa have been studying whether the surgical foreskin is retracted, exposing a large surface procedure can protect against HIV infection, area which is vulnerable to entry of HIV. Also, and also what it would mean to promote for the foreskin is associated with genital ulcer dis- medical reasons a practice that has long held cul- ease (GUD), which makes entry of HIV into tural significance. the body easy.” Results from the first of three major randomized, controlled trials of circumcision were announced at the 3rd International AIDS “It is a procedure that a man Society Conference on HIV Pathogenesis and undergoes once in their life; Treatment in Rio de Janeiro in July. The French National Agency for Research on AIDS and it would then provide Viral Hepatitis (ANRS) sponsored the study some level of protection involving over 3000 volunteers in Orange Farm, for the rest of their life.” an urban area within South Africa’s Gauteng – Maria Wawer Province. The men were randomized to either receive circumcision immediately or defer the procedure for 21 months. Circumcision proved markedly protective. At the interim study eval- Some researchers have likened circumcision uation three times fewer circumcised partici- for boys and men to a partially protective AIDS pants (18) had acquired HIV compared with vaccine. “It is a procedure that a man under- control participants (51). The study’s Data goes once in their life; it would then provide Safety and Monitoring Board halted the trial some level of protection for the rest of their and offered circumcision to members of the life,” says Maria Wawer of Johns Hopkins control group. University in the US. “If circumcision is pro- The results did not surprise many HIV pre- tective, its role in the fight against HIV could vention researchers since an inverse relation- be really very dramatic.” An ongoing trial is ship between circumcision rates and HIV investigating whether male circumcision can prevalence had been noted for years. An analy- help prevent transmission of HIV from men to sis of more than 30 observational studies— women. But even if there is no direct protective cross-sectional, case-control and cohort—sug- effect for women, if male circumcision can gested that circumcision might reduce the risk effectively lower transmission from women to of HIV infection by 42%. The suggestion men in a given population then eventually made sense, biologically. “The foreskin has everyone will benefit—fewer transmitters mean HIV target cells which make it easy for HIV that, overall, incidence rates will decline.

www.iavireport.org 47 Kigozi and Wawer are two of the investiga- banana trees, and a profusion of birds. They tors leading an even larger randomized, con- also live close to the crossroads with Tanzania. trolled trial of male circumcision in progress in The region was the site of considerable troop Rakai Province, Uganda, under the auspices of movements and unrest during Uganda’s civil the Rakai Health Sciences Program. The US war. In the 1980s Ugandan researchers includ- National Institutes of Health (NIH) sponsored ing David Serwadda and Nelson Sewankambo the circumcision study because despite the of Uganda’s Makerere University were drawn considerable body of correlative research, the here by reports of the mysterious illness they precise link between HIV infection and cir- called “Slim Disease.” It later became known as cumcision remained unclear. Public health AIDS. The researchers began studying the pop- experts have held back from recommending ulation and were joined by Wawer, Ron Gray, circumcision as an HIV preventive method Tom Lutalo, and Fred Wabwire Mangen and because the observational studies had not others from the Ugandan Virus Research established whether circumcised men were Institute (UVRI), Johns Hopkins University, protected by circumcision itself or by other and Columbia University. factors. For example, in many parts of Africa Over the years the team has conducted many studies on HIV. The circumcision study is one of their latest. On a typical morning in the Despite the considerable spring of 2005, around 40 potential study vol- body of correlative research, unteers hiked or pedaled their bikes to the Rakai the precise link between HIV village of Kyawanyana. There they gathered under a blue and white striped tent and watched infection and circumcision a video explaining the research. HIV prevalence remained unclear. is high in Rakai—one in eight adults—and the men were looking for ways to protect themselves. “I came here to learn how to avoid circumcised men are much more likely to be STDs,” says one. Muslim, and previous research conducted by After the video, the men were called one by the Rakai Program showed that Muslim men one into small pup tents for individual counsel- in the province tended to have fewer extra- ing, physical exams and testing for HIV and marital partners than non-Muslim men. That other sexually transmitted diseases (STDs). raised the possibility that it was not circumci- They were urged to use condoms and practice sion that protected them but different sexual safe sex. A day or two later, those who met the practices. “The only way you can really find study criteria were invited to randomly select out if circumcision protects men is to take a an envelope which informed them whether group of men who volunteer for a study and they would receive circumcision immediately then randomly assign them to either get the or have to wait until the end of the two-year circumcision right away or to delay the proce- study period. dure,” says Wawer. John Paul Wasa, a counselor, says that most men hope to receive immediate circumcision. “It Putting circumcision to the test might be STD/HIV prevention, it might be sex- Rakai is a province of rolling hills, red dirt ual prowess, it might be any other thing, but roads, and simple mud and brick dwellings. It through the counseling process they get to know is a community on the socio-economic rise, but why we’d want them to remain in the arm in many inhabitants still live off subsistence farm- which they are randomized and the importance ing and do not enjoy electricity or motorized of that.” Rakai investigators know of only three transport. They share the land with cows, corn, cases where volunteers in the control group went

48 www.iavireport.org elsewhere to obtain circumcisions prior to the practice should be promoted widely, and how. end of the study. In Uganda some experts fear that if the demand The Rakai Program performs the circumci- for circumcision grows, villagers seeking to sions in a series of new, technically-advanced avoid the typical charge of roughly 50,000 operating rooms in the small town of Kalicizo. Ugandan shillings—US$30—might turn to Patients undergo circumcisions under local unqualified practitioners. If they re-use instru- anesthesia. As of the spring of 2005 nearly ments between patients without proper sterili- 3000 men had been circumcised, and a roughly zation they risk HIV infection. Every year, equal number had been randomized to serve as poorly-performed circumcisions lead to infec- controls. Only about 400 more surgeries tions and disfigurement. Chief Rakai Program remained. surgeon Dr. Stephen Watya, a consultant urol- Once they are enrolled, circumcised and uncir- ogist at Makerere University’s Mulago Hospital, cumcised men are followed closely for two years has treated the complications of some village and regularly tested for HIV infection. “We are circumcisers. “Recently I saw one young boy also looking at women to see whether circumci- about five years with a severed glans, that’s the sion in the male partner might reduce transmis- head of the penis being chopped off with the sion of HIV and STDs to the woman partner,” circumcision knife,” he says. “Occasionally that says Wawer. This latter research is part of a sepa- happens.” rate, concurrent study funded by the Bill and Melinda Gates Foundation. Rakai is the only one of the three sites to include analysis of male cir- “I think we have shown cumcision’s effect on HIV transmission to that circumcision can be women. acceptable, given the This is just one of the reasons the Rakai Program investigators believe it is essential for compliance we are seeing, their study to continue, even in light of the South given the overwhelming African group’s finding that circumcision had a numbers that are coming powerful protective effect against female-to-male HIV transmission. “There’s always a need to have to us to participate in this.” more than one trial before you implement find- – Godfrey Kigozi ings into policy,” says Kigozi. Officials with the Joint United Nations Programme on HIV/AIDS (UNAIDS) agree. The contrast between the Rakai Program’s “The two other randomized controlled trials, state of the art operating theaters and the clin- currently ongoing in Uganda and Kenya with a ics where many African men receive circumci- combined total of nearly 8000 participants, sions is remarkable. Just a few miles away tradi- remain important to clarify the relationships tional Muslim circumcisers perform their between male circumcision and HIV,” said an operations at a spartan clinic, the Kyotera agency statement. “The potential for negative or Muslim Health Unit. A single bulb dangles uncertain results in the other two trials cannot be from the ceiling of the circumcision room, ruled out at this stage.” which is nearly barren except for a bed. Each circumciser brings his own tools. “This room is Challenges and suspicions small and there are no special facilities here. If Now that at least one of the randomized con- you compare it with the [Kalicizo] theater, this trolled studies has shown that circumcision is far below required standards,” says Sheik might help prevent HIV infection, public Badru Matovu who heads this clinic. Still, health experts are considering whether the long-time circumciser Sheik Abudusamir

www.iavireport.org 49 Abudalazake Kakooza says that with education, your time, you’ll just be like us, you’ll still be many traditional and religious circumcisers in wiped out!’” Uganda have modified their practices in order Father Joseph Kato, a Catholic priest with to decrease the risk of complications and con- the Matale parish in Rakai Province has been taminated equipment. Kakooza says his rate of privy to another concern among his parish- complications is low. But no matter how ioners: that circumcision might turn them into advanced the facility, circumcision is never per- Muslims. “They came with that kind of fear. formed without risk: Rakai researchers report a And I told them this has a medicinal purpose, 0.7% rate of serious complications, and about preventing against HIV, rather than being 1 in 20 patients overall experiences at least something conversional.” Other men express minor complications. worries that their penis size will be reduced, or Even if circumcision is made relatively safe that they won’t be able to resume intercourse. and affordable, how willing will men be to In the US some anti-male-circumcision undergo the procedure? After all, circumcision activists argue that circumcision reduces sexual is more than just surgery. It is a cultural and sensation in men and that this could lead to religious practice, it is wrapped up in tribal even lower rates of condom use. and personal identity, and many myths about Still, the Rakai researchers say that men it remain. have been remarkably willing to undergo circumcision, even before knowing whether it was protective. “One of our secondary end- “As a public health measure, points was to find out whether circumcision it would have to be very could be acceptable in these communities,” carefully introduced into the says Kigozi. “I think we have shown that circumcision can be acceptable, given the com- communities with very, very pliance we are seeing, given the overwhelming strong education and would numbers that are coming to us to participate require a very significant in this.” The South African team also studied the acceptability of circumcision and found paradigm shift.” that 70% of uncircumcised men expressed a – Karusa Kiragu willingness to undergo the procedure if it would reduce the risk of contracting HIV infection. Other acceptability research has Back in the Ugandan village of Kyawanyana yielded similar results, including a large last spring, a group of men gathered for their Harvard AIDS Institute study in Botswana in post-operative check-ups. They say they’ve which over 80% of uncircumcised men said endured the disapproval of their fellow vil- they would undergo circumcision if it was per- lagers. “Most people in our villages, our vil- formed safely and affordably. lage men, tell us that you just want to stop us from having more children, as a form of fam- False sense of security? ily planning,” says one. Another agrees. His The scientists have another concern, though. friends told him “these people just bring out Might circumcision change the men’s sexual the program so that they can castrate you.” A behavior? Perhaps they would feel immune third shares a similar story. “People tell us in from HIV and engage in more risky, unpro- the villages there that we’re just wasting our tected sex, increasing their likelihood of acquir- time. That AIDS, all the same, whether we get ing—and passing—HIV infection. These ques- circumcised or not, AIDS is going to kill us. tions are identical to those that would be raised So all in all they tell us ‘you’re just wasting by the development of a partially protective

50 www.iavireport.org AIDS vaccine. hold it from the people. I think what has to be Jennifer Wagman heads up behavioral combined with the provision is the intensive research at the Rakai Program. She is looking health education and counseling—telling peo- at how men perceive circumcision and whether ple exactly what they have to do to counter their circumcised men engage in practices that perception that maybe because it’s protective might put them at risk for HIV. One of those then they can do whatever they want with potential practices is known as ‘sexual cleans- themselves.” ing.’ “After they’re circumcised they have to go out and have sex with as many women as they can who are not necessarily their wives or main “We have all been looking sexual partners,” says Wagman. “We don’t for additional tools to use know if it’s happening, so we want to find against this epidemic for out.” Public health experts will have to take practices the last 20 years. And it has like this into consideration in any widespread been very disappointing how effort to introduce circumcision. After the South difficult it has been to come African results were released, UNAIDS released a statement calling it “premature to recommend up with new tools. male circumcision services as part of HIV pre- – Maria Wawer vention programmes.” Karusa Kiragu is a behavior change scientist with the Population Council in Nairobi, So far, the men in the Rakai Program study are Kenya. “As a public health measure, it would not reporting higher risk behavior. The potential have to be very carefully introduced into the that circumcision might provide a whole new communities with very, very strong education approach to stemming the tide of HIV has many and would require a very significant paradigm scientists feeling hopeful, including Wawer. “We shift,” she says. “The paradigm of the past was have all been looking for additional tools to use that upon circumcision in many communities, against this epidemic for the last 20 years. And it the boys then go on to become sexually active. has been very disappointing how difficult it has From a public health point of view the para- been to come up with new tools.” An estimated digm would be that yes, you’re circumcised five million people worldwide contracted HIV but no, it doesn’t mean that you now have per- last year alone, and even a partial reduction in mission to go and have sex. So, disentangling HIV risk could save thousands, perhaps millions, that for communities may be difficult.” of lives. Difficult, yes, but possible, says Rakai Program principal investigator Fred Nalugoda. Sheri Fink, MD, PhD, is a freelance writer whose work has If circumcision is confirmed to be effective, he appeared in such publications as The New York Times and says, governments and other agencies should Discover Magazine, and the author of War Hospital: A True make an effort to provide the surgery to as many Story of Surgery and Survival. men as possible. “It would be unethical, once you learn something’s protective, to then with- Originally published in the July/August 2005 edition of IAVI Report.

www.iavireport.org 51 Treatment as prevention Researchers are studying the use of licensed drugs to prevent—rather than treat—HIV infection By Kristen Jill Kresge

hen AIDS was first described in the med- and is being tested in five ongoing clinical tri- Wical literature 25 years ago, there was not a als. “We urgently need new types of prevention single medicine to treat people infected with this tools and PrEP is one of many promising strate- new human virus. Since then more than 20 anti- gies, like microbicides and vaccines,” says retrovirals (ARVs) have been licensed by the US Albert Liu, an investigator for one of the PrEP Food and Drug Administration for the treatment trials in the US. of HIV/AIDS. These drugs have dramatically Researchers first thought that PrEP might be improved the health of millions of HIV-infected an effective approach more than a decade ago people around the globe and are now becoming but the complexities of conducting clinical tri- increasingly available in developing countries als to test the idea has placed them at the fore- where the need is still the greatest. front of debate. Many researchers harbor concerns that giving drugs that are known to be “The concept of using an effective for treating the disease could encourage people to participate in more risk behavior, antiretroviral as a preventive an idea known as behavioral disinhibition, has been tested and proven which could lead to a higher risk of infection. successful in preventing But investigators involved in clinical trials mother-to-child transmission insist that measures are in place to limit this effect. And if found effective PrEP may have of HIV.” the greatest benefit for people who are unable – Jim Rooney to negotiate use of traditional barrier methods and therefore have few options when it comes to HIV prevention. “We desperately need PrEP But with 4.9 million new HIV infections last to protect women in resource-poor settings,” year alone, new ways to stem the spread of HIV says Joep Lange of the University of are more urgent than ever. In response Amsterdam. researchers have turned their attention to novel If the idea of PrEP is borne out in clinical approaches to HIV prevention. One of these trials, many other questions may arise about involves giving the ARVs usually used to treat implementing this strategy on a global basis. HIV infection to try to protect people from Researchers will confront issues of long-term contracting the virus in the first place. The idea drug toxicity when ARVs are taken outside the of healthy people popping pills to stay HIV free controlled environment of a clinical trial. may seem strange, but it isn’t without prece- Other issues like drug pricing and the com- dent. Travelers headed to countries where munity outreach and educational campaigns malaria is endemic will often take drugs to pro- needed to introduce this concept to communi- tect them from becoming infected with this ties may present further obstacles. “PrEP is parasitic disease. Researchers hope that giving not a universal panacea,” says Lange, who ARVs to individuals at high risk of HIV infec- emphasizes that an AIDS vaccine is “still an tion could have the same effect. This idea is absolute priority” since its impact will be far known as pre-exposure prophylaxis, or PrEP, greater.

52 www.iavireport.org Preparing for PrEP The choice of ARV is therefore paramount. The concept of PrEP is not altogether new. Tenofovir, licensed for the treatment of HIV “The concept of using an antiretroviral as a pre- infection, was the first drug that researchers con- ventive has been tested and proven successful in sidered for PrEP. Tenofovir has been on the mar- preventing mother-to-child transmission of ket since 2001 and has a relatively good safety HIV,” says Jim Rooney of Gilead Sciences, the profile. It also has several other characteristics company that manufactures both drugs currently that make it favorable for PrEP, including once- being tested in PrEP trials. Over the last 12 years daily dosing. countless children have been spared from HIV An initial study by Gilead showed that teno- infection because mothers and babies received fovir was able to protect macaques from infec- ARVs during labor or for a short time following tion with simian immunodeficiency virus (SIV) birth (see VAX February 2005 Spotlight article, when given just before or after exposure to the Preventing mother-to-child transmission). virus. However in subsequent studies when ani- Administering ARVs to laboratory or health- mals were treated with tenofovir and exposed care workers after accidental needle-stick expo- repeatedly to a similar virus, the results weren’t as sure to HIV is also a common practice, known promising. as post-exposure prophylaxis (PEP). But in both of these situations the window of exposure to Trials and tribulations the virus is known and healthy individuals only Still, researchers knew the ultimate answers on need to take ARVs for a limited time. The the efficacy of this approach will come from premise of PrEP is that ARVs could be taken on studying tenofovir PrEP in humans and clinical a daily (possibly less frequent) basis for years in trials are now underway (Table 1). The CDC order to protect against the possibility of multi- started a Phase II safety study in February 2005 ple exposures to the virus either through sexual in the US with tenofovir in 400 men who have activity or injection drug use. Giving ARVs, sex with men (MSM) and two larger Phase even if their toxic effects are minimal, to other- IIb/III trials with tenofovir PrEP with 1600 wise healthy people over a long period raises injection drug users (IDUs) in Thailand and safety concerns. 1200 heterosexual volunteers in Botswana.

Ongoing or Planned PrEP Trials

# of Population Location Sponsor Volunteers Being Studied Drug

Botswana CDC 1200 heterosexual men and women tenofovir/Truvada

Ghana FHI 800 high-risk women tenofovir

Peru NIH/UCSF 1400 MSM Truvada

Thailand CDC 1600 IDUs tenofovir

United States CDC 400 MSM tenofovir

Table 1. Ongoing trials to evaluate the safety and efficacy of daily tenofovir or Truvada in preventing HIV infection. All trial participants are healthy, HIV-uninfected individuals. FHI: Family Health International; CDC: US Centers for Disease Control and Prevention; NIH: National Institutes of Health; UCSF: University of California, San Francisco; IDUs: injection-drug users; MSM: men who have sex with men

www.iavireport.org 53 Family Health International, a US-based non- increase their number of sexual partners. profit public health organization, also launched Others like Lange are not as concerned about a series of tenofovir PrEP trials in Malawi, disinhibition. As in any clinical trial, volunteers Nigeria, Cameroon, Cambodia, and Ghana, in PrEP trials will be tested frequently for HIV with funding from the Bill & Melinda Gates infection and counseled on how they can reduce Foundation, but only the Ghana trial is still their risk. “Usually people are better off in a clin- ongoing. Some of the trials were stopped or sus- ical trial than on the outside,” he says. Volunteers pended after activist protests regarding the life- will also have easy access to condoms. “We want time provision of ARV treatment for volunteers to test the efficacy of PrEP on top of what we who become infected during the trial. Others know already works,” Liu adds. were halted for concerns about the ethical or Several studies have analyzed the behaviors of biological parameters of these trials. In Malawi volunteers during prevention trials and the results the government halted the trial due to concerns have been mixed. During the Phase III AIDS vac- that it would foster HIV resistance to tenofovir, cine trial run by VAXGEN, researchers found that which they are now using in treatment. In injection drug users did not increase their risk response to these events the International AIDS behavior during the trial. But Mayer warns that Society held a global consultation on PrEP this may not be a fair comparison. “We can’t say research last year where researchers and activists that what happened in a vaccine trial will happen discussed the issues regarding these trials with PrEP.” Volunteers in vaccine trials may (www.iasociety.org/images/upload/1025.pdf). receive at most three inoculations. “It’s very different taking a pill every day,” he adds, which researchers fear could reinforce a false sense of Questions linger about protection among volunteers on a regular basis. why PrEP is just now All of the ongoing clinical trials are placebo controlled so that researchers can be sure to entering clinical trials, detect any protective effect the drug may offer. but disinhibition was one The trial Liu is coordinating in San Francisco is concern that kept researchers also attempting to evaluate the effects of disinhibition by staggering when volunteers start away from these studies. receiving pills. Only half of the volunteers will receive a daily pill of either tenofovir or placebo for the first nine months of the study, while the Another PrEP trial, conducted by the US others receive nothing. This will allow the study National Institutes of Health (NIH) and the investigators to compare the reported behaviors University of California, San Francisco (UCSF) of volunteers who are taking pills and those who is in the process of getting approval from local aren’t. This information will be valuable to institutional review boards to begin recruiting researchers, but the true impact of disinhibition 1400 MSM in Peru. This study is expected to isn’t likely to be realized until PrEP is adminis- start later this year, according to IMPACTA, a tered widely. Then educational campaigns will Peruvian non-governmental organization. be critical in describing both the promise and Questions linger about why PrEP is just now limitations of this approach. entering clinical trials, but disinhibition was one concern that kept researchers away from One is the loneliest number these studies. Many hesitated to dive into PrEP Researchers have always speculated that a com- research because of fear it could actually bination of ARVs, like that used for HIV treat- encourage volunteers to abandon other proven ment, may work even better for PrEP. At a major methods of HIV prevention like condoms or scientific meeting in the US earlier this year,

54 www.iavireport.org researchers from the CDC presented results from pricing in 97 developing countries. But even at an animal study with the drug Truvada, a single this drastically reduced price of about a dollar a pill containing tenofovir and another drug called day it is expensive for governments struggling to FTC, which supports this hypothesis. This idea, treat those already HIV infected. The company now being called combo-PrEP, may be even bet- does seem willing to negotiate. “If data suggest ter at fending off infection than tenofovir alone that tenofovir or Truvada is safe and effective in and sparked great interest among prevention preventing transmission of HIV, we would con- researchers. In response, some of the ongoing or tinue to work to ensure access at the lowest fea- planned PrEP trials have been modified to test sible cost,” says Rooney. Truvada. The NIH/UCSF trial that will start later this In developing countries it year has been altered to include combo-PrEP instead of tenofovir alone and the CDC plans may be more difficult to to add an additional site to the US safety trial educate communities on where volunteers will receive Truvada rather PrEP and to give out drugs than tenofovir. New volunteers in the CDC trial in Botswana will also receive Truvada, to healthy individuals who while the 70 who were already enrolled will are at high risk for HIV continue on tenofovir. infection if they aren’t Non-viral challenges accustomed to seeking Results from these trials are still several years medical care. away but some investigators are already considering the next steps. All of the current trials are testing daily doses of drug but the next round of Distributing drugs to those most in need studies will evaluate more sporadic use of PrEP would be another challenge for PrEP programs. drugs, according to Lynn Paxton who is running In developing countries it may be more difficult the PrEP trials at the CDC. to educate communities on PrEP and to give out Others are considering how this approach drugs to healthy individuals who are at high risk could be implemented if found effective and one for HIV infection if they aren’t accustomed to of the first considerations on everyone’s mind is seeking medical care. “This is going to have to cost. “The access question is very important to be a team effort,” says Paxton, “but there’s no start thinking about now,” says Liu. Both drugs reason to think that it couldn’t be done with are only available from Gilead and a year’s supply proper planning.” costs on average US$4800 for tenofovir and Regardless of these questions, researchers and $7800 for Truvada. Gilead has provided free activists alike eagerly await the results of the drugs for all of the trials but otherwise has stayed ongoing PrEP trials and the public health oppor- out of PrEP research altogether. tunities this prevention strategy may hold. The company does have an access program for treatment, offering the drug at no-profit Originally published in the May 2006 edition of VAX.

www.iavireport.org 55 Capping infection An ongoing clinical trial is testing whether the contraceptive diaphragm can help lower women’s risk of HIV infection By Sheri Fink, MD, PhD

n old-fashioned birth control method, the spermicide can prevent the transmission of Adiaphragm, could one day soon make a some sexually-transmitted infections (STIs). comeback as a woman-controlled HIV preven- Analogous to the male foreskin, the cervix also tion method. That’s the hope of researchers con- contains some of the same target cells for HIV; ducting a randomized, controlled HIV preven- Langerhans cells, a type of antigen-presenting tion study funded by the Bill and Melinda Gates dendritic cell. A recent prospective study in Foundation and known as Methods for South Africa showed that male circumcision Improving Reproductive Health in Africa may significantly reduce men’s chances of (MIRA) that has enrolled women in Harare, acquiring HIV (see Cutting HIV transmission, Zimbabwe and in Durban and Johannesburg, page 47). South Africa. Investigators from the University Although women can still acquire HIV after hysterectomy, these other findings suggest that shielding the cervix with a diaphragm might Findings suggest that lower the risk of a woman contracting the shielding the cervix with virus. In addition, because relatively high a diaphragm might lower amounts of HIV are shed by cervical cells, covering the cervix during intercourse might the risk of a woman decrease a woman’s infectiousness if she already contracting the virus. has HIV.

Current prevention methods fall short of California at San Francisco (UCSF), With effective AIDS vaccines and microbi- University of Zimbabwe, Ibis Reproductive cides still years away, male and female condoms Health, Medical Research Council of South remain the most reliable method for HIV pre- Africa, and the Perinatal HIV Research Unit of vention. But condom use remains extremely South Africa are assessing whether latex low-one study in the US found that condoms diaphragms used during intercourse can protect were used consistently during heterosexual women from contracting HIV. intercourse only about 19% of the time. Female “Biologically, it’s very plausible that it will condoms, comparable in efficacy to the male work,” says MIRA Principal Investigator Nancy condom in preventing STIs other than HIV and Padian. Contraceptive diaphragms cover the on the market for more than a decade, have cervix, the lower opening of the uterus, and pre- been inadequately supplied and adopted-in vent access to the upper genital tract, both 2005, only 14 million female condoms were thought to be key sites of entry for HIV. available worldwide, compared with 6-9 billion Cervical tissue is much thinner than vaginal tis- male condoms. sue and observational studies have suggested Male circumcision is showing some promise in that other sexually-transmitted pathogens, trials as an HIV prevention method but, even if including those causing gonorrhea and chlamy- proven effective, will require years to implement dia, preferentially infect cervical as opposed to widely. Female-initiated methods are seen as par- vaginal cells and that diaphragms used with ticularly important in light of the fact that

56 www.iavireport.org young, married women are the fastest-growing women ages 19-49, randomized them into group of new HIV infections in many countries, diaphragm and no-diaphragm arms (both and they often have difficulty negotiating con- receive condoms and prevention education), dom use. Both HIV professionals and at-risk and are following them for at least 12 months. populations have shown a keen interest in During quarterly visits the researchers test the expanding HIV prevention options, particularly participants for HIV and STIs and ask them those that are woman-controlled and already about their experiences with the diaphragms. approved for use. The women fill out computer surveys and meet The diaphragm fits both of these criteria but with counselors and clinicians. All women its low usage worldwide and its labor-intensive completing their final visits are offered a initial fitting process cast doubt on whether diaphragm. “Most women are accepting it,” women and health care providers will find the says Project Director Agnes Chidanyika. “They method acceptable. In the US and other coun- look forward to using it, especially those in the tries where oral hormonal contraceptives are affordable and widely available, diaphragms have fallen out of favor as a birth control Those championing the method. In 1995 only 2% of contraceptive users diaphragm claim that its great between the ages of 15 and 44 in the US used the method. Standard diaphragms come in nine advantage over the condom is different sizes and must be fitted in a health the fact that women can clinic and inserted prior to intercourse. Many typically use it without their health care providers stopped recommending them. “There’s somewhat of a provider bias,” partners’ knowledge. says Padian. “Health care providers assume women won’t use them.” Padian’s recent research, however, has been condom arm who haven’t used it.” finding the opposite. “They’re highly accept- In a counseling room at the clinic, a young able,” she says. Her group conducted a six- woman in the diaphragm arm of the study month diaphragm acceptability study in demonstrated diaphragm use on a plastic pelvic Zimbabwe prior to the launch of the HIV pre- model. She grasped the latex, cup-shaped vention study. Nearly all of the 186 partici- diaphragm by its firm, springy lip, squeezed it in pants reported having tried the diaphragm two, and inserted it easily into the model. “To be during the study period. At the study’s conclu- eligible to be in the study you have to be able to sion 96% had used the diaphragm during the insert the diaphragm within five attempts,” says previous two months, however consistent Chidanyika. “We had one or two out of those diaphragm use between visits was low-only 2500 women who couldn’t insert the diaphragm 13-16%. in five attempts. It was fairly easy once they knew how it was done for them to be able to Zimbabwe study insert it.” On a recent afternoon at the MIRA study The young woman said she found her own site in Epworth, a densely-populated suburb of diaphragm comfortable and had used it Harare, Zimbabwe, a dozen or so women throughout the study period except when she arrived for their final study visit. Outside in the tried to get pregnant. As with all barrier meth- dusty sunshine, music blared from a saloon ods, the importance of child-bearing in many next door and peddlers squatted before small societies may be an obstacle to widespread piles of tomatoes and carrots. Here in adoption of the diaphragm as an HIV preven- Zimbabwe the researchers have enrolled 2503 tion method.

www.iavireport.org 57 Those championing the diaphragm claim ful in other countries hit hard by HIV/AIDS. that its great advantage over the condom is the In Zimbabwe in particular, researchers could fact that women can typically use it without scarcely have chosen a more challenging situation their partners’ knowledge. Chidanyika said that in which to conduct their study. The country is was only partly true in the MIRA study, because currently experiencing epic inflation and jobless- participants are asked to use Replens gel when ness. The Epworth study site sits just a few feet inserting their diaphragms. “There’s this myth away from the rubble of countless shanties about dry sex in African countries, so we were destroyed by order of the Zimbabwean govern- worried they might not want to use the ment in the summer of 2005 in a campaign diaphragm because they would have to use the called Operation Murambatsvina or “Drive out gel to ease the insertion,” she says. “But we actu- Trash.” According to a UN-Habitat study, an ally found the gel became quite popular.” estimated 700,000 people lost their dwellings or Chidanyika says the diaphragms were accept- businesses in the campaign. able among the male partners of most women, Over a quarter of the MIRA study partici- who were happy to let their female partners use pants in Zimbabwe were displaced by Operation Murmbatsvina. This could have devastated the study, but MIRA researchers “I don’t think anyone thinks temporarily stopped enrolling new partici- diaphragms will be more pants and channeled all of their energy and resources into tracking participants in order to effective than condoms, keep them in the study. “We went to every- but we’re doing the study body, regardless of whether we just saw them in the situation where many yesterday or we last saw them last year,” says women cannot use condoms.” Chidanyika. “We just tried to find out if they were going to be evicted by Murambatsvina – Nancy Padian and, if they were, which places they were most likely to move to.” The researchers managed to retain a stun- a potential HIV prevention method that their ning 99% of the participants by visiting partners were responsible for and they could not homes, villages, and displaced persons camps, feel. However, this sentiment was not universal, reaching out to alternative contacts, and says Chidanyika. “The problem we did have launching a radio and poster campaign. The with some women is the partner would say if researchers now provide many participants she can use it without me knowing, then she can with bus fare to reach the study site from their be unfaithful.” new locations. Chidanyika says the high retention rate also reflects the enthusiasm of the Challenging study environment diaphragm study participants. “The partici- The MIRA study is being conducted at the pants themselves, they were very interested in epicenter of the HIV epidemic. According to participating in the study and coming back,” the Joint United Nations Programme on she says. HIV/AIDS (UNAIDS) 2006 Report on the Global AIDS Epidemic, HIV prevalence A look to the future among adults ages 15-49 in Zimbabwe is Results from the MIRA study are expected in 20.1% and in South Africa it’s 18.8%. If 2007. If diaphragms prove effective at lowering diaphragms prove to be acceptable and effective HIV transmission, however, those wishing to against the transmission of HIV and STIs at promote wide-scale adoption of the method will these sites, chances are that they will prove use- need to contend with several difficulties.

58 www.iavireport.org The major fear with diaphragms and indeed all cal barriers. Maggie Kilbourne-Brook, program female-controlled methods is that they will lead officer with the group Program for Appropriate to lower condom usage. “I don’t think anyone Technology in Health (PATH), says a single- thinks diaphragms will be more effective than sized device is the main improvement needed. condoms,” acknowledges Padian, “but we’re “It needs to be ‘one size fits many,’” she says, doing the study in the situation where many “which will reduce the procurement cost, the women cannot use condoms.” There is also a fear training cost, and has the potential to become that behavioral disinhibition will result from an over-the-counter device.” women believing that they can stop worrying This conclusion is based on detailed research about contracting HIV if they are using a that PATH, in conjunction with the diaphragm, but this is a consideration with all Contraceptive Research and Development HIV prevention mechanisms and even HIV treatment. The potential problem will need to be countered by education. The diaphragm may be Perhaps the most serious obstacle to future more attractive economically use of diaphragms is the possibility that they will be less acceptable in real settings than for some women; a single they are in the research environment. Over- diaphragm, though initially optimism about the prospects of the female more expensive than a condom, another woman-controlled contra- female condom, may be ceptive and HIV prevention method, is an important cautionary case. While evidence used for several years. suggests that the female condom is effective and easy to use, it has taken a long time to increase uptake for this unfamiliar contracep- Program (CONRAD), has conducted on the tive method. acceptability of cervical barriers. Women who On the positive side, however, female con- had used barriers were asked what they did and doms have been successfully marketed in some did not like about them. Providers, too, were high-prevalence countries. Furthermore, the asked why barriers were not being used in their diaphragm may be more attractive economically clinics and what it would take to bring them into for some women; a single diaphragm, though wider use. Donors and those in charge of pro- initially more expensive than a female condom, curement were also surveyed. The goal was to may be used for several years. uncover the roadblocks to greater use of cervical The main problem with traditional barriers, opening the possibility to create better diaphragms is the cumbersome way they are products. “They’d been around 100 years and fitted. The traditional, labor-intensive method hadn’t really been improved in that time,” says uses rings. The MIRA study, instead, has used Kilbourne-Brook. “We now understand much a method that its directors term a “modified more about vaginal anatomy. Manufacturing fitting scheme.” All women start with one size practices have changed. New materials have been of diaphragm, then the fit is assessed using dig- developed.” ital examination and other sizes are tried as In addition to needing a one-sized product, necessary. the researchers concluded that several other Even this simpler method, however, requires modifications would make diaphragms much a health clinic attendance for a diaphragm fit- more acceptable. “What we need to be able to ting, a potentially costly prospect that may be achieve is to make a device that is easier to associated with stigma. This limitation has led insert and remove than standard products, and developers to pioneer alternate forms of cervi- easier to use and learn to use than the cur-

www.iavireport.org 59 rently available product,” says Kilbourne- tiveness of a microbicide,” says Sharon Hillier, Brook. “It needs to be comfortable for both a microbicides researcher at the University of partners.” Pennsylvania. “Thinking of combinations of The PATH researchers used this information chemical agents like microbicides with physi- to develop an improved diaphragm. Their devel- cal barriers may present a real advance in effec- opment process was further informed by user tiveness.” feedback from women and their partners in Kilbourne-Brook believes it is important for Thailand, South Africa, and the Dominican advocates of various woman-controlled preven- Republic. The resulting product, SILCS, is a sin- tion methods, including cervical barriers, gle-sized silicone diaphragm with a nylon or microbicides, and female condoms, to come polymer spring that fits most women across all of together and devise strategic ways to look at these countries. The researchers expect to begin research questions and procedural and regula- testing the product for contraceptive effectiveness tory hurdles. “Anything that we can do for one in late 2006. of these products will strengthen the future prospects for all of these products as well,” she says. “All of these products can offer a greater If both microbicides and likelihood of protected sex for couples.” Padian diaphragms prove to be agrees, “None of the methods we are looking at are 100% effective.” partially effective at If the MIRA study indicates that traditional preventing HIV transmission diaphragms are protective against HIV trans- then combining them could mission, Padian believes there will be ways to extend the results to the new forms of cervical well offer higher protection. barriers that are being developed. “We’ll be able to generalize somewhat,” she says. “It would be crazy if you had to do a complete A number of other cervical barriers are also other trial.” in the process of being developed and Her hope is that even partial protection approved. The single-sized Lea’s Shield is a sil- against HIV by diaphragms will have a power- icone cervical barrier contraceptive already ful effect on the epidemic. “Even though it’s FDA approved for up to 48 hours of continu- not perfect, it’s better than nothing,” she says, ous use in the US and Europe. Another prod- “especially when women can’t negotiate male uct being tested, the BufferGel Duet, is a dis- condom use. For many women this is posable, one-size diaphragm pre-filled with unequivocally one hundred percent out of the the candidate microbicide and contraceptive question.” BufferGel. Indeed, if both microbicides and diaphragms Sheri Fink, MD, PhD, is a freelance writer whose work has prove to be partially effective at preventing appeared in such publications as The New York Times and HIV transmission then combining them could Discover Magazine, and the author of War Hospital: A True well offer higher protection. “We’re interested Story of Surgery and Survival. in evaluating whether the use of a physical barrier like a diaphragm could advance the effec- Originally published in the July/August 2006 edition of IAVI Report.

60 www.iavireport.org HIV prevention in a pill? Drugs that treat herpes may help reduce HIV transmission By Kristen Jill Kresge

f ongoing clinical trials pan out, it’s possible Partners in crime Ithat one day people could be cutting their risk Herpes is a lifelong infection that causes recur- of HIV infection simply by popping a couple of ring outbreaks of painful ulcers at the surface tis- pills per day. The pills are cheap, safe, and have sues (or mucosae) of the genitals. During the been around for years. The catch? These drugs course of infection the virus moves between peri- don’t target HIV, they fight off herpes. ods of latency and reactivation, when the ulcers Simply suppressing genital herpes could be appear. Numerous studies have found a strong enough to substantially reduce an individual’s risk association between herpes or other genital ulcer of acquiring and transmitting HIV. Researchers diseases and an increased risk of HIV transmis- have long known that sexually transmitted infec- sion. An analysis of previously completed studies tions (STIs) play a role in HIV transmission. Now conducted by Esther Freeman and colleagues at nearly a dozen clinical trials are investigating the London School of Hygiene and Tropical whether drugs that suppress a type of herpes virus Medicine (LSHTM) found that men and women (herpes simplex virus-2 or HSV-2) that causes gen- with genital herpes are at three times greater risk ital herpes can reduce HIV transmission (Table 2). of acquiring HIV. Approaches to HIV prevention that aim to modify behavior are yielding only modest gains against HIV transmission, so many researchers Approaches to HIV are now looking into strategies that focus on biol- prevention that aim to ogy rather than behavior. For example, earlier modify behavior are yielding this year a clinical trial in South Africa found that male circumcision could reduce the risk of men only modest gains against acquiring HIV. HIV transmission, so many Ideally strategies that combine biology and researchers are now looking behavior may provide greater gains in preven- into strategies that focus on tion than either would alone. “Aside from individual behavior change, we don’t really have biology rather than behavior. ways to prevent HIV transmission,” says Anna Wald, an epidemiologist at the University of Washington School of Public Health and Genital ulcers can help HIV establish an infec- Community Medicine in Seattle. “That is the tion by disrupting the physical barrier of the skin starting point of why we are looking at herpes.” and enabling the virus to more easily enter the The current trials will test whether drugs to body. Genital herpes also causes inflammation of suppress herpes can actually reduce HIV trans- the genital tissues, which in turn recruits acti- mission in real world settings, says Jairam vated CD4+ T cells, the primary cells infected by Lingappa, medical director of one of the studies HIV, to the site. Dendritic cells are also recruited organized by the University of Washington. and can entrap HIV particles and carry them to “While epidemiologic studies show a relationship CD4+ T cells in other areas of the body. between HIV and genital herpes,” he says, “we The elevated risk of acquiring HIV may be don’t yet have a clear demonstration of the pub- greatest in the first few months following infec- lic health benefit.” tion with HSV-2, when severe outbreaks of gen-

www.iavireport.org 61 ital ulcers are most common. So controlling these ing the herpes virus by continuous administra- ulcers should reduce HIV transmission, espe- tion of the drug in order to keep it latent. All of cially in sub-Saharan Africa where genital herpes these trials are using the drug acyclovir, an afford- is the most widespread STI. In some regions of able, safe, and proven anti-herpes medication Africa about 80% of the population has acquired efficient at blocking HSV-2. HSV-2 by age 35. Some researchers, including Philippe Mayaud There are also other ways that herpes could of the LSHTM, think providing acyclovir just increase the risk of becoming HIV infected. Even when herpes flares up and ulcers appear could if actual genital sores are not present, HSV-2 can have a significant effect on HIV transmission. He increase the risk of HIV transmission because the is currently involved in three studies, one of two viruses can interact in complicated ways that which is looking at HIV transmission after acy- aggravate the effects of both diseases. clovir is given to women in Ghana and the Central African Republic who come to clinics seeking treatment for genital herpes. Women To demonstrate the possible who consent to be in the study are HIV tested public health benefit of and offered acyclovir three times a day for five knocking down herpes, days or an inactive substance called placebo. Mayaud and his colleagues will take genital sam- researchers are running a ples from all women and will monitor the inter- number of clinical trials to actions between the two viruses in women that evaluate if two types of are also HIV infected. treatments can reduce Mayaud and other research teams are also exploring providing volunteers with a continu- HIV transmission. ous, suppressive regimen of acyclovir therapy. One study is testing this concept in female bar- and hotel-workers in Tanzania. Either acyclovir People infected with HIV and HSV-2 will or placebo is being given to 1000 HIV-infected often have frequent and prolonged outbreaks of and uninfected women in a trial led by Debby genital ulcers because herpes takes advantage of Watson-Jones at the LSHTM. The women that HIV’s ability to weaken the immune system. are HIV uninfected at the start of the trial are This increased expression of the herpes virus in being monitored for HIV infection, while the turn allows for an increase in HIV replication. HIV-infected women are being monitored to see This vicious cycle between HIV and HSV-2 if the suppressive acyclovir regimen decreases the means that suppressing herpes could reduce amounts of HSV-2 and HIV present at the geni- both the risk of acquiring HIV (acquisition) tal mucosae. and the risk of transmitting it to a sexual part- But researchers also want to know if giving ner (infectiousness). continuous acyclovir to people with HSV-2 can reduce HIV acquisition. A large scale study to Herpes suppression on trial answer that question is being conducted by Wald To demonstrate the possible public health ben- and Connie Celum, also of the University of efit of knocking down herpes, researchers are Washington. The study is following women in running a number of clinical trials to evaluate if three African nations (South Africa, Zambia and two types of treatments can reduce HIV trans- Zimbabwe) and men who have sex with men mission. One type will assess the benefit of giving (MSM) in the US and Peru to see if acyclovir can a drug to treat HSV-2 only during outbreaks of reduce their risk of becoming HIV infected. The genital herpes when genital ulcers are present. researchers will also be looking at how well the The other will evaluate the benefits of suppress- drug controls the occurrence and frequency of

62 www.iavireport.org Ongoing Trials of HSV-2 Suppression

Population Treatment Regimen Primary Outcome Sponsor

1600 HIV-/HSV-2+ MSM Suppressive Acyclovir 400 mg HIV infection National Institutes of Health; in USA and Peru.1600 twice daily for University of Washington HIV-/HSV-2+ women 18 months (Coordinating Center) in Zambia, Zimbabwe, and South Africa

2800 discordant couples Suppressive Acyclovir 400 mg HIV transmission to Bill and Melinda Gates in which one partner twice daily for non-infected partner Foundation; University of is HIV+/HSV-2+ up to 24 months Washington (Coordinating in South Africa, given to HIV+/ Center) Kenya, Tanzania, HSV-2+ partner Uganda, Rwanda, Zambia, Botswana

60 HIV+/HSV-2+ MSM Suppressive Valacyclovir 1.0 g HIV shedding University of Washington; in USA daily for 8 weeks GlaxoSmithKline

40 HIV+/HSV-2+ MSM Suppressive Valacyclovir 1.0 g Plasma and mucosal University of Washington; and women in Peru daily for 8 weeks HIV levels GlaxoSmithKline

150 HIV+/HSV2+ women Suppressive Valacyclovir 1.0 g HIV and HSV-2 French National Agency for not needing ARV; 60 on daily for 3 months shedding Research on AIDS and Viral ARV in Burkina Faso Hepatitis

300 HIV+/HSV-2+ women Suppressive Acyclovir 400 mg HIV and HSV-2 Wellcome Trust in Johannesburg, South twice daily for shedding Africa 3 months

1000 female bar-workers Suppressive Acyclovir 400 mg HIV seroconversion Wellcome Trust (HIV+ and HIV-) in Mwanza twice daily for among HIV-; HIV/HSV-2 & Shinyanga, Tanzania 2 years shedding in HIV+

Population: 500 women Episodic Acyclovir 400 mg HIV and HSV-2 French National Agency for (HIV+ and HIV-) with 3 times daily shedding; HIV/HSV-2 Research on AIDS and Viral genital ulcer disease in for 5 days seroconversion Hepatitis Ghana, Central African Republic

500 men and women Episodic Acyclovir 400 mg Ulcer healing and Fogarty International Centre; (HIV+ and HIV-) with 3 times daily HIV/HSV-2 shedding; UK Department for genital ulcer disease for 5 days HIV seroconversion International Development in Lilongwe, Malawi

600 HIV+ men with Episodic Acyclovir 400 mg Ulcer healing, lesional Centers for Disease Control genital ulcer disease 3 times daily HIV shedding; HIV and Prevention; LSHTM in Johannesburg, for 5 days seroconversion South Africa

40 HIV+/HSV-2+ women Suppressive Acyclovir 400 mg Genital HIV shedding Fred Hutchinson Cancer in Cameroon twice daily for Research Center; Institute for 8 weeks the Development of Africa

Sources: Philippe Mayaud and Clinicaltrials.gov

Table 2. Ongoing trials to evaluate episodic or suppressive treatment of HSV-2 for the prevention of HIV acquisition or transmission. The trial participants are either HIV-infected (HIV+) or HIV-noninfected (HIV-) and HSV-2-infected (HSV-2+) or HSV-2-noninfected (HSV-2-). ARV: antiretroviral; MSM: men who have sex with men; LSHTM: London School of Hygiene and Tropical Medicine

www.iavireport.org 63 genital ulcers and whether the participants can not] is a critical window in which to implement adhere to the regimen of two pills daily. “The a public health strategy to reduce transmis- trial of 3200 women and men is over 80% sion,” says Lingappa. “If we can enhance the enrolled with excellent retention and adherence, number of families that maintain one healthy so we are optimistic that we will get an answer parent or adult, that is one of the things we about the degree to which genital herpes should promote.” increases HIV susceptibility,” says Celum. While well-designed, no study can answer every question about HSV suppression. The cou- Stopping transmission ples study is meant to examine acyclovir’s role in Researchers are also interested in studying preventing HIV transmission to the non-infected how continuous HSV-2 suppression can limit partner, but it does not test whether a greater the risk of an HIV-infected person transmitting reduction in intra-couple transmission could the virus to their sexual partners. This question result if both members of the couple took acy- is being studied in a cohort of “HIV discordant” clovir. By studying acquisition and transmission couples, where one partner is infected with both of HIV in two separate trials, the researchers run HIV and HSV-2 and the other partner is not the risk of finding only weak associations in both. But Celum says the team carefully considered combining the trials and decided it would be bet- “Until the day comes when ter to separate the studies to determine the rela- an effective AIDS vaccine is tive impact of acyclovir. developed, researchers must A medicine for the masses? try everything they can to If Mayaud’s trials are successful, he hopes that stem the spread of HIV.” acyclovir will be offered as a standard treatment for genital ulcers when people seek treatment at – Pat Fast a clinic. But providing a suppressive therapy regimen—that is, a 400 mg pill of acyclovir twice a day for years—will be expensive and infected with HIV. Nearly 3000 HIV discordant may be difficult to distribute. Although a year’s couples will participate in such a study at twelve course of generically-produced acyclovir could sites in seven African countries. The HIV- cost as little as US$40 per year in Africa, it infected, HSV-2-infected partner will be given could still be prohibitive in most settings. either acyclovir or a placebo to see if they are at Valacyclovir, the newer form of the drug that reduced risk of passing HIV to their non- can be taken just once a day, is not yet manufac- infected partner, in the context of couples’ coun- tured generically. seling (see Understanding couples voluntary coun- Despite these concerns most researchers argue seling and testing, page 33), treatment of bacterial that if there is a remedy on the shelf that can be STIs, and condom provision. used to reduce HIV transmission it should be If acyclovir proves capable of reducing HIV made available. “Until the day comes when an transmission, the trial results will benefit every- effective AIDS vaccine is developed,” says Pat one—but none so much as the discordant cou- Fast, medical director at the International AIDS ples themselves. HSV-2 is the leading cause of Vaccine Initiative, “researchers must try every- genital ulcers in married couples, says Susan thing they can to stem the spread of HIV.” Allen, a professor at Emory University’s Rollins School of Public Health and a pioneer in study- Originally published in the November 2005 edition of VAX. This story ing HIV-discordant couples. “This time period was adapted from an article by Catherine Zandonella in the May/June [when one partner is infected and the other is 2005 edition of IAVI Report.

64 www.iavireport.org An Interview with… Stephen Lewis Waiting for a breakthrough

Stephen Lewis is the Special Envoy to the United Nations (UN) for HIV/AIDS in Africa. He has served in this capacity for four years and has become an unwavering voice in the battle for the development of new prevention technologies like AIDS vaccines and microbicides that could help to slow or end the pandemic, as well as for the rights of women. Lewis was born in Canada and resides in Toronto, but the majority of his time is spent on the road or in a plane. Whether visiting with affected communities in Africa or at the UN headquarters in New York City, Lewis always commands attention. Prior to his role as envoy, Lewis served as the deputy executive director of the UN Children’s Fund (UNICEF) and also as the Canadian Ambassador to the UN. He spent the early part of his career entrenched in national politics and was once leader of the New Democratic Party in Ontario, Canada. His humanitarian efforts and outstanding oratory skills have earned him numerous honors, including more than 20 honorary degrees. Earlier this year Lewis was named one of the world's one hundred most influential people by US-based TIME magazine. And at 67, Lewis shows no signs of slowing. Lewis recently gave a rousing speech at the opening ceremony of the HIV Pathogenesis and Treatment meeting held by the International AIDS Society in Rio de Janeiro, Brazil. He used the speech to criticize the recent meeting of the G8 nations for “getting caught up in celebrity.” He leveled an abundant amount of praise on the ‘3 by 5’ initiative of the World Health Organization, the progress of The Global Fund to Fight AIDS, Tuberculosis, and Malaria, and the continued dedication of UNAIDS, saying these efforts have made all the difference in the world. Lewis also emphasized the pressing importance of vaccine research. VAX and IAVI Report Science Writer Kristen Jill Kresge spoke with Lewis in July 2005 about progress in battling AIDS in Africa and what new initiatives he thinks may help halt the epidemic’s unchecked spread there.

As envoy for HIV/AIDS in Africa, you are the international media has a sense of what I reporting directly to the Secretary General have found. Then I meet with the Secretary on an entire continent’s epidemic. How do General and discuss with him what I’ve seen and you accomplish this and what do see as together we discuss how that might influence the your main activities as UN envoy? way in which he, and the UN more generally, The primary activities of my job are to visit responds. African countries, meet with the political leader- In the process I have come to understand that ship, meet with groups of people living with advocacy is also a very important component of AIDS, and spend time seeing projects in the the envoy role. I’ve therefore spent a great deal of field. I’ve always seen these last two activities as time speaking around the world at conferences critical so that I can see how the diplomatic and meetings in order to convey what is happen- community can be of greater use. When I come ing in Africa and why it is so desperately impor- back to New York I hold a media briefing so that tant for the world to respond.

www.iavireport.org 65 How has the response to the HIV epidemic Instead of getting discouraged I get angry in Africa changed in your four years as because when you are surrounded by death you envoy? can’t get over it. That’s a difficult question. The envoy role One example is the situation with orphans. has clearly evolved since the early days when I Everyone understands that one of the single most or anyone at the UN didn’t have a substantial important things for orphans is to eliminate all sense of what it would be. The sense of hope school fees so that these kids can get into school, right now is more alive than at any time dur- have peers to play with, and gain some self- ing the previous four years. The tremendous worth. And even though everyone knows that we efforts by the World Health Organization to should abolish school fees, nothing changes year put millions of people on treatment and the after year. I’ll never forgive those who have been evidence, although very slight, of increased indifferent, insensitive, and just paralyzed over resources has made people feel glimmers of such long periods of time. But there’s no point in hope in the midst of pervasive anguish. This being discouraged because futility leads nowhere. Instead, I get neurotic. I’m just one person out of thousands who are “Women are fighting more responding to this from within the UN family and when I think of all the people who are in the and more for their voices field, I don’t know how they hold their emotional to be heard because they fabric together. It’s so incredibly painful on a themselves are so appalled daily basis and I’m in a rage about it. at the carnage.” AIDS is now disproportionately affecting – Stephen Lewis women. What is the situation like in Africa? I feel more deeply now than I ever did before pandemic has been going on for over 20 years that the vulnerability of women is possibly the and we are only now, literally at this moment most terrifying component of the pandemic and in time, beginning to come to grips with it. So about which the world is doing almost nothing. the job has changed in the sense that I feel This is true in Africa, as well as in other regions now more keenly than ever before that we of the world. The women are the core of the soci- must do something to subdue the pandemic. ety—they do the farming, they carry the burden Unfortunately, on the ground things are as of care—yet they are really under siege. The dis- painful as they’ve always been because people proportionate number of infections is huge and are dying in such vast numbers. women are suffering so extensively. Women are fighting more and more for their voices to be How has your attitude changed during heard because they themselves are so appalled at your tenure as envoy? Do you find it diffi- the carnage. cult not to get discouraged? When I started as envoy I was swamped with What is being done on the ground to despair. Now I live in a perpetual rage. I feel an address the vulnerability of women? even greater sense of urgency four years into it. I see very little change on the ground. There is At first I heard all these numbers about the sit- little progress in building a legal infrastructure uation in Africa and I was lost in the data. Now and getting laws in place to protect the property when I travel I just want to save individual and inheritance rights of women. It moves from lives. You reach a point where every single inertia to paralysis. We need the toughest laws human life becomes a matter of obsession. imaginable against sexual violence and marital

66 www.iavireport.org rape, and we need ways to enforce them. We What does that immediately say about what you need to encourage the social empowerment of think is important? women, whether it’s putting girls in school or If we had a Commission on Africa with 14 starting income-generating projects. But I just women and 3 men, we would get a much more can’t get over how slowly this is happening. What valid and significant view of the continent. we have is an absolute vindication of the feminist analysis: when you’re dealing with the inability of Research into new preventive technolo- men to relinquish power and authority, then you gies like AIDS vaccines and microbi- are in real trouble. cides is seen as a critical way for women to become empowered and be able to pro- So what do you think can be done to alter tect themselves from HIV infection. Do the course of the epidemic in women? you think there is enough political I’ve come to the conclusion that we must have action into the search for an AIDS vac- an international women’s agency rooted in the cine? UN. There is a United Nations Fund for Women I remember the first time I met Seth Berkley of (UNIFEM) and it has a budget of around US$20 IAVI and he said to me the most obvious thing in million a year for the whole world. In compari- the world—a vaccine is the ultimate answer. It’s son, UNICEF has a budget of over $1 billion and really strange that we don’t integrate that into the United Nations Development Program absolutely everything we say and do because it is (UNDP) nearly $2 billion. So more than half of the ultimate answer for women, and for every- the world’s population gets a pittance of support one. But this urgency has not gripped everyone from within the UN system. This is not the fault yet, and we’re still not putting enough money, or of the UN; it’s the fault of the member states. energy, into it. And maybe you could get away with that until the dramatic expansion of the pandemic in women, but now there must be an international “…I love the sense that a agency for women. This is the single most impor- vaccine and a microbicide tant reform that could happen within the UN as far as I’m concerned. It dwarfs all other develop- are marching together ment issues. and that these aren’t UNAIDS (the Joint United Nations separate initiatives as they Programme on HIV/AIDS) must also take on have tended to be seen. AIDS as a women’s issue as though there were no tomorrow, because for the women of Africa there You have to fight like hell on is no tomorrow. both fronts simultaneously.” – Stephen Lewis The UK government recently released a report from their Commission on Africa. Did this commission’s report confront the situation facing women? I think the excitement that has been growing The one major flaw in the Blair Commission around a microbicide is pretty legitimate. It looks report, an excellent report in all other respects, as though there may be something not that far was that it is lousy on women. I just ask the ques- down the road and, even with all the limitations, tion, how is it possible that they had 17 commis- over time millions of lives could be saved. But I sioners and only 3 were women? How do you love the sense that a vaccine and a microbicide strike a commission, where you can appoint any- are marching together and that these aren’t sepa- one in the world, and only find three women? rate initiatives as they have tended to be seen. You

www.iavireport.org 67 have to fight like hell on both fronts simultane- However even with debt cancellation and for- ously. The traditional prevention vehicles, indis- eign aid, you don't build economies until you pensable though they are, need a tremendous have fair international trading laws. There is not shot in the arm, and a vaccine or microbicide yet any substantive movement to give the pro- may be just that. ducers in Africa a chance to compete fairly in the world, which would be the strongest way to How important a role does debt relief play repair the economies. in reversing the trend of poverty on the African continent? The UN general assembly recently held its The cancellation of debt in the poorest devel- special session on HIV/AIDS (UNGASS) oping countries is absolutely an obligation that in New York City. Were AIDS vaccines or the Western world should fulfill. If we were able microbicides high on the agenda? Was to cancel over $30 billion of Iraqi debt overnight there discussion on the pressing needs of just because the US wanted us to, then surely the women? world can come together on the cancellation of I sat in on the “so-called” session on gender African debt. That would free a good deal of and AIDS and there was no meaning to that money, otherwise used for servicing debt, to meeting, and I don't care who is offended by invest in social sectors where the needs are great. that. I would say it ranged from fatuous to non- descript. There was nothing in that meeting that would galvanize a response by govern- “The traditional prevention ments to what is happening to women. There vehicles, indispensable was a lot of rhetoric, which is symptomatic of though they are, need a what’s happening—we’re not responding. The Secretary General opened UNGASS by saying tremendous shot in the that although we have made some progress, arm, and a vaccine or most countries have failed to meet their prom- microbicide may be just that.” ises. This isn’t just Stephen Lewis being Cassandra; I’m just mirroring what others are – Stephen Lewis saying. In the materials on prevention produced for the meeting there was absolutely no mention I think, however, that doubling the official about AIDS vaccines or microbicides. How is it development assistance to reach the famous target humanly possible that the people who are of 0.7% GNP [gross national product] is probably responsible for setting out the details on preven- the single most important immediate response. tion forget these important technologies? It just And there we’re in trouble because the US refuses isn’t rooted in the minds of those who have to to embrace the objective. We’re surprisingly also in respond. trouble because Canada refuses to set a timetable for that objective. The development assistance is so You have become such a strong voice for important because if the disease burden of a coun- women’s rights that I wonder how your try is as high as it is in the case of these AIDS- wife has influenced your work. afflicted countries, then you never get economic My wife, Michele Landsberg, has been one growth until you deal with the disease burden, and of the strongest feminist voices in print in that requires resources. This is the argument that Canada for a quarter of a century, and the fem- Jeffrey Sachs makes—once you’ve dealt with the inist analysis has very much become part of my disease burden you can start talking more vigor- own ideology because of her influence. She’s ously about economic growth. been an absolutely extraordinary and uncom-

68 www.iavireport.org promising voice and the power and force of her the highest absolute number of infections in ideas has been unquestionably the greatest the world, then something has to be said influence on my life. about that. If in a country like Zimbabwe you We have been married for 42 years and see the pandemic eviscerating the population, Michele always says that it took her 20 years to there has to be a desperate effort made to con- turn me into a human being, and then the next front the turbulent political situation. It just 20 years were tolerable. I think that’s probably seems to me that the UN cannot be seen as accurate. I also inherited a lot from family, of complicit in the passivity and slowness that course, and was deeply engaged in politics for a characterizes some of the responses, because while, but in terms of what I think is and isn’t people’s lives are at stake. We have a responsi- important in this world, the benchmark for me bility, in a thoughtful way, to say to recalci- has been my wife. trant countries that this isn't good enough and we expect more because we're fighting for How important was your work in politics every life. and how has it shaped your current posi- tion? I love politics and I regarded it as a princi- “…even though treatment pled and useful profession. I served in parlia- is now being rolled out ment for more than 15 years and I am very sad that politics has now descended into such per- it’s happening too slow, too sonal animus and vitriol in the US and in late, and too incrementally. Canada. It’s very different from the days when That drives me crazy.” I was in politics, or when my father was in – Stephen Lewis politics in the 60s and 70s. But I was very lucky, I got into politics when I was 25 and out when I was 40. My political experience has helped me most in the advocacy around How do you get the world to realize the AIDS. consequences of this pandemic? You have to keep at it relentlessly by driving What are the most critical steps the inter- home your arguments, trying to persuade peo- national community can take in advocat- ple, and never allowing your voice to be ing for a suitable response to AIDS? silenced. You have to be tenacious and inde- Let me say something that is a trifle provoca- fatigable. We know that we can save lives tive. The world is now assessing questions of because we have generic antiretroviral drugs at how the UN and the international community a low enough cost that they should be avail- are responding to critical issues like Darfur, the able to everyone. But even though treatment is way it responded to Rwanda, and the way in now being rolled out it’s happening too slow, which it is failing to respond in Northern too late, and too incrementally. That drives Uganda. And national governments have every me crazy. right to disagree with the interpretation of the The criminal negligence on the part of the international community and say go to hell, but Western world has lasted for so long that we’ll I think that with this pandemic everything never be able to compensate for the deaths that changes. We can't allow ourselves the diplomatic have occurred. But you have to continue fight- privilege of always working behind the scenes ing, and one day, unexpectedly, you break and being silent. through. That’s what I’m waiting for. If you think that treatment is rolling out too slowly in South Africa, the country with Originally published in the July/August 2005 edition of IAVI Report.

www.iavireport.org 69 Understanding… other vaccines

Cervical cancer vaccines Introduction of vaccines for HPV may offer lessons for a future AIDS vaccine By Kristen Jill Kresge

ervical cancer is the leading cause of cancer- works so well, but there is still much work to be Crelated mortality in developing countries and done,” says Mark Feinberg, vice president of policy, accounts for more than 290,000 deaths world- public health and medical affairs at Merck. Many of wide each year. Precisely how cervical cancer these same issues may arise when an effective AIDS develops isn’t fully understood but scientists now vaccine is developed and this has many closely widely agree on the cause. Human papillo- watching how the debut of this important vaccine mavirus (HPV), an incredibly common sexually- plays out. “This is a sort of test case for HIV vaccines transmitted infection, is a necessary, although not and there will be a lot of lessons on acceptability and in itself sufficient, step in the development of cer- delivery,” says Jessica Kahn, a pediatrician at vical cancer. Cincinnati Children’s Hospital in Ohio. Routine tests like Pap smears that detect early- stage abnormalities in the cells of the cervix, Behind the virus which are the first signs of cervical cancer, have HPV is one of the most common sexually-trans- substantially reduced the rate of mortality due to mitted infections (STIs) in the world and most this disease in the US. But regular gynecologic studies suggest it infects at least 25% of sexually care is often not available to women in develop- active adults—with one study reporting prevalence ing countries. For these women, a vaccine that close to 80% in a cohort of adolescent women in can prevent cervical cancer is the ultimate solu- the US. Exact prevalence is difficult to pinpoint in tion—and it may soon be a reality. many parts of the world because of the varying sen- GlaxoSmithKline’s (GSK) HPV vaccine candi- sitivity of the assays used to detect the virus. date was submitted to the European Commission There are nearly 120 types of the virus that for approval and licensure in the countries of the infect humans and a third of these primarily cause European Union earlier this year and another HPV genital infection. These HPV types are further vaccine developed by the US pharmaceutical com- classified as high and low risk based on their abil- pany Merck already received approval and licensure ity to cause cancer. HPV types 6 and 11 are in several countries, including the US, Australia, responsible for 90% of cases of genital warts. Two Canada, Brazil, Mexico, Peru, and the countries of of the high-risk HPV types, 16 and 18, are the European Union. Both of the vaccines have responsible for 70% of the cervical cancer cases proven highly effective in large clinical trials. worldwide, according to Kahn, but the predomi- However, even with one promising vaccine in hand nant HPV types can vary geographically and these and another on the way, researchers still face the types are not as common in sub-Saharan Africa or difficult challenge of making these vaccines avail- Asia as they are in North America and Europe. able in developing countries, where immunization There is limited research on the epidemiology against HPV could save the most lives. of HPV infection in developing countries but a Questions about pricing and the ease of adminis- study published in the New England Journal of tering a vaccine to adolescents loom large in many Medicine in 2003 pooled data from 11 case-con- countries where the disease burden is the greatest trolled studies in 2506 women with cervical can- and these may be obstacles to the global use of HPV cer in Morocco, Mali, Colombia, Brazil, Paraguay, vaccines. “It’s very exciting to have this vaccine that Peru, Thailand, the Philippines, and Spain. HPV

70 www.iavireport.org type 16 was the most common with an overall with the virus types included in the vaccine. “It’s prevalence of 59%, reaching 70% in some coun- really hard to do better than that,” says Feinberg. tries. The second most common HPV type was The vaccine was also able to prevent cases of 18, with an overall prevalence of 15%, followed by persistent HPV infection that caused high-grade types 45, 31, and 35. The authors suggest that the CIN and non-invasive cancer associated with predominant HPV type should be considered if strains 16 and 18 by 97% in women who received vaccines are to be created for a specific geographic at least one injection, a more “real world” exam- region. Philippe Monteyne, vice president of ple of the vaccine’s efficacy since people may not worldwide operations for GSK’s cervical cancer return for all 3 inoculations. vaccine program, acknowledges limited regional Gardasil was approved for girls between the ages differences in HPV types but says his company’s of 9 and 26, but ideally a preventive HPV vaccine vaccine “is really useful on a worldwide basis.” would be administered prior to infection, which for such a common virus means vaccinating girls The vaccines and boys before they become sexually active. Not every woman that is HPV infected will Initially this created some controversy in the US develop cervical cancer. Many infections with with some groups arguing, as they do for HIV, that either the high- or low-risk HPV types can be tem- promoting abstinence is a better message. But the porary and cleared easily by the immune system. Advisory Committee on Immunization Practices, a But HPV becomes dangerous when infection with sub-committee of the US Centers for Disease a high-risk type isn’t cleared. A persistent and active Control and Prevention, recently recommended HPV infection can cause pre-cancerous lesions on that girls be routinely vaccinated at age 11 or 12. the cervix known as cervical intraepithelial neopla- sia (CIN) that may eventually lead to non-invasive and then advanced cervical cancer, which can be a …without a doubt introducing life-threatening condition. An unresolved HPV these vaccines in developing infection is also associated with both anal and oral countries “could have cancer in men and women. Preventive HPV vaccines—like Merck’s and a tremendous impact GSK’s—may help reduce the reliance on screen- on mortality.” ing methods in the future. Both candidates con- – Jessica Kahn sist of a single HPV protein that can self assemble into a virus-like particle (VLP), a non-replicating shell that resembles an actual virus particle closely The other preventive HPV vaccine developed enough to fool the immune system into thinking at GSK in Rixensart, Belgium, in collaboration it is encountering a natural HPV infection. with MedImmune was submitted to the Merck’s vaccine, known as Gardasil, was European regulators earlier this year and approval approved and licensed by the US Food and Drug and licensure is expected in 2007. The vaccine, Administration (FDA) in June 2006 and the known as Cervarix, is also a VLP vaccine but only European Agency for the Evaluation of includes HPV proteins from types 16 and 18. Medicinal Products in September based on data GSK has 5 ongoing Phase III efficacy trials with from multiple Phase III efficacy trials in over Cervarix in 28,000 female volunteers. Data show 25,000 women and men. Gardasil contains HPV that 3 doses of the vaccine are 100% effective at proteins from four viral types, HPV 6, 11, 16, preventing persistent HPV infection with the two and 18. In one of their Phase III trials involving types of virus in the vaccine. The vaccine was 12,167 women aged 16-26, 3 doses of the vac- 95% effective at preventing persistent HPV infec- cine were able to prevent all cases of high-grade tion and 93% effective at preventing CIN in CIN or non-invasive cervical cancer associated women who received at least one injection.

www.iavireport.org 71 GSK is only testing its vaccine in women, but researchers must first work to educate communi- Merck has chosen to evaluate the efficacy of ties about the cause of cervical cancer and this Gardasil in both male and female adolescents, as may be particularly difficult in some countries well as in trials with men who have sex with men where discussion of sexually activity is uncom- (MSM). Not only does HPV cause significant dis- mon or even taboo. Vaccinating early adolescents ease burden in males, says Feinberg, it is also likely in some developing countries might also require that vaccinating both men and women will increase new ideas for vaccine delivery since many young immunity levels on a population basis and therefore girls may not be attending school. “There really decrease overall the number of life-threatening isn’t any infrastructure in developing countries for infections in women. Merck has yet to report results administering vaccines to adolescents,” says on the efficacy of Gardasil in male volunteers and Feinberg, who attributes much of the progress their license from the FDA only applies to women. made with immunization programs in developing countries to vaccine administered to infants. Implications for HIV Another obstacle to immunization will be cost. Since both HPV and HIV can be sexually-trans- Gardasil is priced at US$120 a dose and 3 doses mitted and enter the body through the same are recommended for optimal protection. The mucosal tissues, researchers have been studying the final cost of GSK’s HPV vaccine will not be link between these two infections. The cervical released until after licensure. Both companies say lesions caused by persistent HPV infection can they will use a tiered-pricing model for their vac- enhance women’s risk of acquiring HIV because of cines, which means they will charge higher prices increased bleeding and the recruitment of CD4+ T in the US and European markets and lower prices and dendritic cells to the mucosal tissues of the in developing countries. cervix, believed to be a target site for establishment The Program for Appropriate Technology in of HIV infection in women. And a study presented Health (PATH), an advocacy group in Seattle, is at the 2005 International AIDS Society Conference now exploring ways to make HPV vaccines avail- in Brazil found that anal HPV infection was inde- able in developing countries, focusing on both pendently associated with HIV acquisition in a pricing and implementing immunization pro- cohort of 1409 MSM (Abstract no. TuOa0403). grams. Initially the organization is working in Several studies have also found that HIV-infected countries that already have active vaccination individuals are at greater risk for acquiring HPV and programs and high levels of HPV disease burden, the two prove to be perilous partners. Co-infected including India, Peru, Vietnam, and Uganda. individuals are more likely to develop severe cervical PATH will also work on a proposal to the lesions than those only infected with HPV. It is esti- Global Alliance for Vaccines and Immunization mated that HIV-infected women are three to five (GAVI) to explain why funding should be allo- times more likely to develop cervical lesions due to cated for the purchase of HPV vaccines. “We HPV infection. HIV’s ability to hinder the immune expect to look at a range of strategies to encour- system may be at the root of this problem, either age an affordable supply,” says Jacqueline Sherris, directly or indirectly, because it allows HPV to per- program director at PATH. sist longer, making cancer development more likely. New research into the epidemiology of HPV Even people on highly active antiretroviral therapy infection by region may also be an important (HAART) for HIV infection are more likely to consideration in the implementation of these develop serious anal and cervical lesions. vaccine programs, but without a doubt introducing these vaccines in developing countries Rollout plans “could have a tremendous impact on mortality,” There are several significant challenges to says Kahn. implementing HPV immunization programs around the world. Before vaccination can begin Originally published in the February 2006 edition of VAX.

72 www.iavireport.org Malaria vaccines: Renewed promise

By Kristen Jill Kresge

ilip Dubovsky only treated a single case of experimental vaccines can help control malaria. Fmalaria while working as a pediatrician in There is a critical turning point in the parasite’s California, and his diagnosis of this case was development once it enters humans. Vaccines entirely unexpected. While treating a young that act before this point would offer sterilizing patient with appendicitis, he also noticed the tell- protective immunity, because they would pre- tale signs of malaria. Several years after this brief vent immunized individuals from developing an encounter with the parasitic disease, Dubovsky is established malaria infection. Other vaccines the scientific director for a US-based nonprofit that act after this point would work by limiting organization that is devoted to the development the severity of disease. Scientists are currently of a vaccine to help end the scourge of malaria in faced with a similar situation in the pursuit of an developing countries. Malaria, along with tuber- AIDS vaccine. culosis and HIV/AIDS, is among the most deadly communicable diseases, killing nearly 3 million people each year. The Malaria Vaccine “This is the golden age Initiative (MVI), a division of PATH (Program for malaria vaccine research for Appropriate Technology in Health) in Seattle where Dubovsky works, is trying to accelerate the and we are going to see a discovery process for an effective malaria vaccine lot of data coming in over and the field may soon reap the benefits. the next few years.” “This is the golden age for malaria vaccine – Filip Dubovsky research and we are going to see a lot of data coming in over the next few years,” says Dubovsky. “We now have real proof that a malaria vaccine is possible and that it can save the The malaria vaccine candidates that are the lives of children in Africa.” furthest along in development work by the sec- This new evidence was a long time in com- ond route and do not offer complete sterilizing ing. Vaccinologists and parasitologists have immunity. This type of vaccine could still make been trying for decades to develop a vaccine great strides in reducing the mortality associated for malaria. But there were many scientific with malaria and could have immense social and obstacles to overcome first, not the least of economic benefits in the hardest hit areas. In which was decoding the sequence of more countries where malaria is widespread, the para- than 5000 genes that make up the site is responsible for up to one quarter of all Plasmodium falciparum—the most lethal of deaths in children under the age of five. Malaria’s the malaria parasites. After this was accom- burden falls primarily on the younger genera- plished three years ago, the pace of vaccine tions that would eventually become important research gathered speed. “The science is here, contributors to the welfare of both their house- and finally the biotechnology is at a point hold and community. Malaria is also increas- where we can develop promising candidates,” ingly linked with other diseases like AIDS. adds Dubovksy. Children and women, particularly pregnant There are now dozens of promising malaria women that are HIV infected, are dispropor- vaccine candidates in various stages of clinical tionately affected by malaria and in many development. There are two main ways these African countries the diseases overlap geograph-

www.iavireport.org 73 ically. In people who are co-infected, both dis- parasites form it causes the red blood cells to eases can progress more rapidly and this can have rupture resulting in shock, severe anemia, grave implications. coma, and eventually death. A vaccine that acts Meanwhile researchers are continuing the after the parasite reaches the liver would hinder search for vaccine candidates that could pro- reproduction so that fewer parasites make it vide sterilizing protective immunity. “We have into the blood. This type of vaccine would several candidates going forward now, and reduce the severity of disease and lessen the we’ve already eliminated a lot that don’t work. likelihood of death. Researchers refer to a vac- All this is great news,” says Dubovsky. cine that does not offer sterilizing immunity as However the ultimate challenge for the malaria “leaky” because it allows some of the parasites vaccine field will come once a successful candi- to leak through the immune response. date progresses through clinical trials. Then Designing this type of vaccine is now proving a the test will be getting the vaccine to those simpler task than one that induces sterilizing who need it most. immunity. Although a leaky vaccine is not 100% effec- From mosquito to human tive it will allow children to slowly develop nat- A malaria infection occurs when a female ural immunity to the parasite. In areas where mosquito bites a human. In the process, the malaria is prevalent, people are repeatedly bit- mosquito transmits parasites into the blood. At ten by infected mosquitoes and are continu- this point, the parasite is in an early stage of ously exposed to the parasites. This allows them maturity known as a sporozoite. Once inside a to build up some immunity against malaria so human, the parasite goes through a complex that even though parasites are entering the growth process. To reach the next stage the liver, the immune system is controlling their numbers. By the time people reach adulthood, many of them have developed enough immu- Newer and improved strategies nity to avoid severe symptoms and death. for treating malaria involve Children and infants are therefore at the high- taking combinations of est risk for severe malaria and death, and 90% of severe disease occurs between the ages of 5 drugs, as is the strategy months and 3 years. with HIV infection. In the absence of a vaccine other simple interventions are effective at lowering rates of malaria infections. By reducing the number of sporozoites must make the journey to the liver, mosquito bites, insecticide-treated bed nets where they use liver cells to reproduce. This is can reduce the number of infections by 45% in the critical turning point where an established areas where they are used regularly and prop- infection occurs. A sterilizing vaccine would stop erly. But as is often the case, the simplest inter- the parasite before reaching the liver. To do this ventions are often unavailable or not widely successfully it must block all of the parasites accepted. because even if just one sporozoite finds its way There are also anti-malarial drugs that can be to the liver, it can rapidly multiply and still cause taken as prophylaxis before exposure to the par- a lethal infection. asite, but unfortunately these are of little use in After replicating in the liver, the parasite is developing countries because of increasing drug then released into the blood. This stage of the resistance in the parasite in many endemic parasite is called a merozoite. The merozoite areas. One popular anti-malarial to which there then enters red blood cells where it can produce are now high levels of resistance is chloroquine. even more parasites. Once huge numbers of Newer and improved strategies for treating

74 www.iavireport.org malaria involve taking combinations of drugs, company is spending millions of dollars on as is the strategy with HIV infection. Like anti- refurbishing an existing manufacturing facility retrovirals, combination therapies for malaria to produce the vaccine for the trial, according also have high price tags and are not available to Ripley Ballou, vice president of emerging in all areas, making them only feasible as treat- disease at GSK. The company is also investigat- ments where the risk of disease is very high. ing the optimal dosing strategy for the trial. The World Health Organization (WHO) just Ballou predicts that a prime vaccination fol- recently adopted these updated regimens for lowed by a booster shot will likely give the best use in its Roll Back Malaria program after being response. criticized by researchers and activists for treating people with outdated and sub-optimal malaria therapies. Several malaria vaccine trials are currently ongoing Progress in trials in Africa with a robust Several malaria vaccine trials are currently ongoing in Africa with a robust array of candi- array of candidates. dates. There are four candidates in trials that aim to provide sterilizing immunity with an additional nine in earlier development. The Many other research groups are currently selection of candidates that may limit severity of investigating ways to include other parasite disease is even more expansive. Nine candidates proteins in a vaccine candidate to find one that are now in clinical trials and another 28 are still induces sterilizing immunity. Stephan Kappe of in the laboratory. the Seattle Biomedical Research Institute in the The field’s lead candidate was developed by US is researching which of the parasite’s 5000 the pharmaceutical company GlaxoSmithKline genes are required for it to establish infection in (GSK) and is now being readied for a large-scale the liver. Many of the vaccines now in develop- efficacy trial (Phase III) in approximately 13,000 ment have relied on the same handful of pro- children at 6 to 8 sites throughout Africa. This teins to induce an immune response to the par- vaccine candidate, known as RTS,S, seems to asite. Kappe’s work is intriguing to many in the limit disease progression and prevent childhood field who think additional proteins will need to deaths. GSK started malaria vaccine research in be included in a vaccine for it to be completely 1984 and just recently completed a Phase IIb effective at stopping the parasite. trial in Mozambique that enrolled more than 2000 children. Completion of this trial was a Ensuring access landmark in malaria research, according to Although activity and funding in the search Regina Rabinovich, the director of infectious for a malaria vaccine has been increasing diseases at the Bill & Melinda Gates steadily, much of this work has been accom- Foundation. plished with a strikingly small budget. The vaccine was 57% effective at preventing Dubovsky estimates that only US$27 million severe malaria through six months. The RTS,S this year will be spent on malaria vaccines. candidate is composed of a single protein from The partnerships between private companies the surface of the sporozoite attached to a hep- like GSK and non-governmental organizations atitis B virus protein and is delivered with an like MVI have helped keep malaria vaccine adjuvant known as AS02. The vaccine cannot research on the agenda. Industry is reluctant cause malaria or hepatitis B and caused few side to invest in research for products like malaria effects in the Phase IIb trial. Preparations for vaccines that would not be sold in the lucra- the Phase III trial are now underway and the tive US or European markets. Drug prophy-

www.iavireport.org 75 laxis is sufficient and available to travelers discussions are taking place around AIDS vac- from areas where malaria is not prevalent to cines and many in that field are looking at protect them from getting malaria. “For prod- malaria vaccines as a model. ucts like this, there needs to be some promise “A vaccine can be licensed, but until someone that someone is going to buy the vaccine in steps up and says they are going to buy it for their order for industry to make such a large com- country and start massive immunization cam- mitment,” says Ballou. paigns, it doesn’t matter much,” warns Ballou. “You can give the vaccine away for free, and there’s still a cost involved.” “A vaccine can be licensed, To this end, MVI is planning to get a licensed but until someone steps up malaria vaccine included in the WHO’s and says they are going to Expanded Programme on Immunization in developing countries. “It’s the best system we buy it for their country and have and our goal is to get an effective malaria start massive immunization vaccine integrated into it,” says Dubovsky. campaigns, it doesn’t In a recent speech at the Brookings Institution (a US-based public policy think- matter much.” tank) Nelson Mandela reminded policymakers – Ripley Ballou that African countries need improved access to treatment and prevention resources for the three biggest killers: AIDS, malaria, and tuberculosis. Discussions about potential strategies for “Freedom, after all, means nothing to someone making a malaria vaccine available at an left to die at the mercy of these preventable and affordable price are now being held between treatable diseases.” industry and organizations like the Gates Foundation and MVI. Similar planning and Originally published in the May 2005 edition of VAX.

76 www.iavireport.org Rotavirus: Vaccines enter battle against an intestinal virus New vaccines prevent potentially deadly diarrheal disease in infants By Kristen Jill Kresge

lmost all infants, everywhere in the world, in efficacy trials in Africa or Asia, so it’s unclear if Ahave been infected with rotavirus by age they will be as effective at preventing severe dis- five. This common pathogen can cause a range ease in these populations as the already completed of symptoms, from mild gastrointestinal dis- Phase III trials indicated in infants from the US, comfort to the diarrheal disease known as Europe, and Latin America. “That’s the biggest acute gastroenteritis that can lead to serious scientific question that remains,” says Parashar. dehydration. And although even the most Evidence suggests that immune responses severe cases of the disease can usually be induced by orally administered vaccines are treated easily with replenishment of fluids or reduced in these populations. Trials in developing electrolytes, rotavirus kills 600,000 children countries demonstrated the need for additional each year, the vast majority in developing doses of oral polio vaccine to stimulate equivalent countries where access to healthcare services is immunity, and both cholera vaccine and earlier limited. This single virus accounts for about versions of rotavirus vaccine performed less 5% of all childhood deaths worldwide. favorably in these settings. So it is essential that Yet as organizations such as the Program for the new rotavirus vaccines are tested there before Appropriate Technology in Health (PATH), a rotavirus vaccination programs can be imple- Seattle-based non-profit organization, meet with mented around the world. policymakers in developing countries to discuss GSK has already started two trials in Malawi rotavirus, they find many have never even heard and South Africa and Merck plans to initiate tri- of it. These meetings are the first step in prepar- als by the end of the year at yet to be identified ing governments for the introduction of two new sites in Africa and Asia, all of which are being vaccines that may help prevent the tragic conse- conducted in cooperation with PATH. Although quences of this viral infection. data from these studies isn’t expected until 2009, Despite setbacks with an earlier rotavirus vac- organizations like the Global Alliance for cine, which was abruptly revoked over safety con- Vaccines and Immunizations (GAVI), PATH, the cerns, continued efforts by vaccine manufacturers World Health Organization (WHO), and the GlaxoSmithKline (GSK) and Merck culminated CDC are already actively engaged in accelerating earlier this year in landmark clinical trials showing the testing and introduction of rotavirus vaccines that both company’s rotavirus vaccines were in countries where the most deaths from severe highly effective in preventing severe gastroenteri- gastroenteritis occur. tis in infants, and were not associated with similar safety issues. The culprit “Given the challenges and the enormous Many serotypes of rotavirus are currently in resource requirements, it is just amazing that we circulation around the globe, but luckily for vac- actually have two new products,” says Umesh cine developers more than 80% of rotavirus- Parashar, a medical epidemiologist at the US related disease is caused by just four of these Centers for Disease Control and Prevention serotypes. Rotavirus is transmitted orally and (CDC). His enthusiasm for these vaccines is tem- once inside the body, it can trigger the diarrhea pered by only one thing. Neither have been tested and vomiting that together account for the often

www.iavireport.org 77 effective it received approval and licensure from the US Food and Drug Administration (FDA). But just nine months later physicians in the US were advised by the CDC to immediately sus- e n i c

i pend use of the vaccine after a small number of d e M

unexpected cases of intussusception occurred in f o e g infants who received Rotashield. Intussusception e l l o C

is a serious bowel obstruction that happens when r o l y a part of the small intestine folds over itself like a B

, d a s collapsing telescope. If left untreated it can some- a r P

m times be fatal. a r a t a Further analysis showed that most cases of k n e V

. intussusception occurred within two weeks of V . B f infants receiving their first vaccination, suggesting o y s e t Rotashield was the cause. A study by the CDC cal- r u o c culated that the intussusception risk for vaccinated e g a m

I infants was between 1 in 4500 and 1 in 9500. Figure 4. Reconstructed image of the rotavirus particle. “That level of risk was not considered acceptable The major immune response in rotavirus infection is in the US,” says Parashar, where only 20 deaths against the VP7 (yellow) and VP4 (red) proteins on the outer surface of rotavirus. Researchers are using the each year are attributable to rotavirus infection. human rotavirus version of these proteins in a bovine or Wyeth soon withdrew Rotashield from the market simian rotavirus background to construct the new vac- and stopped manufacturing the vaccine. cines, Rotateq and Rotarix. This ignited debate among scientists and bioethicists over whether or not the vaccine could rapid and severe dehydration. In developing still provide benefit in developing countries where countries, where prompt access to healthcare the death toll is much higher. In an article bioethi- services is limited, approximately 1 in 200 chil- cist Charles Weijer of Dalhousie University, dren who are infected with rotavirus will die. Canada said it was “imperialistic to transfer this The personal toll associated with such a perva- standard of care to a country in which 1 in 200 sive virus spurred researchers into developing vac- children die of rotavirus infection.” cines that would completely prevent infection. Weijer calculated that even in a worst-case sce- However they soon changed course when studies nario, the intussusception associated with of natural infection showed that children who are Rotashield would have caused 2000-3000 deaths repeatedly infected with the virus develop some per year, which is far fewer than the 600,000 level of natural immunity that, although not able deaths caused by rotavirus-induced severe gas- to prevent subsequent re-infection, can reduce the troenteritis. risk of developing severe disease. After a second “One of the challenges with this vaccine was infection it becomes unlikely that an infant will that it hadn’t already been tested in Africa and ever experience severe gastroenteritis. “Efforts Asia,” says Parashar. Not knowing if the vaccine were then focused on developing a vaccine to was even effective in these developing-country mimic this effect,” says Parashar. settings made it difficult for policymakers to Several vaccine candidates were developed overlook the possible adverse effects. But if based on different animal strains of rotavirus. Rotashield had been tested simultaneously in One developed by Wyeth called Rotashield was developing countries there may have been greater based on a monkey virus engineered to express enthusiasm for the vaccine preventing rotavirus- proteins from the human rotavirus strain (Figure related death, and possibly even a movement to 4). After clinical trials showed this vaccine to be seek independent licensure.

78 www.iavireport.org Small risk, huge trials Rolling out vaccines Soon after Rotashield’s withdrawal Merck was Before the WHO will recommend rotavirus preparing to take their lead rotavirus vaccine can- vaccination for infants in developing countries, didate into large-scale efficacy trials. Suddenly the where infants are at the greatest risk of develop- trial plans changed dramatically. To rule out the ing life-threatening gastroenteritis, the vaccines possibility of intussusception the Phase III trials must be tested in these populations. Despite the would need to include 60,000-100,000 infants. experiences of Wyeth with Rotashield, neither Both financially and organizationally this was no manufacturer chose to run efficacy trials with small matter. However the company chose to their second-generation vaccines in both devel- move forward and began a placebo-controlled trial oped and developing countries simultaneously. with their rotavirus vaccine, Rotateq, in more than According to Feinberg, Merck decided their large 69,000 infants in 11 industrialized countries. GSK efficacy trial would only be conducted in coun- was faced with a similar situation with their vac- tries where they were confident all possible cases cine, known as Rotarix, and they too pushed of intussusception could be detected and treated ahead with a trial involving 63,000 children in quickly. “Now that we know the vaccine is highly Finland and 11 countries in Latin America. efficacious and well tolerated we want to move These trials are the largest industry-sponsored vac- forward as quickly as possible in resource-poor cine trials ever conducted and both showed that the countries,” he says. vaccines were highly effective. Rotateq prevented This is happening with the help of PATH, 74% of any rotavirus-related gastroenteritis and whose goal is to reduce the delay between initial 98% of severe cases. The vaccine also reduced the licensure of vaccines and availability in developing number of hospital visits for gastroenteritis by 86%. countries. The first step is talking with policymak- Immunization with Rotarix prevented 85% of severe ers in the 72 poorest countries and educating them gastroenteritis cases and associated hospitalizations about the disease and the vaccines. “If we go to and was 100% effective at reducing the most severe countries right now and say we want to talk about cases of the disease. Just as importantly, neither live- rotavirus, they say ‘What’s that?’” says John attenuated vaccine was associated with an increased Wecker of PATH. These countries know they have risk of intussusception. “It was likely a Rotashield- a diarrheal disease but are unaware that rotavirus is specific issue,” says Mark Feinberg of Merck. the cause. “We want to provide a solid evidence A few months after the final data was released, base for developing-country governments, and we Merck received approval to license and market have a long way to go,” he adds. Rotateq in the US and GSK received licensure In the future PATH will also have to explain for Rotarix from the European Commission. the characteristics that differentiate Rotateq from Rotarix is also licensed in Mexico, Brazil, Rotarix, mainly serotype coverage and dosing Philippines, and Singapore. schedule, so that representatives from developing These vaccines were developed without a good countries can choose which vaccine to include in animal model and, even after large studies proved their immunization programs. their efficacy, researchers have yet to identify But in the end their decisions may be mainly exactly what immune response is responsible for driven by price. PATH is now holding consulta- protection. This gives hope to AIDS vaccine tions with the manufacturers on pricing. In the researchers who are working under similar con- US, Merck’s vaccine costs $180 for the three-dose straints. Paul Offit of the Children’s Hospital of course, making it one of the highest-priced child- Philadelphia in the US and one of the co-discov- hood immunizations. Wecker is confident that erers of Rotateq says that in comparison financial subsidies provided by GAVI will help “rotavirus vaccines were much easier to make,” reduce the cost burden in developing countries. yet it still took a quarter of a century of research and development. Originally published in the July 2006 edition of VAX.

www.iavireport.org 79 IAVI gratefully acknowledges the generous support provided by the following major foundation, corporate and government donors.* Alfred P. Sloan Foundation The Netherlands Ministry of Foreign Affairs Basque Autonomous Government The New York Community Trust Becton, Dickinson and Company (BD) Norwegian Royal Ministry of Foreign Affairs Provided with the support of the European Union Bill & Melinda Gates Foundation Pfizer Inc Broadway Cares/Equity Fights AIDS The Rockefeller Foundation Canadian International Development Agency Royal Danish Ministry of Foreign Affairs Continental Airlines The Starr Foundation Crusaid Swedish International Development Agency

Deutsche AIDS-Stiftung Swedish Ministry of Foreign Affairs European Union U.K. Department for International Development Google Inc. Until There's a Cure Foundation The Haas Trusts The U.S. President’s Emergency Plan for AIDS Irish Aid Relief through the U.S. Agency for International The John D. Evans Foundation Development Merck & Co., Inc. The World Bank/Global Forum for Health Research And many generous individuals from around the world. * As of 10/06 IAVI Report Publications

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