NIAID Council Minutes—September 9, 2019

The 193rd meeting of the National Advisory Allergy and Infectious Diseases Council (NAAIDC) convened at 10:30 a.m. on Monday, September 9, 2019, 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 4:32 p.m. The meeting was closed to the public from 8:30 a.m. to 10:15 a.m. and from 11:45 a.m. to 12:00 noon for review and consideration of individual grant applications. Notice of the meeting was published in the Federal Register.

Meeting Attendees

Member Group

Present

Absent

Council Members

  • Dr. Raul Andino
  • Dr. Michael Brenner
  • Dr. Mark Feinberg
  • Dr. Ana Fernandez-Sesma
  • Dr. Amita Gupta
  • Dr. Sally Hodder
  • Dr. Stanley Lemon
  • Dr. Robin Patel
  • Dr. Anuradha Ray
  • Dr. Gwendalyn Randolph
  • Ms. Kay Whalen
  • Dr. Cara Wilson
  • Dr. Marc Jenkins
  • Dr. Karen Nelson

Ad Hoc Members

  • Dr. Raif Geha
  • Dr. Donald Leung
 

Ex Officio Members

  • Dr. Jay Butler
  • Dr. Victoria Davey
  • Dr. Anthony Fauci
  • Lt. Col. Wendy Sammons-Jackson

NIAID Senior Staff

  • Dr. Carl Dieffenbach
  • Dr. Emily Erbelding
  • Dr. Matthew Fenton
  • Dr. Cliff Lane
  • Dr. John McGowan
  • Dr. Daniel Rotrosen
 

Table of Contents

I. Review of Grant Applications
II. Remarks of the Director, NIAID—Anthony S. Fauci, M.D.
III. Guest Speaker—Steven Holland, M.D., director, Division of Intramural Research, NIAID
IV. Report of the Allergy, Immunology, and Transplantation Subcommittee—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 Subcommittee and AIDS Research Advisory Committee (ARAC)–Carl Dieffenbach, Ph.D., director, DAIDS
VII. Adjournment

I. Review of Grant Applications

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

Funding Actions: The Council reviewed 4,762 research and training applications with primary assignment to NIAID for a requested amount of $1,711,753,831 in first-year direct costs and recommended approval of 2,069 applications with $662,003,616 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. Raif Geha, James Gamble Professor of Pediatrics at Harvard Medical School and chief of the Division of Allergy, Immunology, Rheumatology, and Dermatology at Boston Children’s Hospital, and Dr. Donald Leung, Edelstein Chair of Pediatric Allergy-Immunology at National Jewish Health and professor of pediatrics at the University of Colorado.

He also welcomed Dr. Jay Butler, CDC deputy director for infectious diseases, who is the new CDC ex officio member on the Microbiology and Infectious Diseases Subcommittee, replacing Dr. Rima Khabbaz.

Council members Dr. Marc Jenkins and Dr. Karen Nelson were unable to attend the meeting.

Dr. Fauci acknowledged the contributions of four retiring Council members—Drs. Raul Andino, Sally Hodder, Karen Nelson, and Cara Wilson—and presented them with plaques and certificates of appreciation for their service.

Consideration of Minutes of Previous Meeting

Council considered the minutes from the June 3, 2019 meeting and concepts that had been presented and approved them.

Appointments and Transitions

United Nations Secretary-General António Guterres appointed Winnie Byanyima as the executive director of the Joint United Nations Programme on HIV/AIDS, known as UNAIDS.

Staff and Organizational Changes

In the Division of Extramural Activities, Dr. Jay Radke is the new director of the Scientific Review Program.

Dr. Andrea DiCarlo has been selected as the new associate director for radiation countermeasures research and emergency preparedness in the Division of Allergy, Immunology, and Transplantation (DAIT).

Dr. Paula Bryant is the new director of the Office of Biodefense, Research Resources, and Translational Research in the Division of Microbiology and Infectious Diseases (DMID), and NIAID associate director for biodefense product development.

Dr. Sophia Siddiqui has been detailed from the Division of Clinical Research to the Office of the Secretary, Office of Global Affairs, where she will be assigned to the U.S. Embassy in South Africa as health attaché. She will also serve as the regional HHS representative in southern Africa.

Dr. Jim Meegan retired after seven years as director of the Office of Global Research (OGR). Joyelle Dominique will serve as acting director of OGR.

Dr. Linda Birnbaum, longtime director of the National Institute of Environmental Health Sciences (NIEHS), announced her retirement. Dr. Richard Woychik, NIEHS deputy director, will serve as acting director while a national search is conducted for a new NIEHS director.

Dr. Paul Sieving, director of the National Eye Institute, recently retired. Dr. Santa Tumminia, NEI deputy director, will serve as acting director while a search for a new director is undertaken.

Tributes and Awards

Dr. Fauci paid tribute to two former NIH leaders who recently passed away: Dr. James Wyngaarden and Dr. Donald Lindberg. Dr. Wyngaarden, former NIH director, was appointed by President Ronald Reagan and served as NIH director for more than seven years. During his tenure, he led the early biomedical research response to the HIV/AIDS epidemic and the emergence of recombinant DNA technology and other controversial biotechnologies. Dr. Lindberg served as director of the National Library of Medicine for more than 30 years and is remembered for his pioneering work in applying computer technology to biomedical research and health information.

Meetings and Events

In June, Dr. Fauci took part in a one-on-one interview with Washington Post reporter Lenny Bernstein. The interview focused on the progress made in HIV research over the past 38 years, as well as the challenges that remain.

Also in June, Dr. Fauci participated in two Aspen Institute events. The first was an Aspen Health Strategy Group meeting on antimicrobial resistance, where he gave a talk on the history, scope, and drivers of antimicrobial resistance, and scientific approaches being undertaken to address the problem. Dr. Fauci then participated in an Aspen Ideas Festival panel on “Eliminating HIV: Progress, Possibilities, and Roadblocks.”

On June 26, Dr. Fauci discussed NIAID’s priorities, including HIV, Ebola, and other infectious diseases, at The Hill’s Future of Healthcare Summit.

On July 1, Dr. Fauci participated in a meeting on Transforming Vaccine Development at GlaxoSmithKline’s Rockville campus. The meeting brought together people from academia and the public and private sectors to address important strategic questions about vaccines and global health.

On July 30, Dr. Fauci spoke to National Press Foundation fellows about the outbreaks and epidemics that have occurred during his time as NIAID director, and some lessons learned from each. Topics included HIV/AIDS, West Nile virus, SARS, Zika, and Ebola.

Dr. Fauci videotaped a lecture discussing the role of biomedical research necessary to develop new interventions to eradicate malaria. The lecture was played on September 9 at an event in Geneva where The Lancet Commission on Malaria Eradication launched the Malaria Eradication Report.

In the last several months, international delegations and health officials from the World Health Organization, Poland, and India have visited NIAID to discuss areas of mutual interest.

Budget Update

The President’s proposed FY 2020 budget presented to Congress on March 11, 2019, included an overall funding decrease to NIH of 12.6 percent or $4.9 billion below the FY 2019 enacted level.

In June, the House passed an FY 2020 spending bill that would increase NIH’s overall budget by 5.1 percent or $2 billion compared to the FY 2019 budget. The NIAID budgeted amount represents a 5.2 percent increase of $285 million, which includes increases of $60 million for universal influenza vaccine research and $6 million to support the President’s initiative to End the HIV Epidemic in the United States within a decade. The Senate will debate and vote on the FY 2020 budget in mid-September.

NIH will start FY 2020 under a continuing resolution.

Dr. Fauci summarized NIAID’s FY 2020 interim financial management plan under a continuing resolution. Taking a conservative funding approach, our interim R01 payline will be the 10 percentile for non-new investigators and the 14 percentile for new investigators. NIAID does not plan to make programmatic cuts to noncompeting and competing grants. Competing research initiatives will be cut up to 20 percent from their planned budget levels. Our estimated success rates for research project grants will be between 19 and 22 percent.

Legislative Update

On June 13, Dr. Fauci and Dr. Barney Graham of the Vaccine Research Center (VRC) briefed Senator Edward Markey on advances in the development of a universal influenza vaccine, including information about the recent launch of the first-in-human trial of the VRC’s ferritin nanoparticle influenza vaccine candidate.

On July 15, members of the New Democrat Coalition visited NIH. Dr. Fauci, NIH Director Dr. Francis Collins, and other selected NIH leadership participated in a roundtable discussion with the representatives at The Children’s Inn. The representatives also visited the Clinical Center to meet with a patient at the NIAID Primary Immune Deficiency Clinic and learn how the Clinic provides patients with state-of-the-science treatment for rare immune deficiency diseases.

On July 29, the majority and minority clerks for the Senate Labor-HHS Appropriations Subcommittee visited NIH. Dr. Fauci updated them on NIAID research on universal influenza vaccines, antimicrobial resistance, Ebola, and the new initiative to End the HIV Epidemic in the United States.

Since the last Council meeting, NIAID leadership and staff have participated in Congressional briefings and events on potential pandemic pathogens, biodefense research, and food allergy.

Other Information Items

Dr. Fauci began with an update on the Ebola outbreak in the northeastern part of the Democratic Republic of the Congo, providing statistics on the number of confirmed cases and deaths. He noted the use of the ring vaccination approach of vaccinating contacts, and contacts of contacts, to try to prevent the disease from spreading.

Dr. Fauci then summarized the results of the PAmoja TuLinde Maisha (PALM) study, a randomized, controlled trial of four Ebola therapeutics (ZMapp, remdesivir, mAb114, and REGN-EB3). The independent monitoring board met and recommended early termination of the therapeutic trial because of favorable results with two of the four candidates; mAb114 and REGN-EB3 clearly were better than ZMapp and remdesivir.

He presented statistics on confirmed cases of acute flaccid myelitis (AFM) in the United States. NIH awarded a $10 million contract over five years to the University of Alabama at Birmingham to organize and implement an international, multisite study. Dr. Fauci highlighted two studies showing strong evidence of the causal role of non-polio enteroviruses, particularly enterovirus D68, as the etiologic agent in AFM.

In June, HHS Secretary Alex Azar and Department leaders attended a meeting at NIH to discuss how to implement the plan for ending the HIV/AIDS epidemic. NIH has bolstered funding for HIV implementation research in high-burden areas in the United States and is developing a community-based approach. Dr. Fauci presented some global statistics on HIV/AIDS infections and deaths, provided an update on the status of several ongoing trials, and noted his participation in some recent HIV/AIDS meetings.

Dr. Fauci concluded by giving brief research updates on tuberculosis, respiratory syncytial virus vaccine, type 1 diabetes, and autoimmune diseases.

III. Guest Speaker—Steven Holland, M.D., director, Division of Intramural Research, NIAID

Dr. Holland began by giving an overview of the Division of Intramural Research’s (DIR) activities over the last year, which include 637 publications and 220 ongoing clinical studies on site at NIH and international sites.

He reviewed DIR’s priorities, which are:

  • Transformative medicine and biomedical research
  • Bench-to-bedside research taking advantage of NIH’s Clinical Center, as well as domestic and international clinical sites
  • Responding to public health threats, including drug-resistant microbes and emerging viruses
  • Partnering to advance vaccines, therapeutics, and diagnostics for infectious and immunologic diseases

Dr. Holland mentioned DIR leadership changes that have occurred over the last year, along with personnel changes, including recent departures, new hires, recently tenured investigators, and new tenure-track investigators.

The NIH Equity Committee is considering a new proposal to limit laboratory chiefs to a finite duration of service as chief. The current proposal undergoing review is for three terms of four years each (12 years), with discussion after each term. After 12 years, the chief would step down and remain a senior investigator.

Dr. Holland announced recent honors received by DIR staff, including Dr. Yasmine Belkaid who received the 2019 Lurie Prize in Biomedical Sciences, Dr. Mike Lenardo who was elected to the National Academy of Sciences, Dr. Helen Su who received the 2019 Gale and Ira Drukier Prize in Children’s Health Research, and Dr. Maureen Goodenow who received the 2019 Esperanza Award. He also noted DIR staff elected to the American Association of Immunologists Distinguished Fellows Class of 2019–Drs. Anthony Fauci, Ron Germain, Susan Pierce, and Ethan Shevach.

Dr. Holland presented details about a new joint initiative between NIAID, the National Cancer Institute, and the National Heart, Lung, and Blood Institute, to create a single unified program so that every patient undergoing bone marrow transplantation for a nonmalignant disease at the Clinical Center gets cared for the same way by the same doctors and nurses. This approach will allow NIH to collate data and share protocols.

He concluded by highlighting some of DIR’s scientific research in the areas of monoclonal antibodies, microbiome, therapeutics, gene therapy, vaccines, and end-of-life issues.

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

Dr. Rotrosen welcomed the subcommittee members to the 193rd meeting of the National Advisory Allergy and Infectious Diseases Subcommittee meeting.

Dr. Rotrosen presented the following scientific and Division activities:

Staff and Organizational Changes

Andrea DiCarlo, Ph.D., became associate director for the radiation countermeasures research and emergency preparedness in August 2019. Dr. DiCarlo completed her M.S. in animal science in 1992 and her doctorate in cell biology in 1998, both from the University of Maryland, College Park. She then did a postdoctoral fellowship in bioelectromagnetics and radiation normal tissue injury at Catholic University, after which she became a member of their Department of Biology in 2002. In 2004, Dr. DiCarlo was hired as a program officer in NIAID’s radiation nuclear countermeasures program where she has worked for the last 15 years. Her expertise in radiation science and product development has been pivotal in the transition of more than 30 products to Biomedical Advanced Research and Development Authority (BARDA). Dr. DiCarlo has provided critical guidance on advanced product development and licensure under the FDA Animal Rule to academic and industry partners and has been a frequent consultant to other U.S. and international government agencies. She also currently serves as an associate editor for the Journal of the Radiation Research Society.

Patrice Becker, M.D., Dr. Becker joined the Allergy, Asthma, and Airway Biology Branch in August 2019, as chief of the Asthma and Airway Biology Section. Dr. Becker received her M.D. from the New York State program at Sackler School of Medicine, Tel Aviv University. She completed an internship and residency in internal medicine at the University of Maryland Medical Center, followed by postdoctoral clinical and research training in pulmonary disease and critical care medicine at Johns Hopkins University School of Medicine. She then spent 18 years as a faculty member in the Division of Pulmonary and Critical Care Medicine at Johns Hopkins, where her academic research focused on exploring mechanisms of acute and chronic lung injury and remodeling in response to various stimuli. For the last nine years, she was employed by small-mid size biopharmaceutical companies, evaluating anti-inflammatory and immune-modulatory drugs as therapies for autoimmune and rare disorders in multiple therapeutic areas, both in animal models and in randomized controlled clinical trials.

Patricia C. Fulkerson, M.D., Ph.D., Dr. Fulkerson joined the Allergy, Asthma, and Airway Biology Branch in August 2019, as a medical officer in the Food Allergy, Atopic Dermatitis, and Allergic Mechanisms Section. She completed the Medical Scientist Training Program at the University of Cincinnati College of Medicine in 2007 and continued her clinical training with a residency in pediatrics and fellowship in Allergy and Immunology at Cincinnati Children’s Hospital Medical Center. She joined the faculty at Cincinnati Children’s in 2012, where her research was supported by an independent R01-funded grant that focused on delineating the molecular program that orchestrates eosinophil development and functional responses. While at Cincinnati Children’s, Dr. Fulkerson’s clinical practice was focused on patients with eosinophil-associated disorders in the Cincinnati Center for Eosinophilic Disorders.

Angela Kibiy, B.S.N., M.P.H., Ms. Kibiy joined the Autoimmunity and Mucosal Immunology Branch (AMIB) in July 2019, as a nurse project manager. Ms. Kibiy received her Bachelor of Science in Nursing from the University of Eastern Africa-Baraton in 1998, an M.P.H. from Moi University in Eldoret, Kenya, in 2003, and a second M.P.H. from the University of Massachusetts at Amherst in 2012. Ms. Kibiy joins AMIB from the National Eye Institute (NEI) where she served as a research nurse specialist. Prior to her time at NEI, she worked as a nurse consultant and protocol coordinator for the Laboratory of Immunoregulation at NIAID. She also has served as a United Nations volunteer since 2016.

Nicholas Knowlton, B.S., Mr. Knowlton re-joined the Clinical Research Operations Program in July 2019, as a clinical protocol coordinator. Mr. Knowlton received his B.S. in Animal Science from Virginia Tech in 2001. He worked as a preclinical study technician at Covance before joining DAIT in 2005, where he was employed as a contractor supporting the DAIT Clinical Research Committee (DCRC). His duties included serving as a backup for safety reporting, assisting in the development of the DAIT clinical trials database, and other duties.

Selected Funding Opportunities

NIAID

Development of Vaccines for the Treatment of Opioid Use Disorder (BAA-DAIT-75N93019R00009): The objective of this funding opportunity announcement (FOA) is to develop innovative and safe multivalent opioid vaccines that protect against heroin and fentanyl. Anti-opioid vaccines would induce high-affinity antibodies that bind specifically to the target opioid and prevent it from crossing the blood-brain barrier, thus decreasing distribution of the opioid to the brain, blunting early peak exposure, and reducing neurotropic effects and opioid-induced respiratory depression. Awardees will conduct foundational vaccine development activities, including adjuvant screening, immunogen design, and elucidation of fundamental immune mechanisms required to induce protective anti-opioid antibodies. Vaccine candidates will be evaluated in appropriate animal models, and lead candidates will be selected for further testing. Investigational new drug application (IND)-enabling activities and current Good Manufacturing Practice (cGMP) production through early-stage safety and immunogenicity (Phase I) clinical trials of a lead vaccine candidate(s) will be supported.

Limited Competition: Nonhuman Primate (NHP) Radiation Survivor Cohort (RSC) (U01, Clinical Trial Not Allowed) RFA-AI-19-010: The purpose of this request for applications (RFA) is to support continued care for and conduct of specialized research using a unique nonhuman primate (NHP) population: specifically, the preservation, medical monitoring, study, treatment, and intervention in the development of late effects in NHP survivors of radiation exposure. These long-term studies on an NHP radiation survivor cohort will provide a critical understanding of the natural history of radiation exposures, including early and late injuries and disease development. Such research is essential because NHPs most closely resemble humans in their responses to radiation exposure. Application receipt date was May 31, 2019.

Centers for Medical Countermeasures Against Radiation Consortium (U19, Clinical Trial Not Allowed) RFA-AI-19-012: The purpose of this RFA is to support a national network of research centers for development of effective and comprehensive medical countermeasures applicable to all subsets of the civilian population in the event of a radiation incident. Scientific areas of interest include multidisciplinary basic and translational research to support the development of products to assess, diagnose, mitigate, and/or treat the short-, delayed-, and long-term consequences of radiation exposure during and following a radiation public health emergency. Application receipt date was May 31, 2019.

2019 NIAID Omnibus Broad Agency Announcement - Research Area 001: Development of Radiation/Nuclear Medical Countermeasures HHS-NIH-NIAID-BAA2019-01: The purpose of this broad agency announcement is to support the development of safe and effective medical countermeasures (MCMs) to mitigate and/or treat tissue injuries exposure to ionizing radiation from a radiological or nuclear incident, thereby leading to a reduction in radiation-associated morbidities and mortalities. Given the extent of damage sustained after a mass casualty incident, drugs are not expected to be mobilized from the Strategic National Stockpile (SNS) before 24 hours, hence the need for MCMs that are efficacious 24 hours or later post-exposure.

RNCP-Wide Dosimetry Guidance and Monitoring of Sources and Irradiation Protocols (Clinical Trial not Allowed) NIAID-NIH-RFP-NIHAI201800020: The purpose of this request for proposals (RFP) is to define a program-led strategy for respondents who can provide services, facilities, expertise and capabilities to develop a centralized dosimetry harmonization effort that fits the resources and circumstances of projects across the funded Radiation and Nuclear Countermeasures Program (RNCP) portfolio.

Radiation/Nuclear Medical Countermeasure Product Development Support RFP NIAID-DAIT-NIHAI201800019: The purpose of this RFP is to award a contract to an organization that will provide facilities, expertise, and capabilities to advance the development of radiation/nuclear MCMs for the mitigation or treatment of acute radiation syndrome/delayed effects of acute radiation exposure (ARS/DEARE), treatment of internal radionuclide contamination, and support for NIAID's biodosimetry efforts. This solicitation will support research and development of radiation and nuclear medical countermeasures towards approval, licensure, or clearance. The supported work will encompass studies performed in the drug development pathway as well as the administrative foundation necessary to facilitate and coordinate these activities in partnership with NIAID.

Division Activities

Allergy, Asthma, and Airway Biology Branch

Asthma Phenotypes’ Risk Factors and Role of Respiratory Viruses and Bacteria in Exacerbations: Lessons from the NIAID, NIH Inner City Asthma Consortium. On May 22, 2019, as part of the annual meeting of the American Thoracic Society (ATS), in Dallas, Texas, the NIAID-funded Inner-City Asthma Consortium (ICAC) organized a session entitled “Asthma Phenotypes’ Risk Factors and Role of Respiratory Viruses and Bacteria in Exacerbations: Lessons from the NIAID, NIH Inner City Asthma Consortium.” Two experts in the field presented findings on how phenotypes evolve between 7 and 10 years of age and the implication for asthma, distinct risk factors for asthma phenotypes in urban children, and pathways through which respiratory viruses and bacteria influence asthma exacerbations.

Asthma Prediction: New Findings from Cohorts. On May 20, 2019, as part of the annual meeting of the American Thoracic Society (ATS), in Dallas, Texas, NIAID supported a session entitled “Asthma Prediction: New Findings from Cohorts.” Three experts in the field presented findings from individual cohorts and discussed the interplay between maternal factors and the infant gut microbiota and the influence on the risk for allergic asthma, risk factors for respiratory infections and asthma phenotypes in rural and urban birth cohorts, and personalized asthma risk scores from the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPs) and Isle of Wight study.

Fungi in Allergic Airway Disease. On May 30 and 31, 2019, NIAID organized a workshop in Rockville, Maryland, to review and discuss the current state of knowledge on the role of environmental fungi in allergic airway disease (asthma and chronic rhinosinusitis). The workshop featured three sessions discussing 1) epidemiology and fungal pathogenesis, 2) type 2 immunity in allergic fungal disease, and 3) the role of fungi in sinusitis. A manuscript to summarize the workshop is planned.

Innate Lymphoid Cells (ILC): Development, Function, and Role in Allergy and Immune-Mediated Diseases. On June 12 and 13, 2019, NIAID organized a workshop in Rockville, Maryland, to review current knowledge of ILC subsets and their respective functions and roles in normal immune homeostasis and in initiating and maintaining chronic immune-mediated inflammatory diseases, including atopic diseases, and to identify gaps in knowledge and potential therapeutic targets to control these populations in disease situations. The workshop featured two sessions focused on 1) ILC development, differentiation, plasticity and function, and 2) the role of ILC2s in allergic diseases of the skin, airway, and gut. Discussions at the workshop aimed to identify knowledge gaps and approaches to furthering research in these areas, including the development of resources, tools, and reagents that may be needed to advance the field.

Autoimmunity and Mucosal Immunology Branch

Cooperative Study Group for Autoimmune Disease Prevention (CSGADP). On April 24, 2019, DAIT hosted the annual meeting of the Cooperative Study Group for Autoimmune Disease Prevention. The goal of the CSGADP is to develop the knowledge base necessary to design interventions to prevent human autoimmune diseases prior to clinical onset. Investigators funded by the core U01 grants of the CSGADP and by projects funded through the group’s Infrastructure and Opportunities Fund met to discuss their progress and map paths forward in furtherance of the group’s mission.

Viral Mechanisms in Rheumatic Disease. On June 17, 2019, a symposium was held in cooperation with the American College of Rheumatology at the Federation of Clinical Immunology Societies meeting in Boston, Massachusetts. Six invited speakers, including the current chair of DAIT’s Cooperative Study Group for Autoimmune Disease Prevention, discussed their research of potential viral triggers and mechanisms in autoimmune diseases.

Grantsmanship Workshop for Junior Investigators. On June 20, 2019, a workshop titled “Who’s Reading Your Application? How Study Sections are Created” was held at the Federation of Clinical Immunology Societies meeting in Boston, Massachusetts. Organized in cooperation with NIAID’s Scientific Review Program (SRP), this was the latest in a series of lunchtime Federation of Clinical Immunology Societies (FOCIS) workshops intended to educate immunology trainees in critical aspects of the NIH application and review process and provide a forum for their questions and concerns. Presentations from DAIT and SRP staff were followed by a productive general discussion, and several trainees solicited further interactions with DAIT staff after the workshop.

Mucosal Immunology Studies Team (MIST) (https://www.mucosal.org/). On June 13 and14, 2019, DAIT hosted the annual meeting of this cooperative agreement research program in Rockville, Maryland. MIST is composed of fourteen U01 Cooperative Agreement awardees who focus on discovery of novel immune mechanisms, cells, mediators, and pathways operating at the mucosal surface; exploration of innovative hypotheses; and tackling difficult unsolved questions in mucosal immunity. The MIST awardees presented their progress, provided constructive advice on ongoing projects, facilitated sharing of ideas and of newly developed tools, and developed new collaborations. The meeting also provided the awardees of the MIST Scholar Award an opportunity to meet the MIST members, discuss their Scholar Award projects, and receive feedback and advice.

Radiation and Nuclear Countermeasures Program

NIAID, DoD, NASA Interagency Neutron Radiobiology and Dosimetry Workshop. On March 7, 2019, NIAID organized a workshop in Rockville, Maryland. The objective of the meeting was to understand the state of the science for neutron radiobiology as it relates to NIAID, DoD, and NASA scenarios of interest. The meeting included discussions on the complexity of neutron exposures, current understanding of their biological effects, and where there are gaps in knowledge that limit the ability to estimate health impact. The outcomes of the workshop included an increase in awareness, so that experiments can be designed with harmonized neutron dosimetry for more effective and informative studies. The meeting included MCM developers from industry and academia, regulatory experts and government product managers. A written review of the material covered in the meeting is in preparation.

Annual U01 Radiation-Induced Vascular Injury Meeting. On March 19, 2019, NIAID held the U01 Annual Investigator Meeting “Elucidation of mechanisms of radiation-induced endovascular injury and development of treatments/mitigators for radiation-induced endothelial cell and vascular dysfunction.” The objective of the meeting was to provide an update on the progress made in the each U01 grant over the past fiscal year, exchange ideas for refining the research and to provide a framework for collaborations among the investigators. The meeting was attended by the principal investigators (PIs), NIAID staff, regulatory members, and other government agencies with overlapping interest. Following the meeting, several PIs submitted collaborative concepts for supplemental funding to meet the goals of the original RFA.

A Trans-Agency Workshop on the Pathophysiology of Radiation-Induced Lung Injury. On March 20 and 21, 2019, NIAID organized a workshop in conjunction with FDA and BARDA in Rockville, Maryland. The goal was to examine the available animal models for radiation-induced lung injury in comparison to lung injury in humans. Workshop presentations included the natural history of the pathologies associated with lung injury and the how lung injury can be measures by non-invasive means. Discussion were held to assess the strengths and weakness of each model and how the models can be used to advance medical countermeasure development to fulfil an unmet medical need. A workshop report is in preparation for publication.

Cutaneous Radiation Injuries Meeting. On May 5 and 6, 2019, the NIAID, together with colleagues from CDER, FDA and BARDA, organized a workshop in Rockville, Maryland. The purpose of the workshop was to provide a forum for clinical experts in the field of radiation and other skin injuries (e.g., burns, diabetic ulcers, and other wounds) to discuss best practices to assess severity of skin injuries and progression of healing. Other investigators with experience in preclinical modeling of these injuries and in determining efficacy of MCMs to treat radiation-induced skin complications were also involved in the discussion. The goal of the conference was to develop a better understanding of cutaneous radiation injuries, identify the most appropriate animals in which to model the damage, and assess promising treatment approaches. A meeting report documenting consensus information is in preparation, for submission to the journal Radiation Research.

Gilbert W. Beebe Symposium on the Future of Low-Dose Radiation Research in the United States. On May 8 and 9, 2019, the National Academies of Sciences, Engineering, and Medicine organized a symposium with colleagues from NIAID, BARDA, DOE, and NCI, in Washington, D.C., to discuss the future of low-dose radiation research and the need for long-term strategy to guide low-dose research in the United States. The aim of the symposium was to prioritize scientific roles for this field, identify long term goals and criteria to measure success of such an initiative and the logistics involved in the venture. The symposium presentations and discussions are being summarized in a National Academies Proceedings.

 Symposium on Tissue-Resident Immune Cells. From June 4 to 6, 2019, the trans-NIH Geroscience Interest Group hosted a symposium for postdoctoral fellows in Bethesda, Maryland, to highlight research on topics at the interface between the biology of aging and adult-onset diseases and frailties. The symposium focused on tissue resident immune cells, which have diverse functions, and encouraged postdoctoral fellows to consider aging as an experimental parameter in their research related to such cells. NIAID staff served on the steering committee.

Workshop on Imaging Inflammation and Its Resolution in Health and Disease. On June 10 and 11, 2019, a trans-NIH workshop was held in Rockville, Maryland, to bring together practicing physicians, clinical researchers, and imaging tool developers. The goals were to 1) identify clinical needs and opportunities; 2) align research and development efforts toward in vivo imaging-based tools and techniques to monitor an individual's inflammatory and resolution state at the organ level; and 3) thereby lead to better clinical decisions and treatment planning. A meeting report was submitted to FASEB for publication.

NIAID/USUHS-AFRRI IAA Meeting. On July 25, 2019, staff from NIAID and Armed Forces Radiobiology Research Institute (AFFRI) held a planning and update meeting in Bethesda, Maryland. The meeting discussion focused on strategic planning for future studies, and AFRRI principal investigators presented scientific progress over the past year.

Concepts Presented for Clearance

FY 2021 Research Concept Clearances

Asthma and Allergic Diseases Cooperative Research Consortium

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

The subcommittee endorsed and unanimously approved this initiative.

Childhood Asthma in Urban Settings Clinical Research Network

The Network that will be formed by this group of grantees will conduct clinical research primarily with children residing in low-income urban neighborhoods with a focus on the prevention and treatment of asthma and respiratory allergy in this population. By conducting clinical and mechanistic research to understand the immunopathogenesis of the disease, it is anticipated this network will be able to implement innovative, phenotype-specific, immunomodulatory clinical trials tailored to this population.

The subcommittee endorsed and unanimously approved this initiative.

Development of Radiation/Nuclear Medical Countermeasures (MCMs)

This initiative will address gaps and accelerate the research and development of MCMs to mitigate/treat acute and/or delayed radiation syndromes (DEARE).

The subcommittee endorsed and unanimously approved this initiative.

Molecular Mechanisms of Combination Adjuvants

This FOA solicits applications on the mechanism of action of a combination of two or more vaccine adjuvants (combination adjuvant). Adjuvants that are used in these studies must already have shown immune boosting activity when used individually in licensed or unlicensed vaccines (e.g., experimental or candidate vaccines).

The subcommittee endorsed and unanimously approved this initiative.

NHP MHC Allele Discovery and Typing Technology Development

The goal of this program is to accelerate immunological research in nonhuman primate (NHP) models of transplantation, vaccine, and adjuvant development, and infectious and immune-mediated diseases by 1) defining MHC and KIR alleles in multiple NHP species and 2) developing technologies for rapid high-throughput MHC and KIR typing.

The subcommittee endorsed and unanimously approved this initiative.

Clinical Data and Safety Management Center

DAIT’s Clinical Data and Safety Management Center will provide data management and safety desk support for clinical trials in the areas of allergy and asthma, autoimmune diseases, and transplantation and meet regulatory requirements for safety, data integrity and quality.

The subcommittee endorsed and unanimously approved this initiative.

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

Director’s Report

Dr. Emily Erbelding, director of the Division of Microbiology and Infectious Diseases (DMID), chaired the NIAID Microbiology and Infectious Diseases Council Subcommittee meeting on September 9, 2019. Dr. Erbelding thanked Dr. Raul Andino for his service on the DMID Subcommittee. She also provided a DMID personnel update, recognizing new staff appointments made throughout the Division since the last Council meeting, including: Dr. Liliana Brown, director of the Office of Genomics and Advanced Technologies; Dr. Paula Bryant, director of the Office of Biodefense, Research Resources, and Translational Research (OBRRTR), and associate director for Biodefense Product Development at NIAID; Dr. David McNeeley, director of Regulatory Affairs; Ms. Cynthia Rojas, communications health specialist, Office of Scientific Coordination and Program Operations; Dr. Amber Linde, program officer, Virology Branch; Ms. Amanda Ulloa, health specialist in the Translational Research Section, Virology Branch; and Dr. Kimberly Taylor, chief of the Vaccine Development Section, Office of Biodefense, Research Resources and Translational Research.

Following staff introductions, Dr. Erbelding reported on several recent DMID scientific activities. She provided further information on the results of a Phase 1/2 clinical trial that was evaluating whether the experimental prime-boost vaccine known as AdCh3NSmut1/MVA-NSmut was safe and could prevent chronic hepatitis C virus (HCV) infection. The vaccine was found to be safe but not efficacious. The results of the trial were presented at a May 2019 workshop, which also included a discussion of the research and development path forward for candidate HCV vaccines. Since that meeting, DMID has initiated two new projects through its Structural Genomics Centers, including one that focuses on the capsid structure and mapping epitopes that might elicit broadly neutralizing antibodies, and a study focused on the design of E1/E2 heterodimer nanoparticles that might lead to a new candidate vaccine. She also noted that staff would be presenting a new concept for HCV vaccines later in the agenda.

In other news, Dr. Erbelding acknowledged the recent FDA approval of Pretomanid for treatment of drug-resistant tuberculosis, noting that multiple divisions within NIAID, including DMID, played a significant role in its development at virtually every step, preclinical development through clinical evaluation. Dr. Erbelding also noted a recent publication in which scientists used viral sequences of Zika virus isolated from travelers returning from Cuba in 2017 to prove that there was a silent epidemic of Zika with transmission ongoing in Cuba in 2017 after the epidemic had largely subsided in other parts of the Caribbean and Florida. The report illustrates the power of modern genomic tools and open source data, as well as the challenge of Zika surveillance. Finally, she noted two recent publications that implicate nonpolio enteroviruses in acute flaccid myelitis (AFM) outbreaks, particularly EVD68 and A71. These observations and others suggest much more strongly that EVD68 might specifically be the cause of recent AFM cases seen in the United States. She stated that developing a vaccine for the cause of AFM would be of particular interest to DMID.

Concepts Presented for Clearance

The following FY 2021 concepts were presented to the Subcommittee:

Accelerating Discovery of Efficacious Pre-erythrocytic Stage Malaria Vaccines–the objective of this concept is to support basic research on liver stage development of the malaria parasite, including cell biology, immunology, and pathogenesis studies, as well as to design and identify new and highly efficacious pre-erythrocytic stage malaria vaccines, including sporozoite-based vaccines against malaria infection suitable for further downstream development and clinical evaluation. The Subcommittee members expressed significant enthusiasm for building on sporozoite-based vaccine research and capitalizing on studies of malaria liver stage biology and immunity to pre-erythrocytic stages of malaria (sporozoite- and liver-stages) for better vaccine design. The Subcommittee especially emphasized the importance and timeliness of leveraging emerging genetic and immunologic technologies to generate a highly efficacious, whole-organism-based malaria vaccine as well as to better define targets of protective immunity and potential immunogens/candidate vaccines using other vaccine platforms. They noted that such studies could provide improved understanding of immunity in the liver not only for malaria but possibly for other hepatic infections. Program staff were open to the suggestions and will consider additional vaccine technology platforms in addition to the whole-organism platform as part of the proposed research scope.

Rational Design of Vaccines for Hepatitis C–the objective of this concept is to construct a candidate prophylactic vaccine against HCV, test its immunogenicity, and assess the efficacy of the immune responses elicited. The Subcommittee members were highly supportive of this concept to leverage state-of-the-art technology and knowledge of HIV vaccine development to pursue a rational design for an HCV vaccine. In particular, considering the increase in HCV infections in the United States due to the opioid epidemic, the Subcommittee members emphasized the timeliness of the concept. The Subcommittee stressed the need to analyze existing data from previously vaccinated cohorts and examine people who spontaneously clear HCV infection for potential immune correlates of protection. The Subcommittee noted that the research and development community has the tools necessary to solve this problem and recommended that NIAID take a holistic approach in planning for HCV vaccine development, spanning basic research to clinical research, and that in the absence of an ideal animal model, consideration should be given to performing iterative Phase 1 trials in humans to help guide vaccine selection and development.

Understanding Phage Biology to Support the Development of Bacteriophage Therapy–the objective of this concept is to support basic and early translational research to address data gaps that hinder the development and regulation of bacteriophage used to prevent and treat drug-resistant bacterial infections. The Subcommittee members agreed that providing targeted funding and a special emphasis panel review is needed to advance the promising but immature field of bacteriophage therapy. They felt that there are numerous basic and translational aspects of phage biology that need to be understood to fully explore bacteriophage as therapeutics. The Subcommittee members noted that the funding mechanism may catalyze more research in this area, but that additional resources could be needed to address the critical gaps in the field; NIAID is exploring other methods to advance phage therapy research. One Subcommittee member felt that the scope should not be limited to the most urgent resistance threats, as the use of phage therapy for more common infections may also be beneficial. Program agreed that the scope did not need to be limited.

Combating Antibiotic-Resistant Bacteria (CARB) Interdisciplinary Research Units–the objective of this concept is to support multidisciplinary research centers focused on improving our understanding of antibacterial resistance to inform the development of new approaches to prevent, diagnose, and treat antibiotic resistant infections. The Subcommittee members were supportive of establishing Combating Antibiotic-Resistant (CARB) Interdisciplinary Research Units (CARBIRUs) and considered the concept a good investment. In addition, they indicated that the multidisciplinary, multiproject approach with supportive cores was the appropriate mechanism for this concept to further fundamental science discoveries toward new therapeutic strategies. Several Subcommittee members suggested that given the broad nature of the concept, it will be important to make it clear that the emphasis will be on basic discovery and very early translational activities so that the program is complementary to existing NIAID programs supporting later translational activities on antibacterial resistance. Subcommittee members recommended, and staff agreed, that collaborations between grants within the CARBIRU program as well as with other NIAID-supported programs where synergies may exist be encouraged.

Chemistry Center for Combating Antibiotic-Resistant Bacteria–the objective of this concept is to address a key bottleneck in antimicrobial therapeutics discovery by supporting the acquisition, design, synthesis, and delivery of chemical libraries of novel discrete natural products and small-molecules with diverse physicochemical properties, specifically designed for targeting Gram-negative bacterial pathogens. Subcommittee members agreed that the concept for establishing a Chemistry Center for Combating Antibiotic-Resistant Bacteria (CC4CARB) was timely and addressed a critical bottleneck to therapeutics development. Feedback from the subcommittee members included recommendations to clarify how selected design projects would be prioritized for synthesis, including clear guidance about preferred target pathogens. In addition, the subcommittee had questions about how intellectual property (IP) would be handled and whether synthesis of proprietary compounds would be supported. Program staff was appreciative of the specific questions and recommendations for how to improve the focus and clarity. Specifically, with regard to design project prioritization, the contractor will be required to establish and utilize a Scientific Advisory Board (SAB) composed of experts in medicinal and synthetic chemistry and antibacterial drug development. The SAB will review proposals for chemical library designs and recommend those for progression into synthesis, with final approval by NIAID contracting officials. Criteria for prioritization of projects will include a combination of the strength of the scientific rationale for the design hypothesis, the likelihood of beneficial impact, and the chemical feasibility of the design proposal. Proposals that target any Gram-negative pathogens of relevance to human disease will be in scope for consideration; however, projects targeting drug-resistant Enterobacteriaciae, Pseudomonas aeruginosa, and Acinetobacter baumannii will be considered the highest priority in the review. With regard to the question about IP and synthesis of proprietary compounds, it is important to note that all compound structures, synthetic routes, and associated data will be fully disclosed to the public. Because the main utility of compounds resulting from this effort will be used as chemical probes and early hits for drug discovery, IP protection is expected to be important.

Development of Medical Countermeasures for Biothreat Agents, Antimicrobial-Resistant Infections and Emerging Infectious Diseases–the objective of this concept is to support the development of therapeutics, vaccines, and diagnostics for selected infectious diseases, including bioterror agents (PHEMCE Priority Pathogens), emerging biological threats, drug-resistant pathogens, and NIAID-priority pathogens, including fungi, e.g., Coccidioides spp. The Subcommittee members lauded the success of the program to date and agreed that the concept was important to maintain the current capabilities. This concept is purposefully broad for the development of vaccines, therapeutics, and diagnostics and will address unmet needs in public health preparedness in biodefense and emerging infectious diseases and in response to outbreaks. Research topics may be narrowed in scope to target areas of interest and to fill gaps in the portfolio. Several Subcommittee members suggested this effort could tap into existing capabilities and build further infrastructure that could rapidly respond to the needs. Program staff were appreciative of the specific suggestions and will investigate those options.

International Research in Infectious Diseases–the objective of this concept is to provide support for meritorious, high-priority, regionally-relevant infectious disease research by international investigators in resource-constrained countries. Subcommittee members were highly supportive of the concept for International Research in Infectious Diseases (IRID), noting the broad range of research topics covered and previous success of the program. Subcommittee members suggested that the program would benefit from greater advertisement to increase participation in the program. Further, some Subcommittee members suggested that young investigators in eligible countries should be particularly encouraged to apply. Subcommittee members also stressed that basic science studies of infectious diseases need not be limited to those of particular interest to the host country but should include the full range of basic science studies on infectious diseases. Program staff were highly appreciative of these suggestions.

All concepts were unanimously approved.

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

Director’s Report

Carl Dieffenbach, Ph.D.

Dr. Dieffenbach gave special thanks to Dr. Cara Wilson and Dr. Sally Hodder for serving on ARAC.

Budget Update

A budget update on the status of fiscal year (FY) 2020 was given. The House spending package passed in June included a $2 billion increase over FY 2019 and a two-year budget package was signed by the president in August. The Senate is expected to mark up a spending bill by mid-September. It is expected that the new FY will start under a continuing resolution and a full appropriation is expected sometime after. The NIAID FY 2020 interim financial management plan was summarized. Paylines will start at the 10th percentile for established PIs and at the 14th percentile for new PIs. There will be no adjustments to noncompeting and competing grants and research initiatives will be cut up to 20 percent with a goal of keeping success rates between 19 percent and 22 percent. Once there is a federal budget for the year, these numbers will be revised.

Update on the Ending the HIV Epidemic (EHE) Initiative

The President’s EHE Initiative officially begins in FY 2020, but efforts to begin work on this intuitive began in FY 2019. The role of the NIH Centers for AIDS Research (CFARs) and the National Institute of Mental Health (NIMH) AIDS Research Centers (ARCs) for EHE was outlined. CFARs and ARCs will serve as research platforms to support implementation science and will collaborate with CDC, HRSA, IHS, and SAMHSA-funded partners to implement locally relevant approaches. They will also inform local partners on best practices based on state-of-the-art biomedical research findings and will collect and disseminate data on the effectiveness of approaches used in the initiative. A map depicting the locations of CFARs and ARCs and how they overlap with the HIV hotspots in the United States was shown. A FY 2019 CFAR/ARC EHE and Health and Human Services (HHS) Minority HIV/AIDS Funds supported one-year supplement opportunities was released in spring 2019. The goal was to fund locally-defined planning projects generated in collaboration with health departments, clinics, and community groups to design and test implementation techniques. Almost 100 proposals on how best to deliver an evidence-based package or service for the population at the greatest disproportional risk for HIV acquisition or need for treatment were received and 65 supplement awards were made. The distribution of these awards was presented as a Venn diagram in terms of the previously described pillars (diagnose, treat, prevent, respond). Future plans for FY 2020 include a meeting with the awardees and their local-HHS funded partners in Chicago at the end of October 2019, the consideration of scaling up the highly productive CFAR/ARC FY 2019 projects, coordinating and aligning with HHS partners for FY 2020 plans, and working to foster additional EHE targeted applications. The scale of what will be done depends on what is specifically appropriated to the NIH. A change made to the FOA for the clinical trial sites was recently published with a notice of a change for a specific additional section to be added to the applications asking for information about the ability of sites to respond to helping end the epidemic and who their existing partners are within the appropriate community-based organizations.

Timeline for the NIAID HIV/AIDS Clinical Trials Network Recompetition

The recompetition timeline is currently on schedule. The FOAs for the LOCs, SDMCs, and LCs were received by August 1, 2019, and the reviews are expected to be completed by March 2020. The CTU FOAs have a current receipt date of November 18, 2019.

Questions: None

Office of AIDS Research Advisory Committee (OARAC) Update

Richard Chaisson, M.D.

Dr. Chaisson gave a summary of the 51st OARAC meeting held on June 27, 2019. This included the Director’s Report and various recent and upcoming outreach activities, briefings and updates. During the Director’s Report, Dr. Goodenow reported on an initiative at the NIH to address the issue of sexual harassment and professional harassment. A strategy to address these issues is being developed based on a survey taken by NIH employees earlier in the year. One example of change to the culture came from Dr. Collins, who had issued his mandate to avoid speaking at all-male panels at scientific meeting. The NIH Strategic Plan for HIV is in development and will be a five-year plan, rather than two-year plan. A request for information was issued and input was received. A draft of the plan is written and is currently under review with the Office of AIDS Research (OAR) and the Director’s Office. Updates from the Guidelines Committees were presented by Dr. Rohan Hazra from the National Institute of Child Health and Human Development (NICHD). OAR has been engaged in listening sessions around the country. These sessions are an effort on behalf of the NIH to obtain input from the community, affected communities, and partners of NIH researchers. An HIV-related Neurodegeneration Workshop was held at NIH in May 2019. It addressed issues of how HIV affects aging and how aging affects HIV. Questions addressing whether age influences risk of acquisition and outcomes among those infected, if age-associated changes in the immune system effect the reservoir, and if age will influence health via its effect on the virus were discussed. The director of the Office of Sexual and Gender Minority Research at the NIH, talked about the efforts that the office does to coordinate research on sexual and gender minority research to represent the NIH at other institutions and forums around the world, to serve as a resource for investigators, and to try to connect investigators who have mutual interests. José Bauermeister from the University of Pennsylvania, who does operational and implementation research on barriers to diagnosis, treatment, and prevention in sexual gender and minority youth, described a number of studies done to identify some of the attitudinal, behavioral, and structural barriers to receiving HIV testing, PrEP, and referral to HIV care. Dr. Hazra, from NICHD, provided an update on Dolutegravir’s connection to neural tube defects that had been published in the New England Journal of Medicine. There has been a reduction in the estimate and the rate of neural tube defects, in connection with Dolutegravir, is currently 0.3 percent. Finally, Jen Cates, from the Kaiser Family Foundation, was introduced as the new chair of the OARAC.

Questions: None

Concept Review (Approval Requested)

Basic Sciences Program (BSP)

Digital, Limited Interaction Trials and Epidemiology (D-LITE): Targeting HIV Incidence in the United States

Gerald Sharp, Dr.PH.

The purpose of the D-LITE concept is to develop and test electronic, scalable interventions that can be implemented to prevent HIV infections in highest risk U.S. populations. The duration of this new initiative will be for five years, and it is estimated that there will be two awards made for a first-year total cost of $2 million. Potential partners include the National Institute of Mental Health (NIMH) and the National Institute of Child Health and Human Development (NICHD). Digital interventions have been used in an attempt to reduce risk of getting HIV using a variety of methods. The idea in this initiative is to use these approaches, that include online smartphone interventions, to try to prevent HIV by reducing sexual risk behavior and increasing the use of PrEP. Remote methods, such as online surveys and using the mail to collect data and samples, are advantageous as are there are no geographic limitations and only smartphone Internet access and a mailing address is needed. Online recruitment is highly efficient and inexpensive and allows digital intervention trials to be rapidly conducted and results can be available quickly. Digital intervention trials can use both HIV incidence and surrogate outcome measures; are inherently scalable; reduce stigma-related reluctance to visit clinics or meet face-to-face which in turn limits the Hawthorne effect; and reduces cost and time by reducing study infrastructure. LITE studies that dealt with MSM and transgender women, funded by NIAID, NIMH and NICHD, were summarized and showed that areas of their enrollment covered parts of the country that are currently not covered by the “Ending the HIV Epidemic” initiative. The conclusion of these previous studies is that digital methods can enroll large numbers of at-risk HIV-negatives both inside and outside EHE target areas and address problem of PrEP deserts. Researchers can inexpensively and rapidly enroll thousands by using digital engagement and home-based HIV testing, are able to reach diverse populations in rural and urban United States, and can enroll across ages, genders, and race and ethnicities. Past digital interventions have shown promise but are usually too small to use for HIV incidence outcomes. The next step is to conduct larger digital intervention trials with HIV-incidence outcomes, which now is being called D-LITE. Requirements for D-LITE awards include demonstrated ability to enroll sufficient numbers of high-risk individuals in the United States for adequate statistical power for proposed trial; a digitally-delivered primary HIV prevention intervention, preferably with promising pilot data; a plan for referral to care for all participants testing HIV-positive; a milestone plan with enrollment beginning in 12 months and the completion of the trial in 5 years; a plan to eliminate multiple enrollments; a plan to monitor co-enrollment in other studies; and a plan to monitor PrEP usage. Nonresponsive applications include studies of HIV-positive individuals, studies of people outside the United States, studies with expensive prevention interventions not scalable to U.S. populations, and studies requiring an IND. In addition, studies that do not propose technology-focused approaches to establish and follow a large cohort of HIV-negative individuals and are not focused on at least one targeted high-risk group: Latino and black MSM and transgender men and women will be nonresponsive. Reviewers’ comments were presented and addressed and the ARAC committee casted their votes.

Questions/Discussion:

Q: What bothered you about 50 percent minority requirement?

A: Just that it was an arbitrary number without much basis. My thought was that the numbers should be based on data since 38 percent of infections are in blacks and 27 percent are in Latinos

Q: Why are people who inject drugs, and often found in rural, hard to reach areas, not included?

A: We wanted to focus on MSM for this and we are limited by funding. The interventions have to be somewhat specific both to the population, whether it is Latino or black. Injection drug users are different than MSM and it would be a different intervention if they were included.

Comment: I want to ask that there is a rigorous intentional effort to hold people accountable to the study numbers. Hopefully, all of these groups will have community advisory boards, who should be consulted with about what their intents are and ensuring that they are getting access to the populations that you are concerned about.

Q: You appear to be excluding women in the study. With 20 percent of new diagnoses in the United States occurring in women, what is the rationale?

A: LITE included black women and Latino women, but we had no applications for that. I think it is so hard to identify them as they are not on the sex apps. It is not that we want to exclude them, but I do not think this is the mechanism to include them. It takes some other design of a trial.

Comments:

  • It seems paradoxical that you are doing an electronic, digital platform for hard-to-reach populations, and then the answer to black women or people who inject drugs (PWID) is that they are hard to find. That does not make sense to me. There should be some consideration because it seems a little paradoxical that the reason you do not include them is exactly the reason why they are hard to enroll in studies.
  • I would like to propose that we spend some time specifically discussing people who inject drugs with NIDA. This is an ideal opportunity for there to be a linkage in a way that this could be expanded, and if we could get some support, because that is their primary mission. We need to find a way to put women in this and we will. We are going to have to set some targets, and this idea of defining your target of 2X or some number over the group that is responsible for makes sense.
  • From listening sessions at OAR that I have been at, and actually even being at USCA with the community, there are a lot of very active, articulate, educated African American women who are living with or affected by HIV, and they are very willing to work in this space to help identify and work in this area. They are demoralized by the fact that all the attention and research from their perspective is at African American MSM and that there is just no space for them.

Ballot Voting Outcome:

2 Approval

6 Approval with modification(s)

0 Deferral for further information

0 Disapproval

This concept will be modified to align with the ARAC Committee’s comments.

Harnessing Natural Killer (NK) Cells to Prevent, Control, or Eradicate HIV

Cesar Boggiano, Ph.D.

The objective of the Harnessing NK Cells to Prevent, Control, or Eradicate HIV initiative is to foster research on basic mechanisms of NK cell functions (antiviral and immunoregulatory) and to investigate how to exploit NK cells for novel approaches to prevent, control, or eradicate HIV infection. This is a new initiative for a duration of five years. It is estimated that there will be four or five awards for a first-year total cost of $3 million. Current strategies aiming to prevent, control, or eradicate HIV involve adaptive immunity where the effector functions of cytotoxic T cells, helper T cells, B cells, and antibodies are harnessed to attack HIV or to eliminate HIV-infected cells. The adaptive arm of the immune system requires clonal expansion of B and T cells which can take days or weeks whereas the innate immune system, composed of epithelial barriers and white blood cells, can act quickly when there are infections. NK cells, the focus of this initiative, have usually been included as part of the innate immune system, but recently antigen specificity long-lived immunological memory and immunoregulatory functions have demonstrated that they have characteristics of the adaptive immune response. Their role during HIV infection is to recognize HIV-infected cells indirectly by means of antibodies bound to the surface of the infected cells to trigger Antibody Dependent Cellular Cytotoxicity (ADCC), which was previously defined as the correlate of reduced HIV acquisition risk in individuals with low plasma IgA in the RV144 trial. More recently, antigen-specific responses to SIV and HIV have been reported. These interactions may trigger cytotoxic granules that kill the infected cells or cytokines that can block new runs of HIV infection or trigger antiviral programs. Thus, the antigen-specific receptors by which NK cells recognize HIV-infected cells remain to be discovered. A number of publications showing the role of NK cells that support this initiative were briefly discussed. These papers documented NK dysfunction linked to HIV broadly neutralizing antibodies (bNAb) development, evidence of negative impact of NK cells on humoral immune responses in human vaccine studies, NK functions correlating inversely with HIV reservoir size, and depleting NK cells increases SIV replication. Key scientific questions were listed and included what are the mechanisms that regulate NK cell targeting and killing of HIV-infected cells? How do NK cells contribute to induction and development of HIV bNAbs? Can NK cell functions be augmented for more effective HIV vaccination/eradication strategies? Can NK cells be engineered for enhanced targeting and killing of HIV-infected cells? There have been a number of technological advances over the last decade that have led to better understanding of NK biology, including new methods for probing roles of epigenetic modifications in regulating NK cell function and memory; new single-cell approaches, including transcriptomics, multi-color flow cytometry, and mass cytometry to characterize NK cell subpopulations; and emerging data suggesting Chimeric Antigen Receptor-NK (CAR-NK) approaches have reduced toxicity. The scope of the research for this concept includes mechanisms by which NK cells shape HIV immunity, including both immunoregulatory and effector functions; roles for NK cells in HIV bNAb induction and responses to HIV vaccines, including impacts of vectors and adjuvants; factors regulating NK cell-mediated killing of HIV-infected cells, including receptor-ligand interactions; roles for NK cells in controlling HIV reservoir size, reactivation, and post-treatment control; effects of HIV prevention/treatment/eradication strategies on NK cells phenotype and function; strategies to enhance NK cell functions in the context of HIV, including trafficking to lymphoid and mucosal tissues; and analyses of other innate lymphoid cell populations, if the studies fall within the scope of this initiative. Research that includes analysis of NK cells using novel approaches, uses samples from clinical trials, uses animal models, and includes collaboration between basic and translational scientists is encouraged. Excluded from this initiative are clinical trials and studies focused on ADCC or HIV pathogenesis as they are extensively covered in the DAIDS portfolio. Reviewers’ comments were presented and addressed and the ARAC committee casted their votes.

Questions: None

Ballot Voting Outcome:

8 Approval

0 Approval with modification(s)

0 Deferral for further information

0 Disapproval

Novel Therapeutics Directed to Intracellular HIV Targets

Gerard Lacourciere, Ph.D.

The objective of this initiative is to support the development of novel therapeutic strategies directed to intracellular HIV targets. This is a new R21 initiative for a duration of two years. It is estimated that there will be 9 to12 awards made for a first-year total cost of $3 million. Initial efforts to target HIV intracellular proteins focused on the development of small molecular inhibitors and this strategy has been successful for HIV reverse transcriptase, integrase, and protease due to binding to the catalytic site which directly inhibits their intracellular function. However, attempts to develop small molecule therapeutics to other intracellular HIV proteins have been challenging since these proteins lack an active site to be targeted which renders them “undruggable”. Some novel therapeutic platforms have been developed in the last few years that have been actively used in other therapeutic areas that may be useful in overcoming the limitations of small molecule inhibitors of HIV proteins and expand druggability to all intracellular HIV proteins. One concept involves controlling function by controlling intracellular protein levels. Alternatively, proteins can be targeted by the RNA which encodes them. Small molecules now can be developed to bind specifically to certain regions of RNA to inhibit protein translation or affect stability so that RNA is degraded. As many HIV intracellular proteins are known to form protein-protein interactions, disruption of these interactions with a developed therapeutic might be able to inhibit their activity. One last concept that might be a positive therapeutic to pursue is the intracellular targeting of viral proteins for aggregation. Responsive areas of research include therapeutics that target HIV intracellular proteins for ubiquitination and degradation in the proteasome; small molecules targeting viral RNA that would inhibit splicing, block translation, support degradation or stalling of ribosome during translation; development of macromolecules to support the disruption of HIV protein-protein interactions such as HIV protein dimerization or HIV/host cell protein interactions; and therapeutics that selectively cause the intracellular aggregation of viral proteins to prevent viral assembly or inhibit in vivo function. Nonresponsive areas of research are the development of small molecules to inhibit HIV enzyme activity; monoclonal antibodies and biological molecules that target cell surface HIV envelope; molecules that enhance latency reversal; molecules that directly target host cell proteins (host dependency or restriction factors) that interact with intracellular HIV proteins; and the development of HIV antisense nucleic acid therapeutics. This FOA is needed as the current NIH and NIAID portfolio lacks FOAs for drug discovery, in general, and for HIV, in particular. This initiative will support the development of novel therapeutics which target intracellular HIV proteins, including individual HIV proteins, homologous or heterologous complexes of HIV proteins, or complexes of HIV proteins with host proteins, with the goal of obtaining therapeutics that can overcome issues associated with druggability and off-target side effects while providing potent antiviral activity. Reviewers’ comments were presented and addressed and the ARAC committee casted their votes.

Questions: None

Ballot Voting Outcome:

8 Approval

0 Approval with modification(s)

0 Deferral for further information

0 Disapproval

Therapeutics Research Program (TRP):

Long-Acting Treatments for HIV and HIV-Associated Co-Infections

Marina Protopopova, Ph.D.

The objective of this new initiative is to stimulate research efforts in the area of long-acting therapeutics for HIV and HIV-associated tuberculosis (TB) and viral hepatitis. This initiative will have an estimated duration of five years for a first-year total cost of $3.5 million. Adherence remains to be a problem as this is critical to the effectiveness of multidrug antiretroviral therapy. As adherence varies between 27 to 80 percent across different populations in various studies, there is a need for delivery systems that are more convenient to use. Long-acting drugs sustain effective concentration in plasma and target tissue for a prolonged time to enable therapeutic effect, that reduce drug dosing intervals may be a solution to this problem. Among people living with HIV, morbidity and mortality is increasingly driven by co-infections, such as tuberculosis (TB) and hepatitis B and C. The people living with HIV are at 20 times higher risk of acquiring TB with fatality rates of 16 to 35 percent. Thus, long acting agents would allow for infrequent dosing, simplifying treatment regimens, and potentially improving adherence and decreasing drug resistance. There are 2.6 million people co-infected with HIV and hepatitis B (HBV), a life-long disease. As HIV treatment moves towards long acting cabotegravir and rilpivirine, additional long acting treatments will be required for HBV co-infection. The HIV-hepatitis C (HCV) global estimate of burden is 2.75 million. Direct-acting antiviral treatments take 8 to 12 weeks so the utility of long-acting drug formulations as a single dose alternative would increase adherence. It is highly likely that HIV patients receiving long-acting antiretrovirals will require treatment for TB or hepatitis; the development of compatible long-acting drugs for these infections is needed. Current NIAID initiatives for long-acting agents for HIV were outlined and briefly discussed. The TRP portfolio of long-acting therapeutic for HIV and HIV-associated co-infections were listed. For HIV, the current portfolio is composed of grants focused mostly on parenteral drug products (SC, IM, implants) and technologies involve novel formulation platforms, nanotechnology, prodrugs of commercial drugs, polymers, additional strategies to modify properties of existing oral antiretrovirals for use as long-acting injectables. Few groups have targeted/proposed novel molecules/new chemical entities (NCEs) to be developed as long-acting agents and few NCEs are in development by pharma as long-acting antiretrovirals. For HIV-associated co-infections, the TRP portfolio does not contain any long-acting agents for treatment of HIV-associated TB and viral hepatitis and there are no prior initiatives to support that type of research. Target drug products are drugs and drug formulations that can be delivered orally or as injectable, implantable, or transdermal products once per month or less frequently and formulations that contain a single drug or a combination of drugs. Therapeutics should be small molecules and peptides with activity against HIV, HBV, HCV or M. tuberculosis. For HIV, discovery of new molecules and further development of existing compound classes as long-acting agents is sought. For HIV-associated TB and hepatitis B and C, development of new formulations of commercial drugs and discovery of new molecules and further development of existing compound classes as long-acting agents is sought. Responsive areas of research for therapeutics include the use of computational ADME and PK modeling tools in drug design; medicinal chemistry, lead optimization studies, in vitro studies to assess efficacy, ADME, and potential toxicity; use of animal disease models for pharmacological and toxicological evaluations, assessment of drug levels in plasma, local cellular and target tissues, drug release and dosing intervals; use of appropriate animal disease models; and pre-formulation studies that include physicochemical characterization of the selected molecules and formulation development activities. Development strategies should include novel platforms, a multidisciplinary approach, and product development activities. Expertise in multiple scientific areas is required and collaborations are encouraged. Clinical trials are not allowed. Reviewers’ comments were presented and addressed and the ARAC committee casted their votes.

Questions/Discussion:

Q: Disagree that there are few HIV long-acting products; cabotegravir and rilpivirine have made it into phase 3 and are now being submitted has triggered a huge amount of interest across multiple pharma companies to look at other potentially long-acting products. Given the small amount of money in this initiative, might be more value in focusing on HIV because there is some overlap with LEAP? There may be more value in focusing specifically on TB and hepatitis.

A: LEAP is a drug resource program; it is experts that provide the expertise. We want investigators to go back and look at molecules and classes of compounds dismissed during drug development activities but could be made to work now.

Q: Are funds coming exclusively from DAIDS, or are other branches contributing too? An initiative like this surely should have multiple divisions involved?

A: The funds come from DAIDS. If and when we get approval from the Council, then the plan would be to reach out to our colleagues in other parts of the Institute, especially DMID, to seek collaboration on it. We have had some discussions with them, but generally we wait for Council because we find that it's not particularly useful to talk about ideas that may or may not move forward.

Comments:

  • Polypharmacy comes about with dual infections. These drugs need to have, at some level, some development across the two diseases. But that is downstream. We need to have some conversations about how this could be either cost shared or get some degree of permission from the OAR because this would definitely benefit people living with HIV that are co-infected, as well as people who are mono-infected.
  • Although hepatitis, viral hepatitis, has been deemphasized, to have a single dose of a curative therapy would be a huge step forward and benefit many people with HIV and without HIV.
  • We should view this concept on the merits of the science as proposed and let DAIDS work out the details on the funding within the Institute and with the OAR.

Ballot Voting Outcome:

6 Approval

1 Approval with modification(s)

0 Deferral for further information

1 Disapproval

Prevention Sciences Program (PSP):

Transgender People: Immunity, Prevention, and Treatment of HIV and STIs

Jim Turpin, Ph.D.

The purpose of the Transgender People: Immunity, Prevention, and Treatment of HIV and STIs FOA is to support hypothesis-generating research in transgender people with the objective of increasing our understanding of the impact of gender reassignment drugs, hormones, and surgeries on the immune system by characterizing the biophysical and immunological changes that might contribute to increased susceptibility to HIV and STIs and/or impact the safety and efficacy of prevention and treatment strategies. This initiative, a collaboration with the Division of Microbiology and Infectious Diseases (DMID), will have a duration of two years with an estimated two to four awards for a first-year total cost of $1 million. There are an estimated 25 million transgender people worldwide and meta-analysis data shows that on average they have a potential 49-fold higher risk for HIV infection. For transgender women, an estimated 19 percent are living with HIV. There is minimal data available on transgender men; HIV prevalence ranges from 1.4 percent to 8 percent. Overall, there is minimal data, from mostly smaller studies, on STIs in transgender populations and rates are predicted to be higher because of higher prevalence of transactional sex. Significant efforts are being devoted to understanding the public and individual health impact of the sexual or gender minority individual, but there are still major gaps as little is known about the impact of gender reassignment drugs and surgical regimes on transgender people and their susceptibility to HIV and STIs from the biophysical/immunological perspective. Gender reassignment is complex issue and depending on age and the desired sexual characteristics that transgender people want to develop, it can include the use of hormonal, steroidal, and non-steroidal drugs that not only eliminate existing sexual characteristics but create new ones. Hormone doses and plasma target levels are often higher than those used to prevent pregnancy and achieving desired changes and maximal effect can take months to years. Data from recent prevention and treatment clinical trials, MTN 017 and DISCOVER, that enlisted transgender women have shown that drugs are safe and efficacious within this population. However, PK data has shown that transgender women taking feminizing hormone therapy exhibited a seven-fold lower rectal tissue ratio of PrEP's active metabolites compared to cisgender women and men that inversely correlated with estradiol. The concept considerations and scope were discussed and included allowing a broad approach that does not channel applications into a specific scientific niche. This will allow applicants to use existing cohorts, develop an application specific cohort, and support the use and development of in vitro, ex vivo, and animal models as research tools to study the impact of gender reassignment. This FOA emphasizes research focusing on hypothesis-generation, does not specifically define transgender since this is a potentially challenging cohort to acquire and study, and supports in vitro, ex vivo, and animal model development. Clinical trials; behavioral, social and/or intervention research; and development of new drugs or drug delivery systems for transgender people will not be supported. Areas of research interest include immunological and biome characterization of the neo-vagina and neo-penis and the impact of post-surgical femininization and masculinization processes on these tissues; the general impact of exogenous hormone usage and/or non-hormonal drugs to suppress or enhance gender reassignment on genital mucosa; the impact of feminization and masculinization regimens on the rectal and GI mucosa; the impact of chemical and/or surgical menopause or delay of the onset of puberty in preparation for gender reassignment; characterization of the new micro- and macro-environments created by the surgery and hormone use; characteristics and function of the microbiome in the neo-vagina and neo-penis and the role of the source of tissue used to create the neo-vagina and -penis in determining the microbiome; ‘omics and systems biology studies to characterize the impact of gender reassignment on the remaining genital tract, GI tract and neo-organs; PK and PDs of drugs used to prevent and treat HIV and STIs in transgender people development of new in vitro, ex vivo, and animal models to study the cellular, immunological, PK, and PD impact of gender reassignment and maintenance; and the impact of hormone treatment on induction and evaluation of systemic and mucosal immune responses to HIV vaccines, transfused bNAbs, or long-acting antiretrovirals. Success of the initiative will include the creation of data sets for transgender people that allow for identification of biophysical and immunological differences which may impact susceptibility to infection and the safety and efficacy of HIV and STI treatment and prevention strategies or provide evidence that the health disparities observed for transgender people are the sequalae of behavioral and social factors; and the generation of preliminary data and development of the cohorts required to propose hypothesis-driven research to refine and optimize prevention and treatment strategies for transgender people. Reviewers’ comments were presented and addressed and the ARAC committee casted their votes.

Questions: None

Ballot Voting Outcome:

8 Approval

0 Approval with modification(s)

0 Deferral for further information

0 Disapproval

Footprints of Successful Post Exposure Prophylaxis (PEP) and HIV Exposure

Jim Turpin, Ph.D.

The purpose of this FOA is to support hypothesis-generating research with the objective of identifying potential footprints, bioprofiles, that might accompany the use of PEP by analyzing organismal responses to PEP drugs and virus exposure associated with PEP success and failure in human and animal models using the tools of 'omics and systems biology. It is estimated that there will be four to six awards made for a duration of two years for a first-year cost of $2.0 million. Footprints were defined as a complex set of observable differences (proteomic, microbiome, immunological [innate, cellular, humoral]) which identify patterns (systems biology) that can be used to tell the difference between successful and unsuccessful PEP. They should not be confused with biomarkers. PEP is used after possible virus exposure within a timeframe when local infection may have already been established. Successful use of PEP requires high adherence to a daily drug regime and daily pill taking is a known barrier to effective HIV prevention. Ultimately the goal would be to develop new PEP strategies using sustained/extended release technologies to address adherence. To do this, a way to quickly determine if a PEP strategy is working is needed and footprints/bioprofiles could be a tool to support this effort. The hypothesis for the concept is that there are organismal responses detectable using 'omics and systems biology tools that can identify patterns (footprints/bioprofiles) that are sensitive and consistent enough to detect differences between virus exposure and successful and unsuccessful PEP. Examples of potential evidence from publications that footprints/bioprofiles might exist for prevention strategies were listed and discussed. To test the hypothesis, the first step was the creation of this R21 with the aim of generating the preliminary data that might support additional research, if warranted. Applications should support hypothesis-generating research to identify potential PEP and virus footprints/bioprofiles. The use of clinical samples in encouraged, there are no limits or at-risk populations, and footprints/bioprofile analysis must be derived from systems that have been exposed to virus and/or the CDC Guideline PEP regimen or a regimen with published PEP clinical efficacy. The focus of the research is using ‘omics and systems biology tools on HIV animal models using the current PEP regime(s) to identify potential footprints/bioprofiles indicative of PEP drug exposure, virus exposure, and successful and unsuccessful PEP intervention and on samples from individuals who have taken PEP to determine if PEP use is associated with footprints/bioprofiles indicative of successful or unsuccessful prevention of HIV infection. Success will be defined as the ability to provide presumptive evidence that supports or refutes the bioprofiles/footprints concept - evidence that footprints/bioprofiles can be tools for drug development to track virus and PEP drug exposure and/or PEP success/failure (sensitivity, accuracy, and robustness); and preliminary data to support future investigator-initiated or FOA-supported hypothesis-driven research. Reviewers’ comments were presented and addressed and the ARAC committee casted their votes.

Questions:

Q: Skeptical about the plausibility of detecting an infection event that has been successfully dealt with by PEP. How do you imagine such events could be detected post hoc?

A: Part of this initiative comes from the emerging work of Tom Hope where we are seeing in situations where there is prevention, that you are seeding numbers of foci. This concept is a way of determining if this is possible, and if it is, then we might have an interesting new tool to develop future PEP approaches.

Q: You want to be able to detect whether a person was actually infected, and the PEP worked, or that they were not actually infected? What are you going to look for?

A: I agree, as it stands today, we lack the information to really determine whether this can be sensitive and reproducible enough. We do know that, at least in nonhuman primates, the virus is inducing a series of virus antiviral genes within epithelial cells. There are changes that occur and you may be able to sample secretions.

Q: Explain how a footprint that reflects effective treatment can be used for future clinical studies?

A: Future clinical studies are far away. If we begin to develop new PEP strategies and we say that there is a footprint associated with clearance, that footprint can be used in animal models to help us quickly determine if we have an effect or not. In terms of clinical studies, that can be a long period of time and is going to be a different set of funding for a set of focused studies to see if you can detect it with easily obtained secretions or in the blood.

Comment: This is an interesting proposal because you are trying to look at the biological traces of a very early infection that has been aborted. This is a kind of proposal where you are not going to get submissions for this without an RFA because it is too high risk, nobody is going to try to get funded without asking for the applications. The pediatric population is a place where you could look at this because we have large numbers of infants that are getting exposed, but some of them probably are not actually getting exposed; maybe you can see the difference between those kids that are born to moms with HIV.

Comment: Realize that where we are with PEP today is three-drug systemic therapy. There have never been really studies to show that that works except in animals, not in human clinical trials. We have extrapolated from what we know about treatments and PEP is highly effective. Do we really think that there is a biological signature here that will help us identify who PEP is going to fail in, and that we would use that to develop the next PEP regimen?

Ballot Voting Outcome:

3 Approval

0 Approval with modification(s)

3 Deferral for further information

2 Disapproval

This concept was not approved by the ARAC Committee.

Vaccine Research Program (VRP):

Engineering Immunity Through Vaccines

Patricia D’Souza, Ph.D.

The Engineering Immunity Through Vaccines concept originated from a workshop held by NIAID and the National Institute of Biomedical Imaging and Bioengineering (NIBIB) in September 2018 with the idea to bring bioengineers together with immunologists. Workshop topics included optimizing immunogen design, improving immunogen and adjuvant co-delivery, and elucidating and controlling host immune responses. The purpose of this new initiative is to synergize expertise between bioengineers and immunologists to design, display and deliver HIV immunogens coupled with adjuvants/immunomodulators to develop safe and effective preventive HIV vaccines. This two-phase milestone-driven grant mechanism will have a duration of five years. It is estimated that there will be three to four awards made for a first-year total cost of $5 million. Other key features of the program are negotiated milestone incorporated into the Terms of Award and to encourage translational partnerships between industry, academia and government. Three bioengineering approaches, taken from the workshop, were given as illustrative examples of scientific opportunities of potential collaborations. The first example involved the delivery of immunogen and adjuvant to optimize sustained delivery of antigen/adjuvant to enhance vaccine potency. The second example was on self-assembling designer proteins that present antigens in a repetitive array to promote efficient cross-linking of B-cell receptors. The third example is on building immunity with biomaterials that will recruit and reprogram cells, thus creating a highly tunable microenvironment within the host. Other potential topics for this RFA include novel delivery vehicles/modalities of single or multiple antigens, strategies to program immunity or rescue impaired immunity, and image-guided approaches to visualize and characterize immunogens and immune responses. Reviewers’ comments were presented and addressed and the ARAC committee casted their votes.

Questions: None

Ballot Voting Outcome:

8 Approval

0 Approval with modification(s)

0 Deferral for further information

0 Disapproval

Integrated Preclinical/Clinical AIDS Vaccine Development Program (IPCAVD)

Michael Pensiero, Ph.D.

Dr. Pensiero presented two similar, but complimentary initiatives. IPCAVD is a grant/cooperative agreement and the Preclinical Translational Vaccine Development Support for HIV and Other Agents (PTVDS) is a contract. Both have the same overall goals to accelerate the availability of promising clinical trial materials into vials for hypothesis-driven clinical testing, support translational science, to support phase-appropriate CGMP compliant vaccine manufacturing, and product development for clinical research and not commercialization.

The IPCAVD program supports translational research – IND-enabling studies, regulatory, manufacturing, and stability studies, and provides partnering opportunities for academia with Biotech/Pharma and/or CMOs. The early biotech Pharma involvement is key to advance HIV vaccine development. This renewal will have a duration of seven years, which is a change from five years of the previous concept. It is estimated that there will be one or two awards for a first-year total cost of $5 million. IPCAVD supports a multidisciplinary consortium of experts in animal modeling, molecular biology, immunology, GMP manufacturing/regulatory for clinical testing. Specific activities may include later stage translational HIV vaccine research and optimization and all product development stages including process development, formulation studies, analytics, IND-enabling studies, cGMP manufacturing, Fill/Finish, stability, and quality assurance. Funding of clinical studies will not be supported. Historically, this program has fostered several successful and unique partnerships between academia and big Pharma that would not have otherwise occurred. Examples of these partnerships were provided and included the partnership between DAIDS, Crucell/J&J/Janssen, Harvard, MHRP, NIAID, Ragon Institute, and the VTN to advance the Ad26/MVA/mosaic-protein boost platforms. IPCAVD funded products in clinical trials were then briefly described. Program oversite involves pre-determined immunologic/manufacturing Go/No-Go decision points that will be established and incorporated into the notice of award, an External Scientific Advisory Board (ESAB) that will be identified with concurrence of Program that will determine whether sufficient progress has been made to warrant manufacturing, and determination on whether to support manufacturing being made by Program. Some examples of HIV vaccine research to be fostered by this program include the development of novel Env immunogens with increased breadth and potency by eliciting HIV bnAbs; the development of adjuvants to improve potency and mucosal responses of HIV immunogens; improved devices for gene transfer; and improvements in product development processes/formulation to increase yield, purity, scalability, and stability. Changes from the previous IPCAVD involve changing the duration of the award from five years to seven years with the last two years of funding being limited in budget and scope. Years six and seven will support ongoing stability studies, storage, updating regulatory filings, and further vaccine optimization studies. Reviewers’ comments were presented and addressed and the ARAC committee casted their votes.

Comment: There are a few of these examples where, the academic PI is either a founder or a scientific advisory board member of the industrial partner. We should be careful that we are not creating a welfare scheme for PI startup companies. The vetting is important, and the conflict of interest has to be managed carefully.

Ballot Voting Outcome:

8 Approval

0 Approval with modification(s)

0 Deferral for further information

0 Disapproval

Preclinical and Translational Vaccine Development Support for HIV and other Candidate Agents (PTVDS)

Michael Pensiero, Ph.D.

The objective of the PTVDS contract is to provide critical end-to-end gap-filling support for all stages of product development. This is a multiple-award indefinite delivery/indefinite quantity (IDIQ) contract that is the merging of two existing contracts. The duration will be for seven years, and it is estimated that there will be four to six awards made in each task area. The scope of the contract, to provide end-to-end support, includes design, conduct, and evaluation of manufacturing feasibility; full process and product development, including but not limited to: upstream and downstream activities, product characterization, optimization and testing, formulation activities, and technology transfer; formulation development on vaccine-adjuvant interactions; generation of reagents and assays and performance of analytics needed for in-process testing or release of vaccine or other products; performance of compliance audits and qualification of Contract Development and Manufacturing Organizations (CDMOs) for cGMP manufacturing capability; performance of full cGMP manufacturing; conduct of Good Lab Practices preclinical investigational new drug (IND)-enabling studies; provision of quality assurance and regulatory expertise for compliance and strategic planning; preparation of regulatory filings for pre-IND/IND submissions to the FDA; provision of project and document management support; provision of cGMP storage and stability testing programs and oversight of vaccine retains, bulk drug substances, and final drug products; and exploration of alternative mechanisms to accelerate protein, DNA, RNA, small molecule and other immunogen manufacturing timelines. Products in or planned for clinical trials that were generated from Preclinical Development Master Contract (PCMC) were listed and the performance history of previous iterations of the PCMC/Process and Analytics Contract (PAS) contracts were detailed. The rationale for re-competition/combination of previous iterations of these contracts was that while the PCMC and the PAS were successful, the HIV vaccine landscape is requiring more complex platforms for antigen delivery and there is urgent need to expand the pool of contractors that DAIDS can work directly with. The Multi-Award IDIQ mechanism allows for direct communication with each vendor/contractor, provides access to more and better-qualified vendors, helps accelerate advancement of additional novel vaccine platforms by allowing access to a wider range of scientific/technical expertise and capabilities, opens up more competitive pricing, provides greater flexibility to the government, and allows the rewarding of successfully performing vendors with additional task orders. Spending is controlled as each task order is fully negotiated, locking in prices, and will be issued with a base and options that are tied to specific deliverables required by the government. Reviewers’ comments were presented and addressed and the ARAC committee casted their votes.

Questions:

Q: While it makes sense to give the government more control, it also creates the extra work of vetting the contractors. Is there the capacity and the expertise to do that?

A: Currently VRP already spends a lot of time vetting contractors and with communication back and forth. The task areas are designed so that there is quality across each area and each task order. The task orders are written so that the contractors provide project management, regulatory, and quality skills. The goal is to get effective and efficient results.

Ballot Voting Outcome:

8 Approval

0 Approval with modification(s)

0 Deferral for further information

0 Disapproval

Public Comments:

No public comments.

VII. Adjournment

The meeting of the Council adjourned at 4:32 p.m., on Monday, September 9, 2019.

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

-s-

Anthony S. Fauci, M.D.

Chair, National Advisory Allergy and Infectious Diseases Council

Director, National Institute of Allergy and Infectious Diseases

1/8/2020

Date

 
-s-

Matthew J. Fenton, Ph.D.

Executive Secretary

National Advisory Allergy and Infectious Diseases Council

Director, Division of Extramural Activities

National Institute of Allergy and Infectious Diseases

1/10/2020

Date

 

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

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