HIV vaccine clinical trials: An overview

Jackline Odhiambo Vaccines are the most safe and cost-effective HIV, the pathogen that causes AIDS, can be way to prevent and eliminate infectious diseases, transmitted when a person’s body fluids (blood, HIV Vaccine Trials Network disability, and death. Preventive/prophylactic genital secretions) come into contact with those Cape Town, South Africa vaccines given before exposure to a disease of an infected person, through sexual contact (the enable the body to build protective mechanisms main way the disease spreads) or by needle- against infection when one is still healthy, sharing amongst intravenous drug users. HIV Correspondence to: therefore averting future illness. Examples impairs the immune system over time leading to Jackline Odhiambo include vaccines against meningitis, influenza, AIDS. When the body’s white blood cells are Hutchinson Centre Research Institute polio, smallpox, measles, rubella, and hepatitis. destroyed, the ability to fight off other diseases is of South Africa (HCRISA) A vaccine against the human immunodeficiency compromised. Active treatment with anti - First Floor, Wembley Square 3 virus (HIV) would be no exception in terms of retroviral (ARV) drugs, which help to maintain McKenzie Street, Gardens impact in the fight against this pandemic.1 or restore immune function, can keep people Cape Town 8001, South Africa A therapeutic vaccine (which treats disease in healthy for years. To manage and end the spread +27 76 302 5393 individuals who are infected by stimulating the of HIV, a variety of highly effective preventive [email protected] immune system to target diseased cells, thereby strategies, best used in combination, is required. improving immune response and enabling the A comprehensive toolkit to prevent HIV body to curb or exterminate a pathogen) would transmission would include the use of ARVs Abstract also have an impact against HIV by reducing the (antiretroviral therapy as prevention (TAsP) to More than 30 years after the discovery of the infectiousness (viral load) of those already minimize the infectiousness of HIV-infected human immunodeficiency virus as the agent infected. persons, Pre-Exposure Prophylaxis (PrEP), Post- that causes AIDS, an effective vaccine against this deadly disease has yet to be developed. The pathway to the development of a vaccine has been riddled with challenges, many unique to HIV itself. As a result, advocates, scientists, and funders have had to move away from a “home run” philosophy that had anticipated early success. Nonetheless, much has been learned along the way about the genetic diversity of the virus, the limitations of animal studies, and the cultural infrastructure and regulatory challenges involved in testing HIV vaccines. The application of coordinated approaches to face the difficulties outlined in this article is a logical way forward in developing a vaccine. Then even more progress can be made, in spite of all the uncertainties, toward the achievement of a successful vaccine.

A vaccine is a substance that teaches the body’s immune system to recognise and defend against harmful viruses or bacteria by stimulating the production of specific antibodies and thereby producing immunity to a disease.1 Vaccines are prepared from the disease pathogen or its products, or from synthetic substitutes that act like antigens without inducing disease; vaccines are typically administered through injections, orally, or by aerosol.

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Exposure Prophylaxis (PEP)), behavioural developing a vaccine to activate the immune perceived as risky, 10 even more so for HIV. changes, male circumcision, microbicides, needle/ system without adversely affecting it like the Successful development of effective HIV syringe exchange programs, and a vaccine, among virus would is not an easy task. 5 The issue of preventive and/or therapeutic vaccines requires other strategies. 2 If inoculation with a HIV waning immunity over time after receipt of a that many different candidate vaccines be studied vaccine reduces the number of people who vaccine is another challenge. 4 In short, for an simultaneously in different populations around become infected with HIV, there will be a HIV vaccine to be considered successful, it would the world. Research is currently underway on significant decrease in the number of people in have to substantially affect acquisition of different HIV immunisation concepts/modalities the population who can pass the virus on to infection (if preventive), progression of disease for efficacy based on non-human primate studies others. By preventing future infections, spread of among the already infected, or the infectiousness and results from earlier trials, as summarised in the disease can be halted, and in the process, save of the infected (if therapeutic). 6 Table 2. millions of lives. Even if the vaccine were of low Additionally, in Africa, the region hardest hit efficacy and with limited coverage, the effect HIV vaccine development and by the epidemic, HIV vaccine clinical trials face would still be significant from a public health trials unique community, ethical, political, regulatory, perspective. 3 Vaccines are the only prevention The process of HIV vaccine development, and scientific challenges. 16 These challenges modality that do not rely on sustained behaviour testing, and regulation follows much the same include weak or vaccine research–inexperienced modification. 4 pathway as that of other vaccines, with the stages national regulatory authorities (RAs), inade - Although researchers have been working for outlined in Table 1. quately resourced institutions, undeveloped many years to develop a vaccine that would treat clinical and laboratory infrastructure, and sub- or prevent HIV infection, little headway has been Factors to consider for HIV standard participant recruitment strategies that made. Many potential vaccines have been vaccine studies may exploit communities with high rates of developed in the past, but none have been good Developmental strategy complexities illiteracy. enough for approval. (For information on past HIV vaccine development is a challenging, Given these considerations, no entity can and current preventive HIV vaccine trials, see complex, and lengthy process, scientifically and single-handedly overcome the hurdles associated http://www.iavi.org/trials-database/). This is operationally. The number of participants in with HIV vaccine development. Indeed there is because of numerous challenges experienced in vaccine clinical trials is usually greater than in an urgent ethical need for global support, creating a successful HIV vaccine, including the non-vaccine drug trials because vaccines are political will, and collaboration to find a HIV fact that this lentivirus mutates much faster than generally tested more thoroughly, and scrutiny by vaccine. This necessitates significant international other viruses, thereby making it difficult to approval bodies is more intense. 9 The time and cooperation over time, drawing on partners from target. 5 Another reason is that HIV targets the cost resource requirements of testing these various health sectors, intergovernmental organi - immune system, which is the very thing a vaccine vaccines deters investment in vaccine develop - sations, government, research institutions, would try to trigger to elicit protection, so ment by manufacturers; such investment is industry, and affected populations. 4 Countries with scientific expertise and resources must assist countries that lack infrastructure and regulatory and ethical capacity to conduct trials.

Infrastructure and oversight needs Research sites with insufficient infrastructure often need time to develop facilities (clinic, laboratory, and human capacity), which can take some years to achieve – something to be factored in while building developmental strategies to ensure host countries and communities can meaningfully participate in vaccine development, ensure scientific and ethical conduct of vaccine studies, and function as equal partners with other stakeholders in a collaborative process. To facilitate timely approvals of research, regulatory expertise may also need to be strengthened. Regional regulatory harmonisation could hasten the process and enable a wide knowledge-sharing base. The WHO-supported African Vaccine Regulatory Forum (AVAREF) is one such

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Table 1. HIV vaccine development pathway

Stage Description Additional Notes Exploratory5

● Basic laboratory research conducted by academic or government researchers ● Discovery of natural or synthetic antigens that might help prevent HIV or modify effects of the virus. ● Antigens may include virus-like particles (made in the lab for preventive vaccines), or other substances derived from HIV. ● Duration: 2 to 4 years.

Pre-clinical ● Conducted by biopharmaceutical companies. ● Adjuvant (substance that enhances magnitude & studies4,5 ● Tissue-/cell-culture systems used to assess safety/potential toxicities of durability of immune responses elicited by candidate vaccine &, crucially, its immunogenicity (ability to induce an vaccine) may be added to potential vaccine to immune response). make it more effective. ● Extensive animal testing (challenge studies) also done, involving NHPs, or ● Prime-boost technique of vaccination is being non-human primates (monkeys), and other animals. Usually shed some studied, where booster doses are given following light on cellular responses that might be expected in human beings vaccination with primary vaccine to prolong (though protection using these models of prediction has been particularly durability of protection (peak immunogenicity) difficult with candidate HIV vaccines so far). to counteract inadequacy of primary vaccination ● May test for safe starting dose for next phase of research & a safe way to alone (waning effect). administer the vaccine. Injections, including biojectors (needle-free ● Many candidate vaccines flop at this stage as they injections) and infusions have been tested. do not induce desired immune response.4 ● Duration: 1 to 2 years. ● Successful candidate vaccines proceed to clinical studies.

Clinical develop - ● Does not involve vaccinating human subjects & then intentionally ● Information about experimental vaccine, risks ment5,6,7,8 exposing them to HIV. and benefits of study participation, participant ● Starts with Investigational New Drug (IND) application by study sponsor rights & responsibilities is given before seeking (typically a private company) to a Regulatory Authorities (RA) of consent from potential participants, & country(ies) in which vaccine may be marketed. throughout trial participation. ● Study also subject to ethical review. ● IND application includes: description of the ● Vaccine, like other drugs, undergoes a series of clinical trials, Phase I to IV: vaccine manufacturing & testing processes, summary of the laboratory reports, and clinical study proposal. ● Study must have both ethical & regulatory approvals prior to commencement.

Phase I ● Involves a small number of adult participants (20-80) who are at low risk ● The nature of each adverse event is defined in a for HIV acquisition. standardised manner e.g. Injection site pain. ● Conducted to assess safety in humans (tolerability, dose ranges) & ● Immunogenicity analysis include measurements determine immunization regimens. of antibody levels & cell-mediated immunity. ● Follow-up for adverse effects and/or vaccine reactogenicity (local or ● Studies may be blinded or open-label. systemic signs & symptoms post-vaccination like pain, swelling, redness at injection site, fever, malaise etc.). ● Blood samples also drawn to estimate preliminary immunogenicity (type and extent) to HIV elicited by vaccine. ● Responses may or may not be protective against HIV; larger trials needed to determine this. ● Promising results lead to next testing phase. Continued on next page

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Table 1. (Continued) Stage Description Additional Notes Exploratory5

Phase II ● Dosing data is collected; best ● Involves up to several hundred participants. May include some individuals at higher immunisation schedule is risk for HIV acquisition. determined. ● Purpose is to collect more safety data and more detailed assessment of immune ● Best method of vaccine delivery also responses. investigated. ● In Phase IIb studies, more emphasis placed on estimating efficacy. ● Randomized, double-blind, placebo-controlled, parallel group design is mostly used. ● Successful candidate vaccines move on to larger trials.

Approval and ● After successful phase 3 trial proving efficacy, the vaccine would go through an Licensure5,7 approvals process for licensure. ● Sponsor submits a Biologics License Application [BLA] to the Regulatory Authorities (RAs). ● RA will conduct an inspection of the vaccine’s manufacturing facility and approve the product labelling of the vaccine following usability testing.

Post-Marketing ● Similar to other drugs/vaccines, various systems would be used to monitor the ● Key beneficial effects of an HIV Surveillance5 licensed HIV vaccine: vaccine may not be realized directly ● adverse event reporting system & database that health care providers and to vaccinees directly, but at a consumers can report a suspected side effect into (pharmacovigilance). population level through indirect ● continuous inspection of the HIV vaccine manufacturing facilities by RAs. effects (e.g. reduced infectiousness of ● review or conduct of batch tests by RAs to ensure the vaccine is consistently safe infected vaccinees), which are not for public use, unadulterated and efficacious. captured by typical efficacy trial ● phase IV trials. endpoints. ● Higher the incidence, lower the Phase III number of participants and/or ● Large trials involving thousands of people (high risk participants). shorter the follow-up period.5 ● Usually a public-private partnership. ● Assumption is that most participants ● Incidence data in regions where vaccine will get tested is gathered when designing will be exposed to HIV (unprotected study, to inform sample size calculation & duration of follow-up, e.g. with an sex, needle sharing) during follow-up incidence of HIV of 1.5% per year in a population, ~5,000 volunteers would be in study. needed to adequately power the study. ● VE evaluated by comparing rate of ● HIV infection in the population is 1.5% per year HIV infection in active vaccine study ● Tests whether experimental vaccine: arm with that in placebo arm. ● provides any protection against HIV infection, i.e. vaccine efficacy (VE), Differences detected, are further ● delays progression to AIDS should one get infected (by checking viral load or analysed to investigate whether due CD4 count), to chance or attributable to vaccine. ● causes production of antibodies to HIV or other types of immune responses. Normal saline solution or some other ● Also assesses HIV vaccine safety in a large group of people for rare adverse effects. inactive substance may be used as ● Randomised, double-blind, placebo-controlled, parallel group trial design. placebo. ● Study follow-up usually for 2 to 3 years. Participants receive regular HIV testing & risk reduction counselling. That the vaccine is experimental and not yet proven effective is emphasized to study participants. ● The questions of whether, and how well, the vaccine works should ideally be answered by a well-designed, well-planned, well-executed and well-controlled efficacy trial, with a statistically significant result. However, reality with HIV vaccines is that may need to do more than just one phase III trial with the same candidate.

Phase IV ● Vaccine license-holder might elect to conduct these studies once vaccine is approved and in the market. ● Purpose would be to continue to test for vaccine safety, efficacy & other potential issues.

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initiative to build regulatory capacity where there ability to understand the study and consent Vaccine manufacturing capacity is limited framework to approve vaccine studies. processes, legal factors, weak regulatory It is vital that a test HIV vaccine for an efficacy WHO also supports the Developing Country framework, and other factors may increase risk of trial have consistent batch-to-batch production, Vaccine Regulatory Network (DCVRN) in harm to partici pants, and hamper the accessibility with defined, repro ducible specifica tio1ns.18 It strengthening national RAs in low- and middle- to potential participants.18 takes time to formulate a fully income countries where vaccines are Local character ised vaccine, including manufactured.4,5,17,18 Institutional and regulatory communities are stability and data regarding imm - oversight of recombinant DNA often keen to be unogenicity (its ability to provoke an Community engagement research immune response). Capacity to Local communities are often keen to be credible Institutional Biosafety Committees credible partners produce such a vaccine in large partners in HIV vaccine research efforts. To (IBCs) are responsible for in HIV vaccine quantities over a certain period is ensure sound ethics, scientific quality, relevance, reviewing research that involves research efforts. another factor to consider. Adeno - and acceptability of the proposed research in the recombinant DNA, RNA, other virus vector vaccines are popular as affected community, local representatives should potentially infectious material, and vaccine platforms as they satisfy all be approached early; their involvement in the transgenic animals, to provide recommendations the above factors.22 design, development, implementation, and on control of bio hazards associated with the use distribution of results of HIV vaccine research of microbiological agents. Since HIV vaccines fall Impact of non-vaccine prevention measures should be sustained throughout. Community in this category because they could consist of on HIV incidence support on all these fronts is crucial.17,19 substances derived from HIV or other viruses Current and future efficacy trials for HIV-1 , the such as the canarypox, adenovirus, or most common and infectious type, face practical Post-trial access cytomegalovirus vectors, IBCs must review and challenges as effective or partially effective non- When developed, HIV vaccines should be made approve these studies, in addition to the usual vaccine prevention programs23 with agents such available and affordable to the population in need. regulatory and ethics permissions. IBCs as oral PrEP, are projected to decrease the Thus, when the research protocol is developed, it represent the interests of the local community in incidence of HIV-1. This requires consideration should include scientific justifi cation of the terms of public health and the environment.20 during sample size calculation and other study selected population, a balance between risk to For similar reasons a HIV vaccine may be design matters. If there is a decreased incidence study participation and potential benefits to that subject to approval for use as a genetically of HIV-1, larger cohorts would be needed to population, and safeguards from potential harm modified organism (GMO) product in some power the studies sufficiently for demonstration (medical or social) to participants and exploitation countries. For instance, in South Africa yet of efficacy while also assessing safety of of that community. HIV stigma, human rights another layer of approval is required by the the vaccine, so there needs to be a way of discrimination (against women, users of injectable Department of Agriculture, Forestry and monitoring uptake of the prevention drugs, men who have sex with men, and sex Fisheries (DAFF) for ‘‘intentional introduction programme. Depending on uptake or other workers). Limited healthcare options, limited of GMOs into the environment”.21 events, there may need to be design adjustments

Table 2. HIV vaccine concepts currently under study for efficacy in humans

Broadly neutralizing ● Discovered from persons who were able to control the virus naturally without the use of ARVs for over 15 years, monoclonal antibodies where antibodies bind to the CD4 cell site that HIV targets.11 (bnmAbs) ● From in vitro studies, it is hoped that bnmAbs like VRC01 can be used to design reasonably efficacious preventive vaccines that give passive immunity in humans against different HIV strains.12

Vaccines targeting specific HIV- ● Progress made from the Thai prime-boost trial (RV144).13 1 strains a ● Different HIV-1 subtypes (clades) are found in different regions of the world, e.g. HIV-1 subtype C, found in the Southern Africa population, which is the target for the vCP2438 and Bivalent Subtype C gp120/MF59 prime- boost vaccine regimen.14

Global vaccine targeting ● Immunogens (proteins) assembled from natural sequences of different prevalent HIV-1 subtypes (collectively multiple HIV-1 strains . known as a mosaic antigen) to increase the range of immune responses for improved coverage (worldwide).9 ● Initial proof of concept study with the Ad26.Mos4.HIV (Ad26 vaccine) and Clade C gp140 (protein vaccine) prime-boost regimen, is initially being tested in young women at high risk of HIV infection.15 aHIV-1 is one of the two types of HIV and the most common. The other type, HIV-2, is relatively uncommon, is less infectious, and has a lower mortality rate.

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or modification of endpoints for ongoing studies. ment strategies target the induction of both conducted outside of the study, followed by in- Local reviewing bodies need to be aware of humoral immunity (antibody-mediated protec - study HIV-negative test results. When this what is considered the standard of HIV tive response involving B lymphocyte cells that occurs, it can compromise study data if the prevention in their country, communities, or recognize pathogens in blood or lymph) and cell- participant changes risk behaviour, even if study populations in order to assure that mediated immunity (protective response for unintentionally. It is therefore necessary for VISP sponsors address these issues in their trials with pathogen-infected cells, tumor cells, or trans - education to emphasise to all participants the stated aims; appropriate ethical standards must plant ed cells, following activation of antigen- importance of getting all HIV testing done also be upheld.4 sensitized T lymphocyte cells).4,8 through the study or research site until their VISP is no longer detectable. A VISP registry to verify Deficit of appropriate pre-clinical animal Genetic variation of HIV previous study participation and receipt of HIV models The classification of HIV isolates from different vaccine product, to promptly facilitate further Several experimental HIV vaccine approaches in geographical areas into genetic sub-types (clades) HIV testing, is indicated. pre-clinical studies have elicited varying degrees has enabled mapping of the epidemiological of efficacy in non-human primates (chimpanzees, spread of infection, which has led to the rationale Reactogenicity data collection monkeys). Many of these approaches fail in of selecting local isolates from trial sites as the The collection of data on specific adverse clinical testing, underscoring the fact that basis of immunogens to be used in vaccine trials, reactions (reactogenicity) after vaccine although animal models are valuable in various for example subtype B in the Americas, subtype administration is a study process that must be ways, they are yet to be predictive of protection C in Africa, subtype E in Thailand. This implemented well. This would usually be in the in humans. Therefore, we can then only truly heterogeneity in HIV lies particularly in the genes form of diary cards, which are used to collect obtain such information from human trials. This that encode for the gp120 and gp41 proteins. participant-recorded data on temperature, limitation should be considered by regulators Unique circulating forms can also result from injection site reactions such as swelling or when reviewing trial applications. As clinical recombination among the different HIV redness, among other solicited symptoms. These trials are costly (human, financial, materials, subtypes. Despite this knowledge, it remains data contribute to the safety endpoints of vaccine laboratory resources), improvement on animal unclear what the relationship is between this studies, therefore participants need to be well models is warranted.4,8 genetic variability of HIV and any vaccine- trained on completing and returning the tool induced protection observed. Trial investigations (keeping in mind recall bias and varying levels of Unknown immunological correlates of with experimental mosaic vaccines (that use cognitive abilities among participants) such that HIV/AIDS protection proteins assembled from natural sequences of accurate and complete data are collected. While immunogenicity data or a probable mode different prevalent HIV subtypes) may shed of action should be provided to justify some light on this.4,8,18 Sufficient time for antibody development conducting a HIV vaccine trial, not enough is It takes time for sufficient antibodies to develop known currently in the field about the candidate Vaccine-induced seropositivity in the body such that the full protective picture is vaccines/regimens/amount of immunogenic Whereas creating an antibody response is the elicited and can be evaluated. This contributes to response to make rational go/no-go decisions goal of an HIV vaccine, such a response may lead the length of time required for trial participant with vaccine development. With most other to a reactive result if a vaccine recipient were to follow-up. If the study is conducted in a diseases that can be prevented with vaccines, undergo routine HIV testing since these tests population at high risk of acquiring HIV, where there is a correlation between the natural or usually detect antibodies to HIV in the blood, more events could occur in a shorter timeframe, vaccine-induced immune response and the and not the virus itself. This phenomenon is this period could potentially be 3 years; the time protection against infection/disease. With HIV, called vaccine-induced seropositivity (VISP).24 could be lessened if the sample size is very large. a wide range of immune responses are seen when VISP detection and duration rates vary greatly, Correlates analyses should be planned one becomes infected with the virus. Further - depending on the product’s potency, durability, prospectively in efficacy trial designs. Timing and more, these responses do not eradicate all of the dosing, and type of the test being used. frequency of collection of the appropriate infection in the body or prevent progression to For study participants who receive a VISP- specimens post-vaccination and post-infection AIDS. So not only is there no known reliable positive result, this can sometimes lead to (serum, plasma, blood cells, mucosal cells), as well correlate of protection, but even the immuno - incorrect diagnoses, which can cause stress and as the handling and storage of specimens, must be logical mechanism is still unknown whereby a unnecessary complications such as challenges considered. All HIV infections that occur during vaccine might protect, either by preventing the with insurance, military service, blood/tissue prevention trials should be characterized by acquisition of disease or by modulating it. Lack donation, immigration, and pregnancy (a false subtyping and sequencing. Impact of any ARVs (if of clear scientific criteria to support advancement positive antibody test could lead to unnecessary started) on viral load should be factored in. Of into efficacy studies is a challenge. An option ARV treatment of a baby). Testing outside the course, all of this need for data should be weighed would be to submit a trial application without study can also lead to unblinding of the against the operational costs and logistics of these correlates and use the proposed study to participant. This scenario can occur if a “positive” collection (participant study visits, risky or identify them. Current HIV vaccine develop - result is obtained during routine testing invasive sampling, and sample processing).4

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Considerations regarding regulatory bodies 5. The History of Vaccines: An Educational 16. Vardas E, Buttò S, Glashoff R, Malnati MS, Statistical analysis plans submitted to approvers Resource by The College of Physicians of Poli G, Clerici M. Preparing for phase II/III should be clear from the beginning on various Philadelphia. Vaccines for Sexually HIV vaccine trials in Africa. Microbes issues including analysis of overall efficacy and Transmitted Diseases. 2017 [cited 2017 Infect. 2005;7(14):1436–44. subgroup results, timing of unblinding for Nov 11]. Available from: https://www. 17. UNAIDS Guidance Document: Ethical analysis purposes, modified intention-to-treat historyofvaccines.org/content/articles/ considerations in HIV preventive vaccine analysis (if results are discordant, attention vaccines-sexually-transmitted-diseases . research. 2000 should be paid as to why). 6. Follmann D, Duerr A, Tabet S, Gilbert P, 18. 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