Where are we in HIV Vaccine Research & Development? A Guide for Journalists
State of HIV Vaccine Research The last 15 months have been the richest period in HIV vaccine research since the epidemic began 27 years ago, marked by the landmark results of the HIV vaccine clinical trial (RV144) in Thailand, the discovery of broadly neutralizing antibodies, and other advances that are providing important fundamental insights into the human immune response to HIV and are opening up entirely new strategies for HIV vaccine design. Together these preclinical and clinical advances herald the exciting and dynamic era that will bring us closer to the development of a safe and effective vaccine. Among these are: The landmark results of RV144 (the Thai trial), the first time a vaccine has reduced the risk of HIV acquisition in humans; New insights into vaccine design through the ongoing analysis of two large‐scale efficacy trials, STEP and Phambili; Improved understanding of the mucosa as a barrier to HIV infection and early host responses following acute infection; New insights into the immunological and genetic basis by which some individuals (known as elite controllers or long‐term non‐progressors) control infection; The isolation of antibodies with broad neutralizing activity; The demonstration that vaccines can protect monkeys from SIV infection or significantly delay disease; New insights into the potential of mosaic sequences to elicit stronger immune responses in non‐human primates; and The development of innovative strategies to design broadly reactive immunogens that take into account HIV’s extraordinary diversity. This progress and optimism is not limited to HIV vaccines. HIV prevention is the focus of attention following the announcement of the first successful study of a topical microbicide to prevent HIV infection in women (CAPRISA, July 2010).
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Why an HIV Vaccine?
HIV has claimed more than 30 million lives since 1981 and causes more than 2.7 million new infections each year.1 Despite progress in preventing infections through behavioral and other interventions, the number of people living with HIV (now more than 33 million), continues to increase. 2 Historically, vaccines are the best tool to limit or stop the spread of a virus. Smallpox and polio are examples of global killers that have been completely or nearly eliminated with a vaccine. The cost of providing treatment for the one‐third of people who need it today is more than $10 billion per year. But the amount spent on the entire global effort to develop and test HIV vaccines in 2009 was approximately $868 million last year ‐ 10 percent less than 2007 funding.34 Preclinical Advances: Why They Are Important The field of HIV vaccine research has an important opportunity to pursue intensive strategies that exploit the potential of basic discovery, which provides important fundamental insights into the human immune response to HIV and opens up entirely new strategies for HIV vaccine design. Stakeholders of the Global HIV Vaccine Enterprise are making headway. In 2009, scientists at Scripps Research Institute and the International AIDS Vaccine Initiative (IAVI) announced the discovery of two antibodies, which could block most strains of HIV. In July 2010, researchers at the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases (NIAID) discovered two new broadly neutralizing antibodies, which also could prevent HIV infection. In November 2010, a team of researchers from the Ragon Institute of Massachusetts General Hospital (MGH), MIT and Harvard and from the Broad Institute of MIT and Harvard found that slight differences in the structure of a protein in the body that recognizes HIV could explain why some HIV‐infected individuals are able to resist the onset of AIDS without treatment. To learn more, visit http://www.ragoninstitute.org/articles/110410_gwas.html. While developments in preclinical research are likely to continue, more clinical trial activity is also expected. ‐ Continued ‐ 1
UNAIDS, 2008 UNAIDS, 2008 3 International Herald Tribune opinion editorial, “Where is the H.I.V. vaccine?” 8 July 2010. 4 HIV Vaccines and Microbicides Resource Tracking Working Group Report, http://www.hivresourcetracking.org/treatments/vaccines. 2
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HIV Vaccine Clinical Trials: What Trials Are Happening and Where? More than 30 clinical trials of experimental HIV vaccines are currently underway in nearly 25 countries, enrolling thousands of participants. AVAC: Global Advocacy for HIV Prevention, maintains a listing of ongoing vaccine and other prevention trials around the world (http://www.avac.org/ht/a/GetDocumentAction/i/3436). Two of many ongoing trials from which we can expect results in the years ahead are listed below.
HVTN 505: This is a phase II exploratory HIV vaccine clinical study examining whether a two‐ part vaccine regimen can decrease viral load (the amount of HIV in the blood) in study participants who later become infected with HIV. HVTN 505 is being conducted by the NIAID‐supported HIV Vaccine Trials Network (HVTN) and employs a prime‐boost strategy of two investigational vaccines developed by scientists at NIAID’s Vaccine Research Center (VRC): a series of three immunizations with recombinant DNA‐based vaccine (the primer vaccine) over the course of eight weeks followed by a single immunization with a recombinant vaccine (the boosting vaccine) based on a weakened adenovirus type 5 (Ad5) that carries the vaccine contents and helps stimulate the immune system.5 HVTN 073/SAAVI 102: This phase I placebo‐controlled clinical trial is evaluating the safety and immunogenicity of two vaccines: SAAVI DNA‐C2 boosted by SAAVI MVA‐C vaccine in HIV uninfected healthy adult participants (who have not been vaccinated) in South Africa and the United States. The is trial is sponsored by the Division of AIDS (DAIDS), within NIAID at the National Institutes of Health (NIH), an agency of the US Department of Health and Human Services (DHHS). More information can be found on the South African AIDS Vaccine Initiative (SAAVI) web site: http://www.mrc.ac.za/public/q&a_saavi.pdf.
Recently Launched HIV Vaccine Clinical Trials
B003/IPCAVD‐004: A phase I trial began in October 2010 to evaluate the safety and immunogenicity of two preventive HIV vaccine candidates in four different prime‐boost regimens. The candidates are based on vectors made from Ad26 and Ad35, each containing synthetic versions of the Env gene of HIV. The trial aims to enroll approximately 212 healthy volunteers over the next two years. This is a joint effort of the Beth Israel Deaconess Medical Center; the HVTN; the NIAID Division of AIDS; the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University; Crucell and IAVI. More information can be found in an IAVI statement: http://www.iavi.org/news‐center/Pages/PressRelease.aspx?pubID=3185.
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National Institute of Allergy and Infectious Disease, Questions and Answers ‐ The HVTN 505 HIV Vaccine Regimen Study, http://www.niaid.nih.gov/news/qa/pages/hvtn505qa.aspx.
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Recently Launched HIV Vaccine Clinical Trials (Cont’d) HVTN082: The "Twins Study," or "HVTN 082," is a clinical trial to test the safety and immune response to different combinations of two experimental HIV vaccines. The trial began in January 2010 and its main purpose is to learn more about how a person's genetic makeup shapes the way the immune system responds to vaccination. More information can be found on the NIAD‐supported HVTN’s web site: http://www.hvtn.org/science/twins.html. Strategies for HIV Vaccine Design The next phase of human clinical trials will involve complex vaccine designs, which build on the recent preclinical and clinical research discoveries. Three main approaches to the design of a preventive HIV vaccine include:
The Prime‐Boost approach: A combination of two different vaccines is called a prime‐boost approach. In this approach, two vaccines are given in sequence with the goal of inducing the strongest and most comprehensive immune response possible. This was the strategy used in the Thai Trial and is the strategy in the NIAID‐funded HVTN 505 study. The Passive immunization approach: The elicitation of broad and potent HIV‐neutralizing antibodies by active immunization has been a major challenge in HIV vaccine development. While HIV‐neutralizing human monoclonal antibodies have been identified recently, it is not known whether passive delivery of these or similar antibodies, or of antibody combinations, can offer significant protection from HIV infection, and in what epidemiologic settings passive immunization could play a significant role in HIV prevention.6 IAVI, the Vaccine Research Center of NIAID, the Aaron Diamond AIDS Research Center (ADARC) and many others are exploring this approach. The Mosaic vaccine approach: A mosaic vaccine design uses computational methods to create small sets of highly variable artificial proteins of virus, which provide coverage of the diverse forms of HIV circulating in the world today when combined.7 The mosaic concept has been tested on mice and monkeys and the Ragon Institute, Harvard Medical School and the U.S. Military HIV Program (MHRP) are employing this approach in humans.
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6 The Collaboration for AIDS Vaccine Discovery (CAVD), Passive Immunization with Human Monoclonal Antibodies for HIV Prevention, http://www.cavd.org/Pages/RFPImmunization.aspx. 7
Nat. Med. 2010 Mar;16(3):268‐70. L. Corey, et al, “HIV vaccines: mosaic approach to virus diversity.”
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Building on The Thai Trial (RV144) The MHRP and more than 30 U.S. and international collaborators from 20 institutions are initiating intensive laboratory studies to define the immune mechanisms that correlated with vaccine efficacy in the Thai trial, which could allow for improvements to build on and subsequent approaches to develop. Results suggest that the vaccine regimen protected people at lower risk of infection, and the protection was highest at 6‐12 months and then appeared to wane over time. One study the MHRP is exploring involves boosting some of the volunteers in the Thai trial to see if this will extend and increase the immune response. Another proposed study will recruit several hundred new volunteers in Thailand who will receive a similar vaccine regimen as in RV144, plus an additional boost at 12 months. This study would provide insight into the benefit of the additional boost and collect more blood and some tissue samples so that extensive research can be conducted on the study participants’ immune responses. Future clinical studies will likely involve populations with different risk factors/HIV incidence, and will also be executed in other parts of the world where other strains of HIV circulate. For more information on the Thai Trial and follow up studies, please visit http://www.hivresearch.org/research.php?ServiceID=13. Future of HIV Vaccine Research and Development The Global HIV Vaccine Enterprise released its Scientific Strategic Plan for HIV Vaccine Development in the October 2010 issue of Nature Medicine. The Plan, developed by the Enterprise Council and informed by the input of the Enterprise Science Committee and more than 400 researchers, policy makers, funders and advocates worldwide, presents a shared vision and strategy to transform recent scientific advancements and the momentum and opportunities of the past five years into faster, smarter and more productive research to develop an HIV vaccine. 2010 Plan comes at an important moment for the field, a time of exciting progress, renewed optimism and a growing consensus that prevention is the most cost effective way to control the HIV epidemic. Enterprise stakeholders are working to implement the goals and targets identified in the Plan, building on the advancements and work of stakeholders as indicated above. # # # The International AIDS Vaccine Initiative (IAVI), the National Institute of Allergy and Infectious Diseases (NIAD) of the National Institutes of Health (NIH) and the South African AIDS Vaccine Initiative (SAAVI) graciously advised on and/or contributed to this guide.
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