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NIH National Advisory Allergy and Infectious Diseases Council

Minutes of Meeting: May 23, 2011

 

Council Members Present:

  • Dr. Carol Carter
  • Dr. Connie Celum
  • Ms. Dázon Diallo
  • Dr. Michael Holtzman
  • Dr. Norma Kenyon
  • Mr. William McLin
  • Dr. Louis Picker
  • Dr. George Siber
  • Dr. Samuel Stanley
  • Dr. Christel Uittenbogaart
  • Dr. Christopher Walker
  • Dr. Richard Whitley
  • Dr. Jerome Zack

Ex Officio Members Present:

  • Dr. Victoria Davey
  • Dr. Anthony Fauci
  • Dr. Bruce Gellin
  • COL Kent Kester
  • Dr. Rima Khabbaz

Ad Hoc Member Present:

  • Dr. Mark Davis

Ex Officio Members Absent:

  • MG James Gilman

Council Members Absent:

  • Dr. Ann Arvin
  • Dr. Nelson Chao
  • Dr. Regina Rabinovich
  • Dr. Velma Scantlebury
  • Dr. Jenny Ting

NIAID Senior Staff Present:

  • Dr. Hugh Auchincloss
  • Dr. Carl Dieffenbach
  • Dr. Carole Heilman
  • Dr. Marvin Kalt
  • Dr. John McGowan
  • Dr. Daniel Rotrosen

Table of Contents

I. Review of Grant Applications

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 2,510 research and training applications with primary assignment to NIAID for a requested amount of $1,086,038,360 in first-year direct costs and recommended approval of 550 applications for $416,090,482 in first-year direct costs. 

II. Remarks of the Director, NIAID—Anthony S. Fauci, M.D.

Dr. Fauci opened the Council session by welcoming visitors to the meeting. Five Council members, Drs. Arvin, Chao, Rabinovich, Scantlebury, and Ting were unable to attend the meeting. Colonel Kent Kester, Commander of the Walter Reed Army Institute of Research, attended the open session of Council for ex officio member Major General James Gilman.

Dr. Fauci announced the appointment of five new Council members: Ms. Dázon Diallo, SisterLove, Inc.; Dr. Jerome Zack, University of California, Los Angeles; Dr. Michael Holtzman, Washington University in St. Louis; Dr. Norma Kenyon, University of Miami; and Dr. Velma Scantlebury, Christiana Care Transplant Center. He also introduced one ad hoc Council member, Dr. Mark Davis, Howard Hughes Medical Institute scholar at Stanford University, and two special guests from the Bulgarian Ministry of Health, Dr. Hristo Taskov, director, National Center for Infectious and Parasitic Diseases, and Dr. Tonka Varleva, chief of the Directorate of HIV/AIDS and Tuberculosis.

Consideration of Minutes of Previous Meeting

Council considered the minutes of the February 7, 2011, meeting and approved them as written.

Tributes and Awards

Dr. Fauci announced that Dr. Ronald Germain is chief of the new Laboratory of Systems Biology, Division of Intramural Research.

Dr. Fauci paid tribute to Dr. Edwin Kilbourne who passed away in February. Dr. Kilbourne is best known for developing high-yield recombinant vaccines against seasonal influenza.

Dr. Cal Presson, chief of the Lymphocyte Biology unit, Laboratory of Allergic Diseases, was elected to the Board of Directors of the American Board of Allergy and Immunology. Dr. Fauci acknowledged NIAID scientists who received special awards and honors, including three intramural scientists recently elected to the American Association for the Advancement of Science and six elected as fellows to the American Academy of Microbiology.

Meetings and Events

On February 1, Drs. Harold Varmus, Gary Nabel, and Anthony Fauci held a meeting at the NIAID Vaccine Research Center to come up with ideas for developing a vaccine against Epstein-Barr virus.

From February 16 to 18, NIAID cosponsored an international meeting in San Juan, Puerto Rico called, A Reemerging Challenge in the Americas: Opportunities for Dengue Research Collaboration. Dr. Fauci delivered the keynote address and spoke about the Institute’s global research portfolio on dengue.

On March 7, NIAID held a second town hall meeting on restructuring NIAID clinical trials networks. Participants discussed the new infectious diseases leadership group that will focus initially on bacterial antibiotic resistance.

Other meetings of interest to NIAID included an NIH-hosted meeting from March 9 to 11, The Neglected Tropical Diseases: Defining Opportunities to Accelerate Translational Research, and an NIAID-hosted workshop on March 23, Influenza Antiviral Research Pipeline.

NIAID celebrated the 10th anniversary of the NIAID Vaccine Research Center on March 31.

Budget Update

The NIH budget for FY 2011 is $30.8 billion, a 1.0 percent decrease from FY 2010. NIAID received $4.8 billion, a decrease of 0.9 percent from FY 2010. 

NIAID began FY 2011 with a fiscally conservative approach. Now that we have a final allocation, we will support a payline to the 10 percentile for unsolicited investigator-initiated research and the 14 percentile for new and early-stage investigators.

The President’s FY 2012 budget for NIH is $31.8 billion, 3.5 percent more than FY 2011. NIAID’s allocation is $4.9 billion, an increase of 2.9 percent over FY 2011. 

Legislative Update

On May 11, Dr. Fauci accompanied Dr. Francis Collins when he testified on the FY 2012 President’s budget before the Senate Appropriations Subcommittee.

The Senate Appropriations Committee staff visited NIH for a tour of the Vaccine Research Center on April 21. As a follow-up to this visit, the Committee staff toured the NIAID Vaccine Pilot Plant in Frederick, Maryland, and the Integrated Research Facility at Fort Detrick on April 27.

On February 23, Drs. Carl Dieffenbach, Roberta Black, and Jeanna Piper provided an update about our research on microbicides to the staff of the Senate Committee on Foreign Relations. Representatives from the NIH Office of AIDS Research, CDC, USAID, and the Office of the U.S. Global AIDS Coordinator also participated.

On March 9, Dr. Dieffenbach and Dr. Barney Graham participated in a Foundation for AIDS Research congressional briefing on HIV/AIDS prevention.

Other Information Items 

Lancet voted the NIAID-supported research paper, “Effect of Influenza Vaccination of Children on Infection Rates in Hutterite Communities,” paper of the year in biomedical research.

Dr. Fauci presented a new feature on the NIAID Web site called NIAID Showcase. It highlights in words and pictures some notable achievements in the history of NIAID.

Researchers at the Rocky Mountain Laboratory developed a fast and sensitive blood test for human prion disease.

A study funded by NIAID through the Immune Tolerance Network was key to the approval of Rituximab for severe vasculitis.

Dr. Fauci gave brief updates on recent advances in tuberculosis, leprosy, malaria, and asthma, and mentioned the importance of the 2011 World Health Day Theme: Combating Drug Resistance.

The first week in June will be the 30-year anniversary of the first reported cases of HIV. Dr. Fauci summarized some recent breakthroughs in HIV/AIDS research. On May 31, he will give a lecture at NIH entitled “30 Years of HIV/AIDS: A Personal Journey.”

III. Guest Speaker—Daniel Rotrosen, M.D., Director, Division of Allergy, Immunology, and Transplantation—NIAID Strategic Plan for Research on Vaccine Adjuvants

In November 2010, the Institute convened a blue ribbon panel on NIAID research on vaccine adjuvants. The charge to the panel was to recommend strategies to enhance existing programs, propose new programs, and develop research resources from novel adjuvant discovery through clinical applications.

The Institute asked the panel to identify immediate and long-term goals for research and resources in three major areas: basic immunology and early adjuvant discovery, later stage adjuvant development and preclinical testing through Phase I, and clinical assessment of adjuvants.

Dr. Rotrosen gave an overview of the current program goals and some of the future research directions that the panel highlighted.

The panel discussed the value of high-throughput screening and whether this should be an area of future investment. If the Institute is going to continue to put resources into this area, the panel strongly recommended that it address the expertise gap in formulation science.

For future directions, the panel recommended correlating adjuvant mechanisms of action with particular adaptive immune responses. Other areas that the panel addressed were the limitations of current animal models, the importance of focusing on different administration routes, and the need to develop standardized assays to predict in vivo outcomes.

The panel made a major pitch to identify and validate markers to predict efficacy and reactigenicity and to promote cross-divisional and interdisciplinary collaborations. 

IV. Report of the Division of Allergy, Immunology, and Transplantation Council Subcommittee—Daniel Rotrosen, M.D., Director

Dr. Rotrosen welcomed new and returning members to the National Advisory Allergy and Infectious Diseases Council Subcommittee meeting. Dr. Rotrosen informed the members, that it was our esteemed pleasure to have Dr. Mark Davis, director, Institute for Immunity, Transplantation and Infection, Stanford University present on “Rebooting Human Immunology.” He further noted we were also delighted to be hearing today from Dr. Rafi Ahmed, director, Emory Vaccine Center who would be discussing “Measuring Immune Memory in Humans.” Following their presentations, Dr. Helen Quill, chief, Basic Immunology branch gave an overview of “DAIT Human Immunology Research Programs” within the Division.

Following the presentations, Dr. Rotrosen informed the members there were no new staff hires within the Division at this time. Dr. Rotrosen went on to inform the Council members there were four concepts for their review and approval.

The following concepts were presented for the Subcommittee’s consideration:

NIH Tetramer Core Facility: This initiative will support the continuation of the NIH Tetramer Core Facility, a reagent resource that provides custom-made MHC class I, non-classical MHC, and MHC class II tetramers and related products to the research community worldwide. The Subcommittee endorsed and unanimously approved this initiate. 

Asthma and Allergic Diseases Cooperative Research Centers: This initiative will continue to support NIAID's unique and long-standing Asthma and Allergic Diseases Cooperative Research Centers (AADCRC) program that funds research centers across the US to conduct interdisciplinary and translational research in asthma and allergic diseases. The centers coordinate their efforts through a Steering Committee and collaborate with each other through an existing Infrastructure and Opportunity Fund (IOF) that supports small, independent pilot studies. The Subcommittee unanimously approved this initiative. The Subcommittee felt that this initiative provides a valuable resource and an important infrastructure to stimulate and advance research. 

Adjuvant Development Program: The primary objective of the program is to further develop promising vaccine adjuvant candidates known to function by signaling through receptors of the innate immune system. The initiative will support the advancement of novel vaccine adjuvants towards licensure for human use with a focus on the development of adjuvants for vaccines against NIAID Emerging/Re-emerging Pathogens. Included are IND-enabling activities such as optimization of adjuvants and formulations, testing of immunogenicity and protective efficacy in animal models, stability and toxicology testing, cGMP pilot production and manufacturing. The Subcommittee unanimously approved this initiative. The Subcommittee felt that this initiative provides a valuable resource and an important infrastructure to stimulate and advance research.

Clinical Trials in Organ Transplantation in Children: This initiative will enable the conduct of multi-center clinical trials and/or observational studies, with associated mechanistic studies, that will improve our understanding of and/or evaluate interventions to reduce the immune-mediated morbidity and mortality of solid organ transplantation in children. Mechanistic studies associated with these clinical trials and observational studies will specifically address underlying immunologic issues. Furthermore, CTOT-C will continue to work closely with investigators in the Clinical Trials in Transplantation consortium (CTOT), which conducts comparable trials in adults. Both consortia partner with a NIAID-sponsored Data Coordinating Center (DCC). A critical scientific objective will be to integrate a common mechanistic platform of bioassays across CTOT and CTOT-C. The Subcommittee unanimously approved this initiative. 

V. Report of the Division of Microbiology and Infectious Diseases—Carole Heilman, Ph.D., Director

Dr. Carole Heilman, director of the Division of Microbiology and Infectious Diseases (DMID), chaired the NIAID Microbiology and Infectious Diseases Council Subcommittee meeting. After welcoming the Subcommittee, Dr. Heilman referred to the branch chiefs in attendance to introduce their respective new hires.

There were several different updates, reviews, and concept clearances presented during the meeting; summaries follow.

Update: DMID Clinical Trials Leadership Group 

Dr. Heilman provided an update on the status of the planned Leadership Group for a Clinical Research Network for Infectious Diseases Other than HIV. She noted that following the February Council meeting, there were concerns voiced by the infectious diseases research community about the breadth of the proposed network since it could focus on all infectious diseases other than HIV/AIDS. NIAID leadership subsequently issued a statement to report that the primary focus of this leadership group will be to develop and implement a comprehensive clinical research agenda to address bacterial antimicrobial resistance (see: http://blog.aids.gov/2011/02/toward-defining-the-non-hiv-infectious-diseases-leadership-group.html). 

She also reported on the March 7, 2011, Town Hall meeting to discuss the development of the DMID Clinical Trials Leadership Group. This open meeting included presentations by Dr. Anthony S. Fauci, Dr. Heilman and Dr. Carl Dieffenbach, the director of the Division of AIDS (DAIDS). In addition, attendees were able to pose questions to DAIDS Leadership Group Principal Investigators about how the current DAIDS networks are structured and function, and to also pose questions to NIAID Grants Management and Scientific Review staff regarding grant application and review issues. Finally, Dr. Heilman explained that, as appropriate, studies and clinical trials of the new Leadership Group will take place in NIAID-supported clinical trial sites, e.g., the Vaccine and Treatment Evaluation Units and the HIV/AIDS Clinical Trials Units and Clinical Research Sites.

Report of the 2010 Blue Ribbon Panel on Genomics 

Dr. Maria Giovanni, assistant director for Microbial Genomics & Advanced Technology, DMID, provided a brief overview of DMID’s genomics research program, which was initiated a little over 10 years ago. In February 2010, a Blue Ribbon Panel was assembled to review DMID’s current programs and to provide recommendations for future activities. During the last 10 years, DMID has expanded its genomics activities, establishing comprehensive centers and programs that provide the scientific community with needed resources such as reagents, genomic and proteomic data, and analysis tools to conduct basic and applied infectious diseases research. The Panel commended DMID on the range of services provided and the ability to balance competing priorities to address a variety of diverse research needs and communities. The full report was shared with Subcommittee members and can be found on the NIAID Web site. The following genomics concept was presented for the Subcommittee’s consideration.

Concept Clearance: Using “Omics” Technologies for Predictive Modeling of Infectious Diseases, Dr. Valentina Di Francesco, Program Officer

Under this concept, research projects will be conducted that study infectious disease initiation, progression, and outcome in humans. These projects will utilize high-throughput "omics" technologies to develop predictive models of the network configuration and dynamics of genome-wide host/pathogen biochemical interaction networks including, for example, protein/DNA and protein/protein interaction networks, as well as metabolic, regulatory, and signaling pathways. 

Subcommittee members enthusiastically supported the concept and highlighted the importance of ensuring that the data and experimental resources generated under the proposed initiative are rapidly made publicly accessible to the infectious disease research community. The concept was unanimously approved.

Biodefense Research -- Recent Activities 

Dr. Michael Kurilla, director, Office of Biodefense Research Affairs and Associate Director for Biodefense Product Development, provided a broad overview of DMID’s biodefense research activities. DMID’s biodefense research activities span basic, translational and product development activities; greater emphasis has been placed on the latter two areas in recent years, and these activities are facilitated by a wide array of preclinical and clinical services offered by DMID to help advance products along the product development pipeline.

In that regard, Dr. Kurilla described two major DMID service activities that play a key role in the translational and advanced product development arenas. First, DMID offers specialized services, e.g., genomics resources, animal model development, and animal model testing, including that which must be done under biocontainment and that may not be available to either small companies or investigators at academic facilities. Second, DMID offers a series of product-related preclinical and clinical drug and vaccine development activities in order to move products toward licensure. Dr. Kurilla presented case studies of several products that have taken advantage of both types of DMID services.

He also noted that DMID has transferred a number of specific candidate products to the Biomedical Advanced Research and Development Authority (BARDA), within the Office of the Assistant Secretary for Preparedness and Response in the U.S. Department of Health and Human Services, which focuses on advanced development and purchase of the necessary vaccines, drugs, therapies, and diagnostic tools for the Strategic National Stockpile.

In summary, DMID offers a variety of funding mechanisms and preclinical and clinical services for the early product development cycle that helps to advance products to the point where large pharmaceuticals and other entities, e.g., BARDA, can carry forward further product development activities. The following biodefense concept was presented for the Subcommittee’s consideration.

Concept Clearance: Development of Therapeutic and Prophylactic (Vaccine) Countermeasures for Biodefense and Emerging Infectious Diseases (EID) – Dr. Clare Schmitt, Deputy Director, Office of Biodefense Research Affairs

This concept is designed to advance high-priority, promising candidate therapeutics, vaccines, and vaccine technologies toward licensure via a focused, milestone-based development approach. Special emphasis will be placed on therapeutics that have broad-spectrum activity or that address antimicrobial resistance. In addition, this initiative will support the development of new technologies for enhancing biodefense/EID vaccine immunogenicity, efficacy, delivery, and usability. 

The types of activities that are envisioned include: 1) non-clinical research and development including safety and efficacy; 2) lead candidate optimization; 3) development of manufacturing processes, manufacturing/synthesis of cGMP pilot lots, and conduct of extended product stability studies; 4) characterization and release assay development, and qualification and advanced candidate characterization; 5) preparation and submission to the Food and Drug Administration (FDA) of Investigational New Drug (IND) applications and Biologic License Applications (BLA) and conduct of Phase 1 clinical trials; and 6) post-Phase 1 development activities to enable eventual licensure.

The Subcommittee members were very supportive of the concept, and acknowledged NIAID’s role in this area. Of particular interest was the potential to apply advances in biodefense and emerging infectious diseases medical countermeasure development to other public health areas. The Subcommittee unanimously supported the concept.

Report on NIAID XMRV Research Activities

Dr. Catherine Laughlin, chief of DMID’s Virology Branch, provided an update on Xenotropic murine leukemia virus-related virus, or XMRV, a recently identified retrovirus that has been associated with chronic fatigue syndrome (CFS). She reported that DMID is currently supporting a laboratory-based study designed to rigorously evaluate whether the presence of XMRV/MLV nucleic acids in the blood is in fact associated with CFS. Researchers, working with clinicians in six regions across the United States, will compare blood and plasma samples from patients diagnosed with CFS to samples from healthy people who have not been diagnosed with CFS and who are matched to the CFS patients by age, sex, and geography. Study results are anticipated later this year.

Clinical Trials for NIAID Networks

Dr. Carl Dieffenbach, director of the Division of AIDS, NIAID, reported on the development of the DAIDS Clinical Trial Units/Clinical Research Sites Request for Applications (RFA), which will be recompeted to provide the clinical research site infrastructure necessary to conduct clinical trials developed and implemented by the NIAID HIV/AIDS and Antibacterial Resistance Clinical Trials Networks. Dr. Dieffenbach noted that there will be new requirements for the sites in this recompetition, e.g., DAIDS will require a CTU to affiliate with at least two DAIDS-specific networks. He anticipates that the RFA will be released approximately 6 months following the release of the DAIDS and DMID Leadership Group RFAs. 

VI. Joint Meeting of the AIDS Subcommittee, National Advisory Allergy and Infectious Diseases Council and AIDS Research Advisory Committee (ARAC)—Carl Dieffenbach, Ph.D., Director, DAIDS

Dr. Uittenbogaart welcomed the ARAC members, DAIDS representatives, and guests. She presented the minutes of the February 7, 2011, ARAC meeting, and the members approved them with no changes by a hand vote.

 Director's Report

Carl W. Dieffenbach, Ph.D., Director, DAIDS

Dr. Carl Dieffenbach welcomed the ARAC members, attending DAIDS and NIAID representatives, and other guests. He then introduced the following new members- Jerome A. Zack, Ph.D. and Dázon Dixon Diallo, M.P.H. Dr. Zack is a professor in the Departments of Medicine as well as Microbiology, Immunology, and Molecular Genetics at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). His work has shown that the AIDS virus can inhibit the function of hematopoietic stem cells, and he is studying the potential of human embryonic stem cells for hematopoietic gene therapy. Ms. Dázon Dixon Diallo is president and CEO of SisterLove, Inc. and adjunct faculty in Public Health at Morehouse School of Medicine in Atlanta, Georgia. She is a founding board member of SisterSong Women of Color Reproductive Justice Collective.

Budget Update

Dr. Dieffenbach briefed the gathering on the NIAID fiscal year 2011 and 2012 budgets. Since the last ARAC meeting in February, the President signed a bill into law to provide funding for the remainder of this fiscal year (through October 1, 2011). The final allocation for NIH left an overall net decrease of one percent for 2011, because the largest part of the NIAID budget pays for research project grants (RPGs), and policies have been set for RPGs that permit the continuation of existing funding commitments and strong paylines. These policies are exemplified by the one percent reduction from FY2010 levels of noncompeting grants and contracts; payline for unsolicited RPGs fixed at the 10th percentile; support of new principal investigators (PIs) and early-stage investigators (ESIs) through the 14th percentile; and the avoidance of any automatic programmatic adjustments. NIAID is using interim paylines for all other grant types. 

The FY 2012 President’s Budget, presented to Congress February 14, 2011, requested $31.8 billion for the overall NIH budget, a 3.5 percent increase over the FY 2011 amount after the 1 percent was subtracted. The Senate budget hearings for FY 2012 have already taken place. The House has not yet scheduled FY 2012 budget hearings for NIH but plans to begin marking up draft legislation for the Departments Labor and Health and Human Services on July 26, 2011. There is uncertainty about the FY 2012 NIH budget, and some in Congress are pushing for cuts that would roll back funding to FY 2008 levels. Although NIH does not expect this worst case scenario to happen, NIAID has drafted a financial operating plan.

Scientific Highlights

Following recommendations from an Independent Data Monitoring Committee (IDMC), Family Health International (FHI) announced April 18, 2011, that the FEM-PrEP HIV Prevention Study was being stopped due to futility. The study was a Phase III randomized, placebo-controlled, clinical trial assessing the safety and effectiveness of an antiretroviral drug (ARV) called Truvada for HIV prevention among women. Truvada (TDF/FTC) is the brand name for a combination drug that contains tenofovir, abbreviated for tenofovir disoproxil fumurate (TDF) and another active ingredient called emtricitabine (FTC). Both are approved for treating HIV as part of antiretroviral therapy (ART). The ARV, given in a daily oral dose, tested an approach known as pre-exposure prophylaxis (PrEP). The trial was conducted in Kenya, South Africa, and Tanzania and was funded by the United States Agency for International Development (USAID), with early support from the Gates Foundation. The full data from the study, including drug levels, will be available later this year. The early closure of the Fem-PrEP study came as a surprise especially given the positive results of the iPrEx trial announced in November 2010. In that NIAID-funded study, the effectiveness of once-daily Truvada in preventing HIV infected was tested in gay men, transgender women, and other men who have sex with men; it showed that daily Truvada reduced the risk of HIV infection by an average of 43.8 percent with higher reductions corresponding with greater levels of adherence.

In the VOICE study, (Vaginal and Oral Interventions to Control the Epidemic), NIAID is evaluating topical and oral use of Truvada in women. The purpose of VOICE is to estimate effectiveness of daily tenofovir 1 percent gel compared to a vaginal placebo gel, as well as the effectiveness of oral TDF and oral FTC/TDF compared to an oral placebo in preventing HIV infection among women at risk for sexually transmitted infections. VOICE is the first HIV prevention trial that will evaluate two different strategies in the same study and the first effectiveness study of a microbicide in which women will use the gel every day instead of only at the time of sex. The evaluation of the ARV will include not only effectiveness, but safety, adherence, and acceptability to the daily vaginal and oral regimens. Additionally, the study will assess the selection of HIV-1 drug resistance in women acquiring HIV-1 during the trial. The study was initiated in September 2009 and is expected to enroll 5,000 women in South Africa, Uganda, and Zimbabwe; results from VOICE are expected in 2013.

The HIV Prevention Trials Network (HPTN) 052 study is the first major randomized clinical trial to show that treating an HIV-infected individual reduces the risk of sexual transmission of HIV to an uninfected partner. This Phase III, two-arm, multi-site, randomized trial began in April 2005 and was designed to determine whether ART can prevent the sexual transmission of HIV-1 in couples (the majority were heterosexual) where one partner is HIV-positive and the other is negative. The study enrolled 1,763 serodiscordant couples in which the HIV-infected partner had CD4+ T-cell levels between 350 to 550 cells/mm3 within 60 days of entering the study. The trial clearly demonstrated that immediate treatment of the HIV-infected partner substantially reduced the risk of HIV transmission to the uninfected partner by 96.3 percent, compared to the delayed arm. This is extremely important news since previous data about the potential value of ART in making HIV-infected individuals less infectious to their sexual partners came largely from observational and epidemiological studies. The results were announced earlier in May; the HIV-infected participants in the deferred arm will be offered ART, and the study will continue following the participants for at least one year.

HPTN 065 is a multi-component intervention study to assess the feasibility of a community-level test, link to care, plus treat strategy in the United States. There are three components of the study: biomedical (testing and ART), behavioral (positive prevention), and structural (financial incentives). Other innovative features include strategic partnerships with local Departments of Health, the Centers for Disease Control and Prevention (CDC), and community providers; use of routinely collected surveillance data; and a mix of methodologies involving community comparisons, site randomization, and individual randomization. Enrollment began in March 2011, and results are anticipated in the first quarter of 2014.

The NIAID HIV/AIDS Strategic Working Group met on May 11, 2011. The one day meeting encompassed an update on the Promoting Maternal-Infant Survival Everywhere (PROMISE) study, concept review of VOICE follow-up study and DAPY ring study (clinical study using intravaginal rings with prolonged release of a reverse transcriptase inhibitor, diarylpyrimidine (DAPY) analogue), future NIAID clinical trials networks, and input into the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) scientific advisory board.

Discussion following the Director’s Report included questions about PROMISE, and the status of the START and SMART studies. PROMISE will examine the best ways to prevent HIV transmission during pregnancy and breastfeeding, what standard should be used for HIV pregnant women and the impact of HIV/pregnancy on health.

The START study (Strategic Timing of Anti-Retroviral Treatment) will determine whether the immediate initiation of antiretroviral treatment in HIV-infected, treatment-naïve persons with CD4+ counts >500 cells/mm3 is superior, in terms of morbidity and mortality, to deferral of treatment until the CD4+ count declines to <350 cells/mm3. Couples in the deferred arm will be offered ART and will be followed for at least one year. START has passed its milestones and will be continued. The SMART study (Strategies for Management of Anti-Retroviral Therapy) was designed to determine which of two different HIV treatment strategies would result in greater overall clinical benefit.

Concept Review: Clinical Trials Units for NIAID Networks

Carl W. Dieffenbach, Ph.D., Director, DAIDS 
Manizhe Payton, Director, Office of Clinical Site Oversight/NIAID/DAIDS

Plans were discussed for restructuring the HIV/AIDS Clinical Trials Networks. The awards supporting the six current HIV/AIDS networks and clinical trials units are set to expire in 2013 and 2014, respectively. NIAID would like to build on the success of the current infrastructure by expanding the scope of the networks’ activities to include the treatment and prevention of other infectious diseases associated with HIV/AIDS, such as tuberculosis and hepatitis. Among the goals for the networks are: ways to increase both domestic and international collaboration; create transparent mechanisms for leadership to solicit and support ideas from the research community, develop and enable cross-talk from external researchers, and design and implement agendas that address research questions related to specific populations. A Clinical Trial Network is comprised of a Leadership Group (LG) and associated with Clinical Trials Units (CTUs) and Clinical Research Sites (CRSs). Each LG would consist of three components: a Leadership and Operations Center (LOC), a Statistical and Data Management Center, and a Laboratory Center (LC). NIAID’s clinical research priorities will remain prevention, therapeutics, and vaccines with more emphasis on CTUs and increased flexibility.

The objective of the CTUs is to provide the clinical research site infrastructure necessary to conduct clinical trials that are developed by the NIAID HIV/AIDS and Infectious Diseases Clinical Trials Networks. This is a renewal with restructuring, supported by the UM1 cooperative agreement mechanism for seven years. The CTU should be configured to work across multiple networks simultaneously. The goal is to optimize efficiencies among components, through resource sharing or other cost containment measures. We expect to fund a minimum of 25 CTUs, capable of working across different diseases and populations, with emphasis on efficient utilization of resources and cost containment. A CTU will be required to affiliate with at least two HIV/AIDS networks, and affiliation with the DMID Infectious Disease Network is optional. It is anticipated that the number of CRSs per CTU may increase. There is no minimum number of CRSs required, but a CTU may not be composed of greater than eight CRS. The future CTUs would preserve community education and engagement; have increased authority and accountability; and increased ability to contribute to the scientific agenda.

The reviewers (Cohen, Swindells, and Michael) expressed enthusiastic support for the initiative. Additional comments included that NIAID should plans now for building international virtual meetings into clinical trials networks; provide incentives at the CTU level to include junior investigators who often lack funding, but have great intellectual capacity and consider sharing site costs and funding where applicable.

The ARAC members expressed support for the concept and voted approval. 

Program Update: Basic Sciences Program 

Diana Finzi Ph.D., M.P.H. Chief, Pathogenesis and Basic Research Branch
Sandra Bridges Gurgo, Ph.D., Chief, Targeted Interventions Branch

The mission regarding the basic studies of HIV is to understand fundamental mechanisms of viral replication and virus-host interactions, which may eventually be used to develop therapeutic targets. Thus, these talks focused on two goals: 1) to give a broad overview of where science stands in the basic studies on persistent HIV; and 2) to share the vision and strategy for the future.

Tremendous progress has been made in the thirty years since the beginning of the AIDS epidemic. The investment has paid off scientifically in greater knowledge about HIV and other viruses, the immune system, and most importantly, the redirection of a deadly disease into a chronic disease. With highly active antiretroviral therapy (HAART), HIV RNA levels are predictably decreased in plasma and genital compartments of treated individuals. Yet questions remain about the regulation of HIV expression and replication in human immune cells and how reservoirs of infection persist in the body even with HAART.

Physicians assert that an HIV-positive man, the Berlin patient (Timothy Brown) who underwent a stem cell transplant has been cured of HIV as a result of the procedure. Although Brown’s transplant in 2007 was part of a long treatment against leukemia, his case suggests a permanent cure for HIV may be possible.

There are technological limitations to detecting HIV-infected resting memory CD4+ T-cells including: the huge volumes of blood needed to detect a small number of cells (culture assay), PCR-based assays overestimate the amount of replication-competent virus, and the lack of animal models. Additionally, recent studies indicate that two normal physiological processes involved in the maintenance of immunological memory, T-cell survival and homeostatic proliferation, likely contribute to the persistence of latently infected memory CD4 T-cells. In light of this evidence, researchers ask: 1) Are there ways to recognize latently infected cells? 2) Can these cells proliferate without expressing viral proteins? and 3) Does activation of latently infected cells result in cell death or clearance by the immune system?

Even after being on HAART for many years, some patients have transient occurrences of viremia above the detection limit of viral load assays, called viral blips. Where are the blips coming from? What do they represent? The blips may be due to persistence of virus in CD4 cells and other reservoirs, but the mechanism has not been fully characterized. Efforts are ongoing to identify cell populations containing latent virus. New strategies to address residual viral reservoirs include activation alone or combined with a killing modality; replacing target cells with cells that are protected; directly targeting provirus, and direct targeting of cells containing virus.

To effect a cure for HIV infection, different or complementary approaches are needed to target residual virus in HAART-treated patients. Core scientific information about how the virus attacks the body and how the body defends itself is critical to developing translational tools that can lead to therapeutic interventions and vaccines. The NIAID is ready to support these types of innovative projects.

During discussion it was noted that there are there are many small pilot trials or non-network trials, which are encouraged by NIAID, and these do not have DSMB oversight. In response to a question about therapeutic vaccines the initiative entitled Beyond HAART: Innovative Therapies to Control HIV Released was mentioned and in response NIAID expects to receive new ideas.

Update: Office of AIDS Research Advisory Council Committee Meeting 

Christel H. Uittenbogaart, M.D., Chair, ARAC

Dr. Uittenbogaart reviewed the meeting agenda of the Office of AIDS Research Advisory Council (OARAC), which took place March 24, 2011. The theme of the meeting was, “Research Leading to a Cure for HIV/AIDS.” Among the presentation topics were: 

  • Barriers to HIV eradication.
  • Characteristics of residual viremia in patients on suppressive ART.
  • How to rouse a slumbering HIV provirus.
  • Rationale for using immune-based therapeutics to cure HIV infection.
  • Engineering CCR5-negative T cells and Stem cells.
  • Novel approaches for HIV/AIDS therapeutics.

Key discussion points, some of which are included below, concerned viremia, latency, and novel therapies:

  • HIV reservoir is maintained in memory CD4+ T-cells and probably in an additional reservoir.
  • Need functional cytotoxic T lymphocytes to kill reactivated cells.
  • Infectious RNA in cells before treatment is related to residual viremia.
  • In vitro latency model for the study of the therapies to activate HIV (HDAC inhibitors); primary cell model needed.
  • Immune response of the host contributes to HIV latency.
  • Latency is restricted at the level of mRNA transcription.
  • Negative regulators of T-cell activation include PD1 and CTLA-4 among others.
  • Therapeutic approaches should be combinations of drugs to suppress inflammation, anti-PD1, chemokine antagonists, etc.

Concept Review

Targeting Inflammation and Immune Activation in HIV Disease

Sarah Read, M.D., Medical Officer, Division of AIDS, NIAID/NIH

The objective of this concept is to support small pathogenesis-oriented clinical trials designed to evaluate the effect of intervention on persistent inflammation in HIV- infected individuals on effective ART. A translational research gap exists between basic studies of the biology of chronic inflammation in treated HIV disease and larger scale interventional studies performed within the HIV therapeutic clinical trials network. This is a new initiative, supported by the NIH Cooperative Agreement (U01) grant mechanism. The award is for five years with the estimated number of awards being three to four, depending on funding. Reviewers (Celum and Goodenow) agreed that the concept addresses an important and relevant question that will enhance the research pipeline. It was noted that trials from networks that add on activities will not be considered responsive, but trials using the labs within a network, or partner with the networks in a creative way would be considered responsive. Applicants will be strongly encouraged to design focused, hypothesis-driven queries with well-developed collaborations between clinical and laboratory investigators. It was suggested that this be clearly stated in the request for applications (RFA.)

The ARAC members expressed support for the concept and voted approval.

Targeting Persistent HIV Reservoirs 

Karl Salzwedel, Program Officer, Division of AIDS, NIAID/NIH

The objective of this concept is to develop innovative approaches for monitoring and specifically targeting reservoir cells harboring integrated HIV-1 provirus. Of particular interest will be proposals that outline improved methods for quantifying the reservoir of replication-competent virus and strategies for selectively killing reservoir cells or permanently inactivating integrated provirus. This is a new initiative that will utilize the Phased Innovation Award mechanism (R21/R33). The duration of the awards will be five years. The reviewers (McCutchan and Zack) expressed enthusiastic support for the initiative and suggested that the funding opportunity announcement (FOA) should emphasize the need for sensitive, high-throughput single-cell analysis methods to address the challenge of studying rare cells. Reviewers felt that we should emphasize the use of samples from HIV-positive individuals well suppressed on HAART or from relevant non-human primate models as opposed to the many in vitro latency models based on cell lines or primary cells that are driven in vitro into a latent-like state. We agree with this, and we plan to highlight this in the FOA. However, we do recognize that some of the approaches that we’re looking for may require in vitro models to accomplish. So we would prefer not to completely rule out all in vitro systems for this initiative. In response to a question, it was noted that this is an open competition and no preference will be given to Gates Grand Challenges awardees.

Patient Safety Monitoring in International Laboratories (SMILE)

Daniella Livnat, Health Specialist, Division of AIDS, NIAID/NIH

The objective of this concept is to provide a comprehensive, uniform program to evaluate the capability and readiness of laboratories in developing countries to participate in NIAID-funded and collaborative trials; advise and train when deficiencies are identified; and ensure on-going quality of study test results. SMILE provides one contractual resource to help implement Good Clinical Laboratory Practices in non-U.S. laboratories along with the evaluation of testing proficiency to help ensure patient safety as well as trial data quality and comparability in U.S. and non-U.S. NIAID trial sites. This a renewal under a N01 contract with the duration of the award being seven years. In response to reviewers’ (Celum and Birx) comments, the contract will include options to increase the number of labs, and in the case of novel assays, when proficiency testing is not available commercially, NIAID will be able to acquire those proficiency testing services. Also, the contract will link to the African Society for Laboratory Medicine, as suggested by the reviewers.

The ARAC members expressed support for the concept and voted approval.

Small Business Innovation Research (SBIR) Contract Solicitation: Inhaled Delivery of Anti-Tubercular Drugs

Steven Turk, Ph.D., Project Officer, Division of AIDS, NIAID/NIH 

The objective of this concept is to develop new formulations of anti-tubercular drugs to enhance their effectiveness and safety. The goal of the solicitation is to encourage the development of inexpensive and easily administered inhaled formulations of anti-tubercular drugs alone or in combination as a component of multidrug-resistant tuberculosis (MDR TB) and extensively-drug resistant TB (XDR TB) treatment. This is a new topic that will be added to the annual SBIR contract solicitation. One award can be issued for the duration of one year.

In discussion it was noted that whereas only small business concerns would be able to submit proposals, academic investigators still could provide valuable expertise by serving in collaboratory roles. 

The ARAC members expressed support for the concept and voted approval.

Clinical Research Products Management Center (CRPMC)

Ana I. Martinez, R.Ph., Chief, Pharmaceutical Affairs Branch, NIH

The objective of this concept is to support the DAIDS clinical trials effort by providing centralized management and distribution of clinical study products and support for the pharmacy oversight responsibilities of the Division. Some non-network studies may also need assistance from the CRPMC. This a renewal under a N01 contract with seven years duration. Reviewers (Cohen and Swindells) agreed that the CRPMC is essential for HIV clinical research in NIAID. Their recommendations were as follows: 1) continued expansion into the international area, 2) strategies to help overcome barriers and delays for international site participation, and 3) multi-pronged approach to rapid implementation of clinical trials at protocol specific sites.

The ARAC members expressed support for the concept and voted approval. 

VII. Adjournment

The meeting of the Council was adjourned at 4:40 p.m., on Monday, May 23, 2011.

We do hereby certify that, to the best of our knowledge, the foregoing minutes are accurate and complete.

 

-s-

Anthony S. Fauci, M.D.

Chair, National Advisory Allergy and Infectious Diseases Council

Director, National Institute of Allergy and Infectious Diseases

7/2/2011
Date
-s-

Marvin R. Kalt, Ph.D.

Executive Secretary

National Advisory Allergy and Infectious Diseases Council

Director, Division of Extramural Activities

National Institute of Allergy and Infectious Diseases

6/29/2011
Date

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 20, 2013

Last Reviewed August 20, 2013