Meeting Minutes - April 10, 2012

Office of AIDS Research Advisory Council
Thirty-fourth Meeting
April 10, 2012

National Institutes of Health
U.S. Department of Health and Human Services
5635 Fishers Lane Conference Center
Rockville, MD

Members Present: Dr. Sharon L. Hillier (Chair), Dr. Judith Auerbach, Dr. David B. Clifford, Dr. Myron S. Cohen, Dr. Steven G. Deeks, Dr. Carrie E. Foote, Dr. Igor Grant, Dr. Lisa Jacobson, Dr. Ronald Swanstrom, Dr. Irene S. Vernon, Dr. Rochelle Walensky, Mr. Mitchell J. Warren, Dr. Judith N. Wasserheit, and Dr. Craig M. Wilson

Ex Officio Members Present: Dr. Carl W. Dieffenbach, Dr. Kevin Fenton, Dr. Alice K. Pau for Dr. John G. Bartlett, and Dr. Steven M. Wolinsky

Invited Speakers and Guests: Dr. Dan H. Barouch, Dr. James A. Bradac, Dr. Cynthia A. Derdeyn, Dr. Alan Fix, Dr. Barney Graham, Dr. Barton F. Haynes, Dr. James Kublin, Dr. Jeffrey Lifson, Dr. Margaret Julie McElrath, Dr. Robert J. O’Connell, Dr. Harriet L. Robinson, and Dr. David B. Weiner

Welcome and Meeting Overview

The National Institutes of Health (NIH) Office of AIDS Research Advisory Council (OARAC) convened its thirty-fourth meeting at 8:35 a.m. at the Fishers Lane Conference Center in Rockville, Maryland.  Dr. Sharon L. Hillier served as Chair.  She welcomed the OARAC members, invited speakers, and guests. 

The topic of the meeting was new scientific opportunities in AIDS vaccine research.  Dr. Hillier noted that the presentations would focus on the results of the RV144 vaccine clinical trial and the subsequent correlates of risk analysis, as well as ongoing research to develop a safe and effective AIDS vaccine.  The specific issues presented at this OARAC meeting included basic research on the design and development of a vaccine, preclinical studies in nonhuman primates, novel vaccine approaches and strategies for HIV prevention, and current and planned clinical trials of vaccine candidates. 

The minutes of the November 10, 2011, OARAC meeting were approved as submitted.

Director’s Report

Three OAR staff members presented portions of the Director’s report.  Dr. Jack Whitescarver, Director, OAR, was unable to attend the meeting due to illness. 

OARAC Member Changes
Ms. Wendy Wertheimer, Senior Advisor to the Director, OAR, thanked everyone for coming to the meeting.  She reported that the terms of two OARAC members, Ms. Yvonne M. Greene and Ms. Catalina Sol, expired after the previous OARAC meeting and that the term of Dr. Irene S. Vernon will expire after the current meeting.  She thanked Dr. Vernon for her contributions to the OARAC and presented her with a certificate of appreciation from the Secretary, Department of Health and Human Services (HHS).

NIH Personnel Changes
Ms. Wertheimer reported two personnel changes at the NIH:  Dr. Gary H. Gibbons, Director of the Cardiovascular Research Institute at Morehouse University School of Medicine, has been appointed Director of the National Heart, Lung, and Blood Institute (NHLBI), effective this coming summer; Dr. Susan Shurin continues to serve as NHLBI Acting Director and will return to her position as Deputy Director when Dr. Gibbons arrives; and Dr. Christine Grady has been named Chief of the Department of Bioethics at the NIH Clinical Center; previously, she served both as Deputy Director and Interim Chief of the Department. 

Office of National AIDS Policy Personnel Change
Ms. Wertheimer reported that Dr. Grant Colfax has been named to replace Mr. Jeff Crowley as Director, Office of National AIDS Policy (ONAP), at the White House.  Dr. Colfax is a long-time NIH grantee and was most recently Director of the HIV Prevention Section in the San Francisco Department of Health.  Ms. Wertheimer noted that OAR participated in Dr. Colfax’s first meeting with HIV leadership at HHS, held on April 9.

NIH AIDS Budget Update
Dr. Robert Eisinger, Director of Scientific and Program Operations, OAR, referred the OARAC members to the fiscal year (FY) 2013 Congressional Justification for AIDS research provided in their meeting folders.  He stated the FY 2013 Presidential Budget request for NIH is flat over the FY 2012 enacted level and the Trans-NIH budget for AIDS research would remain at the same relative percentage level as the total NIH Budget.  He commented that funding across the scientific areas was about the same as in FY 2011 and FY 2012.  He noted that the final FY 2013 appropriation for the NIH has not yet been received.  Dr. Eisinger stated the FY 2013 research priorities in the Congressional Justification included continued emphasis on basic research, vaccines and microbicides, behavioral and social science research, and research toward a cure for HIV/AIDS.

Dr. Eisinger stated NIH funding for AIDS vaccine research increased significantly in FY 2004 and FY 2006, but it has remained relatively flat in the years since.  He noted that this leveling of the budget reflected the mostly flat budget for AIDS research and for NIH as a whole across this same time period.  He said NIH will continue to place a high priority on AIDS vaccine research and the FY 2013 budget request shows an increase for this area of research even in a time of a flat budget.

Conflict of Interest Statement
Dr. Eisinger asked Council members to review and sign the Conflict of Interest statement provided to them.  He reminded the Council members of the importance of this process.

Aging and HIV  
Dr. Paolo Miotti, OAR Coordinator for Natural History and Epidemiology, presented a brief update on NIH activities related to aging and HIV/AIDS, a topic that the OARAC addressed at its previous meeting.  He reported the OAR has established a working group of non-government experts to provide advice and guidance on this research area.  The working group, that includes two OARAC members, Drs. Clifford and Deeks, will report on the state of the science and research in aging and HIV/AIDS in an upcoming issue of the Journal of AIDS.  The Working Group alsowill sponsor a satellite session at the International AIDS Society (IAS) conference in Washington, D.C., in July 2012.  Dr. Miotti noted that OAR is preparing several funding announcements on aging and HIV that will be issued in FY 2013.  He also stated OAR has established a Trans-NIH Coordinating Committee on HIV and Aging to foster collaborations and information sharing at the NIH. 

Research Toward a Cure  
Ms. Wertheimer reported that Dr. Whitescarver is the co-chair of the international advisory board of the IAS research toward a cure initiative.  She noted that Dr. Deeks and several NIH intramural and extramural scientists serve on the scientific working group that is developing the IAS global scientific strategy for research toward a cure.  This strategy will be released prior to the upcoming IAS conference.  There will be a symposium on this topic at the conference.  Ms. Wertheimer also commented that the FY 2013 Trans-NIH Plan for HIV-Related Research includes a new section that is devoted to research toward a cure.

International AIDS Conference 

Ms.Wertheimer stated NIH is the local scientific partner of the upcoming IAS conference.  She noted that Dr. Whitescarver serves on the overall Conference Coordinating Committee, and OAR is coordinating NIH’s activities in conjunction with the conference.  She noted that the conference is an opportunity to highlight the science of HIV/AIDS and NIH’s role in AIDS research.  Approximately 25,000 participants and 2,000 members of the press are expected to attend.  NIH will have an exhibit and a media booth at the conference.  She commented that NIH is sponsoring a number of special sessions at the conference including:  a satellite symposium on new frontiers in NIH AIDS research; a satellite session on aging and HIV; an OAR-sponsored workshop on ethical considerations on HIV genetics research in international settings; and a grantsmanship workshop.

UPDATE ON OARAC WORKING GROUPS FOR TREATMENT AND PREVENTION GUIDELINES

Dr. Alice K. Pau, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), and Executive Secretary, OARAC Antiretroviral Treatment Guidelines for Adults and Adolescents Working Group, provided an overview of the recent updates of the five treatment and prevention guidelines.  The Guidelines are posted on AIDSinfo.nih.gov.  She noted that all five working groups issued a recommendation in December 2011 that HIV-infected patients receiving antiretroviral therapy (ART) should not receive the 3-month, weekly isoniazid-rifapentine (INH-RPT) regimen for treatment of latent tuberculosis (TB) infection, unless it is given in the context of a clinical trial. 

Dr. Pau reported that the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents were revised in March 2012.  The key revisions include two new sections:  HIV and the older patient, and an antiretroviral (ARV) drug cost table.  Other key revisions pertain to when to start ART; HIV disease and women; and co-infection with 
Hepatitis C (HCV) or TB.  Additional revisions include updates to the drug interaction and characteristics tables and to sections on prevention of secondary HIV transmission, adherence, and adverse effects.

Dr. Pau noted that a revision of the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection is in process and will be issued in summer 2012.  Thereafter, as with the other guidelines, periodic “live” updates will be issued as individual sections are revised.  The revisions completed so far relate to HIV exposure and diagnosis; when to start treatment; adherence in adolescents; monitoring; resistance; and toxicity.  Those sections currently in the revision process pertain to what treatment to start with, management of treatment failure, and the drug and toxicity tables.

Dr. Pau reported that a revision of the Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States is in process and will be issued in summer 2012.  The revisions will address:  ARVs during pregnancy; preconception care; reproductive options for HIV sero-discordant couples; antepartum care management; and coinfections with hepatitis B virus (HBV), HCV, or HIV-2. 

Dr. Pau reported that a revision of the Guidelines for the Prevention and Treatment of Opportunistic Infections among HIV-Exposed and HIV-Infected Children will be issued in June 2012.  She noted that all of the 25 sections are being updated.  In addition to posting on AIDSinfo.nih.gov, the revised guideline will appear in a supplement to the Pediatric Infectious Disease Journal, and the executive summary will appear in the Journal of Pediatric Infectious Disease Society.

Dr. Pau stated that a revision of the Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents will be published in June 2012.  She noted that all of the sections have been updated and future revisions will be more focused and rapidly disseminated, as there will no longer be a printed version of the guidelines.

INTRODUCTION TO MEETING TOPIC 

Dr. Bonnie J. Mathieson, OAR Coordinator for Vaccines Research, introduced the meeting topic by noting that the purpose of the meeting is to address new scientific opportunities in research on AIDS vaccines to prevent HIV infection.  The presentations were selected to cover the broad range of the NIH AIDS vaccine portfolio from basic research through clinical trials for safety and efficacy. 

Dr. Mathieson suggested that it may now be possible to alter the course of HIV infection and disease by integrating prevention and treatment.  Recent studies have energized AIDS researchers with new opportunities in HIV vaccine research based on the availability of data on transmitted-founder HIV variants; new immunological assays for T cells and antibodies; genetic analyses of HIV from infected vaccinees; alternative animal models; new designs of vaccines ready for evaluation; and HIV vaccine candidates being advanced into safety and efficacy testing. 

Dr. Mathieson noted that the virus that is transmitted and/or first replicates in an HIV-infected person may be different from most of the variants found in persons infected for several years.  Researchers are now developing vaccine candidates from the DNA of transmitted-founder HIV.  Using new genetic tools and sequencing of HIV, researchers are learning that even the first vaccine candidates tested in efficacy trials may have had some protective effects.  She commented that researchers are pursuing low-dose challenge experiments in macaques and are developing new animal models to more closely resemble transmission of HIV in humans.

Evaluations of immune responses have expanded dramatically with the capability to measure more responses and, possibly, more relevant cellular immune responses to HIV.  Several of the new HIV vaccine candidates have been shown to induce stronger immune responses and provide protection in more stringent animal models.  Dr. Mathieson commented that scientists using cells from HIV-infected individuals and vaccinees have identified additional antibodies to HIV that can block infection of multiple HIV strains in vitro and in animal models.  New approaches are being developed to isolate antibodies and address other biological effects of these antibodies. 

Dr. Mathieson noted that exploration of these new scientific opportunities in HIV vaccine research is timely, as vaccine candidates capable of eliciting improved immune responses and/or providing protection in alternative animal models are being readied for clinical testing to establish their efficacy for prevention of HIV infection.

POST-RV144 CLINICAL TRIALS

Dr. Robert J. O’Connell, Assistant Chief, Division of Retrovirology, Walter Reed Army Institute of Research, U.S. Military HIV Research Program (USMHRP), presented the latest results from the RV144 vaccine clinical trial.  He also described the plans for bridging between the RV144 trial and the next efficacy study of a vaccine candidate.  The key findings from the RV144 clinical trial include:  a modest efficacy in a population with low incidence of infection; and a higher efficacy at earlier time points, which appears to wane thereafter.  He said that the higher earlier efficacy is comparable to that achieved in other HIV prevention trials and that it suggests that additional doses of the vaccine candidate at later time points may help maintain the protective immune response.  He noted an interest in pursuing implementation of a global vaccine candidate in targeted risk groups if it has an efficacy exceeding 50 percent.

Dr. O’Connell presented the U.S. Army’s threshold requirements for an HIV vaccine including:  licensure by the Food and Drug Administration (FDA); an efficacy of at least 80 percent within 30 days after final vaccination; a shelf life of at least 2 years; and a dosing schedule of four doses.  The USMHRP is pursuing two incremental vaccine strategies.  One is a regional vaccine strategy that builds on the RV144 trial and tests the efficacy of the ALVAC-AIDSVAX or similar vaccine candidates with an additional boost.  The second is a global vaccine strategy that explores diverse approaches and efficacy testing of multi-clade vaccine candidates, to achieve a globally effective vaccine.

Dr. O’Connell elaborated on the regional vaccine strategy by describing the next steps to bridge from the RV144 trial to RV349, the next efficacy study envisioned by the USMHRP.  He noted that three exploratory Phase II immunogenicity trials (RV305, RV328, and RV306) will be conducted in Thailand.  The aims of these studies are to further characterize vaccine immune responses with the ALVAC-AIDSVAX regimen and to assess whether the magnitude and durability of vaccine-induced responses can be improved by altering the schedule of vaccinations.  These studies involve different partners and participants and different vaccine components. 

Dr. O’Connell outlined the USMHRP plans for the RV349 trial that include the use of the ALVAC-HIV prime, as in RV144, and randomization of 3,500 men who have sex with men (MSM) in Thailand.  The target date for initiating this efficacy study is 2014.  This clinical trial will be conducted in partnership with NIH/NIAID.

NEW STUDIES ON MECHANISMS OF POSSIBLE PROTECTION MEDIATED BY RV144 ANTIBODIES

Dr. Barton F. Haynes, Professor of Medicine and Immunology, and Director, Duke Human Vaccine Institute, Duke University Medical Center, addressed the correlates of risk in HIV infection.  He described recent, additional analyses of data from the RV144 trial, and he summarized plans for the next efficacy trial that will address correlates of risk.  He emphasized that the future success of HIV vaccine clinical trials is dependent on defining and understanding the correlates of risk in study participants who are vaccinated to protect against HIV infection.  He defined an HIV correlate of risk as an immune response that predicts potential infection with HIV.  The response may be causally related to protection from infection, or it may only be a surrogate marker for another factor.  

Dr. Haynes addressed several unresolved issues about V1V2 antibodies against the HIV envelope for their role in protection from HIV-1 infection.  Ongoing research is evaluating whether induction of V1V2 antibodies in the RV144 study was causally related to the vaccine candidate used or was only a surrogate marker.  His colleagues have isolated several human monoclonal antibodies (MAbs) from individuals vaccinated for HIV in the RV144 study and are studying the structure, function, and binding capacity of those MAbs.  Two MAbs against the V2 region appear to only neutralize tier-one (easy to neutralize) viruses and not the tier-two viruses associated with HIV transmission.  These findings suggest that viral neutralization may not have been the protective mechanism in the RV144 study.

Dr. Haynes highlighted three critical questions for additional research:  1) Will V2 antibodies isolated from RV144 participants be protective in an animal model, such as rhesus macaques with R5 SHIV infection (and thereby indicate that antibodies are a negative correlate of risk)?  
2) Will the correlates of risk identified in the RV144 study be reconfirmed in studies of the next generation of pox virus/recombinant protein vaccine candidates tested in humans?  3) Can vaccine efficacy be improved beyond the modest level achieved in the RV144 trial?  He described new strategies in vaccine design to amplify antibody responses.  He noted that researchers have developed a new construct to study broadly neutralizing, difficult-to-induce, conformational antibodies such as those to V1V2.  They are designing immunogens that trigger naïve B cells to make the protective antibodies. 

The HIV Vaccine Trials Network (HVTN) 505 trial is the next efficacy trial in which HIV correlates of risk will be assessed.  Dr. Haynes reported that efforts are currently underway to validate a panel of V1V2 antigens by comparing reactions to different immunogens using case-control samples from the RV144 study.  The panel would be used to test hypotheses in HVTN 505 and other new vaccine efficacy trials.

BUILDING ON INSIGHTS FROM HIV VACCINE EFFICACY TRIALS

Dr. Margaret Julie McElrath, Professor of Medicine, Laboratory Medicine, and Global Health at the University of Washington and Senior Vice President, Fred Hutchinson Cancer Research Center, described some of the insights gained from HIV vaccine efficacy trials to design better vaccine candidates and conduct large-scale clinical trials.  She noted that research to define immune correlates of protection in general has led to major advances in understanding how to design and improve upon efficacious vaccines and that this is likely to be the case for HIV vaccines as well.  She encouraged HIV vaccine researchers to include evaluation of immune responses in planning large-scale HIV clinical trials such as HVTN 505.

Dr. McElrath commented on the immune responses already observed in four recent efficacy trials (VAX003, VAX004, STEP, and RV144) that used different vaccine regimens.  She noted that the antibody and T-cell responses identified differ across the trials and that the insights gained from each trial raise questions to pursue.  She emphasized that a better understanding of antibody and T-cell immune responses in general is needed to prevent, treat, and control HIV infection.  She highlighted the need for a broader range of standardized assays, to assess mucosal and innate immune responses as well as B-cell/antibody and T-cell responses.

With regard to HVTN vaccine-elicited binding antibodies, major questions relate to the durability and quality of immunoglobulin G (IgG) binding, the quality of (IgA) binding, and the mucosal response.  Dr. McElrath indicated that there is a need to map the specificities of IgG responses and to identify the best assays for measuring the quality of these responses.  In addition, continued research is needed on T-cell responses and, in particular, on envelope-specific CD4+ responses and the secretion of cytokines such as interleukin (IL)-10 and IL-13.   She noted that other cellular functions are important to evaluate including the epitope recognition for both CD4+ and CD8+ responses observed in several clinical trials.  In addition, a better understanding of cellular antiviral functions through systems biology and novel assays, targeted post-vaccination collection and study of plasmablasts and B cells for MAb production, as well as analysis of CD4+ follicular helper cells are desirable.  Dr. McElrath noted that a Mucosal Working Group of experts in human and nonhuman primate (NHP) mucosal immunology from several networks had been established to study the mucosal responses in HIV prevention and will meet in May 2012.

Dr. McElrath stated that laboratory capacity and expertise now is available to implement comprehensive analyses of vaccine-induced immunity and correlates of protection.  She commented that vaccine researchers need to continue to foster broad collaborations, improve current platforms, and remain open to new technologies that improve the ability to detect and measure potential correlates of protection from infection.

DISCUSSION

The OARAC members commented on several hypotheses emerging from post-analyses of RV144 data. They noted the waning of the vaccine-induced negative effect on risk of HIV acquisition over time and the possible need for and acceptability of periodic vaccine boosts. In contrast to other viral vaccines (e.g., hepatitis B), the HIV envelope proteins have not induced durable antibody responses and some combined prime–boost vaccine approaches yield a longer efficacy in nonhuman primates. They commented that many research groups are studying approaches (e.g., use of adjuvants) to extend the HIV vaccine-induced responses. Several OARAC members noted that the large amount of carbohydrate on the HIV envelope may be a complicating factor in developing an effective vaccine. Additional research is needed to address all of these scientific questions.

BASIC RESEARCH IN HIV VACCINE DESIGN AND DEVELOPMENT

Dr. James A. Bradac, Chief, Preclinical Research and Development Branch, Vaccine Research Program (VRP), Division of AIDS (DAIDS), NIAID, NIH, presented an overview of preclinical HIV vaccine research supported by NIAID.  He highlighted several new initiatives and summarized recent research on neutralizing antibodies. 

Dr. Bradac stated that NIAID’s HIV vaccine programs include basic research and preclinical testing of a broad array of potential AIDS vaccine candidates.  Following the results of the STEP trial in 2008, NIAID refocused its vaccine research portfolio on basic research with targeted initiatives to bolster research on HIV vaccine discovery.  By 2009, NIAID had launched three main initiatives which resulted in funding more than 50 new basic vaccine research grants.  In addition, NIAID launched the Consortium for AIDS Vaccine Research in NHPs and funded two awards last year, for a total of more than $12 million.  The aim of these consortia is to identify HIV vaccine candidates that have a protective effect and to determine the nature of this protection.  He stated that NIAID will announce several additional vaccine funding initiatives in 2012. 

Research on broadly neutralizing MAbs has taken an exciting turn in recent years with the discovery of multiple new targets on the HIV envelope.  Dr. Bradac noted that researchers have increased the number of these MAbs to more than 40 using several new approaches and improved technology.  Many of these MAbs detect previously identified targets, but show increased activity at very low concentrations.  He noted that the continuing challenge in AIDS vaccine research is to learn how to generate these antibodies with a vaccine.  Since these antibodies are generally characterized by high levels of somatic mutations, researchers can identify or infer unmutated ancestors in the germline and are trying to drive the B cell response along the desired pathway.  Dr. Bradac stated that the development of new methodologies for doing this promises exciting results in the future and parallel NHP research will be informative.

RECENT DEVELOPMENTS IN NONHUMAN PRIMATE MODELS FOR AIDS STUDIES

Dr. Jeffrey Lifson, Director, AIDS and Cancer Virus Program, National Cancer Institute, NIH, addressed the use of NHP models for AIDS vaccine studies.  He described promising areas of research with NHPs and noted that dramatic progress in concepts, reagents, and analytical methods allows for more sophisticated NHP studies.  He emphasized that NHP studies will continue to play a critical role in AIDS vaccine research and that multiple NHP models are available to address key scientific questions.

Dr. Lifson noted the advantages of using NHP models since they duplicate many of the characteristics of HIV infection in humans; allow for complete experimental control over the identity, dose, route, and timing of a virus challenge; and provide researchers the ability to collect tissue specimens and test various interventions.  He cited several recent discoveries about mucosal transmission and transmitted-founder viruses in humans that have revolutionized the way in which NHP models are applied.  He commented that it is now possible to apply titered, repeat mucosal challenges that are more likely to reproduce typical clinically relevant exposures to a single virus or a few viruses—thus making the NHP model more relevant.  Researchers using NHPs also have developed techniques for introducing mutations into cloned virus which resemble natural HIV variants and then mixing them into a synthetic swarm to be applied to mucosal tissues.  Dr. Lifson commented that researchers are able to use NHPs to survey the timing, number of variants, localization, and breadth of dissemination of the virus in the blood and other tissues and organs.   

Dr. Lifson noted researchers are attempting to develop HIV variant viruses that will replicate in animals and enable evaluation of AIDS vaccine candidates.  Researchers also are using NHPs to assess the efficacy of different vectors for delivery of therapeutic vaccines that induce both pre-exposure protection and persistent CD4+ and CD8+ responses to multiple challenges.  He commented that researchers have detected extremely low levels of SIV RNA and DNA in long-term, vaccine-protected NHPs - a finding that substantiates the potential for progressive clearance of HIV over time and that sets the stage for ultimately eradicating or curing HIV infection.  

UNDERSTANDING THE HIV-1 TRANSMISSION BOTTLENECK

Dr. Cynthia A. Derdeyn, Associate Professor, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, and Emory Vaccine Center at Yerkes National Primate Research Center, summarized research on the transmission of HIV-1.  She discussed the variability of this transmission and how risk factors influence HIV transmission. 

Dr. Derdeyn’s presentation focused on the transmission of HIV-1 across the genital mucosa, as the predominant mode of HIV-1 infection worldwide.  The frequency of becoming infected with unprotected exposure varies widely, with rates of transmission across different cohorts at 1 in 200–2,000 exposures in female genital mucosa and at 1 in 700–3,000 exposures in male genital mucosa.  The factors modifying transmission include stage of disease, use of hormonal contraceptives, circumcision, presence of genital ulcers or other sexually transmitted infections (STIs), having multiple partners, and socioeconomic status.  Many cases of HIV-1 infection can be attributed to a single HIV variant that is detected in plasma, but cases of multiple variants from a single partner also have been shown to cross the mucosal barrier.  She noted that transmission across the genital mucosa always imposes a severe reduction in viral diversity and that this reduction indicates the genital mucosa can be an effective barrier against HIV-1.  In addition, virtually all of the HIV-1 variants isolated early in infection utilize the CCR5 co-receptor, are dependent on relatively high levels of CD4+ cells and CCR5, and are difficult to neutralize with antibodies.  She suggested that the best time to intervene is early, when viral diversity is reduced. 

Dr. Derdeyn noted that transmitted-founder variants, which are detected very early in HIV-1 infection, may differ phenotypically from the virus circulating in a chronically infected individual.  Since the first description of these variants in 2004, much has been learned about the envelopes of transmitted virus.  She commented that these variants are not enriched in the HIV-infected individual’s genital tract; rather, the reduction in diversity of the virus occurs with transmission.  However, more than one phenotypic trait may be advantageous for transmission and early replication.  Transmission fitness may occur through multiple genetic pathways and/or the methods used to assess the differences may not be physiologically relevant or sufficiently sensitive.  She proposed that systematic comparisons of the viral envelopes from the HIV-infected individual and his/her partner would be needed to identify the differences.

In summary, Dr. Derdeyn listed three high-priority areas for basic research and clinical cohort studies including:  defining and/or enhancing the protective effects of the mucosal barrier; characterizing the immunologic (innate and adaptive) and virologic events that occur during the short time period of reduced viral diversity; and defining the features of transmitted viruses that are needed to establish a new infection.

DISCUSSION

OARAC members, speakers, and guests discussed the genetic diversity of transmitted HIV and the relevance of co-infections in HIV-infected individuals and their partners.  They stated that more research is needed on the association between co-infections (including STIs, malaria, tuberculosis, and parasitic worms), modifying factors (including hormonal contraceptive use), and single variant versus multiple variant HIV infection.  They also noted the need to better understand, at the population level, the association between increased progression of HIV infection and modifying factors (e.g., co-infections) and the need to characterize individuals who are infected with multiple HIV variants.  They noted the importance of being able to reduce the diversity of HIV during the early window of vulnerability, before multiple variants take hold.

OARAC members and speakers commented on the importance of carefully delineating the factors characterizing HIV-infected individuals and their partners.  They noted that a clear understanding of the genetic diversity of HIV and the role of modifying factors is essential for designing HIV vaccines and that different real-life situations can be modeled using NHPs. 

OARAC members and speakers noted that there is a need for collaboration in the development of preventive AIDS vaccines.  They commented that communications and sharing of information between preclinical (including NHP) basic researchers and clinical trial researchers have improved, and they encouraged increased interaction.  They also noted that there is a critical need to maintain and balance funding for basic and clinical vaccine research, as well as the need to revisit the research agenda on therapeutic vaccines for HIV/AIDS.

OARAC members commented on the implications of the HIV Prevention Trials Network (HPTN) 052 findings that ART can be used to prevent HIV infection in serodiscordant couples.  The findings from that study need to be taken into consideration in the design and conduct of future prevention clinical trials.  They noted the international interest in these findings and the ethical decisions that will have to be made regarding access to and provision of new standards of prevention and care.

GM–CSF ADJUVANTED DNA/MVA VACCINES

Dr. Harriet L. Robinson, Chief Scientific Officer and Senior Vice President for Research, GeoVax Laboratories, Inc., described her laboratory’s development of DNA and modified vaccinia Ankara (MVA) HIV vaccine candidates.  These candidates express most of the HIV proteins.  She also described a novel HIV DNA vaccine candidate that contains the DNA for the cytokine, granulocyte-macrophage–colony stimulating factor (GM-CSF).  This DNA vaccine in combination with a recombinant poxvirus (MVA) HIV vaccine appears to amplify the immune responses that correlated with protection against heterologous virus in an animal model.

Dr. Robinson noted that the co-expression of GM-CSF in the DNA prime enhanced the avidity of envelope-specific IgG, enhanced the titers of viral-specific rectal IgA, and increased the per-exposure protection induced by the combined DNA/MVA vaccine.  The correlate for prevention of infection was the avidity of elicited IgG for the envelope of the challenge virus.  In addition, the antibody responses did not decline dramatically over time and the antibody avidity rose slowly over time.  She noted the following unique features of this vaccine candidate including:   1) expression of non-infectious virus-like particles by both the DNA and MVA components; and 2) GM-CSF expression at the site of vaccination where the initial immune response to the DNA vectored protein is induced.  The multi-protein clade B vaccine with GM-CSF as an adjuvant is being tested in HVTN clinical trials.   

A NEW GENERATION OF SYNTHETIC DNA VACCINES FOR HIV

Dr. David B. Weiner, Professor, Department of Pathology and Laboratory Medicine, University of Pennsylvania, described the development of a next generation of DNA vaccine candidates that exhibit dramatically improved potency in NHPs.  The aim of this research on synthetic DNA vaccines is to improve both T-cell and antibody immune responses to prevent a viral challenge.  Some synthetic DNA vaccine constructs are now being tested in phase I clinical trials for HIV prevention and immune therapy.  

Dr. Weiner noted that the DNA SIV vaccine candidate improved T-cell breadth, proliferation, and memory responses, compared with an Ad5 SIV vaccine candidate in macaques.  A subsequent study of several gene adjuvants led to the selection of about a dozen that were potent in stimulating cytotoxic T lymphocytes (CTL), CD4+ T-cells, and/or antibody responses.  This research led to the incorporation of a synthetic DNA vaccine approach in the PENNVAX™-B clinical trial supported by the HVTN, that tested combined vaccine constructs (pGag, pPol, and pEnv) delivered by electroporation (EP)/electrostimulation with and without an IL-12 adjuvant.  The CD4+ and CD8+ T-cell responses and the timing of the responses compared favorably with those achieved in other AIDS vaccine studies.  Dr. Weiner noted that similar positive responses were achieved in a collaborative study of HPV-001 using an enhanced DNA vaccine approach.

Research on an HIV DNA vaccine candidate continues to evolve as more information is gained on possible immunogens and delivery methods.  Although previous DNA platforms have been poor inducers of any immune response in the absence of a viral vector or protein boost, researchers continue to modify other constructs to improve the ability of DNA to generate antibody responses.  Dr. Weiner stated that studies are under way in rabbits and NHPs to use DNA technology to improve induction of mucosal immunity.  Additional studies in macaques and rabbits show that a synthetic, consensus-envelope DNA vaccine candidate, without a protein boost, can induce production of HIV neutralizing antibodies. 

Dr. Weiner described several studies using genetic adjuvants in macaques, to modulate co-stimulation pathways by using a DNA vaccine candidate and two MAbs that target two pathways involved in stimulation of prime T-cell responses.  This adjuvant approach resulted in clear immune responses and, on viral challenge, a decrease in peak viral loads and an almost complete control of viral replication in more than half of the animals.  He also provided an overview on the use of mucosal adjuvants to redirect and expand antibody responses.  The aim is not only to enhance mucosal cellular immune responses, but also to enhance protective B-cell/antibody responses at mucosal sites of infection.  He noted that co-immunization with two mucosal chemokines enhanced serum and vaginal IgA and IgG.  Intravaginal repeat challenge with SIV showed complete protection in some animals or appeared to prevent persistent SIV infection.

Dr. Weiner noted that the use of DNA vaccine candidates allows for improved flexibility in directing and enhancing immune responses.  Researchers are eliciting enhanced antibody and 
T-cell immune responses to SIV challenge in NHPs by utilizing plasmid T-cell adjuvants, antigen design and formulation, plasmid mucosal chemokine adjuvants, new EP approaches and concentrated formulations delivered to the skin, and combinations of these approaches to advance the utility of the DNA vaccine platform.    

NOVEL VECTOR AND ANTIGEN STRATEGIES FOR AN HIV VACCINE

Dr. Dan H. Barouch, Professor of Medicine, and Chief, Division of Vaccine Research, Harvard–Beth Israel Deaconess Medical Center, described research on novel vectors and antigen strategies.  He highlighted the need to explore diverse concepts in the development of improved vaccine regimens.  He suggested two key features for a next-generation HIV-1 vaccine:  vectors that avoid high levels of vector-specific neutralizing antibodies and can be combined into a heterologous prime–boost regimen; and antigens that elicit both humoral and cellular immunity and that optimize immunological coverage of global virus diversity. 

Dr. Barouch noted that substantial research has been conducted with the Ad5 vector, but his laboratory is focusing on alternative rare adenovirus serotypes (Ad26 and Ad35) that differ from Ad5 in seroepidemiology and biology.  He reported the results of two studies using these vectors in rhesus monkeys that afforded partial protection against SIV acquisition and virologic control.  The findings showed that envelope added to Gag-Pol is remarkably effective and appears to be critical to the protection against SIV acquisition.  Dr. Barouch noted that additional analysis indicates that different immune correlates may block acquisition of infection.  Clinical studies are planned using Ad26/MVA regimens expressing HIV-1 mosaic antigens to evaluate this further.  These mosaic antigens are optimized using an in silico bioinformatics approach to align and select sequences to create a polyvalent mosaic cocktail.  These mosaic antigens can augment the breadth of immune responses in NHPs.

Dr. Barouch described a two-part clinical development strategy to pursue the findings from animal research.  This strategy includes:  development of prototype novel Ad vectors expressing a single antigen to test for safety and immunogenicity; and development of complete vaccine candidates involving prime–boost regimens expressing mosaic Gag/Pol/Env antigens.  He summarized the results of a Phase I clinical trial testing the safety and immunogenicity of the Ad26 vector expressing HIV clade A envelope.  The results showed humoral and cellular responses were elicited.  He noted that plans are under way to continue with Phase IIa and IIb efficacy trials beginning late in 2014 or early in 2015. 

Dr. Barouch proposed rapid clinical development of an Ad26/MVA vector approach expressing HIV-1 mosaic antigens, with or without a stable envelope trimer boost.  Clinical testing of this combination is underway based on the results in NHPs that showed priming and boosting with these vectors resulted in expanded antibody responses in breadth, magnitude, neutralization, functionality, and epitopic diversity. 

PASSIVE IMMUNIZATION FOR HIV PREVENTION

Dr. Barney Graham, Chief, Viral Pathogenesis Laboratory and Clinical Trials Core Laboratory, Dale and Betty Bumpers Vaccine Research Center (VRC), NIAID, NIH, discussed the use of MAbs to prevent HIV infection through passive immunization.  He noted that MAbs can be used for passive immunization and as a tool for defining improved active vaccination approaches.  More than 250 monoclonal antibodies are in clinical development worldwide.  Of these, 29 have been licensed by the FDA.  Dr. Graham noted that few of these have been humanized, but with the use of new technologies, most new antibodies in clinical practice are antibodies derived from human B-cells. 

Dr. Graham reported on research at the VRC to develop two types of antibodies— to the CD4-binding site of gp120 (VRC01) and to the membrane proximal external region (MPER) of gp41.   He noted that through a confluence of expertise in B-cell isolation and antibody gene rescue technologies, structural biology, and clinical research, VRC researchers developed the MAb VRC01.  He described the process and noted that the antibody was shown to be broadly neutralizing and protective against SHIV challenge in NHPs.  In subsequent clinical research involving HIV-infected individuals who were slow progressors, the VRC researchers identified more VRC01-like antibody sequences, rescued the genes for these antibodies, and demonstrated overlapping patterns of neutralizing activity. 

Dr. Graham noted that the combination of functional antibody research, deep sequencing technology, and structural biology—used in the development of VRC01—has opened up new ways of thinking on how to proceed in HIV vaccine research.  The researchers have shown that by taking advantage of VRC01’s unusual properties (e.g., high number of somatic mutations, high affinity to gp160 and gp120), they can reconstruct and identify antibody sequences leading back to the unmutated germline.  With this information, it becomes possible to devise gp120s that could bind germline antibody sequences.

In addition to the VRC01’s specificity for the gp120 CD4-binding site, broadly neutralizing potency, and prevention of SHIV infection in NHPs, the antibody shows no evidence of reactivity to normal human tissue (observed with some other MAbs).   Dr. Graham noted that this MAb is currently being manufactured for clinical evaluation with plans to launch Phase I clinical trials in early 2013 in both HIV-infected and uninfected adults, to establish the pharmacokinetics and safety of the vaccine candidate.  The study would be extended subsequently to infants born to HIV-infected treatment-naïve, late presenting mothers in the U.S. and later in an international Phase IIb trial for infants born to HIV-infected mothers who are breast-feeding.

Dr. Graham noted that ongoing research continues to:  optimize the engineering of antibodies; develop the novel MAb discovered to the MPER site; and improve the manufacturing capacity for antibodies.  VRC researchers also are working on the delivery of VRC01-like antibodies by gene transfer.  Parallel efforts are ongoing to use the information gained from passive immunization studies to improve the design of vaccine antigens, vaccine formulation, and dosing regimens.

HIV VACCINE CANDIDATES IN CLINICAL TRIALS

Dr. Alan Fix, Acting Associate Director, VRP, DAIDS, NIAID, NIH, presented an overview of the vaccine candidates and concepts that are currently supported or in the pipeline for NIH-sponsored AIDS vaccine clinical trials.  He noted that the different vaccine candidates and concepts currently supported by NIH utilize a variety of vectors (e.g., DNA, adenoviruses and pox viruses), as well as protein boosts and various adjuvants.  Several Phase I research trials are ongoing that use the Ad5 vector developed at the VRC.  These studies address key scientific questions related to antigen competition, polytopic administration, heterologous inserts or vectors, host factors, and mucosal or innate immunity. 

Dr. Fix described several additional Phase I trials that are evaluating DNA priming schedules or protein boosts.  Two Phase II trials are currently ongoing including HVTN 205, a Phase IIa trial of a DNA/MVA vaccine, and HVTN 505, a Phase IIb trial of a DNA/rAd5 vaccine developed by the VRC.

Dr. Fix stated that NIH plans to initiate several Phase I studies next year of additional vaccine candidates and reagents including studies with:  a poly IC/LC adjuvant; the Ad26/Ad35 mosaic antigen; two DNA vaccine candidates; use of AAV-1 to deliver broadly neutralizing antibodies; and a passive immunoprophylaxis approach.  In the next few years, NIH plans to sponsor clinical research on a replication-competent Ad4 mosaic antigen for mucosal delivery, a multigene polyvalent DNA-plus-protein boost candidate, chimp adenovirus vectors C6/C7, and chimeric alphaviral vectors. 

Dr. Fix described the large array of NIAID-supported collaborative protocols (both clinical trials and observational studies) that are currently active or anticipated.  Several vaccine candidates developed by various companies and research units, including the VRC, are being evaluated in these protocols in the U.S. and/or internationally.    

Dr. Fix noted that the HVTN 505 protocol was amended to serve as a Phase IIb, randomized, placebo-controlled, test-of-concept clinical trial.  The HVTN 505 trial will evaluate the safety and efficacy of a multiclade HIV-1 DNA plasmid vaccine, followed by a multiclade HIV-1 recombinant adenoviral vector vaccine, in HIV-uninfected, Ad5-negative, circumcised men and male-to-female transgender persons who have sex with men.  He stated the trial elevates HIV acquisition to a primary endpoint, expands enrollment to 2,200 participants, revises the length of the study, increases the time per participant on study, and adds exploratory objectives regarding ARV use for HIV prophylaxis. 

ADVANCING HIV VACCINES TO EFFICACY TESTING IN THE HVTN AND LINKING TO OTHER PREVENTION RESEARCH

Dr. James Kublin, Executive Director, HVTN, Fred Hutchinson Cancer Research Center, described the HVTN’s plan to evaluate a pox virus prime and protein boost vaccine concept in South Africa and to link this effort with other clinical studies for combination prevention approaches against HIV infection.  He reported that the pox-protein public-private partnership (P5) has been established to substantiate and extend the results of the RV144 vaccine efficacy trial through a Phase III randomized, placebo-controlled clinical trial.  In this effort, investigators will address whether the level, quality, and duration of vaccine protection can be enhanced by using protein boosts with an alternative adjuvant.  Dr. Kublin noted that the aim is to pursue this strategy as quickly as possible because of its potential for achieving an effective public health intervention against HIV infection.

Dr. Kublin described the organizational structure, protocol, licensing design, operational characteristics, and monitoring plan proposed for this study.  The vaccine candidate, a Sanofi ALVAC recombinant canarypox prime containing clade C HIV genes, boosted with two Novartis clade C envelope proteins with the MF 59 adjuvant, will be evaluated in South Africa among HIV-1-seronegative adults at high risk for HIV infection.  Efficacy will be established as a 50 percent or greater reduction in HIV infection rate at 24 months after first immunization of the vaccine.  Dr. Kublin noted that investigators are pursuing the earliest possible launch date, which could be in 2014 – 2015, but this depends on regional approval of the study as a fast-track initiative. 

Dr. Kublin reported that a collaborative Phase I study is under way in South Africa as part of the preparation for the Phase III clinical trial.  This study is using the same vaccine candidate as used in the RV306 study in Thailand and will yield informative data on HIV correlates and surrogates of immune protection.  He outlined the primary immunogenicity measurements required for a “go/no-go” decision on whether to proceed with the Phase III trial.  He described several vaccine candidates that are currently available or will be available in the next few years that could be tested in HVTN efficacy studies.

Dr. Kublin highlighted some of the challenges in conducting a vaccine efficacy trial.  These include accommodating a potential lag in the availability of potential vaccine candidates, calculating the incidence of HIV-1, and incorporating new findings from other studies into ongoing trials.  Other operational challenges include evaluating the need for, and supporting, expansion of clinical trial sites and collecting biological samples with which to evaluate correlates of protection.  He discussed applying previous field experiences to addressing these challenges in the planned Phase III trial. 

Dr. Kublin noted the other HIV prevention studies that are ongoing in sub-Saharan Africa and the potential for linkages to these sites.  He said that cross-network collaboration is a priority for the HVTN and that the opportunity to control the HIV epidemic is immediate, the resources are limited, and formal studies of combination prevention approaches are needed.  Dr. Kublin further noted that the leadership of the HVTN and the Microbicides Trials Network (MTN) are addressing the potential for collaboration on combination efficacy trials, community- and population-based studies, clinical prevention studies, and training of new investigators.

Dr. Kublin emphasized that AIDS vaccines are urgently needed in the “toolbox” of HIV prevention.  He summarized some of the lessons learned from HVTN clinical trials:  (i) AIDS vaccine candidates can only be thoroughly evaluated through large clinical endpoint studies;

(ii) establishing correlates of protection requires a large and concerted effort early in a trial to establish efficacy; (iii) assays should be selected in advance for “best-performing” immune variables covering unique immunological classes; (iv) study designs should attempt to identify futility and efficacy at the earliest point without compromising the study; and (v) community engagement is critical. 

DISCUSSION

The OARAC members and speakers emphasized that development of a successful AIDS vaccine is essential to stop the global AIDS epidemic.  They recommended continuing the investment in AIDS vaccine research, noting that NIH science and funding “drive” the direction of this research globally.

The OARAC members and speakers noted that AIDS vaccine research is highly complex and comprises both basic and clinical research across scientific disciplines.  They noted that a set of guiding principles is needed to encourage research in the most promising and cost-effective directions for the development of the next generation of vaccine candidates post-RV144.  While the scientific opportunities are very broad, they commented the resources are limited so the support of costly, large-scale clinical trials must be selective and targeted for the best vaccine candidate(s).  They also noted that preclinical studies of vaccine candidates using NHPs should be conducted in a cost-effective manner.   

The OARAC members and speakers noted the enormous enthusiasm and excitement in the field, owing to recent studies and new technologies.  They viewed vaccine research as an important component of emerging combination prevention approaches that include circumcision, treatment as prevention, and prophylactic pre-exposure ART.  They encouraged vaccine researchers to continue to collaborate and share information with other AIDS researchers and to engage behavioral and social scientists in their efforts.  These scientists offer expertise in addressing issues pertinent to participation in clinical trials, such as recruitment and retention of diverse populations, socioeconomic conditions, access to health care and quality of care, stigma, and discrimination. 

The OARAC members and speakers encouraged research that would improve the understanding of HIV subtypes and the importance of mucosal immunity in the early stages of HIV infection.  They noted that different clades may have differences in transmission mechanisms and efficiencies of transmission.  They noted that there is a critical need for additional basic science to explore other vaccine concepts, including a therapeutic vaccine and use of a cytomegalovirus vector.  They commented that any new post-RV144 vaccine candidates must achieve correlates of protection that include reducing the viral load.  OARAC members suggested that the determination of efficacy in a clinical trial could be lower than the standard of 80 to 90 percent that may be achieved with the use of combination prevention approaches. 

The OARAC members and speakers noted that prevention and cure are the ultimate goals of NIH AIDS research.  They anticipated that once a vaccine candidate is validated as successful, industry will vigorously join in and contribute to the research effort.  They acknowledged that significant advances have been made in AIDS vaccine research in the past several years and that there are many opportunities for confronting the AIDS pandemic from a broader perspective.

PUBLIC COMMENTS

William (Bill) Snow, Director of the Global HIV Vaccine Enterprise Secretariat, emphasized the advances in AIDS vaccine research over the past several years and the importance of addressing AIDS vaccines in the context of the global epidemic. 

CLOSING COMMENTS

Dr. Hillier thanked the OAR staff for organizing the meeting and presenting the Director’s Report. She thanked the members, speakers, and guests for their broad consideration of AIDS vaccine research.

ADJORN

The meeting was adjourned at 4:30 p.m. on April 10, 2012.

/Jack Whitescarver, Ph.D./

Jack Whitescarver, Ph.D., Executive Secretary

/ Sharon L. Hillier, Ph.D./

Sharon L. Hillier, Ph.D., Chair