NIAID Council Minutes: January 30, 2017

The 185^th meeting of the National Advisory Allergy and Infectious Diseases Council (NAAIDC) convened at 10:30 a.m. on Monday, January 30, 2017, 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 4:25 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—Maureen Goodenow, Ph.D., director, Office of AIDS Research (OAR), NIH
IV. Report of the Allergy, Immunology, and Transplantation Subcommitee—Daniel Rotrosen, M.D., director, DAIT
V. Report of the Microbiology and Infectious Diseases Subcommittee—Emily Erbelding, M.D., M.P.H., director, DMID
VI. Joint Meeting of the AIDS Subcommitee 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 4,593 research and training applications with primary assignment to NIAID for a requested amount of $1,672,331,516 in first-year direct costs and recommended approval of 2,277 applications with $722,274,568 in first-year direct costs.

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

Dr. Fauci opened the Council session by welcoming visitors to the meeting. He introduced two ad hoc Council members: Dr. Keith Sullivan, James B. Wyngaarden Professor of Medicine, Duke University Medical Center, and Dr. Laurence Turka, co-director of the Center for Transplantation Sciences at Massachusetts General Hospital.

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

Consideration of Minutes of Previous Meeting

Council considered the minutes of the September 12, 2016 meeting and approved them as written.

Appointments and Transitions

On January 13, Dr. Fauci, along with then CDC Director Tom Frieden, Office of the Assistant Secretary for Preparedness and Response Director Nikki Lurie, and HHS Secretary Sylvia Burwell, had an opportunity to brief President Trump’s cabinet on the preparedness and response to emerging pandemic outbreaks.

President Trump’s nominee for HHS Secretary is Dr. Tom Price, a physician and former member of the House of Representatives.

As is customary with a new administration and presidentially appointed officials, NIH Director Dr. Francis Collins submitted his resignation. However, Dr. Collins informed the NIH community that his resignation letter was returned and he is being retained for now.

FDA Commissioner Rob Califf and CDC Director Tom Frieden also resigned, and both resignations were accepted. Dr. Stephen Ostroff is serving as acting FDA commissioner, and Dr. Anne Schuchat is acting CDC director.

Staff and Organizational Changes

Dr. James Gilman is the inaugural CEO of the NIH Clinical Center. He will oversee the day-to-day operations and management of the Center.

Dr. John Gallin, who served as director of the Clinical Center for 22 years, is now NIH associate director for clinical research and chief scientific officer of the Clinical Center.

Dr. Emily Erbelding is the new director of the Division of Microbiology and Infectious Diseases (DMID), NIAID. Dr. Erbelding previously served for six years as deputy director of the Division of AIDS where she was involved in all aspects of scientific program management and support.

In the Division of Allergy, Immunology, and Transplantation, Dr. Martin MacPhee was named the new director of the Clinical Research Operations Program.

The Division of Extramural Activities has four new senior staff. Dr. Kenneth Santora is the director of the Office of Extramural Research Policy and Operations. In the Grants Management Program (GMP), Emily Linde is now the director and chief grants management officer. Emily replaces Mary Kirker who retired in December after 41 years at NIH. Victoria Connors has been named deputy director for GMP and Dhana Khurana succeeds Victoria in her role as GMP branch chief and division coordinator for DMID.

Tributes and Awards

Dr. Fauci paid tribute to the late Dr. Donald "D.A." Henderson, who led the international effort to eliminate smallpox, the only human disease to ever be eradicated. He recognized Dr. Henderson’s many accomplishments in medicine and public health.

On December 7, Dr. Hugh Auchincloss received the American Association of Immunologists Public Affairs Recognition Award for his contributions as NIAID principal deputy director.

Dr. Yasmine Belkaid, chief of the Mucosal Immunology Section in the Laboratory of Parasitic Diseases, won the Sanofi-Institut Pasteur 2016 International Mid-Career Award.

Dr. Pamela Guerrerio, branch chief of the Food Allergy Research Unit in the Laboratory of Allergic Diseases, received the Presidential Early Career Award for Scientists and Engineers.

Meetings and Events

On November 7, Dr. Fauci participated in the William E. Paul Memorial Symposium, which honored Dr. Paul’s numerous contributions to immunology and highlighted his scientific leadership at NIH.

On December 8, Dr. John Mascola, director of NIAID’s Vaccine Research Center, delivered the 2016 Joseph J. Kinyoun Memorial Lecture.

On December 5, internationally renowned cellist Yo-Yo Ma performed as the J. Edward Rall Cultural Lecturer. He and Dr. Collins discussed the intersection of music and science.

On September 11 and 12, NIAID staff, led by Dr. Auchincloss, participated in the Joint Symposium on Infection and Immunity in Beijing. The meeting focused on basic and clinical immunology research.

Representatives from the Institute participated in two scientific meetings in Havana, Cuba. The first meeting, the NIAID-Instituto de Medicina Tropical Pedro Kourí Consultation on Dengue and Zika Studies, was held on October 19. The second meeting, which was held on November 28 to 30, was the Scientific Conference on Arbovirus Research. Dr. Fauci’s presentation addressed the challenges we face as infectious diseases continue to emerge and re-emerge.

Dr. Fauci mentioned that several recent high-level international delegations have come to NIAID to discuss topics of mutual interest.

Budget Update

The President’s Budget for fiscal year (FY) 2018 is expected to be released on February 6.

NIAID continues to operate under a continuing resolution through April 28, 2017, and like most other institutes and centers, NIAID’s budget remains flat.

Separate from the FY 2017 appropriation, NIAID received a $152 million funding supplement to continue Zika research on vaccines, diagnostics, and therapeutics.

NIAID’s interim financial management plan for FY 2017 takes a conservative approach. Our interim R01 payline will be the 10 percentile for established investigators and the 14 percentile for new investigators. NIAID does not plan to make programmatic cuts to noncompeting and competing grants, though competing research initiatives will be cut up to 10 percent from their planned budget level. Our estimated success rates for research project grants will be between 20 and 22 percent.

Legislative Update

In December, President Obama signed into law the 21st Century Cures Act, which reauthorizes appropriations for NIH through FY 2020.

Dr. Fauci summarized some of the leadership changes to congressional committees that are important to NIH. Senator Barbara Mikulski retired from Congress, and Senator Patrick Leahy has replaced her as the ranking member of the Senate Appropriations Committee.

As a result of term limits, a few House committee leadership positions have changed. The new chair of the House Appropriations Committee is Representative Rodney Frelinghuysen, and the new chair of the House Energy and Commerce Committee is Representative Greg Walden.

On September 12, Dr. Fauci hosted Representative Michael Burgess on a tour of the Vaccine Research Center to discuss NIAID Zika virus research.

On September 14, Dr. Fauci participated in a briefing requested by UNAIDS and co-sponsored by Senators Ed Markey and Ben Cardin titled "Start Free, Stay Free, AIDS Free: An Accelerated Framework for Ending AIDS in Children, Adolescents, and Young Women." Following the briefing, Dr. Fauci met with Senator Thad Cochran; Michel Sidibé, executive director of UNAIDS; and Ambassador Deborah Birx, U.S. global AIDS coordinator, to discuss the importance of continued U.S. investment in HIV/AIDS research.

On September 27, Dr. Collins and Dr. Fauci participated in a congressional meet and greet organized by Representative Pete Sessions. It provided members of Congress with an opportunity to discuss important biomedical research with NIH representatives.

On December 1, Dr. Fauci spoke at the World AIDS Day congressional reception. He discussed the need for sustained congressional leadership in addressing the fight against HIV.

Dr. Fauci recognized NIAID staff members who participated in congressional briefings and press events on antibiotic resistance, Zika virus, and a new clinical trial site for NIAID’s Valley Fever treatment trial.

Other Information Items

Dr. Fauci began with an update on Zika, presenting the number of countries and territories with active Zika transmission, statistics on reported cases in the U.S. and U.S. territories, and statistics on Zika-affected pregnancies and outcomes in the U.S.

An interesting study published in December in the New England Journal of Medicine found that 42 percent of infants born to symptomatic Zika-infected mothers had grossly abnormal clinical and/or brain imaging results. Results from several other Zika studies suggest that researchers need to consider more than just microcephaly and think in terms of a congenital Zika syndrome, which includes other clinical manifestations.

Dr. Fauci presented development timelines of potential Zika virus vaccine candidates.

He continued with an HIV/AIDS update, summarizing global and U.S. statistics, and reporting on several high-priority studies that are in progress.

Dr. Fauci concluded by giving brief updates on antimicrobial resistance, CRISPR-Cas9 technology, and guidelines for preventing peanut allergy.

III. Guest Speaker—Maureen Goodenow, Ph.D., director, Office of AIDS Research (OAR), NIH

Dr. Goodenow began by highlighting some of OAR’s responsibilities, which include:

• Coordinating the scientific, budgetary, legislative, and policy elements of NIH HIV/AIDS research
• Developing a strategic plan as a roadmap for allocating funds
• Budgeting, receiving, and dispersing across NIH all funds for HIV/AIDS research
• Ensuring that funds are invested in the highest-priority areas of scientific opportunity in the global fight against HIV/AIDS

She gave a brief history of OAR and listed some of its discovery milestones. Dr. Goodenow acknowledged the foresight and vision by NIH leaders to change the way research was being done in response to the global situation in the early 1980s.

Dr. Goodenow noted how in 30 years, HIV/AIDS went from a fatal and much-feared disease to a treatable disorder with nearly normal life expectancy. She presented global and U.S. statistics, including the number of new cases each year and the demographics of infected people.

Dr. Goodenow concluded by summarizing OAR’s overarching high-priority areas, newly emergent research opportunities for HIV/AIDS, and areas of focus for the future.

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

Dr. Rotrosen welcomed the subcommittee members to the 185^th 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

Sean McCarthy, M.S., R.N. Mr. McCarthy joined the Autoimmunity and Mucosal Immunology Branch as a project manager in July 2016. Sean received his training at D’Youville College School of Nursing in Buffalo, New York. He has over 12 years of experience in clinical trials coordination and management, including distinguished service with Social and Scientific Systems, Inc., located in Silver Spring, and at the National Naval Medical Center.

Megan Morsheimer, M.D., M.P.H. Dr. Morsheimer joined the Transplantation Branch in October 2016 as a medical officer. She received her medical degree from Duke University and her public health degree at the University of Cape Town, South Africa, with a concentration in epidemiology. While in South Africa, Dr. Morsheimer investigated immunologic outcomes of HIV-infected children. Upon returning to the United States, she completed a pediatric residency at University of California, San Francisco, where she also obtained experience in pediatric solid organ transplantation and bone marrow transplantation. Most recently, Dr. Morsheimer completed a post-graduate fellowship in the Division of Allergy and Immunology at Children’s Hospital of Philadelphia (University of Pennsylvania).

Martin MacPhee, Ph.D. Dr. MacPhee joined the Clinical Research Operations Program in January 2017 as director. He received his Ph.D. from McGill University in 1989 and completed a post-doctoral fellowship in the Laboratory of Experimental Immunology/Biological Responses Modifiers Program at NCI. Following his post-doctoral training, Dr. MacPhee was a principal investigator and senior scientist at the American Red Cross where his research focused primarily on improving biological therapeutics related to blood and plasma derivatives. Additionally, Dr. MacPhee was responsible for developing novel products, production processes, and in vitro assays, as well as designing and overseeing preclinical and clinical trials. After leaving the American Red Cross, Dr. MacPhee served as vice president of research and design and intellectual property at Clearant, Inc. While at Clearant, Dr. MacPhee developed technologies for pathogen reduction in tissue allografts and other biologics. After leaving Clearant, he became a principal consultant at M2 Consulting and then became chief scientific officer and executive vice president at STB Lifesaving. While at STB Lifesaving, Dr. MacPhee was responsible for clinical research policy development, clinical research planning and priority setting, and clinical trial oversight.

Gabriel Rosenfeld, Ph.D. Dr. Rosenfeld joined the Office of the Director in August 2016, as a health scientist administrator. He received his Ph.D. from Weill Cornell Graduate School of Medicine in 2013 and completed a post-doctoral fellowship in the Surveillance Research Program at NCI. Dr. Rosenfeld subsequently joined NIAID as a Presidential Management Fellow, completing rotations in extramural divisions at NIAID and NCI. These rotations focused on the development of bioinformatics infrastructure as well as data science research and early investigator training through the use of innovation methodologies.

Rachel Eisinger-Baskin, M.P.A. Ms. Eisinger-Baskin joined the Office of Program Planning, Operations, and Scientific Information in September 2016 as a program analyst. She received her M.P.A in Health Policy and Administration form George Mason University. Prior to joining DAIT, Ms. Eisinger-Baskin was an executive writer and reviewer at the Office of the Secretary at the Department of Veterans Affairs. In this role, she gained extensive experience in policy and process improvement. Prior to working in the Office of the Secretary, Rachel served as a staff assistant in the VA's Office of Management and as a management analyst in the Department of Justice, Office of Inspector General.

Tracia Debnam Ms. Debnam joined the Transplantation Branch in August 2016 as a project manager. Prior to joining DAIT, Ms. Debnam worked with the Immune Tolerance Network Program and most recently Leidos Biomedical Research, Inc.

Scientific Initiatives

Asthma and Allergic Diseases Cooperative Research Centers (U19) (RFA-AI-16-065): The purpose of this funding opportunity announcement (FOA) is to solicit applications from centers that integrate clinical and basic research to conduct studies on 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.

Elucidation of Mechanisms of Radiation-Induced Endovascular Injury and Development of Treatments/Mitigators for Radiation-Induced Endothelial Cell and Vascular Dysfunction (U01) (RFA-AI-16-053): The purpose of this FOA is to provide an opportunity for academic, industry, and government laboratory researchers to address gaps in the understanding of the pathophysiology of radiation injury in the vasculature, and how this damage contributes to overall mortality following radiation exposure. This program will also advance the development of post-exposure treatment approaches targeting the vascular endothelium, with the ultimate goal of licensure of candidate medical countermeasures by the Food and Drug Administration for the radiation/nuclear public health emergency indication.

T-Cell Reagent Resource for the Study of Allergic Diseases (U19) (RFA-AI-16-027): The purpose of this FOA is to support studies to understand the role of allergen epitope-specific T-cell responses in the pathogenesis and treatment of allergic diseases by utilizing allergen epitope-specific reagents. The FOA will also support novel T-cell epitope identification, characterization and validation of important food allergens and aeroallergens that have not been previously studied.

Limited Competition: Clinical Trials in Organ Transplantation in Children (CTOT-C): Mechanistic Ancillary Studies (U01) (RFA-AI-16-078): The purpose of this FOA is to solicit applications from currently funded program directors/principal investigators, Mechanistic Subcommittee members, core laboratory leaders, and clinical site leaders in the "Clinical Trials in Organ Transplantation in Children (CTOT-C)" Program to support the conduct of studies of immune mechanisms using samples and clinical data collected from pediatric solid organ transplant recipients obtained in (a) ongoing or completed CTOT-C clinical studies, or (b) from other clinical trials in which the samples and data were collected with a demonstrably similar level of investigational rigor.

Limited Competition: Follow-up on Subjects and Immunological Assessments in The Environmental Determinants of Diabetes In The Young Study (TEDDY) (UC4) (RFA-DK-16-504): The purpose of this FOA is to invite the program director/principal investigator (PD/PI) of the current Data Coordinating Center (DCC) to apply for The Environmental Determinants of Diabetes in the Young (TEDDY) study, which is an ongoing epidemiological study. This DCC has been involved in study design and data and biosample acquisition and management since the inception of the TEDDY Consortium. This FOA provides support for the TEDDY DCC to continue to follow TEDDY children, allowing collaborators to conduct further studies in the measurement and analysis of immune markers using samples from TEDDY subjects.

APOL1 Long-Term Kidney Transplantation Outcomes Network (APOLLO) Clinical Centers (Collaborative U01) (RFA-DK-16-025): The purpose of this FOA is to support a multicenter, multidisciplinary group of investigators to be known as the APOL1 Long-Term Kidney Transplantation Outcomes Research Network (APOLLO). This FOA runs in parallel with a separate FOA that seeks applications for the APOLLO Network Scientific Data Research Center (SDRC) (RFA-DK-16-024). The APOLLO SDRC will design and conduct studies of a prospective longitudinal cohort to determine the impact of APOL1 genetic variants as susceptibility factors in U.S. kidney transplant recipients who received kidneys from African American donors.

Trophoblast Differentiation and Function (R01 and R21) (PA-16-444/PA-16-445): The purpose of this FOA is to encourage applications from the scientific community to support outstanding research in the area of trophoblast differentiation and function in relation to fertility and pregnancy, including the role of the immune system. It is anticipated that fundamental knowledge gained by this research will act as a solid foundation to hasten treatments for a number of placental-based pregnancy disorders, such as implantation failure, frequent pregnancy loss, preeclampsia, fetal growth restriction, and pre-term birth.

Division Activities

Allergy, Asthma, and Airway Biology Branch

2016 Annual Asthma and Allergic Disease Cooperative Research Center Face-to-Face Meeting (AADCRC). On November 2 and 3, 2016, NIAID sponsored the 11^th annual meeting of the AADCRC investigators in Rockville, Maryland. The one-and-a-half-day meeting of investigators, students, and NIAID program staff included oral and poster presentations from nine NIAID-funded AADCRCs and fostered data-sharing and collaboration between the centers.

Airway Microbiome and Disease Workshop. On November 15 and 16, 2016, NIAID organized a workshop in Bethesda, Maryland on the role of the airway microbiome in asthma and chronic rhinosinusitis. Experts shared their research on the airway microbiome from early infancy, during bronchiolitis, in established pediatric and adult asthma, and in chronic rhinosinusitis. Topics included the potential influence of the microbiome on the development of asthma and on disease severity, as well as opportunities for microbiome altering interventions as a means of therapy. Experts discussed the major gaps in understanding the role of the airway microbiome in disease and proposed potential future study designs that could advance the field.

Basic Immunology Branch

Kinks in the Armor – Bypassing the Immune Barriers of the Skin. On September 19, 2016, DAIT and DMID jointly hosted a workshop in Rockville, Maryland. The objective of the workshop was to discuss the gaps in understanding of how vector-borne diseases are able to establish infections. Experts in the fields of vector biology, vector-borne diseases, and skin immunology discussed: 1) activation of immune cells in the skin by a blood meal of an arthropod vector and their contribution to the response against vector-delivered pathogens; 2) suppression of specific immune functions by vector saliva factors; and 3) the caveats of the mouse models used for this type of research, namely the use of immunologically naïve mice with no history of exposure to uninfected vector bites as well as the use of "clean" (SPF) mice whose immune responses are significantly affected by the lack of prior exposure to environmental microbes. A secondary objective of the workshop was to initiate discussions and collaborations between vector/vector-borne disease researchers and skin immunologists.

Infant Immunity Program Annual Meeting. On September 21 and 22, 2016, the fourth annual meeting of the Infant Immunity Program was held in Bethesda, Maryland. The objective of this program is to define mechanisms underlying the immune responses of neonates and infants to infections or vaccines. Investigators from 15 projects shared research progress, expertise, and updates on collaborations that occurred among the group during the past year.

Adjuvant Discovery and Adjuvant Development Annual Meeting. From September 26 to 28, 2016, the NIAID adjuvant contract programs held a joint meeting in Rockville, Maryland. Adjuvant Development contractors presented progress on their lead formulations, namely: a small molecule RIG-I agonist used in vaccines against emerging RNA viruses; a novel liposomal formulation that delivers QS21 and a synthetic TLR4 agonists as co-adjuvants for vaccines against B. anthracis and West Nile virus; a mutated bacterial toxin which induces strong mucosal immunity when delivered with vaccines against tuberculosis and shigellosis; and a novel oil-in-water nanoemulsion formulation which enhances the efficacy of an influenza vaccine based on plant-derived recombinant H5 protein. Seven Adjuvant Discovery contractors reported on their progress in identifying lead adjuvant candidates after completing extensive high-throughput screening campaigns. These novel compounds target C-type Lectin Receptors, Toll-like Receptors, CD1a, Interferon Regulatory Factors, Mast Cell receptors, and immune checkpoints. Program staff from DAIT and DMID gave presentations on the recently initiated Molecular Mechanisms of Combination Adjuvant (MMCA) program and NIAID-provided resources of potential use to adjuvant researchers, respectively.

Immunity in the Elderly Annual Meeting. On October 4, 2016, the third annual meeting of the Immunity in the Elderly program was held in Rockville, Maryland. NIAID and NIA jointly support this program, with five projects supported by NIAID and three projects supported by NIA. The goal of the program is to understand immune mechanisms that contribute to impaired host responses during infections and in response to vaccines. Investigators presented their research findings and discussed opportunities for collaborations among the members of this program.

Molecular Mechanisms of Combination Adjuvants. On November 8, 2016, NIAID held a kick-off meeting in Rockville, Maryland. Seven U01 cooperative agreements were awarded in fiscal year 2016 with the goal of determining how targeting multiple immune pathways can improve the duration, quality, and magnitude of immune responses enhanced by adjuvants. Investigators provided program descriptions and research updates, and discussed ways to share expertise and reagents across projects.

Cooperative Centers on Human Immunology (CCHI). On December 1 and 2, 2016, the annual meeting of the Cooperative Centers on Human Immunology was held in Rockville, Maryland. Investigators from six U19 centers discussed their latest research results on the molecular mechanisms by which the human immune system is activated and regulated in response to infection and/or vaccination. Investigators also presented new technologies developed to facilitate studies in humans. To encourage collaboration across relevant DAIT programs, a grantee from the Development of Sample Sparing Assays for Monitoring Immune Responses Program was invited to share his latest technology with the CCHI investigators.

Systems Approach to Immunity and Inflammation Annual Meeting. On December 14, 2016, NIAID held a meeting in Rockville, Maryland. 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, and both presented updates on their research findings, biological and computational pipelines, and community outreach efforts.

Autoimmunity and Mucosal Immunology Branch

Cooperative Study Group for Autoimmune Disease Prevention (CSGADP). On October 24 and 25, 2016, the annual meeting for this program was held in Rockville, Maryland. The mission of this program is to engage in scientific discovery that significantly advances knowledge for the prevention and regulation of autoimmune disease. Investigators presented recent highlights from their projects in type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. On the second day of the meeting, the group heard and discussed reports from outside investigators who were awarded funding from the CSGADP for pilot studies in autoimmune disease prevention. Proposals for new pilot studies were also reviewed and approved by the steering committee.

Autoimmunity Centers of Excellence (ACE). On October 26 and 27, 2016, ACE steering committee members and collaborative project leaders convened in Bethesda, Maryland, to discuss the progress and achievements of their shared research agenda. The annual progress report was posted online in December 2016 (autoimmunitycenters.org). ACE continues to be highly productive in supporting outstanding fundamental research into the mechanisms of autoimmunity in humans, including publishing several papers in high impact journals in the past year. ACE is also accelerating and broadening its support of clinical trials of novel therapies for the autoimmune diseases systemic lupus erythematous (NCT01946880, NCT02428309, and one opening 2017), rheumatoid arthritis (NCT02603146), and mechanistic studies in multiple sclerosis (NCT0233096).

Radiation and Nuclear Countermeasures Program (RNCP)

2^nd Animal Model Development Workshop. On September 22 and 23, 2016, DMID, working with the RNCP and representatives of other HHS agencies (BARDA and FDA), organized a meeting in Bethesda, Maryland. The purpose of this workshop was to bring funding agencies, researchers, developers, regulators, and policy makers together to explore unique challenges presented by the development of animal models for the evaluation of medical countermeasures for chemical, biological, radiological, and nuclear (CBRN) threat agents.

Columbia University Kickoff Meeting for Contract HHSN272201600040C. On October 28, 2016, the RNCP held a kick-off meeting in Rockville, Maryland, for the initiation of a new contract with the Trustees of Columbia University. The awarded proposal was submitted by Dr. Guy Garty, in response to the RNCP solicitation – "Development of Radiation/Nuclear Medical Countermeasures or Biodosimetry Devices." Dr. Garty’s planned, three-year project is entitled: "High Throughput Biodosimetry Using a Fully Automated Dicentric Assay on Commercial High-Content Screening Platforms."

62^nd Annual Meeting of the Radiation Research Society (RRS). From October 15 to 19, 2016, RNCP staff partnered with RRS to host a symposium at their annual meeting in Hawaii on "Late Effects of Acute Radiation Syndrome." The goals of the session were to identify areas of concern for organ systems, post-event survival sequelae, and to explore the impact of treatments and care protocols on the development of late effects. Presentations during the symposium included talks on the RNCP-funded maintenance of a long-term, nonhuman primate survivor, and NIAID-funded studies with the Radiation Effects Research Foundation (RERF) to investigate immune-senescence and other late effects of acute ionizing radiation exposure in the survivors of Hiroshima and Nagasaki.

NIAID/BARDA Radiation Portfolio Update Meetings. On October 25, 2016 (medical countermeasures) and December 14, 2016 (biodosimetry), update meetings were held between the RNCP and Biomedical Advanced Research and Development Authority (BARDA) staff. The purpose of these ongoing, twice-yearly meetings, which were requested by the HHS Assistant Secretary of Preparedness and Response, is to provide programmatic transparency, ensure that the funded research programs are aligned, provide advanced information on potential transition of promising candidates, and ensure that there is no scientific overlap between the two agencies’ product research and development portfolios.

National Academy of Sciences (NAS) Beebe Symposium, "30 Years After the Chernobyl Accident: Current and Future Studies on Radiation Health Effects" – On November 1 and 2, 2016, the Nuclear and Radiation Studies Board of the NAS organized the Gilbert W. Beebe Symposium in Washington, DC. The focus of the symposium was to commemorate 30 years of study on radiation health effects of the 1986 Chernobyl nuclear accident. Presentations and discussions were held on advances in dosimetric methods, understanding of immediate and late health effects, congenital disorders, psychological effects, cancer and non-cancer effects, and recognition of achievements in countermeasure development. NIAID co-funded the event and program staff served on the organizing committee, gave a presentation, and chaired sessions.

RITN Late Effects Meeting. On November 14 and 15, 2016, in Rockville, Maryland, the RNCP and the Radiation Injury Treatment Network (RITN) brought together researchers, government, and emergency preparedness representatives to discuss late-physiological effects of radiation exposure on various organ systems. An elevated awareness of gaps in this area of concern informed clinicians and emergency preparedness stakeholders on the long-term effects that radiation survivors may encounter, and highlighted new developments in research and preparedness. The goal of this meeting was to better understand how these long-term effects may impact concept of operations considerations, medical treatment protocols, as well as the development and use of medical countermeasures.

Centers for Medical Countermeasures against Radiation Consortium (CMCRC) Annual Update Meeting. On December 7 and 8, 2016, NIAID sponsored this meeting in Rockville, Maryland. The meeting brought together investigators from the four cooperative agreements to discuss research progress that has been made since inception of the current iteration of the program. The meeting provided an opportunity for exposure of the portfolio to other federal government agency staff who were in attendance, and fostered dialog and collaboration among the CMCRC investigators and program staff regarding future research and development directions.

U01 Annual Update Meeting. On December 15, 2016, NIAID held a meeting in Rockville, Maryland to showcase the scientific progress being made within the third year of eight cooperative agreements. The goal of these awards is to advance the development of products for hematopoietic and gastrointestinal acute radiation syndrome, as well as approaches to mitigate/treat the delayed pulmonary effects arising from an acute radiation exposure. The purpose of the meeting was to encourage continued harmonization of animal models, supportive care and medical management, as well as endpoints across institutes doing studies in these models. In addition, other HHS partner agencies in attendance were provided a program update.

Concepts Presented for Clearance

FY 2018 SBIR Contract Topics

Adjuvant Screening and Discovery for Vaccines and for Autoimmune and Allergic Diseases: The goal of this program is to support the screening of new vaccine adjuvant candidates against infectious diseases or for toleragenic adjuvants for autoimmune or allergic diseases.

The subcommittee endorsed and unanimously approved this contract topic.

Adjuvant Development for Vaccines and for Autoimmune and Allergic Diseases: The goal of each project is to accelerate preclinical development and optimization of a single lead adjuvant candidate or a select combination-adjuvant for prevention of human disease caused by infectious pathogens, or for autoimmune or allergic diseases.

The subcommittee endorsed and unanimously approved this contract topic.

Reagents for Immunologic Analysis of Non-Mammalian Models: This funding opportunity announcement is intended to address the limited availability of reagents (e.g., antibodies, proteins, ligands) for the identification and discrimination of immune cells of non-mammalian models (e.g., arthropods, amphibians, fish, nematodes, marine echinoids).

The subcommittee endorsed and unanimously approved this contract topic.

Development of Sample Sparing Assays: The goal of this proposal is to accelerate commercial development of novel, standardized sample sparing assays that improve monitoring of the immune system using limited amounts of biological sample.

The subcommittee endorsed and unanimously approved this contract topic.

V. Report of the Microbiology and Infectious Diseases Subcommittee—Emily Erbelding M.D., M.P.H., director, DMID

Director’s Report

Dr. Emily Erbelding, the new director of the Division of Microbiology and Infectious Diseases (DMID), chaired the NIAID Microbiology and Infectious Diseases Council Subcommittee meeting on January 30, 2017. Dr. Erbelding noted several senior leadership changes within DMID, including the recent departure of Dr. Fred Cassels, who was chief of the Enteric and Hepatic Diseases Branch; and the upcoming retirements of Dr. Richard Gorman, DMID’s associate director for clinical research, and Dr. Cathy Laughlin, chief of DMID’s Virology Branch. Dr. Erbelding then referred to the branch chiefs and office directors to introduce new staff in their respective programs.

Dr. Erbelding presented four topics for inclusion in the FY 2018 Small Business Innovation Research (SBIR) Contract Solicitation announcement for the Subcommittee’s consideration. She summarized the scientific and programmatic significance of these topics, described the availability and feasibility of the proposed technology, and commented on potential uses.

1. Computational Software Development to Advance Translational Research for Infectious Diseases - to support the development of improved tools to analyze available data sets.
2. Improved Diagnostics for Elimination Programs Targeting Malaria and Select Neglected Tropical Diseases (NTDs) – to support the development of low-cost, diagnostic platforms with appropriate sensitivity and specificity for the detection of subclinical malaria or select NTD infections for use in disease elimination campaigns in resource-limited settings.
3. Induction of Mucosal Immune Response to Parenterally Delivered Vaccines – to support efforts to a) characterize systemic and mucosal immune responses to parenterally-delivered enteric vaccine candidates; and b) determine the best vaccine/adjuvant formulation(s) of current enteric vaccine candidate(s) that induce immune responses at both mucosal and systemic compartments.
4. Novel Vaccine Technologies and Strategies to Promote Sustained Vaccine Efficacy Against Malaria and Pertussis - to support 1) identification of novel vaccine technologies, such as delivery platforms or formulations that induce long-term protection; and b) development of new vaccines or vaccine strategies using technologies that induce long-term immunity and sustainable efficacy.

All four topics were unanimously approved by the Subcommittee.

Dr. Erbelding shared her early observations about DMID’s programs and extensive portfolio. In particular, given recent disease outbreaks such as Ebola and Zika, she indicated that she has been gaining an understanding about how DMID’s infrastructure currently supports emerging and reemerging infectious threats, and whether ongoing operations are best optimized for fighting whatever disease threat comes next. She noted that DMID will always have the responsibility for supporting preclinical activities to combat emerging diseases, noting that the vast majority of DMID’s preclinical resources were mobilized in response to the recent Zika outbreak. She stated that the preclinical infrastructure will need to be continually evaluated to make sure that it is deployable for the next threat. Reflecting on lessons learned in the response to Zika, she also spoke about the importance of clinical preparedness, noting that it will require that DMID build collaborations and partnerships outside of the Division to expand the infrastructure of available clinical sites as needed. This could include using clinical sites overseen by other NIAID divisions, such as the Division of AIDS, sites affiliated with other NIH entities, such as the National Institute of Child Health and Human Development, and those outside of the NIH, depending upon where the next epidemic strikes. Having expanded clinical access will be important with the next challenge and the next response. She told the Subcommittee that she would continue to keep them apprised of DMID’s efforts.

Program, Scientific, and Budget Updates

DMID ‘Omics Update – Dr. Maria Giovanni provided a comprehensive overview of the various programs that fall under the purview of the DMID Office of Genomics and Advanced Technologies. Over the last 15 years, NIAID/DMID has made a significant investment in genomics, functional genomics, structural genomics, systems biology, proteomics and bioinformatics resources, which provide the research community with data sets, technologies, and computational tools to study infectious diseases. She described how the programs have continued to evolve since their inception, and noted that NIAID has been at the forefront, assisting scientists with all aspects of big data, including data access, data management, training, data analysis, workspaces, and computational tools to develop the next generation of modeling, statistical methods, and machine learning algorithms that can be applied to infectious diseases research; providing new strategies for developing diagnostics and therapeutic interventions; and identifying predictive markers of disease and health.

Concepts Presented for Clearance

The following FY 2018 concepts were presented to the Subcommittee:

Partnerships for the Development of Clinically Useful Diagnostics for Antimicrobial Resistant Bacteria (R01) – the objective of this concept is to support milestone-driven projects focused on development of clinically informative, diagnostic platforms that identify select antimicrobial resistant bacterial pathogens and determine associated antimicrobial sensitivity and/or resistance. The Subcommittee voiced strong support for this new Partnerships concept focused on the development of new rapid diagnostics to detect bacteria and determine antibiotic susceptibility. The Subcommittee was particularly enthusiastic about the development of new point-of-care diagnostics. One Subcommittee member requested information about the review process for the Partnership applications. Program staff clarified that these applications are reviewed by special emphasis panels established and coordinated by NIAID’s Scientific Review Program. Reviewers are instructed about the goals of the program and provided with guidance on how to evaluate the unique components of these grant applications, for example, the Research Milestones and Product Development Plan. One Subcommittee member requested examples of appropriate diagnostic methods available for continued product development under this initiative. Program staff described two candidate methods that have established proof-of concept. The concept was unanimously approved.

Partnerships for the Development of Vaccines and Immunophrophylactics Targeting Multiple Antibiotic-Resistant Bacteria (R01) – the objective of this concept is to support the development of vaccines and/or immunoprophylactics targeting multiple Gram-negative pathogens that cause nosocomial infections for which therapeutic options are limited or nonexistent. The Subcommittee expressed support for this new Partnerships concept, which would support the development of vaccines and immunophrophylactics targeting antibiotic-resistant bacteria. It was noted by several Subcommittee members that Partnerships initiatives have been an effective mechanism for advancing translational research and moving scientific fields forward. A Subcommittee member commented that progress in this specific area seemed slow given that the issue of antibacterial resistance has been a priority research area for some time. Dr. Irene Glowinski, DMID deputy director, explained that NIAID has been supporting Partnerships initiatives since 2002, many of which have been broad and encompassed related activities. Furthermore, planning for specific concepts is associated with potential scientific opportunities, and each concept has a two-year planning cycle, spanning concept development through award. This same Subcommittee member inquired about NIAID’s efforts to stay apprised of related activities supported by industry. Program staff informed the Subcommittee that such efforts are undertaken, and reported that for some pathogens identified in the concept (e.g., Pseudomonas aeruginosa) a few vaccines have entered clinical testing, including into Phase 3, but none to date have been shown to be safe and/or efficacious. Another Subcommittee member noted that requesting projects that target more than one Gram negative pathogen through targeting shared antigens is ambitious; it would be simpler to target just a single Gram negative pathogen (perhaps multiple clinically-relevant strains) since there are no licensed vaccines for the particular Gram negatives the concept focuses on. Program staff acknowledged those concerns. The concept was well received by the Subcommittee and received unanimous approval.

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

Dr. Dieffenbach welcomed Cara Wilson as the new ARAC Chair. The following additional new ARAC members were also welcomed: Paul Bieniasz, Ph.D., Dick Chaisson, M.D. and Elizabeth J. McFarland, M.D.

Budget Update

The current administration will release the budget details of FY 2018 on February 6, 2017, so currently no further information is available. Regarding the FY 2017 budget, there is a continuing resolution (CR) until the end of April 2017. The previous administration’s request submitted a year ago means that NIAID funding will remain at the same level. A report card for FY 2016 was presented to show the committee the current status and predictions for the next year. This covered NIAID payline history back to 2005, grant success rates, grant mechanisms, and institute comparative success rates.

Update on the OAR Strategic Fund for High Relevance HIV/AIDS Research

The need to work with OAR to address the highest priority research and where the greatest gaps are and how they can be filled was discuss. These highest priorities were identified, including strategies that use antiretroviral drugs (ARV), various inhibitors and broadly neutralizing antibodies (bNAbs), and the use of these agents individually or in combination for vaccine or non-vaccine prevention, treatment, or cure. One of the research gaps is the limitations in producing immunogens and antibodies. This has created a critical bottleneck in the areas of vaccine-based prevention, non-vaccine prevention, and the use of bNAbs in treatment. This challenge was addressed during the November OARAC meeting which resulted in some conclusions.

Some funding in FY 2016 was lost by NIAID due to realignment and repurposing.

Q: The drop in R01 applications is notable and concerning. Any comments?
A: It is partly a coding issue as in the past some TB and some basic immunology were coded as being AIDS related. Not sure if there is a true drop in the number of applications.

SBIR Contract Proposals

Dr. Dieffenbach asked for assistance with a new SBIR contract research topic that the Division will support through the NIH Omnibus SBIR contract solicitation. This initiative will look at ways to improve the cell substrate. Can the production of HIV antigens be improved by changing the biology of the cell (such as reducing inappropriate protein cleavage or glycosylation) and used to produce the vaccine? Dr. Dieffenbach summarized the scientific and programmatic significance of these topics, described the availability/feasibility of the technology, and commented on potential uses. The idea is to use CRISPR-Cas9 tools to modulate molecular pathways within the cells to enhance envelope production in mammalian cell lines to enhance protein purification.

Discussion

Q: Consider setting clear goalposts. We know what we had with BG5 and 5 SOSA from KBI. We want a substantial improvement if we want to move from Phase I to Phase II. What about analytics?
A: We agree completely. That’s the advantage of having this be a contract because we can put these things in as milestones where they can be completely enforceable and nothing will move to Phase II unless these milestones are met. There will clearly have to be some analytics developed that will go on in parallel with this. Analytics will be an important component of how the group sets up the evaluation of the substrate and its production capacity so I think it’s all integrated.

Q: There is an SBIR grant mechanism basically covering the same ground. Is this intended to replace that?
A: No, it is intended to engage slightly bigger industry with more resources than we can currently put through the grant. It is such an important area requiring a "full-court press." Much of this is repurposing money already set aside for the SBIR program.

Q: What will be the total amount of resources?
A: No specific amounts are allowed to be given here due to rules, but it is not as large as some of the other initiatives seen. Essentially, we are repurposing money that had already been set aside for SBIRs so no additional money is coming out of the Division.

Q: Is the money going to be spent only on developing technology or will it also include selection of the envelopes?
A: A technology cannot be done in the absence of working on specific high-priority immunogens. That’s part of the selection criteria during SBIR review. We will give applicants examples of what we think are the best envelopes to be working on given where the field is right now. A good mixture of Clade C envelopes and some of other transmitter founders would be ideal.

Q: Are contracts reviewed in a similar way to grants? How many applications are expected for the existing SBIR? Will there be a study section?
A: Yes, it is a peer reviewed process, and there is an evaluation panel that scores them. Additionally, questions can be asked and answered that may raise or lower the score dependent on the applicant’s answers. Grants do not have this process. For the SBIR, three to four applications are expected this time around given the stringency which is required in terms of a small company to do this type of work. This is focused on small business.

[The committee was asked to mark their ballots electronically at this time.]

Ballot Voting Outcome:
12 Approval
0 Approval with the modifications(s)
0 Deferral for further information
1 Disapproval

Programmatic Updates

Prevention research is going through an amazing time as four major trials were launched in 2016. Quick enrollment is sought so that answers can be quickly obtained. Dr. Dieffenbach described his talks with Dr. Linda-Gail Bekker on radio and TV in South Africa (SA) as part of the HVTN 702 rollout. Several drugs companies in the U.S. and in Europe were impressed with this media saturation approach and the speed of the roll-out.

Renewal of HIV/AIDS Clinical Trials Networks
This will become an important topic that will be discussed more fully over the next four to five ARAC meetings. Future key dates including concept approval, FOA release, application deadlines, reviews, and awards for the renewal were stated.

Office of AIDS Research Advisory Committee (OARAC) Update
Roy Gulick, MD, MPH, Chair, OARAC

The five OARAC working groups that represent the guidelines panels, their key leadership, and volunteers were recognized. A brief update of all the guidelines panels and the changes made within the last year was given. These guidelines continue to be consulted online from around the world. The Strategies for an HIV Cure meeting held in November 2016 before the OARAC meeting that had attendees from across the country was outlined. The OARAC meeting was summarized and included talks from representatives from the six Martin Delaney Collaboratories.

Programmatic Overview: Key Accomplishments and Future Directions

Basic Sciences Program (BSP)
Diana Finzi, Ph.D.

The BSP encompasses three branches that cover different areas: Epidemiology (EB), Pathogenesis and Basic Research (PBRB), and Targeted Interventions (TIB), and essentially focuses on very early stage basic science that supports a wide range of programs. Funding comes from solicited and unsolicited grants. BSP works with therapeutics and vaccine programs and areas that fall in-between programs. The current budget, grants, and contracts for the three branches will be overviewed. Starting with EB, EB is focusing on two different areas: 1) working hard to partner with other institutes to study outcomes of HIV disease and 2) to lead efforts as to how, when, and where transmissions of HIV occur. Recent studies demonstrate that advances in treatment have resulted in similar life expectancy of treated HIV-infected individuals to uninfected individuals. However, treatment does not fully restore health. Treated HIV-infected individuals still have significantly higher risk of complications generally associated with aging such as cardiovascular disease, lung, liver and kidney diseases, cancer, and neurocognitive disorders. Also, behavioral issues such as taking medications and smoking are major challenges for people who are infected with HIV. For example, a recently published modeling study demonstrated that cigarette smoking has an impact on life expectancy of people with HIV that is comparable to the impact of HIV infection itself. The study emphasizes that smoking cessation should be a priority in all HIV treatment programs. Behavioral issues and outcomes of diseases associated and/or enhanced with HIV infection represent important areas that require further understanding of possible pathogenic mechanisms. EB seeks to partner closely with relevant institutes that specialize in those diseases to facilitate such studies. This will help continue the tracking and understanding of HIV disease outcomes. In the EB effort to understand where HIV transmissions continue to occur at high rates, one goal is attempting to determine where viral loads are effectively suppressed both at a high international level but also more locally, using appropriate tools. Examination of one dataset in the International Epidemiologic Databases to Evaluate AIDS (IeDEA), a resource generated from an international consortium with sites from over 130 countries that collects clinical data on over 1.7 million adults and children throughout the world, showed initiation of ART at higher CD4 counts in all regions of the world from 2007, but improvement is still needed everywhere. On a granular level, modeling studies on the dynamics of HIV spread between individuals have shown that concentrating efforts on those with the highest HIV transmission risk scores would have greater impact on preventing widespread transmission than unfocussed efforts. Cell phones, big data, and other resources will be used to understand clusters of HIV infected and transmission patterns.

Our basic sciences research consists of many projects that cover diverse areas, in the last 5 to 10 years centering on HIV disease in the presence of ARV drugs and focusing on residual virus. The Martin Delaney Collaboratories were re-awarded last year and these grants support coordinated basic, translational, and clinical research focused on developing strategies to achieve an HIV cure, defined either as sustained HIV remission or eradication. Each of the six-funded collaboratories has the capabilities to carry out preclinical and early clinical studies to test new single or new combinational strategies for HIV cure and a private sector partner responsible for rapid research translation. A great scientific challenge, that of measuring residual virus in people undergoing treatment, remains a problem despite the numerous assays available. Each assay provides a measurement of different parts of the virus and there is no clear correlation between values generated by different assays. This results in wide intra- and inter-assay data variability in the measurements of frequency of replication-competent virus, total virus, or defective virus. Further complicating this issue, ratios of different forms of the virus vary greatly between infected individuals. The difficulty of measuring residual virus continues to fuel discussion about which measurements are most relevant for cure and continues to be a contentious topic of discussion in the field. Well known is what happens when people suspend therapy; virus rebounds rapidly. The latent reservoir of virus is extremely stable over many years while on HAART. The mechanisms responsible for the stability of the reservoir are not understood. Recent findings suggest that clonal expansion may contribute to maintenance of the stability of the reservoir of latently infected cells. Of note, clonal cell populations behave differently, and it has recently shown that larger clonal populations will be less likely to reactivate in the presence of reactivating drugs. Clearly, more work is required on this area. Ways to modify or manipulate the immune system using targeted interventions and biologicals including bNAbs, DARTS (Dual Affinity Re-Targeting for HIV Suppression) or antibody blocking of α4β7 integrins (that prevent leukocyte transmigration and reduce inflammation) are some of the ongoing and novel approaches for long-lasting control of HIV infection.

Discussion

Q: How justified is the solicited funding which accounts for half of the budget by BSP especially as the majority of previously paradigm shifting breakthroughs have come from unexpected sources? Unsolicited areas of research need to be protected.
A: Agreed. When stating "solicited," the categories are quite broad and not as bad as it seems. This approach is trying to target people toward very broad areas of research such as "cure" or targeting residual viral reservoirs.

Q: What we have learned from cure research is that it will be difficult to achieve. How long should certain lines of research be continued if there is not much progress? Can it be sustained?
A: We know the target, it has been defined quite clearly so we are not working in the absence of an idea of what to target. I agree that this is a difficult problem to overcome and agree that the reactivation strategy is a tough road to take.

Q: There is a sentiment in the field that cure research does not have to be at the same quality to have a good chance of receiving funding as other areas of HIV research.
A: I agree. We are interested in continuing to stimulate other areas of research in the basic science of HIV (stimulating work on restriction factors, as an example).

Q: Could you comment on the MACS and the WIHS?
A: We plan to stay very involved but need to partner with other institutes for their expertise and financial support.

Therapeutics Research Program (TRP)
Sarah Read, M.D.

An overall TRP focus was presented together with the organization and portfolio which included research support contracts that help the clinical trials networks. SBIR contracts that cover a broad array of topics have also been solicited over the last several years. The bulk of the projects in numerical and monetary terms are those that involve clinical trials comprising interventional and observational studies. The four main research focus areas outlined share the main goal of improving outcomes of people living with HIV.

(I)   Novel treatment strategies. Trials that have recently concluded or will end soon have addressed the questions of when and what to start in terms of antiretroviral therapy. A 1^st line therapy trial (A5257), 2^nd and 3^rd line therapy trials (A5273, A5288), and the START trial were discussed. Subsequent to these trials, the research strategies have focused on developing a pipeline of formulations and novel drugs for prevention and therapy that would improve access and adherence to therapy. A number of initiatives have helped to stimulate this field which also complements programs in the pharmaceutical industry. Several funding announcements were made within the last year to discover small molecules and formulations. A research resource R24 grant was used to fund the Long-Acting/Extended release for Antiretrovirals Program (LEAP) resource for communication and data sharing between investigators in this field. A consultation was organized to address the knowledge gaps in drug resistance (DR) and several conclusions were made such as HIVDR in diverse clades require better understanding and that HIVDR testing is needed for specific populations and settings.

(II) HIV Cure/Sustained Remission. Research approaches to date have focused on HIV quantification, latency reversing agents, and immune-based therapies to deplete or control viral reservoirs. Various initiatives have been published to address these approaches and future efforts will focus on eliciting an enhanced immune response to clear or control reservoirs. Interesting results from therapeutic vaccine studies in nonhuman primates (NHP) have been published showing reduced SIV RNA copy numbers using Ad26/MVA in combination with TLR stimulation compared with sham treated animals. However, robust evidence of efficacy of vaccines has not yet been shown in humans. The use of monoclonal Ab including broadly neutralizing Abs (bNAbs) have been used in various trials and some published results were summarized. In general they showed modest delays in time to viral rebound but not enough to result in sustained remission. Combinations of bNAbs are being studied and funding initiatives are now being prepared to examine modification of bNAbs and their effects on reservoirs.

(III) Comorbidities. Chronic residual inflammation and activation are known to occur in HIV infected individuals. A recent study reported that markers of inflammation (IL-6 and d-dimer) were shown to predict AIDS and serious non-AIDS events (SNAEs) in patients enrolled in specific HIV treatment trials. Efforts have been focused on elucidating which pathways contribute to immune activation in the setting of treated HIV infection in order to identify potential therapeutic targets interventions to reverse any detrimental effects. Collaborations with other funders will be sought to examine end organ disease; the REPRIEVE trial is an example of a trial funded through collaboration with NHLBI in order to test the potential for statins to prevent major cardiovascular events in HIV-infected individuals.

(IV) Coinfections. The TB epidemic is critically important especially for those living with HIV, and it is the leading infectious disease cause of death in the world. Several key statistics were presented including that people living with HIV (PLWH) are 21 to 34 times more likely to develop active TB, but there are critical gaps in TB/HIV knowledge. TB research priorities were outlined and REPORT sites were discussed. The importance of Hepatitis B in HIV individuals and research priorities were outlined.

Discussion

Q: For REPRIEVE only 40 percent have been enrolled after two years. Why is this and what is DAIDS’ view on whether it’s on target?
A: We are closely tracking enrollment along with NHLBI, the funder of the trial. There have been a number of issues related to international site start-up, but this is typical for trials of that size. The enrollment number probably does not give an accurate reflection of enrollment capacity of certain international sites. We also anticipate adding additional sites. A PR campaign was set up by NIAID’s Office of the Director communication team to boost for enrollment so we hope it will have a positive influence. We will continue coordinating with NHLBI to identify other means to boost enrollment.

Q: I am struck by the absence of implementation science. I would argue that this is an important area to focus on from an NIH perspective.
A: We look to partner with other funders and stakeholders in this regard. Additionally, PSP directs strategies for treatment as prevention.

Q: Has improved animal models for TB been proposed? Organization of TB is lacking in terms of money that allows people to coalesce on certain topics. What do you intend to do and how well coordinated will you be with DMID and other funders like the Gates Foundation? How rigorous will you be in forcing people not to just have their model of choice?
A: I agree that funding has been a problem. We have formed a team comprised of members from DAIDS, DMID, DAIT, and DIR which is focused on TB vaccine research and animal models have been discussed. We are inspired by the vaccine models funded by the DAIDS vaccine program and how productive they can be if done in a rigorous way. We need to put resources behind it.
Comment: It’s almost a go big or go home approach. Dabbling won’t help. The two divisions need to come together otherwise you might be wasting money.

Q: With such a broad research agenda, can you give us an idea of how much is domestic versus international effort for all therapeutics?
A: This is difficult to answer as each focus area is very different. Cure is very domestic. Some high-risk projects were done at domestic sites only whereas TB is truly international. Cardiovascular care is similar in partner countries so it was easier to expand REPRIEVE internationally. But it really depends on what is the coinfection and where it is, the co-morbidity, and the prevalence. But overall maybe 50/50 as things balance out.

Vaccine Research Program (VRP)
Mary Marovich, M.D.
 

The priorities in HIV research and development are twofold:

1. Fundamental research to inform vaccine design

2. Vaccine development research

The overall presentation broadly covered two main areas:

• HIV vaccine discovery and design advances
• Future directions for vaccines

There are currently several ongoing Phase I/IIa U.S.-based trials for HIV vaccine development including one study within the P5 program and recently a Clade B Env protein was produced that will be vialed and tested domestically.

Immune traits linked with bNAb production were discussed. These bNAbs are unusual, are highly somatically mutated and only occur in a certain proportion of individuals. Such individuals have been examined to learn the conditions under which these neutralizing antibodies develop. Published studies comparing HIV-1 infected individuals who did or did not make bNAbs showed several different immune profile patterns including higher frequency of autoantibodies and circulating memory T follicular helper (Tfh) CD4+ cells but lower frequency of regulatory CD4+ T cells. Understanding these observations may help us better understand and potentially induce bNAb development. Studies in HIV-infected infants reveal a more rapid development of bNAb responses (less than one year) and these infant bNAbs are less hyper-mutated when compared to adults. This indicates alternative pathways and potentially fewer tolerance checkpoints as the immune system is not fully developed.

Lymph Node Fine Needle Aspiration (LNFNA) is based on an old technique but now used, in primates and humans who are infected or have received vaccines, as a newer approach for fine mapping the immune response without sample bias. Key science and publications involving immunogen priming and driving NAbs were discussed. Most in the field recognize that more than one HIV immunogen will be required and sequential immunizations. Priming and boosting immunogens will be needed to induce bNAb development. These must engage the germline, drive affinity maturation to potentially accelerate the immune response to yield Ab with neutralizing activity. Several studies were summarized that proved the proof of concept of this approach in different sophisticated mouse models. SHIV models as tools for bNAbs were discussed. A key point was that mutation patterns in NHP compared to humans who make bNAb were very similar or identical indicating that this may not be a random event and could serve as a "molecular guide" to vaccine design.

Future directions were next discussed that centered on efforts to support acceleration of Ab manufacturing and other "delay areas." To summarize, vaccine concepts in clinical testing, the Pox Protein (P5) trial, Janssen Collaboration, and Antibody Mediated Protection (AMP) studies were briefly discussed. Importantly, it is unclear if bNAbs can prevent HIV acquisition and testing this concept is done as part of the AMP study. The VRP programmatic update concluded by reviewing the 2016 VRP workshops.

Discussion

Q: For the RV144 trial, did the strategy change for the adjuvant?
A: Yes. A problem with RV144 is the durability of the effect. So, the adjuvant was changed from alum to MF59 to induce a more durable Ab response. The immunogens were also modified so that the ALVAC inserts would reflect relevant Clade C sequences for the regional population being studied in South Africa.

Q: Should the reference finding be discounted?
A: Fundamentally we are aware. This has been incorporated into the design. This is complicated and would require a much longer conversation. There is data supporting MF59 that may not have seen.

Q: Is there data in the Clinical Center from VRC01 that did not work?
A: Fundamentally, we think that HIV infection and treating chronically infected individuals are very different. Having neutralizing antibodies on board in the right place at the right time should confer protection from HIV which is actually very inefficient at transmission. But we will only get the answer through study.

Prevention Sciences Program (PSP)
Sheryl Zwerski, D.N.P.

The high-level PSP objectives, the networks and programs involved to achieve the objectives, the accomplishments of the previous year, and future directions were overviewed. The PSP comprises four branches and, in general, in collaboration with other institutes seek to:

• Reduce HIV incidence in population at risk
• Improve treatment as prevention by optimizing testing, linkage to care and treatment cascade
• Support development of low-cost point of care (POC) assays
• Improve HIV treatment in pregnant women, adolescents, children, and infants
• Support efforts in diagnosis, prevention, and treatment of TB and other co-infections in the maternal/child population.

The major programs and networks that achieve these goals were outlined:

1. Contract Resources for Microbicides and Prevention (CRMP) which was awarded in 2016
2. Mucosal Environment in HIV Prevention (MEHP)
3. Preclinical Innovation Program (PIP)
4. Integrated Preclinical/Clinical Program (IPCP)
5. Sustained Release of ARV for Treatment and Prevention
6. Methods for Prevention Packages Program (MP3)
7. Increased Knowledge and Innovative Strategies to Reduce HIV Incidence (iKnow)
8. HIV Prevention Trials Network (HPTN)
9. International Maternal Pediatric and Adolescent Clinical Trials (IMPAACT)
10. Microbicide Trials Network (MTN)

Key program highlights were discussed and included PROMISE which showed a high infant survival rate of 98.9 percent; the ASPIRE dapivirine intravaginal ring trial results were discussed at CROI to determine a way forward. From this, the HOPE trial was initiated which is an open-label, follow-on trial where women can decline use of the dapivirine ring without being removed from the trial. A different way of adherence counselling would be examined in this study.

Future studies beyond 2017 included:

1. A focus on sustained release products
2. Focus on multi-purpose prevention technologies
3. Consideration of requiring future products to provide systemic protection regardless of the delivery platform
4. Improve the understanding of the context between prevention mucosal and population level
5. The use of simulation science and other innovations to improve decision making regarding large trial
6. Increase focus on adolescent prevention
7. Improve treatment and prevention cascades
8. Formulate and test integrated prevention strategy packages
9. Focus on achieving appropriate safety and PK/PD of new ARV for pregnant women, children, and adolescents
10. Partner with other DAIDS programs, NIAID divisions to transform TB diagnosis, prevention, and treatment for pregnant women and children

Discussion

Q: What do you foresee as any consent or ethical issues when working on prevention in children?
A: It is a huge problem due to the regulatory and legal issues surrounding research for individuals under 18 years of age or the age of consent in a particular country. But, it has been done following lots of negotiation at several sites in the U.S. in the Truvada PrEP study of the Adolescent Trials Network and the MTN023 dapivirine ring study where 15 to 17 year old young women took part. Subsequently, workshops were held on this issue with members from the IRB and FDA and ethicists. Due to the complexities of the issue, conversations should be continued together with these representatives and possibly with ministries of health and also emphasize that a third of all new infections in 2015 occurred in adolescents 15 to 24 years of age.

Q: What have been the barriers to getting new drugs into the pediatric and adolescent population?
A: There is a certain amount of inertia, or at least delay, built into the current system. We have engaged in consultations regarding what is required to move drug studies into younger children in order to streamline and speed up the process. The FDA and WHO have said that efficacy seen in adults meant that one could assume efficacy in children. Therefore, large time-consuming efficacy trials in children will not always be needed and only basic safety and PK information would be required for children to move forward. Going slowly has been seen as a means to protect the children, but they also need the new optimized drugs as much as adults so moving forward quicker would be actually better for them.

VII. Adjournment

The meeting of the Council adjourned at 4:25 p.m., on Monday, January 30, 2017.

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.