NIAID Council Minutes: September 21, 2015

The 181st meeting of the National Advisory Allergy and Infectious Diseases Council (NAAIDC) convened at 2:05 p.m. on Monday, September 21, 2015, 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 12:30 p.m. and from 2:05 p.m. to 4:30 p.m. The meeting was closed to the public from 8:30 a.m. to 10:15 a.m. and from 2:00 p.m. to 2:05 p.m. 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. Report of the Allergy, Immunology, and Transplantation Subcommittee—Daniel Rotrosen, M.D., director, DAIT
IV. Report of the Microbiology and Infectious Diseases Subcommittee—Carole Heilman, Ph.D., director, DMID
V. Joint Meeting of the AIDS Subcommittee and AIDS Research Advisory Committee (ARAC)–Carl Dieffenbach, Ph.D., director, DAIDS
VI. 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 4,646 research and training applications with primary assignment to NIAID for a requested amount of $1,291,281,564 in first-year direct costs and recommended approval of 2,093 applications with $535,363,996 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 three ad hoc Council members, Dr. Raul Andino, professor in the Department of Microbiology and Immunology, University of California, San Francisco; Dr. Donna Farber, associate director of the Columbia Center for Translational Immunology, Columbia University Medical Center; and Dr. John Kearney, distinguished professor of microbiology, University of Alabama School of Medicine in Birmingham.

Three Council members, Drs. Norman Baylor, Gurjit Khurana Hershey, and Chris Wilson, were unable to attend the meeting.

Dr. Fauci acknowledged the contributions of four retiring Council members—Drs. Adaora Adimora, Mavis Agbandje-McKenna, Jonathan Karn, and Georgia Tomaras—and presented them with plaques and certificates of appreciation for their service.

Consideration of Minutes of Previous Meeting

Council considered the minutes of the May 18, 2015 meeting and approved them as written.

Staff and Organizational Changes

Dr. Fauci announced some temporary staff reassignments because of personnel changes in the Department of Health and Human Services.

On October 1, Dr. John McGowan will begin serving a six-month assignment as interim NIH deputy director for management on a half-time basis. He will temporarily replace Dr. Colleen Barros who is on a detail as HHS assistant secretary for administration until a permanent assistant secretary is hired.

Dr. Jill Harper, NIAID associate director for science management, will take on some of Dr. McGowan’s responsibilities during this time.

Dr. Kathryn Zoon stepped down as director of NIAID’s Division of Intramural Research. Dr. Hugh Auchincloss, NIAID’s principal deputy director, will serve as acting director until a permanent director is selected.

Dr. Fauci mentioned several other recent high-level NIH retirements and appointments. Dr. Alan Guttmacher retired as director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Dr. Catherine Spong, NICHD deputy director, is acting director while a national search is conducted for a permanent replacement.

On November 1, Dr. Thomas Insel will step down as director of the National Institute of Mental Health. Dr. Bruce Cuthbert will serve as acting director while a national search is carried out to find a permanent director.

In June, Dr. Walter Koroshetz was appointed the new director of the National Institute of Neurological Disorders and Stroke. Dr. Koroshetz replaces Dr. Story Landis who retired last October.

Dr. William Riley, who served as the acting director of the NIH Office of Behavioral and Social Sciences, was appointed as permanent director.

On July 1, Dr. Jack Whitescarver stepped down as director of NIH’s Office of AIDS Research. Dr. Robert Eisinger is serving as acting director while a search is underway for a permanent director.

Dr. Sally Rockey left her position as NIH deputy director for extramural research. Dr. Larry Tabak is acting director until a replacement is chosen.

Ms. Adrienne Hallett has been named NIH associate director for legislative policy and analysis.

In NIAID’s Division of AIDS, Dr. Joseph Fitzgibbon was selected as chief of the Drug Development and Clinical Sciences Branch in the Therapeutics Research Program.

Dr. Richard Williams is now chief of the Immunology and Emerging Infections Branch in NIAID’s Technology Transfer and Intellectual Property Office.

Tributes and Awards

Dr. Fauci paid tribute to Dr. William Paul, chief of the Laboratory of Immunology since 1970, who recently passed away. Dr. Paul was best known for his groundbreaking work on T-cell and cytokine biology, including his discovery of interleukin-4. He was director of the NIH Office of AIDS Research from 1994 to 1997. Dr. Paul received many awards and honors over his long career and will be greatly missed.

Last month, Dr. Allen Cheever, formerly of the Laboratory of Parasitic Diseases, passed away. Dr. Cheever’s lifelong interest in schistosomiasis led to many discoveries related to the pathogenesis of the disease.

Dr. Fauci paid tribute to former Congressman Louis Stokes who died last month. In June 2001, NIH dedicated Building 50 as the Louis Stokes Laboratories to commemorate his strong support of biomedical research. Congressman Stokes believed NIH, through its research, could help reduce health disparities among poor, disadvantaged, and underserved populations.

The online magazine Politico named three NIAID scientists among the 50 top thinkers, doers, and dreamers in 2015 for their work on Ebola—Drs. Nancy Sullivan, Julie Ledgerwood, and Cliff Lane.

In June, Dr. Josh Milner, chief of the Genetics and Pathogenesis of Allergy Section in the Laboratory of Allergic Diseases, received the 2015 Phadia Allergy Research Forum Award, an international honor sponsored by Thermo Fisher Scientific.

Meetings and Events

In May, the United Nations Economic and Social Council convened its 2015 Partnerships Forum. Dr. Fauci participated in a panel discussion “Partnerships in Support of Strengthening Health Systems: Building Resilience to Pandemics.” The discussion focused on the Ebola outbreak in West Africa.

In June, Dr. Fauci briefed Leslie Dach, senior counselor to HHS Secretary Sylvia Burwell, and other HHS officials about NIAID’s Ebola work at NIH and in Africa. Dr. Fauci gave them a tour of the Special Clinical Studies Unit in Building 10.

Chinese Vice Premier Liu Yandong and other high-ranking officials visited NIH in June to renew a memorandum of understanding on emerging and re-emerging infectious diseases. HHS Secretary Burwell and NIH Director Dr. Francis Collins hosted the event, which included a symposium on Ebola.

Also in June, Dr. Fauci participated in two Aspen Ideas Festival Spotlight Health panel discussions, one on infectious diseases and the other on the looming antibiotic crisis.

Over the summer, NIAID, the Pan American Health Organization, and the World Health Organization cohosted a three-day interdisciplinary research workshop “Expert Consultation on Chikungunya Disease in the Americas.” During the workshop, experts shared knowledge about the epidemiology and pathogenesis of Chikungunya disease, assessed the risk of an epidemic throughout the Americas, identified critical knowledge gaps, and discussed potential collaborative research opportunities.

In July, Dr. Fauci and several NIAID staff members met with representatives of the Japan Agency for Medical Research and Development (AMED) to introduce the newly established organization to NIH leadership. At the meeting, they discussed the future of AMED and interactions it might have with NIH, and NIAID in particular.

Also in July, Dr. Agnes Binagwaho, minister of health in Rwanda and Harvard Medical School senior lecturer, delivered the Barmes Global Health Lecture “Medical Research and Capacity Building for Development: The Experience of Rwanda.”

Budget Update

In February, President Obama released his FY 2016 budget request to Congress. The FY 2016 budget request provides NIH with a 3.3 percent or $1 billion increase over FY 2015. However, 65 percent of the increase is for earmarks that direct NIH institutes to address specific research areas. The remaining 35 percent is allocated to fund additional research project grants.

NIAID’s increase is the largest among the institutes but is composed entirely of earmarks.

NIH most likely will start FY 2016 operating under a continuing resolution that usually extends funding at the same level as the previous fiscal year. Two issues associated with passing the FY 2016 budget that still need to be addressed are caps on discretionary spending and the debt ceiling.

NIAID will begin FY 2016 with a conservative funding 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 competing grants and initiatives. Initially we will fund noncompeting grants at 90 percent of committed levels, and once we have a final budget, we will restore these to their full commitment amount. Our estimated success rates for research project grants will be between 20 and 23 percent.

Legislative Update

On May 27, Dr. Fauci briefed a staff delegation from the Senate Health, Education, Labor, and Pensions Committee about the activities of the Special Clinical Studies Unit at the NIH Clinical Center. He updated them on the significant role that the Unit played in addressing the ongoing Ebola outbreak.

On June 18, Dr. Linda Lambert, chief of the Respiratory Diseases Branch, DMID, and her colleagues briefed Senator Sheldon Whitehouse’s staff on clinical research to advance candidate vaccines and therapeutics conducted at NIAID’s Vaccine and Treatment Evaluation Units.

On July 1, Dr. Carl Dieffenbach, director, DAIDS, provided information on the research contributions of our Multicenter AIDS Cohort Study to staff of Senate Minority Whip Dick Durbin.

On July 2, Dr. Dennis Dixon, chief of the Bacteriology and Mycology Branch, DMID, briefed House Majority Leader Kevin McCarthy’s staff on NIAID’s plans to collaborate with CDC and Duke University to conduct a randomized controlled trial of a treatment for the fungal disease, coccidioidomycosis. On August 27 at the Third California Coccidioidomycosis Collaborative Meeting of state and local public health officials, Dr. Dixon gave an update on implementing this trial.

On July 23, Dr. Lambert participated in a multiagency briefing on Middle East Respiratory Syndrome coronavirus (MERS-CoV) for staff of the House Energy and Commerce Committee. She provided a similar MERS-CoV briefing for Senate Health, Education, Labor, and Pensions Committee staff on July 31.

On September 16, Dr. Carole Heilman, director, DMID, briefed Representative Christopher Smith on NIAID’s Lyme disease portfolio.

On September 17, Dr. Cliff Lane, deputy director for clinical research and special projects, updated staff of the Senate Appropriations Committee on the progress of our Ebola clinical trials in West Africa.

Congress is pursuing legislation designed to advance the pace and progress of medical research and innovation. On July 10, the House of Representatives passed the 21st Century Cures Act, which would reauthorize NIH and create an NIH and Cures Innovation Fund that would provide $1.75 billion a year in mandatory funding to NIH for five years. The Senate is working on a related initiative, with details expected later in 2015.

Other Information Items

Dr. Fauci began with an update on Ebola and a reminder that it’s the one-year anniversary of when the first U.S. Ebola patient arrived in Texas. He presented updated statistics on the total number of cases and deaths in West Africa and showed that the new confirmed and probable cases of Ebola infections per week have gone down dramatically.

Dr. Fauci acknowledged Dr. Cliff Lane’s work on Ebola over the last year 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.

Dr. Fauci gave an update on research that NIAID’s intramural program is doing on MERS-CoV, which includes vaccine and therapeutic studies. He concluded with a brief update on HIV/AIDS, including information about several HIV/AIDS conferences and results from studies.

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

Dr. Rotrosen welcomed the subcommittee members to the 181st meeting of the National Advisory Allergy and Infectious Diseases Subcommittee meeting.

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

Staff and Organizational Changes

Ling Li, Ph.D. Dr. Li joined the Office of Regulatory Affairs in May 2015 as a regulatory officer. She received her Ph.D. in microbiology from the University of Alabama at Birmingham, and completed post doctorate training at the Department of Pharmacology, Yale University. Dr. Li is a Diplomate of the American Board of Toxicology and has extensive experience in drug discovery and development across multiple therapeutic areas working in the pharmaceutical industry. Dr. Li has experience in microbiology, immunology, pharmacology, pharmacokinetics and toxicology, and was responsible for filing several INDs for drug candidates in infectious disease, immunologic diseases, and metabolic disorders.

Amanda Rudman Spergel, M.D. Dr. Rudman Spergel joined DAIT as a medical officer in the Allergy, Asthma, and Airway Biology Branch in August 2015. She received her medical degree from The Pennsylvania State University College of Medicine and completed her residency training in internal medicine at the George Washington University School of Medicine and Health Sciences. Previously, Dr. Spergel was a clinical post-doctoral fellow at the Allergy and Immunology Clinical Training program and has been a member of the Laboratory of Host Defenses, Genetic Immunotherapy Section. Dr. Rudman Spergel is board certified in internal medicine and allergy and immunology.

Frosso Voulgaropoulou, Ph.D. Dr. Voulgaropoulou returned to DAIT as a program officer in the Autoimmunity and Mucosal Immunology Branch (AMIB) in May 2015 after spending 12 years in the Targeted Interventions Branch in DAIDS. She originally joined NIAID as a program officer in the Asthma, Allergy, and Inflammation Branch in 2002. In her new position with AMIB, she assumes responsibility for programmatic activities in primary immunodeficiency diseases.

Scientific Initiatives

Request for Information (RFI): Input on NIAID Data Sharing Repository, Immunology Database and Analysis Portal (ImmPort), and Services (NOT-AI-15-045): NIAID’s Division of Allergy, Immunology, and Transplantation (DAIT) is seeking input from the research community with expertise and interest in public data repository management and services.

Mucosal Immunology Studies Team (MIST) (U01) (RFA-AI-15-023): The purpose of this funding opportunity announcement (FOA) is to solicit applications from institutions proposing studies to break new ground in understanding of immune defense mechanisms and immune regulation at the mucosal surfaces. The program is to discover and define novel basic immune mechanisms, cells, mediators, and pathways that provide a more complete understanding of mucosal immune defense mechanisms; to explore innovative hypotheses; and to address difficult unsolved questions in mucosal immunity.

Asthma and Allergic Diseases Cooperative Research Centers (U19) (RFA-AI-15-032): This FOA invites applications from single institutions or consortia of institutions to participate in the Asthma and Allergic Diseases Cooperative Research Centers (AADCRC) program. The program will support 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.

Division Activities

Understanding Host Defense in Atopic Dermatitis. On May 8, 2015, NIAID organized a symposium on host defense in atopic dermatitis as part of the annual Society of Investigative Dermatology Meeting in Atlanta, Georgia. The session highlighted data from the NIAID-supported Atopic Dermatitis Research Network and related atopic dermatitis research. Experts in the field presented lectures on the role of the microbiome in atopic dermatitis (AD), adaptive immunity in AD and its implications for management of recurrent infections, skin barrier defects in AD, and innate immune responses in AD.

The Early Evolution of Asthma: From Birth to Disease Expression. On May 18, 2015, NIAID organized a session on the early evolution of asthma from birth to disease as part of the annual meeting of the American Thoracic Society, in Denver, Colorado. Inner City Asthma Consortium researchers presented data from the Urban Environment and Childhood Asthma birth cohort, describing the development of asthma and the immune system from birth to age 7 years. Additional data was presented from the Asthma Phenotypes in the Inner City study, describing the asthma phenotypes identified by this study in mid-childhood to adolescence.

Improving the Treatment for Allergic Rhinoconjunctivitis and Asthma Through Allergen Immunotherapy. On June 17, 2015, NIAID and the Agency for Healthcare Research and Quality (AHRQ) cosponsored a workshop entitled “Improving the Treatment for Allergic Rhinoconjunctivitis and Asthma Through Allergen Immunotherapy” in Rockville, Maryland. The workshop was organized in response to a 2013 AHRQ comparative effectiveness review entitled “Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma.” The report identified a number research gaps including: 1) the need for direct comparison of sublingual versus subcutaneous immunotherapy, 2) the need to compare single allergen versus multiple allergen immunotherapy, 3) the need to assess whether immunotherapy has a disease-modifying activity in preventing the atopic march in young children, and 4) the need to assess, study, and define optimal immunotherapy dosing strategies and schedules. The workshop featured a summary of the state of the science and presentations and discussion on study designs addressing the four identified knowledge gaps.

Prevention and Treatment of Food Allergy and Tolerance Induction.On June 18, 2015, NIAID sponsored a workshop entitled “Prevention and Treatment of Food Allergy and Tolerance Induction” in Rockville, Maryland. Results of the Learning Early About Peanut Allergy study tested the preventive efficacy of early introduction of peanut in the diet of infants at high risk for peanut allergy. Participants offered input on the most appropriate next steps in the design and execution of studies to prevent other types of food allergy. Presenters described potential new avenues for research on immune tolerance in the context of allergy. The workshop concluded with a general discussion of strategies and potential problems for the induction of immune tolerance in allergic diseases.

Keystone Conference on “The Arthropod Vector – Controller of Transmission.” From May 12 to 17, 2015, NIAID organized a Keystone conference in Taos, New Mexico. The goal was to discuss the contribution of arthropod vectors to the transmission of vector-borne infectious diseases. Topics included immunomodulation by vector saliva, the skin’s immune response to vector-borne pathogens, and vector immunity to human pathogens they transmit. Two major focus areas of the conference were the exploration of novel strategies to interfere with vector-borne pathogen transmission by targeting vectors or vector-derived factors, and novel opportunities for collaborations between investigators from complementary research areas. Researchers from 15 countries attended the conference.

Infant Immunity Program Annual Meeting. On August 26 to 27, 2015, the third annual meeting of the Infant Immunity Program was held in Rockville, Maryland. DAIT and DMID jointly support 15 projects in this program, with 2 projects funded by DMID and 13 projects funded by DAIT. Investigators and project staff presented updates and recent achievements in understanding aspects of innate and adaptive infant immune development and regulation, mucosal immunity, and immunoregulatory mechanisms in the infant lung. The meeting provided a venue for investigators to exchange ideas and establish collaborations to foster advances within the program.

Immunity in the Elderly Annual Meeting. On September 4, 2015, the second annual meeting of the Immunity in the Elderly program was held in Vienna, Austria (preceding the Immunosenescence: Hot Topics and Interventions satellite meeting of the European Congress of Immunology, September 5 to 9). NIAID and the National Institute on Aging (NIA) jointly support this program; NIAID funds five projects and NIA funds three. The goal of this program is to develop a better understanding of the immune mechanisms involved during the aging process that contribute to impaired immune responses and result in severe infections and dampened responses to vaccines in this population. Investigators discussed progress in their project goals, challenges and strategies in recruitment of research subjects, and their future goals.

Preparation and Review of Your NIH Grant Application Workshop. On June 26, 2015, NIAID led a workshop at the annual meeting of the Federation of Clinical Immunology Societies (FOCIS) in San Diego, California, aimed at enhancing junior investigators’ understanding of the preparation and peer review of NIH grant applications. The workshop, organized and led by staff from the Autoimmunity and Mucosal Immunology Branch and NIAID’s Scientific Review Program, featured a mock peer review session conducted by FOCIS investigators and NIAID staff, followed by a question-and-answer session and discussion.

NIAID/BARDA 2015 Pediatric Acute Radiation Syndrome Medical Countermeasures (MCM) Conference. On June 10, 2015, NIAID and Biomedical Advanced Research and Development Authority (BARDA) held a conference on pediatric acute radiation syndrome in Rockville, Maryland. Speakers focused on the scenarios that would occur in a radiological or nuclear emergency including pediatric populations, FDA regulatory considerations and challenges, pediatric animal model development, clinical requirements, and product development in the context of a pediatric population.

2015 Annual Meeting of the Centers for Medical Countermeasures Against Radiation (CMCR). On June 23 to 24, 2015, the CMCR annual meeting was held in Rockville, Maryland. CMCR investigators presented the research progress made during the entire funding period of their programs. The meeting also facilitated continued dialog and collaboration among the CMCR investigators and program staff regarding future research and development directions.

Kickoff Meetings for BAA-NIAID-DAIT-NIHAI2014001. On June 9 and June 22, 2015, contract initiation meetings were held in Rockville, Maryland for two newly awarded contracts within the Radiation and Nuclear Countermeasures Program (RNCP). Contractors from LignaMed, LLC, a company developing a synthetic flaxseed active component to minimize pneumonitis and fibrosis from radiation exposure to the lung, presented an overview of their preliminary data and planned statement of work. On June 22, contractors from BCN Biosciences presented their early studies and plans to test their novel compound, 512, to mitigate radiation-induced early and late lung injury.

NIAID/IRSN Meeting on Cellular Therapies for Treatment of Radiation Injuries. On July 28 to 29, 2015, the NIAID RNCP cohosted a meeting with the Institute of Radiation Nuclear Security (IRSN) in Paris, France. Twenty-seven invited speakers and moderators discussed the regulatory and logistical challenges, as well as the potential benefits of using stem cell therapies as treatments for the different sub-syndromes of radiation injury, including hematopoietic, gastrointestinal, lung, and skin. The meeting organizers plan to generate a consensus document for publication to more widely disseminate the content and recommendations from the meeting.

NIAID/BARDA Medical Countermeasures Portfolio Update Meeting. On June 25, 2015, members of the NIAID RNCP met with program managers responsible for radiation medical countermeasures development at the Biomedical Advanced Research and Development Authority (BARDA). The purpose of the meeting, requested by the HHS assistant secretary of preparedness and response, was to provide programmatic transparency, insure that the funded research programs at each sister agency are aligned, and that there is no scientific overlap between the two portfolios.

Division Advisory Council Presentation

Alison Deckhut-Augustine, Ph.D., Basic Immunology Branch, presented a Report on The Developing Infant Immune System.

Alkis Togias, M.D., Allergy, Asthma, and Airway Biology Branch, presented In Search of Allergic Disease Prevention: Current NIAID Considerations.

Donna L. Farber, Ph.D., professor, Columbia University Medical Center, presented Compartmentalization and Functional Regulation of Infant T Cells in Tissues.

John F. Kearney, Ph.D., distinguished professor, University of Alabama School of Medicine, presented Long-Term Effects on Emerging B Cell Repertoire in Neonatal Exposure to Environmental Organisms Dampen Allergic Airway Disease and Type 1 Diabetes Later in Life.

Concepts Presented for Clearance

FY 2017 Research Concept Clearances

Cooperative Study Group for Autoimmune Disease Prevention (CSGADP): The long-term goal of this program is to develop the knowledge base necessary to design interventions for the prevention of autoimmune disease that could be administered efficiently and safely to individuals at risk or to the general population, including infants and children. While such interventions might also be useful in established disease, the focus of this program is on prevention rather than therapy. For the purpose of this initiative, "prevention of autoimmune disease" is defined as halting the development of an autoimmune disease prior to clinical onset by means other than systemic immunosuppression.

The subcommittee endorsed and unanimously approved this initiative.

Allergen Epitope Validation Resource: The objectives of this request for applications are to:

1. Continue identifying T-cell epitopes of major allergens associated with food allergy, asthma, and allergic rhinitis.
2. Characterize T-cell epitope-induced responses in accurately phenotyped populations of patients with the above allergic conditions.
3. Identify T-cell epitopes that can be targeted for immunotherapeutic approaches or can serve as predictors of natural history or responses to treatment.

The subcommittee endorsed and unanimously approved this initiative.

Immunity in Neonates and Infants: This initiative will support research to define the ontogeny of immune responses in neonates and infants and mechanisms to understand their limited immune effector functions to infections and vaccinations. Information obtained from this program may be applied to the design of improved vaccines and therapies to combat infections in these populations.

The subcommittee endorsed and unanimously approved this initiative.

IV. Report of the Microbiology and Infectious Diseases Subcommittee—Carole Heilman, Ph.D., director, DMID

Director’s Report

Dr. Carole Heilman, director of the Division of Microbiology and Infectious Diseases (DMID), chaired the NIAID Microbiology and Infectious Diseases Council Subcommittee meeting on September 21, 2015. Dr. Heilman referred to the branch chiefs and office directors to introduce new staff in their respective programs. Dr. Heilman then recognized Dr. Raul Andino, who joined the Subcommittee as an ad hoc member. Dr. Andino is a virologist and professor at the University of California, San Francisco in the School of Medicine, Department of Microbiology and Immunology. Following introductions, Dr. Heilman provided a brief report on the U.S. Government Policy for Institutional Oversight of Life Sciences Dual Use Research of Concern, which will take effect on September 24, 2015.

Program, Scientific, and Budget Updates

Update: NIAID Partnerships Program Review

Dr. Michael Kurilla, director of DMID’s Office of Biodefense, Research Resources, and Translational Research and NIAID associate director for biodefense product development, reported on NIAID’s recent Partnerships Program review. NIAID’s Partnerships Program, established more than a decade ago, has fostered many new research collaborations between experts from different disciplines of academia and industry to advance the preclinical development of candidate products to the investigational new drug (IND) application stage. In 2014, DMID enlisted an outside group to conduct a survey of investigators who received Partnerships Program funding support from 2002 through 2010 in an effort to assess the impact of the program on product development. A wide array of metrics, including technical validation, candidate product development status, and follow-on funding, were considered. Overall, the response rate was strong and the feedback from grantees was very positive; about 85 percent of the respondents credited the program with helping them to advance their product down the developmental pipeline. Dr. Kurilla shared a number of notable success stories.

Concepts Presented for Clearance

The following fiscal year 2017 concepts were presented to the Subcommittee:

Preclinical Models of Infectious Diseases: The objective of this concept is to support the development and refinement of, as well as access to, animal models to facilitate countermeasure development.

The Subcommittee enthusiastically supported the concept, emphasizing its importance in providing a critical resource to the research community. Comments and questions were divided equally between the scientific objectives of the initiative and the administrative processes for managing current and future awards. Subcommittee members asked about how the size and complexity of the current program is managed, how decisions are made regarding which models to develop, and if the current capacity is adequate to address the number of requests that are received. Program explained that this is a Division-wide program administered cooperatively by a team of program staff representing the different branches that are responsible for individual task orders. The process for qualification and selection of service requests is made available to the public on the NIAID website. Program further noted that this service is intended to assist investigators in filling gaps in their ability to pursue the development of their products, rather than an all-inclusive product development service. Subcommittee members inquired specifically about humanized mouse models and a MERS model in camels. Program indicated that these models are within the scope of the current contract and will be included in the scope of the new initiative. Finally, a Subcommittee member asked about other similar types of programs, and program cited this as the only program of this type that has the described breadth of scope. The concept was unanimously approved.

Discovery/Development of Novel Therapeutics for Eukaryotic Pathogens: The objective of this concept, a component of the NIAID Partnerships Program, is to stimulate discovery and validation of novel targets, and ultimately to identify novel therapeutics against eukaryotic pathogens.

The Subcommittee voiced strong support for the NIAID Partnerships Program, noting that it complements related DMID research and product development-related objectives and provides an important mechanism to assist academic and industrial communities with translational research and development efforts. In particular, the Subcommittee supported the programmatic effort to stimulate therapeutic discovery and development for eukaryotic pathogens of clinical concern. There was appreciation for the translational research opportunities enabled by recent advances in systems biology and development of synthetic disease models for these pathogens. One member noted that the focus on “underrepresented” pathogens was highly appropriate. The concept was unanimously approved.

Partnerships for Countermeasures Against Select Pathogens: The objective of this concept is to support preclinical development of countermeasures against select pathogens (NIAID Category B and C Priority Pathogens; Viral Hemorrhagic Fever agents).

The Subcommittee noted the importance of this type of NIAID Partnerships Program initiative, and recognized the role of the program in stimulating innovative translational efforts. One Subcommittee member requested insight on the relationship between this program and the NIAID SBIR program with regard to funding levels, budgets and applicant eligibility. Program pointed out that the two programs differ in a number of ways, including:

• The SBIR program is available only to qualified small-business applicants and therefore excludes many academic and foreign applicants, as well as some industry organizations. The Partnerships Program is open to most applicants and encourages applications from academic and foreign institutions, many of which are leading efforts in development of countermeasures against NIAID priority emerging infectious diseases.
• SBIR-funded projects typically involve two research phases with restricted budgets, each requiring submission of an application. Partnerships Program R01 awards can support up to five years of research/development.

The concept was unanimously approved.

Structural Genomics Centers for Infectious Diseases: The objective of this concept to apply state-of-the-art, high-throughput structural genomics technologies to experimentally characterize the three-dimensional atomic structures of targeted proteins from organisms that cause infectious diseases; provide the scientific community with resources to characterize molecular functions and biochemical properties of selected targets; and perform structure-guided target discovery.

The Structural Genomics Centers for Infectious Diseases (SGCIDs) concept was enthusiastically received by the DMID Subcommittee. The Subcommittee commended DMID on the outstanding productivity and accomplishments of the SGCIDs since their inception in 2007. A Subcommittee member asked about interactions between the SGCIDs and the Protein Structure Initiative (PSI) funded by the National Institute of General Medical Sciences (NIGMS). Program explained that SGCIDs are complementary to the PSI initiative, and there have been coordinated activities and information exchange between the two programs. Another Subcommittee member commented that fostering greater interactions with the scientific community will further enhance the value of protein structures for advancing basic and translational research in infectious diseases. Program informed the Subcommittee that such interactions were already taking place through collaborations and outreach activities, and would continue in the future. A suggestion was made to encourage the use of emerging new technologies, such as cryo-electron microscopy, for structure determination. Overall, the Subcommittee recognized the value of the SGCIDs to the scientific community, and enthusiastically supported renewal of the SGCID program. The concept was approved with a unanimous vote.

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

The AIDS Research Advisory Committee met on Monday, September 21, 2015, from 10:30 a.m. to 4:40 p.m., at the Natcher Conference Center on the NIH campus in Bethesda.

Participating members included: Stephen W. Mason (Chair), Amanda Castel, Sharon L. Hillier (by phone), Earnest Hopkins, Jonathan Karn, David O’Connor, William G. Powderly, Georgia Doris Tomaras, Deborah Persaud, and John Guatelli; ex officio members included Victoria J. Davey and Jonathan Mermin (by phone). NIAID representatives included Carl Dieffenbach, Emily Erbelding, Mary Marovich, Sarah Read, Diana Finzi, Manizhe Payton, Carol Worrell, and Sheryl Zwerski. Mark Mueller served as executive secretary.

Those not present included: Henry Masur, Col. Nelson Michael, and Chris Wilson.

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

Dr. Mason welcomed everyone. ARAC members approved the minutes of the May 18, 2015 ARAC meeting. [Note: Director’s Report and Office of AIDS Research Advisory Committee (OARAC) Update were not given due to new agenda time constraints.]

Concepts Presented for Clearance

Vaccine Research Program (VRP)

NIAID Preclinical Development Support: Dr. Michael Pensiero explained the objective for this third program iteration is a flexible contract mechanism supporting activities needed to avoid a funding gap and advance clinical research reagents or highly promising HIV prophylactic vaccine candidates into clinical research trials. There will be one award for a duration of seven years. He described activities to be supported, provided a brief history of the contract, and discussed selected accomplishments. In response to the reviewers’ request for information on the process by which CMOs are selected and the need to emphasize the quality assurance process of immunogen production, Dr. Pensiero explained the sequence of the process for accessing PCMC resources, resulting in the final quality release of products by DAIDS. Reviewers, Dr. Georgia Tomaras and Col. Nelson Michael, recommended approval. Dr. Pensiero answered further questions regarding size of contracts and amounts expended over the program duration. He clarified that funding must be available to cover any options that might be exercised. The last request for proposals had $82 million obligated, but spent $70 million because some options were not exercised. Regarding prioritization, he explained VDRG does a technical assessment to see if proposals makes scientific sense. Dr. Pensiero then collates the assessments and prepares an executive summary so the VRP director and DAIDS director can decide how that fits in the DAIDS portfolio. Big ticket items are discussed within NIAID leadership; a transparent, internal, collective decision-making process.

ARAC members voted to accept the concept, marked their ballots, and passed them to Mark Mueller.

Ballot Voting Outcome

• Approved                                           11
  Approved with modifications                 0
  Deferral with further information            0
  Disapproval                                         0

Staged Vaccine Development (SVD): Dr. Michael Pensiero explained the objective to rapidly commence manufacture of promising candidate vaccines showing safety and immunogenicity in preclinical/early clinical trials for use in advanced clinical trials. There will be two to three awards for a seven-year duration; the request was also for a three-year approval to reissue annually. The Vaccine Research Program’s unmet needs are: 1) advancement of promising HIV vaccine candidates quickly and efficiently into manufacturing when needed and 2) preservation of established partnerships (e.g., academic-industry), given the uncertain commercial environment for supporting HIV vaccine development.

The reviewers, Dr. Tomaras and Col. Michael, had asked for clarification of activity types that would and would not be supported by this mechanism, including costs. Dr. Pensiero explained the SVD process, pointing out that with support the Phase I immunogenicity evaluation would move on to advanced development: SVD Stage I, completion of a product development plan and initiation of activities to prepare for Current Good Manufacturing Practice (CGMP) manufacture ($200,000 total for up to two years), after which there would be a go/no-go decision. If go, the process moves on to SVD Stage II, down-selection, process/analytical assay development, CGMP manufacture, formulation, and release of product for clinical trials ($5 million/year for three years). Then onto SVD Stage III, continuation of ongoing stability program, storage of materials and data, and updating regulatory submissions ($2 million total for two to three years). He listed six lead HIV vaccine platforms, and explained that unlike the HIV Vaccine Design and Development Team (HVDDT) and the Integrated Preclinical-Clinical AIDS Vaccine Development (IPCAVD), the SVD will be more limited in scope to support exclusively the manufacture of candidate vaccines, especially for advanced development. Both reviewers recommended approval.

Q: Stage I seems small and long compared to other activities. How did program come up with that amount for two years?
A: They are not locked into two years, and the $200K is a nominal amount to put a contract mechanism into place, which can be modified later, if necessary.

Q: Could a product development plan be started from the beginning to overlap with Stage I?
A: There needs to be a carrot for industry’s side, since it can take 1½ years to get the data and therefore the $200K will provide that incentive. Yes, there could be an early development plan.

Q: Are the six products listed in the presentation the ones that will be funded and how/when will they be prioritized?
A: Most likely. As the direction of the research shifts, the pre-selected platforms will change over the next iterations of the SVD.

ARAC members voted to accept the concept, marked their ballots, and passed them to Mark Mueller.

Ballot Voting Outcome

• Approved: 10
• Approved with modifications: 1
• Deferral with further information: 0
• Disapproval: 0

B Cell Immunology Program for HIV-1 Vaccine Development (BCIP): Dr. Malaspina explained that this program’s purpose is to encourage multidisciplinary teams to explore and exploit complexities and developmental plasticity of B cells for inducing potent, durable, and protective adaptive immune responses against HIV-1. This initiative will support basic and preclinical research and clinical samples analysis to evaluate parameters critical for programming desired B-cell functions. Projects will be hypothesis driven and mechanistic in nature. She discussed the roles of B cells and the function of antibody (Ab) molecules in providing layers of protection, but pointed out that little is known about how B-cell subsets may be controlled or the molecular reprogramming of antigen (Ag)-specific memory B cells, or how to modulate and maintain Ab effector functions. She provided examples of past B-cell initiatives, and pointed out that the B-Cell Help Immunology Program (BCHIP) program announcement has not attracted many prominent B-cell immunologists to the HIV-1 research field.

Reviewers, Dr. Tomaras and Dr. Wilson, through their written comments, described this initiative as exciting and much needed, offering two suggestions: 1) increase funding level for each award to support a productive union between basic B-cell immunologists and HIV-1 vaccine scientists. More money per award should result in more scientific synergy; 2) ask for the response to HIV-1 to be benchmarked against the response to other infectious agents or model systems in order to determine the degree to which the biology is general or specific to HIV-1 and other systems. Program plans to reduce the number of R01s from two to five to two to three, and will add to examples of responsive research studies that benchmark the response to HIV-1 immunogens against the response to other infectious agents of model systems. Reviewers recommended approval.

Dr. Mason said the comparative aspect of the request for applications (RFA) should be a bigger component, since there is a lot known about B-cell vaccinology in response to HBV and HPV antigens. Though there may be special circumstances why they are protective, a lot could be learned with respect to tolerance from these other infection systems. Dr. Malaspina said that component can be strengthened.

Regarding co-PIs, Dr. Tomaras noticed the word “encourage” was added, but suggested language such as “highly encouraged, but not required.” She said it is possible prominent B-cell immunologist may not want to be a co-PI, and this raises R01 issues regarding leadership. They may just want more money for their lab without having a young investigator as co-PI. Dr. Malaspina said they would consider a change of language.

Dr. O’Connor thought a lot of HIV research drives B-cell immunology. He asked if there is disconnect between B-cell immunologists and HIV T-cell immunologists. Dr. Dieffenbach explained that within DAIT, they have a huge set of programs using classic ova and other immunogen sets, including vital microscopy, to see what is going on within lymph nodes. To be able to further exploit this would be the advantage of such collaborations. The more DAIDS can attract such applicants, the better its B-cell immunology will be. He added that if ARAC members want to back off on requiring dual PIs, they should write this on their ballots.

Dr. Mason said having dual PIs would make a stronger collaboration, since both PIs would be responsible for the research. Dr. Dieffenbach added that in part this is a peer review issue. When an RFA committee reviews it, if there are no preliminary data and no evidence of collaboration, those grants scored poorly. The collaboration will have to have been already formed, and there is a need for preliminary data on a grant of this size, so a letter definitely will not be sufficient. The other issue is the percent of effort. One could get by with a lower percent effort if one were not co-PI, and that would still have a profound impact on the grant.

Dr. Karn asked if there are plans for co-assessment of funding. Dr. Dieffenbach said the program was co-developed and cofunded. The relationship has gotten stronger over the years. He clarified that for this particular grant, there is no cofunding, but there is in related programs.

Dr. Malaspina emphasized that now is a good time for collaboration and agreed to the idea to highly encourage, but not require co-PIs. Dr. Dieffenbach pointed out that the Office of AIDS Research (OAR) has been an essential component in this process. Dr. Malaspina added that OAR has also been part of the organizing committee for all of the recent sponsored meetings that brought together immunologists and HIV-1 experts.

ARAC members voted to accept the concept with modification to encourage but not require co-PIs, marked their ballots, and passed them to Mark Mueller.

Ballot Voting Outcome
Approved                                          2
Approved with modifications               9
Deferral with further information          0
Disapproval                                       0

Nonhuman Primate Cellular Immunology for AIDS Vaccine Research and Development: Dr. Nancy Miller explained the objective to provide cellular immunology laboratory support for AIDS vaccine studies conducted under NIAID’s Simian Vaccine Evaluation Unit (SVEU) contracts; to ensure assay standardization and comparability of studies. This is a renewal for one seven-year award. The Nonhuman Primate (NHP) Cellular Immunology Core Laboratory conducts high quality, standardized assays to evaluate cellular immune responses in AIDS vaccine studies conducted in NHPs. These assays are essential for the evaluation of the immunogenicity of candidate vaccines and for potentially identifying immune responses responsible for controlling virus replication and/or reducing risk of acquisition in immunized NHPs. The centralized laboratory assays ensure data standardization and comparability across studies. Assessments can confirm the immunogenicity of HIV vaccines prior to clinical testing in human efficacy trials. Cellular immune responses at mucosal sites can be consistently evaluated in the NHP model, something difficult to do in human trials. Dr. Miller reviewed the current contract and listed several vaccine studies conducted in NHPs for which the NHP Cellular Immunology Lab has conducted assays.

Reviewers, Dr. O’Connor and Col. Michael, asked how protocols developed under this award are shared with the community, and how the lab provides training to interested investigators. Dr. Miller explained the current contractor has transferred the ELISpot assay to outside investigators, and she pointed out the new contract requires transfer of assays to investigators upon request on an ad hoc basis. Reviewers also asked how the lab will be integrated into dialogues on assay comparability, best practices, and innovative approaches, and how the awardee will interface with other consortia that are measuring cellular immunity in NHP vaccine studies. Dr. Miller said that in the new contract, the contractor will be asked to invite investigators with relevant assay expertise to participate in annual contract site visits, either as advisors or as panel participants, and that the program will continue to facilitate contractor communications with multiple investigators in the course of the acquisition and conduct of assays for SVEU studies. In addition, there will be funding available for the contractor to participate in formal assay comparisons or quality assurance studies, if needed.

Finally, the reviewers asked how the lab will integrate with B-cell and humoral assay development that form the basis of innovative approaches, such as systems serology. Dr. Miller replied that the lab is acquiring capability to assess antigen-specific B-cell responses, to quantitate the cells, and eventually be able to look at the location of B cells that will generate antibodies. Further, in recognition of the increasing understanding of the interaction of humoral and cellular immune functions (in addition to neutralizing antibodies and CTLs), the current lab is working with investigators to acquire assays that measure antiviral functions provided by cells other than T cells. Dr. Miller said the new contract has requirements to acquire and conduct assays that measure cellular immune responses that can be triggered by SIV or HIV-specific antibodies. Reviewers agreed this program fulfills important functions and should continue.

Dr. Karn asked if there are plans for integration with some of the other primate core labs, and cited the NCI cores on NHPs, in virology and in situ hybridizations. He said he sees a convergence between HIV vaccines and some of the studies on therapeutic vaccines in NHPs.

Dr. Miller explained NIAID’s interagency agreement with NCI labs, and those labs have been looking at the number of transmitted viral variants, and they have sequenced those. She said there is a good deal of communication among investigators in the primate field. Many of these investigators already have these connections. This keeps everyone relevant and open to change when change is necessary. This helps ensure assays will be in place when needed.

Dr. Tomaras said the focus initially looked like it was on CD8, but there has been a step away from the use of ELISpot since that is not predictive of efficacy. She asked how this has kept in line with findings from human clinical trials, and if this has changed this program’s assays, such as looking at polyfunctional T cells, etc.

Dr. Miller said it has changed. It was originally set up with ELISpot, which gives an assessment of the relative strength of a cellular response, but ELISpot assay results have not been correlated with vaccine protection. The current lab has a flow cytometric core and has been working on setting up assays to assess T cell polyfunctionality within the contract. This program may be a little behind the human field. Some investigators in the SVEU supplied vaccine assays for the program’s studies, giving the program time to set up its own assays.

Dr. Mason asked if any of the vaccine concepts, after testing and evaluation with the assays used, have led to no-go decisions so they were not advanced to clinical trials. Dr. Miller said that they have recently completed a DNA/MVA study with Harriet Robinson that showed no protective benefit in the animals that received an immune modulator, GM-CSF with the vaccines. Dr. Robinson has eliminated the GM-CSF from the planned clinical trial. This type of study helps the field prioritize and advance.

Dr. Tomaras asked how data are managed and supported with all of these different vectors and platforms. Dr. Miller explained the core has its own data management system. They do not report raw data to the program, which receives the processed results. The program has a database that captures the structure of the studies and the vaccine immunization schedules, which allows the program to compare across studies. As they move into more flow cytometry-related assays, they may need to invest more in database support.

ARAC members voted to accept the concept, marked their ballots, and passed them to Mark Mueller.

Ballot Voting Outcome

• Approved: 11
• Approved with modifications: 0
• Deferral with further information: 0
• Disapproval: 0

Prevention Sciences Program

Risks of Adolescence and Injury in HIV Susceptibility (RAIS): Dr. Kristen Porter explained the objective to support anatomical and physiological basic science research into the injured anogenital tracts and mucosal environment of the adolescent. She discussed definitions of adolescent (14 to 19 years), trauma/injury, and wound healing, and pointed out increasing AIDS deaths in adolescents. She discussed the factors associated with adolescent anogenital injury/trauma in the U.S. and globally, pointing out the total percentage of HIV infections in U.S. adolescents (13 to 24 years-old) is 26 percent, whereas globally total percentage of infections in adolescents (15 to 24 years-old) is 40 percent. Violence correlates with HIV incidence, ranging from 20 percent to 90 percent. She discussed scientific gaps: studying adult and adolescent anogenital tracts; the effects of age and trauma/injury in the GI tract; virus interaction with wounded/healing mucosa; the process of wound healing/resolution and how this may negatively impact HIV susceptibility and the safety and efficacy of prevention products; and in vitro and animal models studying impact of trauma/injury and age on HIV susceptibility.

RAIS is part of an ongoing effort to understand how vaginal and colorectal mucosal changes impact HIV susceptibility and potential safety and efficacy of prevention products and their delivery systems. She identified adolescence and injury as potential modifiers of HIV susceptibility and discussed differences between pre-pubescent genital tissue and mature genital tissue, and the process of tissue injury response.

Reviewers, Dr. Adimora and Dr. Hillier, asked for clarification of targeted cohorts [e.g., adolescent boys, men who have sex with men (MSM), trauma to the gut] and their inclusion in clinical studies. Dr. Porter explained the FOA will include language clarifying these populations inclusion and emphasized GI tract changes due to maturation and injury are included in RAIS-supported research. Clinical research (not trials) will likely be difficult, given local laws protecting vulnerable populations (adolescents). She emphasized the RFA will state that applicants consult with specialists, and have in-depth institutional review board discussions prior to application submission to determine proposed research feasibility. Reviewers strongly supported this concept, but were concerned that the funding amount for such important research seems inadequate.

Dr. Tomaras asked if RAIS could look at adolescent mucosa; is it more receptive to a vaccine regimen, inducing types of immune responses, allowing maturation differently or faster than in a vaccinated adult. Dr. Porter said there is possibility, but RAIS doesn’t support vaccine research.

Dr. Adimora said investigators involved in women’s health have called for this type of research for years, and young MSM investigators should also call for this type of research. She applauded program clarification of the concept, saying this will increase application numbers and quality.

Dr. Hillier reiterated that reviewers felt strongly this is an underserved topic and are unsure what application types program will get; the RFA is broad and covers anal/rectal and general sexual violence, as well as adolescents. It will be interesting to see if this RFA type generates better research and more focused effort at the intersection between these populations and enhanced HIV susceptibility. She praised program for ensuring that there is good feasibility for any type of clinical sample collection, given complexity of working in sexual violence and adolescence.

Dr. Karn had concern that a hypothesis has not been investigated; namely, that there is a physiological difference in susceptibility to infection related to age. Just because incidence is higher, which may be because of risk behavior, does not mean there is a physiological difference enhancing susceptibility. Dr. Karn said program may lose out if it pushes the hypothesis too hard. Dr. Porter said there may not be a physiological difference; it may be all behavioral. However, tenofovir metabolism is more rapid in adolescents than in adults. In terms of drug development, this could be important. RAIS is sufficiently broad to promote investigator innovation.

Dr. Mason saw an opportunity for comparative studies, because in the case of HPV, vaginal as well as anal transmission have clear correlates with wounding and wound healing that might lead to some understanding for HIV. He worries about the difficulty of finding appropriate cohorts for clinical research. He does not think the analogy to tenofovir is applicable because that is only a metabolism effect, and metabolism in that case has nothing to do with the anogenital tract. Dr. Porter said that depends on how the drug is delivered. In some cases, it is delivered directly into the anogenital tract. Regarding the cohort, she said in the RFA they have specific language about sexually transmitted infections that have a correlation with HIV infection. She agreed it is difficult to get these cohorts, but program provides examples that illustrate it is possible.

Dr. Castel emphasized the importance of establishing increased susceptibility of anogenital tract infection. Getting a quantitative sense of the extent of exposure is going to be very important. Dr. Dieffenbach ensured appropriate language to that effect. Dr. Castel said another issue is feasibility for inclusion; the HVTN has extensive experience enrolling these participants. The program can draw on that experience so these individuals can be engaged in clinical trials.

ARAC members voted to accept the concept, marked their ballots, and passed them to Mark Mueller.

Ballot Voting Outcome

• Approved: 8
• Approved with modifications: 1
• Deferral with further information: 1
• Disapproval: 0

NIAID Office of Global Research

U.S.-China Biomedical Collaborative Research Program and U.S.-Brazil Biomedical Collaborative Research Program: Mr. Handley presented the jointly funded initiatives with counterpart organizations in China and Brazil. Objectives are to increase U.S. scientists’ access to infectious disease and immunology opportunities; complement U.S. scientists’ research funding; stimulate cofunding for U.S. scientist-identified research priorities and projects; facilitate collaboration with local partner assistance; foster long-term basic, clinical, and translational research collaboration.

The U.S.-Brazil collaboration is new. The U.S.-China collaboration is a renewal. Proposed award duration is three years with Brazil and five years with China. The number of awards is to be determined. He discussed drivers of NIAID international engagement, activities to enhance international engagement, criteria to select cofunded program partners, and the overall review and funding model. He provided a summary of the first five years of the U.S.-China Joint Collaborative Research Program (2011 to 2015), and outlined the proposal for the next five years including participating ICs, opportunities, and research areas. He covered the same areas outlining the U.S.-Brazil proposal.

Funding for U.S.-China has NIH funding up to $5 million/year total. NIAID ~$1 million/year. NSFC: complementary funding.

Funding for U.S.-Brazil has U.S. program partners up to $3.5 million/year. Brazilian partners: complementary funding.

Reviewers, Dr. Hammer and Dr. Powderly, recommended approval, requesting program:

• Clearly delineate types of research allowable (basic, clinical, translational, etc.)
• Be specific on pathogens and scientific areas of research that would be responsive
• Be clear about what would be excluded (e.g., clinical trials)

Dr. O’Connor asked if any component of the mechanism might streamline the Brazilian regulatory approval process to make initiating projects easier, once funding is decided. Mr. Handley said one reason for developing this program was to develop trust and understanding that would encourage the Brazilians to change onerous regulatory requirements. He explained that the regulatory requirements that cause most delay only apply when foreign funding is awarded to a Brazilian investigator. In this program, no NIH funding is awarded to the Brazilian investigator so the special foreign-funding regulatory review is not triggered. The Brazilian investigators will be supported by a grant from the Brazilian National Council for Scientific and Technological Development (CNPq).

Over the last two years, Brazil’s understanding of the challenges the U.S. faces, led to some process streamlining. He explained that process improvements are especially difficult because the review process is to a large degree driven by legislative requirements. We hope this joint program will continue to encourage improvements.

Dr. Mason asked how discrepancies in scoring between U.S. and China are resolved. Mr. Handley explained that there is a negotiation process so that only applications found meritorious by both NIH and China’s National Natural Sciences Foundation (NSFC) are funded. Over the first five years of the U.S.-China program, scoring discrepancy diminished. In part, because NSFC review quality has improved as they understood and utilized NIH criteria.

ARAC members voted to accept the concept, marked their ballots, and passed them to Mark Mueller.

Ballot Voting Outcome (U.S.-Brazil)

• Approved: 10
• Approved with modifications: 0
• Deferral with further information: 0
• Disapproval: 0
  (1 reviewer did not mark a ballot)

Ballot Voting Outcome (U.S.-China)

• Approved: 11
• Approved with modifications: 0
• Deferral with further information: 0
• Disapproval: 0

Basic Sciences Program (BSP)

Limited Interaction Targeted Epidemiology (LITE): Dr. Gerald Sharp presented this proposed new initiative’s purpose to support research to better predict people who will become HIV-positive in the U.S. by creating and following extremely large cohorts of the HIV-negatives at highest risk of infection. Duration of awards will be two years initially; with an additional three years of funding if seroconversion milestones are met. First year total cost will be $4 million. The estimated number of awards is four to six. Dr. Sharp explained the problematic consistently high incidence of HIV infections in the U.S. and the question of how to target prevention efforts to the highest risk subgroups. A first step considers the CDC 2013 U.S. surveillance rates of HIV infection diagnoses per 100,000 population among adults and adolescents by sex and race/ethnicity, which shows the highest incidence rates among men for black/African American males and among women for black females. Men who have sex with men (MSM) account for 81 percent of annual HIV diagnoses among men or 84 percent if MSM who inject drugs are included. Among females, the major risk group is heterosexuals at 86 percent. Targeting black, Hispanic, and white MSM addresses 80 percent of the male HIV epidemic and 95 percent of the MSM epidemic. Targeting black heterosexual women addresses 53 percent of the female epidemic and 62 percent of the female heterosexual epidemic.

He asserted that the solution is extremely large, limited interaction (electronic) cohort studies, which are less expensive than face-to-face studies, more scalable, avoid enrollment bias, reduce the Hawthorne effect, reduce socially desirable responding, and are not geographically constrained. He referred to studies showing feasibility of electronic cohorts among MSM and black women. Eighty-five percent of those 18 to 29 years of age own smart phones and 97 percent have internet access. He discussed the LITE program goals and a milestone-driven, two-phase process.

Reviewers were Dr. Adimora and Dr. Castel. Dr. Adimora recommended approval, with modifications, commenting that using electronic methods to enroll and follow large numbers of MSM is good, but questioned whether it would work for black women. Dr. Sharp replied that electronic enrollment and follow-up are not required and applicants must demonstrate feasibility of their methods and meet seroconversion goals. Dr. Adimora recommended limiting MSM to black men because of high incidence rates. Dr. Sharp responded that limiting the initiative to black men would capture only 35 percent of the male epidemic and 41 percent of the MSM epidemic; program prefers broader inclusion of men. Dr. Adimora’s suggested program ensures grantees have referral programs for identified seropositives. Dr. Sharp said grantees must demonstrate appropriate referral mechanisms.

Dr. Castel recommended approval and commented:

• Six to eight grants to be supported by a total of $4 million is not enough.
• The need for a large sample size to find seroconverters may result in recruiting people from disparate geographic and social networks and make it harder to address the prevention epidemiology research goals.
• Recruitment of black women using these methodologies may be difficult.
• Limit MSM to black men.

Dr. Sharp replied:

• Program reduced the expected grant number to four to six grants (annual total costs of $666,000 to $1 million per grant).
• Even if cases come from disparate geographic areas, there may be an underlying behavior link that might be addressed through prevention, especially if electronic methods are used. Generalizability of the cohort findings will be a reviewable criterion.
• There is no requirement that black women be recruited electronically (alternative ways might include: health fairs, mobile testing venues, free clinics, hairdressers, churches, and social meeting sites and, as suggested by one of the reviewers, black women visiting their loved ones in prison). Although not required, the large sample size needed may mean subjects are followed electronically due to the high cost of face-to-face visits.
• While the female epidemic is concentrated in black women, among men considerable risk remains among all MSM.

The main topics of the ensuing discussion were:

• The primary focus should be on young black MSM and black women.
• Making the program too restrictive will discourage innovative proposals.
• It has always been difficult to recruit black men, and it is crucial that NIAID demonstrates that DAIDS grants are focused on those at highest risk.
• What is needed is multiple steps in the milestones.
• Have clear targets around seroconversion; program needs to enroll minority populations.
• Getting large populations through innovative recruitment processes would allow investigators to look at subpopulations.
• Some concern over a required minimum rate of seroconversion because it might lead to over-enrollment of populations with higher rates and, therefore, little sampling of underrepresented populations. Need balance between seroconversion rates, inclusion of diverse populations, and go/no-go decisions across these parameters.
• If ARAC votes deferral, it will have exactly the same discussion in January. The purpose of this initiative is to create new and innovative, robust methods. The key part is: can you get the target population?

As a result of this discussion, Dr. Dieffenbach restated the proposed modifications:

• There should be a milestone seroconversion rate.
• Bounds will be set on recruitment.
• There will be a milestone at the end of year one that if investigators are not getting the appropriate populations, their grant will be ended.

ARAC members voted to accept the concept, marked their ballots, and passed them to Mark Mueller.

Ballot Voting Outcome

• Approved: 0
• Approved with modifications: 9
• Deferral with further information: 0
• Disapproval: 1
  (1 reviewer did not mark a ballot)

Prevention Sciences Program

Prevention Innovation Program (PIP): Dr. Turpin presented the objective to support innovative proof-of-concept/feasibility research to advance fields of microbicides, pre-exposure prophylaxis (PrEP), nonvaccine biomedical prevention, and multipurpose prevention technologies (MPT). This is an R01 renewal. First year cost will be $1.8 million. Duration of awards will be four years. Number of awards will be two to three. The total cost per award will be $400,000. Objectives and goals are harmonized with other downstream prevention programs. Dr. Turpin noted that this is the third PIP initiative iteration, and he reviewed the overarching research goals.

Dr. Turpin described the role of PIP in the prevention pipeline, discussed its place in the historical context of innovative prevention programs, and reported on the PIP program status. The PIP III scientific objective is to create a sustainable pipeline of prevention products.

Dr. Turpin explained that age-appropriate formulation strategies (AFS) are being developed because of the growing proportion of HIV infections that are occurring in adolescents. He said there are known metabolic, physiological, and behavioral differences that could impact product safety, efficacy, and adherence in infants, children, and adolescents. Until now formulation development for infants and children has consisted primarily of adapting adult formulations for use, rather than purpose formulating for the appropriate age, weight band and acceptability desires. He reviewed AFS objectives.

Dr. Turpin said that a potential win-win situation is that inclusion of the AFS objective in the PIP offers a unique opportunity to explore formulation science and drug delivery technologies in these populations. Comparing PIP III to past PIP iterations, he showed:

1. No significant change in the structure of the applications.
2. Maintained scientific focus from previous iterations.
3. Added supporting age-appropriate formulation strategies (AFS) as a new PIP scientific focus.

Reviewers, Dr. Hillier and Dr. Karn, asked if biotech/industry have a role in the RFA. Dr. Turpin said the program includes language to encourage biotech/industry to participate in all RFAs. In PIP I and II biotech/industry partners were active collaborators in 50 percent of awards, and in 63 percent of awards, the program obtained compounds from large pharmaceutical companies, which maintain active communications with the grant team. Regarding the AFS objective, both reviewers supported inclusion of adolescents, but expressed concern that the concept needs to be very clear on the role of infants and children in the AFS due to the very different inherent risks associated with these populations. Program acknowledged these issues and modified the concept to address this concern. Dr. Turpin said that although there are physical, practical, and theoretical challenges associated with inclusion of AFS and these populations in the PIP, program perceives this high-risk/innovation research as offering a unique chance to:

• Initiate development of novel drug delivery methods for the AFS populations with an established funding mechanism (PIP) that has a history of supporting innovative formulation research.
• Determine if AFS research is feasible using the PIP/Innovation program approach.

Regarding appropriateness of this approach for adolescents, Dr. Mason wondered if the answer has to do with RAIS, in terms of developing a cohort of high-risk children, and not just utilizing them for those types of studies but moving them into testing PIP formulations. Dr. Turpin said they are trying to bring them into the PIP because the PIP looks at mechanisms of transmission susceptibility and connecting that to the development of the product. So they are echoing some of the same language as the RAIS for wound healing and wound resolution. Theoretically, RAIS would come first and PIP would follow it. They hope for synergy between the two programs. This could help investigators think about next steps using both mechanisms.

Dr. Powderly read age-related development as one area, noted that age-related developments is one relevant research area, but not a requirement. Program may get applicants that fail in review from difficulty of doing those studies. Is it advisable to carve it out separately? Dr. Dieffenbach said program discussed it internally and think it’s a good first experiment. They will monitor it, and if there is a need, they can carve it out in a future initiative.

Dr. Turpin said program has developed milestones to measure potential success or failure of the AFS, so they should be able to make the decision regarding whether PIP is the appropriate venue for the AFS. Dr. Mason said the other issue is maintaining the interest of large pharma, especially with so few of them in this arena. It is increasingly difficult to get new drugs. He asked if there is a chance of a connection with the new drugs synthesis taken up at the last ARAC. Dr. Turpin said they moved away from doing new drug synthesis within PIP. They relied more on in-silico methods to try using existing libraries potentially to identify new molecules. For treatment, it can be difficult to get access to drugs, but for an entryway program such as PIP, they have not had difficulty getting large pharma to give investigators access to what he calls their “wastebasket” drugs. Development gets more difficult when they go into the Integrated Preclinical/Clinical Program, where there is clinical development discussion.

ARAC members voted to accept the concept, marked their ballots, and passed them to Mark Mueller.

Ballot Voting Outcome

• Approved: 11
• Approved with modifications: 0
• Deferral with further information: 0
• Disapproval: 0

Therapeutics Research Program (TRP)

Advancing HIV Therapeutic Vaccine Science: Dr. Stephen Smiley presented the objective to identify and optimize immune responses that can be induced by vaccines to sustainably suppress viral loads in HIV-infected individuals. This is a new initiative, with a duration of five years, a first-year total cost of $4 million, and an estimated two to three awards. He explained prior clinical trials have been disappointing and a more systematic approach is needed. Natural responses to infection are ineffective and immune dysregulation is prevalent during chronic infection. However, there are some promising avenues:

• T cells
  • CD8 T cells are implicated in natural protection by elite controllers
  • CD4 T cells are implicated in post-treatment control (VISCONTI)
• NK cells
  • Implicated in post-treatment control (VISCONTI)
• B cells
  • bNAb and ADCC look promising for preventive vaccines

The approach will be to:

• Propose a desired immune response and vaccination strategy
  • Hypothesis-driven; mechanistic
• Run small, multi-arm, comparative trials in virologically-suppressed individuals
  • First trial must start within 12 months of award
  • Enrollment milestones will be required and enforced

To identify and optimize responses, investigators will:

• Measure the quality, quantity, and durability of responses at baseline compared to those elicited by vaccine regimens
• Correlate immune and virologic responses
• Work iteratively to improve responses

These small, iterative trials focused on vaccine-inducible control and correlates fill a DAIDS portfolio gap.

Both reviewers, Dr. Wilson and Dr. Hammer, recommended approval. Dr. Wilson, in a teleconference with program staff, commented that the gap to be addressed is the lack of nimble, iterative, and head-to-head early stage human comparisons of candidate vaccines, adjuvants, and immune modulators or combinations. Regarding starting the first trial within 12 months of award, he said he strongly favors relaxing this requirement for subsequent trials. He also urged program to foster stronger idea and preliminary results sharing with the most closely related of the other DAIDS initiatives and to be open to adaptive, as well as comparative, trial designs. Dr. Smiley said program agrees.

Dr. Hammer said requiring the first clinical trial to start within 12 months of award essentially limits the applicant pool to those with a product ready for testing in humans, or imminently so. He asked if there could be some flexibility in this requirement so that truly innovative approaches will not be missed. Dr. Smiley emphasized that to ensure timely initiation of trials, the program wishes to retain this requirement. The iterative nature of the research should ensure incorporation of innovative strategies. Dr. Hammer also suggested that the FOA should make clear how this program differentiates itself from the other DAIDS programs, and regarding immune assays, make clear that applicants should strive for innovation. Dr. Smiley said program agree and will address them in the FOA.

Dr. Karn expressed concern about overloading this program with reservoir measurements, which will complicate many of the trial designs. Dr. Smiley explained that they are not going to prescribe which assays the investigators need to include. He said they would like to see some reservoir measurements included, but in his opinion, the residual viremia measures will be more relevant for this initiative.

Dr. Mason said there is great opportunity here to take things that have been in the clinic and do combination studies. That will be key here, because many previous therapeutic vaccines and immunomodulators have proven to be ineffective in clinical studies when tested alone, but they may become effective when two are used together. He thinks Dr. Karn is correct in warning program away from the types of reservoir measurement assays that require leukapheresis, especially if multiple leukapheresis are necessary since it is very expensive.

Dr. Karn said applicants may think this initiative expects trials to include treatment interruptions, so program may want to comment in the RFA. Dr. Smiley said they did not want to exclude them, but will make it clear that this should not be the primary virologic endpoint. Rather, there need to be quantitative measures short of treatment interruptions. Dr. Mason said that if the program sees stellar movement or functional immune measurements during some trial, then they might be tempted to support a treatment interruption.

ARAC members voted to accept the concept, marked their ballots, and passed them to Mark Mueller

Ballot Voting Outcome:

• Approved: 11
• Approved with modifications: 0
• Deferral with further information: 0
• Disapproval: 0

Other Business

Dr. Dieffenbach said that in January, the OAR process will be further along, so it will be useful for ARAC to hear the current state of where this process has ended up. Additionally, two OARAC meetings will have occurred. One is coming up in November focused on HIV vaccines, so there will be a fair amount of that type of activity. Also, at the January meeting there will be the usual program highlights about where we are on research on each of the respective programs―vaccines, prevention, and therapeutics. There will also be a Strategic Working Group meeting January 26 to 27. In closing, Dr. Dieffenbach thanked Dr. Adimora, Dr. Tomaras, and Dr. Karn for their service as they rotate off ARAC.

VI. Adjournment

The meeting of the Council adjourned at 4:30 p.m., on Monday, September 21, 2015.

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.