The 173rd meeting of the National Advisory Allergy and Infectious Diseases Council (NAAIDC) convened at 10:30 a.m. on Monday, February 4, 2013, in Conference Rooms E1/E2, Building 45, National Institutes of Health. Dr. Anthony S. Fauci, director, National Institute of Allergy and Infectious Diseases (NIAID) presided as chair.
In accordance with the provisions of Public Law 92-463, the meeting was open to the public from 10:30 a.m. to 11:40 a.m. and from 1:00 p.m. to 4:30 p.m. The meeting was closed to the public from 8:30 a.m. to 10:15 a.m. and from 11:40 a.m. to 12:00 p.m. for review and consideration of individual grant applications. Notice of the meeting was published in the Federal Register.
Council Members Present:
Ex Officio Members Present:
Council Members Absent:
Ex Officio Members Absent:
NIAID Senior Staff Present:
Table of Contents
The National Advisory Allergy and Infectious Diseases Council convened in closed session to consider applications in allergy and immunology, microbiology and infectious diseases, and AIDS.
Funding Actions: The Council reviewed 3,862 research and training applications with primary assignment to NIAID for a requested amount of $1,091,503,919 in first-year direct costs and recommended approval of 1,994 applications with $594,556,616 in first-year direct costs.
Dr. Fauci opened the Council session by welcoming visitors to the meeting. He announced the appointment of four new Council members: Ms. Maria Acebal, former CEO of the Food Allergy and Anaphylaxis Network; Dr. Norman Baylor, Biologics Consulting Group; Dr. Robert Belshe, St. Louis University School of Medicine; and Dr. Diane Griffin, Johns Hopkins University. Four Council members, Maria Acebal and Drs. Ting, Karn, and Gellin were unable to attend the meeting.
Ex officio Council member Major General James Gilman retired. Brigadier General Joseph Caravalho, Jr., commander of Fort Detrick, Maryland, will replace him.
Dr. Fauci noted that Mary Nuss, NIAID’s committee management officer, will retire in May. Mary began working at NIH in 1985 and has worked in NIAID’s Division of Extramural Activities since 2000.
Consideration of Minutes of Previous Meeting
Council considered the minutes of the September 24, 2012, meeting and approved them as written.
Consideration of Operating Procedures
Council reviewed the 2013 Council operating procedures and adopted them as written.
Staff and Organizational Changes
Dr. Fauci announced the appointment of Dr. Jill Harper as NIAID associate director for science management.
In November, Dr. Gary Nabel, director of the Vaccine Research Center (VRC), left NIAID to join Sanofi Pasteur. Dr. John Mascola will serve as acting director of VRC while NIAID conducts a search to fill the position.
Dr. Susan Old is the new deputy director of the Division of Extramural Activities Arne Fleisher has been named chief of the Operations and Engineering Branch, Office of Cyber Infrastructure and Computational Biology.
Dr. Mary Marovich was appointed director of the Vaccine Research Program in the Division of AIDS.
In DAIT, Dr. Bert Maidment is the new associate director for radiation countermeasures research and emergency preparedness, and Dr. Alkis Togias is the new chief of the Allergy, Asthma, and Airway Biology Branch.
Dr. Fauci announced the recent retirement of four scientists from the Division of Intramural Research.
After more than 50 years at NIH, Dr. Al Kapikian retired as chief of the Epidemiology Section, Laboratory of Infectious Diseases. Dr. Kapikian and his colleagues were the first to identify the norovirus as a cause of gastroenteritis. He also led a 25-year effort to develop the first licensed vaccine for rotavirus.
Dr. Michael Parnell retired as chief of the Rocky Mountain Veterinary Branch. In his 24 years at NIAID, he focused on the development of new animal models for infectious diseases research.
Dr. Robert Purcell, who came to NIAID in 1963, retired as chief of the Hepatitis Virology Section, Laboratory of Infectious Diseases. His career focused on hepatitis viruses, and he made fundamental discoveries in hepatitis C epidemiology, pathogenesis, and immunology.
Dr. Ronald Schwartz retired as chief of the Laboratory of Cellular and Molecular Immunology. He came to NIH in 1972 and made important contributions in the field of T-cell clonal anergy.
In December, Dr. Richard Nakamura was named director of the Center for Scientific Review.
In November, the Board of the Global Fund to Fight AIDS, Tuberculosis, and Malaria appointed Dr. Mark Dybul as its new executive director.
Tributes and Awards
Dr. Emmie de Wit, a postdoctoral fellow in the Laboratory of Virology, was selected to receive the 2013 NIH Women Scientist Advisors Scholar Award.
Dr. Dean Metcalfe, chief of the Laboratory of Allergic Diseases, received the American Academy of Allergy, Asthma, and Immunology Distinguished Scientist Award.
Meetings and Events
In October, Dr. Fauci traveled to multiple sites in South Africa where NIAID has established research collaborations. In Johannesburg, he presented a lecture at Witwatersrand University Medical School and visited several associated research organizations and laboratories at the National Institute of Communicable Diseases. In Pretoria, Dr. Fauci attended the annual scientific meeting of Project Phidisa. In Durban, he visited the McCord Hospital and the University of KwaZulu-Natal.
On December 18 and 19, HHS sponsored an international workshop at NIH entitled “Gain-of-Function Research on Highly Pathogenic Avian Influenza H5N1 Viruses.” The workshop provided a forum for sharing multidisciplinary international perspectives on research that aims to increase airborne transmissibility, increase pathogenicity, or alter the host range of highly pathogenic avian influenza H5N1 viruses in order to prepare for a possible pandemic.
In December, Dr. Francis Collins announced three implementation plans in response to recommendations developed by the Advisory Committee to the Director. The proposed initiatives, which are designed to help strengthen the biomedical research enterprise and sustain the global competitiveness of the U.S. scientific community, include 1) the Future Biomedical Research Workforce, 2) Diversity in the Biomedical Research Workforce, and 3) Data and Informatics.
The President’s FY 2013 budget request held NIH at the FY 2012 funding level.
NIAID is operating under a continuing resolution (CR) that expires on March 27, 2013. Under the CR, NIH received an increase of 0.6 percent over FY 2012.
Dr. Fauci summarized a number of complex issues that are converging to complicate the FY 2013 budget scenario and creating a situation that could potentially cause harm to NIH research programs. NIH could face a five to eight percent budget reduction.
Under the CR, NIAID is taking a conservative funding approach. Dr. Fauci summarized possible approaches if NIAID receives a flat budget or a budget cut.
Dr. Fauci presented Senate and House committee and subcommittee leadership changes that occurred following the November 2012 elections.
On November 27 at the Forum for Collaborative HIV Research, Dr. Fauci presented Representative Henry Waxman with the 2012 C. Everett Koop Award.
On January 18, Gray Handley briefed the House Appropriations Committee in preparation for a Congressional delegation to Bangladesh and India.
Also on January 18, Drs. Carl Dieffenbach and Jack Whitescarver briefed staff of Representative Henry Waxman on NIH activities related to research on a cure for HIV/AIDS.
Other Information Items
Dr. Fauci began with an overview of emerging and reemerging infectious diseases that occurred in 2012. December 2012 was the 20th anniversary of the Institute of Medicine’s publication Emerging Infections: Microbial Threats to Health in the United States. Dr. Fauci and Dr. David Morens summarized the 20year period in an MBio publication Emerging Infectious Diseases in 2012: 20 Years After the Institute of Medicine Report. Dr. Fauci presented a few examples of NIAID research that addressed some of the issues from the original report.
Dr. Fauci gave brief updates on HIV/AIDS, influenza, anthrax, hepatitis C, and pediatric food allergies.
Dr. Gibbons emphasized the important role our current scientific leaders have as stewards of the scientific enterprise and mentors for the next generation of scientists in the biomedical workforce. He stressed the need for a diverse biomedical workforce, to value the health of all communities, and to elucidate and eliminate health inequities.
Dr. Gibbons presented some of NHLBI’s successes and stated the importance of ICs’ collaborating and using available resources. Once a discovery is made, it is essential to have a strategy to implement and translate the discovery into clinical practice and public health outcome.
To address the issue of health inequities, we may need to integrate different disciplines at multiple levels. Areas to focus on include a person’s environment and individual characteristics, such as biology, genome, and family circumstances.
Dr. Gibbons concluded by emphasizing the need to form knowledge networks that bring scientists together in cross-disciplinary ways. We have many potential opportunities to learn from and collaborate with each other. Most importantly, we need to prepare the next generation to take science in a more integrative and less discipline-bound way.
Dr. Hackett welcomed all of our recurring and new Subcommittee members of the National Advisory Allergy and Infectious Diseases Council. Dr. Hackett announced that Dr. Alkis Togias was selected as the chief, Allergy, Asthma, and Airway Biology Branch, and Dr. Bert Maidment was selected as the associate director for radiation countermeasures research and emergency preparedness within the Division. In addition, Dr. Hackett further noted Dr. Carmen Rios recently joined the Radiation and Nuclear Countermeasures Program, and Drs. Theresa Allio and Lyudmila Lyakh both joined the Office of Regulatory Affairs as regulatory officers.
Dr. Hackett took the opportunity to inform the Subcommittee members that it was a pleasure to have Dr. Scott Presnell, Benaroya Research Institute at Virginia Mason present on “Leveraging Cutting-Edge Web Technologies for the Publication and Dissemination of Systems Immunology Data.” Also, Dr. Adam Asare, Senior Director, Data Analysis and Data Management Biomarkers & Discovery Research, UCSF Immune Tolerance Network would be presenting “Advancing Translational Research Through Web-Portal Access to Clinical Trials Data, Analysis and Bio-Repository Information.” In addition, Dr. Hackett noted that Dr. Helen Quill, chief, Basic Immunology Branch would present “Generation and Analysis of Meaningful Human Immune Response Data” along with Dr. James McNamara, chief, Autoimmunity and Mucosal Immunity Branch presenting “Introduction to Tools for Bioinformatics in the Immune Tolerance Network.”
Following the presentations, Dr. Hackett announced there were three research concept clearances for review and approval by the Subcommittee.
FY 2015 Research Concept Clearance
Human Immunology Project Consortium: This initiative will support a consortium of human immune profiling research centers that will identify and characterize diverse states of immune system at rest and following infection, vaccination against infectious diseases, or treatment with vaccine adjuvants; and will create a database of human immune profiles and accompanying data analysis tools as a new bioinformatics resource for the scientific community. The Subcommittee endorsed and unanimously approved this initiative.
DAIT Statistical and Clinical Coordinating Center: This initiative recompetes the biostatistical, data management, and clinical trial operations awards as a comprehensive and consolidated project that supports clinical research studies and trials in allergy and asthma, autoimmunity, and transplantation. The DAIT Statistical and Clinical Coordinating Center (DAIT-SACCC) will provide complete biostatistical and operational support for clinical trials in the area of allergy and asthma, autoimmune diseases, and transplantation. The Subcommittee endorsed and unanimously approved this initiative.
Human Leukocyte Antigen (HLA) Region Genomics in Immune-Mediated Diseases: The goal of the HLA Region Genomics in Immune-Mediated Diseases program is to define the association between variations in human leukocyte antigen and natural killer cell immunoglobulin-like receptor (KIR) genetic regions and immune-mediated diseases, including risk and severity of disease, and organ, tissue, and cell transplantation outcomes. The program will continue to generate high quality HLA- and KIR-disease association data, correlated with patient phenotypes that will be submitted to publically accessible databases. The Subcommittee endorsed and unanimously approved this initiative.
Dr. Heilman introduced three new Subcommittee members: 1) Norman W. Baylor, Ph.D., president and CEO of Biologics Consulting Group, Inc., and formerly with the Food and Drug Administration; 2) Robert B. Belshe, M.D., professor of medicine, pediatrics, and molecular microbiology and director of the Center for Vaccine Development at Saint Louis University; and 3) Diane E. Griffin, M.D., Ph.D., university distinguished service professor and Alfred and Jill Sommer Chair of the W. Harry Feinstone Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health. Dr. Heilman then referred to the branch chiefs and office directors to introduce new staff in their respective programs.
Following introductions, Dr. Heilman provided a general overview of DMID’s major research activities and programs for the benefit of the new Subcommittee members, briefly describing DMID’s organizational chart, mission, and breadth of research activities, which cover all infectious diseases other than HIV/AIDS. She also described DMID’s collaborative strategic planning process for developing targeted solicitations, spanning all offices and branches within DMID. She then provided an update on the new NIAID Leadership Group for a Clinical Research Network on Antibacterial Resistance, noting that peer review of submitted applications recently took place, and awards are planned for early FY 2014.
Dr. Heilman reported that staff would begin presenting FY 2015 concepts for clearance at today’s meeting. All of the concepts to be presented today are ongoing components of DMID’s clinical research portfolio. Dr. Richard Gorman, DMID’s associate director for clinical research, then provided a broad overview of DMID’s clinical programs in an effort to provide context for the concepts that would be presented for clearance later in the meeting.
Report: DMID Clinical Research Activities
Dr. Gorman described the structure of DMID’s clinical group, which serves all DMID branches. This group encompasses the Office of Regulatory Affairs, which helps to prepare DMID’s regulatory submissions; the Office of Clinical Research Affairs, which includes medical monitors who are engaged in the pharmacovigilance of DMID’s clinical research protocols; and the Office of Clinical Research Resources, which includes medical officers who lend clinical expertise to the development of clinical protocols throughout the Division. Dr. Gorman also described several of DMID’s focused clinical research and clinical trials programs supported at the branch level, for example, the Tropical Medicine Research Centers. He provided data on the types of pathogens and products addressed by these programs; the range of studies supported, e.g., clinical research through phase IV clinical trials and described several specific examples of recent or ongoing clinical efforts supported by DMID.
FY 2015 Concepts Presented for Clearance
All concepts presented to the Subcommittee for approval are recompetitions of ongoing clinical support programs.
Dr. Celum welcomed the ARAC members, DAIDS representatives, and guests. She presented the minutes of the September 24, 2012, ARAC meeting, and members approved by a show of hands.
OFFICE OF AIDS RESEARCH ADVISORY COMMITTEE: UPDATE
Judith Wasserheit, M.D., M.P.H., OARAC Liaison
Dr. Wasserheit reviewed the OARAC meeting, which was held on Thursday, November 8, 2012, at Fishers Lane in Rockville, MD. The focus of the meeting was “HIV and Women’s Risk and Prevention: Back to Basics;” with the goal of providing recommendations to address research gaps.
The introduction to the November meeting was given by Sharon L. Hillier, Ph.D. from the University of Pittsburgh School of Medicine and chair of the OARAC. The first segment of the session focused on anatomy, histology, and endocrinology of HIV risk in women; the second on increased HIV risk in women associated with biological factors over the life cycle, from functional immunology to the genital tract microbiome to semen and sex. The final segment of the meeting centered on exogenous factors that included metagenomics of the female genital tract, sexual violence, along with anal and genital pharmacokinetics.
Among notable discussion points were the: 1) controversial impact of hormonal contraceptives; 2) increased HIV risk associated with non-lactobacillus-dominated genital microbiome; 3) impact of sex and semen on HIV risk and effectiveness of Pre-Exposure Prophylaxis (PrEP) and microbicide use; 4) commonness of anal intercourse among U.S. heterosexual women; 5) impact of stress in HIV+ women on HIV progression; and 6) value of animal explant models in assessing PrEP/microbicide candidates. Meeting participants noted that central and local hormones mediate changes in the female-genital-tract (FGT), which in turn contribute to women’s risk of HIV infection and other sexually-transmitted infections (STIs).
In the U.S. and globally, women are at markedly increased risk of heterosexually-transmitted HIV infection compared with men. The risk of HIV is particularly increased during adolescence and puberty as well as in the luteal phase of the menstrual cycle and pregnancy.
OARAC meeting participants suggested priority research investments should include:
During discussion ARAC members noted that data from multiple studies have shown anywhere from a zero to two-fold increase in HIV acquisition risk in women using primarily long-acting progestins. Mostly observational data have been the source of varying inferences about hormonal contraceptives, and it was noted that data observational studies will not likely resolve the conundrum. There has been some discussion, among the Gates Foundation and others, about more rigorous analysis and a randomized trial of long-acting reversible contraception (e.g., injectables, implant, and IUD) that may help address this issue. Following the OARAC meeting, it was also mentioned that another meeting was held in which the use of explant tissue as a surrogate for in vivo efficacy and certain other aspects of antiretroviral treatment and prevention was discussed and minutes for that meeting should be available shortly.
Carl W. Dieffenbach, Ph.D., Director, DAIDS
Dr. Dieffenbach welcomed the attendees and introduced the following new ARAC members – David O’Connor, Ph.D., Stephen Mason, Ph.D., and Deborah Persaud, M.D.
New ARAC Members
DAIDS Personnel Updates
Since tracking of the NIAID payline history began in 2005, Dr. Dieffenbach noted that the payline has steadily declined over time; however, in the last two years, the payline has stabilized to the tenth percentile. The overall success rate of 23 percent for research project grants (RPGs) reflects an increase (up by 10 percent) in the number of applications and the number of awards in 2012. A slight decrease in the number of AIDS applications and new RPG awards occurred, which includes activities in DAIDS, Division of Allergy, Immunology, and Transplantation (DAIT), and the Division of Microbiology and Infectious Diseases (DMID).
The data show a 19 percent success rate for the AIDS NIH Research Project Grant Program (R01s) in 2012. Fewer program project grants (P01s) were funded from a larger application pool, resulting in a success rate of 13 percent. The success rate for AIDS Exploratory/Developmental Research Grant Awards (R21s) was 19 percent. Across NIH and NIAID, the comparative success rates of RPGs and R01s have been relatively consistent, partly driven by the drop in AIDS program project grants.
Beginning in FY 2012, the NIAID budget will no longer pass through funds to the Global Fund. The budget status is currently on continuing resolution (CR), which expires on March 27, 2013. The CR included a slight budget increase of 0.6 percent over the FY 2012 funding level. The final FY 2013 budget has yet to be determined and along with the FY 2014 Presidential request (PR), will be significantly impacted by several complex issues: 1) sequestration--delayed to March 1 and may be extended further; 2) CR expires March 27 and could be extended; and 3) U.S. Government (USG) debt ceiling, suspended through May 18, 2013.
The American Taxpayer Relief Act is the bill delaying implementation of sequestration to March 1, 2013. The Act encompasses new tax revenue to a total of about $12 billion per year with savings in government efficiencies of the same amount. Although the impact to the NIH budget is uncertain, the expected size of the cuts will be in the range of 5.0 to 9.0 percent. Congress may attempt to use the annual appropriations process to gain additional FY 13 budget cuts. In the interim guidance for FY 2013, NIAID is making awards at the 90 percent funding level with plans to cut funds for competing initiatives up to 20 percent. The most optimistic predicament regarding the 2013 financial plan is a final flat budget on level with FY 2011 and FY 2012. One of the questions for ARAC entails which specific activities should be protected from cuts, or what areas can absorb larger funding cuts. In general, DAIDS would like to protect the highest priority research from cuts.
With respect to the impact on funded networks, Dr. Dieffenbach stated that all network funding will occur in FY 14; network funding is somewhat truncated for this year as current awards are extended by about seven months. Consequently, the networks may not be drastically impacted, possibly leaving them with a budget cut near the 10 percentile. Network investigators may wish to revisit funding after determining how the scientific agenda has evolved since the application process. Normally, the PR request is submitted to Congress on the first Monday evening of February. In the current situation, the PR request will be probably delayed due to the complex political environment and may be submitted in March or later. Adjustments to funding will need to be made accordingly.
A question was asked about dollar amounts of grants decreasing or capped while post-doctoral and graduate student compensation is increasing—how can this situation be resolved and lab work get accomplished? Dr. Dieffenbach replied that the option to write for more money is always an option although the modular budget is administratively easier. No discussion has been given to changing the size of the standard R01 above $250K.
DAIDS sponsored a meeting, “Strategies for an HIV Cure”, on November 28-30, 2012, in Washington, D.C. The purpose of the meeting was to gather researchers affiliated with each of the three NIH-funded Martin Delaney Collaboratories, investigators in complementary disciplines, and community members for active discussion about scientific results and HIV cure approaches. This first-time conference was oversubscribed with more than 300 registered attendees and over 50 cutting-edge talks and discussion forums on 15 different session topics.
Dr. Dieffenbach commented about the timeline for Leadership Groups, noting that letters of intent (LOI) were due August 28, 2012, and the due date for the receipt of applications was September 28, 2012. The period of review is rapidly approaching (May 2013), and grants will be awarded in late December 2013 or early January 2014. Applications under the Clinical Trials Unit (CTU) requests for applications (RFAs) were due January 29, 2013.
The Strategic Working Group (SWG) meeting was cancelled for February 5, 2013. The next SWG meeting will convene on June 4-5, 2013, or September 17-18, 2013. Future SWG meeting dates include: January 28-29, 2014, June 3-4 2014, and September 16-17, 2014, though not every date may be used.
The NIAID AIDS Vaccine Research Subcommittee (AVRS) will meet February 6, 2013, in Natcher, and will focus on the work of the Duke and Scripps Centers for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID). The 4th Annual Conference of the Consortium of Universities for Global Health (CUGH) will take place March 14-16, 2013, at the Marriott Wardman Park Hotel in Washington, D.C.
PROGRAMMATIC OVERVIEW: KEY ACCOMPLISHMENTS AND FUTURE DIRECTIONS
Basic Sciences Program (BSP)
Diana Finzi, M.P.H., Ph.D., Chief, Pathogenesis and Basic Sciences Branch
Dr. Finzi presented a thorough overview of the Basic Sciences Program, noting that it is composed of three branches: Epidemiology, including a sub-branch of Ethics; Targeted Interventions; and Pathogenesis and Basic Research. Combined, the branches have an annual budget of roughly $200 million.
The BSP supports nascent research ideas and fosters basic science mainly through unsolicited grants, which may bear fruit in diverse areas such as vaccines, therapeutics, and prevention. The Epidemiology Branch encompasses two cohort domestic studies: the Multicenter AIDS Cohort Study (MACS) and the Women’s Interagency HIV Study (WIHS), in addition to an international consortium known as the International Epidemiologic Databases to Evaluate AIDS (IeDEA). The primary focus in the Epidemiology Branch is disease outcomes over time as well as transmission and prevention. The pooled data collected from multiple settings in the IeDEA will help inform the World Health Organization (WHO) and others about future research needs and global public health. The Ethics team performs an important role in integrating bioethics with research; areas of emphasis include cure research for HIV individuals who are otherwise doing well and the storage and use of specimens and repositories as well as issues related to the treatment of pregnant women and on conducting research in developing countries.
The Pathogenesis and Basic Research Branch (PBRB) holds the Reagent Program that provides free reagents to investigators worldwide. The PBRB oversees the Centers for AIDS Research (CFARs), consisting of 21 centers throughout the U.S. where investigators can promote local collaborations and develop better science infrastructure. The Targeted Interventions Branch (TIB) holds several different contracts, including two on therapeutic vaccines and one on developing assays and in vitro testing and one for testing in vivo (in mice) and for developing a new humanized mouse model. In general, the BSP contracts provide services to investigators that cannot be provided through grants.
The scientific interests of PBRB and TIB are beginning to converge around a cure for HIV/AIDS, which is of primary importance to the program as a whole. Ongoing activities in Basic Research and Targeted Interventions revolve around host cell and HIV interactions, cure-related strategies, and cell-based therapies. Scientists have learned that the killing of HIV-infected cells is critical to a cure and better ways to eliminate viral reservoirs must be found. This has led to greater discussion with both therapeutic and vaccine focused researchers, as the idea of therapeutic vaccines, immunomodulation, or other approaches to eliminate viral reservoirs have become stronger. In terms of cure efforts, the program is focusing on how to target residual viral reservoirs for elimination. They are advancing studies focused on the elimination of persistently-infected cells along with new methods to accurately measure the frequency of these cells that, with can be induced to produce replication-competent. Current antiretroviral therapy (ART), which targets replicating viruses, can decrease and keep plasma viremia at levels below detection by standard assays, but it does not eradicate latent or non-replicating viruses. The current gold standard in the measurement of viral persistence is the quantitative viral outgrowth assay (QVOA) in which the frequencies of infected cells is expressed as infectious units per million (IUPM) resting CD4+ T cells. Because QVOA requires large volumes of blood from several donors and is expensive and labor intensive, efforts will be made to make the assay more accessible to HIV researchers (possibly through a contract) and research will be stimulated towards finding a better assay.
Several strategies to investigate elimination of HIV infection have been proposed, including combined strategies “shock and kill” (where CD4 cells are stimulated to express viral proteins and CD8s are induced to kill more effectively), targeted gene knock-out and cell-based therapies. Future initiatives will include: targeting persistent HIV reservoirs (TaPHIR); targeting latently infected cells without reactivation; and developing innovative therapies to eliminate HIV (in conjunction with the National Heart, Lung, and Blood Institute and other Institutes).
Dr. Finzi concluded by saying that the Program wants to sustain efforts in cure, improve upon characterizing the reservoir of latently infected cells, and to determine if there are ways to eliminate those cells without reactivation. Toward this end, discussions are underway with colleagues in several other Institutes and where appropriate, they will look to collaborate.
In response to questions, Dr. Finzi noted that future initiatives must strike a balance between cure research and basic pathogenesis and other fundamental research. There was also a question about animal models, and it was noted that scientists should use animals wisely and focus on immune response studies in humans where appropriate.
Therapeutics Research Program (TRP)
Sarah Read, M.D., Director
The TRP research focus is centered on planning, implementation, and evaluation of a scientific agenda for the preclinical development and clinical testing of therapies to treat HIV infection and AIDS, its coinfections (e.g. tuberculosis and hepatitis C) and co-morbidities in adult and pediatric populations. Five branches comprise the TRP: the Complications and Co-infections Research Branch (CCRB), Drug Development and Clinical Sciences Branch (DDCSB), Maternal, Adolescent and Pediatric Research Branch (MAPRB), TB Clinical Research Branch (TBCRB), and HIV Research Branch (HIVRB).
The TRP portfolio encompasses 136 active grants and ten contracts covering critical infrastructure that include among others: Immunology Quality Assurance (QA), Virology QA, Clinical Pharmacology QA, and Quality Control (QC), and Patient Safety Monitoring in International Laboratories (SMILE). High priority areas of research correspond to the branch titles and stress co-morbidities in the setting of suppressive ART.
The success of HIV therapeutics is evidenced by the Food and Drug Administration (FDA) approval of over 30 antiretrovirals (ARVs) and combination therapies. Major accomplishments of TRP, and specifically of the clinical trials networks, are critical findings affecting standard of care with the following examples: 1) superiority of the (non-nucleoside reverse transcriptase inhibitor [NNRTI]) efavirenz (EFV) plus two or three nucleoside reverse transcriptase inhibitors (NRTIs) versus three NRTIs; 2) no significant differences between the three-drug and four-drug antiretroviral regimens; and 3) efavirenz-based regimens virologically superior to two NRTI plus lopinavir/r (combination of two protease inhibitors in the same pill) regimens.
Various clinical studies have examined whether first-line treatment combinations are effective over others as well as the optimal time to initiate therapy. Toward this end, the INSIGHT network is conducting START (Strategic Timing of Anti-Retroviral Treatment), a large international randomized trial, to evaluate the timing of starting HIV medications, particularly in those HIV-infected patients with CD4 counts higher than 500. The study includes eight sub-studies and has nearly 90 percent enrollment at 232 sites around the world.
In the area of pediatric therapeutics, the TRP is committed to testing the safety and pharmacokinetics (PK) of ARVs currently approved for the treatment of adults. Novel drugs and drug combinations represent another field of interest, including anti-CD4 monoclonal antibodies as well as sustained release formulations of approved ARVs. Recently, a solicitation was released for small business innovation research (SBIR) contracts concerning sustained release formulations; the solicitation was well-received and proposals will be reviewed in March.
HIV and its co-morbidities are associated with immune activation/inflammation and in turn with poor clinical outcomes. Many possible points of intervention exist, beginning with the drivers of inflammation such as damage in secondary lymphoid tissues and co-pathogens to key pathways that down-regulate the inflammatory response. Several pathogenesis studies are in progress to study the contribution of different pathways of immune activation. An additional focus of TRP is end-organ and metabolic diseases, including those related to bone, cardiovascular and lipid disorders, neurological compromise, and aging.
Despite advances in therapeutics, an HIV cure remains elusive. The reported case of the “Berlin patient”, with a cure through transplantation, has inspired greater research efforts. Past studies have examined the role of ongoing viral replication as it affects cure and have tested for decay of the latent reservoir with intensification of antiretroviral therapy. Discordant results have been reported with various strategies to reduce residual HIV-1 viremia.
The elimination of HIV reservoirs to affect a cure may not only involve reactivation of latent HIV but also an effective therapeutic vaccine. Recent data have established the key point that a therapeutic vaccine can impact latent reservoirs. Among the future directions toward a cure are evaluating combinations, such as a reactivating agent and immunologic intervention; examining the role of transplantation in greater detail; and determining the consequences of very early therapy in infants. Future projects are being considered to evaluate the latent reservoir in HIV-infected infants and children under ART, and to test strategies to eliminate infected cells in a proof-of-concept trial.
In the last five years, dramatic progress has been made in the identification of efficacious interventions for the prevention of mother to child transmission (PMTCT). PROMISE (Promoting Maternal Infant Survival Everywhere) (P1077) is a research study in the IMPAACT (International Maternal Pediatric Adolescent AIDS Clinical Trials) network designed to address the optimal antiretroviral-based intervention required for preventing HIV transmission in infected pregnant and postpartum women. Critical questions for the study revolve around circumstances including antepartum and intrapartum transmission, breast feeding, and preservation of maternal health after the risk period for MTCT. Enrollment is anticipated through 2013 for P1077 breast feeding and formula feeding mothers and through 2014 for P1077 sites where antepartum HAART is the standard of care.
TRP also supports many activities related to HIV co-infections, most importantly TB and hepatitis C virus (HCV). TB research comprises efforts in therapeutics, diagnostics, and prevention. The AIDS Clinical Trials Group (ACTG) sponsors A5295, an observational and longitudinal study in TB diagnostics to evaluate pulmonary TB suspects in HIV-infected and HIV-uninfected individuals. TRP is also working with Aeras to develop TB vaccines for pediatric populations. Several drugs are in development for HCV treatment along with plans to identify host and risk factors for HCV acquisition and improve diagnostics.
During the discussion, Dr. Read noted that the case of the “Berlin patient” gave impetus to cure research as well as the need to safely and cost-effectively resolve persistence, especially at an early stage. She noted that TRP’s focus on TB and HCV is because these co-infections lead to the greatest disease burden globally; however, research continues in malaria, HPV (human papilloma virus), and other HIV-related co-infections. TRP also works closely with DMID, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and outside groups to coordinate efforts and limit duplication. Dr. Dieffenbach agreed with comments that the need for equipoise and ethics must be ongoing; the dearth of literary references on ethics makes for a slow process, but enterprise-wide sharing of ethics information is encouraged. Toward that end, the final report of the Promise ethics review panel was mentioned and will be circulated to the committee.
Prevention Sciences Program (PSP)
Sheryl Zwerski M.S.N., C.R.N.P., Acting Director
The objectives of the PSP involve the delivery of HIV prevention tools at the population level by: 1) creating and sustaining a pipeline for non-vaccine products such as sustained delivery methods and combination modalities; 2) validation and constant refinement of rational algorithms for product testing and data acquisition; 3) supporting assay development in an optimized and cost-efficient manner; 4) supporting appropriate safety and efficacy testing; 5) supporting efforts to improve treatment and patient care; 6) supporting mathematical modeling integrated with prevention strategies; and 7) developing partnerships to accomplish prevention measures. PSP works closely with the other divisions within the Institute, with other NIH Institutes, including NIMH, NIDA, NICHD, and OAR, as well as other U.S. government agencies, such as Centers for Disease Control and Prevention (CDC) as well as USAID, specifically on microbicide development, and with Office of the Global AIDS Coordinator in collaboration with the HPTN to examine the implementation of combination prevention. In addition, PSP works closely with foundations and development partners, including Bill and Melinda Gates Foundation, CONRAD and the International Partnership for Microbicides. There are also a number of industry partnerships.
The PSP has three major branches: Preclinical Microbicide & Prevention Research (PMPRB), Clinical Prevention Research (CPRB), and Clinical Microbicide Research (CMRB). The Preclinical Branch focuses mainly on solicited programs. The Clinical Prevention Branch is primarily responsible for the work and oversight of the HIV Prevention Trials Network, although there are some non-network grants. Similarly, the Clinical Microbicide Branch works largely with the Microbicide Trials Network.
Within the Clinical Prevention Branch is the MP3 Program, which was developed to increase collaborations between behavioral, biomedical, and clinical scientists, modelers, and trialists, to facilitate design and testing of optimal combination, prevention combination packages in specific target populations. There have been two rounds of the RFA that has been released, the first in 2008, and the second in 2010. There were a total of ten projects between the two releases that were funded. They have all been making very good progress and one of the teams has received additional funding for a full scale trial of a prevention package that was developed in their MP3 project.
For the HIV Prevention Trials Network (HPTN), the HPTN 052 study was a critically important accomplishment. It examined the effect of ART on infectivity and HIV transmission in serodiscordant couples. It enrolled 1750 serodiscordant couples in nine countries to help determine if antiretroviral treatment prevent transmission in serodiscordant couples, and what are the clinical benefits to HAART in asymptomatic individuals. The study was able to achieve 96 percent efficacy in preventing transmission for those who were the HIV positive person and the couple went on HAART early. More recent data about the clinical benefits to HAART for the asymptomatic individuals were presented at IAS, and there do appear to be clinical benefits to earlier HAART. The study was “Science” breakthrough of the year in 2011.
Because the networks are being recompeted, Ms. Zwerski did not talk about future network priorities. Rather she summarized the current status of the network, including setting priorities for a robust scientific agenda; developing the capacity to locate high risk populations; developing an oral PrEP agenda, including adherence; bridging from proof of concept to effectiveness, and combination prevention; contributing to laboratory science and statistical advances; developing strong community partnerships and high ethical standards; and the development of the HPTN scholars program to mentor young investigators.
Among the Microbicide Trials Network’s (MTN) many advances is the completion of the MTN-003 VOICE (Vaginal and Oral Interventions to Control the Epidemic) study. The study results will be released at the 2013 Conference on Retroviruses and Opportunistic Infections (CROI). Moving forward, the MTN is committed to other activities including the ASPIRE Intravaginal Ring study (Phase III trial of Dapivirine ring in Africa—sustained delivery); its rectal microbicide agenda; microbicide use in pregnancy and the pregnancy outcomes registry (EMBRACE/MTN-016), combination microbicides, community engagement efforts and the work of a contraception action team, which is looking at this issue of hormonal contraception effects on acquisition and transmission of HIV.
The future plans for PSP include the following:
Ms. Zwerski noted that maintaining the status of those who have tested HIV-negative presents a considerable challenge, and necessitates the integration of social and behavioral sciences into prevention research. The acceptability of prevention tools in early and late stage trials is critical to success.
Behavioral scientists will be helpful in assessing patient acceptability and assisting patients in understanding personal risk.
Vaccine Research Program (VRP)
Mary Marovich, M.D., Director
Dr. Marovich reviewed the HIV vaccine research priorities and the organization of VRP. VRP consists of two main branches: Preclinical Research and Development (PRDB) and Vaccine Clinical Research (VCRB). The PRDB contains three subdivisions: Vaccine Translational Research, Preclinical Research, and Vaccine Discovery. The VCRB is divided into two teams: Medical Officers and Laboratory Sciences.
Vaccine development strategies can be viewed in terms of empiric and rational approaches. The RV144 trial represents an empiric approach and remains the only clinical link to efficacy. This study reported 31 percent protection in the vaccine arm at the 3.5 year time point. The results suggested waning durability of the vaccine and the notion that durability could be boosted.
RV144 Correlates Update:
The Pox-Protein Public Private Partnership (P5) was established in 2010 to build on the RV144 results and has initiated a multi-step process to develop future vaccine components. Interim studies are further assessing immune correlates, protein boosting, and adjuvants among other characterizations.
The Mucosal Immunology Working Group consists of 27 investigators inside and outside of the Network with the mission of identifying critical areas in understanding HIV- specific cellular immunity in the mucosa. The focus includes standardization of mucosal sampling and testing, identification of potential biomarkers, and realization of correlates in both nonhuman primates (NHPs) and humans. A short-term goal is to incorporate standard mucosal assays in ongoing clinical trials, e.g., HVTN 076, VCR016, and RV262.
In the rational vaccine development strategy, structure-based envelope (Env) immunogen design serves as a major target. Neutralizing antibodies are probably the key to maximal protection, especially prior to exposure. The provision of neutralizing antibodies could be offered through the passive transfer of IgG or via gene-based vectors. However, a primary question remains unanswered: Can broadly neutralizing antibodies (bNAbs) be induced by a vaccine? Infected humans can produce bNAbs naturally, but what about through vaccination? Broadly neutralizing antibodies have been found that are potent and target conserved regions of the HIV envelope, for example, the CD4 binding region and V2/V3 glycan region. The underlying idea is to use the virus and envelope to drive immunogen design.
Another strategy in rational vaccine development uses knowledge of B cell lineage and ontogeny to guide immunogen design. HIV-specific bNAbs are rare and apparently take a long time to develop, perhaps years. The study of clonal lineages of HIV-1 Env antibodies in humans, from infection to early unmutated ancestors, should provide insights into antibody maturation during infection and upon vaccination. The outgrowth of these studies could lead to compression or acceleration of bNAb development and possible serial coaching of humoral immunity in the form of a vaccine. The premise is to use the antibodies to identify vaccine targets. The antibody receptor could bind to the vaccine candidates such that the better the binding, the stronger the avidity, the more potent the induced neutralizing antibody.
An additional option in rational vaccine development involves novel strategies evaluated in NHPs. An example is use of a rhesus cytomegalovirus vector carrying several simian immunodeficiency virus genes (RhCMV-SIV vector --Louis Picker laboratory) to control SIV infection after challenge. An experimental AIDS vaccine consisting of a rhesus cytomegalovirus (CMV) vector carrying several SIV genes showed protection in about half of the NHPs challenged with low-dose SIV. Potent and persistent SIV-specific CD4+ and CD8+ T cell responses were elicited with strong “effector memory” (TEM) bias or the capacity for adaptive expansion. The RhCMV-SIV vector may constitute a model for a human therapeutic vaccine.
Further experiments in NHPs have used combinations of novel vectors. Recent data from Dan Barouch’s lab has shown the protective efficacy of Ad26/MVA (modified vaccinia Ankara) and Ad35/Ad26 regimens in rhesus monkeys. Adenovirus serotypes Ad26 and Ad35 are less common worldwide than Ad5 and elicit immune responses different from those of Ad5. The key finding in the Barouch lab data was that for the first time, both acquisition and viral load (VL) effects were found within the same vaccine strategy. Upcoming novel vectors may include replication-competent vectors and chimp adenovirus vectors.
Currently, the only ongoing efficacy study is HIV Vaccine Trials Network (HVTN) 505, a Phase IIb domestic trial (n=2500) with the following characteristics:
The study vaccines were made by the Dale and Betty Bumpers Vaccine Research Center (VRC), which is part of NIAID. The VRC candidate is a DNA prime with an Ad5 boost, using Multigenic, multiclade (A, B, C) inserts. Participants must be Ad5 sero-negative and circumcised and enrollment is nearly complete. The study endpoints are viral load and acquisition (check if vaccines lower viral load and protect against HIV infection).
Dr. Marovich concluded with current challenges in vaccine development, among which are determining whether and how bNAbs can be induced or if the immune system can be effectively bypassed using vector-based Ab production. Another concern is the capacity to streamline clinical trials in terms of glycoprotein production demands, regulatory ‘bottlenecks’, and more rapid transition into efficacy testing.
Questions about adaptive trial design were raised in discussion and it was noted that they have been proposed as a way to accelerate HIV vaccine development by integrating multiple test-of-concepts into clinical trials. Adaptive study design would allow a trial to change course in response to newly acquired data as it is evaluated. Such trial designs might quickly eliminate poor vaccine candidates, promote promising candidates, and provide important information about the basic immunology of HIV prevention. It was noted, however, that in general, the Center for Biologics Evaluation and Research (CBER) within the FDA does not look favorably upon adaptive clinical trial design; however, discussions and workshops have been held, many in affiliation with the HVTN and the Statistical Center for HIV/AIDS Research and Prevention (SCHARP), regarding how the design might be effective for an HIV vaccine study.
It was also noted that a therapeutic HIV vaccine (as opposed to a preventive vaccine) is designed to boost the body’s immune system to HIV and better control the infection, for example in adults with acute or recent HIV infection who are taking ART. A therapeutic vaccine is an important part of a functional cure, e.g., combination strategy with a reactivation agent and will receive greater priority with time over several DAIDS programs. This area of research is not under the purview of the VRP, but rather a growing area within the Therapeutics Research Program.
Given that there was no public comment, before concluding the meeting, Dr. Dieffenbach suggested scheduling a call with ARAC members with a budget update, to discuss funding priorities and to review the agenda for the upcoming meeting. A table highlighting investment dollars by program and area, specific to NIAID will be posted on the ARAC Web site.
The meeting of the Council adjourned at 4:30 p.m., on Monday, February 4, 2013.
We do hereby certify that, to the best of our knowledge, the foregoing minutes are accurate and complete.
Anthony S. Fauci, M.D.
Chair, National Advisory Allergy and Infectious Diseases Council
Director, National Institute of Allergy and Infectious Diseases
Matthew Fenton, Ph.D.
National Advisory Allergy and Infectious Diseases Council
Director, Division of Extramural Activities National Institute of Allergy and Infectious Diseases
Anthony S. Fauci, M.D.
Chair, National Advisory Allergy and Infectious Diseases Council
Director, National Institute of Allergy and Infectious Diseases
Matthew Fenton, Ph.D.
National Advisory Allergy and Infectious Diseases Council
Director, Division of Extramural Activities National Institute of Allergy and Infectious Diseases
These minutes will be formally considered by the Council at its next meeting; any corrections or notations will be incorporated in the minutes of that meeting.
Last Updated June 10, 2013
Last Reviewed June 10, 2013