The 175th meeting of the National Advisory Allergy and Infectious Diseases Council (NAAIDC) convened at 10:30 a.m. on Monday, September 16, 2013, in Conference Rooms E1/E2, Building 45, National Institutes of Health. Dr. Anthony S. Fauci, director, National Institute of Allergy and Infectious Diseases (NIAID) presided as chair.
In accordance with the provisions of Public Law 92-463, the meeting was open to the public from 10:30 a.m. to 11:45 a.m. and from 1:00 p.m. to 4:35 p.m. The meeting was closed to the public from 8:30 a.m. to 10:15 a.m. and from 11:45 a.m. to 12:00 p.m. for review and consideration of individual grant applications. Notice of the meeting was published in the Federal Register.
Council Members Present:
Ex Officio Members Present:
Ad Hoc Members Present:
Council Members Absent:
Ex Officio Members Absent:
NIAID Senior Staff Present:
Table of Contents
The National Advisory Allergy and Infectious Diseases Council convened in closed session to consider applications in allergy and immunology, microbiology and infectious diseases, and AIDS.
Funding Actions: The Council reviewed 3,457 research and training applications with primary assignment to NIAID for a requested amount of $1,265,336,061 in first-year direct costs and recommended approval of 1,706 applications with $647,907,959 in first-year direct costs.
Council member Dr. Mavis Agbandje-McKenna was also unable to attend the meeting.
Dr. Fauci introduced three ad hoc Council members—Dr. James Gera, University of Wisconsin; Dr. Susan Lynch, University of California San Francisco; and Dr. Lawrence Stanberry, Columbia University College of Physicians and Surgeons.
Consideration of Minutes of Previous Meeting
Council considered the minutes of the June 3, 2013, meeting and approved them as written.
Staff and Organizational Changes
In August, Ralph Tate, director, Office of Mission Integration and Financial Management, retired after 12 years of service to NIAID. Dr. Fauci summarized some of the numerous contributions he made to the Institute.
In DAIDS, Dr. Diana Finzi has been selected as the new director of the Basic Sciences Program.
Dr. Frank DeLeo was appointed chief, Laboratory of Human Bacterial Pathogenesis, Division of Intramural Research.
In DAIT, Dr. Johanna Schneider is the new chief of the Office of Program Planning, Operations, and Scientific Information.
Tributes and Awards
Dr. Fauci paid tribute to Dr. John Swanson, former chief of the Laboratory of Microbial Structure and Function, Rocky Mountain Laboratories, who passed away suddenly in July. In the 1980s, Dr. Swanson helped revitalize the Rocky Mountain Laboratories by championing the latest tools and methods in microbiological investigation. He’s also credited by many with starting internationally recognized research programs on the bacteria that cause gonorrhea, chlamydia, and Lyme disease.
Meetings and Events
In June, NIAID and other NIH staff met in Durban with South African AIDS investigators, leadership of the South African Medical Research Council (MRC), and other biomedical research organizations to discuss AIDS-related mutual interests. Discussions continued during a subsequent visit to NIAID by a delegation from the South African Ministry of Science and Technology.
As a result of these meetings, a new joint solicitation is being developed with the South African MRC for research on HIV/AIDS, tuberculosis, and AIDS-associated cancers. U.S. and South African scientists will be eligible to apply.
In June, Dr. Grant Colfax, director, White House Office of National AIDS Policy, visited the Vaccine Research Center.
On August 1, HHS Secretary Kathleen Sebelius visited NIH and held a roundtable discussion with NIH institute directors followed by a town hall meeting for NIH employees.
On August 2, Dr. Fauci met with Georgian Minister of Health David Sergeenko and Georgian Ambassador Archil Gegeshidze. The delegation explored opportunities for cooperation in the areas of cancer, hypertension, HIV/AIDS, and related comorbidities.
NIAID recently updated its Strategic Plan, which outlines our priorities in five major areas: 1) infectious diseases (non-AIDS), including emerging and reemerging diseases and biodefense; 2) HIV/AIDS research; 3) allergy, immunology, and immune-related diseases; 4) essential foundations such as research resources and infrastructure; and 5) global health. To read the entire plan, go to NIAID Strategic Plan 2013.
In April, President Obama presented his FY 2014 budget request to Congress, which includes a compromise that replaces the across-the-board spending cuts with a combination of program reductions and new revenues. Because the FY 2013 budget was late and uncertain, the President’s FY 2014 budget request used FY 2012 as the comparable budget. The FY 2014 budget request provides NIH with a 1.5 percent increase over FY 2012. NIAID would fare better than most other ICs because of the transfer of approximately $27 million from NIMH to expand collaborative efforts to integrate behavioral sciences into biomedical approaches to enhance prevention and treatment while decreasing the burden of living with HIV.
Then Dr. Fauci compared the enacted FY 2013 budget with the President’s FY 2014 budget request. This comparison provides NIH with a 7.5 percent increase and NIAID with an 8.2 percent increase over the FY 2013 enacted level.
With the end of the fiscal year approaching, it’s likely that Congress will pass a continuing resolution (CR) to keep the government operating.
Dr. Fauci summarized NIAID’s interim financial management plan for FY 2014 under a CR. NIAID will support a payline to the 6 percentile for established investigators and the 10 percentile for new and early-stage investigators. NIAID plans to make programmatic adjustments to competing grants, cut competing research initiatives by up to 20 percent, and fund noncompeting grants at 80 to 90 percent of committed levels.
On June 17, Senate Majority Leader Harry Reid visited the NIH Clinical Center and met with Dr. Francis Collins, Dr. Fauci, and several other NIH institute directors. The visit focused on the critical research NIH does, including NIAID’s efforts to develop a universal flu vaccine.
On July 16, Representative David Schweikert visited NIH and met with Dr. Collins, Dr. Fauci, and some other NIAID scientists to learn about NIH and NIAID research on valley fever.
On June 27, Dr. Lee Hall, chief, Parasitology and International Programs Branch, DMID, and Dr. Jesse Goodman, chief scientist, FDA, testified before a hearing of the House Foreign Affairs Subcommittee on Africa, Global Health, Global Human Rights, and International Organizations. They provided an overview of NIAID research to address neglected tropical diseases.
Other Information Items
PEPFAR recently celebrated its 10th anniversary. Dr. Fauci and Dr. Eric Goosby, ambassador in charge of the Office of Global Health at the State Department, wrote an editorial in the Huffington Post outlining the successes and accomplishments over the 10 years.
In June, WHO issued new HIV recommendations calling for earlier treatment. Dr. Fauci summarized the updated WHO antiretroviral guidelines.
In July, Dr. Fauci presented the keynote lecture at the STI and AIDS World Congress 2013 held in Vienna.
On June 24, NIAID hosted a Middle East Respiratory Syndrome Coronoavirus (MERS-CoV) expert consultation. The consultation brought together experts to address critical gaps in MERS-CoV knowledge and to discuss and map out a strategy. To read the report, go to Middle East Respiratory Syndrome Coronoavirus (MERS-CoV) Research: Current Status and Future Priorities.
Dr. Fauci gave brief updates on influenza, tuberculosis, malaria, gonorrhea, pertussis, vasculitis, and transplantation research.
Dr. Kathryn Zoon gave an overview of the Division of Intramural Research’s (DIR) strategic priorities for FY 2013 and FY 2014. These priorities include advancing transformative biomedical research to generate knowledge and countermeasures that enhance national and global public health; supporting bench-to-bedside-to-bench research by linking basic, translational, and clinical researchers with the NIH Clinical Center and NIAID international sites; and enabling rapid response to public health threats.
DIR’s budget for FY 2014 is uncertain, but it has decreased over the past four years. To cope with budget reductions, DIR has cut contracts, supply budgets, and personnel in laboratories; closed a laboratory; and consolidated animal programs in Maryland and Montana under a single program director.
Three senior investigators retired last year and three more plan to retire this year. Dr. Zoon noted that three tenure-track investigators were not recommended for tenure, one new tenure-track investigator was appointed, and two tenure-track investigators received tenure. She also recognized DIR scientists who received distinguished honors and awards.
The Board of Scientific Counselors met in December and June and reviewed several DIR laboratories and performed tenure-track midpoint reviews.
Dr. Zoon concluded by highlighting some of DIR’s scientific achievements in the areas of influenza, MERS-CoV, and dengue vaccine.
Dr. Rotrosen welcomed back all of our recurring subcommittee members of the National Advisory Allergy and Infectious Diseases Council. Dr. Rotrosen announced that Johanna Schneider has joined DAIT as director of Office of Program Planning, Operation, and Scientific Information (OPPOSI).
Dr. Rotrosen went on to announce that Dr. Alkis Togias, chief, Allergy, Asthma, and Airway Biology Branch would present an “Overview of the Inner City Asthma Consortium.” In addition, Dr. Rotrosen informed the subcommittee members that it was a pleasure to have Dr. James Gern, M.D., University of Wisconsin School of Medicine and Public Health present “Factors Influencing Early Age Atopy and Wheezing: The Urban Environment and Childhood Asthma Study” and Dr. Susan Lynch, Ph.D., University of California, San Francisco, Colitis and Crohn’s Disease Microbiome Research Core present “The Effect of House Dust Microbiome on Atopy and Wheezing.”
Following the presentations, Dr. Rotrosen announced there were five research concept clearances for review and approval by the subcommittee.
Fiscal Year 2014 Research Concept Clearance
SBIR Contract Solicitation Topic: Adjuvant Development: The goal of this initiative is to accelerate preclinical development of a single lead adjuvant candidate for prevention of human disease caused by non-HIV disease pathogens. Phase I activities depending on the developmental stage at which an adjuvant is entered into the Program, the offeror may choose to perform one or more of the following: 1) optimization of one candidate compound for enhanced safety and efficacy; this may include structural alterations or modifications to formulation; 2) establishment of an immunological profile of activity and immunotoxicity that can be used to evaluate the capability of the adjuvant to advance to human testing; or 3) preliminary studies in a suitable animal model to evaluate the protective efficacy of a lead adjuvant:vaccine combination. Phase II activities extended preclinical studies that may include IND-enabling studies.
The subcommittee endorsed and unanimously approved this initiative.
Fiscal Year 2015 Research Concept Clearance
Modeling Immunity for Biodefense: This initiative will support the development, refinement, and validation of computational models of the immune system, through inclusion of companion immunologic experimentation. It will also support pilot projects, summer schools, and symposia to make computational modeling more accessible to the broader research community.
Immune Models Integration Project: The main objective of this initiative is to support the development and validation of a computational modeling framework. This framework would integrate existing and newly developed computational models of immunity to provide a tool to study immune responses at various scales or levels: signaling/molecular interactions, cell-cell interactions, systemic function, and phenotype.
Atopic Dermatitis Research Network: As with the two previous ADRN initiatives, this initiative aims to understand defense mechanisms of the skin, by focusing on differences between skin of non-atopic individuals and patients with atopic dermatitis (AD). AD subjects have defects in both their immune response and skin barrier. The ADRN has carefully phenotyped AD patients and normal individuals and identified at least three pairings in which one group has reduced host defense compared to the other. In each of the following sets, the first group has reduced host defense: (a) severe compared to moderate or mild AD; (b) AD with history of eczema herpeticum (ADEH+) compared to AD with no history of EH (ADEH-); and (c) genetically filaggrin-deficient subjects vs. subjects who are not genetically filaggrin deficient. The network aims to evaluate defense mechanisms in these subsets. Based on data from the current ADRN, promising research areas to pursue include studying the genetic and epigenetic basis of host defense abnormalities; evaluating the immune and skin barrier impairments leading to cutaneous viral (e.g., herpes simplex) and bacterial (e.g., Staphylococcus aureus) infections; and evaluating the role of the skin microbiome in host defense. Additional promising research includes evaluating the role of proteins in both the stratum corneum (filaggrin) and the tight junctions (claudin), and identifying defects in cutaneous immune responses to vaccines (both T and B cell defects).
Consortium of Food Allergy Research: This initiative will develop approaches to prevent and treat IgE-mediated food allergy by supporting 1) clinical trials to test these approaches and 2) state-of-the-art studies to evaluate the mechanisms underlying the outcomes of these trials. The focus is similar to that of the FY 2010 initiative. However, this new initiative includes a greater emphasis on mechanistic studies and their integration with clinical trials.
The subcommittee endorsed and unanimously approved this initiative.
Dr. Carole Heilman, Director of the Division of Microbiology and Infectious Diseases (DMID), chaired the NIAID Microbiology and Infectious Diseases Council Subcommittee meeting on September 16, 2013. After welcoming the Subcommittee, Dr. Heilman once again acknowledged departing member Dr. George Siber for his service; she also introduced today’s ad hoc member, Dr. Lawrence Stanberry, Chairman of the Department of Pediatrics at Columbia University in New York City. Dr. Heilman then referred to the branch chiefs and office directors to introduce new staff in their respective programs.
Following introductions, Dr. Heilman provided a general overview of DMID’s Fiscal Year 2013 budget, which is primarily divided between biodefense and emerging diseases funds and immunology and infectious diseases funds; there is also a small pool of AIDS-related funds. She also reported on the breakdown of these funds for grant-related activities versus contract-related activities within DMID. The funds that turn over each year, which are the pool of funds that provide for DMID’s targeted initiatives, fluctuate each year and are a very small proportion of DMID’s total budget; the rest of the funding makes up the commitment base for ongoing grants and contracts.
Dr. Heilman also highlighted two publications that were shared with the subcommittee members: a copy of the Global Vaccine Action Plan (GVAP), which is designed to enhance coordination across the global community by outlining the steps necessary to achieve the vision of the Decade of Vaccines Collaboration between the Gates Foundation, NIAID, and The World Health Organization; and a Vaccine Journal supplement, published in April 2013, which outlines the implementation of the GVAP.
Finally, Dr. Heilman reported that a new Small Business Innovation Research contract solicitation announcement had been released, which highlights two topics of interest to DMID: Oral Formulations for Drugs of Public Health Importance and Adjuvant Development.
Report: Update: DMID Sexually Transmitted Infections Research Portfolio
Dr. Carolyn Deal, chief of the Sexually Transmitted Infections Branch, provided a comprehensive overview of DMID’s sexually transmitted infections research program, reporting on recent scientific achievements and proposed future directions. She described in detail the current five overarching goals of the program, which include: 1) efforts to address antibiotic resistance, e.g., multiple drug-resistant Neisseria gonorrhoeae; 2) development of new and improved diagnostics, including point of care diagnostics; 3) efforts to address neglected and emerging sexually transmitted diseases, e.g., syphilis and chancroid; 4) increased focus on improving adolescent health through the availability of new vaccines and development of novel therapeutic strategies such as biofilm disruptors and probiotics, and 5) research efforts aimed at reducing premature birth and stillbirth.
FY 2015 Concepts Presented for Clearance
Novel Alternate Model Systems for Enteric Diseases (NAMSED): The proposed focus of the Novel Alternate Model Systems for Enteric Diseases (NAMSED) concept is the development of model systems that mimic pathophysiology to provide relevant predictive outcomes for human enteric diseases; as described, the program would support integrated research approaches that advance understanding of enteric diseases by overcoming obstacles that inhibit the advancement of basic science and product development. Subcommittee members lauded the strategy to fuse the fields of infectious diseases and tissue engineering and noted that this is an exciting frontier for these scientific communities. One subcommittee member sought clarification as to the distinctions between the objectives of NAMSED and the ongoing ERIN program and was reassured by Program’s response that, although ERIN technological advances inspired the translational direction of NAMSED, the ERIN awards will end before the onset of NAMSED. Another subcommittee member asked how DMID can ensure that the fusion with tissue engineering extends to other infectious disease communities beyond enteric diseases; Program noted that NAMSED will pilot the division’s interest in this area and also noted that the 2014 General Meeting of ASM has a session in development that focuses broadly on infectious diseases and bioengineering. In response to other queries, program assured the subcommittee that enteric viruses will be included in the eventual initiative. The concept was unanimously approved.
Defining the Immune Response to HCV: The committee recognized the outstanding accomplishments of the Hepatitis C Cooperative Research Centers program from its inception, when it was very difficult to study an intractable virus, to the present. The committee also agreed on the unfulfilled need to understand the immunological determinants of the dual clinical outcome of HCV in order to design urgently needed vaccines. There was some concern that exclusive focus on HCV might preclude important insights that could be gained from knowledge of immune responses to other persistent viruses. Program responded that the immune response to HCV would only be properly understood in the context of the human response to other infections like hepatitis B virus and HIV, and that investigators studying HCV are often also studying these other viral infections. It was noted that the chimpanzee model of HCV infection is no longer available for vaccine development, and the potential availability of promising new animal models as a replacement was discussed. There was consideration of the merits of a U19 mechanism for this concept as opposed to R01. Explanation was provided that projects would necessarily require the use of clinical patient cohorts involving clinicians and other personnel in hospital units. Thus, these complex studies needed the organization and resources best contained within cooperative centers. Furthermore, there was extensive discussion about how the purpose and goals of this proposed initiative would complement ongoing investigator-initiated efforts. The concept was approved with a single dissenting vote.
The meeting adjourned at 3:26 p.m.
The AIDS Research Advisory Committee (ARAC) met on Monday, September 16, 2013, from 1:00 p.m. to 4:30 p.m., at the Natcher Conference Center on the NIH Campus in Bethesda, Maryland.
Participating members were Connie Celum (Chair), Dazon D. Diallo, Adaora Adimora, Georgia D. Tomaras, Dave O’Connor, Susan Swindells, Stephen Mason, Jonathan Karn, and Jerome A. Zack. Ex officio members Vicky J. Davey, Henry Masur, Jerome Kim (for Nelson Michael) and Office of AIDS Research Advisory Council Committee (OARAC) Liaison, Judith N. Wasserheit, also participated. NIAID representatives included Carl Dieffenbach, Mary Marovich, Manizhe Payton, Emily Erbelding, Diana Finzi, Sheryl Zwerski, and Sarah Read. Mark Mueller served as executive secretary.
Welcome and Approval of MinutesConnie Celum, M.D., Chair, ARAC
Dr. Celum welcomed the ARAC members, DAIDS representatives, and guests. She presented the minutes of the June 3, 2013, ARAC meeting, and the members approved them with no changes by a hand vote.
Director’s ReportCarl W. Dieffenbach, Ph.D., Director, DAIDS
Dr. Dieffenbach welcomed the attendees and acknowledged the members who are rotating off ARAC after this meeting-Mitchell Warren (absent), Susan Swindells, and the Chair, Connie Celum along with the OARAC liaison, Judy Wasserheit. Each one was thanked for outstanding service and given a certificate of appreciation.
Dr. Dieffenbach reported updates in DAIDS staffing:
President Obama presented his FY 2014 budget request to Congress in April 2013, which incorporates a compromise offer that replaces sequestration with a combination of program reductions and new revenues. Due to the delay and uncertainty associated with appropriating the FY 2013 budget, the FY 2014 President’s budget request was based on using the FY 2012 as the comparable budget; consequently, NIH is provided with a 1.5 percent budget increase over FY 2012. If NIH were to receive the President’s budget level, the overall NIH increase would be 7.5 percent compared to the FY 2013 enacted level, with an 8.2 percent increase for NIAID.
NIAID fared slightly better than most of the other NIH Institutes and Centers (ICs), primarily due to the transfer of $27 million from the National Institute of Mental Health (NIMH). These funds will expand collaborative efforts with NIMH to better integrate behavioral science into biomedical approaches to enhance prevention and treatment of HIV. With so few days left in FY 2013 and no 2014 budget, NIH most likely will operate under a continuing resolution (CR) beginning October 1.
FY 2014 will continue to be a challenging year because discretionary spending caps, imposed by the sequester, may result in budget cuts of between 1 to 5 percent. With the great uncertainty about the FY 2014 budget levels, the NIAID interim plan, operating under the CR, takes a very conservative approach. The payline will be provisionally set at the 6 percentile; if the sequester results in a budget cut of 1 to 5 percent, the payline may be maintained at the higher 8 percentile. The amount allocated for competing initiatives would be cut by up to 20 percent, and the budget for non-competing research project grants (RPGs) would be initially funded at 80 to 90 percent of committed levels, with adjustment ultimately proportional to the final budget.
Scientific and Programmatic Updates
Dr. Dieffenbach noted some highlights from the International AIDS Society (IAS) Pathogenesis Conference held in Kuala Lumpur, Malaysia, this past July.
William Spreen from ViiV Healthcare presented safety and pharmacokinetic data on the repeat dose co-administration of GSK1265744 and TMC278, the first such study involving these long-acting parenteral nanosuspensions in healthy adults. GSK744 is an inhibitor of HIV integrase strand transfer; TMC278 LA is an investigational long-acting nanosuspension for injection of rilpivirine, a marketed Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) for oral use (Janssen). The combined formulations, which were generally safe and well-tolerated, have potential application in HIV treatment and in pre-exposure prophylaxis (PrEP).
Also presented were the results of the ENCORE study, a randomized double-blind trial that showed a reduced 400 mg dose of efavirenz (EFV) -- Truvada fixed-dose combination pill (efavirenz [NNRTI] once daily plus nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) tenofovir and emtricitabine) had fewer side effects and greater viral suppression compared to Truvada in the standard dose with 600 mg EFV.
An update was provided at the conference on two stem cell transplant patients who underwent observed, IRB-approved treatment interruptions. In contrast to the Berlin Patient, the donor stem cells did not carry the CCR5-delta-32 mutation and were susceptible to HIV infection. The patients remained on antiretroviral therapy (ART) during the transplant process and were only permitted deferral of therapy when the viral load stabilized at low levels in blood and gut tissue. Both patients were still without detectable HIV RNA or DNA in peripheral blood mononuclear cells (PBMCs) upon weekly sampling for 7 and 15 weeks, respectively.
Dr. Dieffenbach noted DAIDS, the Division of Clinical Research (DCR), and the Collaborative Clinical Research Branch (CCRB) are organizing a meeting over the next several months to examine the role of Graft versus Host Disease (GVHD) in the era of stem cell transplantation.
At the IAS conference, early efficacy data from animal models indicated that broadly neutralizing antibodies show activity in prevention, treatment, and cure-related uses.
The World Health Organization (WHO) released their revised Treatment Guidelines at the IAS conference. For the first time, the guidelines combine recommendations across the continuum of HIV care, including recommendations on HIV testing, counseling, and the use of anti-retroviral (ARV) drugs for HIV prevention. Additionally, the guidelines encourage enhanced services to patients living with HIV, such as linking individuals to the appropriate adjunctive treatment and general care along with maintaining and monitoring ART.
This year of 2013 marks the third anniversary of the release of President Obama’s comprehensive National HIV/AIDS Strategy (NHAS) to achieve a more coordinated response to the domestic HIV epidemic. Dr. Dieffenbach was invited to speak at the White House to celebrate the anniversary and spoke on “addressing the care continuum through research.” The director is also participating on an HIV Care Continuum working group, tasked with developing specific recommendations for the President on actions that can be taken to improve outcomes along the HIV care continuum. The President plans to announce the recommendations on World AIDS Day (1 December 2013).
Leadership Groups/Clinical Trial Unit (LG/CTU) Timeline
In the process for the new HIV/AIDS clinical trial networks, the following updates:
Additional Meetings This Week
Next ARAC and SWG Meetings
Dr. Dieffenbach thanked Rona Siskind for her many years of service as the executive secretary and presented her with a plaque of appreciation.
During the Q&A, Dr. Dieffenbach noted that as the co-chair of the Research and Data Committee for the President’s NHAS continuum of care initiative, prevention is being advanced as essential to the continuity of HIV/AIDS healthcare. The planned GVHD workshop (Sarah Read, Diana Finzi et al) will encompass many aspects of transplant immunology, such as mechanistic dissection of immune therapy used in cancer, cellular effectors, activation and suppression of immune tolerance, and a range of immune response activities. A comment was made about the need for conversation regarding the 20 year impact on the epidemic of the expanded HIV/AIDS definition by the Centers for Disease Control and Prevention (CDC).
Concept Review (approval requested)
Vaccine Research Program
Innovation for HIV Vaccine Discovery (IHVD)Jon Warren, Ph.D., Program Officer/Microbiologist, Vaccine Research Program, DAIDS, NIAID
The objective of this concept is to stimulate investigator-initiated research on innovative, high risk/high impact novel vaccine approaches and on critical questions related to vaccine discovery that may provide long term, safe protection from the acquisition of HIV infection. It is a new program for 2015 and will use the R01 mechanism. The duration is up to four years with a first year total cost of $2.0 million. The initiative, similar to the two previous IHVD incarnations (FY 2012 and FY 2014), will support areas of basic vaccine discovery research that have not as yet been fully explored and may lead to the identification of new target molecules or approaches towards an HIV vaccine. This program represents the only major entry-level venue for pre-advanced R&D solicited applications.
The initiative supports original, unconventional research and does not require preliminary data. New paradigms in basic research and “outside-the-box” thinking on vaccinology are needed to develop an AIDS vaccine. Examples of responsive research may include but are not limited to the following approaches: 1) to elicit durable cellular responses and/or broadly neutralizing antibodies against HIV and/or SIV; 2) to direct protective adaptive and innate immune responses to relevant mucosal sites; 3) to develop new animal models, vectors, assays, and adjuvant and/or vaccine formulations, specifically linked to a novel vaccine intervention strategy; 4) to answer key questions on systemic and mucosal immune responses to HIV infection in humans. Nonhuman primate (NHP) model evaluation of the hypothesis will be encouraged.
The reviewers (Tomaras and O’Connor) enthusiastically supported the continuation of this initiative as a commendable effort to fill an important gap and to foster innovation in HIV vaccines. In response to reviewer comments, the program will encourage investigator participation from different areas and networks in addition to requesting that applicants communicate with the request for application point-of-contact for guidance in identifying collaborators with relevant clinical experience and existing sample sets.
During the Q&A, Dr. Warren responded that although therapeutic vaccines are explicit examples of non-responsive research to this initiative, therapeutic vaccines have traditionally been a large part of the DAIDS vaccine portfolio. Dr. Dieffenbach added it seemed inadvisable to mix the request for innovative research on both preventive and therapeutic vaccines because in general, the focus is separate scientifically; also, a Phase 2b trial of a HIV/AIDS therapeutic vaccine is in progress. With regard to the consideration of research without preliminary data, Dr. Warren stated he would emphasize to the committee that the lack of funding often precludes preliminary data, particularly with groundbreaking research. The greater issue may be demonstrating the feasibility of a project. Even though preliminary data are not required, in the past, most applicants have included it.
The ARAC members expressed support for the concept and voted approval.
Prevention Sciences Program
Prevention Innovation Program (PIP II)Mucosal Environment and HIV Prevention II (MEHP II)Jim A. Turpin, Ph.D., Chief, Preclinical Microbicides and Prevention Research Branch, PSP, DAIDS, NIAID
Dr. Turpin briefly reviewed the lessons that have been learned from high profile HIV prevention trials over the last few years, such as the value of pharmacokinetics (PK) in determining adherence to a prevention strategy, and outlined the associated complexities of human behavior, product attributes, and exposure. Dr. Turpin stated that further research into pharmacokinetic/pharmacodynamics (PK/PD) relationships is central to understanding the potential efficacy of HIV prevention strategies. The preclinical program endeavors to address the need for a sustainable nonvaccine biomedical prevention pipeline and support efforts to optimize the interactions of prevention candidates with the genital and GI mucosa. PIPII and MEHPII are designed to enable these goals with MEHP II directed toward basic research.
Dr. Turpin presented these two initiatives successively. The objective of PIP II is to support innovative proof-of-concept/feasibility research needed to advance the fields of microbicides, PrEP, nonvaccine biomedical prevention, and multipurpose prevention technologies (MPT). This is a renewal with restructuring, supported by the R01 mechanism. The award is for four years with an expected number of awards to be four to eight, and a first year total cost of $2.4 million. The objective of MEHP II is to better understand the impact of HIV prevention strategies, i.e. microbicides, PrEP, and MPTs, on the male and female genital and rectal mucosa, as well as the role the mucosal environment plays in altering the efficacy and safety of a prevention strategy. Understanding these interactions will allow for optimization and further development of HIV prevention strategies to be more efficacious, safe and consistently utilized through mechanisms like the PIP. This initiative constitutes a renewal with restructuring through the R01 mechanism. The number of awards is two to four with duration of four years, and a first year total cost of $1.2 million.
The reviewers (Adimora and Karn) expressed high enthusiasm for both initiatives, commenting that the concepts are timely and complementary with the need clear. Drs. Adimora and Karn suggested the importance of incorporating PK/PD determinations within the RFAs and that additional Program oversight may be required for the selection of the Go/No-Go decision criteria in the PIP. Additionally, the reviewers indicated virological issues related to developed products must be addressed, and Program agreed to provide more language to this effect. Finally, the reviewers commented that the Program should consider ways to facilitate efficacy testing in low incidence populations in future initiatives.
During the Q&A, Dr. Turpin responded that the Go/No-Go decisions will be initially determined by peer-review; and based on past experience, the assessments should be relatively easy to make.
Dr. Turpin also indicated, although not spelled out in the concept sheet, an acceptable scientific approach might include the combination of an existing vaccine and a prevention strategy for development under the PIP. Regarding new methods to measure adherence, Dr. Turpin noted many novel concepts and cutting edge ideas are waiting for the funding to develop them, and the PIP would allow the opportunity to assess potential product value and viability. While the challenge continues for principal investigators to expand the employment of a particular prevention product from healthy users to more at-risk populations, the primary goal of the MEHP and the PIP is to understand the susceptible mucosal environments and innovative design of new drugs, delivery systems and other prevention strategies, respectively. Collectively, these programs will provide the background biological knowledge, innovative drugs and delivery systems, perceptibility studies and adherence monitoring techniques to maintain a nonvaccine based biomedical prevention pipeline that will provide efficacious and safe prevention strategies, which are more acceptable to all populations. Under the PIP, Program is encouraging research on multipurpose prevention technologies (MPTs), while at the mucosal level, Dr. Dieffenbach added that DAIDS has great interest in fostering innovation to biologically detect initial exposure to HIV, whether through the MEHP or other programs. Dr. Turpin noted the Program has been building the applicant pool by urging international collaborations, leading to solidly competitive packages, including proposals which include characterization of the microbiome at mucosal sites.
Therapeutics Research Program
Synthesis of Therapeutic Agents for Treatment of Infectious DiseasesMohamed Nasr, Ph.D., Chemist, Drug Development and Clinical Sciences Branch, DAIDS, NIAID
The objective of this initiative is to provide resources for the synthesis of promising microbicides and compounds for the treatment of HIV and opportunistic infections including tuberculosis (TB). This is a renewal, supported by the N01 (contract) mechanism. The one award is for seven years with one base year and six options to extend.
The synthesis contract will synthesize chemicals, in compliance with current FDA Good Manufacturing Practice (GMP) regulations when required, in quantities needed for testing in either in vitro screens, animals, or early Phase 1 clinical studies. The goal of the initiative is to further the development of promising compounds by providing resources to investigators who have not identified a corporate sponsor so that they might address specific, applied, and drug synthesis issues.
The reviewers (Cohen and Mason) recommended approval and noted that the contract has permitted “the synthesis of hundreds of compounds for hundreds of investigators.” The Program agreed and confirmed the assessment by the substantial number of resulting publications and labs receiving reagents on a yearly basis.
During the Q&A, Dr. Nasr responded that the contract was essential, particularly for those compounds unavailable in sufficient quantities (samples). Dr. Dieffenbach added the contract provided a centralized mechanism to create a stable of defined products, free of charge, and filling a gap in reagent production.
Host-Directed TB Therapy: New ApproachesRichard Hafner, M.D., Chief, TB Clinical Research Branch, DAIDS, NIAID
The objective of this concept is to identify and characterize adjunctive host-directed therapy (HDT) agents to improved treatment outcomes for HIV-associated tuberculosis. It is a new program and will use the U01 cooperative agreement mechanism. The number of awards will be one to three, for a duration of five years with the first year total cost of $2.4 million.
This initiative will be the first specific funding mechanism to support development of promising host-directed agents to improve the outcome of TB treatment in HIV infection. Types of agents that may be studied include small-molecule agents that modulate destructive immune-mediated inflammatory responses (cytokine inhibitors, eicosanoid synthesis pathway inhibitors, etc.); agents to allow host immune cells to prevent or inhibit cell entry and survival of TB through reversal of functional defects; stimulate the immune clearance of TB; or directly protect tissues from inflammatory damage. A plan for a proof-of-concept (POC) clinical trial is required.
The reviewers (Swindells and Zack) were very supportive of the initiative and agreed it had potential to generate viable agents to improve HIV-TB treatment outcomes. In response to reviewer requests for clarification, the Program indicated the list of agents presented was not exclusive but only examples; it was also clarified that all improved animal models, e.g., humanized rodents would be responsive, not just NHP models. The Program noted agents under study would need to be linked to subsequent performance of a POC clinical trial, and preclinical work as a stand-alone project would not be responsive. The participation of the Division of Microbiology and Infectious Diseases (DMID) is under discussion.
During the Q&A, Dr. Hafner indicated these adjunctive agents would be for the treatment of active TB and not for latent TB infection (LTBI) at the present time. A comment was made concerning the need for thoughtful consideration to what gets funded since the effects of HDT agents are complicated and associated with unanswered questions, including a dearth of animal models related to immune responses.
Some of the HDT agents by necessity impact the ontogeny of the host immune response to Mycobacterium tuberculosis infection, leading to more efficient bacterial clearance and shortening of TB treatment. The core idea is that the existent HDTs will reach sufficient biological plausibility and effectiveness to justifiably allow expansion into standard regimens for TB. A suggestion was to focus on the list of potentially useful agents that have been FDA approved rather than a more extensive repertoire of drugs with unknown consequences. In response to a question about the relationship between HDTs and the management of HIV, Dr. Hafner noted drug interactions and effects on microbial persistence must be addressed in multiple ways, one of which is better animal models.
Office of Global Research
U.S.-South Africa Collaborative Biomedical Research Program on HIV, TB, and HIV-related MalignanciesEmily Erbelding, M.D., Deputy Director, DAIDS, NIAID
The objective of this concept is to foster collaboration between scientists from the U.S. and the Republic of South Africa (RSA) in basic, epidemiologic, translational, and applied research. It is a new program and will use the R01 and R21 mechanism. The number of awards will be 10 to 15, with the duration of up to five years; the proposed set-aside funds will come from both the U.S. and the RSA in the amount of $4 million/year each.
Funding commitments from NIH sources represent amounts being considered at the program level; they have not been approved by all involved councils and are contingent upon Congressional funding appropriations. Of note, funding from RSA Medical Research Council (MRC) will be ‘gifted” to NIH accounts so that all procedures related to initiative development and publication, review, and ultimate awards will be through standard NIH mechanisms.
The reviewers (Celum and Cohen) commented that this was an important concept to support and that the RSA was an important focus country in the scientific areas of HIV and TB. They noted the RSA could support innovative science by expanding its extramural program and that there are already established scientists in South Africa who get NIH funding. The reviewers also stated the concept would have the greatest success in building the scientific community in SA if it brought in new investigators, e.g., early stage investigators (ESIs). They recommended that any collaborative bilateral program be designed to build a robust infrastructure in the RSA. As far as scientific focus areas within TB and HIV, they recommended that the funding opportunity announcement (FOA) call for broad concepts, allowing for reviewers to identify the most innovative and meritorious proposals.
During the Q&A, Dr. Erbelding responded that no leverage would probably result from this initiative toward streamlining the SA in-country regulatory pathway.
Therapeutics Research Program and Prevention Sciences Program
Small Business Innovation Research (SBIR) Contract TopicsDaniella Livnat, B.SC., Drug Development and Clinical Sciences Branch, DAIDS, NIAID
The objective of this concept is to complement the grant SBIR funding mechanism and achieve the DAIDS scientific mission by encouraging systematic investigative and technical innovation in specifically identified areas. It is a new program, using the annual SBIR contract solicitation. The number of awards for each research topic will be one to three, with the duration of one year for phase I awards. No additional set-aside funds are required; the funding will come from the general SBIR pool.
The NIAID component of the solicitation for NIH and CDC SBIR contract proposals covers three topic areas: 1) biomedical methods to quantify adherence to prevention clinical trial study products and strategies; 2) simple, inexpensive assay for five common HIV resistance mutations; and 3) oral formulations for antibiotics of public health importance. Phase I and Phase II activities were outlined for each topic. The topics have been published and proposals are due on November 25, 2013; proposals will be reviewed by peer-review panels. Proposals deemed acceptable by the review panel and by NIAID will be considered for funding.
During the Q&A, it was noted that oral formulations may not be applicable for all antibiotics of public health importance, and other delivery mechanisms may be better; yet for some antibiotics currently available only as injectables, oral formulations may be more palatable, provided efficacy is equivalent or better. Dr. Dieffenbach added that the solicitation represents specific use of the SBIR contract mechanism with already targeted money, allowing important reformulation of, for example, TB drugs. Judicious selection of proposals and equal weight to approaches are dependent on the quality of applications and the level of response. These topics, particularly the oral reformulation, constitute pilots that are deliberately restrictive for the present but may be broadened in the future.
ARAC members were asked to cross out the capreomycin, mistakenly unchanged on the ballot, to ensure that the vote is for drugs for public health and not specifically for capreomycin. The ARAC members expressed support for the concept and voted approval.
The meeting of the Council adjourned at 4:30 p.m., on Monday, September 16, 2013.
We do hereby certify that, to the best of our knowledge, the foregoing minutes are accurate and complete.
Anthony S. Fauci, M.D.
Chair, National Advisory Allergy and Infectious Diseases Council
Director, National Institute of Allergy and Infectious Diseases
Matthew Fenton, Ph.D.
National Advisory Allergy and Infectious Diseases Council
Director, Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Anthony S. Fauci, M.D.
Chair, National Advisory Allergy and Infectious Diseases Council
Director, National Institute of Allergy and Infectious Diseases
Matthew Fenton, Ph.D.
National Advisory Allergy and Infectious Diseases Council
Director, Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
These minutes will be formally considered by the Council at its next meeting; any corrections or notations will be incorporated in the minutes of that meeting.
Last Updated December 11, 2013