Meeting Minutes - November 12, 2015

Office of AIDS Research Advisory Council
Forty-First Meeting
November 12, 2015

National Institutes of Health
U.S. Department of Health and Human Services
5601 Fishers Lane Conference Center
Rockville, MD

Members Present: Dr. Roy M. Gulick (Interim Chair), Dr. Robert W. Eisinger (Executive Secretary), Mr. Moisés Agosto-Rosario, Dr. Myron S. Cohen, Dr. Monica Gandhi, Dr. Priscilla Hsue, Dr. Daniel R. Kuritzkes, Dr. Ronald T. Mitsuyasu, Mr. Mitchell J. Warren, Dr. Darrell P. Wheeler, Dr. Craig M. Wilson
Ex Officio Members Present: Dr. Carl W. Dieffenbach, Division of AIDS, National Institute of Allergy and Infectious Diseases
Ad Hoc Members Present: Dr. David Celentano, Dr. Elizabeth Connick, Ms. Dázon Dixon Diallo, Dr. Scott D. Rhodes, Dr. Charles Wira
Invited Speakers and Guests: Dr. Susan P. Buchbinder, Dr. Lawrence Corey, Dr. Barton Haynes, Dr. Rohan Hazra, Dr. Peter D. Kwong, Dr. John R. Mascola, Dr. Sallie R. Permar, Dr. William R. Schief

WELCOME AND MEETING OVERVIEW

The National Institutes of Health (NIH) Office of AIDS Research Advisory Council (OARAC) convened its 41st meeting on November 12, 2015, at the Fishers Lane Conference Center in Rockville, MD. Roy M. Gulick, M.D., OARAC Interim Chair and Professor, Department of Medicine, Weill Medical College of Cornell University, welcomed OARAC members, invited speakers, and guests. Dr. Gulick introduced the agenda and stated the overall goal of the meeting addressed the next steps in the field of HIV vaccine research.

APPROVAL OF MINUTES

The minutes of the April 16, 2015 OARAC meeting were approved as written.

CONFLICT OF INTEREST STATEMENTS

Robert W. Eisinger, Ph.D., Executive Secretary, OARAC, and Acting Director, Office of AIDS Research (OAR), asked members to sign and turn in their conflict of interest forms, and stated it is NIH policy to complete a financial disclosure form prior to each meeting.

ACTING DIRECTOR’S REPORT

Dr. Eisinger welcomed everyone to the 41st OARAC meeting and noted the following personnel changes:

Michael S. Lauer, M.D., has been named NIH Deputy Director of Extramural Research and Director of the Office of Extramural Research (OER).
Walter J. Koroshetz, M.D., is the new Director of the National Institute of Neurological Disorders and Stroke, and co-chair of the NIH Brain initiative.
William T. Riley, Ph.D., is the new Director of the Office of Behavioral and Social Science Research (OBSSR) as of July 30; he was previously Acting Director of that office.
Eliseo J. Pérez-Stable, M.D., is the new Director of the National Institute on Minority Health and Health Disparities.
Alan E. Guttmacher, M.D., has retired as Director for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) effective September 2015; Catherine Y. Spong, M.D., is the new Acting Director of NICHD.
Tom Insel, M.D., stepped down as Director of the National Institute of Mental Health (NIMH); Bruce Cuthbert, Ph.D., now serves as Acting Director of NIMH.
Dr. Eisinger is serving as Acting NIH Associate Director for AIDS Research and Acting Director of the Office of AIDS Research (OAR) as of July 1, 2015. There is a national and international search occurring for a permanent OAR Director.

Dr. Eisinger noted that William E. Paul, M.D., Chief of the Laboratory of Immunology at the National Institute of Allergy and Infectious Diseases (NIAID), and former Director of OAR from 1994-1997, passed away. He will be greatly missed for the vision and humility he brought to the office. Dr. Paul first conceived of the NIH Vaccine Research Center.

Dr. Eisinger welcomed Dr. Gulick as the new Interim Chair of OARAC. Dr. Eisinger stated there is no federal appropriation yet for FY 2016. The NIH is operating under a continuing resolution (CR) at the FY 2015 level of funding. The current CR will end in December.

UPDATE ON OARAC WORKING GROUPS FOR TREATMENT AND PREVENTION GUIDELINES

Dr. Gulick updated the OARAC on the treatment and prevention guidelines. He highlighted the increasing access of the guidelines by health care providers through the website. In the past 12 months, the Adult and Adolescent Antiretroviral (ARV) guidelines received more than half a million-page views. He also presented a mock-up of the mobile app for the guidelines that has been developed over the past year and is expected to be useful, interactive, and up-to-date.

Report on Adult and Adolescents ART Guidelines

Dr. Gulick highlighted a special release to the guidelines on July 28, 2015, addressing when to start antiretroviral therapy (ART). This change resulted in strengthening the recommendation from AII (for CD4 350-500) and BIII (for CD4 >500) to A1 for all patients. The panel’s overall recommendation remains the same -- ART is recommended for all HIV-infected individuals regardless of CD4 counts. Details about the rationale for this most recent change and global response include:

The revision is based on publications in the New England Journal of Medicine of the START study (Strategic Training of Antiretroviral Treatment) and the Temprano study. Both showed a 50 percent reduction in morbidity and mortality among HIV-infected patients with CD4>500 who started ART early.
All major guidelines including the Australian Guidelines, the British HIV Association, and the WHO are now in alignment.

Dr. Gulick announced that the panel would release a 1-page recommendation in the coming weeks based on STRIBILD, a new co-formulation of 4 ARVs that was FDA approved on November 5, 2015. Details about the new co-formulation include:

The co-formulation is a four-drug, one pill regimen including Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir alafenamide (TAF).
This combination with TAF produces a lower plasma concentration of TFV when compared to tenofovir disoproxil fumerate (TDF). Clinical trials have shown this leads to potentially less renal and bone toxicities than TDF.
This represents a step forward in preserving a potent agent with lower toxicity.
This is a fixed dose combination tablet approved for ART-naïve patients and patients who are virologically suppressed, with no evidence of resistance to the components.

The recommendations for adolescents using sexual maturity rating (SMR) are that stages I-III (pre-puberty) follow pediatric guidelines and SMR stages IV-V (post-puberty) should use adult/adolescents guidelines.
Dr. Gulick informed the panel of the Health Resources and Services Administration (HRSA) survey that is asking for feedback from HIV clinicians regarding the treatment guidelines. The next update of the guidelines is tentatively scheduled for early 2016.

Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents

Dr. Gulick reported that these guidelines are now available in electronic format so they can be easily updated. New developments in these guidelines include:

Rapidly changing clinical management of Hepatitis C virus (HCV), including linking to the Infectious Diseases Society of America (IDSA) and the American Association for the Study of Liver Diseases (AASLD) on the website.
Changes in clinical management of syphilis, candida, toxoplasmosis, cytomegalovirus (CMV), human papillomavirus (HPV), and Cryptococcosis.
Updates on drug availability and minor changes in specific drug and diagnostic test recommendations.

Update on Pediatric Opportunistic Infections (OI), Pediatric Antiretroviral Therapy (ART), and Perinatal Guidelines

Rohan Hazra, M.D., Chief of the Maternal and Pediatric Infectious Diseases Branch of the Eunice Kennedy ShriverNational Institute of Child Health and Human Development, NIH, reported on the guidelines for the Prevention and Treatment of OIs in HIV-exposed and HIV-infected children.

OIs:

These guidelines were published in November 2013.
Mark Abzug, M.D. and Sharon Nachman, M.D. are the external co-chairs.
The plan is to review all sections over 2 years with posting of updates with revision for all sections by December 2016.

Pediatric ART Guidelines Update

Dr. Hazra stated that the guidelines were last updated in March 2015. He noted that:

Several dosing recommendations had been updated. An update to these guidelines is expected in 2016.
The leadership structure changed and that Peter Havens, M.D., is the Chair and there will be three vice chairs.

Perinatal Guidelines Update

Dr. Hazra stated that the latest perinatal guidelines were published in August 2015. The updates include changes in doses for the use of ARVs during pregnancy, including initiating ART as soon as HIV is diagnosed during pregnancy. The doses also include the preferred protease inhibitor of darunavir (boosted with ritonavir). Efavirenz is the preferred non-nucleoside reverse transcriptase inhibitor and raltegravir is the preferred integrase inhibitor. A new round of revisions is anticipated in mid-2016. Major updates will be posted sooner.

UPDATE ON NEW OAR PROCESSES

Dr. Eisinger presented an overview on the new NIH HIV/AIDS research priorities and new OAR processes. He highlighted that recent advances in HIV/AIDS research are leading to unprecedented scientific opportunities. NIH represents the largest public investment for AIDS worldwide. OAR’s responsibility is to ensure that AIDS funding is going toward the highest priority research areas. To that end, the following activities have recently occurred:

Lawrence Tabak, Ph.D., NIH Principal Deputy Director, established and chairs a small working group of NIH Institutes, Centers, and Offices (ICOs) Extramural and Intramural leadership to address the scientific and programmatic role of OAR.
A vigorous national and international search was launched on July 31, 2015, for a new OAR Director. The search committee is co-chaired by Josephine P. Briggs, M.D., Director, National Center for Complementary and Integrative Health (NCCIH), and Griffin P. Rodgers, M.D., Director, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

On August 12, 2015, the NIH Director, Francis S. Collins, M.D., Ph.D., issued a statement to focus research to end the AIDS pandemic. The statement identified four overarching AIDS research priorities for the next 3 to 5 years:

Reducing HIV incidence, including with vaccines;
Next generation of HIV therapies with better safety and ease of use;
Research toward a cure; and
Prevention and treatment of HIV-associated comorbidities and co-infections.

He also identified three crosscutting areas: basic research, health disparities, and training.

Priority Research Areas for Use of AIDS Funds

NIH guidelines were developed for the use of AIDS funds based on:

OAR Advisory Council HIV/AIDS Research Portfolio Review Working Group Report (issued May 2014).
FY 2015 Trans-NIH Plan for HIV-Related Research – reflecting input from the scientific and academic community, scientific foundations, and community constituency groups.
NIH leadership.

A Notice was released in the NIH Guide for Grants and Contracts on August 12, 2015, to inform the scientific community that these guidelines will be applied to determine priority for receiving AIDS funding beginning in FY 2016. Dr. Eisinger also noted that these guidelines will not be used to assess the scientific merit of grants, contracts, or intramural projects, but will be used to determine the use of AIDS funding. The guidelines also included a schematic for standardizing pro-rating level of support for projects containing both AIDS and non-AIDS components.
Dr. Eisinger listed the following High-Priority Research Areas for Use of AIDS Funds:

Development/testing of AIDS vaccine, microbicide, pre-exposure prophylaxis (PrEP) candidates, and strategies to improve HIV testing and entry into treatment.
Development/testing of HIV treatments that are long acting, less toxic, and have fewer side effects and complications.
Novel strategies for research toward a cure.
Prevention and treatment of HIV-associated comorbidities, co-infections, and related complications.
Basic research on HIV transmission, pathogenesis, and immune dysfunction.
Research to reduce health disparities in HIV incidence and treatment.
Training to conduct high-priority research.

Dr. Eisinger described Medium-Priority research areas for use of AIDS funds to include projects where HIV/AIDS is a meaningful component of the project and/or knowledge about HIV is enhanced by the project. Several examples of these were described:

The project includes people, or biological specimens from people, who are living with HIV, are HIV exposed, and/or are at elevated risk for HIV infection as part of a broader sample or as a comparative cohort.
The project addresses health and social issues clearly linked with HIV transmission or acquisition, pathogenesis, morbidity and mortality, and stigma, and examines them in the context of HIV such as other infectious pathogens and diseases, non-infectious pathogens and diseases, substance use and/or addiction, and mental health disorders.
The project meaningfully includes HIV/AIDS, or SIV, outcomes or endpoints.
The project results will advance HIV treatment or prevention and/or provide tools and techniques and/or capacity beneficial to HIV research, including training and infrastructure development.

Dr. Eisinger listed the following Low-Priority research areas as projects that will not be supported with AIDS dollars including:

Natural history and epidemiology that is entirely focused on co-morbidity and does not have any focus on or inclusion of HIV (e.g., malaria, TB, and drug abuse).
Basic virology on pathogens that are co-infecting but not in the context of HIV infection, and basic immunology studies of general relevance but not specific to HIV.
Examples of these include:

- Basic virology and neurobiology research of co-infecting pathogens not in the context of HIV infection (e.g., Herpesviruses, HPV, TB, Malaria, hepatitis C and B, syphilis, Cryptococcus, flaviviruses, JC virus, etc.).
- Basic cancer-related immunology studies not in the context of HIV infection.
- Studies of co-morbidities of general relevance, but not in the context of HIV (e.g., diabetes, lipid defects, endocrinology).
Data analysis and systems tools that are not HIV-related (e.g., genomics studies of little or no relevance to HIV).
Studies of behaviors (e.g., sexual activities and drug use activities) or social conditions (e.g., economic distress) that have multiple negative outcomes where HIV/AIDS is only one of many outcomes being studied without a focus on how HIV/AIDS is unique in that context (i.e., it is just mentioned as potentially relevant).

Dr. Eisinger noted there are special areas for priority considerations including NIH-wide programs involving a component of HIV/AIDS research, such as: Clinical and Translational Science Awards (CTSAs), National Primate Research Centers (NPRCs), and Cancer Centers. He also stated that OAR will develop a pro-rating schematic for projects with AIDS and non-AIDS components that will be based on the percentage of the scientific focus on AIDS in the project.

Portfolio Review

Dr. Eisinger reported that OAR and a small panel of IC scientific staff are conducting an AIDS portfolio review of all grants, contracts, and intramural projects funded with AIDS dollars in FY 2014 and scheduled to re-compete in FY 2016. The outcome of this portfolio review is to determine the extent to which the current AIDS program is aligned with the new overarching HIV/AIDS research priorities. This review will identify projects that are “low-priority” research projects that will not be supported with AIDS dollars when they re-compete in FY 2016 or considered for funding after the ICs’ Board of Scientific Counselors (BSC) review of intramural projects. Results of the portfolio review will be presented at the NIH Advisory Committee to the Director (ACD) meeting on December 10-11, 2015.

New OAR Processes in FY 2016

Dr. Eisinger outlined the following new OAR processes for FY 2016:

Revision of Center for Scientific Review (CSR) referral guidelines and restructuring of the AIDS Integrated Review Group (IRG) study sections
Review of Funding Opportunity Announcements (FOAs) – OAR is reviewing draft FOAs and Requests for Proposals (RFPs) to ensure that these are aligned with high priority HIV/AIDS research.
Following the FY 2016 Appropriation, OAR, in consultation with the NIH Director, may utilize its 3 percent transfer authority to transfer AIDS funds between ICOs.
OAR will require that all new and competing renewal projects (e.g., grants, contracts, and intramural projects) are aligned with the highest overarching HIV/AIDS research priorities.
All new and competing renewal projects will be pro-rated on the basis of the proportion of their AIDS focus.
The OAR Discretionary Fund will have set receipt dates and templates developed for ICO requests to support administrative supplements, R13 conference grant applications, intramural projects, and the first year of new grants.

FY 2016 3rd and 4th Quarter Review/Analysis and FY 2017 Trans-NIH AIDS Budget

For the 3rd and 4th Quarter Review and Analysis, Dr. Eisinger informed the OARAC of the following:

Goal: ensure all projects are aligned with the highest priorities and appropriately coded by Strategic Plan code and SIC code.
Process: OAR scientific staff members will review coding for all new projects reported into ARIS to ensure appropriate coding. OAR staff members will work with ICOs to resolve any issues regarding priorities and coding.

Dr. Eisinger updated the OARAC on the FY 2017 Trans-NIH AIDS Budget as follows:

OAR provided guidance for the development of the IC AIDS Budget Submissions.
Each new, recompleting, and expanded initiative must be aligned to one or more of the overarching HIV/AIDS research priorities.
OAR will develop the NIH AIDS Budget in consultation with the NIH Director.
OAR will provide each ICO with a list of the initiatives that will be supported with the AIDS funding level.

In conclusion, Dr. Eisinger reiterated that the purpose of these processes is to ensure resources are targeted to ensure the development of a safe and effective vaccine, strategies for a cure, and, ultimately, an end to the AIDS pandemic and an AIDS-free generation.

INTRODUCTION TO OARAC TOPIC

Bonnie J. Mathieson, Ph.D., Chair, HIV/AIDS Vaccine Coordinating Committee, and Coordinator of Vaccine Research, OAR, reported on recent progress in this field, identified key NIH partners, and provided an overview of the day’s presentations that will highlight challenges in HIV vaccine studies.
Dr. Mathieson reported the field is in the best of times given numerous developments:

New technologies are looking at subsets of cells giving clues about the types of T and B cells needed for immune responses, as well as innate factors in immune responses.
There have been significant improvements in the development of animal models using chimeric Simian-Human Immunodeficiency Viruses (SHIV) and Knock-in Mice to ask questions about basic B cell response challenges related to vaccines.
Insights into the development of B cell and antibody responses are beginning to reveal needed approaches to triggering B cells to obtain more and better antibodies against HIV.
New designs of immunogens, including new vectors and new designs of HIV envelope proteins that can be formed or used as immunogens.
Progress in preclinical studies, combining concepts and approaches to develop designs or strategies that may result in more functional immune responses against the HIV envelope.
Pre-clinical studies evaluating novel delivery systems and new endpoints.
Results of clinical studies confirming prior animal and human studies

Dr. Mathieson described the following three studies to outline ways researchers are using new approaches and analyses:

Reduced transmission was seen with the combination vaccine vector and envelope protein boost. When analyzing different types of responses, the use of FC receptors by the antibodies was an important component of the protective immune response. This study highlights the importance of looking at the function of the antibody rather than just the specificity of the binding site. (Barouch et al., Science, 2015).
Antibodies that do not have broad neutralizing activity can have an effect on the number of transmitted founder variants that are established. (Santra et al., PLOS Pathogens, 2015).
A series of studies shows that an antibody to a receptor that is not an HIV antigen itself is blocking the ability of cells either to be infected or to move from the site where they are infected in mucosal transmission. (Byrareddy et al., Nature Medicine, 2014).
In one of many studies searching for correlates of protection, vaccinated animals uninfected after virus challenge had characteristics that matched several of the markers found in the correlates of risk analyses done on the RV144 trial. These parallel animal and human studies have been valuable to pursue. (Pegu et al., J Virol, 2013).

Dr. Mathieson provided the OARAC with an overview of the day’s presentations, noting that all of the presenters were asked to demonstrate where opportunities or gaps exist. Specifically: The status of clinical studies and new considerations will be presented by Lawrence Corey, M.D., Susan Buchbinder, M.D., and Sallie Permer, MD, Ph.D. Studies that could take a product or approach into test of concept will be presented by Barton Haynes, M.D., and John Mascola, M.D. New insights for immunogens will be presented by William Schief, Ph.D., and Peter Kwong, Ph.D.

Dr. Mathieson acknowledged that NIH is not the only agency engaged in the development of an HIV vaccine. There are many long-standing and new partners including the Bill and Melinda Gates Foundation (BMGF), the U.S. Military HIV Research Program, U.S. Agency for International Development, International AIDS Vaccine Initiative (IAVI), and vaccine companies including Sanofi, Novartis/GSK, and Janssen, as well as multiple small companies, including GeoVax, Profectus, etc.
She commented that the field is closer to a vaccine than ever before. She outlined her perspective on the challenges in HIV vaccine research including:

Limited resources to address gaps in basic research and preclinical studies as well as product development
Product manufacturing issues that have slowed clinical research
Envelope proteins that are much harder to produce than anticipated and have led to problems with stability, clipping, and aggregation, and other issues that have to be overcome by teams of scientists and engineers. The NIAID/Division of AIDS had a meeting earlier this year to better understand these problems.
Scale-up of vectors under good manufacturing practice (GMP) requires more stringency than that encountered in preclinical studies.
Other interventions to protect against HIV are shifting populations at risk with undefined impact. Despite the fact that the drugs for PrEP can prevent HIV infection, analysis indicates that adherence is a major problem in some populations. Further, some drugs may be more effective in some populations than others (e.g., men versus women).

FOCUSING THE IMMUNE RESPONSE ON BROADLY NEUTRALIZING EPITOPES OF HIV

Dr. William Schief, Professor at The Scripps Research Institute, and Director of Vaccine Design, International AIDS Vaccine Initiative Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, gave a presentation entitled, “Reductionist Vaccine eDesign to Induce Broadly Neutralizing Antibodies against HIV.”

Dr. Schief’s laboratory focuses on designing and engineering proteins to elicit broadly neutralizing antibodies (bnAbs). He presented results showing that the CHAVI-ID group at Scripps has identified a select few bnAbs that are both very potent and neutralize a broad range of HIV strains. His laboratory strives to induce a strategic combination of these antibodies to potently protect against many strains of HIV. Structural biologists at Scripps have elucidated how these antibodies bind to their epitopes on HIV. He described the binding locations that vary widely across the classes of bnAbs, so an effective vaccine must induce multiple bnAbs. He suggested that the VRC01-class antibodies are promising candidates for HIV vaccines.

VRC01-class antibodies and their binding to HIV

To infect CD4 T cells, HIV binds to the human HIV receptor, CD4.
Structural studies of HIV and VRC01-class antibodies show that VRC01 antibodies mimic CD4 in binding to the gp120 component of HIV envelope (outer layer of the virus glycoprotein), thereby inhibiting binding of HIV to CD4.
The heavy chain of VRC01-class antibodies mimics CD4, whereas the light chain does not.
VRC01 binding is restricted in two ways: 1) The gp120 binding site is small, so both antibody chains are not able to fit; and 2) HIV has a number of glycans stationed around the CD4 binding site that block antibody access.
Some mutated variants of VRC01 have adapted to effectively bind gp120 of selected HIV strains and could be targeted for vaccine development.

The germline B cells do not have a high affinity for gp120 proteins, but Dr. Schief’s laboratory has identified a protein sequence representing the outer domain of gp120 that contains the main section of the epitope for VRC01-class antibodies. To address the nuances of effective binding, his laboratory has created an engineered outer domain (eOD) of gp120 that binds VC01-class antibodies. They then displayed 60 copies of the eOD on self-assembling nanoparticles and showed that B cells are activated when exposed to these eOD self-assembling nanoparticles. His group has embarked on development of an HIV vaccine strategy as follows:

Initiate an immune response using eOD self-assembling nanoparticles to preferentially select B cells in a lineage that could lead to mutated VRC01-class antibodies.
Introduce a first boost by introducing a SOSIP trimer (a specifically mutated, cleaved, but stable gp140 trimer) engineered to lack the obstructive glycan(s) to focus selective pressure on the heavy chain rather than the light chain. This may introduce antibodies that neutralize some tier 2 viruses.
Introduce a second boost with a SOSIP trimer engineered to have a small glycan to select the light chain CDR1 mutation that also may stimulate antibodies that could neutralize tier 2 viruses.
The final boost will use a fully native accordance trimer with full-sized glycans to select the antibody mutations accommodating those glycans. Together, these candidate vaccine components could comprise an HIV vaccine strategy that would illicit broadly neutralizing antibody (bNAb) activity with a VRC01-class response.

Dr. Schief’s laboratory has designed two engineered outer domains of gp120: eOD-GT6 first, followed by eOD-GT8. eOD-GT8 showed improved binding to artificial, germline-reverted VRC01-class precursors but not true VRC01-class human precursors. This led to binding studies using eOD-GT8 that showed that eOD-GT8 does have sufficient affinity and effectively binds to true VRC01-class precursors in human naïve B cells. This study, along with statistical models, indicates that the B cell targets needed to initiate vaccine-induction of VRC01-class bnAbs are present in humans.

Dr. Schief also presented a study in transgenic mice which were modified to contain the VRC01 heavy chain paired with the native mouse light chain (called VRC01 VH mice). Results showed that when the VRC01 gVH mice were immunized with eOD-GT8 there was a robust serum antibody and B cell response. As a follow-on study, this group isolated the antibodies produced from the eOD-GT8 immunization in VRC01-VH mice to test the antibody’s response to the first boost immunogen candidate (a native trimer lacking a glycan) in the proposed vaccine design. The study showed that the induced antibodies do effectively bind the proposed boost immunogen.
Dr. Schief outlined his conclusions and next steps:

True VRC01-class precursors that bind eOD-GT8 are present in humans at a low but detectible frequency that supports the feasibility of germline targeting in a human vaccine.
Efforts are underway to produce eOD-GT8 60mer for a human clinical experiment to determine if the vaccine can activate precursors and generate VRC01-class memory B cells in humans.
The eOD-GT8 60mer performs well in VRC01 VH mice.
The laboratory is now iteratively testing boosting regimens in VRC01 gVH mice and aims to induce VRC01-class bNAbs in this mouse model.
The goal is to use these studies to inform the design of human clinical trials: can we induce VRC01-class bnAbs in humans?
The reductionist approach offers one route to HIV bNAb induction.
The laboratory is addressing other epitopes/bnAbs with this approach.

ADVANCING HIV VACCINES AND THE INTERSECTION OF SCIENCE AND VACCINE PRODUCTION

Dr. Lawrence Corey, President and Director Emeritus, HIV Vaccine Trials Network (HVTN), Fred Hutchinson Cancer Research Center, and Professor, Departments of Medicine and Laboratory Medicine, Divisions of Vaccine and Infectious Disease, University of Washington, discussed several scientific approaches toward an HIV vaccine, their impact on next steps for HIV vaccines, and challenges to manufacturing and advancement in vaccine science and development.

Current Scientific Approaches for Developing an HIV Vaccine

Dr. Corey outlined several studies attempting to answer the following questions:

Can non-neutralizing antibodies be potent enough to achieve desirable (>50 percent) vaccine efficacy (VE) for at least 2 years?
Is neutralization, as currently measured in vitro, associated with vaccine protection and will this be of a sufficient magnitude to overshadow other design approaches? Can we design and manufacture envelope proteins to achieve such levels of neutralization? Validating the concept of neutralization in the HIV field is important.
Can boosting CD4+ T cell responses to HIV envelope improve VE or will it reduce VE? Where is a balance between having a potent immunogen and antibody producing protection?
Can unusual CD8+ T cell responses provide additional protection against acquisition of HIV-1 and will live virus vectors (CMV/vaccinia) produce tissue resident CD8+ T cell responses that enhance VE?

Dr. Corey outlined the impact that the Thai trial (RV144) had on the vaccine development field, noting it was an awakening of the importance of non-neutralizing antibodies. The results were met with surprise and skepticism leaving researchers wondering how the canary pox vector (ALVAC) and gp120 together induced vaccine efficacy (VE). He noted that the scientific community and the funders came together and established the RV144 Correlates of Protection Program, an integrated scientific and biostatistical program to define what immune responses after vaccination were associated with VE, with funding from NIAID and the Bill and Melinda Gates Foundation (BMGF). Data from that case control effort were synthesized and results include the following:
Immune Responses Associated with VE in RV144 included:

Several types of non-neutralizing antibodies to HIV-1 were correlated with reduced HIV-1 acquisition.
Antibodies to the conserved region of V2 were highly correlated with efficacy.
Polyfunctional CD4+T cell responses to HIV-1 envelope independently correlated with VE.
Essentially no CD8+ T cell responses were detected in the RV144 regimen.
No significant neutralizing antibody responses (0/20 clinical isolates were neutralized by the vaccine).
Some immune responses (serum IgA to HIV envelope) enhanced HIV-1 acquisition.

He noted that six assays emerged as related to VE. The last three were specific to vaccines with low plasma IgA responses:

The binding of IgG antibodies to the Variable Regions 1 and 2 (V1V2) region of gp120
The binding of plasma IgA to env
The magnitude of CD4 T cells specific for HIV-1 env
The avidity of IgG antibodies for env
Antibody dependent cellular cytotoxicity (ADCC)
Neutralizing antibodies

Dr. Corey cited several other results from the Correlates Protection Program including:

The Risk of HIV infection correlated inversely with antibodies directed against the first and second HIV-1 envelope variable regions or V1V2 and correlated directly with envelope specific IgA antibodies in the plasma.
As study of the kinetics of vaccine-induced immune response and vaccine protection based on RV144 shows that all of the measured correlates (IgG V1V2 scaffold antibody, IgG gp120, IgG V3 CRF01, and CD4iEnv) peaked shortly after acquisition and gradually waned over time. Waning of these responses correlated directly with waning protection.
Compared to placebo, those with high antibody had a significantly reduced rate of acquisition. Correlation between VE in RV144 as a function of IgG V1V2 of the HIV-1 envelope antibody levels appear linear, but it is still possible that future studies will show non-linear higher efficacy of 60-80 percent.
Data from Rolland, et al. 2012 corroborates that amino acid residues 169 and 181 in V2 of the HIV-1 envelope are important.
Functional characteristics of the V1V2 antibodies are that 1) several monoclonal antibodies isolated from RV144 recipients mediate ADCC activity against CRF01-AE isolates; 2) these antibodies also exhibit high activity against a wide variety of isolates in virion capture assays, as well as limited neutralization; and 3) the ADCC, neutralization, and virion capture activity of V1V2 monoclonals are synergized by monoclonals to the C1 region.
CD4+ T cell responses, especially those that exhibit a polyfunctional response, influence RV144 protection suggesting CD4 function that influences B cell response is important.

How Do These Data Lead to Better Next Steps in Vaccine Development?

Dr. Corey described how the data led to the hypothesis that enhancing non-neutralizing antibody functions will lead to better VE and this hypothesis will be tested by the P5 and Crucell Programs. He described these partnerships:

The P5 purpose is to build on RV144 data and ultimately license a pox-protein based HIV vaccine with the potential for broad and timely public health impact. The strategy is to continue to build public-private partnerships critical for success, including: 1) work with host countries to support a flexible regulatory strategy in target populations and regions and 2) generate and incorporate knowledge from the assessment of next-generation vaccine concepts.
The P5 partnership built on the RV144 data. The scientific strategy for the ALVAC/Protein Phase 2 Program was to construct an ALVAC-HIV-C (vCP2438) and a bivalent subtype C (gp120/MF59) and look at the boost at 12 months (in recognition of waning immunity) to optimize the regimen by increasing potency and durability. This strategy was constructed very quickly.

Dr. Corey outlined the timelines in the P5 program as follows:

October 2009 - RV144 results reported at the AIDS Vaccine meeting in Paris.
April 2010 - the decision to move to reproduce and improve on the RV144 result by reproducing the trial in Southern Africa was made (Clade C). The considerations of which envelopes (Envs) to use began.
July 2010 - Novartis/Sanofi MOU signed and Sanofi selection of Clade C strain for ALVAC vector made.
September 2010 - NIAID contract to Novartis was modified to accomplish Env selection, preclinical activities, and process development for manufacturing and support of Novartis staff.
July 2011 - P5 selects TV-1, 1086.C as the HIV Envs to be produced.
February 2015 - HVTN 100 opens; 4 years to produce the gp120 lots.
August 2016 - HVTN 702 scheduled to open; 3-month delay due to ALVAC production issues.

Dr. Corey presented the HVTN strategy for the Phase 3 Program as follows:

HVTN 097 was designed to evaluate RV144 vaccine regimen in the Republic of South Africa (RSA) and compare immunogenicity to that observed in Thailand. (South Africans reacted to RV144 regimen as well as Thais, perhaps a bit better).
HVTN 100 was a standard phase 1 trial of the clade C products to decide whether to proceed to phase 3. HVTN 100 uses a similar regimen to HVTN 097 with a 12-month booster. To move to HVTN 702, HVTN 100 results must meet certain criteria, including demonstrating at least a 60 percent prevalence of VIV2 binding antibody responses at 12.5 months.
HVTN 702 would be a classic phase 3 pivotal randomized controlled trial (RCT) assessing efficacy and safety aimed at licensure.

Dr. Corey raised a number of important questions to consider for planned or future vaccine clinical trials including:

What are the tools available to achieve 70 percent or 80 percent VE?
Will boosting with a “Neutralizing” immunogen synergize with the non-neutralizing antibodies elicited by an RV 144 like regimen?
Will enhancing envelope-specific T cell responses add additional VE?
Can CD8+ T cell responses provide additional protection against acquisition of HIV-1 and will live virus vectors (CMV/vaccinia) produce tissue resident CD8+ T cell responses that enhance VE?
Can a vaccine regimen be constructed that combines all of the above into a >90 percent effective vaccine approach?

Dr. Corey noted that despite momentum and synergy in the last 5 years, discovery is outpacing translation. He reported that although the strategy for follow up from the RV144 trial was outlined and consensus reached among funders and researchers within 6 months of the results, and companies engaged within 10 months, it took 5 years to manufacture the candidates because HIV vaccines are not a priority for biotech or pharma companies at certain organizational levels. He also indicated that P5 continues to be plagued by this fact. A similar situation exists for nearly every single new HIV vaccine concept. Dr. Corey outlined three central concepts:

Preclinical small animal and nonhuman primate (NHP) models are not always accurate predictors of immunogenicity of either T cell or critical B cell responses in humans.
The prevailing restriction of ideas has also proven to be wrong, as demonstrated by RV144.
Many designs do not perform as well as desired and therefore the vaccine candidates need to be tweaked, redesigned, or parked.

These concepts require developing and effectively operationalizing a cost-effective translational manufacturing system that matches the iterative pace of discovery and the magnitude of the ever-rising cost and human morbidity of the global HIV epidemic.

Dr. Corey reflected on the current state of Good Manufacturing Practice (GMP) for HIV vaccines, observing that of the 27 HVTN phase 1/2 studies in the last 3 years, 10 (37 percent) have had major delays due to manufacturing issues. For non-Vaccine Research Center (VRC) studies, the numbers are 10/22 or 45 percent. Reliable manufacturing has occurred in only a limited number of organizations (VRC: Merck, Janssen, Genentech). These VRC in-house “inventor/manufacturers” are the most reliable and have the benefit of learned history and greater consistency. He commented that contract manufacturers experience a much higher frequency of mistakes and a delay rate of nearly 75 percent.

Dr. Corey elaborated on the GMP production roadblock issues and proposed a number of concrete suggestions for expediting vaccine development:

Establish a dedicated manufacturing facility for HIV envelope immunogens with stable team leadership and key personnel.
Pay to keep all of the manufacturing slots available to the HIV vaccine field.
Allow teams to develop expertise to manufacture CHO produced proteins reliably and with a history of problem solving.
Provide $25 million to make 10 proteins a year.
Establish oversight and an experienced committee of funders and consistent scientific committee to select immunogens.
Reward companies with a million dollar a year bonus for meeting quality and quantity timelines.

Dr. Corey presented two of his 2003 slides highlighting bottlenecks that continue to stymie progress, illustrating how challenging the roadblocks can be.

Discussion

The following points were highlighted by OARAC members and presenters during the discussion:

Individual manufacturers are not the problem as much as the individualistic system, highlighting the need for funders and investigators to collaborate to build a team that focuses on HIV vaccines. When a dedicated facility is “in house” and has the clear support of leadership, the process is smoother.
Validating that neutralizing antibody activity in the HIV field is important in terms of the level needed to achieve protection in humans.

VACCINE TRIALS FOR U.S. POPULATIONS AT RISK: WHERE DO WE GO FROM HERE?

Dr. Susan Buchbinder, Director, Bridge HIV, San Francisco Department of Public Health and Clinical Professor of Medicine and Epidemiology, University of California at San Francisco, outlined PrEP success in the United States and the Americas and implications for future vaccine trials.

Dr. Buchbinder began with a summary of HIV/AIDS epidemiology, including CDC statistics and incidence in a variety of trials, with the following key points:

Infections continue to increase in men who have sex with men (MSM).
There is high HIV incidence in MSM in the United States, South America, and Europe (all clade B areas). Disparities are significant, with much higher rates of diagnosis among younger men and among Black/African American, multiple race, and Hispanic/Latino populations.
In the U.S., HIV incidence is the highest amongst MSM aged 25-34, with the number diagnosed increasing between 2009 and 2013. HIV incidence also increased among MSM in the 13-24 age group, with the black/African American population overrepresented.
Rates of HIV diagnoses are lower for women than men, but race/ethnic disparities for women follow the same pattern as for men. A substantial number of new infections occur in women. Despite many efforts, researchers have been unable to recruit sufficient numbers of high HIV incidence cohorts of women, with Haiti as a likely exception.

Dr. Buchbinder stated that despite progress in pre-exposure prophylaxis (PrEP) programs, a vaccine is still needed because uptake and adherence over time is a challenge for non-vaccine prevention methods; specifically, PrEP works but only if it is taken. For women, some studies show effectiveness and some do not. Problems include adherence and the fact that TDF concentrates 10-100 times more in rectal tissue than cervico-vaginal tissues and fluids.

Dr. Buchbinder summarized three studies (iPrEX, Demo Project, and ATN110) to further underscore the need for a vaccine in addition to PrEP due largely to a lack of adherence in high-risk populations.

iPrEx Open Label Extension (OLE) had variable PrEP engagement. All participants who were still HIV seronegative from a previous study were invited to participate and were given the option to take PrEP, with one year to decide. About 75 percent enrolled and about 75 percent of those enrolled chose to take PrEP. By the 12-week period, only 29 percent of the group that had decided to initiate PrEP had levels commensurate with protection. Known HIV seropositive partners and individuals with non-protective sex, as well as transgender women, young people, and populations with lower levels of education were associated with lower uptake of PrEP.
The PrEP Demo Project took place in three sites, including San Francisco City Clinic (N=300), Miami-Dade County downtown STD clinic (N=157), and Whitman Walker Health, Washington DC (N=100). High risk activities were significantly and independently associated with the decision to take PrEP, but those who decided to take PrEP were also more likely to be older, white, and have higher education, which is not the target population. Only 7 percent of enrolled participants were African American. Being African American was independently associated with a lower likelihood of having protective levels of PrEP, and they were 70 percent less likely than whites to have protective levels after adjusting for site and other variables.
ATN110 looked at PrEP in 18-22year-old MSM. Out of 200 people enrolled, more than half were black and 17 percent were Hispanic/Latino. At week 4, 8, and 12, only half of the participants had protective levels. When clinic visits dropped to every 3 months, having protective levels in the blood dropped significantly.

A new study, HPTN 073, is specifically focused on black MSM and therefore should be a critically important study.
Dr. Buchbinder stated that although PrEP is becoming more popular and works when taken by MSM, uptake and adherence is harder to achieve and sustain in the highest risk populations. Therefore, she noted that a HIV vaccine is still needed. She outlined four potential trial design considerations, highlighting her belief that the best way is offering PrEP at no charge to all MSM populations and allowing people to change their mind about PrEP during the trial, with the following trial design considerations:

PrEP placebo which is not ethical for MSM in the United States.
Vaccine + PrEP versus PrEP which requires all participants to be willing to take PrEP, only tests vaccine with PrEP (may require co-administration for licensure).
Vaccine + PrEP versus vaccine versus PrEP which requires all participants to be willing to take PrEP. The efficacy of vaccine is not yet known – available data suggest vaccine is inferior to PrEP with optimal adherence.
Vaccine versus placebo; both arms can access PrEP which allows participants who do or do not want PrEP to change their mind.

Dr. Buchbinder summarized current PrEP demonstration projects in the Americas:

Demonstration projects are occurring all over the United States, which is one way to provide people free PrEP, which is approved here.
PrEP is not approved for prevention in Peru, but some demonstration projects are occurring there and Brazil.
As of June 2014, approximately 3,500 individuals were enrolled in United States implementation and demonstration projects. An additional 1,500 participants were in PrEP Projects worldwide, with non-U.S. enrollment projected to total more than 7,000 participants.

Dr. Buchbinder concluded that HIV infections are increasing in young MSM of color in the United States and are high in other populations of MSM in Clade B regions as well. PrEP can be highly effective, but uptake and adherence may be low in those populations that may most benefit from it. While several vaccine candidates are available or in development; selection of the best combination(s) to move forward with will depend on immune markers, funding, and consensus. She underscored the need to test vaccine candidates in the most vulnerable populations in the United States, including MSM, high incidence cohorts from other regions, and Clade B women.

Discussion

The following issues were highlighted during the discussion of this topic by the OARAC members:

In clinical trials, the approach is to separate therapeutic decision makers (clinicians) from the vaccine trial investigators.
The study design scenario of recruiting and having a period of time where PrEP is the only intervention, and then enrolling those who reject PrEP, was not offered in the presentation because it forces people to choose, asking people who choose not to take PrEP to never take PrEP.
The difference between Peru, Brazil, and the African countries is that clinical investigators in those countries are requesting to get PrEP because they need the studies to get licensure. It is important to respect decision-making by clinical investigators in their countries.
It would be complex, but technically possible, to analyze when people go on and off PrEP and whether the efficacy of prevention would be increased during the time that they are on PrEP. The more relevant issue is whether a vaccine is having an additional preventive impact by further lowering the incidence, regardless of whether the study participant is on or off PrEP.
With respect to decisions surrounding incidence versus case rate, bridging designs and designs that link studies to other parts of the world would be helpful to see if the immune response correlating with protection is also present with women in the Americas.
Looking at social determinants of health is essential and that is why the studies that assess these parameters are critical.
Education is part of the problem with adherence, but some people do not want to take a pill, (even when they are acknowledging risk and enrolling in an HIV vaccine clinical trial.) People conceptualize risk in many different ways.
As HIV treatment regimens became less toxic, the differences in groups started to disappear. Hopefully, this also happens with PrEP.
Vaccine uptake may have similar issues impacting VE with certain populations, leading to an unfortunate situation where VE is clear for certain populations and it is not conclusive for others. This is why HPTN 073, which has now concluded, is such an important study.
Dr. Craig Wilson, who co-chairs the ATN110 study of 18-22 year olds clarified that the incidence of HIV was 4 percent in the first year, and in the second year with the option of taking PrEP, the incidence was 9 percent. He emphasized that clinical trials need to enroll younger study participants.

THE PATH TO AN HIV VACCINE

Dr. Barton Haynes, Director, Duke Human Vaccine Institute, and Director, Duke Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), Duke School of Medicine, presented on progress and roadblocks encountered in HIV vaccine development, as well as next steps, and future opportunities.

Dr. Haynes noted that the induction of bnAbs is an immunologic problem. Unlike other disease vaccines, understanding the immunological mechanism(s) eliciting these antibodies is critical. The goal is to recreate with vaccination the events that transpire with HIV infection to generate bnAbs. bnAbs are not often made due to the unique nature of these antibodies, specifically immune tolerance controls, and bnAb induction routinely is outcompeted by dominant non-neutralizing envelope epitopes. He described CHAVI-ID research in this field.

Wilton B. Williams et al., Science, 349: aab1253, 2015 looked at the diversion of HIV-1 vaccine–induced immunity to Env gp41 cross-reactive with microbiota. Immunization of humans with a vaccine containing HIV-1 Env gp120 and gp41 components, including the membrane-proximal external region (MPER) of Env, induced a dominant non-neutralizing B cell response primarily from a pre-existing pool of gp41 B cells cross-reactive with gut microbiota. This response diverted the vaccine-stimulated antibody response away from smaller subdominant B cell pools capable of reacting with potentially protective epitopes on HIV-1 Env gp120 and gp41.
Recapitulating what happens in infection with antibodies inducing viral mutantsis important for progress in HIV vaccines. Researchers found that there is a continuum and breadth of bnAbs with about 20 percent of individuals that have very high levels of these antibodies. When looking at one bnAb lineage as it developed, virus heterogeneity occurred prior to development of bnAbs. Therefore, deciding which Env to choose to recreate this event is the challenge.
Cooperation of B cell lineages to induce HIV-1 bnAbs can be observed. Using the CH235 cooperating antibody lineage, researchers demonstrated that antibodies can select for mutant viruses resistant to the first antibodies and these escape viruses are very sensitive to and drive the induction of a second lineage of bnAbs. Researchers have been able to characterize two bnAb lineages against HIV, one that gives rise to two CD4 binding site bnAb lineages, and another that gives rise to a V3 glycan bnAb lineage, with longitudinal sampling over 6 years from time of infection.
Dr. Haynes’ laboratory has created a method for designing immunogens to drive bnAb pathways that involves isolating a clonal lineage of protective Ab targeted for induction, inferring the germline, unmutated common ancestor (UCA) and early intermediate Abs (IA) in the Ab clonal lineage and then using UCAs and IAs as templates to design immunogens with high-affinity UCA and IA binding.

Dr. Haynes summarized research on the initiation of the CD4 binding site bnAb lineage in the CH103 germline knock-in mouse model. For this research, the HIV envelopes from the CH505 individual were selected as vaccine immunogens. CH505 transmitted founder (TF) and Env variants generated over a 136-week period during viral evolution drove affinity maturation of the CH103 bnAb lineage. This discovery is potentially a promising line of research for immunization, testing whether sequential Env immunization can activate the B cells in the germline of CD4 binding site CH103 bnAb in CH103 germline knock-in mice. His group went on to study the initiation of the CD4 binding site CH103 ortholog germline lineage in rhesus macaques. In this study, immunization of rhesus macaques with CH505 sequential Envs induced bnAb-like B cell lineage maturation. The progression of maturation in this study was limited to the initial stages of bnAb development, but still holds some promise for further studies.

Dr. Haynes discussed whether it is possible to design a sequential Env immunogen that will be predicted to drive both CH103 and the CH235 CD4 binding site bnAbs. After testing 150 envelopes in binding assays with CH103 and CH235 bnAb lineage antibodies, a new set of 6 Env immunogens was selected that were predicted to drive both. He discussed the importance of animal studies by describing progress in a study where rhesus macaques are infected with a new CH505 SHIV.

Dr. Haynes outlined the following next steps that are needed:

Produce an expanded set of sequential immunogens with the Envs selected by the cooperating lineages for other bnAbs, not just CD4 binding site.
Produce sequential Envs as stabilized soluble trimers (in collaboration with Dr. Peter Kwong, VRC); and membrane bound trimers (Drs. Munir Alam and John Kappes.).

Dr. Haynes noted that research opportunities include knowledge of the biology of bnAb development, new SHIVs and humanized bnAb knock-in mice, B cell lineage immunogen design/Sequential Envs, and trimers as immunogens.

Dr. Haynes described progress in studying CMV vectored SIV antigens as follows:

Certain strains of primate CMV with SIV gene inserts induce T cell responses that appear to control SIV infection in ~50 percent of NHPs (Hansen, S, Picker L et al., Nature, 473: 523, 2011)
A subset of animals clear virus to undetectable levels (Hansen, S, Picker L et al., Nature, 502: 100-4, 2013).
HLA-E and HLA-II Restricted T cell responses. Louis Picker’s RhCMV68-1 SIV vector stimulates MHC-II and MHC-E-restricted CD8 T cells instead of classical MHC-Ia-restricted T cells. Preliminary experiments indicate these may be important for protection and are under further investigation.

Dr. Haynes described progress in Mosaic T Cell Antigen Inserts research as follows:

In silico homologous recombination of genetic sequences were designed to optimally cover T cell epitope diversity in HIV Env observed in the LANL/NIAID database (Fischer W, Korber, B et al., Nat. Med. 13: 100, 2007)
These “Mosaic” inserts induce broader T cell responses than wild type Envs (Nat. Med. 16: 319, 2010; Nat. Med. 16: 324, 2010) and protect from low dose SHIV challenges (Cell 155: 531, 2013)
The CHAVI-ID Mosaic Clinical Trial team is working with HVTN investigators to execute a Phase I clinical trial, HVTN 106, comparing wild-type Env, M consensus Env, and trivalent mosaic Envs for induction of diverse T cell responses. The trial completed enrollment in October 2015.

Dr. Haynes outlined next steps: to evaluate the comparative immunogenicity of the different Env proteins in the HVTN 106 trial; to produce the next generation of mosaics called conserved/mosaics: to incorporate genes for the conserved/mosaic designs into attenuated CMV; and to conduct iterative human clinical trials. Dr. Haynes highlighted two opportunities in the area of cellular immunity to HIV, including knowledge of new mechanisms of CD8 T cell control of HIV and new immunogen designs for combating HIV diversity for T cell recognition.
Dr. Haynes concluded his presentation with the following points:

Scientific breakthroughs in HIV vaccine research include new bnAbs and Env evolution pathways that define new vulnerable sites for blocking HIV infection and new modes of T-cell control of HIV and inserts to overcome HIV diversity.
New strategies for immunogen design include focused T cell responses, novel T-cell responses induced with CMV vectors, and Mosaic and conserved insert designs to broaden immune responses which are guiding nature’s B-cell response pathways.
New immunogens, including designs targeting germline, naive B cell receptors, (e.g., B-Cell Lineage Design); designs from new trimers, and/or selection of HIV variants that may be more relevant for certain routes of transmission.
New models for testing vaccines, including new SHIVs and human immunoglobulin VH and VL knock-in mice for most specificities of bnAbs need to be supported with appropriate resources.
New vaccine candidates and approaches need to be studied in humans with clinical grade materials as quickly as possible to refine or triage concepts. Resources need to be allocated to produce clinical trials materials for small iterative Phase 1 clinical trials.
Substantial collaboration is occurring among the NIH-funded research groups, including the NIAID Vaccine Research Center, Duke CHAVI-ID, Scripps CHAVI-ID, NIAID/Division of AIDS, NCI Frederick Cancer Research Facility, and NICS Comparative Sequencing Program.

IMMUNOLOGIC INTERVENTIONS TO ELIMINATE PEDIATRIC HIV INFECTIONS

Dr. Sallie Permar, Associate Professor of Pediatrics, Duke Human Vaccine Institute, Duke University School of Medicine, presented background on the continuing need for pediatric HIV vaccines, three immediate opportunities for immune-based interventions, and existing vaccine safety and immunogenicity data in infants.

Needs and Gaps in Pediatric HIV

Dr. Permar noted the importance of developing additional pediatric interventions. She cited that:

More than 200,000 new infant HIV-1 infections occur annually despite increased antiretroviral (ARV) drug availability. This figure includes ~50 percent breast milk - oral transmission.
16 percent of HIV-infected women continue to transmit the virus to their infant.
Over 60 percent of HIV-infected women take combination antiretroviral therapy (ART) during pregnancy, but many fewer continue ART postpartum and during breastfeeding.

The current gaps identified by Dr. Permar include: ARV-based prevention of mother-to-child transmission (MTCT), including missed testing for HIV-1 during pregnancy, late arrival for antenatal care, undiagnosed acute maternal infection, ARV resistance in the mother or infant, and poor maternal adherence/access to ARVs. Although ARVs are effective in reducing the rate of transmission, some drug combinations are associated with higher rates of prematurity/infant death as reported from the PROMISE trial. She commented that ARVs alone will not eliminate pediatric HIV.

Opportunities for immune-based interventions to reduce infant HIV-1 transmission

Dr. Permar outlined three opportunities for immune-based interventions to reduce infant HIV-1 transmission, outlining their rationale, current progress, and future plans.

The first opportunity described by Dr. Permar is to enhance protective maternal antibodies in HIV-1 infected women during pregnancy by vaccination with HIV envelope-based vaccines. The rationale for this maternal vaccination is multiple: 1) It is an “altruistic vaccine” where immunization of the mother protects the infant (similar to tetanus/pertussis immunization strategies); 2) It may temporarily enhance maternal antibodies against her own virus in cooperation with maternal ARV; 3) Immunoglobulin G (IgG) is naturally transferred across the placenta in late pregnancy and is one of the reasons that infant HIV infections cannot be diagnosed using standard HIV antibody-dependent tests until after 12 months; and 4) mucosal delivery of milk HIV Env-specific IgG and immunoglobulin A (IgA) could block infection via the infant’s GI tract. Relevant research includes the following:

A study of antibody responses associated with reduced risk of transmission found maternal anti-V3 IgG, “Tier 1” HIV neutralization, and CD4 blocking antibodies to be co-linear predictors of reduced MTCT risk. The maternal antibodies were not bnAbs, but they are similar to antibodies induced by gp120 vaccines that only yield weak neutralizing antibodies against Tier 1 isolates. These results led to the hypothesis of an underlying mechanism of protection, further supported by the two studies cited below.
Vaccine-elicited HIV neutralizing responses is usually limited to weak “Tier 1” virus neutralizing antibodies, yet there is evidence that these responses could mediate autologous virus neutralization: 1) Moody et al., Cell Host Microbe, 2015 established that classic Tier 1 neutralizing monoclonal antibodies (mAbs) could mediate autologous virus neutralization of Tier 1B/2 viruses; 2) Permar et al., Journal of Clinical Investigation, 2015 found that V3-specific mAbs isolated from a non-transmitting mother mediated autologous virus neutralization and selective immune pressure against the virus. Current flu vaccines also elicit this kind of response where immunization with a second vaccine strain boosts antibody responses to the original.
Two studies exploit this phenomenon of “original antigenic sin” to enhance autologous antibody responses in HIV-infected pregnant women: 1) Bartlett et al. 1998 showed that boosting with a heterologous Env could raise autologous responses via “original antigenic sin” and V3-specific responses can be boosted in HIV-infected individuals ; and 2) Haynes et al. 1993 showed priming with one V3 immunogen in uninfected individuals and boosting with a heterologous immunogen efficiently raised titers to the initial, priming strain.
Wright et al., JID, 1999, used recombinant gp120 antigen to vaccinate HIV-infected mothers. Dr. Permar and colleagues examined stored samples from this trial and found that in some mothers, there was a rise in the V3-specific antibody responses, or the ability to neutralize tier 1 viruses from those vaccinated mothers. Missing from this assessment is whether the antibody responses that were induced by this vaccine enhanced the mother’s ability to neutralize her own virus.

Dr. Permar outlined a plan to vaccinate women, who are HIV-infected and on ART, with a recombinant gp120 to determine if it is possible to enhance their ability to neutralize their own virus. Dr. Permar plans to recruit women from HIV treatment clinics, who have detectible virus present in their plasma, so virus can be isolated before immunizations are initiated. The vaccinated women will be monitored to determine if they make new antibodies, which can enhance the ability to neutralize autologous virus variants. The trial will begin as immunogens become available.

Dr. Permar described a second opportunity involving passive immunization infants at high risk of HIV infection at birth whose HIV-infected mothers either sought antenatal care late in their pregnancy, or who are currently failing to fully suppress their HIV with their current ARV regimen. The International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network study P1112 on the pharmacokinetics and safety of the bnAb, VRC01, administration to newborn infants has begun accrual.

A third opportunity involves active immunization of infants at birth that will be breastfeeding. Dr. Permar described the rationale as follows:

Efficacy in infants can be demonstrated with short-lived protection of about 1 year. RV144 was 60 percent efficacious in the first year.
Infants make vaccine-elicited IgG responses to HIV gp120 protein that are high in magnitude and of surprisingly long duration.
Infants make no detectable IgA responses to pox/protein immunization.
Newborns have minimal prior exposure to environmental/microbiota antigens.
Infant immunization could be boosted in preadolescence for broad, mature antibody responses prior to sexual debut.

Dr. Permar described the striking disparity in HIV prevalence between male and female high school students in rural South Africa, with significantly higher prevalence among young women – starting at age 15. The high prevalence of HIV among high school students highlights the importance of early vaccination.

Dr. Permar outlined four studies related to active immunization of infants at birth and reviewed the results of vaccine-elicited responses in two vaccine trials completed in Pediatric AIDS Clinical Trials Group (PACTG) during the mid-1990s. Recent analyses from samples from these trials found there was a 22-fold higher V1V2 IgG antibody response in the Chiron immunized infants compared to RV144-vaccinated adults and 56 percent of infants still had responses detectable at 2 years, whereas the adult responses waned after 6 months. Additionally, comparisons of adult versus pediatric trial samples found that infants respond uniquely well to rgp120 with MF59 adjuvant, with peak antibody responses being more than 20 percent higher than responses observed in adults. Researchers were able to isolate HIV Env-reactive mAbs from one Chiron Env/MF59-vaccinated infant when Env-specific mAbs were compared between adults and infants, significantly longer heavy chain CDR3 length of the infant antibody, as well as a similar heavy chain somatic mutation rate in adults and infants.

Dr. Permar next discussed upcoming clinical trials, beginning with information about safety in infants. Three previous clinical trials of neonatal immunization with ALVAC/Env products demonstrated safety including Env/MF59 in PACTG 230 Chiron trial, ALVAC/Env in PACTG 326, and ALVAC in HPTN 027. MF59 also has been used in infant influenza vaccine trials with demonstrated safety. Some studies have looked at potential interference with response to Expanded Program of Immunization (EPI) vaccines when using new adjuvants. Future planned studies of HIV vaccines in infants also will monitor responses to these other vaccines, although no interference of the immune responses to childhood vaccines has been seen to date.

IMPAACT 2004 is planned to be a randomized placebo-controlled study that will use ALVAC vCP2438 with a Clade C gp120 genetic insert, provided by Sanofi and bivalent recombinant rgp120 proteins (TV1 and 1086) in MF59 from GSK. This is the same combination of products that will be used in the HVTN 701 study in South Africa. For the infants, a lower dose (15mcg/dose) will be used because previous studies suggest higher doses do not yield better outcomes and lower doses will allow for more doses to be available. Vaccines will be administered at 0, 2, 8, and 20 weeks of life, with potential long-term follow-up with adolescent boosters.
All groups will be followed for 2 years and those vaccinated for up to 4 years to learn the durability of the antibodies.

The study objectives are to assess the safety and immunogenicity of three candidate infant HIV vaccine regimens (gp120-only, conventional prime-boost, accelerated prime-boost regimen) and determine which regimen induces early (10 week) envelope V1V2-specific IgG response of greater magnitude compared to placebo recipients. Secondary objectives include assessing durability of response through the normal breastfeeding time period (up to 18 months) and potential for late boosting in the cohort.

Dr. Parmer presented the current timeline of maternal/infant active and passive HIV vaccine trials. She stated that P1112 is ongoing, IMPAACT 2004 is expected to start around September 2016, and maternal immunization phase 0/1 will begin around November 2016. (The latter 2 trials are now delayed several months because of product issues.)

Discussion

The following points were raised during the OARAC members’ discussion of this topic:

Demonstrating efficacy with infant trials is a challenge and will require large sample sizes, raising questions about the cost/benefit given progress with PrEP and other solutions.
Current transmission rates, due to low adherence to ARV regimens during breastfeeding, look similar to those for PrEP trials at 2 percent. This translates to a 4,000-person trial, which is a similar size to the PROMISE trial that was completed in 4-5 years.

ACTIVE AND PASSIVE IMMUNIZATION FOR HIV-1 PREVENTION

Dr. John Mascola, Director, Vaccine Research Center (VRC), NIAID, NIH, highlighted a new era of HIV active and passive immunization that features many natural examples of highly potent antibodies with the capability to make vaccine immunogens that mimic the structures of native virus and key viral epitopes, and new highly potent antibodies with potential for passive prevention of infection. The fundamental challenge in HIV vaccination is converting neutralizing epitopes detected to immunogens inducing bnAbs and translating that knowledge into vaccines or a series of vaccines.
Dr. Mascola described the state of the field by summarizing developments toward the next generation of vaccines and what is still missing, specifically:

The HIV envelope and the BG 505 stabilized protein are now known structures. This is important because HIV envelope protein vaccines such as gp120s or gp140s are suboptimal because they bind to non-neutralizing antibodies. This may distract the immune response from sub-dominant, protective responses. Inducing as many neutralizing antibodies as possible is necessary. Other trimers with different isolates are being developed.
Further refinements in the crystal structure allow researchers to make improved trimers.
Making epitope-specific antigens is now possible, and tracking immune responses to specific epitopes to evaluate new immunogens also is feasible.
Significant progress has occurred in animal studies and on limited numbers of antigens, but moving this into human clinical trials is an important future step.
Manufacturing of any vaccine candidate is a major challenge because vaccine products cannot go directly from laboratories to full-scale manufacturing, but requires process development for production and purification involving manufacturing engineers. Proteolytic cleavage or clipping of envelope proteins is a result of skipping this step.

Dedicated manufacturing facilities/plants are necessary for production of HIV envelope vaccine candidates under current “Good Manufacturing Practice” (cGMP), because iterative studies must cycle between Phase I trials in the clinic and back to the laboratory to test and optimize candidate immunogens. These types of facilities are very limited in government and these need to be expanded, requiring specialized personnel, additional funding, and time. Dr. Mascola also discussed progress in passive immunization including new highly potent antibodies and their potential for prevention of infection. He noted the following specific points:

As a wide array of human monoclonal antibodies now are available, designing passive immunity studies in humans is possible. The initial questions to consider include: Can an antibody that is capable of neutralizing most HIV isolates in vitro (a bnAb), prevent infection in humans? If so, what level of antibody is needed for protection?
The optimal profile for an antibody product for prevention of HIV-1 infection is:
1. Potent enough to use at relatively low dose and cover 95-99 percent of viral diversity
2. Given by subcutaneous injection (1-2ml) once every 3-4 months
3. High clinical efficacy (80-90 percent).
Nonhuman primate (NHP) studies indicate that the new generation of bnAbs are highly effective, providing complete protection against chimeric SHIV strains at relatively low serum concentrations. However, no human data currently exist as proof of concept that bnAbs will protect from HIV infection. The CD4 binding site antibody VRC01, described as a potent and broad antibody, has advanced through a number of preclinical studies and has been produced under cGMP at the VRC for clinical studies.

The VRC recently completed phase 1 trials of VRC01 in both HIV-infected and uninfected human volunteers. Preclinical, in vitro studies predicted VRCO1 could neutralize 80-90 percent of diverse viruses, in all HIV clades. In vivo activity was confirmed in the study of HIV-infected volunteers with detectable viral load. The Phase 1 trials also suggest that VRCO1 can attain physiologically functional levels in uninfected individuals and maintain 10 ug/ml in plasma for up to 8 weeks with a single infusion. This allows for the possibility of bimonthly dosing for a prevention study.

A new passive antibody phase IIB efficacy study (Antibody Mediated Prevention = AMP trial – HVTN 703/HPTN 081) will be the first clinical trial to assess if a passively infused monoclonal antibody can prevent HIV-1 infection. The PK study is currently ongoing. The larger AMP study would enroll potentially 3,900 persons and would administer two different doses at 10 mg/kg or 30 mg/kg by intravenous infusion and will be conducted in two high-risk populations including MSM at selected sites in the Americas and women in sub-Saharan Africa. Dr. Mascola commented that if the passive antibody phase IIB efficacy study demonstrates prevention from infection, moving it to the next level in adults would require an antibody approximately 10 fold more potent than VRC01, with 95-99 percent coverage of viral diversity versus 85 percent for VRC01, and a low enough dose to be given by subcutaneous injection once every 4 months versus IV infusion every 2 months. Antibodies or combinations of antibodies with these characteristics exist in the laboratory today, but would be several years away from testing.

Dr. Mascola summarized passive antibody prevention and the new era of HIV active and passive immunization with the following points:

Animal models suggest neutralizing antibodies can provide complete protection against HIV-1 infection, but proof-of-concept in humans is necessary; studies are planned in adults and infants.
Making vaccine immunogens mimicking the native viral Env spike and key viral epitopes is possible. Clinical trials will need to determine whether these induce the kind of antibodies that are needed to prevent infection.
Next steps include cGMP production, clinical trials, and new immune assessments, (e.g., B-cell technologies.)
Proof-of-concept passive antibody prevention is occurring with the AMP trial.
Use of mAbs to prevent infection is possible with foreseeable engineering, e.g., improved potency, extended half-life, and reduced cost with large-scale production.

Discussion

The following issues were raised by OARAC members during the discussion:

Studies are planned to test two of these newer human monoclonal antibodies together in humans. After proof of concept, antibodies could be co-formulated or produced as bispecific antibodies.
An approach using a long-acting broadly neutralizing antibody in combination with a long-acting ARV is under discussion.
Currently, antibody manufacturing is relatively expensive, but scale-up could move the cost closer to that of traditional vaccines.
One of the challenges with a long acting injectable is the long tail at a sub-therapeutic level for a long time, but the lower level for prevention is not currently known.
There is significant interest in antibody-vectored agents using RNA instead of DNA, possibly leading to months of antibody expression.

IMMUNOGEN DESIGN INTEGRATING HIV-1-ENV TRIMERS WITH REPRODUCIBLE ANTIBODY LINEAGES

Dr. Kwong, Chief, Structural Biology Section, Vaccine Research Center, NIAID, NIH, presented on HIV-1 Env research after the results of the RV144 trial, the concept of reproducible antibody lineages, and implications for vaccine design.

HIV-1 Env since the Thai HIV vaccine clinical trial, RV144

Dr. Kwong presented the structural studies on the HIV envelope (HIV-1 Env) trimer showing how the HIV envelope changes shape during its various stages of ligand binding, making it uniquely difficult as a target for vaccine development. He described how studies have gradually determined the physical and atomic-level structure of HIV-1 Env trimer, including a site defined by a new set of antibodies that interact with both gp120 and gp41. These studies have revealed a layered envelope architecture and the basis of conformational mobility. Crystallization studies also have defined a more complete structural view of the membrane-proximal external region (MPER) of the HIV-1 envelope. Finally, both the liganded and unliganded, soluble, modified trimers, of HIV-1 Env, complete with glycan shields, have been stably crystallized and atomic level structures determined. Dr. Kwong noted that HIV is unlike other viruses because of its ENV-conformational variability, its extensive sequence variation, and its extraordinary glycan shielding. Most antibodies to other viruses (such as flu) do not detect glycans, but broadly neutralizing antibodies that recognize the HIV-1 Env-trimer need to accommodate N-linked glycan.

Reproducible Antibody Lineages

Dr. Kwong commented that B cells from different donors develop unique antibodies against the same antigen. However, for HIV vaccine development, induction of a specific class of antibodies against HIV that are broadly neutralizing and similar in multiple donors provides a possible pathway to eliciting a select class of broadly neutralizing antibodies by vaccination. Studies have shown that VRC01-class antibodies from VH1-2 germline occur in multiple donors, neutralizing up to ~95 percent of HIV-1 isolates, and have similar modes of HIV-1 recognition. However, VRC01-class antibodies have two issues that may pose problems for vaccine development: 1) the germline, unmutated common ancestor (UCA) immunoglobulin genes do not interact with detectable affinity with most HIV-1 Envs; and 2) they require many years of somatic hypermutation (SHM) to neutralize HIV effectively. Studies have shown that with particular priming of the immune response, VRC01-class antibody pathways can be stimulated. Studies over time of the SHM in a patient who developed the CH235 antibody, which is similar to the VRC01-class antibody, show that all CD4 binding site antibodies show similar requirements of precise epitope targeting and affinity maturation. Substantial SHM is related to intrinsic germline gene mutability, and, VRC01-class of bnAbs and other similar antibodies are predetermined to achieve a particular type of SHM over time. Several groups of investigators now are studying how to predictably achieve the necessary SHM for HIV-1 env recognition. Another vulnerable site on the HIV-1 envelope is the V1V2 site, targeted by a second group bnAbs, one of which is PG9. Studies investigating V1V2 antibody binding show that several bnAbs bind to the apex of the intact trimer and that this subgroup of V1V2-directed antibodies engage the HIV envelope through a common mechanism even though the atomic level details differ slightly among antibodies. Researchers now agree that, in addition to CD4-binding bnAbs, V1V2-directed antibodies make up another class of HIV-binding antibodies (PG9 class) that appear to be reproducible in multiple donors, and thus may be a good target for vaccine studies.

Vaccine Implications

The goal of an HIV-1 vaccine is to achieve reproducible elicitation of a broadly neutralizing antibodies. In addition to all of the Env-immune evasion that confounds standard vaccinology approaches, another difficulty that current immunizations take at least 18 weeks to obtain feedback; and other methods for inducing antibodies such as SHIV infection, take even longer (1 year or more). Dr. Kwong suggests one way forward is to use a variety of strains and vaccine strategies to initiate B cell development and to enhance the breadth with ontogeny-based immunogens that have been detected in individuals that have produced bnAbs. He showed that germline-targeting with Env trimers can provide a means to both engage germline and to mature intermediate bnAbs. A proposed combination immunogen would involve:

V1V2 from selected HIV-1 Env strains
HIV-1 Env trimer that binds to the germline of the CD4 binding site antibodies
Combined with an Env trimer stabilized in the pre-fusion closed state, not triggered by CD4 binding.

Dr. Kwong concluded his presentation by stating that:

initial success has been seen with RV144 involved immunization with HIV Env.
conformational fixation of the pre-fusion, closed Env state is required for elicitation of autologous neutralizing antibodies.
reproducible antibody lineages against the CD4 binding site and V1V2 apex have been identified.
A combination of conformationally fixed trimers that engage the appropriate germline B cell lineages and reproduce the selection and expansion of ontogeny-based intermediates is worth considering.

GENERAL DISCUSSION

OARAC members and presenters discussed and addressed issues on establishing sex differences in vaccine response, promoting PrEP, infant vaccine development, future strategies for HIV prevention, and specific recommendations for NIH.

Establishing sex differences in vaccine response

OARAC members and presenters discussed the difficultly in continued research to establish sex differences in vaccine benefits between men and women, because of the difficulty in identifying women who are at high risk of Clade B HIV infection. In future studies, the exclusion criteria should not eliminate women who use different types of contraceptives or those who have sexually transmitted diseases as these reflect real world circumstances. Research on HIV vaccines should examine the effects of hormonal treatment that may have profound effects on immune responses, particularly in young women. To increase statistical power of these studies, the changing use of hormonal control for fertility control should be monitored over time.

Promoting PrEP in more populations

OARAC members commented that HIV vaccine development will be difficult with the increasing use of ARV-based PrEP. They suggested that resources should be mobilized to promote PrEP and prevent unnecessary infections in the vaccine trials. The past several years have seen progress with the physician, public health, and pharmaceutical communities advocating for access and use of PrEP, but additional education is needed within the populations where it is necessary to optimize uptake and adherence. Currently, one of the major issues is provider recommendation, because health care providers who treat adolescents specifically have not been recommending PrEP.

Clarification on infant vaccine development

OARAC members acknowledged the example of an infant vaccine against Hepatitis B being recognized, over time, as the optimal strategy for protection of adolescent infection. While it is clear that polysaccharide vaccines do not work well in infants, they can respond extremely well to protein conjugate vaccines, which may enable the increased recognition of HIV epitopes with complex carbohydrates.

Additional OARAC discussion points

OARAC members acknowledged that vaccine efficacy trials inform us about immune correlates and what vaccine approach works. However, there was agreement that the vaccine field should be seeking to define a wider array of HIV targets other than just the V1V2 loop. One of the approaches that was discussed was the macaque studies conducted by the Louis Picker and colleagues using a CMV-vectored SIV vaccine, and the need to move these studies as soon as possible into clinical trials.
The OARAC members acknowledged that there may be many different paths to a vaccine and it is important to maintain a discipline around the diversity of research paths, because the “right” path is unknown.
They also discussed issues on the need for accurate use of language when communicating the complexities of the research. They noted that it is important to communicate a plan and identify a pharmaceutical partner that may be willing to take on production if the clinical trials demonstrated efficacy.
The OARAC members also recognized that although the field has focused primarily on antibodies, some investigators are working on T cell vaccines as well.

Discussion of priorities

Dr. Eisinger asked the OARAC members to identify HIV prevention priorities given the uncertainty about the budget. There was unanimous consensus and endorsement that there is a clear need for a dedicated manufacturing facility to produce vaccine candidates, to better understand uptake, both of PrEP and of vaccines, and to conduct clinical trials in the United States among minority and racial ethnic populations, especially MSM. The Council members also identified the following issues as critical to the development of a safe and effective HIV vaccine as well as other HIV prevention strategies: Continue exploring multiple approaches in a balanced way.

Bring vaccine candidates to clinical trials, including at least one trial with a trimer.
Provide industry an incentive to participate earlier in the research.
Increase and continue collaborative efforts between NIH, academia, and industry.
Increase efforts to implement PrEP access through interventions and venues that are more widely used in communities where incidence of HIV infection is high.
Continue to investigate how to improve uptake of any HIV prevention modality and the complex, related factors that increase risk of infection.
Involve community members in the design, conduct, and analysis of research, which informs outcomes.
Study gender including during uptake and inclusion; no longer continue dividing studies between men and women.
Investigate combining long-acting hormonal contraceptives and long-acting injectables for women.
Promote a wider adoption of ARV-based PrEP.

PUBLIC COMMENTS

No members of the public requested time to comment.

CONCLUDING COMMENTS

Dr. Gulick concluded by highlighting common themes from the meeting in regards to important progress in the HIV vaccine field. He cited several examples of recent progress that was highlighted in today’s meeting including:

SUMMARY OF PROGRESS

There is an increased emphasis on the best immunogen(s) and how they are designed.
The VRC is making progress with plans for evaluating VRC01 in phase 1-3 clinical trials.
Additional research is needed on broadly neutralizing antibodies (bnAbs) including potency, half-life, combination therapy, and other strategies.
Plans for pediatric vaccines trials are progressing.
Understanding how bnAbs function and how to induce them is important for HIV vaccines. There also is an increasing recognition of the importance of non-neutralizing antibodies and T-cell responses. Addressing how to put these together without adverse outcomes will be essential.

Suggested Next Steps

Develop an HIV vaccine. After 25 years of HIV vaccine history, an immunologic problem was identified, requiring a detailed look into the basic science. However new coordination and collaborations now exist that should move this HIV vaccine field forward.
Strengthen and facilitate the transition between basic science observations, translational research, and adoption in the clinic.
Continue to pursue a diversity of multiple HIV vaccine approaches.
Address challenges in manufacturing of immune-based products. This includes better coordination of HIV vaccine efforts among government, industry, and the community.
Address resource limitations in order to accelerate vaccine and other HIV prevention efforts.
Identify approaches to provide HIV vaccines and PrEP to the communities people who need them.

CONCLUDING COMMENTS

Drs. Gulick and Eisinger thanked presenters for outlining challenges, gaps, and next steps in HIV vaccine research. They also thanked the OARAC members for their participation in the meeting discussions.

ADJOURN

Dr. Gulick adjourned the 41st meeting of the OARAC at 5:00 p.m. on November 12, 2015.

/Robert W. Eisinger, Ph.D./
Robert W. Eisinger, Ph.D., Executive Secretary

/Roy M. Gulick, MD/
Roy M. Gulick, MD, Interim Chair

This page last reviewed on December 12, 2022