The 170th meeting of the National Advisory Allergy and Infectious Diseases Council (NAAIDC) convened at 10:30 a.m. on Monday, January 30, 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 Member Present:
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 2,743 research and training applications with primary assignment to NIAID for a requested amount of $1,069,139,055 in first-year direct costs and recommended approval of 682 applications with $318,076,022 in first-year direct costs.
Dr. Fauci opened the Council session by welcoming visitors to the meeting. He announced the appointment of five new Council members: Dr. Ada Adimora, University of North Carolina; Dr. Mavis Agbandje-McKenna, University of Florida; Dr. Enriqueta Bond, QE Philanthropic Advisors; Dr. Jonathan Karn, Case Western Reserve University; and Dr. Georgia Tomaras, Duke Human Vaccine Institute. Ex officio members Dr. Rima Khabbaz and Major General James Gilman were unable to attend the meeting.
Dr. Fauci introduced two ad hoc Council members, Dr. Robert Belshe, St. Louis University, and Dr. Donald Leung, National Jewish Hospital in Denver.
Council considered the minutes of the September 19, 2011, meeting and approved them as written.
Consideration of Operating Procedures
Council reviewed the 2012 Council operating procedures and adopted them as written.
Dr. Fauci announced that Dr. Matthew Fenton has been appointed acting director of the Division of Extramural Activities. Dr. Fenton comes from the Division of Allergy, Immunology, and Transplantation, where he was chief of the Allergy, Asthma, and Airway Biology Branch.
Dr. Fauci paid tribute to Dr. Franklin Neva, who died in October. Dr. Neva was a renowned virologist, parasitologist, clinician, and former chief of NIAID’s Laboratory of Parasitic Diseases.
At the end of December, Dr. Neil Goldman retired from his position as senior associate director for scientific operations and planning, Division of Intramural Research.
Dr. Louis Miller, head of the Malaria and Cell Biology Section, Laboratory of Malaria and Vector Research, received the Walter Reed Medal for his distinguished accomplishments in the field of tropical medicine.
Dr. Sonja Best, chief of the Innate Immunity and Pathogenesis Unit, Laboratory of Virology at Rocky Mountain Laboratories, received a Presidential Early Career Award for Scientists and Engineers.
Dr. Fauci recognized three long-time NIAID grantees who received the 2011 Nobel Prize in Physiology or Medicine. Drs. Bruce Beutler, Scripps Research Institute, and Jules Hoffmann, University of Strasbourg, were honored for their discoveries on the activation of innate immunity. The late Dr. Ralph Steinman, Rockefeller University, received the prize for his discovery of the dendritic cell and its role in adaptive immunity.
Just before Christmas, Congress appropriated NIH’s FY 2012 budget. NIH received an overall increase of 0.8 percent, with the institutes and centers receiving an increase of approximately 0.3 percent.
Congress also voted to eliminate the National Center for Research Resources (NCRR) and to establish the National Center for the Advancement of Translational Sciences (NCATS). About $280 million of NCRR’s programs and funds went to NIH’s Office of the Director and the remaining programs and funds went to NCATS and several other ICs.
Dr. Fauci summarized NIAID’s financial management plan for FY 2012. NIAID will support a payline to the 10 percentile for established investigators and the 14 percentile for new and early-stage investigators. There will be no inflationary increase for noncompeting grants, and NIAID’s estimated success rate will be 21 to 22 percent.
Representative Denny Rehberg, chair of the House Appropriations Subcommittee on Labor, HHS, and Education, visited the NIH Clinical Center on November 28. Dr. Fauci briefed him on NIH research including NIAID activities that have had a significant impact on public health.
Dr. Francis Collins, Dr. Harold Varmus, and Dr. Fauci met with Chairman Rehberg on December 13 to emphasize the domestic and global importance of NIH research.
On October 11, Dr. Fauci met with Representative Michael Burgess and updated him on NIAID’s research activities.
On December 5, Dr. Fauci was the guest speaker at a Congressional staff briefing. He discussed NIH’s role in fighting infectious diseases and how NIH support for basic, translational, and clinical research has led to unprecedented gains in global health.
Since the last Council meeting, Dr. Alan Fix, Dr. Carl Dieffenbach, and Dr. Annette Rothermel also participated in Congressional briefings.
Dr. Fauci gave an update on HIV/AIDS, focusing on combination HIV prevention. He highlighted a transforming study led by Dr. Mike Cohen, HPTN 052, which has changed the way researchers are looking at the relationship between prevention and treatment. Science magazine voted it as the scientific breakthrough of the year.
The results of this study prompted Secretary Clinton to come to NIH in November and give a talk on the possibility and goal of an AIDS-free generation.
President Obama gave a World AIDS Day talk about ambitious new goals for PEPFAR including raising the benchmark for 2013 to get six million people on antiretrovirals.
Dr. Fauci briefly discussed non-HIV vaccines and their importance throughout a person's life. He also noted NIAID’s involvement with vaccines for cancer, malaria, influenza, chlamydia, and chikungunya virus.
Dr. Fauci concluded by commenting on the controversy surrounding recent H5N1 studies.
Lieutenant General Eric B. Schoomaker presented perspectives on the relationship between NIAID and the Department of Defense (DOD).
He explained the difference between DOD’s and NIAID’s approaches: DOD’s research is requirement-driven, whereas NIAID’s research is investigator-driven. Their missions reinforce each other but are not interchangeable.
Infectious diseases remain one of the major threats and biggest challenges on the battlefield and around the world in military operations. DOD develops products with the help of NIAID, industry, and academia and then organizes a logistical path that brings materials to the field.
These partnerships are advantageous to the organizations involved, leveraging their strengths and capabilities.
LTG Shoomaker presented several examples of collaborations between the U.S. military and other agencies.
DOD will continue to collaborate with NIAID and other agencies to advance and protect the health of the military, with long-term implications for public health.
Dr. Rotrosen welcomed the subcommittee members of the National Advisory Allergy and Infectious Diseases Council. Dr. Rotrosen took the opportunity to inform the subcommittee members there would be an update given by Marshall Plaut, M.D., Allergy, Asthma, and Airway Biology Branch, on “NIAID Networks for Atopic Dermatitis Research,” and a presentation by Donald Y. M. Leung, M.D., Ph.D., professor and head, Division of Pediatric Allergy and Immunology, National Jewish Health who is the principle investigator of a major “Atopic Dermatitis Research Network.”
Dr. Rotrosen noted that he wanted to further mention just briefly, a high level division update, one that Dr. Fauci mentioned earlier which was Dr. Matthew Fenton, chief of DAIT’s Allergy, Asthma, and Airway Biology Branch, is serving as the acting director of the NIAID’s Division of Extramural Activities and the expectation is he will be appointed director of that Division sometime in the next few months. Finally, Dr. Quan Chen joined DAIT as a member of the bioinformatics team. He has been working in the field of bioinformatics for the past decade, and most recently, as manager, Scientific Computing and Programming at the Core Genotyping Facility, NCI.
Dr. Rotrosen acknowledged there were five concepts for review and approval that would follow the scientific presentation.
The following concepts were presented for the Subcommittee’s consideration:
Collaborative Network for Clinical Research on Immune Tolerance: This initiative will renew NIAID's successful Immune Tolerance Network (ITN), a consortium of basic and clinical scientists that: (1) develops a scientific agenda for clinical trials and mechanistic studies of various approaches to tolerance induction; (2) designs and conducts clinical trials at all phases to determine the feasibility, safety, toxicity and efficacy of tolerogenic intervention strategies for multiple immune system diseases; (3) designs and conducts research to delineate the underlying mechanisms of immune tolerance in conjunction with clinical trials undertaken by the ITN as well as research projects sponsored by other Federal and private sector organizations and companies and; (4) develops, tests and validates assays to measure the induction, maintenance and loss of immune tolerance in humans.
For this initiative, tolerance is broadly defined as specific lack of an immune response to targeted antigens (e.g. alloantigens, autoantigens, or allergens) by any of a variety of approaches including deletion, induction of anergy, immune deviation, sequestration, or suppression. Approaches may target antigen specific receptors, molecules of the co-stimulation pathways, homing molecules, or other relevant approaches; and may use any of a variety of agents including antigen, peptides, altered peptides, monoclonal antibody blockade, cytokines, cellular therapies, molecularly engineered cells or tissues, DNA vectors, or other relevant molecules.
Since its inception, the ITN has been funded as a contract; in FY 2014, this initiative will be funded as a cooperative agreement. While the configuration of the ITN under a cooperative agreement has not yet been determined, it is possible that the ITN may consist of up to three separate, but related, awards. These three awards may be leadership component (including funding of sites), laboratory component, and scientific component.
The subcommittee unanimously approved this initiative.
Autoimmunity Centers of Excellence: This initiative is to renew NIAID's Autoimmunity Centers of Excellence (ACE) program, a cooperative network of integrated basic, pre-clinical and clinical research centers that: (1) conduct single site and multi-site cooperative clinical trials and studies of mechanisms of action of new tolerance induction and immune modulation interventions in multiple autoimmune diseases; (2) accelerate early translation of basic findings into clinical application; (3) facilitate the utilization of clinical materials for basic research studies; (4) enhance the exchange of information between basic scientists and clinicians and among various specialists involved in treating autoimmune diseases; and (5) promote a collaborative approach to clinical and basic research among multiple institutions in various geographic areas.
The Autoimmunity Centers of Excellence include multidisciplinary, interactive research projects focused on elucidation of the basic mechanisms of autoimmunity, understanding of self-tolerance and/or immune modulation in autoimmune disease, and an integrated clinical component for piloting of novel immunotherapies for autoimmune disease. The inclusion of central cores and an integrated clinical network facilitates basic investigation, clinical studies/trials, and the application of basic research findings in the clinical setting. The program does not restrict the focus to particular autoimmune diseases, and programs evaluating more than one disease are encouraged. A noted change: To improve clinical trial performance, the renewal will also solicit solely clinical groups in addition to integrated basic-clinical programs. The current program will be split into two networks: ACE Mechanistic Studies Network (AMSN) and ACE Clinical Trials Network (ACTN). These will be solicited by two separate RFAs and reviewed separately. Collaboration between AMSN and ACTN will be promoted at steering committee level and through use of AMSN Opportunities Pool.
In the subsequent Council concept discussion, Council member Dr. Ting raised two key concerns:
Program staff also noted that the substance of these concerns will be discussed with members of the research community during the development of the RFAs.
The Subcommittee endorsed and unanimously approved this initiative.
Adjuvant Discovery Program: The primary objective of this initiative is to identify novel adjuvant candidates for vaccines against NIAID Emerging/Re-emerging Pathogens. High-throughput screening will be used to identify potential new adjuvant candidates. Lead adjuvant candidates will be structurally modified to optimize efficacy while reducing reactogenicity and determine the mechanism of action of the lead adjuvant. Although the effectiveness of the lead compounds as vaccine adjuvants has to be demonstrated in vivo using an animal model, contractors will also establish the clinical relevance of the adjuvants using a human in vitro system.
The Subcommittee unanimously approved this initiative.
Clinical Trials in Organ Transplantation: This initiative will support clinical trials in organ or cellular transplantation with associated studies of immune mechanism. The goal of this research is to improve the outcome of organ transplantation by (a) evaluating innovative therapies that will increase graft survival without medication-induced injury; (b) identify and validate biomarkers of immune activation, immune quiescence, and pending graft injury in urine, blood, or tissue biopsies that will allow individualization and optimization of anti-rejection therapy (c) increase our understanding of the mechanisms underlying allograft rejection and injury.
This initiative will support multicenter clinical trials, with associated studies of immune mechanism, in heart, lung, kidney, liver, and intestinal transplantation. Clinical trials of non-hematopoietic cellular transplantation as replacement therapies are included, as are those of transplantation of bone marrow or mesenchymal stem cells, or of immunologically active cells, as adjuncts to organ transplantation. Studies of hematopoietic cell transplantation and of pancreatic islet transplantation are excluded. This is a renewal of RFA-AI-08-015; the inclusion of cellular therapies is an expansion of that RFA.
Inner City Asthma Consortium: This initiative is considered a renewal of the current Inner-City Asthma Consortium contract. Under this award, a scientific and administrative center will be created. This center will establish subcontracts with clinical and basic science sites to perform clinical trials and clinical studies and related mechanistic research. This initiative will support the (1) develop allergen immunotherapies to mitigate and\or prevent the effects of inner city specific allergens on asthma; (2) continue the unique inner city asthma birth cohort URECA through adolescence, specifically at least through 15 years of age; (3) investigate the role of the host (GI, respiratory) and home microbiome in inner city asthma; (4) develop and implement innovative, phenotype-specific, immunomodulatory clinical trials for the treatment and\or prevention of inner city asthma; and (5) investigate the pathogenesis and mechanism of specific inner city asthma phenotypes.
Dr. Carole Heilman, Director of the Division of Microbiology and Infectious Diseases (DMID), chaired the NIAID Microbiology and Infectious Diseases Council Subcommittee meeting on January 30, 2012. After welcoming the Subcommittee, Dr. Heilman introduced two new Subcommittee members: Dr. Mavis Agbandje-McKenna, professor in the Department of Biochemistry and Molecular Biology and Director of the Center for Structural Biology in the College of Medicine at the University of Florida, and Dr. Enriqueta Bond, a founding partner of QE Philanthropic Advisors and previous president of the Burroughs Wellcome Fund. She then introduced Dr. Robert Belshe, Professor of Infectious Diseases and Immunology at Saint Louis University School of Medicine, who was in attendance as an ad hoc member and would later provide a report on the Herpevac Trial for Women. She then referred to the Branch Chiefs in attendance to introduce their respective new hires.
Dr. Heilman provided background on the planned DMID Clinical Trials Leadership Group focused on Antibacterial Resistance (AR) and updated the Subcommittee on the status of this new research effort. Specifically, she informed the Subcommittee that a request for applications (RFA) for this Leadership Group was released earlier in the month, and that applications are due June 1, 2012. She reported that DMID would be holding a webinar on March 5, 2012, to provide information and respond to questions from the research community about this new program. The webinar will include presentations by NIAID scientific review and grants management staff, as well as DMID staff members Dr. Dennis M. Dixon and Dr. Carolyn Deal, who will discuss the scientific scope and DMID’s current AR research portfolio, and the new program’s structure and function, respectively.
Dr. Heilman noted that the 2012 edition of the Jordan Report would be released shortly, and promised to share with the Subcommittee the link to the report on the NIAID Web site once it was available. DMID first developed this vaccine research and development “state of the science” report 30 years ago, and update it on a regular basis for the research community. She also noted the recent celebration of DMID’s Vaccine and Treatment Evaluation Units (VTEU) 50th anniversary. The VTEUs provide a ready resource for the conduct of clinical trials to evaluate promising vaccines and treatments for infectious diseases, and have played a key role in NIAID’s effort to develop new and improved vaccines and therapies.
Finally, Dr. Heilman reported that DMID recently held two external program reviews: one focused on the DMID Centers of Excellence for Influenza Research and Surveillance (CEIRS) program (which was one of the concepts considered by the Subcommittee on this date), and one focused on DMID’s international research portfolio, which spans all branches and offices in DMID. Subcommittee member Dr. Samuel Stanley was part of the CEIRS review, and Dr. Kent Kester participated in the international research portfolio review; they provided the Subcommittee with a brief report on each activity. Dr. Stanley reported that the CEIRS review was both rigorous and comprehensive, and noted that the extensive background materials provided in advance and access to DMID staff and CEIRS investigators was tremendously valuable in assessing the program. He acknowledged the pivotal role the network played in the 2009 H1N1 influenza outbreak, which demonstrated their ability to respond to emerging infectious disease threats, a critical component of why the network was created. In summary, Dr. Stanley reported that the review was positive, and he commended DMID for supporting the CEIRS program, noting that it provides a tremendous resource for research on influenza.
Dr. Kester reported on DMID’s international research portfolio review, noting that the review panel was impressed by the scope, the breadth, and the forward-thinking approaches DMID has employed to anticipate new infectious disease threats, pursue new research opportunities, and address the needs of our partners overseas. He commended DMID for supporting a comprehensive array of activities to facilitate international research, spanning dedicated research programs, training efforts, and clinical research support, among other activities.
Dr. Heilman stated that reports were being developed for both reviews and that she would share them with the Subcommittee once they are available.
Dr. Robert Belshe provided a comprehensive summary of the Herpevac Trial for Women, a randomized, double-blind, controlled Phase III clinical trial investigating a vaccine to protect women against genital herpes disease. NIAID has helped support the trial in collaboration with GSK since 2002. The study results were recently published in the New England Journal of Medicine.
Following Dr. Belshe’s report, Dr. Carolyn Deal, chief of the Sexually Transmitted Diseases Branch, the DMID component engaged in the day-to-day conduct of the trial, noted that the trial generated a rich data set that continues to be used for follow on studies and data analysis. Several additional manuscripts are currently in preparation, and DMID is planning a workshop on next generation herpes vaccines.
Dr. Irene Glowinski, DMID’s deputy director, provided an update on DMID’s preclinical services activities. She noted that DMID has revamped and consolidated these services into five large and comprehensive programs over the past several years, and that the new programs are more integrated and comprehensive than previous efforts, offering the Institute greater flexibility and efficiency. Dr. Glowinski described the capabilities of these programs and shared recent usage metrics. She also provided several examples of how these services have been used to facilitate the development of specific products.
The following three concepts were presented to the Subcommittee for their review and approval:
Concept Clearance - Centers of Excellence for Influenza Research and Surveillance: The objective of this program is to carry out a variety of activities, including: determining the prevalence of avian influenza viruses in animals in close contact with humans; understanding how influenza viruses evolve, adapt and transmit; and identifying immunological factors that determine disease outcome. Subcommittee members enthusiastically supported the concept and highlighted the importance of this ongoing effort, noting that it is a critical program that NIAID should maintain, given the public health threat posed by influenza viruses. One Subcommittee member noted that the accomplishments were impressive, in particular the program’s rapid and multi-faceted response to the 2009 H1N1 pandemic. The CEIRS program was also recognized for providing excellent training opportunities for young academicians. The members unanimously approved the concept.
Concept Clearance - Genomic Centers for Infectious Diseases: The goal of this program is to support state-of-the-art, large scale, cost effective Genomic Centers to enhance the understanding of pathogens and related microbes and their interactions with the host, microbiome and environment. This initiative will support Centers for sequencing, genotyping, metagenomics, transcriptomics, next generation technology development and genomic data analysis and tools to study infectious diseases. Subcommittee members enthusiastically supported the current program. One member stated that the concept was timely and will allow NIAID to continue to provide high quality genomic data sets. In particular, they noted that the proposal to increase services for genomic data analysis for large scale, complex data sets will meet a critical need for the infectious diseases research community. The concept was unanimously approved by the Subcommittee.
Concept Clearance - Bioinformatics Resource Centers for Infectious Diseases: The goal of this program is to provide integrated bioinformatics resources to support basic and applied infectious diseases research. This program will support Centers that will develop data management solutions, computational analysis and visualization tools, workbenches, and web interfaces. In addition, it will provide integrated data sets and educational outreach training to the scientific community. Subcommittee members enthusiastically supported the current program and highlighted the importance of further developing bioinformatics capacity to support genomics research. The concept was unanimously approved by the Subcommittee.
Dr. Connie Celum, chair, welcomed the ARAC members, DAIDS representatives, and guests. She presented the minutes of the September 19, 2011, ARAC meeting, and the members approved them 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 extended a special welcome to the three guest speakers: Drs. Joseph Romano, Steven Deeks, and Nancy Haigwood. The invited speakers were included in an expanded meeting format to help frame the initiatives and highlight specific research areas. Dr. Dieffenbach noted that Dr. Celum had to leave at the scheduled break, and subsequently, he would act as chair. He then introduced the following new NIAID Council AIDS Subcommittee/ARAC members - Adaora Adimora, M.D., Jonathan Karn, Ph.D., and Georgia D. Tomaras, Ph.D.
Dr. Dieffenbach provided an overview of the NIAID fiscal year 2012 and 2013 budgets. He noted that just before Christmas, Congress appropriated the FY 2012 budget, and both NIH and NIAID received small budget increases. The President signed the budget bill into law on December 23, 2011. The potential budget cuts in FY 2012 to NIAID, fortunately, did not occur. Overall, the FY 2012 NIAID budget was an improvement (0.3 percent increase), small though it was, over the FY 2011 budget, which had reflected the first cut to NIAID’s funding level in more than 35 years.
NIAID’s financial management plan for FY 2012 mirrors last year’s plan in that 10 percentile paylines are projected for experienced investigators and 14 percentile for new investigators. There will be no inflationary increase for noncompeting grants per NIH policy. The NIAID estimated success rate will be approximately 21 to 22 percent in FY 2012. The policies for programmatic adjustments, type 2 cap, selective pay, and bridge awards are the same as last year’s.
On February 13, the President is expected to submit his FY 2013 budget request to Congress. It is anticipated that both the House and Senate Appropriations Subcommittees for Labor, HHS, and Education will announce their schedules for the FY 2013 appropriation hearings shortly after the President submits his budget request. Beginning in January 2013, due to The Budget Control Act of 2011, approximately $100 billion per year might be sequestered from budgets across the federal government. Few in Congress want across-the-board cuts of up to 10 percent or more in FY 2013, but Congress must pass into law detailed plans to prevent severe cuts before the sequestering occurs. Consequently, NIAID, along with other federal agencies, must have plans in place to handle possible budget cuts.
Research project grants (RPGs) are awards made for investigator-initiated research proposals and/or in response to a funding announcement or program announcement. The NIAID overall success rate in funding RPGs in 2011 was 20 percent. The success rate for NIAID Investigator Initiated Program Project Applications (P01s) was 24 percent in 2011. No unsolicited AIDS P01s were funded in 2011. The funding success rate for exploratory/developmental grants (R21s) was relatively poor at 17 percent. The FY11 comparative success rates for NIAID AIDS (including AIDS and AIDS-related activities in DAIDS, DAIT, and DMID) were 22 percent for RPGs and 19 percent for R01s (NIAID Clinical Trial Implementation Grants).
The international HIV prevention trial, HPTN 052 sponsored by NIAID, was chosen by the journal Science as the 2011 Science Breakthrough of the Year. Findings from the clinical trial were released in May 2011, followed by publication of the results in the New England Journal of Medicine in August. The HPTN 052 study showed that antiretroviral (ARV) medications can treat as well as prevent the transmission of HIV-1 infection from infected heterosexual individuals to their uninfected partners.
HPTN 052 was initiated in 2005 and enrolled 1,763 HIV-serodiscordant couples in nine countries. Antiretroviral medicines, begun when infected heterosexual individuals were relatively healthy versus delayed treatment in advanced disease, reduced the risk of heterosexual transmission by 96 percent. Thus, treating HIV-infected people with ARVs significantly reduces transmission to partners, achieving complete and sustained virological suppression.
Dr. Dieffenbach noted the context in which these results should be considered. Healthcare delivery in terms of HIV is a continuum, beginning with awareness and testing moving to linkage-to-treatment and prevention, to viral load suppression and decreased transmission. In each step along the cascade, HIV-infected people can be lost through lack of diagnosis, intervention, and retention, resulting in lower coverage and diminishing returns in terms of the number of people on treatment.
On December 21, 2011, the U.S. Food and Drug Administration (FDA) announced that it had approved expanded use of the HIV drug ISENTRESS (raltegravir) with other antiretroviral agents for the treatment of children and adolescents ages 2-18. ISENTRESS (product of Merck) is the first drug in a new class of ARVs (integrase inhibitors) to be approved for children in nearly 10 years. Raltegravir inhibits the insertion of HIV-1 DNA into human DNA by the integrase enzyme, thus limiting viral replication and infection of new cells. In combination with other ARVs, the drug may decrease the level of HIV in the blood and may improve the number of CD4+ T cells.
The FDA approval to expand the indication for ISENTRESS was based on data from an ongoing Phase I/II open-label, multicenter trial (P1066) through the International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) network. FDA approval of ISENTRESS represents the exceptional collaboration among NIH, the pharmaceutical company Merck, and IMPAACT.
The journal Nature Methods selected genome editing with engineered nucleases as the Method of the Year 2011. The technology will allow scientists to introduce specific modifications into targeted genomic sites with the potential to treat human diseases, including HIV/AIDS.
NIAID is restructuring the NIAID Clinical Trials Networks to create an infrastructure that can accommodate both HIV/AIDS research and research involving non-HIV/AIDS infectious diseases. Toward that end, NIAID has issued five funding opportunity announcements (FOAs), which will support leadership groups for clinical research networks in selective areas of HIV/AIDS research. FOAs soliciting applications for Clinical Trials Units (CTUs) will be released soon as well.
A question was raised about how well new investigators did who were funded in 2009-2010. There is no data yet, but this is something NIAID will continue to track. In discussing NIAID’s vision of implementation science, it was noted that given current budget constraints and priorities, research in this area is limited. The Department of Health and Human Services (HHS) supports collaborative work among the Centers for Disease Control and Prevention (CDC), NIH, and other relevant agencies for this purpose. However, NIAID’s order of priorities is to first protect basic research activities, then demonstrate proof of concept, and finally to follow through on implementation.
Judith N. Wasserheit, M.D., M.P.H.ORAC Liaison
Dr. Wasserheit gave a recap of the November 10, 2011, OARAC meeting, which focused on AIDS research in men who have sex with men (MSM). The meeting covered opportunities and challenges in epidemiology, clinical and behavioral factors of HIV infection, and recent prevention research among MSM. MSMs are one of highest risk groups for HIV, and few evidence-based interventions (EBIs) are available to them. Key points from the meeting included the following:
The Committee asked if preferable alternatives to the term “MSM” were identified during the OARAC meeting. None were but it was flagged as an issue and concerned parties were reminded that MSM constitutes an overall term, which can be broken down into more sophisticated components (bisexual, transgender, etc.).
Sheryl Zwerski, M.S.Acting Director, Prevention Science Program, DAIDS
Ms. Zwerski reviewed the clinical proof of concepts that have altered the field of HIV non-vaccine biomedical prevention, from the CAPRISA (Center for the AIDs Programme of Research in South Africa) 004 Tenofovir gel trial in 2010 to VOICE (Vaginal and Oral Interventions to Control the Epidemic), a major HIV prevention study in women. (She also noted that the Prevention Sciences Program has recently created a Preclinical Microbicide and Prevention Research Branch to accompany the two clinical branches and that Dr. Fulvia Veronese is the newly appointed Assistant Director for Translational Research.)
Prevention science continues to evolve, focusing on:
Joe Romano, Ph.D.Consultant (Gates Foundation and others); President, NWJ Group, LLC; Wayne, PAMicrobicide Trials Network (MTN)/Tenofovir Gel Development Team
Dr. Romano provided an overview of the microbicide pipeline, outlining the multiple approaches and product options in various states of study and maturation. Significant investment has been made in product advancement, invention, and clinical evaluation, particularly ARVs. Among the many challenges to a sustainable pipeline are: (i) lack of consensus prioritization on early stage candidates in an era of diluted resources and (ii) limited regulatory input, especially during the preliminary stages of development.
The need remains for “high-impact” products with the following characteristics:
In discussion, it was noted that industry has long used the desired product profile to assess potential value relative to prioritization within the discovery and development portfolio. For example, proof of concept for a long-acting product having multiple indications without issues of poor adherence would be high impact and high priority. The selective pressure (provided by drugs) on HIV viruses that favors the development of resistance is recognized as a problem, particularly with ARVs. The driver of ARV production has been mostly the availability in the field, but the conflict between systemic use and selective pressure is noted. With regard to follow-up in the wake of studies of Truvada (tenofovir/emtricitabine), governing agencies are most concerned about safety. If products such as Truvada are released for general population use, we would expect specific guidelines for patient management and safety. At this point, there are only a few ARV alternatives that exist and they are in very early stage development.
Dr. Romano also discussed dual-indication products. These are products that would for example, not only prevent HIV infection, but also potentially help address some of the cofactors, like HSV infection or prevent pregnancy. They also provide an opportunity to achieve greater product uptake, where we can potentially leverage populations who are using contraceptives if we had an additional HIV prevention capability in those products, we’d already have some meaningful venues into those populations in terms of achieving product uptake.
One question concerned Pharma’s enthusiasm for the development of dual-use products. The bottom line with Pharma is what can they sell but production is limited by both resources and technical feasibility. The Gates Foundation and others have sought to answer this question and have found public interest in dual-use products. The Gates Foundation will release strategies concerning public health and multi-purpose products in March 2012.
There are also studies on single-dose, long-acting injectable anti-viral drugs. The Gates Foundation is sponsoring studies on long-acting injectable, multiple-dose and single-dose (rectal/vaginal).
Jim A. Turpin, Ph.D. Program Officer and Acting Branch Chief Preclinical Microbicides and Prevention Research Branch (PMPRB)/NIAID/DAIDS/PSP
Dr. Turpin presented two concepts for initiatives for review and approval: the PIP and the IPCP-MBP. The overarching scientific objectives of the preclinical non-vaccine biomedical prevention program are to:
The objective of the PIP is to support innovative proof-of-concept/feasibility research needed to support and advance the fields of Microbicides, PrEP, non-vaccine biomedical prevention, and MPT. This is a new initiative, supported by the R01 award mechanism. The award is for four years with the estimated number of awards being four to eight.
The objectives of the IPCP-MBP program are to: 1) stimulate a strong, diverse base in preclinical discovery and development of new topical microbicides and biomedical prevention; 2) develop combination and sustained release strategies for vaginal, penile, rectal, oral, and/or injectable use; and 3) support translation from preclinical to pre-Phase 1 clinical studies. Pre-clinical, high-risk studies will drive the engine of a sustainable pipeline. This initiative will utilize the NIH multi-project (U19) cooperative agreement grant mechanism and is a continuation adjusted in scope. Support covers four years of preclinical science and five years of clinical science.
Reviewers (Celum and Warren) enthusiastically agreed that the concepts address concerns about new products entering the pipeline and expand the prevention program to cover systemic and biomedical aspects. Specific suggestions were to clarify the relationships among relevant programs such as the Microbicide Innovation Program (MIP), PIP, IPCP-MBP, and the Next Generation PrEP Program (NGP) and to provide a timeline relating the concept to previous programs.
It was pointed out that to ensure coordination program staff will utilize different communications vehicles, including workshops that would bring together specialists in reproductive health, vaccines, and microbicides. It was also noted that as a consequence of programmatic changes, proposals may or may not be more conservative. Experience suggests investigators will rise to the challenges, and some will offer high-risk proposals in support of avant-garde research to advance the science. Staff will communicate specific interests to investigators and proposals will be prioritized based on their degree of innovation.
Committee expressed support for both concepts and voted approval by a show of hands.
Susan F. Plaeger, Ph.D.Director, Basic Sciences Programs, NIAID/DAIDS
The focus of the BSP is on identifying, understanding, and eradicating HIV-1 reservoirs, particularly in ARV treated individuals, in addition to affecting a cure. Although finding a cure for HIV infection remains challenging, it may be possible. A cure means permanent remission in the absence of therapy or permanently purging HIV reservoirs. The only current example of a cure is a man with HIV who was suppressed on Highly Active Antiretroviral Therapy (HAART) and developed acute myeloid leukemia. The patient, Timothy Ray Brown, nicknamed “The Berlin Patient” received bone marrow stem cell transplants—from a donor with a mutated form of the CCR5 gene such that cells did not express the CCR5 HIV co-receptor – along with immune suppression and chemotherapy for his leukemia. After the patient’s transplant he discontinued antiretroviral therapy. To date, doctors have not detected HIV-DNA or HIV-RNA in his system, and he has reverted to being HIV-seronegative. While hematopoietic stem cell transplant is not feasible for most people with HIV, the Berlin patient represents proof-of-concept for a cure.
The DAIDS approach towards a cure involves follow-up supporting several lines of research from basic to clinical, including: FY 09-14 Basic Research on HIV Persistence (R21, R01); in the FY 11 Martin Delaney Collaboratory: Towards an HIV-1 Cure (U19); as well as an FY 12 initiative, Beyond HAART, Innovative therapies to control HIV (P01), FY 13: Targeting Persistent HIV Reservoirs (R21/R33), and an FY 14 concept being presented by Dr. Karl Salzwedel.
Steven G. Deeks, Ph.D. Professor of Medicine, University of California, San Francisco (UCSF) Recipient of one of the Martin Delany Collaboratories
Dr. Deeks discussed how a cure for HIV infection will be clinically defined and the potential mechanisms of HIV persistence in bodily compartments. Two approaches underlie the research to cure HIV – the search for a sterilizing cure and a functional cure. The sterilizing approach aims for complete eradication of all replication-competent virus. One strategy would be to eliminate latent HIV by inhibiting pro-latency signaling and/or by reactivating HIV transcription directly. A functional cure is defined as long-term viral suppression in the absence of antiretroviral therapy and is analogous to the cancer remission model. It occurs in about one percent of natural infections. One strategy for a functional cure would be to enhance HIV-1-specific immunity. Since a sterilizing cure will likely need an effective way to clear virus-producing cells, these strategies may be synergistic. For example, enhanced immunity would facilitate the clearance of reactivated latently infected cells.
During long-term effective HAART, HIV resides almost entirely in CD4+ T cells, central memory cells and transitional memory cells to be specific. Mechanisms of HIV persistence may include: 1) low-level (cryptic) viral replication, including cell-to-cell transfer of HIV and 2) a long-lived reservoir of resting CD4+ T cells. Emerging evidence suggests that virus may persist in lymph nodes and the gut, especially the ileum, even when almost no virus is present in the blood. Chronic inflammation and/or immune dysfunction may drive HIV persistence through several non-mutually exclusive mechanisms (upregulation of “negative regulators,” homeostatic proliferation, increased target cells, lack of effective HIV-specific T cells). Numerous studies and projects in each of the three Martin Delaney Collaboratories, as well as the ACTG, are addressing how to defeat HIV persistence by targeting multiple mechanisms.
During the discussion, the point was made that non-human primate studies should shed some light on concerns about the risk of HAART to the central nervous system. It was also noted that there is great patient impetus toward gene therapy trials, mainly driven by drug fatigue and other long-term clinical issues. The persistence of HIV in the reproductive tract in HIV-infected patients should also be easily testable.
Sequelae of HIV and interventions are intertwined, so parallel measurements will be required—CNS, immunological, viral load, etc. The ileum, lymph nodes, and liver are prime examples of areas of the body in which HIV reservoirs may be lurking, but the technical capacity to analyze virus in these compartments is a missing resource.
Karl Salzwedel, Ph.D. Program Officer Pathogenesis and Basic Research Branch/Basic Sciences Program/NIAID/NIH
Dr. Salzwedel noted that recent reports suggest that low-level viral production and infection may persist in sanctuary sites such as lymph nodes and the terminal ileum and in specific cell types (tissue macrophages, for example) during HAART. This may, in part, be due to cell-to-cell spread of HIV and lower than expected intracellular concentrations of ARV drugs in certain tissues.
The objective of this potential research initiative is to develop innovative strategies for improved delivery of ARV drugs and other agents to specific cell types or tissue compartments that serve as reservoirs of persistent virus production and infection. The solicitation is new and will be supported by the R01 mechanism. The award is for five years and will help maintain programmatic balance by funding innovative research focused on eliminating self-replenishing reservoirs that persistently produce virus, as opposed to latent reservoirs.
Reviewers (Karn and Zack) enthusiastically supported the concept since it fills an important gap in NIAID’s initiatives on curative strategies for HIV. The persistent “active” reservoir may be distinct from that of the latent reservoir, and basic and translational studies in this area will enhance our understanding of persistent viremia in the presence of HAART and the source of rebound virus upon treatment interruption.
When questioned about the need for a separate initiative focused on persistent “active” reservoirs given the perceived superficial distinction between latent and active reservoirs, staff noted that the distinction lies in fundamental differences in the strategies needed to overcome latent vs. active reservoirs: latent virus must be activated; whereas, actively produced virus must be shut down. While the initiative will focus on human studies, high risk studies will necessarily require animal models. Committee members felt that the initiative shows timely programmatic response to a changing scientific environment; they expressed support for the concept and voted approval by a show of hands (marked ballots to be collected and counted).
Alan Fix, M.D. Chief, Vaccine Clinical Research Branch (NIAID/DAIDS/VRP/VCRB)
In addition to anticipated clinical trials in follow-up to RV144, VRP remains committed to supporting research that fosters novel concepts and a balance of basic and clinical research. The concepts to be presented today are intended to support research that explores new ideas, ranging from early-stage innovative discovery concepts to translational research leading to clinical trials.
Nancy L. Haigwood, Ph.D. Professor and Senior Scientist, Oregon National Research Primate Center, Oregon Health & Science University
Dr. Haigwood gave a brief update on the types of vaccine products that have been tested in clinical trials, summarized the major problems that confront AIDS vaccine developers, and finally summarized the work that she is carrying out in her laboratory to address the problem of inducing broadly reactive neutralizing antibodies.
Several vaccine efficacy trials have been carried out in recent years, testing recombinant envelope proteins, adenovirus vectors and poxvirus vectors. Earlier trials testing gp120 proteins showed no efficacy in the populations tested, MSMs and IVDUs. Trials with replication-defective adenovirus vectors demonstrated that while the vaccines were immunogenic, the vaccines themselves appeared to result in an enhancement of HIV infection in certain populations with pre-immunization adenovirus immunity. The RV144 trial, testing avian poxvirus vectors and gp120 proteins, yielded a low degree of efficacy. Follow-up studies point to antibody as a likely correlate of risk in that trial but it is not clear what component of the vaccine regimen was responsible for the observed protection.
HIV infection induces the production of neutralizing antibodies but the antibodies generated early after infection are generally type-specific. Heterologous neutralizing antibodies arise with time in 10-25 percent of infected individuals as the response matures in parallel with the continuous evolution of the viral envelope to evade neutralizing antibodies. Dr. Haigwood’s central hypothesis is that the evolution of the quasispecies env gene resulting in mutated virus surface Env proteins is driving the development and broadening of the neutralizing antibody response. Her lab has addressed this hypothesis by designing vaccines based on representative Env proteins from the HIV quasispecies found in a clade B-infected individual who was able to generate a broad neutralizing antibody response, and immunizing rabbits and nonhuman primates sequentially with these different immunogens. Her initial experiments have shown that with this strategy she is able to partially mimic, in rabbits and nonhuman primates, the in vivo development of neutralizing antibodies as observed in HIV-infected humans. Her lab continues to study the immune response in individuals who exhibit broadly reactive neutralizing antibodies in hopes of using the information gleaned from those studies to design immunogens better able to induce these types of antibodies.
Jon Warren, Ph.D. Microbiologist, AIDS Vaccine Discovery, NIAID/DAIDS/VRP/VDB
The objective of this concept is to stimulate investigator-initiated research on innovative, high risk/high impact novel vaccine approaches that may provide long-term, safe protection from acquisition of HIV infection. Preliminary data are not required, and in its absence, reviewers will evaluate the investigator along with the institutional capacity to conduct the proposed research. The solicitation is new and will be supported by the R01 award mechanism and is for up to four years.
The initiative will address responsive research such as deciphering protective aspects of mucosal innate immunity amenable to vaccine induction. The initiative will also cite non-responsive research, for example, incremental improvements of approaches already under development or combination strategies. Investigators new to the HIV vaccine field are encouraged to apply, and cross-disciplinary collaborations are strongly encouraged.
Reviewers (McCutchan and Tomaras) enthusiastically supported the concept and approved the solicitation with modification(s). The reviewers cautioned against overly restricting incremental improvements of approaches already under development by defining it as non-responsive research. Instead, it was suggested that existing approaches would be responsive if they are uniquely built upon novel concepts or strategies that specifically targeted areas identified as responsive research. Program staff agreed with this comment and will modify the initiative to further clarify what is responsive. Members were asked to recognize, however that it is somewhat subjective and that not all areas of responsive research can be identified in the RFA.
In discussion, it was mentioned that durability of the HIV antibody response in the context of a new approach would be considered an example of “responsive” research and that innovation is a very important criterion in terms of incremental steps.
The ARAC members expressed support for the concept and voted approval by a show of hands, with the modification to clarify what is considered responsive based on the discussion.
Michael Pensiero, Ph.D. Product Development Team Leader, AIDS Vaccine Discovery, NIAID/DAIDS/VRP/VDB
The objective of this solicitation is to support all stages necessary to translate advanced innovative vaccine concepts toward clinical research studies. This concept is considered new although the program was begun several years ago and took a hiatus in FY 10. In the past, the program brought together investigators who otherwise might not have collaborated. The initiative will utilize the multi-project (U19) cooperative agreement grant mechanism, is for five years, and the number of awards is one to two. The funding of clinical studies will not be supported under this program. The concept fills a need to support an investigator-initiated, multidisciplinary “translational” program that is as systematic and integrated.
Examples of areas of HIV vaccine research that will be addressed by the renewal of the IPCAVD program include: development of novel Env immunogens; development of novel vaccine vectors and gene delivery platforms; and improved devices for gene transfer. The reviewers (Michael, Birx, and Goldenthal) were extremely positive and voted for approval of the initiative renewal.
Reviewers acknowledged the limited availability of funds but recommended increased flexibility, for example, considering a seven year mechanism instead of five and the occasional funding of clinical trials. Program staff said they would explore the issue of extending the award duration to two years for meritorious research.
Committee members expressed support for the concept and voted approval by a show of hands.
The meeting of the Council was adjourned at 5:00 p.m., on Monday, January 30, 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 15, 2013