2013 REPORT 2 3 6 4 10 33 36 malaria. ontents A monoclonal antibody vaccine that A monoclonal antibody vaccine seasonal both pandemic and targets . influenza designedvaccine A genetically-modified . cancer of pancreatic the treatment for protection for vaccine An irradiated against

C ...... Pipeline in the Vaccines Innovative ...... in Development Vaccines Glossary...... Process Drug Development/Approval Preventative Vaccines: Positive Positive Preventative Impact...... Vaccines: ..... Development Vaccine in Advances Scientific States...... in the United Successes Vaccine • • • path and regulatory The development is candidates face that these vaccine of all development As with the complex. - must pre the majority of vaccines drugs, of clinical testing before years through vail the gen- use by for can be approved they in other advances public. However, eral such as genomics and scientific fields, - becom are technologies, manufacturing useful in the development ing increasingly effortsThe continued vaccines. of new within biopharmaceutical of researchers the ecosystem, and across companies techniques and pursuing new who are - cre development, in vaccine strategies opportunitiesate tremendous protect to life-threatening more against many in the future. diseases

- A therapeutic vaccine for HIV infection for vaccine A therapeutic intended to delay disease progression. disease delay to intended

- vac cancer a new In 2010, tack disease. cancer of prostate the treatment cine for and States, in the United approved was vaccines immunotherapeutic more many in development. are - com research biopharmaceutical Today, for 271 vaccines developing panies are neurological cancer, diseases, infectious and other diseases. allergies disorders, are: in development Among the projects • Nearly 300 Vaccines Are in Development; in Development; Are Vaccines 300Nearly Treatment and on Prevention Focuses Research used been have vaccines years, many For - infec devastating prevent successfully to such as smallpox, measlestious diseases the data from to According and polio. and Control Disease for Centers U.S. diseases 10 infectious (CDC), Prevention eradicated 90 percent at least been have vaccines. to States thanks in the United millions of children This has protected illness. needless from and families the triumphs illustrate These public health have that vaccines major contributions around lives countless made in saving years, In the past several the world. understanding of our growing through the molecular underpinnings of disease new many and technological advances, including developed, been have vaccines (HPV)one against human papillomavirus cervical to cancer, that can lead infections against the anthrax guard to a vaccine to and a vaccine exposure, virus before in infections high- pneumococcal prevent risk populations. preventing only for not are But vaccines some help the body diseases, infectious by activating range of illnesses fight a and at recognize to the immune system

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presented by america’s biopharmaceutical research companies biopharmaceutical research america’s by presented Vaccines Vaccines Through of Disease Treatment A Report and Prevention on the n De icines i Med Key Issues

Innovative Vaccines in the Pipeline of the parasite is enough to cause an immune response, but not cause the disease, thus leading to protection against any Building on the transformational successes to date, the future malarial bite infection. future of vaccines—both for the prevention and treatment of disease—offers great hope for improving and preserving C ervical Cancer—A live, attenuated Listeria monocyto- public health in the United States and across the globe. The genes (LM)-based immunotherapy is in development for 271 medicines in development span a wide array of diseases, the treatment of women who already have cervical cancer and employ exciting new scientific and technical knowledge. as a result of infection by the human papillomavirus (HPV). Here are a few examples of the promising vaccines in the The vaccine targets the HPV gene E7, which is responsible pipeline: for the transformation of HPV-infected cells into dysplastic or malignant tissue. The vaccine is engineered to secrete a Malaria—A malaria vaccine in development has shown to fusion protein that instructs the body’s immune system to be 100 percent effective in early clinical trials in preventing destroy the tumors. the transmission of the disease from infected mosquitoes to humans. The vaccine builds on initial knowledge gained in HIV Infection—A therapeutic vaccine in development is tar- the 1970s, where researchers demonstrated that long-term geting the low-mutating (conserved) parts from the protein protection against malaria was possible when volunteers p24 of the HIV virus. The vaccine consists of four peptides received thousands of bites from radiated infected mosqui- that are modified to increase the immune response against toes. The vaccine in development uses a weakened form of the conserved parts of the p24 protein. A sustained immune the whole sporozoite, a life-stage of the parasite Plasmo- response against the p24 protein has shown to be associ- dium falciparnum that causes malaria. This weakened form ated with delayed disease progression.

Milestones in Vaccine Development

2013 egg-free vaccine first therapeutic 2010 cancer vaccine (U.S.)

2007 avian flu vaccine

2003 nasal flu vaccine

hepatitis B vaccine 1981

polio vaccine 1952

rabies vaccine 1885 first vaccine ever developed is for smallpox 1796

2 Medicines in Development Vaccines 2013 Key Issues

Influenza—A monoclonal antibody (mAb) vaccine in and is a fully synthetic nanoparticle vaccine engineered to development targets both pandemic and severe seasonal mimic the properties of natural pathogens to elicit an im- influenza A virus infections. The mAb vaccine, made from mune response. recombinant human antibodies from human B-cell cultures, specifically targets the M2 protein of the virus, which is es- sential for the influenza virus to function normally. “More than two-thirds of new vaccines developed in the last 25 years have been Pancreatic Cancer–A potential treatment for pancreatic developed from the United States.” cancer is a combination of two therapeutic vaccines. The Source: PhRMA 2013 Vaccine Fact Book treatment combines a Listeria-based vaccine that has been engineered to express the tumor-associated antigen mesothelin and allogeneic pancreatic cancer cells that are Preventative Vaccines: genetically-modified to secrete the immune-stimulant, Positive Impact to Health and Society granulocyte-macrophage colony stimulating factor (GM-CSF). The cells are irradiated to prevent further cell growth Vaccines are one of the most profound achievements of bio- although they stay metabolically active. Sequential adminis- medical science and public health. Spanning more than 200 tration of the vaccines in animal studies have demonstrated years of research and development, 10 infectious diseases enhanced tumor-specific T-cell and anti-tumor responses. have been at least 90 percent eradicated in the United States thanks to vaccines. This has protected millions of children S moking Cessation–One in a new class of targeted vac- and families from avoidable illness. cines in development induces an antigen-specific immune activation for smoking cessation and relapse prevention. The prevention of disease has an enormous impact on the It is made from biocompatible and biodegradable materials health of individuals, but also the health of communities and

Research & Hope Awards On September 11, 2013, PhRMA, along with distinguished members of the medical, patient, and provider communities, presented the second annual Research & Hope Awards. This year’s program highlighted the history, progress and promising future of vaccines and immunization. PhRMA proudly presented the following awards:

The Research & Hope Award for Academic or Public Research in Vaccine Development Presented to individuals or a team from academic or government institutions for outstanding research in the area of vaccine development. 2013 award presented to: Douglas R. Lowy, M.D., and John T. Schiller, Ph.D., National Cancer Institute

T he Research & Hope Award for Biopharmaceutical Industry Research in Vaccine Development Presented to individuals or team from a biopharmaceutical company for outstanding research in the area of vaccine development. 2013 award presented to: GlaxoSmithKline Malaria Vaccine Team

The Research & Hope Award for Patient and Community Health Presented to an individual or organization that has had a significant impact educating parents, health care providers or students about the importance of childhood immunizations and facilitating increased vaccinations in their community. 2013 award presented to: Linda Y. Fu, M.D., Children’s National Medical Center

To learn more about the dedicated researchers honored with the 2013 Research & Hope Awards, please visit www.phrma.org/awards.

Medicines in Development Vaccines 2013 3 Key Issues

economies by reducing health care costs and avoiding lost pro- Today, there are 204 active clinical trials for vaccines, in- ductivity. Preventative vaccines are given to individuals, but see cluding 107 that have not yet started recruiting patients or their greatest benefit when entire populations are immunized. are just now seeking volunteers to participate and another When a high level of vaccination is achieved in a community 97 that are active, but not recruiting new patients. Those with an effective vaccine, disease transmission can be success- interested in obtaining more information about these vaccine fully interrupted. When disease transmission is interrupted, clinical trials, go to www.clinicaltrials.gov, the clinical tests even those who did not receive the vaccine, or those who did database of the National Institutes of Health. not receive immunity from the vaccine, benefit from vaccination and will be protected from the disease. This is known as herd immunity—where sufficient immunization coverage prevents Scientific Advances in Vaccine the transmission of the disease to an otherwise susceptible Development population. This is especially important for the young, the Using promising new scientific approaches, researchers are elderly and those with compromised immune systems. building on the successful history of vaccination against Because vaccines are given to healthy people, including chil- infectious diseases. For example, advances in areas such as dren, there can be concerns over the possible risks associated genomics are enabling researchers to develop therapeutic with them. While some negative reactions after vaccination vaccines including immunotherapies for some types of cancer can be attributable to the vaccine itself, many are unrelated. and other diseases and conditions. In addition, vaccines today Numerous research studies have shown that the risk of not are not limited to injectables—new delivery methods include immunizing a community against certain communicable dis- nasal sprays, powders and transdermal applications, among eases is far greater than the perceived risk of the vaccination. others. Some recent examples of scientific advances include: Vaccines are highly studied before they are used in the gen- eral population and highly regulated after approval. Biophar- Therapeutic Cancer Vaccines maceutical researchers are focused on continuing to improve There are varied approaches to creating a vaccine to treat the safety and delivery of vaccines for healthy communities. cancer—they can boost the body’s immune response to fight

Recent Successes in Vaccine Use

Broadening Protection against Shingles • Shingles is caused by the same virus (varicella-zoster virus) that causes chickenpox in childhood. In patients that develop shingles, it can lay dormant in certain nerves for years and flare-up in adults causing severe pain and blisters that can last for a very long time. Shingles tends to affect older people and those with weakened immune systems. A vaccine approved in 2006 for people age 60 and older was recently approved to include people 50-59 years of age. About 200,000 people between the ages of 50-59 get shingles each year.

Protecting Newborns from Pertussis • Pertussis (whooping cough) is a very contagious bacterial disease and one of the most commonly occurring vaccine-preventable diseases in the United States. In recent years, reported pertussis cases have been on the rise—there were more than 40,000 reported cases in 2012—and the Advisory Committee on Immunization Practices (ACIP) now recommends that all pregnant women receive the Tdap vaccine (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine). Vaccinating women during pregnancy will stimulate maternal anti-pertussis antibodies that should pass to the newborn providing protection against pertussis until they are old enough to be vaccinated themselves. Prior to this recommendation, only pregnant women who never received the Tdap vaccine received the vaccine.

4 Medicines in Development Vaccines 2013 Key Issues

cancer, they can stop the cancer from growing or slow its a syringe; and a vaccine that is not rendered ineffective if growth, and can assist the immune system to locate and kill stored at warmer temperatures, making it useful in areas the cancer. Two immunotherapy vaccines have been recently where cold storage is limited. approved by the Food and Drug Administration, one for the treatment of prostate cancer and the other for melanoma. Egg-free Influenza Vaccines Historically, vaccines against influenza were grown in fertilized Unraveling the Mystery of Deadly Bacteria chicken eggs, leading to long development times, which make Scientists have identified the reason some humans are par- it difficult to respond to public health emergencies such as the ticularly susceptible to infection by the bacterium Staphylo- “swine flu” pandemic in 2009 and ensure enough supply of coccus aureus or staph—which kills about 100,000 Ameri- the seasonal flu vaccine each year. Egg-free vaccines are also cans each year. Researchers at Vanderbilt University recently important in that they provide a viable treatment option to reported that genetic variations in human hemoglobin can those with egg allergies. make certain people resistant to staph infections. In 2012, the first cell-culture-derived vaccine was approved Vaccine Combinations to Prevent and to protect against seasonal influenza in adults. It is manufac- Treat HIV infection tured using full-scale cell-culture technology, an alternative to traditional egg-based production. Cell-culture technology Recent research provides insight into how immune response uses a mammalian cell line rather than chicken eggs to grow provides protection against HIV infection. In a preclinical virus strains. study, novel vaccine combinations were found to provide partial protection against HIV infection and some combina- This year the first 100 percent egg-free influenza vaccine was tions substantially reduced the viral load after infection. approved for the prevention of influenza in adults. It is a novel protein recombinant vaccine for the prevention of seasonal New Methods for Vaccine Development influenza disease and is the first to be made in a 100 percent Live recombinant vaccines use an attenuated (weakened) virus egg-free system without growing influenza viruses, so it can from one disease as the delivery vehicle for another infec- be made quickly and without the risk of infections. tious disease. This approach is used to enhance the immune response or is used when the virus being treated (such as HIV) is too potent and would actually cause the disease.

DNA vaccines consist of DNA that is coded for a spe- cific antigen—a protein to which the immune system will respond. The DNA vaccine is injected into the body where prevention it produces the antigen and elicits an immune response VACCINATION against the antigen. is better than a cure! New Delivery Methods Researchers are running preclinical studies looking at Source: PhRMA 2013 Vaccine Fact Book using a stomach bacterium to deliver vaccines through hepatitis A NOW PREVENTABLE food, like yogurt or drinkable liquids. Harmful genes are hepatitis B NOW PREVENTABLE removed from the bacterium and replaced with those from the virus, such as influenza, to stimulate an immune cancer caused by viruses NOW PREVENTABLE response in the individual. pneumonia NOW PREVENTABLE

Other new delivery methods include inhalable powders, TARGETED FOR ELIMINATION rubella nasal sprays, a transdermal patch that contains several TARGETED FOR ELIMINATION measles microscopic needles that delivers the vaccine instead of TARGETED FOR ELIMINATION polio ERADICATED smallpox

Medicines in Development Vaccines 2013 5 Vaccine Successes in the United States

Overview • Measles infection causes encephalitis (inflammation of the brain) for one in 1,000 infected individuals. Over- • The current U.S. vaccination schedule for children be- all, measles infection kills two of every 1,000 infected tween birth and age 6 recommends immunizations for individuals. In contrast, the combination MMR (measles, 14 different diseases. Each disease for which vaccina- mumps and rubella) vaccine results in a severe allergic tions are recommended can cause serious illness or death reaction only once in every million vaccinated individu- in unvaccinated populations, and those diseases might als, while preventing measles infection. The benefits of quickly begin to appear again if vaccination rates drop. vaccine-acquired immunity extraordinarily outweigh the The United States has seen mumps outbreaks in recent serious risks of infection. years since vaccination rates have dropped, with severe • Before the varicella vaccine became available, chickenpox complications and hospitalizations required for some infections resulted in 10,000 hospitalizations and caused patients. And before the introduction of the Hib (Hae- more than 100 deaths each year in the United States. mophilus influenzae type b) vaccine, Hib meningitis Even uncomplicated cases of chickenpox cause children to affected more than 12,000 American children annually, miss a week or more of school, with a caregiver missing killing 600 and leaving many others with seizures, deaf- work to care for the sick child. ness, and developmental disabilities. After introduction of the vaccine, the number of deaths from Hib dropped to fewer than 10 per year. Diseases Covered by Vaccines in the United States

• Most vaccines prove to be highly effective. After receiving • Diphtheria once was a major cause of illness and death the second dose of the MMR vaccine (measles, mumps among children. The United States recorded 206,000 and rubella) or the stand-alone measles vaccine, 99.7 cases of diphtheria in 1921, resulting in 15,520 deaths (a percent of vaccinated individuals are immune to measles. case-fatality ratio of 7.5 percent). Diphtheria death rates The inactivated polio vaccine offers 99 percent effective- range from about 20 percent for those under age 5 and ness after three doses. The varicella (chickenpox) vaccine over the age of 40, and up to 10 percent for those ages is between 85 percent and 90 percent effective in pre- 5–40. Since the introduction of effective immunizations, venting all varicella infections, but 100 percent effective in starting in the 1920s, diphtheria rates have dropped preventing moderate and severe chicken pox. dramatically in the United States and other countries that vaccinate widely. Between 2004 and 2008, no cases of VACCINATION prevention is better than a cure! diphtheria were recorded in the United States. • Haemophilus influenzae type b, commonly known as Hib, is a bacterium that can cause severe infections, diphtheria no mortalities since 2004 particularly in young children, including meningitis, pneu- monia and cellulitis (skin infections). The vaccine protects toxoid introduced against the diseases caused by Hib, which are numerous and can be severe. Collectively, these Hib-caused infec- tions are referred to generally as “Hib disease.” Before the Hib vaccine was introduced in 1985, about 20,000 children younger than age 5 developed severe Hib disease in the United States each year, and about 1,000 died. By 2006, the number of reported Hib cases was down to only 29 for the year. Today, the majority of fatalities from

Incidence rate Hib disease are reported in developing countries where per 100,000 population the Hib vaccine is not widely used, but fatalities still occur 1920 1926 1936 1946 1956 1966 2004 in developed nations when vaccination rates drop. Source: www.cdc.gov/diphtheria/clinicians.html; www.vaccinedecision.info/cgi-bin/viewcontent.cgi?article_id=24

6 Medicines in Development Vaccines 2013 Vaccine Successes in the United States

globally among young children in a year. A vaccine to is better than a cure! VACCINATION prevention protect against measles was developed in the 1960s and was quickly adopted. Widespread vaccination programs, including the Measles Initiative, launched in 2001 by the American Red Cross, the United Nations Foundation, the measles targeted for elimination U.S. Centers for Disease Control and Prevention, UNICEF and the World Health Organization, contributed to global decreases in measles cases until the case count among children fell as low as 118,000 by 2008. Since 2008, however, vaccination campaigns have suffered from fund- 1960 1971 2009 ing cutbacks, allowing the highly contagious disease to 3,000,000–4,000,000 MMR 99% REDUCTION roar back, despite the relatively low cost of vaccinating a INFECTIONS ANNUALLY VACCINE IN CASES ANNUALLY INTRODUCED child against measles (typically less than $1).

• Mumps are caused by a virus, and its symptoms include low-grade fever, respiratory problems, and, most notably, swelling of the salivary (parotid) glands below the ear,

Source: www.cdc.gov/measles/vaccination.html; known as parotitis. While parotitis is the most easily rec- www.historyofvaccines.org/content/timelines/measles ognized symptom of mumps, it occurs only in about 30 • Human papillomaviruses (HPV) belong to a large family percent to 40 percent of all cases. Up to 20 percent of of viruses, only some of which are sexually transmitted. infected individuals may experience no symptoms at all. In Certain types of HPV cause genital warts. Other HPV the United States, cases of mumps have dropped by 99 types are the main cause of cervical cancer, and some are percent since the introduction of a vaccine in 1967. Unlike associated with anal, penile, mouth, and throat cancers. measles and rubella, however, mumps has not yet been HPV is very common: one recent study showed that eliminated in the United States. nearly 27 percent of women ages 14-59 tested positive for • Pertussis, also known as whooping cough, is an extreme- one or more strains of HPV. Rates for men are likely to be ly contagious disease caused by a bacterium. After symp- similar. The U.S. Food and Drug Administration approved toms first appear, the disease can take anywhere from a vaccine for four types of HPV in 2006 and another vac- cine that protects against two types of HPV in 2009. The recommended age for HPV vaccination of females is 11-12 VACCINATION prevention is better than a cure! years. Catch-up vaccination is recommended for females ages 13-26 who have not been previously vaccinated. The vaccine may also be given to males ages 9 through 26 to HUMAN VACCINES reduce their likelihood of acquiring genital warts. HPV vac- papillomavirus cines have been shown to be most effective when given PREVENT before exposure to HPV through sexual contact. HPV16/HPV18 infection that causes

• Measles is an extremely contagious disease caused by a OF CERVICAL virus that is easily spread through the air. Its symptoms 70% CANCER o include fever (which may rise to 104 F or higher) and REDUCED coughing, as well as its infamous rash. Measles can lead HPV prevalence by to complications ranging in severity from diarrhea to en- IN TEENAGE cephalitis (swelling of the brain), with adult patients typi- 56% GIRLS cally experiencing more severe complications. Although the disease is rarely fatal in developed countries, the but only 32% of eligible 13-17 year olds received the vaccine death rate can be quite high in underdeveloped nations. Source: The Journal of Infectious Diseases, June 2013; As recently as 2000, measles caused 1.1 million deaths PhRMA 2013 Vaccine Fact Book

Medicines in Development Vaccines 2013 7 Vaccine Successes in the United States

weeks to months to fully run its course. Eventually the • Few diseases frightened parents more in the early part of patient experiences bouts of rapid coughing followed by the 20th century than did polio (the common name for the “whooping” sound that gives the disease its common poliomyelitis). Polio tended to strike in the warm summer name as they try to inhale. Pertussis can be extremely months, sweeping through a few towns as an epidemic dangerous for infants and young children, with the high- every few years. Though most people recovered quickly est percentage of complications occurring in children less from polio, some suffered temporary or permanent than 6 months of age. The most common complication paralysis and even death. Many polio survivors were dis- is bacterial pneumonia, which is also the most common abled for life. Polio has no cure, so prevention is the most cause of deaths from pertussis. Although cases of pertus- effective means to combat it. In about 95 percent of all sis have dropped dramatically in the United States since polio cases, the person has no symptoms at all. The rest the introduction of the pertussis vaccine, the disease has of polio cases can be divided into three types: abortive caused widespread outbreaks when vaccination rates have polio (mild illness), non-paralytic polio (mild illness with dropped. A recent outbreak in California led to the deaths neurological symptoms), and paralytic polio (includes the of five infants in the first six months of 2010. first signs of paralysis). Fewer than 1 percent to 2 percent of people who contract polio become paralyzed. In most • Streptococcus pneumoniae bacteria, also called pneumo- cases of paralytic polio, the patient recovers completely. coccal bacteria, are one of the leading causes of illness However, for a certain number of people, paralysis or in young children. At least 90 types of pneumococcal muscle weakness remains for life. In severe cases of para- bacteria are known to exist. They can cause pneumonia lytic polio, the throat and chest may be paralyzed. Death as well as bloodstream infections (bacteremia), meningitis, may result if the patient does not receive artificial breath- sinusitis, and middle ear infection, among other illnesses. ing support. Between 2 percent to 5 percent of children Collectively, the different illnesses caused by Streptococcus affected with paralytic polio die; for adults, 15 percent to pneumoniae are referred to as pneumococcal disease. 30 percent die. Because of widespread vaccination, polio Invasive pneumococcal disease can be fatal; survivors of was eliminated from the Western Hemisphere in 1994. meningitis may have permanent injury, including brain Today, it continues to circulate in a handful of countries, damage, seizures, or hearing loss. Each year in the United with occasional spread to neighboring countries. (Endemic States, pneumococcal bacteria cause more than 4,800 countries are Afghanistan, India, Nigeria, and Pakistan.) cases of invasive pneumococcal disease in children younger Vigorous vaccination programs are being conducted to than age 5. Among this group, about 5 percent die from eliminate these last pockets. Polio vaccination is still recom- the infection. Of those who survive, some are left with mended worldwide because of the risk of imported cases. permanent injury. Pneumococcal bacteremia (bloodstream infection) cases total more than 50,000 each year in the • Rotavirus is the most common cause of severe diarrhea United States (bacteremia occurs in approximately 25 per- in children and infants worldwide. Before a vaccine was cent of all pneumococcal pneumonia cases). The mortality introduced in the United States, the disease caused more rate for those with pneumonia complicated by bacteremia than 400,000 doctor visits and 200,000 emergency is approximately 20 percent, but may be as high as 60 room visits each year, resulting in as many as 60 deaths percent for elderly patients. Pneumococcal meningitis cas- annually in children younger than age 5. Globally, rota- es total about 3,000 each year in the United States, and virus kills more than 500,000 children under age 5 each the mortality rate ranges from 10 percent to 30 percent. A year, with most deaths occurring in developing countries. pneumococcal vaccine that protected against 14 different In 2006, the newly licensed rotavirus vaccine RotaTeq strains was licensed in 1977 and was expanded to protect was recommended as routine infant immunization and in against 23 strains in 1983. However, it is most effective 2008, the Food and Drug Administration licensed another in adults. A separate vaccine for children was licensed in rotavirus vaccine, Rotarix, for use in infants in the United 2000 and was expanded to include protection against 13 States. The CDC has carefully monitored incidence of strains in 2010. Since the initial recommendation, invasive rotavirus disease in the United States since 2000. Their pneumococcal disease in children has dropped by nearly studies show that the number of positive test results for 80 percent in the United States. rotavirus was substantially lower than the median ob- served during 2000-2006.

8 Medicines in Development Vaccines 2013 Vaccine Successes in the United States

• Rubella is caused by a virus, and although rubella is 1949. After intensive vaccination campaigns in the 1960s sometimes called “German measles,” the rubella virus is not and 1970s, the last case of wild smallpox in the world related to the measles virus. Rubella symptoms include low- occurred in Somalia in 1977. (Today, certain U.S. military grade fever, respiratory problems, and most notably a rash personnel and some civilian workers receive the smallpox of pink or light red spots. In children, illness from rubella vaccine due to the threat of bioterrorism.) infection is usually mild. Complications from rubella are •  is a disease of the nervous system caused by more common in adults. A woman who contracts rubella Tetanus bacteria. The symptoms of tetanus include lockjaw (the infection during pregnancy can pass the infection to the most recognizable of its physical effects), stiffness, and developing fetus. Such pregnancies are at risk of spontane- problems swallowing. Later symptoms include severe ous abortion or premature birth. If the fetus survives, the muscle spasms, seizure-like activity, and severe nervous child may suffer from a wide range of birth defects, includ- system disorders. Generally, between 10 percent and 20 ing deafness, eye defects, cardiac defects, mental retarda- percent of tetanus cases result in death, though fatali- tion, bone lesions, and other abnormalities. Together, the ties are more likely among patients older than age 60 defects are known as congenital rubella syndrome (CRS), and among unimmunized individuals. The extreme rarity which is the chief danger of rubella disease. From 1964- of tetanus cases among individuals immunized up to 10 1965, before the development of a vaccine against the years prior to infection suggests an efficacy rate of nearly disease, a rubella epidemic swept the United States. During 100 percent for the tetanus vaccine. Immunity levels do that short period, 12.5 million cases of rubella developed, decrease with time, however, so that boosters against and 20,000 children were born with CRS: 11,000 were tetanus are recommended every 10 years in order to deaf, 3,500 blind, and 1,800 mentally retarded. As of maintain protection against the disease. 2004, rubella was declared eliminated in the United States. • Yellow fever is a viral disease spread by the bite of • The history of smallpox, which is caused by a virus, holds infected mosquitoes. Globally, the disease infects about a unique place in human health and medicine. One of 200,000 people per year, causing fever, chills, nausea, the deadliest diseases known to humans, smallpox is also vomiting, muscle pain, and headache, and has no cure. the only disease to have been eradicated by vaccination. While many yellow fever patients recover after 3-4 days of Some estimates indicate that worldwide deaths from symptoms, approximately 15 percent enter a second phase smallpox numbered more than 300 million during the of the illness after a remission. The second phase includes 20th century. The last U.S. wild smallpox case occurred in a return of high fever, as well as jaundice; abdominal pain and vomiting; bleeding from the mouth, nose, eyes, or VACCINATION prevention is better than a cure! stomach; and deteriorating kidney function. Up to half of the patients who experience the second phase may die. In all, yellow fever kills 30,000 people globally each year. The yellow fever vaccine provides protection for 30 years ERADICATED or more—possibly for life—and for 95 percent of those smallpox vaccinated, offers protective immunity against the disease within a week. Yellow fever vaccination is typically per- formed only in areas where the disease is endemic, but it is available (and sometimes required) for those traveling to regions where the virus is still widespread.

Source: 1796 1967 1980 Edward Jenner creates World Health Organization World Health Organization “The History of Vaccines,” A Project of the College of first smallpox vaccination pushes eradication efforts declares smallpox eradicated! Physicians of Philadelphia, www.historyofvaccines.org

Source: www.historyofvaccines.org/content/timelines/smallpox

Medicines in Development Vaccines 2013 9 Vaccines in Development

Allergy

Product Name Sponsor Indication Development Phase*

Cat-SPIRE Circassia hypersensitivity to cat dander Phase III (cat allergy vaccine) Oxford, United Kingdom www.circassia.co.uk

CYT003 Cytos Biotechnology allergic asthma (monotherapy) Phase II (toll-like receptor 9 agonist/ Schlieren, Switzerland www.cytos.com Immunodrug™ vaccine)

DBV-712 DBV Technologies peanut hypersensitivity Phase II (peanut allergy epicutaneous Bagneux, France (Fast Track) www.dbv-technologies.com immunotherapy)

EMP-123 Allertein Therapeutics peanut hypersensitivity Phase I completed (peanut allergy vaccine) Fairfield, CT

grass pollen extract Stallergenes seasonal allergic rhinitis application submitted sublingual vaccine Norwell, MA www.stallergenes.us

JRC-LAMP vaccine Immunomics Therapeutics Japanese red cedar pollen allergy Phase I Hershey, PA www.immunomix.com

MK-3641 Merck seasonal allergic rhinitis application submitted (ragweed allergy vaccine Whitehouse Station, NJ www.merck.com sublingual tablet)

MK-7243 Merck seasonal allergic rhinitis application submitted (grass pollen allergy Whitehouse Station, NJ www.merck.com immunotherapy tablet vaccine) ------seasonal allergic rhinitis Phase III (pediatric) www.merck.com

MK-8237 Merck allergic rhinitis, Phase III (house dust mite allergy Whitehouse Station, NJ allergic rhinoconjunctivitis www.merck.com immunology tablet vaccine) ------allergic asthma Phase II www.merck.com

Pollinex® Quattro Grass Allergy Therapeutics prevention of grass pollen Phase III injectable MPL allergy vaccine West Sussex, United Kingdom hypersensitivity www.allergytherapeutics.com

Pollinex® Quattro Ragweed Allergy Therapeutics prevention of ragweed pollen Phase III injectable MPL allergy vaccine West Sussex, United Kingdom hypersensitivity www.allergytherapeutics.com

Pollinex® Quattro Tree Allergy Therapeutics prevention of tree pollen Phase II injectable MPL allergy vaccine West Sussex, United Kingdom hypersensitivity www.allergytherapeutics.com

QGE031 Novartis Pharmaceuticals allergic asthma Phase II (anti-IgE antibody) East Hanover, NJ (see also other) www.novartis.com

*For more information about a specific medicine or company in the report, please use the website provided.

10 Medicines in Development Vaccines 2013 Vaccines in Development

Allergy

Product Name Sponsor Indication Development Phase

ragweed allergy immunotherapy Stallergenes seasonal allergic rhinitis Phase I vaccine Norwell, MA www.stallergenes.us

ragweed allergy vaccine sublingual Greer Laboratories seasonal allergic rhinitis Phase III Lenoir, NC www.greerlabs.com

Cancer

Product Name Sponsor Indication Development Phase

abagovomab Menarini ovarian cancer Phase III (mAb therapeutic vaccine) Florence, Italy www.menarini.com orphan drug

ADXS-HPV Advaxis recurrent cervical cancer, Phase II (live, attenuated Listeria Princeton, NJ cervical intraepithelial neoplasia www.advaxis.com monocytogenes [Lm] vaccine) ------anal cancer Phase I/II www.advaxis.com

AE-O vaccine Antigen Express ovarian cancer Phase I Worcester, MA www.antigenexpress.com

AE37 Antigen Express breast cancer, prostate cancer Phase II (peptide vaccine) Worcester, MA www.antigenexpress.com

AE-M Antigen Express malignant melanoma Phase I (peptide vaccine) Worcester, MA www.antigenexpress.com

AGS-003 Argos Therapeutics first-line kidney cancer Phase III (personalized dendritic Durham, NC (Fast Track) www.argostherapeutics.com cell-based vaccine) ------metastatic kidney cancer Phase II (monotherapy) www.argostherapeutics.com

AlloStim™ Immunovative Therapies solid tumors Phase I/II completed immunotherapeutic vaccine Shoham, Israel www.immunovative.co.il

astuprotimut-R GlaxoSmithKline malignant melanoma, Phase III (MAGE-A3 recombinant Rsch. Triangle Park, NC non-small-cell lung cancer (NSCLC) www.gsk.com antigen-specific cancer ------immunotherapy) bladder cancer Phase II www.gsk.com

Medicines in Development Vaccines 2013 11 Vaccines in Development

Cancer

Product Name Sponsor Indication Development Phase

AVX701 AlphaVax advanced or metastatic Phase I/II (CEA-expressing VRP vaccine) Rsch. Triangle Park, NC CEA-expressing colorectal cancer www.alphavax.com

AVX901 AlphaVax late-stage HER2-expressing breast Phase I (HER2-expressing VRP vaccine) Rsch. Triangle Park, NC cancer www.alphavax.com

BiovaxID® Biovest International indolent follicular lymphoma Phase III dasiprotimut-T Tampa, FL (Fast Track) www.biovest.com (personalized lymphoma vaccine) ------orphan drug mantle-cell lymphoma Phase II www.biovest.com

BPX-201 Bellicum Pharmaceuticals metastatic castration-resistant Phase I (dendritic cell vaccine) Houston, TX prostate cancer www.bellicum.com

breast cancer vaccine MabVax Therapeutics breast cancer Phase I (mAb vaccine) San Diego, CA www.mabvax.com

breast cancer vaccine TapImmune breast cancer Phase I (HER2/neu therapeutic vaccine) Seattle, WA www.tapimmune.com

cancer vaccine Bayer HealthCare Pharmaceuticals follicular lymphoma Phase I (autologous idiotype vaccine) Wayne, NJ (prevention of relapse) www.bayerpharma.com

cancer vaccine Immunitor USA cancer Phase I/II (oral) College Park, MD www.immunitor.com

CB-10-01 Cosmo Pharmaceuticals malignant melanoma Phase II (hTRT vaccine) Lainate, Italy www.cosmopharmaceuticals.com

CDX-1401 Celldex Therapeutics solid tumors expressing the NY-ESO-1 Phase I/II (mAb cancer vaccine) Needham, MA protein www.celldextherapeutics.com

CG201 CG Therapeutics solid tumors Phase II Seattle, WA

CRS-207 Aduro BioTech metastatic pancreatic cancer Phase II Berkeley, CA (with GVAX pancreas vaccine) www.adurobiotech.com ------mesothelioma Phase I www.adurobiotech.com

CV-301 breast Bavarian Nordic metastatic breast cancer Phase II (immunotherapeutic vaccine) Mountain View, CA www.bavarian-nordic.com

CV-301 colon Bavarian Nordic colon cancer Phase II (immunotherapeutic vaccine) Mountain View, CA www.bavarian-nordic.com

12 Medicines in Development Vaccines 2013 Vaccines in Development

Cancer

Product Name Sponsor Indication Development Phase

CV-301 lung Bavarian Nordic lung cancer Phase I (immunotherapeutic vaccine) Mountain View, CA www.bavarian-nordic.com

CV-301 ovarian Bavarian Nordic ovarian cancer Phase I (immunotherapeutic vaccine) Mountain View, CA www.bavarian-nordic.com

CVac™ Prima Biomed late stage ovarian cancer Phase II/III MUC-1 cancer vaccine Sydney, Australia www.primabiomed.com.au

DCVax®-Brain Northwest Biotherapeutics glioblastoma Phase III dendritic cell vaccine Bethesda, MD www.nwbio.com orphan drug

DCVax®-Head & Neck Northwest Biotherapeutics head and neck cancer Phase I completed dendritic cell vaccine Bethesda, MD www.nwbio.com

DCVax®-Liver Northwest Biotherapeutics liver cancer Phase I completed dendritic cell vaccine Bethesda, MD www.nwbio.com

DCVax®-Lung Northwest Biotherapeutics lung cancer Phase I completed dendritic cell vaccine Bethesda, MD www.nwbio.com

DCVax®-Ovarian Northwest Biotherapeutics ovarian cancer Phase I completed dendritic cell vaccine Bethesda, MD www.nwbio.com

DCVax®-Pancreas Northwest Biotherapeutics pancreatic cancer Phase I completed dendritic cell vaccine Bethesda, MD www.nwbio.com

DCVax®-Prostate Northwest Biotherapeutics prostate cancer Phase III dendritic cell vaccine Bethesda, MD www.nwbio.com orphan drug

DN24-02 Dendreon HER2-positive urogenital cancer Phase II (lapuleucel-T) Seattle, WA (adjuvant therapy) www.dendreon.com (active cellular immunotherapy) ------breast cancer, colorectal cancer, Phase I ovarian cancer www.dendreon.com

DNX-2401 DNAtrix glioblastoma Phase I (oncolytic virus vaccine) Houston, TX www.dnatrix.com

DPV-001 UbiVac NSCLC Phase II (immunotherapy vaccine) Portland, OR www.ubivac.com

DPX-0907 Immunovaccine breast cancer, ovarian cancer, Phase II (single-dose depot vaccine) Halifax, Canada prostate cancer www.imvaccine.com

Medicines in Development Vaccines 2013 13 Vaccines in Development

Cancer

Product Name Sponsor Indication Development Phase

DPX-Survivac Immunovaccine ovarian cancer Phase I/II (peptide vaccine) Halifax, Canada www.imvaccine.com

EP-2101 Biotech Synergy NSCLC Phase II (multi-epitope cancer vaccine) San Diego, CA

ETBX-011 Etubics colorectal cancer Phase II (adenovirus vector vaccine) Seattle, WA www.etubics.com

FANG™ vaccine Gradalis colorectal cancer, malignant Phase II autologous tumor cell vaccine Carrollton, TX melanoma, ovarian cancer www.gradalisinc.com

FBP vaccine Galena Biopharma endometrial cancer, ovarian cancer Phase I/II (folate-binding protein E39 Lake Oswego, OR www.galenabiopharma.com vaccine)

G-100 prophage cancer vaccine Agenus newly diagnosed glioma Phase II (vitespen) Lexington, MA www.agenusbio.com orphan drug

G-200 prophage cancer vaccine Agenus recurrent glioma Phase II (vitespen) Lexington, MA www.agenusbio.com Orphan Drug

GI-4000 GlobeImmune colorectal cancer, NSCLC, Phase II (tarmogen T-cell stimulator) Louisville, CO pancreatic cancer www.globeimmune.com

GI-6207 GlobeImmune medullary thyroid cancer Phase II (tarmogen T-cell stimulator) Louisville, CO www.globeimmune.com

GI-6301 GlobeImmune chordoma, metastatic tumors Phase I (brachyury peptide vaccine) Louisville, CO www.globeimmune.com

GL-0817 Gliknik head and neck cancer, myeloma Phase II (MAGE-A3 immunomodulator Baltimore, MD www.gliknik.com vaccine) orphan drug

GRNVAC 1 Geron acute myeloid leukemia (AML) Phase II (dendritic cell vaccine) Menlo Park, CA www.geron.com

GV1001 KAEL-GemVax pancreatic cancer Phase I (hTERT RNA vaccine) Seoul, South Korea www.kaelgemvax.com

HS-110 Heat Biologics NSCLC Phase II Chapel Hill, NC www.heatbio.com

14 Medicines in Development Vaccines 2013 Vaccines in Development

Cancer

Product Name Sponsor Indication Development Phase

HyperAcute® Lung NewLink Genetics NSCLC Phase II/III tergenpumatucel-L Ames, IA www.linkp.com

HyperAcute® Melanoma NewLink Genetics malignant melanoma Phase II completed lung cancer immunotherapy Ames, IA www.linkp.com

HyperAcute® Pancreas NewLink Genetics pancreatic cancer Phase III algenpantucel-L Ames, IA (Fast Track) www.linkp.com orphan drug

ICT-107 ImmunoCellular Therapeutics glioblastoma Phase II (autologous dendritic cell-based Woodland Hills, CA www.imuc.com vaccine) orphan drug

ICT-121 ImmunoCellular Therapeutics glioblastoma Phase I (dendritic cell vaccine) Woodland Hills, CA www.imuc.com

IMA901 immatics biotechnologies kidney cancer Phase III (multi tumor-associated peptides Tuebingen, Germany www.immatics.com cancer vaccine) orphan drug

IMA950 immatics biotechnologies glioblastoma Phase I (tumor-associated peptide vaccine) Tuebingen, Germany www.immatics.com

IMCgp100 Immunocore malignant melanoma Phase 0 Oxon, United Kingdom www.immunocore.com

IMF-001 ImmunoFrontier solid tumors Phase I (protein vaccine) Tokyo, Japan www.immunofrontier.com

IMT-1012 Immunotope breast cancer, ovarian cancer Phase I (multi-peptide antigen Doylestown, PA www.immunotope.com immunotherapeutic vaccine)

ISF35 Memgen chronic lymphocytic leukemia (CLL) Phase II (recombinant immunotherapy) San Diego, CA (monotherapy), non-Hodgkin's www.memgenbio.com lymphoma ------CLL (combination therapy) Phase I www.memgenbio.com

M-200 prophage cancer vaccine Agenus malignant melanoma Phase III (vitespen) Lexington, MA www.agenusbio.com Orphan Drug

Medicines in Development Vaccines 2013 15 Vaccines in Development

Cancer

Product Name Sponsor Indication Development Phase

melanoma mAb vaccine MabVax Therapeutics melanoma Phase I San Diego, CA www.mabvax.com

melapuldencel-T California Stem Cell malignant melanoma Phase II (cancer immunotherapy vaccine) Irvine, CA www.californiastemcell.com

MVA-BN® HER2 Bavarian Nordic breast cancer Phase I/II HER-2/neu-based modified Mountain View, CA www.bavarian-nordic.com vaccinia ankara (MVA) vaccine

MVA-BN® PRO Bavarian Nordic prostate cancer Phase I/II PSA/PAP-based modified vaccinia Mountain View, CA www.bavarian-nordic.com anakara (MVA) vaccine

neuroblastoma vaccine MabVax neuroblastoma Phase I San Diego, CA www.mabvax.com

NeuVax™ Galena Biopharma node-positive breast cancer Phase III E75 cancer vaccine Lake Oswego, OR www.galenabiopharma.com (nelipepimut) ------node-negative breast cancer Phase II www.galenabiopharma.com ------prostate cancer Phase II www.galenabiopharma.com

Oncophage® Agenus renal cell carcinoma Phase III vitespen Lexington, MA (Fast Track) www.agenusbio.com orphan drug

OncoVAX® Vaccinogen stage II colorectal cancer Phase III completed colorectal cancer vaccine Frederick, MD www.vaccinogeninc.com ------stage III colorectal cancer Phase II (Fast Track) www.vaccinogeninc.com ------kidney cancer, melanoma Phase I/II www.vaccinogeninc.com

ONT-10 Oncothyreon solid tumors Phase I (therapeutic vaccine) Seattle, WA www.oncothyreon.com

OPT-822 Optimer Pharmaceuticals breast cancer Phase II/III (immunotherapy vaccine) San Diego, CA www.optimerpharma.com

oregovomab Quest PharmaTech ovarian cancer Phase II orphan drug Edmonton, Canada www.questpharmatech.com

ovarian cancer mAb vaccine MabVax Therapeutics ovarian cancer Phase II San Diego, CA www.mabvax.com

16 Medicines in Development Vaccines 2013 Vaccines in Development

Cancer

Product Name Sponsor Indication Development Phase

ovarian cancer stem cell therapy California Stem Cell ovarian cancer Phase I Irvine, CA www.californiastemcell.com

PEK fusion protein vaccine HealthBanks Biotech USA cervical intraepithelial neoplasia Phase I Irvine, CA www.healthbanks.com.tw

POL-103A Polynoma malignant melanoma Phase III (polyvalent shed-antigen vaccine) San Diego, CA www.polynoma.com orphan drug

polyclonal antibody stimulator Cancer Advances gastric cancer, pancreatic cancer Phase III orphan drug Durham, NC www.canceradvancesinc.com ------colorectal cancer Phase II www.canceradvancesinc.com

PRAME antigen-specific GlaxoSmithKline malignant melanoma, NSCLC Phase I cancer immunotherapeutic Rsch. Triangle Park, NC www.gsk.com

Prostvac® Bavarian Nordic metastatic prostate cancer Phase III rilimogene galvacivepvac Mountain View, CA (Fast Track) www.bavarian-nordic.com

Provenge® Dendreon recurrent early-stage prostate cancer Phase III sipuleucel-T Seattle, WA www.dendreon.com ------early-stage prostate cancer Phase II (neoadjuvant therapy) www.dendreon.com

PSMA vaccine AlphaVax prostate cancer Phase I Rsch. Triangle Park, NC www.alphavax.com

PT107 Pique Therapeutics NSCLC Phase II (allogeneic tumor cell vaccine) Durham, NC www.piquetherapeutics.com

PVX-410 OncoPep smoldering myeloma Phase I/II (therapeutic cancer vaccine) North Andover, MA www.oncopep.com

REIC gene therapy Momtaro-Gene prostate cancer Phase I (reduced expression in Okayama, Japan www.mt-gene.com immortalized cells)

rindopepimut Celldex Therapeutics first-line glioblastoma Phase III (EGFR varient III vaccine) Needham, MA (Fast Track) www.celldextherapeutics.com orphan drug ------recurrent glioblastoma Phase II (Fast Track) www.celldextherapeutics.com

Medicines in Development Vaccines 2013 17 Vaccines in Development

Cancer

Product Name Sponsor Indication Development Phase

sarcoma mAb vaccine MabVax Therapeutics sarcoma Phase II San Diego, CA www.mabvax.com

SL-701 Stemline Therapeutics glioma Phase I/II (dendritic cell vaccine) New York, NY www.stemline.com

small-cell lung cancer mAb vaccine MabVax Therapeutics small-cell lung cancer (SCLC) Phase I San Diego, CA www.mabvax.com

tecemotide (L-BLP25) EMD Serono NSCLC Phase III (MUC1 antigen-specific Rockland, MA (Fast Track) www.emdserono.com cancer immunotherapy) Oncothyreon www.oncothyreon.com Seattle, WA

TeloB-Vax Adamis Pharmaceuticals prostate cancer Phase I telomerase cancer vaccine San Diego, CA www.adamispharma.com

TVI-Brain-1 TVAX Biomedical glioma Phase II (cellular immunotherapy vaccine) Lenexa, KS www.tvaxbiomedical.com

TVI-Kidney-1 TVAX Biomedical renal cell carcinoma Phase II (cellular immunotherapy vaccine) Lenexa, KS www.tvaxbiomedical.com

V503 Merck HPV-related cancers Phase III (virus-like particle [VLP] vaccine) Whitehouse Station, NJ (see also infectious diseases) www.merck.com

V930/V932 Merck cancer Phase I completed (cancer vaccine) Whitehouse Station, NJ www.merck.com

V935 Geron solid tumors Phase I (telomerase inhibitor vaccine) Menlo Park, CA www.geron.com Merck www.merck.com Whitehouse Station, NJ

VGX-3100 Inovio Pharmaceuticals cervical dysplasia Phase II (HPV type 16/18 DNA vaccine) Blue Bell, PA (see also infectious diseases) www.inovio.com

WT1 antigen-specific cancer GlaxoSmithKline breast cancer Phase I/II immunotherapeutic Rsch. Triangle Park, NC www.gsk.com

WT2527 Sunovion Pharmaceuticals hematological malignancies, Phase I (peptide vaccine) Marlborough, MA solid tumors www.sunovion.com

18 Medicines in Development Vaccines 2013 Vaccines in Development

Infectious Diseases

Product Name Sponsor Indication Development Phase

ACAM529 Sanofi Pasteur herpes simplex virus (HSV) infection Phase I Swiftwater, PA www.sanofi.com National Institute of Allergy and Infectious Diseases Bethesda, MD

ACAM-Cdiff Sanofi Pasteur prevention of Clostridium difficile Phase III (toxoid vaccine) Swiftwater, PA infection (Fast Track) www.sanofi.com

ACE527 TD Vaccines prevention of traveler’s diarrhea Phase II (ETEC vaccine) Odense, Denmark caused by Escherichia coli infection www.tdvaccines.com PATH www.path.org Seattle, WA

acellular pertussis vaccine Novartis Vaccines prevention of diphtheria, tetanus Phase I completed Cambridge, MA and pertussis www.novartisvaccines.com

ADVAX Aaron Diamond AIDS Research Center HIV infection prevention Phase I completed (DNA vaccine) New York, NY www.adarc.org International AIDS Vaccine Initiative www.iavi.org New York, NY www.ichorms.com Ichor Medical Systems ------San Diego, CA HIV infection prevention Phase I completed (new delivery system) www.adarc.org www.iavi.org www.ichorms.com

AE-AI vaccine Antigen Express prevention of avian flu Phase I Worcester, MA www.antigenexpress.com

AE-H vaccine Antigen Express prevention and treatment of Phase I Worcester, MA HIV infection www.antigenexpress.com

Aflunov™ Novartis Vaccines prevention of influenza A virus Phase II influenza A virus H5N1 vaccine Cambridge, MA H5N1 subtype www.novartisvaccines.com (flu cell culture) (pre-pandemic)

AGS-004 Argos Therapeutics HIV-1 infection Phase II (personalized dendritic Durham, NC www.argostherapeutics.com cell-based vaccine)

anthrax vaccine National Institute of Allergy and prevention of anthrax Phase I (oral) Infectious Diseases (NIAID) www.paxvax.com Bethesda, MD PaxVax San Diego, CA

Medicines in Development Vaccines 2013 19 Vaccines in Development

Infectious Diseases

Product Name Sponsor Indication Development Phase

ASP-0113 Astellas Pharma US prevention of cytomegalovirus (CMV) Phase III (plasma DNA-based vaccine) Northbrook, IL infection www.astellas.com orphan drug Vical www.vical.com San Diego, CA

AVX101 AlphaVax prevention of HIV-1 infection Phase I completed (monovalent HIV vaccine) Rsch. Triangle Park, NC www.alphavax.com

AVX502 AlphaVax influenza (young adults and elderly) Phase I (influenza vaccine) Rsch. Triangle Park, NC www.alphavax.com

AVX601 AlphaVax prevention of CMV infection Phase I (cytomegalovirus vaccine) Rsch. Triangle Park, NC www.alphavax.com Novartis Vaccines www.novartisvaccines.com Cambridge, MA

Bexsero® Novartis Vaccines meningococcal group B infection Phase II meningococcal vaccine group B Cambridge, MA www.novartisvaccines.com quadrivalent recombinant vaccine

BioThrax® Emergent BioSolutions anthrax (post-exposure prevention) Phase III anthrax vaccine adsorbed Rockville, MD (Fast Track) www.emergentbiosolutions.com (subcutaneous)

CR6261 CruCell treatment of influenza A virus Phase I (mAb/influenza vaccine) Leiden, Netherlands infection www.crucell.com

DCVax-001/CD-2401 Celldex Therapeutics prevention and treatment of Phase I (recombinant protein vaccine) Needham, MA HIV infection www.celldextherapeutics.com Rockefeller University New York, NY

dengue DNA vaccine U.S. Naval Medical Research Center prevention of dengue fever Phase I Silver Spring, MD www.vical.com Vical San Diego, CA

dengue fever vaccine Sanofi Pasteur prevention of mild to severe Phase III Swiftwater, PA dengue fever (Fast Track) www.sanofi.com

dengue vaccine GlaxoSmithKline prevention of dengue fever Phase I (TDENV-PIV) Silver Spring, MD www.gsk.com U.S. Army Medical Research and Materiel Command Fort Detrick, MD

DENVax™ Inviragen dengue Phase II tetravalent hybrid dengue Fort Collins, CO www.inviragen.com virus vaccine

20 Medicines in Development Vaccines 2013 Vaccines in Development

Infectious Diseases

Product Name Sponsor Indication Development Phase

DermaVir™ Patch Genetic Immunity treatment of HIV-1 infection Phase II DNA topical patch vaccine McLean, VA www.geneticimmunity.com

DTP-HepB-Polio-Hib Merck diphtheria, tetanus, pertussis, Phase III hexavalent vaccine Whitehouse Station, NJ hepatitis B, poliomyelitis, www.merck.com (PR5IV419) Sanofi Pasteur Haemophilus influenzae type b www.sanofi.com Swiftwater, PA (pediatric)

Ebola DNA vaccine Crucell prevention of Ebola virus infection Phase I Leiden, Netherlands www.crucell.com Vaccine Research Center (NIAID) Bethesda, MD

Fluad® Novartis Vaccines influenza virus infection Phase III influenza virus vaccine Cambridge, MA (children and elderly) www.novartisvaccines.com (H1N1/H3N2/type-B strains)

Fluzone® QIV ID Sanofi Pasteur influenza virus infection Phase III quadrivalent inactivated Swiftwater, PA www.sanofi.com influenza vaccine intradermal

FVH1 DNA-based influenza vaccine Inovio Pharmaceuticals influenza A virus H1N1 subtype Phase I Blue Bell, PA www.inovio.com

GelVac™ Nanotherapeutics influenza virus infection Phase I H5N1 influenza virus Alachua, FL www.nanotherapeutics.com vaccine-nasal dry powder

GEN-003 Genocea Biosciences treatment of HSV infection Phase I/II (herpes simplex virus type-2 Cambridge, MA www.genocea.com therapeutic vaccine)

GI-5005 GlobeImmune hepatitis C virus (HCV) infection Phase II (tarmogen T-cell immunity Louisville, CO www.globeimmune.com stimulator)

GS-4774/GI-13020 Gilead chronic hepatitis B virus (HBV) Phase I (tarmogen T-cell immunity Foster City, CA infection www.gilead.com stimulator) GlobeImmune www.globeimmune.com Louisville, CO

Medicines in Development Vaccines 2013 21 Vaccines in Development

Infectious Diseases

Product Name Sponsor Indication Development Phase

GSK134612 GlaxoSmithKline prevention of meningococcal groups Phase III (MenACWY-TT conjugated vaccine) Rsch. Triangle Park, NC A, C, Y and W-135 infections www.gsk.com (children) ------prevention of meningococcal groups Phase II A, C, Y and W-135 infections www.gsk.com (adults, adolescents, infants)

GSK2392102A GlaxoSmithKline prevention of staphylococcal Phase I (Staphylococcus aureus vaccine) Rsch. Triangle Park, NC infection www.gsk.com

GSK2654909A GlaxoSmithKline prevention of H9N2 avian influenza Phase I (immunostimulant vaccine) Rsch. Triangle Park, NC virus infection www.gsk.com

GSK2654911A GlaxoSmithKline prevention of H9N2 avian influenza Phase I (immunostimulant vaccine) Rsch. Triangle Park, NC virus infection www.gsk.com

GSK3003891A GlaxoSmithKline prevention of respiratory syncytial Phase I (immunostimulant vaccine) Rsch. Triangle Park, NC virus (RSV) infection www.gsk.com

H1N1 seasonal influenza virus Vaxart prevention of seasonal H1N1 Phase I vaccine San Francisco, CA influenza virus infection www.vaxart.com

H5N1 (pre-)pandemic influenza GlaxoSmithKline prevention of influenza A virus application submitted virus vaccine Rsch. Triangle Park, NC H5N1 subtype www.gsk.com (pandemic use in adults) ------prevention of influenza A virus Phase III H5N1 subtype www.gsk.com (pediatric pandemic use)

H5N1 influenza vaccine Novavax prevention of influenza A virus Phase II (recombinant VLP vaccine) Rockville, MD H5N1 subtype www.novavax.com (seasonal use) ------prevention of influenza A virus Phase I H5N1 subtype www.novavax.com (pandemic use)

H5N1 influenza virus vaccine Vaxart prevention of influenza A virus Phase I San Francisco, CA H5N1 subtype www.vaxart.com

HBV-002 Hawaii Biotech prevention of West Nile virus infection Phase I completed (recombinant subunit vaccine) Aiea, HI www.hibiotech.com

22 Medicines in Development Vaccines 2013 Vaccines in Development

Infectious Diseases

Product Name Sponsor Indication Development Phase

hepatitis C vaccine therapy GlaxoSmithKline prevention of HCV Phase I/II (Ad6NSmut) Rsch. Triangle Park, NC www.gsk.com

Heplisav™ Dynavax prevention of HBV application submitted hepatitis B vaccine 1018-ISS Berkeley, CA www.dynavax.com conjugate

HerpV Agenus treatment of HSV-2 infection Phase II herpes simplex vaccine Lexington, MA www.agenusbio.com

HibTITER™ Nuron Biotech prevention of Haemophilus influenzae Phase II Hib CRM197 conjugate vaccine Exton, PA type B infection www.nuronbiotech.com (pediatric)

HIV recombinant vaccine GlaxoSmithKline HIV disease immunotherapy Phase II Rsch. Triangle Park, NC www.gsk.com

HIV recombinant vaccine GlaxoSmithKline prevention of HIV infection Phase I Rsch. Triangle Park, NC www.gsk.com

HIV vaccine Crucell prevention of HIV infection Phase I Leiden, Netherlands www.crucell.com Beth Israel Deaconess Medical Center Boston, MA International AIDS Vaccine Initiative New York, NY

HIV vaccine GeoVax Labs prevention of HIV infection Phase II Smyrna, GA www.geovax.com

HIV vaccine GeoVax Labs treatment of HIV infection Phase I/II Smyrna, GA www.geovax.com

HIV vaccine PaxVax prevention of HIV infection Phase I San Diego, CA www.paxvax.com

HIV vaccine Novartis Vaccines HIV infection Phase I Cambridge, MA www.novartisvaccines.com

HIV vaccine Profectus Biosciences prevention of HIV infection Phase I (MAG pDNA) Baltimore, MD www.profectusbiosciences.com

HIV vaccine Profectus Biosciences prevention of HIV infection Phase I (rVSV) Baltimore, MD www.profectusbiosciences.com

HIVAX™ GeneCure Biotechnologies HIV-1 infection Phase I replication-defective HIV-1 vaccine Norcross, GA www.genecure.com

Medicines in Development Vaccines 2013 23 Vaccines in Development

Infectious Diseases

Product Name Sponsor Indication Development Phase

IC31 Novartis Vaccines prevention of influenza virus Phase I (seasonal influenza vaccine) Cambridge, MA infection www.novartisvaccines.com Valneva Vienna, Austria

IC43 Novartis Vaccines prevention of nosocomial Phase I (Pseudomonas aeruginosa vaccine) Cambridge, MA (hospital-acquired) infection www.novartisvaccines.com Valneva involving Pseudomonas aeruginosa Vienna, Austria

IC84 Novartis Vaccines prevention of Clostridium difficile Phase I (recombinant fusion protein Cambridge, MA infection www.novartisvaccines.com vaccine) Valneva Vienna, Austria

Imvamune® Bavarian Nordic smallpox Phase III smallpox vaccine Mountain View, CA (liquid formulation) www.bavarian-nordic.com ------smallpox Phase II (freeze-dried formulation) www.bavarian-nordic.com

influenza A virus H1N1 vaccine CEL-SCI prevention and treatment of Phase I (L.E.A.P.S.™) Vienna, VA influenza A virus H1N1 subtype www.cel-sci.com

influenza A virus H3N2 vaccine Novartis Vaccines prevention of influenza A virus Phase I Cambridge, MA H3N2 subtype www.novartisvaccines.com

influenza A virus H5N1 GlaxoSmithKline prevention of influenza A virus Phase I cell culture-based vaccine Rsch. Triangle Park, NC H5N1 subtype (pandemic use) www.gsk.com

influenza A virus H5N1 vaccine Baxter Healthcare prevention of influenza A virus Phase I Deerfield, IL H5N1 subtype www.baxter.com

influenza A virus vaccine H1N1 Medicago USA prevention of influenza A virus Phase I Durham, NC H1N1 subtype www.medicago.com

influenza A virus vaccine H5N1 Medicago USA prevention of influenza A virus Phase I Durham, NC H5N1 subtype www.medicago.com

influenza A virus vaccine H5N1 iBio prevention of influenza A virus Phase I Newark, DE H5N1 subtype www.ibioinc.com

influenza A virus H7N9 vaccine Novavax prevention of influenza A virus Phase I Rockville, MD H7N9 subtype www.novavax.com

24 Medicines in Development Vaccines 2013 Vaccines in Development

Infectious Diseases

Product Name Sponsor Indication Development Phase

influenza A virus vaccine H9N2 Baxter Healthcare prevention of influenza A virus Phase I/II completed Deerfield, IL H9N2 subtype www.baxter.com

INO-3401 Inovio Pharmaceuticals influenza A virus H5N1 subtype Phase I completed (DNA vaccine) Blue Bell, PA www.inovio.com

INO-3510 Inovio Pharmaceuticals influenza A virus H1N1 subtype, Phase I (DNA vaccine) Blue Bell, PA influenza A virus H5N1 subtype www.inovio.com

INV21 Inviragen hand, foot and mouth disease Phase I (enterovirus A vaccine) Fort Collins, CO www.inviragen.com

ITV-1 Immunotech Laboratories HIV infection Phase I (immune therapeutic vaccine-1) Monrovia, CA www.immunotechlab.com

LIQ-001 Liquidia Technologies influenza virus infection Phase I completed Rsch. Triangle Park, NC www.liquidia.com

Lyme disease vaccine Baxter Healthcare prevention of Lyme disease Phase I/II Deerfield, IL www.baxter.com

malaria vaccine Crucell malaria Phase I completed (recombinant, Ad35-CS) Leiden, Netherlands www.crucell.com

malaria vaccine GenVec malaria Phase I/II Gaithersburg, MD www.genvec.com U.S. Naval Medical Research Center Silver Spring, MD

malaria vaccine Sanaria malaria Phase I/II (PfSPZ) Rockville, MD www.sanaria.com

MEDI-550 MedImmune prevention of pandemic influenza Phase I (pandemic influenza virus vaccine) Gaithersburg, MD www.medimmune.com

MEDI-559 MedImmune prevention of RSV infection Phase I (PRVV) Gaithersburg, MD (pediatric) www.medimmune.com

MenABCWY Novartis Vaccines prevention of meningococcal groups Phase II multivalent conjugate vaccine Cambridge, MA A, B, C, Y and W-135 infections www.novartisvaccines.com (adolescents)

Meninge ACYW Sanofi Pasteur meningococcal infection Phase II second-generation meningococcal Swiftwater, PA www.sanofi.com conjugate infant vaccine

Medicines in Development Vaccines 2013 25 Vaccines in Development

Infectious Diseases

Product Name Sponsor Indication Development Phase

MMR vaccine GlaxoSmithKline prevention of measles, mumps and Phase III (live attenuated trivalent vaccine) Rsch. Triangle Park, NC rubella www.gsk.com (GSK209762)

Mosquirix™ GlaxoSmithKline prevention of malaria Phase III malaria vaccine Rsch. Triangle Park, NC (Plasmodium falciparum) www.gsk.com

NB-1008 NanoBio prevention of influenza virus Phase I (intranasal vaccine) Ann Arbor, MI infection www.nanobio.com

NDV-3 NovaDigm Therapeutics prevention of candidiasis, prevention Phase I (recombinant protein vaccine) Grand Forks, ND of staphylococcal (MRSA) infection www.novadigm.net

NmVac4 JN-International Medical prevention of meningococcal groups Phase I (meningococcal vaccine groups Omaha, NE A, C, Y, and W-135 infections www.jn-vaccines.org ACWY conjugate vaccine)

norovirus bivalent vaccine LigoCyte Pharmaceuticals (Takeda) norovirus gastroenteritis Phase I/II Bozeman, MT www.takeda.com

NTHi recombinant vaccine GlaxoSmithKline prevention of non-typeable Phase I (GSK2838497A) Rsch. Triangle Park, NC Haemophilus influenzae www.gsk.com

NuThrax™ Emergent BioSolutions anthrax Phase II anthrax vaccine adsorbed with Rockville, MD (post-exposure prevention) www.emergentbiosolutions.com CPG 7909 adjuvant

Optaflu® Novartis Vaccines prevention of influenza virus Phase III influenza virus vaccine Cambridge, MA infection www.novartisvaccines.com (flu cell culture)

PanBlok® Protein Sciences prevention of influenza A virus Phase I/II influenza A virus H5N1 vaccine Meridian, CT H5N1 subtype (pandemic) www.proteinsciences.com

PENNVAX™-B Inovio Pharmaceuticals prevention and treatment of HIV Phase I DNA vaccine (clade B) Blue Bell, PA infection www.inovio.com

PENNVAX™-G Inovio Pharmaceuticals prevention and treatment of HIV Phase I DNA vaccine (clade A, C, D) Blue Bell, PA infection www.inovio.com

PER.C-flu Crucell prevention of influenza virus Phase II Leiden, Netherlands infection www.crucell.com

PF-05212366 Pfizer meningitis B Phase III (MnB rLP2086) New York, NY (adolescent and young adult) www.pfizer.com

26 Medicines in Development Vaccines 2013 Vaccines in Development

Infectious Diseases

Product Name Sponsor Indication Development Phase

PF-06290510 Pfizer staphylococcal infection Phase II (4-antigen Staphylococcus aureus New York, NY www.pfizer.com vaccine, SA4Ag)

PF-06425090 Pfizer Clostridium difficile colitis Phase I New York, NY www.pfizer.com

plague vaccine injectable DynPort Vaccine Yersinia infection Phase II completed Frederick, MD www.csc.com/dvc

Preflucel™ Baxter Healthcare prevention of influenza virus Phase III seasonal influenza virus vaccine Deerfield, IL infection www.baxter.com

PreviThrax® Emergent BioSolutions anthrax Phase II recombinant protective antigen Rockville, MD (Fast Track) www.emergentbiosolutions.com (rPA) anthrax vaccine, purified

Pseudomonas aeruginosa Sanofi Pasteur prevention of ventilator-associated Phase I antibody fragment product Swiftwater, PA pneumonia www.sanofi.com

PXVX-0103 PaxVax prevention of influenza A virus Phase I (influenza A virus vaccine H5N1) San Diego, CA H5N1 subtype www.paxvax.com

PXVX-0200 PaxVax cholera Phase I (oral, live attenuated vaccine) San Diego, CA www.paxvax.com

Quadracel® Sanofi Pasteur diphtheria, tetanus, pertussis and Phase III diphtheria and tetanus toxoids and Swiftwater, NJ polio vaccine www.sanofi.com acellular pertussis vaccine adsorbed (in children 4-6 years of age) combined with inactivated poliomyelitis vaccine

rabies VRVg Sanofi Pasteur prevention of rabies infection Phase II (purified vero rabies vaccine) Swiftwater, PA www.sanofi.com

recombinant botulinum neurotoxin DynPort Vaccine Company prevention against botulinum Phase II vaccine Frederick, MD neurotoxin types A and B www.csc.com/dvc U.S. Department of Defense Washington, DC

respiratory syncytial virus Novavax prevention of RSV infection Phase II recombinant nanoparticle vaccine Rockville, MD www.novavax.com

Medicines in Development Vaccines 2013 27 Vaccines in Development

Infectious Diseases

Product Name Sponsor Indication Development Phase

rotavirus vaccine Sanofi Pasteur prevention of rotavirus infection Phase II (live attenuated tetravalent Swiftwater, PA www.sanofi.com oral vaccine)

SAV001 Sumagen HIV-1 infection Phase I (genetically attenuated, irradiated and Seoul, South Korea www.sumagen.co.kr chemically inactivated HIV vaccine)

S. pneumoniae pediatric GlaxoSmithKline prevention of Staphylococcus Phase II next-generation recombinant Rsch. Triangle Park, NC pneumoniae www.gsk.com conjugated vaccine

S. pneumoniae vaccine Novartis Vaccines pneumococcal infection Phase I Cambridge, MA www.novartisvaccines.com

SparVax™ PharmAthene anthrax Phase II recombinant protective antigen Annapolis, MD (pre- and post-exposure prevention) www.pharmathene.com (rPA) anthrax vaccine

streptococcal B vaccine conjugate Novartis Vaccines group B streptococcal infection Phase II Cambridge, MA www.novartisvaccines.com

Streptococcus pneumoniae vaccine Sanofi Pasteur meningitis and pneumonia Phase I Swiftwater, PA www.sanofi.com

TG-4040 Transgene hepatitis C Phase II (vector-based therapeutic vaccine) Rockville, MD www.transgene.fr

tuberculosis recombinant Sanofi Pasteur prevention of tuberculosis Phase I subunit vaccine Swiftwater, PA www.sanofi.com

tuberculosis recombinant vaccine Aeras prevention of tuberculosis Phase II (GSK692342) Rockville, MD www.aeras.org GlaxoSmithKline www.gsk.com Rsch. Triangle Park, NC

tuberculosis vaccine Aeras prevention of tuberculosis Phase I Rockville, MD www.aeras.org Crucell www.crucell.com Leiden, Netherlands

tuberculosis vaccine Aeras tuberculosis Phase I (ID 93/GLA-SE) Rockville, MD www.aeras.org Infectious Disease Research Institute Seattle, WA

28 Medicines in Development Vaccines 2013 Vaccines in Development

Infectious Diseases

Product Name Sponsor Indication Development Phase

tularemia vaccine DynPort Vaccine prevention of tularemia Phase I Frederick, MD www.csc.com/dvc

typhoid vaccine Novartis Vaccines prevention of typhoid Phase II Cambridge, MA www.novartisvaccines.com

V114 Merck prevention of pneumococcal Phase II (pneumococcal 15-valent Whitehouse Station, NJ infection www.merck.com conjugate vaccine)

V212 Merck prevention of herpes zoster Phase III (heat-treated varicella-zoster virus Whitehouse Station, NJ www.merck.com [VZV] vaccine)

V503 Merck prevention and treatment of HPV Phase III (virus-like particle [VLP] vaccine) Whitehouse Station, NJ infection www.merck.com (see also cancer)

Vacc-4x Bionor Pharma HIV-1 infection Phase II (intradermal vaccine) Oslo, Norway www.bionorpharma.com

varicella zoster recombinant GlaxoSmithKline prevention of herpes zoster Phase III vaccine Rsch. Triangle Park, NC www.gsk.com

VAX-102 VaxInnate seasonal influenza A virus infection Phase I/II (Flagellin.HuHA) Cranbury, NJ www.vaxinnate.com

VAX-125 VaxInnate pandemic influenza A virus infection Phase II completed (Flagellin.HuHA) Cranbury, NJ www.vaxinnate.com

VAX-128 VaxInnate prevention of influenza A virus Phase I (recombinant vaccine) Cranbury, NJ H1N1 subtype www.vaxinnate.com (pandemic)

VAX-161 VaxInnate prevention of influenza A virus Phase I (recombinant vaccine) Cranbury, NJ H5N1 subtype www.vaxinnate.com (pandemic)

VGX-3100 Inovio Pharmaceuticals human papillomavirus infection Phase II (HPV type 16/18 DNA vaccine) Blue Bell, PA (see also cancer) www.inovio.com

VGX-3400 Inovio Pharmaceuticals prevention of influenza A virus Phase I (DNA vaccine) Blue Bell, PA H5N1 subtype www.inovio.com

visceral leishmaniasis vaccine Infectious Diseases Research Institute visceral leishmaniasis Phase I Seattle, WA www.idri.org

Medicines in Development Vaccines 2013 29 Vaccines in Development

Infectious Diseases

Product Name Sponsor Indication Development Phase

VRC-HIVADV014-00-VP GenVec prevention of HIV infection Phase II completed (HIV-1 recombinant adenovirus Gaithersburg, MD www.genvec.com vaccine) Vaccine Research Center (NIAID) Bethesda, MD

VRC-HIVADV027-00-VP GenVec prevention of HIV infection Phase I (HIV adenovector Ad35 vaccine) Gaithersburg, MD www.genvec.com Vaccine Research Center (NIAID) Bethesda, MD

VRC-HIVDNA016-00-VP Vaccine Research Center (NIAID) prevention of HIV infection Phase I (HIV adenovector Ad35 vaccine) Bethesda, MD www.vrc.nih.gov

Neurological Disorders

Product Name Sponsor Indication Development Phase

AD02 vaccine Affiris Alzheimer’s disease Phase II (amyloid-beta protein inhibitor) Vienna, Austria www.affiris.com GlaxoSmithKline www.gsk.com Rsch. Triangle Park, NC

AD03 vaccine Affiris Alzheimer’s disease Phase I (amyloid-beta protein inhibitor) Vienna, Austria www.affiris.com GlaxoSmithKline www.gsk.com Rsch. Triangle Park, NC

ATX-MS-1467 EMD Serono multiple sclerosis Phase I (synthetic peptide-based vaccine) Rockland, MA www.emdserono.com

BHT-3009 Bayhill Therapeutics relapsing-remitting multiple sclerosis Phase II completed (DNA vaccine) Palo Alto, CA www.bayhilltx.com

CAD106 Novartis Pharmaceuticals Alzheimer’s disease Phase II (amyloid beta-protein inhibitor) East Hanover, NJ www.novartis.com

imilecleucel-T Opexa Therapeutics secondary progressive multiple Phase II The Woodlands, TX sclerosis (Fast Track) www.opexatherapeutics.com

30 Medicines in Development Vaccines 2013 Vaccines in Development

Neurological Disorders

Product Name Sponsor Indication Development Phase

IR208 Immune Response BioPharma multiple sclerosis Phase II (immunostimulant vaccine) New York, NY www.immuneresponsebiopharma. com

UB-311 United Biomedical Alzheimer’s disease Phase II (liquid intramuscular amyloid Hauppauge, NY www.unitedbiomedical.com beta protein inhibitor vaccine)

V950 Merck Alzheimer’s disease Phase I Whitehouse Station, NJ www.merck.com

vanutide cridificar Janssen Alzheimer Immunotherapy Alzheimer’s disease Phase II (ACC-001/PF-05236806) South San Francisco, CA www.janimm.com Pfizer www.pfizer.com New York, NY Other

Product Name Sponsor Indication Development Phase

AE-IG Antigen Express genetic disease Phase I (RNA interference vaccine) Worcester, MA www.antigenexpress.com

Diamyd® Diamyd Medical type 1 diabetes Phase III autoimmune diabetes vaccine Stockholm, Sweden www.diamyd.com orphan drug

DiaPep277® Andromeda Biotech type 1 diabetes mellitus Phase III subcutaneously-injected synthetic Yavne, Israel (newly diagnosed) www.andromedabio.com peptide immunomodulator orphan drug

HLA-DQ2 peptide vaccine ImmusanT celiac disease Phase I Cambridge, MA www.immusant.com

insulin B-chain vaccine Orban Biotech type 1 diabetes mellitus Phase I completed Brookline, MA www.orbanbiotech.com

PF-05402536 Pfizer smoking cessation Phase I (smoking cessation vaccine) New York, NY www.pfizer.com

PF-06413367 Pfizer smoking cessation Phase I (smoking cessation vaccine) New York, NY www.pfizer.com

PF-06444752 Pfizer asthma Phase I (immunoglobulin-E vaccine) New York, NY www.pfizer.com

Medicines in Development Vaccines 2013 31 Vaccines in Development

Other

Product Name Sponsor Indication Development Phase

QGE031 Novartis Pharmaceuticals bullous pemphigoid Phase II (anti-IgE antibody) East Hanover, NJ (see also allergy) www.novartis.com

Ravax® Immune Response BioPharma rheumatoid arthritis Phase III rheumatoid arthritis vaccine New York, NY www.immuneresponsebiopharma. com

RiVax™ Soligenix ricin poisoning Phase I ricin vaccine Princeton, NJ (pre-exposure) www.soligenix.com orphan drug

SEL-068 Selecta Biosciences smoking cessation Phase I (smoking cessation vaccine) Watertown, MA www.selectabio.com

TA-CD Celtic Pharma cocaine abuse Phase II (immunotherapeutic vaccine) Hamilton, Bermuda www.celticpharma.com National Institute on Drug Abuse Bethesda, MD

The content of this report has been obtained through public, government and industry sources, and the Adis “R&D Insight” database based on the latest information. Report current as of August 16, 2013. The medicines in this report include medi- cines being developed by U.S. based companies conducting trials in the United States and abroad, PhRMA-member companies conducting trials in the United States and abroad, and foreign companies conducting clinical trials in the United States. The information in this report may not be comprehensive. For more specific information about a particular product, contact the indi- vidual company directly or go to www.clinicaltrials.gov. The entire series of Medicines in Development is available on PhRMA’s website. A publication of PhRMA’s Communications & Public Affairs Department. (202) 835-3460 www.phrma.org | www.innovation.org | www.pparx.org Provided as a Public Service by PhRMA. Founded in 1958 as the Pharmaceutical Manufacturers Association. Copyright © 2013 by the Pharmaceutical Research and Manufacturers of America. Permission to reprint is awarded if proper credit is given.

Pharmaceutical Research and Manufacturers of America • 950 F Street, NW, Washington, DC 20004

32 Medicines in Development Vaccines 2013 Glossary

Alzheimer’s disease—Progressive and dysplasia is also called cervical intraepi- ally, determining factors include whether chronic deterioration of all mental thelial neoplasia, or CIN. the drug will have an impact on such functions. Early manifestations include factors as survival, day-to-day function- —Also a decrease in attention span, impaired cervical intraepithelial neoplasia ing, or the likelihood that the disease, if called cervical dysplasia, or CIN. powers of concentration, some per- left untreated, will progress from a less sonality change and forgetfulness. As Clostridium difficile—A bacterium that severe condition to a more serious one. the disease progresses, there is a loss produces an irritating toxin that causes a Filling an unmet medical need is defined of computational ability, in addition to form of colitis characterized by profuse, as providing a therapy where none exists word-finding problems and difficulty with watery diarrhea with cramps and low- or providing a therapy which may be ordinary activities. Ultimately, there is grade fever. potentially superior to existing therapy. severe memory loss, complete disorien- Once a drug receives Fast Track designa- tation, social withdrawal, loss of inde- cytomegalovirus (CMV)—A DNA virus tion, early and frequent communication pendence, and is fatal. It is the seventh related to the herpes virus, affecting between the FDA and a drug company is leading cause of death in the United mostly neonatal infants and immuno- encouraged throughout the entire drug States. compromised individuals. CMV can development and review process. The occur without symptoms or result in mild frequency of communication assures that application submitted—An application flu-like symptoms. questions and issues are resolved quickly, for marketing has been submitted to often leading to earlier drug approval diabetes—A chronic disease due to a the U.S. Food and Drug Administration and access by patients. (FDA). The application can either be an disturbance of the normal insulin mecha- NDA (new drug application) or a BLA nism causing problems in metabolizing glioblastoma—The most common pri- (biologic license application). sugar. Symptoms may include excessive mary brain tumor and one of the most thirst, hunger, urination and weight loss. aggressive forms of brain cancer, primar- botulism—A severe, sometimes fatal Type 1 is the more severe form, requiring ily affecting adults over the age of 50. food poisoning caused by ingestion of insulin treatment. Type 2, in most cases, food containing botulin and characterized can be controlled by a combination of glioma—A type of brain tumor arising by nausea, vomiting, disturbed vision, dietary measures, weight loss, and oral from the supporting glial cells within muscular weakness, and fatigue. medication. the brain. Gliomas make up about 60 percent of all primary brain tumors and breast cancer—A malignant tumor that Ebola virus—The cause of Ebola hemor- are frequently malignant. has developed from cells in the breast. rhagic (bloody) fever, a severe, often It is the most common form of cancer in fatal disease in humans and nonhuman Haemophilus influenzae—A type of women and is the second-leading cause primates (monkeys, gorillas, and chim- bacteria found in the respiratory tract of cancer death in women, exceeded panzees). Researchers believe that the that causes acute respiratory infections only by lung cancer. virus is animal-borne (zoonotic) and is and meningitis in children but rarely in normally maintained in an animal host adults. cervical dysplasia—The abnormal that is native to the African continent. growth of cells on the surface of the hematological malignancies—Cancers cervix. Although it is not cancer, it is Fast Track—A process designed to of the blood or bloodforming tissues, considered a precancerous condition. facilitate the development and expedite such as leukemia, Hodgkin’s and non- Most cases of cervical dysplasia occur in the review of drugs to treat serious Hodgkin’s lymphomas, AIDS-related women ages 25 to 35, although it can diseases and fill an unmet medical need. malignancies, multiple myeloma, myelo- develop at any age. While all causes of The status is assigned by the U.S. Food dysplasia and myeloproliferative disorders. cervical dysplasia are not known, most and Drug Administration. The purpose —Inflammation of the liver cases of cervical cancer and severe hepatitis is to get important new drugs to the with accompanying liver cell damage or dysplasia are caused by infection of the patient earlier. Fast Track addresses a death, caused most often by viral infec- cervix with a persistent, high-risk strain broad range of serious diseases. Gener- tion, e.g., hepatitis B, and C. of human papillomavirus (HPV). Cervical

Medicines in Development Vaccines 2013 33 Glossary

herpes simplex virus—A strain of herpes it also causes widespread blood infection papillomavirus—The papillomavirus is virus that may lie dormant in nerve tis- (sepsis), which is more damaging and the viral agent of warts, believed to be sue and can be reactivated to produce dangerous. Both meningitis and meningo- contagious and mostly harmless, affect- painful sores of the anus or genitals. coccal sepsis are major causes of illness, ing only the skin’s topmost layer. death, and disability worldwide. herpes varicella zoster virus (HVZ)— Phase 0—First-in-human trials conduct- Also called shingles, consists of very MRSA (methicillin-resistant Staphylo- ed in accordance with FDA’s 2006 guid- painful blisters on the skin and affects coccus aureus)—A type of bacteria that ance on exploratory Investigational New areas innervated by specific nerves. It is resistant to certain antibiotics, includ- Drug (IND) studies designed to speed may appear in adulthood as a result of ing methicillin and other more common up development of promising drugs by having had chicken pox (caused by the antibiotics such as oxacillin, penicillin and establishing very early on whether the varicella virus) as a child. amoxicillin. Staph infections, including agent behaves in human subjects as was MRSA, occur most frequently among pa- anticipated from preclinical studies. HIV infection—Presence of antibodies tients in hospitals and healthcare settings. in the blood to the human immunodefi- Phase I—Safety testing and pharmaco- ciency virus (the virus that causes AIDS). multiple sclerosis—Progressive disease logical profiling in humans. HIV-1 refers to the most common strain of the central nervous system in which —Effectiveness and safety test- of the virus found in U.S. AIDS patients. scattered patches of the covering of Phase II ing in humans. nerve fibers (myelin) in the brain and influenza—A viral infection of the respi- spinal cord are destroyed. Symptoms —Extensive clinical trials to ratory tract that causes fever, headache, Phase III range from numbness and tingling to demonstrate safety and efficacy in muscle ache and weakness. There are paralysis and incontinence. humans. three main types of influenza virus: A, B and C. A person who has had an attack myeloma—A malignant condition char- pneumococcal infections—Caused by with the type C virus acquires antibodies acterized by uncontrolled proliferation Streptococcus pneumoniae, or pneumo- that provide immunity against that type of plasma cells (a class of white blood coccus, a Gram-positive human patho- for life. Anyone who has been infected cells) in bone marrow. Symptoms include genic bacterium. The organism causes with a certain strain of the type A or B pain and destruction of bone tissue, many types of pneumococcal infections, viruses acquires immunity to that strain. numbness and paralysis, kidney damage, including pneumonia, otitis media, Both the A- and B-type viruses oc- anemia, and frequent infections. meningitis, sepsis, endocarditis, and brain casionally alter to produce new strains abscess. S. pneumoniae is the most noroviruses—A group of viruses that that may be able to overcome immunity. common cause of bacterial meningitis in cause the “stomach flu,” or gastroenteri- Type B is fairly stable, but type A is high- adults and children and one of the top tis. Symptoms usually include nausea, ly unstable, and new strains of it arise two isolates found in ear infection (otitis vomiting, diarrhea, and some stomach constantly throughout the world. media). Pneumococcal pneumonia is cramping. Sometimes people also have more common in the very young and the malaria—A serious parasitic disease, a low-grade fever, chills, headache, very old. spread by the bite of the Anopheles muscle aches, and tiredness. The illness mosquito. Malaria is characterized by often begins suddenly and lasts for one prostate cancer—An uncontrolled (ma- severe fever and chills and complications or two days. lignant) growth of cells in the prostate affecting the kidneys, liver, brain and gland that is located at the base of the Orphan Drug—A drug to treat a blood. urinary bladder and is responsible for disease that has a patient population helping control urination as well as form- meningococcal disease—Describes of 200,000 or less, or a disease that ing part of the semen. Prostate cancer infections caused by the bacterium has a patient population of more than is the second leading cause of death of Neisseria meningitides. It carries a high 200,000 and a developmental cost that males in the United States. mortality rate if left untreated. While it will not be recovered from sales in the is best known as a cause of meningitis, United States.

34 Medicines in Development Vaccines 2013 Glossary

rotavirus—A group of viruses that are germs commonly found on the skin or tuberculosis—An infectious disease wheel-like in appearance and are a major in the nose of healthy individuals. Most caused by the organism Mycobacterium source of infant diarrhea throughout the of the time, these bacteria cause no tuberculosis, which is passed from per- world. problems or result in relatively minor son to person by breathing in airborne skin infections, but staph infections droplets (from coughing or sneezing). sarcoma—A malignant tumor that arises don’t always remain skin-deep. In some The bacteria multiply in the lungs and from deep body tissues, such as muscle, circumstances, they may invade the in some cases can spread to the lymph bone or fibrous tissue. bloodstream, urinary tract, lungs or nodes. A person’s immune system most smallpox—A contagious, disfiguring heart. Skin infections caused by staph frequently will attack and heal the infec- and often deadly disease caused by bacteria include: boils, impetigo, cellulitis, tion, causing a scar on the lung. the variola virus. The first symptoms of and scalded skin syndrome. tularemia—Also called “rabbit fever” or smallpox usually appear 12 to 14 days Staphylococcus aureus—A common “deerfly fever,” caused by the bacterium after infection. During the incubation bacterium that is a frequent cause of Francisella tularensis found in animals period of seven to 17 days, an infected hospital infections, including pneumonia, (especially rodents, rabbits, and hares). It person looks and feels healthy and can’t surgical wounds, and systemic blood is a potentially serious illness that can be infect others. Following the incubation infections. fatal if not treated with the right antibi- period, a sudden onset of flu-like signs otics. and symptoms occurs, including fever, streptococcal infections—There are two headache, severe fatigue, and sometimes types of “strep” infections—group A and varicella zoster—Chicken pox and vomiting, diarrhea or both. A few days group B—both of which are treated by herpes zoster are caused by the varicella later, the characteristic smallpox rash ap- antibiotics. Group A strep causes strep zoster virus, chicken pox being the acute pears as flat, red spots (lesions). Within throat, scarlet fever, impetigo, toxic invasive phase of the virus and zoster a day or two, many of these lesions turn shock syndrome, cellulitis, and necrotiz- (shingles) being the reactivation of the into small blisters filled with clear fluid ing fasciitis (flesh-eating disease). Group latent stage. (vesicles) and later with pus (pustules). B can cause blood infections, pneumo- —Three Gram-negative ba- The rash appears first on the face, hands nia, and meningitis in newborns. Adults Yersinia cilli Yersinia species cause infection in and forearms, and later on the trunk. can also get group B strep infections, humans: Y. enterocolitica causes gastro- The distribution of lesions is a hallmark especially if they are elderly or already enteritis; Y. pseudotuberculosis causes of smallpox and a primary way of diag- have health problems. Strep B can cause mesenteric lymphadenitis; and Y. pestis nosing the disease. urinary tract infections, blood infections, causes plague. skin infections, and pneumonia in adults. staphylococcal infections—Caused by Staphylococcus bacteria, which are

Medicines in Development Vaccines 2013 35 The Drug Discovery, Development and Approval Process

Developing a new medicine takes an average of 10-15 years; For every 5,000-10,000 compounds in the pipeline, only 1 is approved. Drug Discovery and Development: A LONG, RISKY ROAD

DRUG DISCOVERY PRECLINICAL CLINICAL TRIALS FDA REVIEW LG-SCALE MFG Y

5,000–10,000 250 5 VEILLANCE ONE FDA-

VER COMPOUNDS APPROVED O DRUG

PHASE PHASE PHASE ARKETING SUR 1 2 3 -M ST NUMBER OF VOLUNTEERS PRE-DISC 20–80 100–300 1,000–3,000 A SUBMITTED 0.5–2 IND SUBMITTE D 3–6 YEARS6–7 YEARS ND

YEARS PHASE 4: PO The Drug Development and Approval Process The U.S. system of new drug approvals is in people. The IND shows results of previous ate statistically significant evidence to confirm perhaps the most rigorous in the world. experiments; how, where and by whom the new its safety and effectiveness. They are the lon- studies will be conducted; the chemical structure gest studies, and usually take place in multiple It takes 10-15 years, on average, for an experi- of the compound; how it is thought to work in sites around the world. mental drug to travel from lab to U.S. patients, the body; any toxic effects found in the animal according to the Tufts Center for the Study of New Drug Application (NDA)/Biologic License studies; and how the compound is manufac- Drug Development. Only five in 5,000 com- Application (BLA). Following the completion tured. All clinical trials must be reviewed and ap- pounds that enter preclinical testing make it to of all three phases of clinical trials, a company proved by the Institutional Review Board (IRB) human testing. And only one of those five is analyzes all of the data and files an NDA or BLA where the trials will be conducted. Progress approved for sale. with FDA if the data successfully demonstrate reports on clinical trials must be submitted at both safety and effectiveness. The applications On average, it costs a company $1.2 billion, least annually to FDA and the IRB. contain all of the scientific information that the including the cost of failures, to get one new Clinical Trials, Phase I—Researchers test the company has gathered. Applications typically medicine from the laboratory to U.S. patients, drug in a small group of people, usually between run 100,000 pages or more. according to a recent study by the Tufts Center 20 and 80 healthy adult volunteers, to evaluate for the Study of Drug Development. Approval. Once FDA approves an NDA or BLA, its initial safety and tolerability profile, deter- the new medicine becomes available for physi- Once a new compound has been identified in mine a safe dosage range, and identify potential cians to prescribe. A company must continue the laboratory, medicines are usually developed side effects. to submit periodic reports to FDA, including as follows: Clinical Trials, Phase II—The drug is given any cases of adverse reactions and appropriate Preclinical Testing. A pharmaceutical company to volunteer patients, usually between 100 and quality-control records. For some medicines, conducts laboratory and animal studies to show 300, to see if it is effective, identify an optimal FDA requires additional trials (Phase IV) to biological activity of the compound against the dose, and to further evaluate its short-term evaluate long-term effects. targeted disease, and the compound is evalu- safety. Discovering and developing safe and effective ated for safety. Clinical Trials, Phase III—The drug is given to a new medicines is a long, difficult, and expensive Investigational New Drug Application (IND). larger, more diverse patient population, often process. PhRMA member companies invested an After completing preclinical testing, a com- involving between 1,000 and 3,000 patients estimated $48.5 billion in research and develop- pany files an IND with the U.S. Food and Drug (but sometime many more thousands), to gener- ment in 2012. Administration (FDA) to begin to test the drug