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This meeting will tackle a range of challenges facing researchers working towards the development of an HIV / AIDS vaccine, and will counter each presented challenge with a possible solution. These challenges include developing HIV vaccines to prevent or control infection, genetic diversity of the virus, and predictive models of infection. The symposium will also cover other (non-scientific) challenges and mechanisms that can be used to reduce HIV transmission now and in conjunction with a future vaccine.
Presented by
Photo credit: CDC/ Dr. A. Harrison; Dr. P. Feorino For a complete list of sponsors, please click the Sponsorship tab.
Agenda
* Presentation times are subject to change
Wednesday, May 19, 2010
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9:00 AM
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Welcome
Jennifer Henry, PhD, New York Academy of Sciences
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9:05 AM
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Overview of the Challenges
Yegor Voronin, Global HIV Vaccine Enterprise
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9:15 AM
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Viral genetic diversity and the control of HIV/AIDS: challenges and opportunities
Michael Worobey, University of Arizona
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| 9:45 AM |
Novel Vectors and Antigens for a Next Generation HIV-1 Vaccine
Dan H. Barouch, DVR, Beth Israel Deaconess Medical Center
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10:20 AM
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Coffee Break
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10:45 AM
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Recent Progress in Isolating HIV-1 Broad Neutralizing Antibodies
Sanjay Phogat, International AIDS Vaccine Initiative
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11:15 AM
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Using Epitopes Recognized by Monoclonal Antibodies as Vaccine Templates
Susan Zolla-Pazner, NYU School of Medicine and Veterans Affairs Medical Center
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11:50 AM
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New Insights into Immunologic Vulnerabilities of Highly Pathogenic SIV
Louis J. Picker, Oregon Health & Science University
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| 12:30 PM |
A Protective Live-Attenuated AIDS Vaccine Suppresses Innate Immunity and Inflammation in Immunized Rhesus Macaques
Chris Miller, University of California
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1:10 PM
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Lunch Break
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| 2:00 PM |
Insights from Recent Clinical HIV Vaccine Trials That Can Guide Future Vaccine Designs
Juliana M. McElrath, Fred Hutchinson Cancer Research Center
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2:40 PM
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Clinical and Preclinical Studies for DNA and Recombinant MVA Vaccines Expressing HIV-1 Virus-Like-Particles
Harriet L. Robinson, GeoVax Inc.
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3:15 PM
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Update of the Thai Phase III HIV Vaccine Trial: The Way Forward
Jerome Kim, Walter Reed Army Institute of Research
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3:55 PM
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Coffee Break
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4:20 PM
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HIV Vaccine Research Today, the Global HIV Vaccine Enterprise, and the Enterprise Scientific Strategic Plan
Alan Bernstein, Global HIV Vaccine Enterprise
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4:50 PM
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Panel Discussion: Where Are We Going and What's Next?
Moderated by Sarah Schlesinger and Alan Bernstein
Dan H. Barouch, Chris Miller, Mitch Warren, Louis J.Picker
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5:25 PM
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Closing Remarks
Sarah Schlesinger, The Rockefeller University
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5:30 PM
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Networking Reception
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Speakers
Organizers
Sarah Schlesinger, MD
The Rockefeller University
Sarah J. Schlesinger is a research associate professor in the laboratory of cellular immunology and physiology at The Rockefeller University and a research scientist at The Aaron Diamond AIDS Research Center, a world-renowned biomedical research institute. Dr. Schlesinger has been actively engaged in HIV/AIDS and HIV vaccine research for 10 years, and has published over 50 papers on the subject. Dr. Schlesinger led the Dendritic Cell program at the Division of Retrovirology at the Walter Reed Army Institute of Research (1990-2002). She is now an active member of the research team at Aaron Diamond that is devoting considerable efforts to develop a vaccine to halt the spread of the AIDS epidemic.
Yegor Voronin, PhD
Global HIV Vaccine Enterprise
Yegor Voronin is Science Officer at the Global HIV Vaccine Enterprise (Enterprise). In this role, he is responsible for the implementation of the vision of the Enterprise through identification, development, and management of Scientific Strategic Plan- related initiatives and activities. Prior to joining the Enterprise, Dr. Voronin did his postdoctoral training with Dr. Michael Emerman and Dr. Julie Overbaugh at the Fred Hutchinson Cancer Research Center (FHCRC). For over ten years he has studied HIV and other retroviruses on a variety of different levels, from their potential use as gene therapy vectors at the West Virginia University, to molecular mechanisms of reverse transcription at the National Cancer Institute, to viral population genetics and evolution at the FHCRC. Dr. Voronin holds a master’s degree in molecular biology from Novosibirsk State University in Russia and Ph.D. in biochemistry from West Virginia University.
Jennifer Henry, PhD
The New York Academy of Sciences
Speakers
Dan H. Barouch
Beth Israel Deaconess Medical Center
Dr. Dan Barouch received his Ph.D. in immunology from Oxford University and his M.D. from Harvard Medical School. He is currently Associate Professor of Medicine at Beth Israel Deaconess Medical Center and Harvard Medical School. His laboratory focuses on studying the immunology and virology of HIV-1 infection and developing novel vaccine strategies. He has demonstrated that cellular immune responses can partially control viral replication, but that the virus can readily escape from immune control. In particular, he has shown that adjuvanted DNA vaccines and viral vector-based vaccines expressing HIV-1 and SIV antigens can elicit potent cellular immune responses that partially control pathogenic virus challenges in rhesus monkeys. His laboratory has also developed a series of rare serotype and chimeric adenovirus vector-based vaccines that overcome the critical problem of pre-existing immunity to the common adenovirus serotype 5 (Ad5) vector in the developing world. Dr. Barouch received two NIH U19 Integrated Preclinical/Clinical AIDS Vaccine Development (IPCAVD) program grants to construct these vaccine vectors, to explore their immunogenicity and protective efficacy in rhesus monkeys, and to advance optimal vaccine candidates into clinical trials. He identified Ad26 as an optimal rare serotype vector and Ad5HVR48 as a hexon-chimeric vector for clinical development, and phase 1 clinical trials with these novel HIV-1 vaccine vectors are currently in progress. His laboratory is a key part of the Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD), the NIH Center for HIV/AIDS Vaccine Immunology (CHAVI), and the Ragon Institute of MGH, MIT, and Harvard. Dr. Barouch is also highly committed to teaching students, clinical fellows, research fellows, and junior faculty and to providing clinical care to patients with infectious diseases.
Alan Bernstein
Global HIV Vaccine Enterprise
Dr. Alan Bernstein is the inaugural executive director of the Global HIV Vaccine Enterprise. As Executive Director, Dr. Bernstein oversees the Enterprise Secretariat in implementing activities to support the goals and mission of the Enterprise, most significant of which is the development of a 2010 Scientific Strategic Plan. Prior to leading the Enterprise, Dr. Bernstein served as the founding president of the Canadian Institutes of Health Research (CIHR) where he helped build the organization into one of the world’s leading research agencies, supporting more than 11,000 health researchers with an annual budget of US $1 billion. An internationally renowned researcher, Dr. Bernstein has authored more than 200 peer-reviewed scientific publications. His contributions to embryonic development, stem cells, hematopoiesis and cancer have been recognized by various institutions including the Royal Society of Canada, the National Cancer Institute of Canada and Institut de Recherche Clinique de Montreal.
Jerome Kim
Walter Reed Army Institute of Research
Jerome H. Kim, M.D., is currently Deputy Director (Science) and Chief, Department of Molecular Virology and Pathogenesis, Division of Retrovirology, Walter Reed Army Institute of Research (WRAIR) (U.S. Military HIV Research Program), a multidimensional, international research program encompassing vaccine research and development, HIV prevention research, and clinical research. He also serves as the HIV Vaccines Product Manager, U.S. Army Medical Materiel Development Activity, Fort Detrick, MD. Dr. Kim, a Colonel in the United States Army Medical Corps, started his military career in the Air Force, assigned to the Department of Retroviral Research, Division of Retrovirology, WRAIR. After a brief exodus, he entered Army service in 2000 in the Department of HIV Vaccine Research, Division of Retrovirology, WRAIR. Prior to serving as Deputy Director (Science), Dr. Kim was the Chief, Department of Retrovirology, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand (2004-2008). He has also been the Chief, Biomedical Research Service, Tripler Army Medical Center (2002-2004) and Assistant Chief, Department of HIV Vaccine Development, MHRP (2000-2002). Dr. Kim’s research interests include HIV molecular epidemiology, host genetics, and HIV vaccine development. He serves as a reviewer for scientific journals and has served on consultations for the World Health Organization and the Global HIV/AIDS Vaccine Enterprise. Dr. Kim is a Clinical Associate Professor of Medicine at the John A. Burns School of Medicine, University of Hawaii. He is a Fellow of the American College of Physicians and a Fellow the Infectious Diseases Society of America. Military honors include Army Commendation Medal and Air Force/Army Meritorious Service Medal with 3 oak-leaf clusters, and the Order of Military Medical Merit. Dr. Kim graduated Phi Beta Kappa with highest honors in Biology and high honors in History from the University of Hawaii, Manoa in 1980, where he won the Library Prize for Pacific Islands Area Research and the Arthur Lyman Dean Prize in the Humanities. He graduated from the Yale University School of Medicine in 1984. Dr. Kim completed his training in Internal Medicine (1987) and fellowship in Infectious Diseases (1990) at Duke University Medical Center and was elected into Alpha Omega Alpha while at Duke.
Juliana M. McElrath
Fred Hutchinson Cancer Research Center
Dr. Julie McElrath is a Member of Fred Hutchinson Cancer Research Center; Professor, Department of Medicine, University of Washington; Co-Director of the Vaccine and Infectious Disease Institute and directs the Immunology and Vaccine Development Program. Dr. McElrath has clinical attending responsibilities on the Fred Hutchinson Cancer Research Center Infectious Diseases consult service for the Seattle Cancer Care Alliance and University of Washington Hospital. She is also the Principal Investigator and Director of the HVTN Laboratory Program and Seattle Vaccine Trials Unit.
Her current research pursues a vaccine that will protect against HIV-1 infection and deeper understanding of the components of immunity that contribute to control of HIV-1 disease. Dr. McElrath has built and maintains a successful international HIV vaccine laboratory program, conducted translational immunological research in humans in a multicenter setting. She has contributed fundamental understanding of how HIV-1 enters the mucosa to establish infection, and mechanisms of potential reduced susceptibility to infection in seronegative persons repeatedly exposed to HIV-1. In conjunction with a highly productive research program, she has assumed a leadership role or been a major contributor in a number of integrated programs at the national and international level to advance a coordinated effort to tackle the HIV epidemic through prevention efforts. She has mentored numerous junior faculty, young investigators, and graduate students in their career paths.
Dr. McElrath received her bachelor's degree from Furman University, Greenville, SC; her Ph.D. and M.D. degrees from the Medical University of South Carolina, Charleston; her clinical training in infectious diseases at Columbia Presbyterian Medical Center, New York; and her post-doctoral training in molecular immunology at the Rockefeller University in New York.
Chris Miller
University of California
Christopher J. Miller, D.V.M., Ph.D. is a Professor of Pathology, Microbiology and Immunology in the School of Veterinary Medicine and an Adjunct Professor of Medicine in the School of Medicine. Dr Miller is a veterinarian and virologist, a core faculty member of the Center for Comparative Medicine and a Staff Scientist at the California National Primate Research Center. His laboratory utilizes non-human primate models of AIDS and influenza A virus infection to define the pathogenesis of these viral infections, study the nature of protective antiviral immunity, and test vaccines and immunotherapeutic strategies to prevent AIDS and influenza.
Louis J. Picker
Oregon Health & Science University
Dr. Louis J. Picker is currently the Associate Director of the Vaccine and Gene Therapy Institute, Head of the Pathobiology and Immunology Division of the Oregon National Primate Research Center, and Professor of Pathology at the Oregon Health & Science University. Dr. Picker was recruited from the Department of Pathology at the University of Texas Southwestern Medical Center at Dallas where he served as a Principal Investigator, Medical Director of the Flow Cytometry and Clinical Immunology Laboratory, and Co-Director of the Division of Hematopathology and Immunology. He received his medical degree at the University of California, San Francisco in 1982, did an internship, residency, and chief residency in Anatomic and Clinical Pathology at the Beth Israel Hospital in Boston, Massachusetts from 1982-86, and received advanced training in Immunopathology and Experimental Pathology at Stanford University Medical Center in Palo Alto, California from 1986-89. Dr. Picker is well-known for his work elucidating memory T cell physiology in humans and non-human primates, including mechanisms of T cell homing, mechanisms of protection against persistent pathogens, AIDS vaccine development, and the immunopathogenesis of AIDS-causing lentiviruses, authoring over 140 journal articles in these areas. He has served on numerous advisory panels and study sections at the NIH and various private foundations, and is currently a member of the National Institute of Allergy and Infectious Diseases Council (DAIDS subcommittee) and the AIDS Vaccine Research Subcommittee. He is also executive consultant at VGTI-Florida, a newly established research institute at Florida’s treasure coast.
Sanjay Phogat
International AIDS Vaccine Initiative
Dr. Sanjay K. Phogat is a Principal Scientist at the International AIDS Vaccine Initiative's AIDS Vaccine Design and Development laboratory located in Brooklyn, N.Y. He is also a Principal Investigator of the IAVI Neutralizing Antibody Consortium (NAC). His research focus is on HIV-1 broad neutralizing antibodies, including HIV-1 envelope glycoprotein-based immunogen design and their presentation on a particulate platform. In addition, Dr. Phogat is involved with the IAVI medicinal chemistry research program in India, a partnership with the Indian government's Department of Biotechnology and supports several projects that are within the organization's Innovation Fund portfolio. In fact, Dr. Phogat was integrally involved in the recent discovery of two new potent and broadly neutralizing antibodies against HIV, PG9 and PG16, a finding that grew out of the Innovation Fund and IAVI's network of research centers in the developing world. Prior to joining IAVI Dr. Phogat worked at the Vaccine research center. Dr. Phogat received numerous awards during his career: to name a few, the prestigious gold medal given by the late Excellency President of India K. R. Narayanan, Technology transfer awards by the National Cancer Institute and the Fellows award for research excellence by NIH. Dr. Phogat is also a founding member of NIH visiting Fellows committee, a board member of Global Alliance of Indian Biomedical Professional and former secretary of Fellows Committee (FELCOM).
Harriet L. Robinson
GeoVax Inc.
Dr. Harriet L. Robinson, Chief Scientific Officer at GeoVax Inc., a biotech company specializing in the development of HIV/AIDS vaccines, has a multi-protein clade B DNA/MVA vaccine in phase 2a clinical trials through the US HIV vaccine Trials Network (HVTN). The vaccine was developed in Dr. Robinson’s former laboratory at the Emory Vaccine Center in collaboration with Dr. Bernard Moss’s laboratory at the US NIH and researchers at the US Centers for Disease Control and Prevention. The vaccine DNA is used to prime the immune response and the recombinant MVA to boost the immune response. The recombinant MVA can also be used to prime and boost the immune response. Dr. Robinson co-founded GeoVax to facilitate taking the vaccine from the research laboratory to clinical use. Dr. Robinson, former Asa Griggs Candler Professor of Microbiology and Immunology at Emory University and Chief of the Division of Microbiology and Immunology at the Yerkes National Primate Research Center, is internationally recognized for her work on HIV/AIDS vaccines, her pioneering studies on the use of recombinant DNA for vaccination and her seminal studies on insertional mutagenesis and oncogene transduction in retroviral induced cancers. She received her Ph.D. from the Massachusetts Institute of Technology and her post doctoral training at the Virus Laboratory, University of California Berkeley. Dr. Robinson is active on several Editorial Boards and has consulted for the US NIH, the US Food and Drug Administration, the World Health Organization, and the Gates Foundation.
Michael Worobey
University of Arizona
Michael Worobey is an evolutionary biologist who grew up in British Columbia and received a BS in the Department of Biological Sciences, Simon Fraser University in 1997. He then moved to the University of Oxford, receiving a DPhil from the Department of Zoology (2001) and doing postdoctoral work as a Research Fellow of St. John's College. Since 2003 he has been a faculty member in the Department of Ecology and Evolutionary Biology at the University of Arizona, where he is an Associate Professor. He uses an evolutionary approach to investigate the origins, emergence, and control of pathogens, in particular rapidly evolving retroviruses and RNA viruses such as HIV and influenza virus.
Susan Zolla-Pazner
NYU School of Medicine and Veterans Affairs Medical Center
Susan Zolla-Pazner is a biologist who has devoted her professional life to areas of Immunology where basic research intersects with the needs of modern medicine. By 1981, Dr. Zolla-Pazner had an established reputation for studying the immune systems of individuals with cancer. At that time, she was asked to consult on several patients who had an unusual type of tumor. These patients were the first patients to be seen with a new form of Kaposi's sarcoma, a tumor related to the disease which, only later, became known as AIDS. In the three decades since, Dr. Zolla-Pazner has authored more that 260 scientific papers on AIDS and related illnesses. She collaborates actively with researchers around the world and has support through the National Institutes of Health, the Department of Veterans Affairs, and the Bill and Melinda Gates Foundation for her studies to develop an AIDS vaccine and to train students and health care professionals from India, Cameroon and China in the prevention, diagnosis and treatment of AIDS and tuberculosis.
Sponsors
For sponsorship opportunities please contact Cristine Barreto at cbarreto@nyas.org or 212.298.8652.
Presented by
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Grant Support
This program is supported by an educational grant from Merck & Co., Inc.
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Abstracts
Viral genetic diversity and the control of HIV/AIDS: challenges and opportunities
Michael Worobey, University of Arizona
The rapid accumulation of mutationsinSIV and HIV strains presents great challenges to treatment and, especially, vaccination development efforts. At the same time, these mutations leave a useful record of when and where important lineages emerged and spread both within hosts and between hosts at local and worldwide levels. These patterns can reveal (1) the key evolutionary and ecological processes underlying ‘successful’viral lineages; (2) the timing of key events in viral emergence; and (3) evolutionary processes relevant to vaccine design and other control efforts. Analyses of archival human and wild primate samples using ‘relaxed’ molecular clock phylogenetic methods have uncovered much of the timeline of SIV and HIV evolution. Early HIV-1 sequences show that extensive diversity was already present in the Democratic Republic of the Congo by 1960, placing the ancestor of the M group near the beginning of the twentieth century. The subsequent emergence of the virus from Africa appears to have begun as early as the 1960s and was characterized by a surprisingly low frequency of epidemically successful dispersal events. On the other hand, analyses of SIV suggest it has a vastly longer history than the HIV lineages derived from it. These insights suggest that colonial-era urbanization may have set the stage for the HIV/AIDS pandemic and, crucially, that HIV-1 lives close to the edge of extinction: changes in human ecology may have allowed it to become established, but compensatory efforts could conceivably have similarly dramatic effects on reducing the viability of HIV-1 populations, at least in some settings.
Novel Vectors and Antigens for a Next Generation HIV-1 Vaccine
Dan H. Barouch, PhD, Beth Israel Deaconess Medical Center
Rare serotype Ad vectors such as rAd26 and rAd35 are biologically substantially different than rAd5 vectors. We have evaluated rAd26 and rAd35 vectors expressing SIV antigens in immunogenicity and challenge studies in rhesus monkeys, and we have recently advanced a prototype rAd26 vector expressing HIV-1 Env into a phase 1 clinical trial. Importantly, this vector has proven safe and immunogenic in humans at doses of 109 vp, 1010 vp, and 1011 vp. We have also assessed the capacity of vector-specific CD4+ T lymphocytes to traffic to mucosal surfaces following rAd vaccination in rhesus monkeys, and we have observed that trafficking of vector-specific CD4+ T lymphocytes to colorectal mucosa does not occur more readily in monkeys with baseline vector immunity as compared with monkeys without baseline vector immunity. In addition, we have demonstrated that computationally optimized “mosaic” HIV-1 Gag/Pol/Env antigens substantially expand cellular immune breadth and depth as compared with consensus or natural sequence antigens in rhesus monkeys. Taken together, these data suggest that a rAd35/rAd26 prime-boost vector regimen expressing mosaic HIV-1 antigens should be evaluated in clinical studies.
Recent progress in Isolating HIV-1 Broad Neutralizing Antibodies
Sanjay Phogat, IAVI
The ability to elicit broadly cross-reactive neutralizing antibodies (bNAbs) is a major challenge in the development of an HIV-1 vaccine capable of neutralizing the array of viruses in circulation. Nevertheless, a number of HIV-1 infected donors have broadly neutralizing sera and a handful of broadly neutralizing monoclonal antibodies have been isolated from clade B infected donors arguing that a vaccine strategy based upon eliciting broadly protective antibodies is feasible. The bNAbs isolated to date tend to display less breadth and potency against non-clade B viruses and they recognize epitopes on the viruses that have not yet been exploited to induce broadly neutralizing responses. Over the past few years systematic screening and mapping studies have identified HIV-1 clade B and non-clade B infected donors with broad neutralizing serum activity. These studies include IAVI protocol G, in which a large-scale systematic evaluation of neutralizing breadth in the sera of about 1,800 HIV-1 donors was completed. Protocol G identified of the order of 10-15% donors with broad neutralization, a subset of donors (elite neutralizers) were identified with outstanding potency and breadth of serum neutralization and these donors are being prioritized for the generation of novel bNAbs. Approximately 30,000 B cells from a Protocol G donor were plated out, single cells activated and supernate screened directly for function in a microneutralization assay to identify a family of six somatically related bNAbs, termed “PG antibodies”. The prototype antibodies, PG9 and PG16, target a conserved epitope on the variable loops V1/V2 and V3 of gp120, primarily in a native Env trimer context. The Vaccine Research Center at the NIAID using NIH cohorts, and B-cell sorting strategy has identified two novel anti-CD4bs bnAbs. Finally, CAVD investigators using clinical cohorts infected with non-clade B HIV-1 and improved EBV immortalization approach have identified a bnAb to the CD4bs with potency and breadth similar to b12. These additional new bNAbs to different targets on HIV-1 Env will accelerate and support novel immunogen design, screening and selection strategies and will likely make them valuable tools for HIV-1 vaccine design.
Using Epitopes Recognized by Monoclonal Antibodies as Vaccine Templates
Susan Zolla-Pazner, NYU School of Medicine and Veterans Affairs Medical Center
Bioinformatics analysis of gp120 sequence data demonstrates structural conservation in the 2nd and 3rd variable loops (V2 and V3) of gp120. Immunochemical data provide evidence of antigenic conservation in V2 and V3, and immunochemical and functional studies of monoclonal antibodies that target quaternary neutralizing epitopes (QNEs) composed of regions of V2 and V3 also provide evidence of cross-reactivity reflective of structural and antigenic conservation in this compound epitope. Since antibodies to these regions can mediate virus neutralization, these regions of the HIV-1 Envelope should be included among the targets of an AIDS vaccine intended to induce neutralizing antibodies. In order to target structurally-conserved, sequence-variable regions of a protein, 3D visualization is required; this can be accomplished through physical methods (crystallography and NMR) and through molecular modeling. Indeed, these approaches have revealed a generic structure for the V3 loop, and have recently been applied to the design of V3-scaffold immunogens that contain variants of this generic V3 structure. Several such immunogens have been synthesized and tested for antigenicity and immunogenicity in rabbits and shown to induce cross-clade neutralizing antibodies. The data indicate that it is possible to induce neutralizing antibodies to conserved epitopes in variable regions, providing a practical pathway for further development rationally-designed HIV vaccines.
New insights into immunologic vulnerabilities of highly pathogenic SIV
Louis J. Picker, Oregon Health & Science University
The rapid onset of massive, systemic viral replication during primary HIV/SIV infection and the immune evasion capabilities of these viruses pose fundamental problems for vaccines that depend upon initial viral replication to stimulate effector T cell expansion and differentiation. We hypothesized that HIV/SIV vaccines designed to elicit and maintain differentiated “effector memory” T cell (TEM) responses at sites of viral entry and initial amplification might improve efficacy by impairing viral replication at its earliest, most vulnerable stage. We therefore developed SIV protein-encoding vectors based on rhesus cytomegalovirus (RhCMV), the prototypical inducer of life-long TEM responses, for use as a HIV/AIDS vaccine prototype. RhCMV vectors expressing SIV Gag, Rev/Nef/Tat, and Env persistently infected rhesus macaques, regardless of pre-existing RhCMV immunity, and primed and maintained robust SIV-specific CD4+ and CD8+ TEM responses in the absence of neutralizing antibodies, Vaccine regimens including these vectors have demonstrated complete protection of ~50% of vaccinated RM against progressive infection after intra-rectal challenge with highly pathogenic SIVmac239. These data suggest a new paradigm for AIDS vaccine development: that vaccines capable of generating and maintaining HIV-specific TEM might allow for complete control of HIV infections in the first few days following sexual exposure.
Insights from Recent Clinical HIV Vaccine Trials That Can Guide Future Vaccine Designs
Juliana M. McElrath, Fred Hutchinson Cancer Research Center
Recent results of two large-scale international HIV vaccine trials highlight the importance of understanding the basic mechanisms of inducing long-term immunologic memory that can protect against the diverse circulating strains of HIV at mucosal sites of exposure. Candidate HIV vaccine regimens have consistently targeted cellular and/or humoral immunity, but achieving greater potency and breadth of these responses have been difficult. This presentation will report recent findings in clinical trials, examining both innate signatures and adaptive responses, and contrast responses induced by various vaccine approaches that may be important in guiding new vaccine designs.
Clinical and Preclinical Studies for DNA and Recombinant MVA Vaccines Expressing HIV-1 Virus-Like-Particles
Harriet L. Robinson, GeoVax Inc
A Phase 1 clinical trial testing DNA priming and MVA boosting and MVA priming and boosting has shown excellent safety and unique patterns of immunogenicity in a study conducted by the HIV Vaccines Trials Network (HVTN 065). The GeoVax DNA and MVA-vectored HIV vaccines use single recombinant moieties to express non-infectious, immature, virus-like-particles bearing native forms of Env. This vaccine design was originally tested and developed using rhesus macaque-SHIV models. The clinical trial HVTN 065 first tested a dose escalation of two doses of DNA (0.3 mg. or 3 mg) followed by two doses of MVA (1x107 or 1x108 TCID 50)(DDMM) at 8 week intervals. Following the demonstration of immunogenicity, two additional regimens at the full dose were tested. These delivered a single dose of DNA followed by two doses of MVA (DMM) or three doses of MVA (MMM) at weeks 0, 8 and 24. No significant systemic adverse events were associated with the various regimens and the most severe local reactogenicity was limited to moderate grade reactions in <30% of the participants receiving full dose MVA inoculations. The full dose regimen using two DNA primes and two MVA boosts elicited the highest levels of CD4+ and CD8+ T cell responses (76% and 42% responders respectively) whereas the three doses of MVA elicited the highest Env-specific antibody responses. The DDMM regimen is currently in a Phase 2a study (HVTN 205); and, given the results of the Thai trial and recent preclinical findings (see below), Phase 2a testing of the MVA-only regimen is being planned. Preclinical studies in rhesus macaques using SIV239 prototypes of the HIV vaccines in full dose DDMM and MMM regimens were recently completed. For a measurement of vaccine efficacy, these studies used a repeat intrarectal heterologous challenge with E660 SIV (MID40) (a dose of 40 to 400 times higher than experienced in a typical human exposure). Both the DDMM and MMM regimens induced immune responses that protected 25% (2/8) of the challenged animals through 12 weekly challenges. Following 6 challenges, 60% of the MMM vaccinated animals were protected, whereas only 40% of the DDMM vaccinated animals were protected, suggesting that protection for the simpler MMM regimen was at least as good, if not better than the DDMM regimen. Interestingly, expression of granulocyte-monocyte colony stimulating factor (GM-CSF) in the DNA prime, increased protection against the 12 weekly challenges to a highly encouraging 70% (5/7). The GM-CSF-adjuvatned group had higher avidity anti-Env Ab, higher frequencies of neutralizing Ab for a tier 1 variant of E660 (E660.11) and higher frequencies of anti-HIV IgA in rectal secretions. The use of the GM-CSF adjuvant for the GeoVax DNA/MVA vaccine regimen is being advanced into clinical trials as part of the GeoVax pipeline.
Update of the Thai Phase III HIV vaccine trial: the way forward
Jerome Kim, Walter Reed Army Institute of Research
Background: In September 2009 the Thai Phase III collaboration reported the results of a prime-boost HIV vaccine study in 16,000 18-30 year old Thai men and women. The vaccine showed, for the first time, that a vaccine combination could provide modest protection (31.2%, 95% CI 1.1, 52.1) against infection over a 42 month period of follow-up. There was no effect on post infection viral load or CD4 T cell counts. Results: Additional analyses and laboratory studies have provided further insight. First, the vaccine efficacy may have been more apparent in persons at lower risk of HIV infection. In addition, vaccine efficacy may have been higher in the period immediately after vaccination and declined thereafter. These observations suggest that a strategy involving a booster injection at 12 months may prolong the durability of the response and potentially providing protection to persons at higher risk. Laboratory studies have suggested a waning of the humoral immune response. ADCC data appear very similar to prior Phase I/II studies. Finally, analysis of breakthrough infections appears to suggest that the Env predominance of responses seen in HIV negative vaccine recipients persists in vaccine recipients who become infected. Peptide mapping of these responses shows distinct peptide recognition by vaccine and placebo recipients with breakthrough infection and sequencing of the breakthrough viruses has commenced. The broadly constituted Scientific Working groups have now started to look for potential correlates of protection. Proposals for future trials in Thailand and elsewhere are now being reviewed. Conclusion: The ALVAC-HIV and AIDSVAX B/E prime-boost HIV vaccine regimen may reduce the risk of HIV infection in a community-based population in Thailand with largely heterosexual risk and did not affect post-infection viral load or CD4 count. While modest and likely without immediate public health benefit, the results offer insight for future research. A comprehensive approach for the elucidation of a correlate/surrogate of protection and plans for follow-on clinical studies will be presented.
HIV vaccine research today, the Global HIV Vaccine Enterprise, and the Enterprise Scientific Strategic Plan
Alan Bernstein, Global HIV Vaccine Enterprise
The development of safe and effective HIV vaccines will be absolutely essential to ending the AIDS epidemic. This is a time of both great progress and significant challenges in HIV vaccine research. Advances such as RV144 (the Thai trial) and the discovery of new neutralizing antibodies are important steps forward, but significant challenges and obstacles remain. The opportunities presented by recent advances in HIV vaccine research must be carefully chosen and efficiently exploited. Turning these opportunities into real scientific progress requires an exceptional level of collaboration across the field. The Global HIV Vaccine Enterprise is an unprecedented collaboration of HIV vaccine researchers, funders, policy makers and advocates, working to promote effective research, answer the most pressing questions and overcome the greatest obstacles to developing safe and effective HIV vaccines. This presentation provides a broad overview of the state of the field and the major challenges that confront us, including the need to maximize learnings from vaccine clinical trials, incorporate new research approaches into HIV vaccine development and expand the participation of young and early-career investigators and developing world research institutions. The presentation will also provide an brief overview of the updated Global HIV Vaccine Enterprise Scientific Strategic Plan, a global roadmap for HIV vaccine research developed with the participation of more than 100 researchers from across the world, to be released later this year.
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