NIAID Council Minutes: June 6, 2016

The 183rd meeting of the National Advisory Allergy and Infectious Diseases Council (NAAIDC) convened at 10:30 a.m. on Monday, June 6, 2016, 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 4:05 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 noon for review and consideration of individual grant applications. Notice of the meeting was published in the Federal Register.

Table of Contents

I. Review of Grant Applications
II. Remarks of the Director, NIAID—Anthony S. Fauci, M.D.
III. Guest Speaker—John R. Mascola, M.D., director, Vaccine Research Center
IV. Report of the Allergy, Immunology, and Transplantation Subcommittee—Daniel Rotrosen, M.D., director, DAIT
V. Report of the Microbiology and Infectious Diseases Subcommittee—Carole Heilman, Ph.D., director, DMID
VI. Joint Meeting of the AIDS Subcommittee and AIDS Research Advisory Committee (ARAC)–Carl Dieffenbach, Ph.D., director, DAIDS
VII. Adjournment

I. Review of Grant Applications

The National Advisory Allergy and Infectious Diseases Council convened in closed session to consider applications in allergy and immunology, microbiology and infectious diseases, and AIDS.

Funding Actions: The Council reviewed 4,308 research and training applications with primary assignment to NIAID for a requested amount of $1,553,048,873 in first-year direct costs and recommended approval of 2,240 applications with $716,968,091 in first-year direct costs.

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

Dr. Fauci opened the Council session by welcoming visitors. He introduced two ad hoc Council members: Dr. Ralph Baric, professor of epidemiology and of microbiology and immunology, University of North Carolina, and Dr. Bruce Beutler, director of the Center for the Genetics of Host Defense, and the Raymond and Ellen Willie Distinguished Chair in Cancer Research, University of Texas Southwestern Medical Center.

Council members Dr. Robert Belshe and Ms. Maria Acebal were unable to attend the meeting.

Consideration of Minutes of Previous Meeting

Council considered the minutes of the January 25, 2016 meeting and approved them as written.

Staff and Organizational Changes

Dr. Robert Califf is the new FDA commissioner.

In March, Doug Brooks stepped down as director of the Office of National AIDS Policy. Dr. Amy Lansky has been named acting director.

In April, Dr. Francis Collins named Eric Dishman as director of the Precision Medicine Initiative. Dr. Collins also announced his selection of Dr. Matthew Gillman as director of the Environmental Influences on Child Health Outcomes Program, also known as ECHO.

Dr. Maureen Goodenow has been selected as the new director of the Office of AIDS Research (OAR). Dr. Goodenow succeeds Dr. Robert Eisinger who has served as the OAR acting director since Dr. Jack Whitescarver retired in 2015.

Dr. Collins recently announced that Dr. Patricia Flatley Brennan will be the new director of the National Library of Medicine.

Tributes and Awards

Dr. Ron Germain, chief of the Laboratory of Systems Biology and chief of the Lymphocyte Biology Section in NIAID’s Intramural Program, was elected to the National Academy of Sciences. Dr. Germain conducts pioneering research in systems biology by using novel imaging methods and other techniques to study basic aspects of innate and adaptive immune function.

Three intramural scientists have been elected as fellows in the American Academy of Microbiology:
Dr. Yasmine Belkaid, chief of the Mucosal Immunology Section in the Laboratory of Parasitic Diseases; Dr. Jason Brenchley, chief of the Immunopathogenesis Section in the Laboratory of Parasitic Diseases; and Dr. Kim Hasenkrug, chief of the Retroviral Immunology Section in the Laboratory of Persistent Viral Diseases.

Meetings and Events

On March 15, Dr. Fauci delivered a videotape keynote address at the second Global Vaccine and Immunization Research Forum held in Johannesburg, South Africa. NIAID, the Bill and Melinda Gates Foundation, and WHO cohosted the Forum, which provides an opportunity to discuss research related to the Global Vaccine Action Plan 2011 to 2020.

On March 30, Dr. Fauci and Drs. Hugh Auchincloss and Barney Graham met with a high-ranking Cuban public health delegation that made a historic visit to NIH. They discussed ways to strengthen and expand scientific exchange in areas of mutual interest.

On April 5, Dr. Ramanan Laxminarayan gave the 2016 John LaMontagne Memorial Lecture, “The State of the World’s Antibiotics.”

On April 6, Dr. Fauci met with South Korean Vice Minister of Health and Welfare Dr. Moonkyu Bang, who led a scientific delegation that visited NIH. Discussions focused on infectious diseases research, particularly MERS-CoV.

On April 18, Dr. Fauci participated in the Bill and Melinda Gates Foundation-NIH Third Annual Consultative Workshop held at NIH. Workshop discussions centered on a variety of global health issues, including two areas of NIAID research: the Zika virus response and HIV prevention science.

Budget Update

For FY 2016, NIH and most institutes received an average increase of 6.6 percent. NIAID received a 6.7 percent increase over FY 2015, which included an earmark of $100 million for antimicrobial resistance research in support of the President’s Combating Antibiotic-Resistant Bacteria Initiative.

Dr. Fauci summarized NIAID’s financial management plan for FY 2016. The Institute’s R01 payline is the 13 percentile for established investigators and the 17 percentile for new investigators. NIAID will not make programmatic adjustments to competing, unsolicited awards; noncompeting grants; or research and development awards. Program initiatives may be cut by up to 10 percent in order to sustain investigator-initiated awards. NIAID’s estimated success rate will be between 21 and 23 percent.

On February 9, the President released his FY 2017 budget request to Congress, which includes an increase for NIH of 2.6 percent over the FY 2016 level. Dr. Fauci noted that most institutes and centers have a flat budget, and the 2.6 percent increase will go to NCI for the National Cancer Moonshot Initiative and to NIH’s Office of the Director for the Precision Medicine and BRAIN Initiatives.

The President also requested $1.9 billion in emergency funding for Zika virus-related initiatives, with $277 million directed to NIAID to support development of diagnostics, vaccines, therapeutics, and vector control strategies for Zika and other vector-borne diseases.

Legislative Update

On February 10, Dr. Fauci testified on Zika before a joint hearing of two subcommittees of the House Foreign Affairs Committee. He discussed how our commitment to flavivirus research has been critical to mounting our ongoing response to Zika. Dr. Tom Frieden, director CDC, and Dr. Ariel Pablos-Menendez, assistant administrator of USAID, also participated in the hearing.

On February 11, Drs. Fauci and Frieden testified at a hearing of the Senate Appropriations Subcommittee on Labor, Health and Human Services, and Education on emerging public health threats as well as the administration’s emergency funding request for Zika.

On February 24, Dr. Fauci testified at two hearings about Zika virus; one before the Senate Committee on Health, Education, Labor, and Pensions and the other before the House Committee on Oversight and Government Reform.

Dr. Fauci participated in two more hearings related to Zika virus. On March 2, he testified at a hearing of the House Energy and Commerce Subcommittee on Oversight and Investigations, and on May 12, he joined Dr. Anne Schuchat from CDC and Mayor Mitch Landrieu of New Orleans at a hearing of the House Democratic Steering and Policy Committee.

On February 29, Dr. Fauci, Dr. Collins, and several other institute and center directors met with Representative Tom Cole, chair of the House Appropriations Labor-HHS Subcommittee, and several Subcommittee members and staff during a visit to NIH.

On March 12, Dr. Collins, accompanied by Dr. Fauci and several other institute directors, testified before the House Labor-HHS Appropriations Subcommittee on the FY 2017 NIH budget request.

On April 11, NIH welcomed Senator Barbara Mikulski to campus to thank her for her commitment to NIH and say farewell. Senator Mikulski will retire at the end of the year and will be greatly missed.

Other Information Items

Dr. Fauci began with an update on Zika, presenting statistics on countries or territories considered Zika transmission regions and reported cases of Zika virus disease in the U.S. He also confirmed that after doing a number of studies, there is sufficient evidence to infer a causal relationship between prenatal Zika virus infection and microcephaly and other severe brain abnormalities.

Dr. Fauci gave an overview of Zika-related activities that have occurred over the last several months, including White House briefings and meetings, an NIH symposium, media interviews, public forums, high-level delegation meetings with Brazil, an HHS expert consultation, and promising research.

Dr. Fauci acknowledged Dr. Cliff Lane’s work on Ebola and summarized the status of the three PREVAIL (Partnership for Research on Ebola Virus in Liberia) trials—a vaccine trial, a treatment trial, and a survivor trial.

He concluded by giving updates on HIV/AIDS, dengue, influenza, malaria, peanut allergy prevention, and transplantation.

III. Guest Speaker—John R. Mascola, M.D., director, Vaccine Research Center

Dr. John Mascola began by noting that the Vaccine Research Center (VRC) was built in 2000 mainly to do research on HIV that would lead to developing an effective HIV vaccine. However, over the last 10 years, the portfolio of diseases for which VRC does research and vaccine development has grown significantly.

First, he focused on Zika virus vaccine development, expanding on Dr. Fauci’s remarks. Dr. Mascola gave some background about Zika virus, when it was first identified, outbreaks, and how the virus moved across the Pacific Ocean and into the Americas.

Zika virus is a flavivirus, a group of well-known viruses that includes West Nile, Japanese encephalitis, and dengue. Encouraging findings suggest that Zika virus is one serotype, so sera from recent outbreaks will recognize and neutralize viruses from years ago. Other promising news is that there are several effective flavivirus vaccines, so we know a lot about the biology, which allows us to do vaccine development. Dr. Mascola summarized VRC’s Zika research and outlined the vaccine development timeline with plans to start a human Phase I trial in September.

Dr. Mascola continued by giving a detailed update on VRC’s Ebola vaccine research activities, highlighting some significant publications and research. VRC is collaborating with DARPA and working with MedImmune to make antibody mAb114. They will be planning Phase I studies in early 2017 to understand the safety and pharmacokinetics.

IV. Report of the Allergy, Immunology, and Transplantation Subcommittee—Daniel Rotrosen, M.D., director, DAIT

Dr. Rotrosen welcomed the subcommittee members to the 183rd meeting of the National Advisory Allergy and Infectious Diseases Subcommittee meeting:

Dr. Rotrosen presented the following new staff members, scientific and Division activities:

Staff and Organizational Changes

Julia Shaw, Ph.D. In February 2016, Dr. Shaw joined the Basic Sciences Section of the Transplantation Branch as a program officer. She received her Ph.D. from the University of California, Davis, in Microbiology. She completed her post-doctoral fellowship at the Ecole Nationale Veterinaire d’Alfort in Maisons-Alfort, France, and was subsequently awarded a Cancer Research Training Award to continue her post-doctoral training as an intramural scientist with the National Cancer Institute’s Vaccine Branch. Dr. Shaw’s research focused on immune responses to infection in human mucosal tissue and vaccination in mouse and nonhuman primate models.

Scientific Initiatives

Informatics Methodology and Secondary Analyses for Immunology Data in ImmPort (UH2) (PAR-16-253): The purpose of this funding opportunity announcement (FOA) is to support the development of new or improved informatics tools and methods for the reuse of shared data in the immunology study repository, ImmPort, and to support secondary analyses of existing immunology datasets to address basic and clinical immunology questions.

Maintenance of NIAID Specific Pathogen-Free Macaque Breeding Colonies (RFP-NIAID-DAIT-NIHAI2016062): The purpose of this request for proposals (RFP) is for the maintenance, care, expansion, and breeding of government-owned specific pathogen-free (SPF) cynomolgus macaque (Macaca fascicularis) and Indian-origin rhesus macaque (Macaca mulatta) colonies.

Notice of a Change in the Eligibility Information in RFA-AI-15-051 "Consortium for Food Allergy Research: Clinical Research Units (UM1)" (NOT-AI-16-035): The purpose of this notice is to inform potential applicants of a change in the eligibility information in the FOA RFA-AI-15-051 titled, "Consortium for Food Allergy Research: Clinical Research Units (UM1)."

Notice of Availability of Administrative Supplements on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) (NOT-AI-16-046): The purpose of this notice is to stimulate research in the areas of Myalgic encephalomyelitis/chronic fatigue syndrome. ME/CFS is a debilitating and complex illness. There are still many knowledge gaps about ME/CFS, including key aspects of the etiology, diagnosis, pathophysiology, and treatment. NIH is committed to supporting research to better understand ME/CFS.

Development of Radiation/Nuclear Medical Countermeasures or Biodosimetry Devices (BAA-NIAID-DAIT-NIHAI2015042): This broad agency announcement (BAA) will advance lead candidate MCM or lead biomarkers/devices toward eventual FDA approval or licensure to assess/mitigate/treat radiation-induced injuries and thereby improve survival following a radiological event.

Consortium for Food Allergy Research: Clinical Research Units (UM1) (RFA-AI-15-051):
Consortium for Food Allergy Research: Leadership Center (UM2) (RFA-AI-15-050):
Consortium for Food Allergy Research: Clinical Research Units (UM1) (RFA-AI-15-051): The purpose of this FOA is to solicit applications for the Clinical Research Units (CRUs) for the NIAID Consortium for Food Allergy Research (CoFAR). The CoFAR CRUs are responsible for implementation of clinical trials and studies for the Consortium. In addition, the CoFAR CRUs will propose multi-center, cutting-edge clinical trials in the areas of prevention and treatment of food allergy. The CoFAR Leadership Center will define the initial overall research strategy of the CoFAR including design and oversight of cutting-edge clinical trials and clinical studies to advance prevention and management strategies and to improve knowledge on the origins and the pathophysiology of IgE-mediated food allergy.

Cooperative Study Group for Autoimmune Disease Prevention (U01) (RFA-AI-16-003): The purpose of this FOA is to solicit applications from institutions or consortia of institutions to participate in a cooperative study group focused on prevention of human autoimmune disease. The goal of the FOA is to develop the knowledge base necessary to design selective preventive interventions that could be administered efficiently and safely to the general population or to individuals at risk of autoimmune disease, including infants and children.

Immunity in Neonates and Infants (U01) (RFA-AI-16-001): The purpose of the FOA is to advance knowledge and understanding of mechanisms that regulate the development and function of the neonatal and infant immune system during the first year of life. This initiative seeks to discover and define immune mechanisms in response to commensal bacteria, vaccines, infections (including HIV), allergens, and environmental pollutants.

Nonhuman Primate Transplantation Tolerance Cooperative Study Group (U01/U19) (RFA-AI-16-007/RFA-AI-16-008): The purpose of this FOA is to advance current knowledge of the developing immune system during the first year of life and to encourage innovative approaches to more fully understand the distinct characteristics of neonatal/infant immune responses.

Improvement of Animal Models for Stem Cell-Based Regenerative Medicine (R01) (PAR-16-093): The purpose of this FOA is to encourage research project grant (R01) applications from institutions and organizations proposing research aimed at characterizing animal stem cells and improving existing, and creating new, animal models for human disease conditions for testing regenerative medicine applications.

Improvement of Animal Models for Stem Cell-Based Regenerative Medicine (R21) (PAR-16-094): The purpose of this FOA is to encourage exploratory/developmental research grant (R21) applications from institutions and organizations proposing research aimed at characterizing animal stem cells, improving existing, and creating new animal models for human disease conditions for testing regenerative medicine applications.

Indo-U.S. Vaccine Action Program (VAP) Small Research Grant Program (R03) (PA-16-163): The purpose of this FOA is to support collaborative research projects on infectious diseases, including immunological characterization, between U.S. and Indian investigators, that will lead to improved vaccines for infections in India, the South Asian region, the U.S., and globally.

Division Activities

Allergy, Asthma, and Airway Biology Branch

IgE Regulation in Allergic Disease Workshop. On April 19-20, 2016, NIAID held a workshop in Rockville, MD. The workshop featured five sessions designed to evaluate current information available on the induction, maturation, and regulation of IgE-producing B cells, the mechanics of IgE-FceRI and IgE-FceRII interactions and downstream signaling pathways in B cells and innate immune cells, analysis of the BCR repertoire in allergen epitope-specific responses, and the development of therapeutic inhibitors that interfere with IgE-mediated effector pathways. Discussion explored potential avenues of further research in the area, including addressing research gaps, increasing the understanding of IgE mechanisms, and the potential for developing new therapeutic approaches for allergic diseases.

Allergen Immunotherapy, Today and Tomorrow: Session I. Inhalant Allergens for Allergic Rhinitis and Asthma: NIAID Morning Course at the AAAAI Meeting. On March 4, 2016, NIAID organized a symposium Allergen Immunotherapy, Today and Tomorrow: Session I. Inhalant Allergens for Allergic Rhinitis and Asthma at the annual meeting of the American Academy of Allergy, Asthma, and Immunology (AAAAI) in Atlanta, GA. Five experts presented lectures on T cell epitope changes during allergen immunotherapy and allergen exposure, a unique T cell subset (TH2A) in allergen immunotherapy, peptide immunotherapy in allergic rhinoconjunctivitis and asthma, the comparative potency of sublingual vs. subcutaneous immunotherapy, and strategies to mitigate the risks of systemic reactions to subcutaneous allergen immunotherapy.

Allergen Immunotherapy, Today and Tomorrow: Session II. Immunotherapy with Food Allergens: NIAID Afternoon Course at the AAAAI Meeting. On March 4, 2016, NIAID organized a symposium Allergen Immunotherapy, Today and Tomorrow: Session II. Immunotherapy with Food Allergens at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in Atlanta, GA. During the meeting, investigators provided updates on the use of epicutaneous peanut to treat peanut allergy, insights from mechanistic studies on food allergy, low-dose immunotherapy in very young children to treat peanut allergy, epigenetic changes during food allergy immunotherapy, and findings on peanut tolerance following prolonged avoidance in the LEAP-On study.

Lessons from Functional Genomics: New Data from the AADCRC. On March 4, 2016, NIAID organized a symposium Lessons from Functional Genomics: New Data from the AADCRC at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in Atlanta, GA. Three investigators presented lectures on genomic approaches to new treatments for asthma, eosinophilic gastrointestinal disorders, and insights into the contribution of ORMDL3 in asthma.

Microbial Regulation of Allergic Airway Inflammation: Lessons from the AADCRC. On March 4, 2016, NIAID organized a symposium Microbial Regulation of Allergic Airway Inflammation: Lessons from the AADCRC at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in Atlanta, GA. Three NIAID-funded researchers presented lectures on determinants of rhinovirus illness severity, regulation and induction of airway inflammation by mycoplasma pneumonia CARDS toxin, and viral-epithelial interactions in airway inflammation.

Prostaglandin Regulation of Allergic Diseases. On March 5, 2016, NIAID organized a seminar Prostaglandin Regulation of Allergic Diseases at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in Atlanta, GA. Two investigators discussed the effector and regulatory functions of PGE2 in allergic inflammation, and the products of the different arms of the prostaglandin pathways that govern distinct biological effects.

Epigenetic Mechanisms in Allergic Disease. On March 5, 2016, NIAID organized a symposium Epigenetic Mechanisms in Allergic Disease at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in Atlanta, GA. Three investigators presented lectures on epigenetic mechanisms that modulate food allergy, epigenetic regulation of AERD, and epigenetic regulation of transcriptional response to cytokines in airway cells.

Novel Endotypes of Asthma: Lessons from the AADCRC. On March 7, 2016, NIAID organized a symposium Novel Endotypes of Asthma: Lessons from the AADCRC at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in Atlanta, GA. Three investigators presented lectures on topics including aspirin-exacerbated respiratory disease, pollution-induced asthma, and allergic “Th2 high” asthma.

State-of-the-Art: Update from the AADCRC Food Allergy Research Centers. On March 7, 2016, NIAID organized a symposium State-of-the-Art: Update from the AADCRC Food Allergy Research Centers at the annual meeting of the American Academy of Allergy, Asthma and Immunology in Atlanta, GA. Three investigators presented lectures on topics including mechanistic studies in T cells during food allergen immunotherapy, microengraving-based profiling of human food allergic immune processes, and surrogates of persistent tolerance among the T and B lymphocyte antigen-specific responses during peanut oral immunotherapy.

Basic Immunology Branch

Contemporary Topics in Immunology: Systems Immunology, Infant Immunity, and Adjuvant Science. On January 28 and 29, 2016, NIAID cosponsored a scientific symposium with the Indian Department of Biotechnology (DBT) in New Delhi, India, in conjunction with the Indo-U.S. Vaccine Action Plan (VAP) Joint Working Group annual meeting. The symposium consisted of presentations by both U.S. and Indian scientists, with ample time for discussion, to support the main meeting goals, which were to highlight scientific progress of ongoing VAP-supported collaborative projects between U.S. and Indian investigators in the area of systems immunology and to foster future collaborations in infant immunity and adjuvant science, research areas of great interest to both NIAID and DBT.

Systems Approach to Immunity and Inflammation Annual Meeting. On March 2 and 3, 2016, the annual meeting of the Systems Approaches to Immunity and Inflammation U19 Program was held in Rockville, MD. The goal of the Systems Immunology program is to identify, through the use of forward genetic screens, previously unappreciated immune regulatory genes, signaling pathways, or mechanisms. Two multicenter research consortia are supported under this program; both presented updates on their research findings, biological and computational pipelines, community outreach efforts, and their future plans.

The Impact of Mycobacterium tuberculosis Immune Evasion on Protective Immunity: Implications for TB Vaccine Design. On March 7 and 8, 2016, NIAID organized a workshop held in Rockville, MD, to address the immunological shortcomings in defense against Mycobacterium tuberculosis (Mtb) infection. The objectives of the workshop were to explore gaps in understanding Mtb immune evasion mechanisms and to identify potential immune targets for design of new vaccines or inventions capable of preventing disease. Participants were asked to focus on distinct immune mechanisms at play during the different phases of the infection. The workshop was a component of a larger NIAID effort, involving all three extramural scientific divisions, to foster development of an effective TB vaccine.

Protective Immunity in Special Populations Annual Meeting. On May 10, 2016, the annual meeting of the Protective Immunity in Special Populations (PISP) contract program was held in Rockville, MD. Investigators from the three NIAID contracts described progress in their investigation of the immune mechanisms that may explain the diminished immune response of older adults to infections or vaccination. This meeting also encourages scientific collaborations between projects and fosters program success.

Development and Function of the Infant Immune System. On May 14, 2016, a symposium was held at the American Association of Immunologists annual meeting in Seattle, WA. This session highlighted cutting-edge research results in the area of infant immunology research. Investigators presented data and progress on the layering of the human immune system and transitioning to an adult phenotype, cytokine networks in infants, environmental factors influencing early immune development, and the role of the microbiome in immune system development and function.

NIH Grants Workshop: Demystifying the Grant Application Submission, Review, and Funding Process. On May 15, 2016, a workshop was held at the American Association of Immunologists annual meeting in Seattle, WA. The workshop provided participants with an overview of NIH grant submission, assignment, review, and funding opportunities.

Immune Mechanisms of Virus Control (IMVC) Program Annual Meeting. On May 24 and 25, 2016, NIAID convened the annual meeting for the IMVC program in Rockville, MD. This program consists of eight multiproject cooperative agreement grants (U19s) addressing various immunological questions focused on the host response to viral infection or vaccination. The goal of this meeting was to provide a venue for the investigators to present their progress within the past year to DAIT staff. Additionally, it facilitated the exchange of ideas amongst the IMVC awardees and provided a venue to establish new collaborations among the investigators.

Modeling Immunity for Biodefense Annual Program Progress Meeting. On June 2, 2016, the first annual meeting of the Modeling Immunity for Biodefense Centers was held in Rockville, MD. The projects focused on different aspects of influenza vaccination and infection. Updates on the four U19 projects funded in May 2015 were discussed. And the investigators presented plans for an upcoming 2016 summer school, “Computational Immunology for Immunologists,” June 20 to 23, 2016, and symposium, “Influenza Immunology: Data, Systems, and Models,” June 24, 2016.

Radiation and Nuclear Countermeasures Program (RNCP)

2016 Kickoff Meeting of the Centers for Medical Countermeasures against Radiation Consortium (CMCRC). On February 23, 2016, theCMCRC annual meeting was held in Rockville, MD. CMCRC investigators from the four newly-awarded cooperative agreements presented on research that is planned for the next five years of the program (original CMCRC awards were made in 2005). The meeting provided an opportunity for exposure of the portfolio to other federal government agency staff that were in attendance, and also fostered dialog and collaboration among the CMCRC investigators and program staff regarding future research and development directions.

NIAID/FDA Scientific Forum #9: Exploring Late Effects of Radiation. On February 25, 2016, NIAID convened a scientific meeting in White Oak, MD. FDA attendees included personnel from both review and liaison divisions from the Center for Drugs Evaluation and Research and the Center for Devices for Radiological Health. Speakers presented subject matter pertinent to the management or radiation injuries, both in humans and in surrogate animal models.

NIAID/BARDA Medical Countermeasure (MCM) and Biodosimetry Portfolio Update Meetings. On February 18, 2016 (medical countermeasures portfolio) and April 25, 2016 (biodosimetry portfolio), update meetings were held between the RNCP and Biomedical Advanced Research and Development Authority (BARDA) staff. The purpose of these meetings, requested by the HHS Assistant Secretary of Preparedness and Response, was to provide programmatic transparency, ensure that the funded research programs are aligned, and that there is no scientific overlap between the two funded portfolios.

Concepts Presented for Clearance

FY 2018 Research Concept Clearances

Development of Radiation/Nuclear Medical Countermeasures or Biodosimetry Biomarkers/Devices: This initiative will address gaps and accelerate the research and development of medical countermeasures against acute and delayed radiation syndromes. The initiative will also advance the development of the approaches currently used for detecting levels of radiation exposure to inform triage and medical interventions.

The subcommittee endorsed and unanimously approved this initiative.

Adjuvant Development Program: The objective of this solicitation is to support the development of one adjuvant per award toward licensure for human use through the conduct of one or more of the following activities:

• Optimization of one candidate compound for enhanced safety and efficacy; this may include structural alterations or modifications to formulation or delivery.
• Establishment of an immunological profile of activity and immunotoxicity that will be of use to evaluate the capability of the adjuvant to advance to human testing.
• Conduct preclinical IND-enabling studies such as pilot lot or cGMP manufacturing of adjuvant or adjuvant:vaccine, toxicology, stability testing, and pharmacokinetics/absorption, distribution, metabolism, and excretion studies.

Depending on the developmental stage at which an adjuvant is entered into the program, the offeror may choose to perform some or all of the IND-enabling studies described above.

The subcommittee endorsed and unanimously approved this initiative.

Asthma and Allergic Diseases Cooperative Research Centers: With the continued rise in the prevalence of asthma and allergic diseases worldwide, the program aims to investigate the mechanisms underlying the onset and progression of diseases of interest, including asthma, rhinitis (allergic and non-allergic), chronic rhinosinusitis, atopic dermatitis, food allergy, and drug allergy. The overarching goal of the program is to improve the understanding of the pathogenesis of these conditions and to provide a rational foundation for new, effective treatments and prevention strategies.

The subcommittee endorsed and unanimously approved this initiative.

Clinical Trials in Organ Transplantation in Children (U01) (Limited Competition): Research supported under this FOA will focus on understanding graft dysfunction and/or loss and immune-mediated morbidity and mortality in pediatric transplant recipients. This limited competition funding opportunity will leverage the samples and data gathered from CTOT-C's unique cohort of well-characterized patients, as well as the consortium infrastructure to carry out timely hypothesis-driven mechanistic studies.

The subcommittee endorsed and unanimously approved this initiative.

V. Report of the Microbiology and Infectious Diseases Subcommittee—Irene Glowinski, Ph.D., acting director, DMID

Dr. Irene Glowinski, acting director of the Division of Microbiology and Infectious Diseases (DMID), chaired the NIAID Microbiology and Infectious Diseases Council Subcommittee meeting on June 6, 2016. Dr. Glowinski formally introduced DMID’s two new Subcommittee members: Dr. Raul Andino, a professor of microbiology and immunology at the University of California, San Francisco, where he specializes in RNA viruses with a focus on molecular biology, immunology, and evolutionary biology; and Dr. Karen Nelson, president of the J. Craig Venter Institute (JCVI). She then referred to the branch chiefs and office directors to introduce new staff in their respective programs.

Program, Scientific, and Budget Updates

Overview of DMID’s Preclinical Services Program

Dr. Clare Schmitt, deputy director of DMID’s Office of Biodefense, Research Resources, and Translational Research (OBRRTR), provided an overview of DMID’s Preclinical Services (PCS) Program, noting that several of the concepts that would be considered by the Subcommittee today are currently active components of DMID’s PCS effort.

This comprehensive suite of services spans five main areas: a biorepository, in vitro assessments for microbial activity, animal models of infectious diseases, and therapeutic and vaccine development services. The goal of these services is to provide critical information necessary to advance products and lessen the fınancial risks associated with investing in product development. Dr. Schmitt described briefly the application and review process, noting that program staff assess requests against multiple criteria to ensure the Institute is supporting promising and scientifically feasible concepts. She also noted that DMID carefully tracks the use of these services through a dedicated Management Information System, which in turn helps DMID track scientific accomplishments. Dr. Schmitt reported several metrics associated with these services, for example, the number of unique institutions and countries that have been assisted with these services. Finally, Dr. Schmitt highlighted several examples of how DMID has helped advance specific candidates along the product development pathway, for example testing candidate Ebola vaccines under BSL-4 conditions and supporting the development of ZMapp, an experimental new therapy for Ebola.

Concepts Presented for Clearance

The following FY 2018 concepts were presented to the Subcommittee:

In Vitro Assessments for Antimicrobial Activity–the goal of this concept is to renew a program to provide in vitro screening services to assess antimicrobial activity (antiviral, antibacterial, antifungal, anti-mycobacterial, and/or anti-parasitic) of new or existing compounds. Subcommittee members were enthusiastic about the concept. One Subcommittee member expressed interest in understanding how DMID determines which compounds to test through this program. Program staff indicated that compound submitters learn about these services via both the NIAID Resources website and from their program officers. Program staff noted that subject matter experts within DMID’s branches discuss and determine which compounds should be tested in which in vitro screens. These internal branch discussions are often followed by communications with submitters regarding which compounds among a series of related compounds should be tested initially. Program staff also noted that results can be supplied rapidly to submitters and that, when appropriate, follow-up tests may be conducted fairly expeditiously. Program staff also described how the in vitro testing programs are integrated with other preclinical services provided by DMID. Finally, program staff indicated that the existing infrastructure allows for a rapid response to new threats. The Subcommittee unanimously approved the concept.

Nonclinical Services for the Development of Interventional Agents for Infectious Diseases–this concept would renew a program that aims to advance the nonclinical development of therapeutic candidates and diagnostics for infectious diseases and biological toxins. Subcommittee members indicated that this program is important for the research community to help facilitate drug development. One Subcommittee member asked on what scale compounds would be supplied to investigators in order to support their nonclinical development programs. Program staff indicated that up-to-kilogram amounts could be provided to support a full range of in vitro and in vivo testing, a response that elicited immediate approval from the Subcommittee member. Another Subcommittee member noted that the quality of the work under this program must remain at a high caliber in order to best serve investigators’ research programs. Program staff wholeheartedly agreed that quality should remain high and noted that monitoring of contractors’ work is rigorous. The Subcommittee unanimously approved the concept.

Systems Biology: The Next Generation for Infectious Diseases–this concept would advance the use of systems biology approaches to identify biosignatures of infectious diseases potentially predictive of health status, risk, severity, disease progression, and response to therapeutic interventions. A Subcommittee member, who is familiar with DMID’s currently-active Systems Biology Program, noted that investigators supported under the program are making great strides in expanding their understanding of the “biology behind the scenes,” and he was supportive of the aims of this new concept, which would continue DMID’s Systems Biology Program. He noted that DMID’s current systems biology efforts are focused primarily on tuberculosis and influenza, and encouraged greater diversity (e.g., other infectious diseases) going forward. Another Subcommittee member asked how this concept related to the recent DMID systems biology antibiotic resistance awards. Program staff replied that all investigators supported through these efforts, including those supported under the targeted antibiotic resistance initiative, would attend the same annual meeting and be encouraged to collaborate on a variety of scientific activities. Another Subcommittee member commended DMID for recognizing the need to handle the vast amounts of data generated through systems biology and other ‘omics efforts, and recognized current efforts to facilitate access to the data by the DMID Bioinformatics Resource Centers. Program staff responded that DMID was committed to pushing beyond data collection and developing new computational tools and algorithms that may lead to next generation predictive modeling methods. Finally, a Subcommittee member commended DMID’s efforts to gather host data because such efforts have been limited to date. The Subcommittee unanimously approved the concept.

International Research in Infectious Diseases, Including AIDS–this concept would support small grants in eligible (resource constrained) foreign countries for infectious diseases research. The Subcommittee members were enthusiastic about the concept, which is a renewal. One Subcommittee member praised the move from R03s to R01s since it allows foreign researchers sufficient time and resources to complete meaningful research. Program staff also noted that this program allows scientists who have trained in the U.S. to return home and receive adequate funding to contribute on an international level. The Subcommittee unanimously approved the concept.

VI. Joint Meeting of the AIDS Subcommittee and AIDS Research Advisory Committee (ARAC)—Carl Dieffenbach, Ph.D., director, DAIDS

Welcome and Approval of Minutes
Stephen Mason, Ph.D., Chair, ARAC

Dr. Mason welcomed everyone. ARAC members approved the minutes of the January 25, 2016 meeting.

Director’s Report

Dr. Dieffenbach introduced the three new members of ARAC and the Council: Dr. Aftab Ansari, a professor in the Department of Pathology and Laboratory Medicine at Emory University School of Medicine; Dr. Cara Wilson, professor of medicine in the Division of Infectious Diseases at the University of Colorado School of Medicine; and Dr. Sally Hodder, director of the West Virginia Clinical and Translational Science Institute and a professor of medicine at West Virginia University School of Medicine. He also reported that NIH Director Dr. Francis Collins has announced that Dr. Maureen Goodenow will become the NIH associate director for AIDS research and director of the Office of AIDS Research. She comes to NIH from the University of Florida in Gainesville, where she is a professor of pathology and immunology and has a named chair, the Stephany Holloway University Endowed Chair in AIDS Research. She plays an active role at PEPFAR, where she is the acting director of the Office of Research and Science within the State Department.

Dr. Dieffenbach gave the NIAID budget update. He explained that in effect NIAID has been level-funded since the early 2000s, with an increase of 6.7 percent for FY 2016. However, this increase was all within the other extramural divisions and intramural as set-asides for specific diseases, such as antimicrobial resistance, Alzheimer’s, and Precision Medicine. The DAIDS level of funding was fixed at the FY 2015 operating budget level. Across NIAID, the paylines remain at the same percentile of 13 percent for established PIs and 17 percent for new PIs. There are no adjustments to competing and noncompeting grants. Research initiatives continue to be cut by 10 percent, which results in an estimated success rate across the divisions of about 21 to 23 percent. New DAIDS grant applications are up about 9 percent this fiscal year, and NIAID in general is up about 10 percent. Even though NIAID has a raised payline this fiscal year, the increase in applications has a net effect of dampening the success rate. Regarding the President’s FY 2017 budget, which proposes a 2.7 percent increase for NIH, Dr. Dieffenbach explained that everything is tied up in the Moonshot or Precision Medicine, and that many of the major institutes are level-funded in the President’s budget. There has been no movement in Congress on the proposed budget. In addition, the President requested $2.7 billion to deal with the current Zika virus crisis. The Senate version that passed was $1.2 billion. The House version was $.7 billion, with the requirement that all the money be spent in FY 2016. Citing NIAID Director Tony Fauci’s earlier talk, Dr. Dieffenbach reported that the number of Zika-infected people in the U.S. is in the range of 600 to 700, and that more than 159 of them are pregnant women. This situation will continue to unfold as the summer goes on.

Scientific Highlights

Dr. Dieffenbach announced that NIAID and the Bill and Melinda Gates Foundation (BMGF), the funders, along with partners Sanofi, GSK, and MHRP, will start a follow-on trial in late October or early November based upon the product that was shown to have efficacy in the RV 144 trial in Thailand. The trial has go/no-go criteria, which were vetted by the Strategic Working Group (SWG), and the vaccine to be used was evaluated extensively in HVTN 100. The immune responses met and exceeded the key immunogenicity markers. Dr. Dieffenbach described this as a big step forward for NIAID, BMGF, and the P5 partners.

He also reported on highlights from the Conference on Retroviruses and Opportunistic Infections (CROI), focusing on two trials: the dapivirine ring trial, run by the International Partnerships for Microbicides (IPM), and the Study to Prevent Infection with a Ring for Extended Use (ASPIRE), run by the Microbicide Trials Network (MTN). He provided brief statistics on the relative reduction, concluding that both studies showed a modest level of efficacy. Both studies show an influence of age, but is it due to biology, adherence, some aspect of the ring, or the drug product itself that needs to be taken into account? Dr. Dieffenbach described the consultation of stakeholders held at Fishers Lane and reported the consensus that the HOPE trial, which had been evaluated by the SWG but had not yet begun, should be implemented with a modified design to better assess the acceptability and adherence of trial participants. He said that the network has the goal of opening the HOPE trial around the start of the International AIDS Society (IAS) 21st International AIDS Conference in Durban, South Africa, July 18 to 22, 2016. He pointed out that IPM will move forward with their own version of an open-label extension study.

Dr. Dieffenbach provided a brief update of the January 2016 SWG meeting, which discussed PHOENIx, a pilot study of MDR TB cases and their household contacts. It is close to accrual and will likely open in the second quarter of 2017. They also discussed the Antibody Mediated Prevention (AMP) trials. Originally one trial, it has now been broken into two trials (HVTN 704/HPTN 085), one in the Americas and one in sub-Saharan Africa. They are open and enrolling participants. Another study that was presented was a double-blind, double-dummy evaluation of what turns out to be an every eight-week injection of Cabotegravir, compared to oral Tenofovir FTC as PrEP in infected MSM and transgendered women. This study is scheduled to open the fourth quarter of 2017. Plans for a women’s study will most likely be presented at the SWG meeting on September 13. AVRS will have the time slot after the Council meeting in January. Dr. Dieffenbach will present a report card on the full fiscal year at the ARAC meeting in January.

Office of AIDS Research Advisory Committee (OARAC) Update

Dr. Roy Gulick gave detailed updates for the five sets of guidelines that the OARAC working groups have been revising and summarized the two OARAC meetings that have occurred since the last ARAC meeting. Updates have been or are being made to: 1) the adult and adolescent treatment guidelines; 2) the adult/adolescent opportunistic infection guidelines; 3) the pediatric treatment guidelines; 4) the pediatric opportunistic infection guidelines; and 5) the perinatal guidelines. Dr. Gulick discussed the increasing number of domestic and international page views of the guidelines and the development of mobile app for the guidelines.

The first of the two OARAC meetings concerned HIV vaccines and had as its purpose to document progress, revisit challenges, reconsider remaining questions, and discuss what more needs to be done to move the field forward. Presentations were made by several investigators, and the group agreed that an HIV vaccine is still needed in 2016 and that vulnerable populations continue to be MSM worldwide and heterosexuals and children in the developing-world. It was noted that there has been improvement in the field due to collaboration, integration, and coordination. There was approval of recent discoveries: development of broadly neutralizing antibodies and their diverse binding sites; the fact that the HIV envelope trimer 3-D structure and sequence has been solved; the appreciation of the importance of nonneutralizing antibodies and T-cell responses; the success of PrEP studies; and the success of prevention of mother-to-child transmission. Challenges identified were: the need for a diversity of approaches (broad versus specific); problems associated with investigator bias (e.g.,some are more interested in T-cell responses, others in antibody responses, and whether this has helped or hindered the field over time); manufacturing issues; the design of immune-based therapy studies, given the current standard of care, including treatment as prevention; how to show that an additional immune- based therapy works above and beyond what has already been identified to work; coordination of efforts, timing and urgency; community acceptance and uptake; funding.

The second OARAC meeting concerned microbicides and PrEP and addressed possible next steps. Based on several investigator presentations, the group agreed that even though substantial progress has been made in the field, one size does not fit all. People need options, and different strategies will appeal to different people. There was a feeling that new strategies are needed and that it is appropriate to incorporate end-user perspectives as early as possible and to decrease barriers. Also discussed were: newer formulation of current ARVs; long-acting injectables and implantables; better ways of measuring adherence (e.g., DBS, hair, drug taggants); clinical trial design (becoming increasingly challenging for microbicides and PrEP) and how to show that something new is better than what is already being used. Noninferiority designs were also considered, but one of the problems with these designs is if there are no seroconversions it is impossible to tell if the intervention worked or if the population was not at risk.

Concepts Presented for Clearance

Vaccine Research Program (VRP)

Nonhuman Primate (NHP) Core Laboratories introduced by Dr. Alan Schultz
Dr. Schultz introduced the multistage NHP Core Laboratories supporting NHP Vaccine Studies. The session covered five preclinical vaccine concepts, four of which are contracts that are linked together, and one grant program. He pointed out that the VRP has maintained a set of contracts to evaluate immunogenicity and efficacy of vaccine concepts in NHP for several years, explaining the activities of the Simian Vaccine Evaluation Units (SVEUs), which are laboratories or facilities that house nonhuman primates, do the immunizations, collect the samples, and provide OLAW and IACUC compliant care of the animals. The seven-year contracts that fund these units were last competed four years ago when two incumbents, ABL and BIOQUAL located in Rockville, successfully re-competed and a new contactor, Tulane, was added. He then presented an overview of what the entire system was set up to do. An original rationale for creating the SVEUs was for doing pilot studies, so investigators could generate preliminary data to determine whether their ideas really did have some merit. In recent years, the SVEUs have been conducting large trials of concepts of high programmatic interest, such as a large DNA/MVA study, development of VSV preclinically, which led to an attenuated vector and platform tested for efficacy, and a collaboration with NCI to model RV144 in the SIV system.

NHP Core Humoral Immunology Laboratory for AIDS Vaccine Research and Development–presented by Dr. Nancy Miller for FY 2018
This N01 renewal contract provides state-of-the-art capability to assess characteristics and functions of the SIV-specific and HIV-specific antibodies generated in response to candidate AIDS vaccines administered to NHP in SVEU and other studies to ensure standardization and comparability of assays and evaluation of vaccines across studies. The importance of NHP models is that they provide a critical resource to test different candidate AIDS vaccines, to interrogate the immune responses elicited by the immunogens, and ultimately to test the efficacy of the vaccine using a virus challenge. The current contract is very productive as demonstrated by a partial list of recent SVEU studies for which the core lab conducted assays. In addition to providing SVEU support, the core lab conducts virus neutralization assays for an estimated 100 non-SVEU studies a year, which illustrates the lab’s availability upon request to assist AIDS vaccine investigators. To be able to conduct the virus neutralization assays, the lab develops virus panels with different neutralization properties representing a spectrum of circulating strains. The lab also conducts humoral immunoassays for other antibody properties such as binding specificity and affinity, and ADCC (antibody-dependent cellular cytotoxicity). The contractor will be expected to acquire and develop assays to maintain state-of-the-art capability. The reviewers, Dr. Aftab Ansari and Dr. David O’Connor, recommended approval. Reviewers’ comments were addressed. To questions regarding why there is a single lab and how the lab is monitored, Dr. Miller explained a single lab offers standardization and cost efficiency. The lab is validated for quality assurance and quality control by outside QA/QC. A single assay from the validation standardization is carried out by three different technicians. The lab has annual protocol and lab reviews, and gets feedback from the field. When asked about the labs ability to take on new assays, Dr. Miller explained past experience showing good ability for adding assays and functions.

Ballot Voting Outcome
11 Approval
0   Approval with modification(s)
0   Deferral for further information
0   Disapproval

NHP Virology Laboratory for AIDS Vaccine Research and Development–presented by Dr. Que Dang for FY 2018
This is a renewal of the current N01 contract, and the program expects to award one contract for seven years. The objective of the virology core is to provide centralized services to ensure standardization and comparability of the viral RNA load assays to assess HIV or SIV vaccine efficacy in preclinical studies. The core will measure viral RNA level from NHP samples taken from SVEU vaccine studies. This assesses vaccine efficacy by determining whether the vaccine has either prevented virus replication, delayed replication, or partially controlled replication. Having one central laboratory doing this work helps ensure comparability of results across different HIV vaccine studies. Testing of vaccine efficacy in these studies can help inform clinical product development for human trials. On average, this contract laboratory performs 5,000 assays a year. For the renewal contract, the contractor is expected to maintain high-quality state-of-the-art assays to detect viral RNA. The scope of the contract remains unchanged, and the contract’s laboratory will continue to improve and optimize sensitivity and reproducibility of the assays. The reviewers, Dr. Aftab Ansari and Dr. David O’Connor, recommended approval. Reviewers’ comments were addressed, and members voted.

Ballot Voting Outcome
11 Approval
0   Approval with modification(s)
0   Deferral for further information
0   Disapproval

NHP Core Functional Genomics Laboratory for AIDS Vaccine Research and Development–presented by Dr. Jon Warren for FY 2018
The objective of this core laboratory activity is to apply and refine high-throughput functional genomics, evaluating vaccine-induced responses and, ultimately, to identify responses that predict vaccine efficacy. Program is requesting that this renewal initiative be for a single, seven- year N01 contract award. They plan to maintain the same approach, namely to apply high- throughput transcriptomics to generate gene expression profiles of high-priority studies with the goal of identifying signatures to better define correlates of protection and predict vaccine efficacy. They will try to adopt new platforms as they are developed and continue to develop, optimize, and validate these assays over time. The contractor is required to maintain electronic records of results, and if the results are useful to the research community, they will be deposited in a public functional genomics data repository. The proposed contract activities are limited to NHP transcriptomic and some microbiome sequencing and does not support a systems-biology approach. Dr. Warren gave examples of successful projects under the current contract and cited two NHP vaccine projects illustrating how investigators can leverage transcript data from one project obtained from a public database and then independently show nearly the same protection from acquisition-associated gene transcript profiles observed in other projects. One of those projects, the Picker Protocol, includes for the first time extensive microbiome sequencing. It is anticipated that during the next 10 years RNA sequences will become cheaper, faster, with higher throughput, and possibly be able to detect single RNA molecules. Further, lower RNA inputs will likely be usable, and new technologies will permit extracting readable RNA from fairly crude sources. The program hopes to incorporate these advances as soon as they become available. The reviewers, Dr. Aftab Ansari and Dr. David O’Connor, recommended approval of the concept and their comments were addressed, and members voted.

Ballot Voting Outcome
11 Approval
0   Approval with modification(s)
0   Deferral for further information
0   Disapproval

Reagent Resource Support Program for AIDS Vaccine Development–presented by Dr. Jon Warren for FY 2018
The objective of this renewal seven year N01 contract is to continue to acquire reagents, assays, and services required for evaluating preclinical immunogenicity, safety, and efficacy for studies within the AIDS Vaccine Research Program. Some examples are: viral gene products, with associated peptides, adjuvants, cytokines, virus stocks, and expression vectors; monoclonal/polyclonal antibodies; small-scale and large-scale production; and purification of recombinant proteins. An essential value of this contract to the program is its flexibility and efficiency. He provided recent examples of support for SVEUs and their core labs (challenge stocks, vaccines, overlapping peptide sets), investigators in the NIAID grant portfolio (reagents, such as monoclonal antibodies and assays), and occasionally in-vivo titration of uncommon challenge stocks. Both reviewers, Dr. David O’Connor and Dr. Aftab Ansari, recommended approval. Reviewers’ comments were addressed, and members voted.

Ballot Voting Outcome
11 Approval
0   Approval with modification(s)
0   Deferral for further information
0   Disapproval

Innovation for HIV Vaccine Discovery (IHVD)–presented by Dr. Jon Warren for FY 2018
As with the four previous IHVD initiatives, this proposed initiative has essentially the same objective: To stimulate research on risky, yet novel, vaccine approaches as a way to discover how to achieve durable and safe protection from acquisition of HIV. The requested renewal initiative will be a four-year R01 with first-year direct costs support of up to $350,000, and with up to $150,000 additional support for NHP or humanized mouse studies. The program has budgeted this initiative for a $1.68 million first-year total cost. Specifically, the program is proposing support for high-risk/high-impact, original, and perhaps unconventional research that does not require preliminary data. The aim is to support early entry-level vaccine research and development by creating an environment that allows the testing of novel hypotheses and approaches. The program encourages new investigators to apply and encourages cross- disciplinary collaborations. He explained that this is a milestone-driven R01 mechanism designed to mitigate multiyear funding risk, wherein the program and the PI negotiate pre-award go/no-go criteria for support beyond year two. Well-performing projects can proceed, but those not meeting these criteria will be wound down. This initiative is being proposed because new paradigms are needed. He said that unavoidable risk is acceptable as long as the probability of success is reasonable, and emphasized that they are looking for stringent testing of ideas that provide more than just incremental knowledge. He pointed out that among all current IHVD awardees, 23 percent are new PIs. It was asked if application of the second year go/no-go criteria could be considered for other awards to allow greater funding flexibility. The answer was that, due to the innovative, higher risk nature of IHVD, it is appropriate here, but it is not being considered beyond this type of program. It was also asked if DAIDS found innovative applicants since this started in 2012 that led to other studies. Dr. Warren said a contractor’s evaluation of the program indicates success. New RNA vector and some vaccines in advanced development are by investigators that had grants related to this program. The two reviewers, Dr. John Guatelli and Dr. David O’Connor, recommended approval. Reviewers’ comments were addressed, and members voted.

Ballot Voting Outcome
11 Approval
0   Approval with modification(s)
0   Deferral for further information
0   Disapproval

Prevention Sciences Program (PSP)

Pilot Clinical Trials Targeting HIV Reservoirs in Children–presented by Dr. Devasena Gnanashanmugam
The objective is to support small pilot clinical trials using immunotherapeutic and other interventions to reduce or control the latent HIV reservoirs in children. Program anticipates these will be U01 grants, and they expect two to three awards. Although the rate of perinatal transmission has decreased in recent years, the global burden of disease among children living with HIV is still high. Approximately 2.4 million children live with HIV globally, and only a small percentage of them receive antiretroviral therapy (ART). Of those who do receive ART, they will be on therapy throughout their lives, so they will be on therapy for a much longer time than those who began therapy as adults. As a result, the problems of drug toxicity, lack of adherence, and the emergence of drug resistance may be much more pronounced in children than in adults. Children have limited drug and formulation options. HIV remission would have wide-ranging benefits for children, their families, and treatment programs. However, the field of pediatric remission and cure research is in its early stages and current interventional clinical trials focus on providing very early therapy. Some barriers that limit development of this area are: an evolving, but limited understanding of the HIV reservoir in children, which is likely to be different than in adults; difficulties measuring the reservoir; the expectation of evidence of safety of interventional agents, which usually comes from adult trials prior to clinical trials in children. Given these challenges and the early stage of the field of pediatric remission and cure research, opportunities are needed to stimulate this area. Such opportunities are likely to expand the pool of potential investigators and provide support for state-of-the-art laboratory assays that will be needed to measure reservoirs. The two reviewers, Dr. Deborah Persaud and Dr. Cara Wilson, approved the concept, commenting that this is an ambitious and critical RFA to mobilize the field. The reviewers also commented that the program should consider opening eligibility to international sites and include older children and adolescents. The program agreed and plans to do so. Another comment was a concern about whether there were enough agents in the pipeline to support these trials and if additional preclinical studies to evaluate reservoir size, tissue reservoirs, etc., are warranted as a first step. The program anticipates more agents will be available by the time the FOA is published and applications are due. The reviewers suggested that the program consider broadening the scope of this RFA to include pathogenesis and preclinical studies focused on viral reservoirs. Dr. Gnanashanmugam listed other funding opportunities currently addressing these needs:

• PA-15-271: Understanding HIV Persistence in Infants
• RFA-A1-11-010: The Infant Immune System: Implications for Vaccines and Responses to Infections
• RFA-HD-14-026: Evaluation of the Latent Reservoir in HIV-Infected Infants and Children with Early Antiretroviral Treatment and Virologic Control

Another reviewer comment was that the related adult reservoir RFA requires that preliminary data exist that latently-infected cells can be eliminated by the proposed approach and, therefore, should not be required for this RFA. The program agreed. The last reviewer comment was that the program consider being more explicit that therapeutic approaches could effect a cure, reduce reservoir size, induce a functional cure, or potentially reduce inflammation. The program agreed and will include more specific language in the RFA. Dr. Gulick asked how the program interacts with networks, like IMPAACT and Adolescent Trials Network. Dr. Gnanashanmugam explained that these studies will more likely be investigator-initiated and there will be an opportunity for an investigator to collaborate with IMPAACT, if that is appropriate, but it is unlikely that these awards will take place exclusively within the IMPAACT Network, because DAIDS has that network. Dr. Persaud said it is complicated, but it is important to remember that pediatric HIV infection is not just in newborns. It spans a life course through age 24, which is the covered age. She emphasized that there are data showing early long-term treatment alters reservoir size. Dr. Gnanashanmugam agreed that immnotherapeutics have a very important role in virologic control. She said it is important to have a pediatric agenda that is developed in parallel with testing these agents in the older children, 18 and older, 16 and older, and then move down to younger age groups, if needed.

Ballot Voting Outcome
11 Approval
0   Approval with modification(s)
0   Deferral for further information
0   Disapproval

Simulation Science for HIV: Optimizing New Intervention Strategies Prior to Clinical Trials–presented by Dr. David Burns
The objective of the initiative is to: develop and validate synthetic databases and related tools to examine HIV transmission dynamics and make epidemic projections; estimate the impact of HIV treatment and prevention interventions in priority populations and settings; and to make these resources available to other qualified researchers. The R61/R33 mechanism is being considered, the duration of awards would be up to five years total, and the program estimates that two to three awards could be made. Mathematical modeling and simulation have proven very useful in studying infectious diseases, including HIV. A few groups began modeling and simulating community-level impact of combination prevention strategies for HIV, taking into account available information on sexual network characteristics, mixing within and between communities, coverage levels for different prevention modalities, and other variables. The program believes that modeling and simulation offer a strategy for down-selecting prevention interventions and optimizing those that go into clinical trials. This could both accelerate research and reduce costs. This initiative would be a phased-award mechanism. Phase 1 would support milestone-driven development and validation of synthetic databases and related tools that can be used to examine transmission dynamics and estimate the impact of prevention interventions and strategies. Phase 2 would support the development of a platform for making these tools available and releasing them to other investigators. The reviewers, Dr. Sally Hodder and Dr. Chris Wilson, are supportive of this initiative, with one important caveat: They asked that key barriers to achieving these objectives be identified and addressed, particularly the concern that access to critical data sets be available. Dr. Burns explained that to address these questions, the program held a consultation in partnership with NIMH and the Bill and Melinda Gates Foundation. The participants were confident that they could achieve these objectives, but they cited three potential challenges: gaining full access to high-quality data for priority populations; forming multidisciplinary teams composed of modelers, epidemiologists, and clinical trialists; and obtaining funding. They agreed that data from well-designed, ongoing studies are available for U.S. and other Western countries, particularly for MSM populations. High-quality data exist, but are less widely available for key populations in sub-Saharan Africa, although this is improving.

There are growing efforts to increase access to key data sets. In January 2015, IOM released the report “Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risk,” and supporting documents. Since January 2016, there has been a series of Perspectives and Editorials in the New England Journal of Medicine on these efforts. NIH has required data sharing since 1996, beginning with DNA sequences, mapping information, and crystallographic coordinates. Current NIH Data Sharing Policy “expects and supports” the “timely release and sharing” of final research data from NIH-supported studies for use by other researchers. Currently available data, together with other data that will become available by the time these projects start, should make a number of valuable projects possible under this initiative. Reviewers’ questions are followed by the program responses:

Will the funding be sufficient to achieve the objectives of the RFA?

• Funding currently allocated to this initiative ($2.7 million) should be sufficient to make two or three awards.

Who would have access to the synthetic databases and related tools that are developed by these projects and how would they be maintained?

• The resources developed by these projects would be made available to all qualified investigators. Applicants would need to propose a plan for maintaining their database and related tools.

Who would determine whether a project advances from the R61 to the R33 phase?

• An internal committee overseeing the projects would assess whether all key milestones have been met before approving advancement to the R33 phase.

Dr. O’Connor asked if there is a provision to allow applicants to budget in, with the expectation that the databases or shared products be maintained for some period of time beyond the end of the award itself. Dr. Burns replied that the program has begun to discuss the possibility of a contract for that. There is also the possibility that because this would potentially be so useful to the networks in the future, they might incorporate it into the networks. Dr. Mason asked why the R61 mechanism is being proposed, since it is used for higher budgets. Dr. Burns said he was advised that this was the best mechanism. Dr. Dieffenbach said that it is more than just the collection of data. It is building the models and a fair amount of iterative science. In support of Dr. Burns’ point about the number of groups that need to collaborate to make and validate the model, Dr. Dieffenbach said that the R61 mechanism provides the level of support and the years better than the R21.

Ballot Voting Outcome
11 Approval
0   Approval with modification(s)
0   Deferral for further information
0   Disapproval

Basic Sciences Program (BSP)

Tracking HIV Networks Through Phylodynamics–presented by Dr. Lillian Kuo
This concept’s purpose is to leverage HIV genotyping databases to monitor transmission network dynamics in near to real-time, thereby enabling more precise and efficient targeting of testing and interventions to key populations. This is a new PAR for an R01, with an anticipated duration of five years. The first year total cost would be $2.64 million. The number of awards is estimated to be four to six. To understand how the current epidemic is evolving, it is important to focus resources on populations and locations where new infections are occurring at the highest rate. Tracking HIV networks through phylodynamics specifically addresses the UNAIDS 90/90/90 goals and would facilitate 90 percent of HIV-positive individuals to be diagnosed, 90 percent to be on treatment, and 90 percent of individuals to remain virally suppressed by harnessing of phylogenetic sequence data. Phylogenetic analyses of HIV sequences collected from HIV-positive individuals allows transmission networks and clusters to be mapped. However, traditional methods require extensive computational resources and time. In contrast to phylogenetics, phylodynamics incorporates a time element to identify transmission clusters as they emerge and begin to expand. The scientific gap is that this requires access to live HIV genotyping databases to track sequences as they are collected. This would entail newer, faster technologies that are not dependent on complex phylogenetic tree construction. Dr. Kuo provided an example of an implementation study using near real-time phylodynamic monitoring of HIV transmission hotspots from routine HIV genotyping. The scope of research in this proposed concept may include one or more of the following: interdisciplinary collaborations between academic phylogeneticists, testing laboratories, and/or groups that maintain live HIV genotyping databases. Another example would be optimization of approaches for performing phylodynamic analyses and modeling in close to real-time, or proof of concept studies leveraging phylodynamic data to better understand how to target HIV testing, prevention modalities, or drug resistance and adherence monitoring to specific local populations or geographic regions. The reviewers, Dr. Amanda Castel and Dr. Sally Hodder, described the concept as ambitious, and much needed to facilitate identification of the highest risk groups to curb epidemics at the local and regional levels. Dr. Kuo clarified that “real-time” analyses are expected to be in the range of a few days to a few weeks from the initiation of genotyping. Reviewers commented that this will require buy- in and collaboration with state and local health departments to successfully access population- level data, and that this should be a required element of the PAR. Dr. Kuo agreed and will ensure that collaborations with health departments or testing labs will be a component of the PAR. Reviewers expressed a concern that the level of funding may not be sufficient to obtain and analyze new, incoming sequences. Dr. Kuo said the hope is that the investigators will leverage existing resources already in place for HIV genotyping as the standard of care.

Dr. Mermin mentioned this is a large area of activity for the CDC. Probably about half of people living with HIV are in public health jurisdictions requiring reporting of HIV pol sequences. As an example, CDC has analyzed 40,000 sequences, shown connections, and shown these infection clusters are increasingly being identified and responded to in a concerted way. It would be interesting to know if there is a way to leverage these data in responding to identified clusters.

CDC would be interested in helping out. This could be a useful public health tool.

When we promote linking with health departments, do we mean it to be U.S.-focused? Or is there space for international sites collecting data? The Program anticipates foreign components would be allowed, but are most interested in U.S. epidemic and ideally the contact institution would be domestic.

Ballot Voting Outcome
9   Approval
0   Approval with modification(s)
0   Deferral for further information
1   Disapproval

Centers for AIDS Research (CFAR) and Developmental Centers for AIDS Research (concepts A and B)–presented by Ann Namkung Lee for FY 2018
The purpose of the CFAR program is to foster quality HIV/AIDS research by increasing collaborations and multidisciplinary research within an institution, between institutions, and by enhancing translation of basic research findings into vaccine, therapeutic, prevention, and HIV cure concepts in a synergistic and cost-effective manner.

This is a renewal of the CFAR and Developmental CFAR (D-CFAR) initiative (P30) through a PAR, with a duration of five years. The CFAR program is co-funded by 10 NIH Institutes (ICs). The CFAR program is managed by representatives from each of the co-funding ICs, as well as the Office of AIDS Research and the Fogarty International Center. The first year total cost requested for NIAID is $5.2 million. It is estimated that four or five awards will be made in FY 2018. The CFAR program was introduced and approved in 1988, with the most recent renewal in 2014. Dr. Lee explained that to be eligible for both a CFAR and a D-CFAR, an applicant institution has to have a minimum of $10 million of NIH HIV/AIDS research funding.

Applicants applying for a D-CFAR are allowed to apply for $750,000 in direct costs per year for five years. For standard CFARs, there is a three-tier funding structure dependent on the amount of NIH HIV/AIDS research funding at an applicant institution. Standard CFAR applicants can apply for $1.5 million, $2.25 million, and $3 million in direct costs per year for five years. There are currently 19 actively-funded CFARs and no D-CFARs.

Dr. Lee explained that the overarching mission of both D-CFARs and standard CFARs is to:

• Support high-priority HIV/AIDS research through scientific leadership, infrastructure, and core services that are not available through other traditional mechanisms
• Stimulate multidisciplinary and international scientific collaboration
• Foster scientific communication and community outreach
• Provide training, education, and mentoring
• Support new scientists and emerging scientific areas in HIV/AIDS research with pilot grant funding

The reviewers asked about the level of success of the CFARs in fostering between-institution collaborations. Over the years, the CFARs have formed a number of inter-CFAR partnerships. Currently, there are 13 inter-CFAR groups collaborating on HIV research ranging from comorbidities to integrated clinical databases.

The reviewers questioned having the same minimum funding requirement for both D-CFAR and standard CFAR applicants. The minimum funding eligibility requirement for D-CFARs and CFARs is the same to ensure that a D-CFAR applicant institution is able to maintain the required level of funding needed to compete for a standard CFAR. Given a level funding climate, $10 million is fairly good floor for this eligibility requirement.

The reviewers, Dr. Amanda Castel and Dr. John Guatelli, recommended approval for the D-CFAR and CFAR concepts because they are essential mechanisms to drive science, develop careers, provide mentorship, and encourage collaboration.

Ballot Voting Outcome
Centers for AIDS Research
10 Approval
0   Approval with modification(s)
0   Deferral for further information
0   Disapproval

Developmental Centers for AIDS Research
10 Approval
0   Approval with modification(s)
0   Deferral for further information
0   Disapproval

Public Comment

None.

VII. Adjournment

The meeting of the Council adjourned at 5:00 p.m., on Monday, June 6, 2016.

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

Council will formally consider these minutes at its next meeting; any corrections or notations will be incorporated in the minutes of that meeting.