The 172nd meeting of the National Advisory Allergy and Infectious Diseases Council (NAAIDC) convened at 10:30 a.m. on Monday, September 24, 2012, 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 5:00 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:
Ad Hoc 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 2,530 research and training applications with primary assignment to NIAID for a requested amount of $869,791,637 in first-year direct costs and recommended approval of 317 applications with $45,724,801 in first-year direct costs.
Dr. Fauci opened the Council session by welcoming visitors to the meeting. He introduced three ad hoc Council members, Dr. William St. Clair, chief, Division of Rheumatology and Immunology, Duke University; Dr. Marcus Clark, co-director, Knapp Center for Lupus and Immunology Research, University of Chicago; and Dr. Larry Schlesinger, chair, Department of Microbial Infection and Immunity, Ohio State.
Two Council members, Drs. Bond and Chao, were unable to attend the meeting.
Dr. Fauci acknowledged the contributions of four retiring Council members—Mr. William McLin and Drs. Samuel Stanley, Christopher Walker, and Richard Whitley—and presented them with plaques and certificates of appreciation for their service.
Council considered the minutes of the May 14, 2012, meeting and approved them as written.
Dr. Francis Collins appointed Dr. Chris Austin as director of the National Center for Advancing Translational Sciences (NCATS).
At the end of June, Mr. William Gillen, NIAID deputy executive officer and director of the Office of Administrative Services (OAS), retired. Ms. Marilyn Kunzweiler is the new director of OAS.
In DAIDS, Dr. Sarah Read was named director of the Therapeutics Research Program.
Dr. Fauci paid tribute to Dr. Norman Letvin, professor of medicine, Harvard, and chief, Division of Viral Pathogenesis at Beth Israel Deaconess, who recently passed away. Dr. Letvin was a world authority on the biology of retrovirus infections in nonhuman primates. He was a valued collaborator at the NIAID Vaccine Research Center and the Center for HIV/AIDS Vaccine Immunology (CHAVI).
On July 23, President Obama named recipients of the Presidential Early Career Award for Scientists and Engineers. Dr. Peter Crompton, chief of the Intramural Malaria Infection Biology and Immunity Unit, Laboratory of Immunogenetics, and Dr. Nihal Altan-Bonnet, an NIAID grantee at Rutgers, received the award.
During the 19th Annual International Poxvirus Conference, Dr. Bernard Moss, chief, NIAID Laboratory of Viral Diseases, received the Lifetime Achievement Award for his outstanding contributions to the field of virology.
Dr. Calman Prussin, chief, Lymphocyte Biology Unit, Laboratory of Allergic Diseases, will serve as 2013 vice-chair elect of the American Board of Allergy and Immunology.
In July, Dr. Fauci and Professeur Jean Francois Delfraissy signed a letter of intent between NIAID and the French National Agency for Research on AIDS and Viral Hepatitis to collaborate on a program of HIV research and development.
In August, NIAID celebrated the 125th anniversary of NIH and paid tribute to Joseph J. Kinyoun, who founded the ancestor institution of the modern NIH, by expanding a Web site that explores his legacy. To learn more about Dr. Kinyoun, go to Dr. Joseph J. Kinyoun: Father of the NIH.
In September, the Indo-U.S. Vaccine Action Program (VAP) celebrated its 25th anniversary in New Delhi with a conference to review VAP accomplishments, a scientific symposium on human immunology and infectious diseases, and the release of a commemorative publication. Dr. Carole Heilman, director, DMID, Mr. Gray Handley, NIAID associate director for international research affairs, and several prominent extramural scientists participated.
From September 7 to 9, Dr. Fauci participated in “The Celebration of Science” to commemorate the global impact of previous scientific discoveries and help jumpstart a new era of scientific discovery.
In February, the President submitted his FY 2013 budget request that held NIH at FY 2012 funding levels. The House and Senate have been unable to agree on FY 2013 funding for U.S. government agencies. With little time to complete appropriations bills, Congress passed a six-month continuing resolution (CR) to keep the government operating through March 27, 2013.
The CR funds the government at $1.047 trillion, the level agreed to in last year’s Budget Control Act, which is about 0.6 percent higher than the FY 2012 government-wide funding level. However, the CR does nothing to prevent automatic cuts that would take place under sequestration if a long-term budget agreement is not passed by January 2, 2013.
In August, Republican staff to the House and Senate Appropriations Committees toured selected NIH and CDC research sites in Brazil and Guatemala, including the NIAID-supported HIV Clinical Trials Networks site at the University of Sao Paulo Medical Center. Gray Handley participated in the Brazil tour.
On May 23, Dr. Carl Dieffenbach, director, DAIDS, briefed congressional staff on NIAID-funded HIV/AIDS research at an event sponsored by amfAR and the AIDS Vaccine Advocacy Coalition (AVAC). On June 20, Dr. Dieffenbach also participated in an amfAR-sponsored congressional staff briefing that focused on curing AIDS.
Over the summer, NIAID leadership and program officials participated in several congressional briefings and events on Lyme disease.
The 19th International AIDS Conference was held in Washington, D.C., from July 22 to 27. Dr. Fauci gave the opening scientific plenary on ending the HIV/AIDS pandemic. His talk showed the links between basic and clinical research, developing interventions, and implementing the interventions with the possibility of ending the HIV/AIDS pandemic.
To end the pandemic, we will need to implement the tools we have through programs like PEPFAR and the Global Fund, but in a sustainable way, such as capacity building, health systems strengthening, new partner coordination, and removing legal, political, and stigma barriers.
An HIV vaccine meeting in Boston on September concluded that an HIV vaccine in pandemic infection is more important in maintaining control than in the initial control of the pandemic. In addition, an HIV vaccine would play an important role in eliminating, maintaining elimination of, and eradicating HIV.
Dr. Fauci gave an update on the voluntary moratorium on research involving highly pathogenic avian H5N1 influenza. Investigators have agreed to extend the moratorium in order to develop fundamental principles of the types of research that can go forward.
Dr. Kathryn Zoon gave an overview of the Division of Intramural Research’s (DIR) strategic and scientific portfolio priorities for FY 2013. These priorities include stabilizing the portfolio of basic research in infectious diseases and immunology in the face of a declining budget; supporting drug and vaccine research and development; supporting clinical research; succession planning of senior investigators; and recruiting new tenure-track investigators as DIR’s budget permits.
DIR’s projected budget for FY 2013 is $329 million, which is a five percent cut from FY 2012. To cope with budget reductions, DIR plans to reduce the number of laboratories, principal investigators, and contracts; cut overall budgets of principal investigators based on the Board of Scientific Counselors’ reviews; reduce administrative overhead; collaborate with the Clinical Center to reduce the costs of clinical trials; and pursue cooperative research and development agreements.
Dr. Zoon announced that in FY 2012 several DIR laboratories merged, and in FY 2013 DIR plans to abolish one laboratory. She noted personnel changes, including four tenure-track investigators who did not proceed to tenure, three new tenure-track investigators, one newly tenured investigator, and seven retirements and anticipated retirements. Dr. Zoon also recognized DIR scientists who received distinguished honors and awards.
DIR instituted three new international programs and started a new trans-laboratory initiative on barrier immunity and repair.
The Board of Scientific Counselors met in December and June to review several DIR laboratories and perform midterm and final tenure-track reviews.
Dr. Zoon concluded by highlighting some of DIR’s scientific achievements.
Dr. Rotrosen welcomed returning members to the National Advisory Allergy and Infectious Diseases Council Subcommittee meeting. Dr. Rotrosen subsequently announced new staff members within the division: Ms. Susan Booher in the Autoimmunity and Mucosal Immunology Branch as a Project Manager, Dr. Sanaz D. Hamrah in the Clinical Research Operations Program as a Clinical Research Pharmacist, Dr. Mark Robien in the Transplantation Immunobiology Branch as a Medical Officer, and Dr. Lisa M. Wheatley, in the Allergy, Asthma, and Airway Biology Branch as a Medical Officer.
Dr. Rotrosen then informed the subcommittee members there would be a number of presentations on the division’s Autoimmune Centers of Excellence:
Dr. Rotrosen finally announced there were no research concepts for clearance.
Dr. Carole Heilman, Director of the Division of Microbiology and Infectious Diseases (DMID), chaired the NIAID Microbiology and Infectious Diseases Council Subcommittee meeting on September 24, 2012. After welcoming the Subcommittee, Dr. Heilman acknowledged retiring Subcommittee members Rich Whitley, Sam Stanley, and Chris Walker, and thanked them for the advice they have provided during their tenure. She also introduced ad hoc member, Dr. Larry Schlesinger, a Professor of Medicine, Chair of the Department of Microbial Infection and Immunity, and Director of the Center for Microbial Interface Biology at Ohio State University.
In her report to the Subcommittee, Dr. Heilman noted that a new SBIR contract solicitation had recently been released and that two areas of interest to DMID were highlighted: multiplex diagnostics and improved formulation of both first- and second-generation TB drugs.
Dr. Heilman provided an update on two initiatives that had previously been presented to the Subcommittee. First, she noted that applications for the new NIAID Leadership Group, which is focused on antibacterial resistance, were received June 1 and that peer review is slated for the winter, with awards in early FY 14. Second, the new Funding Opportunity Announcement for the Centers of Excellence for Translational Research, which build upon NIAID's Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases Research (RCE) program (2003-2014), is currently under development and should be released later this year.
Dr. Heilman then shared background information on two activities DMID staff has been working on during the past year. First, she described a project DMID undertook to document DMID’s biodefense accomplishments in the decade since the September 11 attacks, documenting NIH involvement in the development of new countermeasures that improve the nation’s health. This was expanded to include examples beyond biodefense, describing successes in some of the most challenging areas such as antimicrobial resistance, influenza, tuberculosis, and malaria. The result is a growing library describing DMID’s role in research discoveries that are transforming prevention, diagnosis, and treatment of a multitude of infectious diseases. A Web site is currently being built to showcase these stories.
Dr. Heilman then introduced the afternoon session, which included reports in two program areas requested by the Subcommittee (Hepatitis C and tuberculosis) and two concept clearances (Sexually Transmitted Infections Cooperative Research Centers and the Tuberculosis Research Units); information would also be provided on how DMID works with the Division of AIDS in the area of TB research. She encouraged Subcommittee members to continue to suggest topics of interest so DMID could provide updates at future council meetings.
DMID’s Hepatitis C Virus (HCV) Program Officer, Dr. Rajen Koshy, provided information on the history and prevalence of HCV and summarized important research accomplishments over the past two decades, many stemming from the DMID-supported Hepatitis C Virus Cooperative Research Centers Program (HC CRCs). Current research efforts are primarily focused on the immune response to virus infection and the host factors that are involved. Importantly, these studies involve a variety of well-developed patient cohorts, facilitating the rapid translation of laboratory findings to clinical investigations.
In addition, ongoing research through these centers and other DMID-supported investigator-initiated efforts have resulted in the identification of several potential drug targets ripe for further exploration. Dr. Koshy noted that there has been a robust industry response to drug development using these targets, and that approximately 60 are currently in development. DMID offers a wide variety of preclinical services spanning the drug development pathway to complement industry efforts. Finally, Dr. Koshy reported that DMID recently launched a Phase I/II trial of a prophylactic vaccine candidate for HCV.
The Subcommittee members thanked Dr. Koshy for the informative report, and one member, well versed in this field, noted that the HCV CRCs have helped support early-stage research activities associated with almost every major scientific advance in this field.
Dr. Christine Sizemore, Chief of DMID’s TB, Leprosy and other Mycobacterial Diseases Program, provided an overview of DMID’s TB research program, noting that DMID leads NIAID’s TB effort through the support of a broad range of research activities focused on the development of new TB tools, including drugs, vaccines, and diagnostics. Complementing these research activities are multiple collaborative efforts with other U.S. government agencies and multilateral organizations worldwide that provide a platform to discuss strategies for ensuring that the tools being developed can be utilized in a variety of public health settings, recognizing that TB disease varies from region to region.
Importantly, Dr. Sizemore reported that DMID’s efforts contributed to the preclinical and clinical development of diverse vaccine and drug candidates that are now in the product development pipeline for TB. Dr. Sizemore also highlighted the many preclinical and clinical resources DMID makes available to the research community to foster the development of new TB products, lowering the risk to pharmaceutical companies and not-for-profits to undertake further product development. She also noted that the DAIDS provides advanced clinical development resources as well for research efforts specifically focused on TB in the context of co-infection with HIV.
DMID plans to modify the Tuberculosis Research Units program when it is recompeted in FY 14 (concept clearance below) by integrating human clinical research with innovative and high-quality animal modeling studies. Dr. Sizemore noted that this integration is expected to facilitate the development of more predictive, targeted and interpretable animal models and enhance the ability to select drug and vaccine candidates for further development.
This concept would support clinical and animal studies to better characterize the dynamics of TB infection and the transition to active pulmonary disease, with an emphasis on the paucibacillary phase (low levels of bacterial load in tissues and secretions). Subcommittee members were enthusiastic about the concept, and agreed with the proposed restructuring, recognizing the importance of addressing the issues of latency and persistence in tuberculosis research through integrated, multidisciplinary, and multinational teams. One Subcommittee member encouraged program staff to undertake continuous assessment of the work that will be conducted through the TBRUs to ensure that the science remains highly innovative and adds value to the field and that unsuccessful research projects will be identified on a regular basis and replaced with new approaches within the scope of the program. Dr. Sizemore was also asked to articulate how the research conducted through the TBRUs will contribute to the translation of biomedical knowledge into new tools to control TB (e.g., drugs, vaccines and diagnostics). Dr. Sizemore responded that through the integration of clinical research and animal modeling, it is expected that the back-translation of clinical findings in immunology, microbiology and pathology into animal studies will result in more disease relevant animal models. These animal models are expected to be operationalized through DMID’s preclinical services programs to help improve the selection of clinical candidates for later clinical testing. The Subcommittee unanimously approved the concept.
This initiative is aimed at stimulating multidisciplinary, collaborative, and synergistic research strategies for sexually transmitted infections (STIs) and developing and evaluating control and prevention strategies to reduce their public health impact. In this recompetition, NIAID plans to focus on syndromes and/or clinical outcomes that may encompass several pathogens. In addition, each Center will be required to support a Career Development and Training Program to help mentor investigators who are new to the field.
The Subcommittee commented that STIs are a current and ongoing public health problem that are unrecognized and underestimated. They believe this program addresses an unmet medical need, one that has a significant impact in adolescent and minority populations. The Subcommittee was very supportive of the incorporation of new areas of investigation, such as the microbiome. The Subcommittee unanimously approved the concept.
Dr. Celum welcomed the ARAC members, DAIDS representatives, and guests. She presented the minutes of the May 14, 2012, ARAC meeting, and they were approved with no changes by a hand vote.
Carl W. Dieffenbach, Ph.D., Director, DAIDS
Dr. Carl Dieffenbach welcomed the ARAC members, attending DAIDS and NIAID representatives, and other guests. He noted two DAIDS organizational changes: 1) Dr. Susan Plaeger, the Director of the Basic Sciences Program retired earlier this summer; and 2) Dr. Sarah Read has been selected as the Director of the Therapeutics Research Program (previously acting director). Dr. Dieffenbach announced that the following three members will be retiring from the Council and presented each with a certificate of appreciation: Dr. Karen Goldenthal, Dr. Maureen Goodenow, and Dr. Judith Lieberman (unable to attend the meeting).
Dr. Dieffenbach acknowledged the recent death of renowned HIV/AIDS researcher, Norman L. Letvin, M.D. (1949-2012) and his many contributions to primate vaccine studies. Dr. Letvin was a founding investigator/member of the NIH Vaccine Research Center at NIAID as well as Professor of Medicine at Harvard Medical School and Chief of the Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center. He was a valuable member of the Center for HIV/AIDS Vaccine Immunology (CHAVI) and a leader in the field of nonhuman primate and HIV vaccine research.
In February, the President put forward a budget request for FY 13 that held NIH at the FY 12 level. Perceived percent changes in funding to several NIH institutes reflect the formation of the new National Center for Advancing Translational Sciences (NCATS) and the consolidation of various programs under NCATS.
Currently, NIH is operating through a six-month continuing resolution (CR), which funds the government from October 1, 2012, to March 27, 2013. However, the CR, recently enacted by both the full House and Senate, does not avert automatic cuts that would take place under sequestration. Sequestration will go into effect if a long-term budget agreement, or another appropriate measure, is not passed by January 2, 2013. The White House (Office of Management and Budget or OMB) estimates sequestration would cut U.S. science budgets by 8.2 percent.
Dr. Dieffenbach noted that he briefed congressional staff on NIAID-funded HIV/AIDS research at an event sponsored by the Foundation for AIDS Research (amfAR) and the Global Advocacy for HIV Prevention (AVAC) in May. He gave a presentation to congressional staff again in June at another event sponsored by amfAR.
The International AIDS Conference was held in Washington, D.C. this past July, back in the U.S., after over 20 years. Over 20,000 attendees from 183 countries came to the meeting that had more than 200 sessions, 19 plenary lectures, and 185 satellites sessions. At the opening plenary, Dr. Fauci inspired the audience with a talk about the best way to end the HIV epidemic; he reviewed key milestones in basic science, which have enabled the development of treatment and prevention strategies and discussed the momentum for a cure—either in terms of eradication or a functional cure.
Also, at the opening plenary, U.S. Secretary of State Hillary Clinton described new funding initiatives, a shift in PEPFAR (The President's Emergency Plan for AIDS Relief) to building health infrastructure, and the need for combining prevention effort worldwide. Mr. Phil Wilson, the President and CEO of the Black AIDS Institute, spoke about the disproportionate impact of HIV on blacks and encouraged community along with advocacy groups to directly address misperceptions about treatment and prevention.
At the AIDS Conference, the NIH held a panel discussion, which was intentionally co-sponsored in the Global Village because it was then open to the general public as well as conference delegates, and was free of charge. The program highlighted the collaborative efforts of several organizations to curb the AIDS epidemic in the District of Columbia (D.C.), including NIH, the Centers for AIDS Research (CFAR), and District academic institutions.
In July, NIH launched a large, multinational phase III trial known as A Study to Prevent Infection With a Ring for Extended Use or ASPIRE. The study aims to determine whether the drug dapivirine can safely prevent HIV infection when continuously released in the vagina from a silicone ring replaced once a month. With a projected enrollment of nearly 4,000 participants in five countries, women will be assigned randomly to receive either a silicone ring containing 25 milligrams of dapivirine or a placebo silicone ring. The ring was developed with Gates support by the International Partnership for Microbicides and Queens University Belfast (Northern Ireland). The results of the trial are expected in early 2015.
NIAID made two grant awards in July for the new Centers for HIV/AIDS Vaccine Immunology & Immunogen Discovery (CHAVI-ID). The seven-year awards went to Duke University (Bart Haynes) and Scripps Research Institute (Dennis Burton); first year funding for both awards totals to $31 million. Additionally, NIH awarded $7.8 million to fourteen grantees in response to a (request for applications) RFA for innovative HIV vaccine approaches. These are four-year awards that will allow investigators to build on recent discoveries about the basic biology of HIV.
The AIDS Vaccine 2012 meeting convened in Boston, from September 9 to 12, and Dr. Fauci among others emphasized the importance of HIV vaccine research in the context of combination HIV prevention strategies, such as voluntary medical male circumcision, pre-exposure prophylaxis (PrEP), anti-retroviral therapy (ART), and testing and counseling. Dr. Fauci noted that using a vaccine in conjunction with other prevention strategies creates a new paradigm. Vaccine design has become more complicated; but a vaccine is still required to maintain control of the epidemic and eradicate HIV disease.
NIH and especially NIAID have the data from the Multicenter AIDS Study (MACS) and the Women’s Interagency HIV Study (WIHS), which can be availed to further investigate treatment of HIV infection and related illnesses in older individuals. To understand how long-term HIV infection appears to accelerate the aging process, NIAID is seeking applications for multidisciplinary studies of HIV/AIDS and aging.
DAIDS is also sponsoring a scientific meeting focused on the development of innovative strategies to cure HIV infection. Strategies for an HIV Cure—the CURE Workshop will be held November 28 to 30, 2012, in Washington, D.C. The purpose of the workshop is to bring together researchers associated with each of the three NIH-funded Martin Delaney Collaboratories, HIV cure researchers, investigators from complementary disciplines, and community members. The Web site for more information and registration should be online in the near future (www.blsmeetings.net/HIVCureMeeting).
One of the major activities involving NIAID for the past two years has been the restructuring of the NIH/NIAID clinical networks. The Network Leadership applications are due September 28. The scientific reviews will occur March 2013, and Council review will follow later in the fall.
The funding opportunity announcement (FOA) for the clinical trials units was released in April, and two grantsmanship workshops have been held to assist those interested in applying for the funding related to the clinical trial units (CTUs) and their associated clinical research sites (CRSs). The last of the workshops will convene in Johannesburg (South Africa) in October. The CTU applications are due in January 2013 with the earliest start date in FY 15.
James Bradac, Ph.D., Chief, Preclinical Research and Development Branch, Vaccine and Prevention Research Program, DAIDS
The mission of the AVRS has been revised in the last year, returning to its roots in the coordination of basic research activities; clinical trials related issues and discussions will be delegated primarily to the Strategic Working Group (SWG).
Minor Changes to the Subcommittee:
Dr. Bradac capsulized the last two AVRS meetings; one was the Joint SWG/AVRS meeting in January 2012 and the other AVRS meeting in May 2012. He noted the overview given by Dr. Kublin at the joint meeting, where Dr. Kublin outlined the organizational structure of the HIV Vaccine Trials Network (HVTN) and its three main areas of activity:
The Programs in the RSA are designed to answer several critical questions that among others include: 1) Will DNA + NYVAC + protein elicit antibody responses similar to those seen in RV144? and 2) Is there an accelerated DNA priming regimen that can synchronize the protein boost across regimens? By necessity, some questions will be answered before the protocols are initiated based on the analysis of prior data.
Important comments from the joint meeting were:
One of the principal presentations from the AVRS meeting (NHP models) in May was delivered by Dr. Brandon Keele who discussed the following:
General considerations in the use of NHP models for vaccine studies;
A main point made by Dr. Keele was the current availability of experimental mucosal exposure models in the NHP via rectal, vaginal, or penile routes that recapitulate what is seen in human HIV infection. The May meeting also emphasized the cooperative interactions within the newly awarded Consortia and planned collaborations between Consortia as well as the need to build connections from basic and translational research to clinical research. The connections should include sample sharing and joint meetings.
Future meeting dates for the AVRS
Feb 5-6, 2013 AVRS + SWG
Sept 17-18, 2013 AVRS
Kevin Ryan, Ph.D., Deputy Director and Acting Director, Vaccine Research Program (VRP), DAIDS
“Halt the spread of HIV infection by defining highly effective prevention strategies including a preventive HIV vaccine.”
The preceding statement summarizes the overall mission of the Vaccine Research Program within DAIDS. Specifically, the program aims to:
The scientific advances in 2012, particularly those resulting from the lab studies of RV144 vaccine responses that have identified correlates of HIV acquisition risk, have driven the quest to understand the full implications of these observations. The primary objective is to reach a better understanding of the best approaches for immunogen discovery, immunization strategy, and clinical trial design. The upcoming four initiatives will provide key support across the entire spectrum of VRP programs, from basic vaccine discovery through clinical research.
Dr. Ryan introduced the invited speaker, Dr. Rama Amara who discussed an overview of his work in HIV vaccine development, preceding the presentations of the concept reviews.
DNA/MVA HIV Vaccines: Basic Research to Clinic
Rama Amara, Ph.D., Professor, Emory Vaccine Center, Yerkes National Primate Research Center, Department of Microbiology and Immunology, Emory University, Atlanta, GA
Dr. Amara summarized the studies he has carried out over the past 15 years, funded by multiple NIAID mechanisms that lead from basic discovery research to the testing of experimental vaccines in human clinical trials. He then presented in some detail his current HIV vaccine research.
HIV/SIV infection can be divided into two phases:
The hallmark of HIV infection is the transient loss of CD4+ T cells in the peripheral blood, lymphoid organs, and mucosal tissues; a partial restoration of CD4+ T cells occurs followed by a slow decline over time and finally, at very low CD4 counts, the manifestation of AIDS. About 80 percent of the total CD4+ T cells are in the gut, and about 70 percent of the CD4+ T cells are depleted from the body within a few weeks after infection.
The window of maximal opportunity for a vaccine to prevent infection is short, perhaps 3 to 4 days, when small founder populations initiate infection at the mucosal site of virus exposure. The virus disseminates through draining lymph nodes, ultimately leading to systemic infection and establishment a viral reservoir in lymphoid tissues. Importantly, both neutralizing and non-neutralizing antibodies (Abs) contribute to protection at mucosal surfaces.
Until recently, studies in animal models (macaques) used a single high dose of virus, resulting in no prevention, but viral control. With the realization that infection dose can influence the challenge outcome, virus is now titered and utilized in repeat moderate doses, yielding prevention and viral control as well as more faithfully mimicking human HIV infection.
One vaccine strategy is a heterologous prime boost in which the first administration or the prime generates a pool of memory lymphocytes for a quicker and stronger response to the second administration-- the boost. The boost is a modified pox virus (MVA) carrying HIV DNA. Both vaccines express immature virus-like particles (VLPs, non-infectious) displaying native forms of the HIV envelope (Env) protein. In the last ten years, the focus of the vaccine field has been directed towards T cell-based vaccines. The current focus has shifted to antibody responses, partly due to the encouraging results from the Thai RV144 trial.
A critical question is: Can we further enhance the immunogenicity and efficacy of the DNA/MVA vaccine to prevent HIV infection? The approach being explored is to enhance the avidity and mucosal homing of anti-viral Abs using Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) and CD40L (soluble CD40 ligand) as adjuvants. GM-CSF and CD40L adjuvants reduce acquisition of repeat dose intra-rectal SIVsmE660 infection. Significant correlation has been found between avidity of the elicited IgG against the native form of E660 Env of the challenge virus and the number of challenges to infection. Protection is less dependent on neutralizing activity, and the correlate is avidity of the binding antibody, similar to findings suggested by the RV144 trial where the correlate seemed to involve binding antibody to the V2 loop of Env. The results are also consistent with the enhanced avidity by both adjuvants. The mechanism(s) are still unknown. Studies suggest CD40L promotes germinal center formation in the lymph node and the generation of T-follicular helper-like cells.
Plans are moving forward to human studies. The GM-CSF-adjuvanted HIV clade B vaccine, produced by Geovax with funding through a NIAID IPCAVD award, will soon enter phase 1 studies in the U.S. and will be carried out by the HVTN. Also, CD40L-adjuvanted HIV-1 vaccines are being made.
Thandi Onami, Ph.D., Program Officer, Vaccine Clinical Research Branch, VRP
The objective of this concept is to support multidisciplinary teams that will investigate structural and conformational features of glycosylation to aid immunogen design and to elucidate how differential glycosylation impacts the quality of the immune response. The solicitation is new with the duration of awards for up to five years, standard for R01s.
Earlier efforts to pursue glyco-analysis approaches in HIV research were often unsuccessful as the technology was not yet mature. Recent recognition that many potent broadly neutralizing antibodies (bnAbs) bind glycans has coincided with the nascent development of refined tools for detailed glycan examination.
The April 2012 NIH workshop, “Functional Glycomics in Vaccine Design” was well-attended with over 300 registrants. The workshop stimulated several collaborations and interest in HIV from a fresh cadre of investigators. The PA-12-05: Functional Glycomics in HIV Vaccine Design (R01) was issued in February 2012; seven applications were received and favorably reviewed; however, none were in the fundable range.
This initiative will support areas of glycosylation and basic vaccine discovery research that have not been fully exploited as well as fund approaches to better characterize the complex role of glycans in HIV immunogen design. Examples of responsive research include: Env N-glycans and evolution of antibody response; and modulation of immune responses. Non-responsive research examples include: microbicide or drug development and the isolation of new monoclonal antibodies (mAbs).
Reviewers (McCutchan and Tomaras) expressed enthusiasm for the concept along with its timeliness and suggested emphasis on the need for immunogen design research. In response to reviewer comments, staff prioritized the research areas, emphasizing the need for immunogenicity and immunogen design and highlighting the need for studies dissecting glycan sites and structure. In discussion, the committee asked about the extent to which this will be a truly multidisciplinary effort and the challenges of bringing this initiative to the attention of and garnering interest from glycobiologists. Staff noted that they have already had numerous inquiries from glycobiologists following the workshop. There were also questions about the review process and it was noted that the study section would be broadened to facilitate discussion about the science. Finally, Dr. Onami noted that anyone who had responded to the earlier PA could apply to this RFA; the RFA considers all applications new so even an application that has been reviewed before and not funded has a new shot at this RFA.
The ARAC members expressed support for the concept and voted approval.
Michael Pensiero, Ph.D., Vaccine Translational Research Team Leader, Preclinical Research and Development Branch, VRP
The objective of this initiative is to place NIAID/VRP in a position to commence rapidly with the manufacture of promising candidate vaccines for use in advanced clinical trials that have shown safety and immunogenicity in pre-clinical/early clinical trials. The solicitation is in the form of a N01-Broad Agency Announcement (BAA); the concept is new with seven year duration of the awards, and the anticipated number of awards is five to seven.
The initiative will support a three-staged contract approach for the scaled manufacture vaccine candidates that have been tested pre-clinically/clinically and have shown promise as prophylactic HIV vaccines. The milestone-driven contract stages consist of: stage I product development planning, stage II manufacture, and stage II regulatory/stability.
SVD will have limited scope in that it will be used exclusively for manufacture of candidate vaccines, especially for advanced development. This contract mechanism will complement the existing Pre-Clinical Master Contract, which is primarily used for specific and limited gap-filling activities such as pre-clinical toxicology and regulatory support among others. The reviewers (Michael and Goldenthal) considered this an important initiative because currently NIAID grantees in the pre-clinical area have difficulty moving products into advanced clinical development and recommended approval. The reviewers felt that the initiative provides a mechanism for NIAID to quickly advance products within existing NIAID-funded programs as well as those with other funding mechanisms from other ICs or outside of NIH. In discussion, the committee asked about the potential to work with the Division of Microbiology and Infectious Diseases (DMID) and indeed this contract can offer a potential platform for DMID in their vaccine development efforts.
Other questions helped members to better understand the duration of each stage of development. There is some flexibility for the length of stage I but NIAID will need to verify that a manufacturer can do what is being proposed (e.g., manufacturing capability, GMP compliance, etc.,) before moving forward to the next step. In addition, stage I cannot be for more than two years. The milestones in stage II will be both time- and production- dependent. Funding all stage I grantees to the next stage is highly unlikely and depends on the success meeting the milestones of the first stage of the project as well as available monies and the scientific need in the vaccine field. Investment in this type of development is risky and is the reason big pharmaceuticals will not invest in it. In order for additional applicants to apply for stage I development another broad agency announcement would need to be released at a future date.
Stuart Shapiro, M.D., Vaccine Discovery Team Leader, Preclinical Research and Development Branch, VRP
The objective of this concept is to provide a centralized resource for the compilation and analysis of genetic sequences, immunological epitopes, and associated data for HIV-1 and related lentiviruses. The mechanism is by Interagency Agreement (IAA), a renewal of ongoing efforts with the duration of the award for seven years.
NIAID started the HIV Database and Analysis Unit in 1987 through an IAA with the Department of Energy (DOE), and the Database has been located at Los Alamos National Laboratory since its inception. The current Database Unit consists of three relational databases available on the Internet and accessible to anyone (http://hiv-web.lanl.gov) and includes the following: HIV Genetic Sequence Database (1987); Immunology Database (1995); and the NHP HIV/SIV Vaccine Database (2000).
The proposed enhancements of the HIV Database and Analysis Unit activities will entail:
The reviewers (Goodenow, McCutchan, and Tomaras) recommended that the essential components should be renewed and that the proposed enhancements were excellent ideas. However, the reviewers noted that the deep sequence database will be a challenge; it was already planned that the initial plans for this new database would be peer-reviewed, but in response to the reviewers’ concerns a mid-term review is now being planned. The reviewers’ suggestion that the deep sequence database accept anti-envelope antibody data was also accepted. Additionally, instead of discontinuing the NHP HIV/SIV Vaccine Database, the reviewers requested a survey of current and potential users to determine if improvements can make the database more useful. Staff noted that this would be explored as a separate initiative at a later date.
In discussion there was a question about working with journals to encourage scientists to deposit deep sequencing results in the database. Staff said that this was a good idea and acknowledged the need for a data repository becomes more evident as the technology is universally utilized.
This initiative seeks to accelerate the discovery of an HIV/AIDS vaccine by providing support for the Global HIV/AIDS Vaccine Enterprise Secretariat. GHAVE is an alliance of independent HIV vaccine research funding and advocacy organizations dedicated to accelerating the development of a preventive HIV vaccine. The mechanism is by N01or contract and is a renewal with the duration of the award for seven years.
The contract supports the Enterprise Secretariat to perform multiple activities to facilitate consultation and communication along with collaboration and data-sharing among the Enterprise partners. A growing need exists for strategic-level coordinated planning with major funders to avoid duplication of effort or working at cross-purposes. The Secretariat, supported by this initiative, is composed of six individuals who inform, operationalize, execute, and communicate Board decisions.
A key part of the Secretariat’s duties is to promote collaborative dialog across the vaccine research field, and the Secretariat has hosted several consultations on subjects such as clinical trial designs and the RV144 trial results. A key goal of the Secretariat is to advance vaccine research by resolving scientific disagreements or other potential roadblocks. The GHAVE initiative funding is committed for the first year only; as with most contract awards, NIAID may choose to not exercise funding options for any or all years after year one.
The reviewers (Celum and Cohen) recommended approval. Drs. Ryan and Dieffenbach noted that this contract funds the “nuts and bolts” of the Secretariat, and although other funding may be sought under the 501(c)(3) status, without NIAID’s input, the 501(c)(3) ceases to exist. Discussion focused on the role of the Enterprise overall, its importance as a coordinating body among various funders of HIV vaccine research, the value of the HIV Vaccine conference that they organize and the contributions of other co-funders. Overall, committee members said they gained a better appreciation of the Enterprise’s goals and the value of a strategic-level venue for funder planning. They gained a better understanding of how the Enterprise can help minimize duplication of research efforts and optimize the coordinated timing of interrelated research projects.
Diana Finzi, Ph.D. Chief, Pathogenesis and Basic Research Branch, DAIDS
Dr. Finzi noted that the three concepts to be considered have common themes—none can be supported through smaller grant mechanisms; all are essential to providing the core activities upon which grantees can build; and all three have evolved to become significant resources for the HIV scientific community.
The invited speaker Ms. Lisa Jacobson, introduced by Dr. Finzi, gave an overview of the HIV epidemic among men who have sex with men (MSM), preceding the presentations of the three concept reviews.
Lisa P. Jacobson, Johns Hopkins University, Bloomberg School of Public Health, Department of Epidemiology, Baltimore, MD
HIV infections are occurring at high rates among MSM in the U.S. and account for a disproportionate burden (61 percent of new infections in 2009) of new HIV cases. As the HIV epidemic is not decreasing and is in fact increasing among some sub-populations of MSM research on the intersection of HIV, treatment, aging and comorbidities is important. Dr. Jacobson noted that while life expectancy has increased with treatment it is still below that of the general population.
Statistics (2009) show a 21 percent increase in HIV incidence for persons aged 13 to 29 years, mainly due to a 34 percent increase in young MSM, particularly black MSM. Among white MSM, HIV infection is not concentrated at any one age, but remains persistent across all age levels.
Several challenges are specific to black MSM in the U.S., including the following:
Among black MSM, a key prevention target is to increase treatment and increase support for adherence throughout the community. The era of HAART (highly active antiretroviral therapy) has meant that more men are aging with HIV and experiencing age-related complications. HIV should more rightfully be thought of as a chronic condition for men well treated for HIV, yet experiencing significant morbidity associated with HIV and its treatment. Cohort studies of HIV are necessary to differentiate the risk of aging and HIV on AIDS and non-AIDS morbidities.
It is very important that older men start treatment earlier to help improve their health status over time. In the U.S., the proportion of the HIV/AIDS population that is older than 50 years is increasing and is expected to reach 50 percent of the HIV/AIDS population by 2015.
Research suggests that having an AIDS diagnosis is one of the strongest predictors for sequelae such as cardiovascular disease, frailty, and kidney disease.
Looking at frailty, defined as the loss of physiologic reserves where individuals have a higher rate of disability, the increase in this parameter is significantly different from the uninfected, beginning at 50 years and beyond in age. Related to frailty is monocyte/macrophage activation as well as T cell activation. The risk factors for frailty include a history of AIDS and hepatitis C.
Among the questions that remain unanswered are:
Carolyn Williams, Ph.D., M.P.H., Epidemiology Branch, Basic Sciences Program, DAIDS
This is an initiative for the renewal and limited expansion of the Multicenter AIDS Cohort Study (MACS). The MACS cohort will continue as a cooperative agreement, and the renewal is for five years. The dollar amount of one year funding, between NIAID and NCI, depending on the budget, will be a maximum of $16.7 million for one year. That would fund one data management center and four clinical sites. The MACS has several co-funding institutes as well as a number of investigator-initiated grants that are aligned with the MACS such that a range of NIH institutes are included.
The MACS was begun in 1984 with the enrollment of over 5000 MSM (>2000 HIV-positive and >3000 HIV-negative but at risk) at clinical research centers across the U.S. It is the longest running HIV cohort study in the world and continues to elucidate the natural and treated history of HIV infection in MSM.
The MACS FY 14 renewal will seek applications in a limited competition from the four current clinical institutions to follow HIV-positive and HIV-negative but at risk MSM. Cohort studies such as the MACS have the optimal design to understand disease processes in long-term chronic illness in the current standard-of-care environment.
The reviewers (Celum and Cohen) recommended approval, noting the uniqueness of the MACS as a repository with a large dataset over many years that is well suited to address key questions. They also approved of the suggested recruitment of additional minority men and men on new therapies, and agreed that a rolling cohort is a good way to proceed. The Advisory Board is essential and will help the MACS stay cutting-edge.
During the discussion, the comment arose that in addition to biological data, MACS should consider tracking social and behavioral determinants. A suggestion was given that transgender individuals should be identified along with any behavior-social aspects of the gender change. Also, MACS should try to include men who do not self-disclose MSM behavior. Another suggestion was made to bring in a rural and/or southern site given the MSM epidemic among minority males in that region. The inclusion of younger men of color, not just MSM, was also discussed. Staff acknowledged the value of these suggestions and also noted the importance of not losing men already enrolled at current sites. There was also a question about the extent to which support of junior investigators has occurred. The committee felt that long range planning is important so that the most important questions are addressed and cost-effectiveness is considered.
Given members’ concern about inclusion of men in southern and/or rural areas, the concept was approved with the modification that the ability to include such sites be explored as the cohort seeks to expand enrollment.
Roger Miller, Ph.D., Targeted Interventions Branch, Basic Sciences Program, DAIDS
The objective of this concept is to assist academic and private sector investigators in advancing the development of their therapeutics or topical microbicides for the treatment or prevention of HIV. The mechanism is through N01 (contract), and the initiative is a renewal with the duration of the one award for seven years.
This solicitation will support DAIDS drug discovery and evaluation programs by providing a contract to evaluate potential HIV therapeutics and topical microbicides via in vitro assays utilizing standard and high throughput screening (HTS) formats. Limited public and private sector funding of translational research is an impediment to bringing new therapeutic and prevention leads to clinical trials. The contract mechanism gives DAIDS flexibility in developing assays needed for drug discovery and development.
The reviewers (Goodenow and Lieberman) supported the concept and recommended approval. The reviewers had several suggestions that they felt were adequately addressed in discussion included the need to have: clear outcomes, milestones and metrics for success for the in vitro testing activity; details of the interaction along with the pipeline activities; criteria for assays/compounds to enter into and move along the pipeline; a focus on gaps in therapeutics; and a focus on reservoirs of HIV latency, or drug resistance, that might not be targeted by available drugs.
In discussion, the question came up as to whether or not this program should combine both therapeutics and microbicides and the distinct challenges of each were noted. It was noted that this was a small resource and the intent is not for NIAID to become a full drug company but to provide the resources that many institutions don’t have access to or the expertise to do on their own. The committee agreed and voted to approve the concept.
Paul Black, Ph.D., Targeted Interventions Branch, Basic Sciences Program, DAIDS
The objective is to provide a dedicated animal model resource as a standardized platform for the evaluation of novel HIV therapeutic approaches. The mechanism is through N01 (contract), and the initiative is a renewal with the duration of the award for seven years.
This initiative will support NIAID/DAIDS drug discovery and evaluation programs by providing a contract to evaluate potential HIV therapeutics in a small animal model. At present, much of the R&D activity is in small businesses and academia, which often do not have the experience and/or expertise working with HIV-1 infected animal models. The proposed mouse models provide a bridge from in vitro studies to more costly non-human primate studies and early-phase clinical studies.
The current award specifies the use of the SCID-huThy/Liv model. In this model, immunocompromised SCID (Severe Combined Immunodeficiency) mice are "humanized" by implanting donor human thymus and liver lymphoid tissue; the human tissue implants are allowed to grow to a mature state. The humanized animals with mature human lymphoid tissue implants are then infected with HIV-1. This initiative continues the use of the SCID-huThy/Liv mouse model and adds a second model that supports systemic and mucosal HIV infection in mice and permits longitudinal treatment studies. The concept represents the only DAIDS supported contract resource for evaluating the efficacy of potential HIV therapeutics in vivo from 2014 forward.
The reviewers (Zack and Karn) recommended approval, noting “the strong continuing need for humanized mouse models in the development of HIV therapeutics.” In addition, the reviewers suggested the concept would be strengthened by including plans for CURE research since this is a priority for DAIDS (and it will be incorporated into the RFP) and by more extensive advertising of the contract proposal and resource (which will be done). They also suggested that there be some type of outside review to evaluate requests for contract resources and staff noted that there are already two DAIDS committees that provide such guidance with outside review obtained, as needed.
The meeting of the Council adjourned at 5:25 p.m., on Monday, September 24, 2012.
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 August 05, 2013