NIAID Council Minutes: January 28, 2019

The 191st meeting of the National Advisory Allergy and Infectious Diseases Council (NAAIDC) convened at 10:30 a.m. on Monday, January 28, 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 3:15 p.m. The meeting was closed to the public from 8:30 a.m. to 10:30 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

Council Members Present:

Dr. Wendy Book
Dr. Michael Brenner
Dr. Amanda Castel
Dr. Mark Feinberg
Dr. Ana Fernandez-Sesma
Dr. Stephen Galli
Dr. John Guatelli
Dr. Sally Hodder
Dr. Marc Jenkins
Dr. Gurjit Khurana Hershey
Dr. Stanley Lemon
Dr. Robin Patel
Ms. Kay Whalen
Dr. Cara Wilson

Ex Officio Members Present:

Dr. Victoria Davey
Dr. Anthony Fauci
Dr. Rima Khabbaz

Ad Hoc Members Present:

Dr. Jacques Banchereau
Dr. Angus Thomson

Council Members Absent:

Dr. Raul Andino
Dr. Karen Nelson

Ex Officio Members Absent:

Lt. Col. Wendy Sammons-Jackson

NIAID Senior Staff Present:

Dr. Hugh Auchincloss
Dr. Carl Dieffenbach
Dr. Emily Erbelding
Dr. Matthew Fenton
Dr. Clifford 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—H. Clifford Lane, M.D., director, Division of Clinical 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 4,336 research and training applications with primary assignment to NIAID for a requested amount of $2,117,574,783 in first-year direct costs and recommended approval of 2,007 applications with $894,958,598 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. Jacques Banchereau, director of Immunological Sciences at the Jackson Laboratory for Genomic Medicine, and Dr. Angus Thomson, distinguished professor of surgery and immunology at the Thomas E. Starzl Transplantation Institute at the University of Pittsburgh.

Council members Drs. Michael Brenner, Wendy Book, and Stephen Galli participated by teleconference. Council members Drs. Raul Andino and Karen Nelson were unable to attend the meeting.

Consideration of Minutes of Previous Meeting

Council considered the minutes of the September 17, 2018 meeting and approved them as written.

Staff and Organizational Changes

On January 7, Dr. Bruce Tromberg was sworn in as director of the National Institute of Biomedical Imaging and Bioengineering.

Dr. Fauci announced two new appointments to senior-level positions in the Office of Strategic Planning, Initiative Development, and Analysis. Dr. Johanna Schneider was selected as the new chief of the Strategic Planning and Evaluation Branch, and Dr. Dolan Ghosh will serve as the branch chief for the newly established Data Analytics and Research Branch.

In the Division of Extramural Activities (DEA), George Kennedy has been named chief of the Microbiology and Infectious Diseases Contracts Branch A in the Office of Acquisitions.

Three senior-level staff members recently retired: Dr. Carole Hudgings, senior advisor to NIAID Deputy Director Dr. Hugh Auchincloss; Dr. Maria Giovanni, director of the Office of Genomics and Advanced Technologies in the Division of Microbiology and Infectious Diseases; and Dr. Hortencia Hornbeak, director of the Scientific Review Program in DEA.

Tributes and Awards

Dr. Fauci noted the passing of President George H.W. Bush. President Bush was a good friend of NIH and remained engaged in HIV/AIDS-related issues throughout his presidency.

Dr. Fauci paid tribute to Dr. Steve Katz, director of the National Institute of Arthritis, Musculoskeletal, and Skin Diseases, who passed away in December.

Two NIAID grantees won 2018 Nobel Prizes. Dr. James Allison, University of Texas MD Anderson Cancer Center, received the Nobel Prize in Physiology or Medicine with Dr. Tasuku Honjo for their work on inhibitors of negative immune regulation. Dr. George Smith, University of Missouri-Columbia, shared the Nobel Prize in Chemistry for his work on the phage display of peptides and antibodies.

Two NIAID scientists were recently elected to the National Academy of Medicine: Dr. Yasmine Belkaid, director of the NIAID Microbiome Program, co-director of the NIH Center for Human Immunology, and chief of the Metaorganism Immunity Section in the Laboratory of Immune System Biology, and Dr. Steve Holland, director of the Division of Intramural Research and chief of the Immunopathogenesis Section in the Laboratory of Clinical Immunology and Microbiology.

Dr. Bibiana Bielekova and Dr. Julie Ledgerwood, two of NIAID’s accomplished clinical investigators, were elected to the American Society for Clinical Investigation.

Meetings and Events

Several international delegations and health officials visited NIAID over the last several months. Dr. Fauci met with Dr. Soumya Swaminathan, World Health Organization (WHO) deputy director-general for programmes, and Dr. Stewart Simonson, WHO assistant director-general for general management; Dr. Hugh Auchincloss met with a delegation from the Research Council of Norway; and Dr. Fauci met with Dr. Xu Shaofa, director of the Beijing Chest Hospital, and his colleagues.

On September 17, Dr. Fauci took part in a symposium at Children’s National Hospital in Washington, D.C., highlighting a new partnership between NIAID and Children’s Hospital and discussing future research opportunities.

CDC Director Dr. Bob Redfield presented the Kinyoun lecture on November 13. He discussed the unprecedented use of opioids in the United States and their impact on infections associated with sharing and reusing needles to inject drugs and other behaviors linked to illicit drug use.

On December 11, NIH and the Bill and Melinda Gates Foundation held the fifth annual consultative workshop on global health. Many of the topics discussed were NIAID areas of interest.

Budget Update

On September 28, the President signed H.R. 6157 into law, which provided NIH with a $2 billion increase from fiscal year (FY) 2018. Dr. Fauci noted that this was the first time in 22 years that NIH has begun the fiscal year operating under a full budget instead of a continuing resolution.

NIH received an overall increase of 5.4 percent. NIAID received a 4.8 percent increase, which included an additional $37 million earmarked for combating antibiotic-resistance bacteria research and $40 million for developing a universal influenza vaccine.

Dr. Fauci summarized NIAID’s FY 2019 financial management plan. Our R01 payline is set at the 14 percentile for established principal investigators (PIs) and the 18 percentile for new PIs. NIAID does not plan to make programmatic cuts to noncompeting and competing grants. Competing research initiatives were cut up to 15 percent from their planned budget level. Our estimated success rates for research project grants will be between 21 and 24 percent.

Legislative Update

Dr. Fauci outlined some of the leadership changes in Congress since the democrats are now in control of the House of Representatives. Nancy Pelosi is Speaker of the House, returning to this role after serving as Speaker from 2007 to 2011. Representative Kevin McCarthy was elected House Minority Leader.

Leadership of Senate congressional committees remains the same as in the previous Congress. In the House of Representatives, Nita Lowey is chair of the House Appropriations Committee, and Kay Granger is the ranking member. Rosa DeLauro is chair of the House Labor-HHS Appropriations Subcommittee, and Tom Cole is the ranking member. Dr. Fauci also presented House leadership changes for the House Energy and Commerce Committee; Health Subcommittee; Oversight and Investigations Subcommittee; and House Oversight and Reform Committee.

On September 20, Dr. Fauci participated in a briefing on Funding the Dream: Celebrating 15 Years of PEPFAR, where he recounted the history of the creation of PEPFAR and reiterated the need for sustained investment in PEPFAR to continue and expand on its successes.

On September 25, Dr. Barney Graham of the Vaccine Research Center (VRC), participated in a briefing of the Congressional Baby Caucus to discuss VRC efforts to develop a universal influenza vaccine that would provide durable protection against multiple strains of influenza.

On December 13, Dr. Fauci briefed members of the House Energy and Commerce Committee on NIAID’s research efforts on acute flaccid myelitis (AFM).

Dr. Fauci noted that NIAID proposed instituting its own DP2 award. The DP2 mechanism, or New Innovator Award, is used by the Common Fund as part of its high-risk, high-reward program. NIAID’s New Innovator Award pilot program proposes funding approximately 10 new investigators each year using the DP2 mechanism.

Other Information Items

Dr. Fauci began by mentioning the G-Finder Report, which is released every year and provides information on global funding for neglected diseases. In 2017, NIH funded 39 percent of global funding for neglected disease research and development.

He provided statistics on the number of confirmed cases and deaths related to the Ebola outbreak in the Democratic Republic of the Congo.

Dr. Fauci briefly described AFM, a disease with sudden onset of limb weakness and MRI findings demonstrating spinal cord lesions largely restricted to gray matter. The risk factors for AFM are unknown, and there is no proven treatment. Most cases occur in children and are usually preceded by a respiratory or febrile illness. He presented statistics on confirmed cases of AFM in the United States and mentioned that NIAID is participating in a notice of interest encouraging research on AFM and Guillain-Barré Syndrome.

He continued with an update on HIV/AIDS, noting 30 years of World AIDS Day commemorations and highlighting several recent scientific meetings and publications.

Dr. Fauci spoke at the U.N. General Assembly High-Level Meeting on the fight against tuberculosis (TB). In September 2018, we released the NIAID Strategic Plan for Tuberculosis Research, which aligns with WHO and U.S. government activities. He also mentioned two recent publications on promising TB vaccine approaches.

He concluded with brief updates on influenza, gonorrhea, and food allergy.

III. Guest Speaker—H. Clifford Lane, M.D., director, Division of Clinical Research, NIAID

Dr. Cliff Lane began by providing statistics from the 2014 to 2016 Ebola outbreak in Guinea, Sierra Leone, and Liberia, which was the largest outbreak in history. NIAID received invitations from health officers in these countries to work with them to establish clinical research programs, including the Partnership for Research on Ebola Virus in Liberia (PREVAIL).

He continued with an update on the 2018 Ebola outbreak in the Democratic Republic of the Congo (DRC), noting that drawing on experiences from the 2014 to 2016 outbreak has proven to be useful during this outbreak. Dr. Lane summarized NIAID’s work with DRC’s Institut National de Recherche Biomedicale (INRB) and other international partners to implement the PAmoja TuLinde Maisha (PALM) clinical trial through a collaborative effort coordinated by the WHO.

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

Director’s Report

Dr. Rotrosen welcomed the subcommittee members to the 191st meeting of the National Advisory Allergy and Infectious Diseases Subcommittee meeting.

Dr. Rotrosen presented the following scientific and Division activities:

Staff and Organizational Changes

Annette L. Rothermel, Ph.D., became chief of the Section on Autoimmunity and Primary Immunodeficiency Diseases in October 2018. Dr. Rothermel received her Ph.D. in microbiology and immunology from Thomas Jefferson University, Philadelphia, Pennsylvania, and completed post-doctoral training in immunology at the Scripps Research Institute in San Diego, California. Prior to joining DAIT, she held a faculty position at Yale University where she conducted research focused on inhibitors of apoptosis and their role in cancer and immunity and was a senior research scientist at the RW Johnson Pharmaceutical Institute where her research focused on developing and assessing the function of humanized monoclonal antibodies. Dr. Rothermel joined DAIT in January 2003 as a program officer in the Autoimmunity and Mucosal Immunology Branch.

Selected Funding Opportunities

NIH

Radiation Biodosimetry Assays and Devices (U01, Clinical Trial Not Allowed) (RFA-AI-18-045): The purpose of this funding opportunity announcement (FOA) is to develop biomarkers, assays, methods and/or devices to assess and triage civilian exposures during a radiation public health emergency. These approaches should be rapid, reliable, inexpensive, and easy-to-use, and should distinguish between the worried well and exposed individuals, determine radiation dose in an affected group, and predict acute and/or delayed radiation injuries to organ systems.

Notice of NIAID’s Interest in Continued Support of High Priority Immunology Grants (NOT-AI-18-024): From FY 2016 to FY 2018 NIAID supported high-priority immunology grants beyond the Institute’s payline to address a decline in NIAID immunology applications and to maintain a robust portfolio of immunology research (PAS-15-055, “High Priority Immunology Grants”). Based on the success of this program, NIAID will continue to support a small number of investigator-initiated R01 immunology applications received in response to PA-18-484 NIH Research Project Grant (Parent R01, Clinical Trial Not Allowed) that score beyond the Institute’s payline.

Molecular and Genetic Characterization of Inborn Errors of Immunity, R01 and R21 (PAR-19-078, PAR-19-079): The purpose of these FOAs is to advance the experimental validation and functional characterization of genetic variants in coding and non-coding genomic regions that result in inborn errors of immunity/primary immunodeficiency diseases and to elucidate the molecular, cellular, and immunological mechanisms of these disorders. Understanding the genetic basis of primary immunodeficiency disorders is essential for their diagnosis, prognosis, and the development of precision therapeutics.

Division Activities

Allergy, Asthma, and Airway Biology Branch

Mast Cell Activation Syndrome (MCAS) Workshop. On September 7, 2018, NIAID organized a workshop in Rockville, Maryland, to review and discuss the current state of knowledge of MCAS. The workshop focused on clinical practice, identification of knowledge gaps, and discussions on how to address these gaps. The workshop featured presentations on current understanding of the topic, followed by four panels discussing: 1) Contextualization of the MCAS and MCAS like—endotypes and diagnostic workups, 2) Proposals for current management, 3) Research on mechanisms (typtase, other mediators, surface receptors, signal transduction), and 4) Education for patients and providers, managing expectations and outcomes. A manuscript to summarize the workshop is planned.

2018 Annual Asthma and Allergic Disease Cooperative Research Center Face to Face Meeting (AADCRC). On November 5 and 6, 2018, NIAID sponsored the  13th annual face-to-face meeting of the AADCRC investigators in Rockville, Maryland. The one-and-a-half-day meeting of PIs, co-investigators, students, and program staff included oral and poster presentations from the 11 NIAID-funded research Centers, as well as 3 NIAID-funded Program Project grant teams, and a special session featuring the work of AADCRC opportunity fund-supported young investigators.

Transgenerational Epigenetics in Allergy. On November 13, 2018, NIAID organized a workshop in Rockville, Maryland, to review the current state of knowledge, identify gaps, promote collaborative thinking and research, and make recommendations for future research on transgenerational epigenetics in allergy. International experts reviewed available data, discussed questions that can be answered by past and current cohorts, and identified additional clinical and mechanistic questions which require further studies in human and/or animal models.

Basic Immunology Branch

Annual Adjuvant Discovery Program Meeting. The last meeting of the FY 2014 DAIT Adjuvant Discovery contract program was held on October 22 and 23, 2018, in Rockville, Maryland. Seven contract groups reported on their progress in identifying lead adjuvant candidates after successfully completing extensive high-throughput screening campaigns. Two contract groups had received supplemental Zika funds and reported on progress made with novel Zika vaccines formulated with adjuvants from their parent contracts. The meeting also included a guest speaker, from the Research and Production Center for Microbiology and Virology in Kazakhstan, who described the institute’s efforts to identify novel plant-based saponin adjuvants.

Vaccines for the Treatment of Opioid Abuse Disorder. On October 23 and 24, 2018, NIAID, National Institute on Drug Abuse (NIDA), and Office of Research Infrastructure Programs jointly hosted a workshop in Rockville, Maryland, to identify knowledge gaps and historical challenges in the development of vaccines to help treat substance abuse and develop strategies to address them. The workshop was part of the NIH HEAL (Helping to End Addiction Long-term) Initiative, a comprehensive, trans-agency effort to accelerate scientific solutions to stem the national opioid public health crisis. NIDA supports basic, applied, and translational research to advance understanding of opioids and the treatment of opioid use disorders; including support of programs to develop vaccines to treat substance use disorders. NIAID supports robust programs in basic immunology, vaccine adjuvant discovery/development, and vaccine development. The meeting participants included NIAID and NIDA-supported investigators, which resulted in dynamic, trans-disciplinary discussions that have led to the establishment of several collaborations between investigators from the two fields.

Immune Mechanisms of Virus Control (IMVC) Program Annual Meeting. On October 31 and November 1, 2018, NIAID convened the annual meeting in Rockville, Maryland, for the IMVC program by webinar. This program consists of eight multiproject cooperative agreement grants (U19s) addressing various immunological questions focused on the host response to viral infection or vaccination. The overall goal of this meeting was to provide a venue for the investigators to present their progress within the past year to NIAID staff. At this final meeting, investigators shared progress for the last four or more years of work on these projects.

Trained Immunity Workshop. On November 14, 2018, NIAID held a workshop in Rockville, Maryland, to discuss current knowledge of and future directions for the field of trained immunity. The workshop was composed of three session: molecular mechanisms of innate memory; innate effectors; and trained immunity in vaccination and adjuvant development. The sessions included presentations from leaders in the field that included: defining trained immunity and exploring its mechanisms of action; the role of trained immunity in heterologous protection against infectious diseases; influence of trained immunity on the development of long-term adaptive immunity, harnessing trained immune mechanisms for treatment of immune-mediated diseases, and approaches for employing/developing vaccine adjuvants and therapeutics to trigger trained immunity.

Molecular Mechanisms of Combination Adjuvants (MMCA). On November 15 and 16, 2018, NIAID held the second annual meeting of the MMCA Program in Rockville, Maryland. Dr. Mihai G. Netea was invited as a guest speaker to open the meeting and describe the potential to develop adjuvants targeting trained immunity. The meeting continued with presentations from the seven funded MMCA investigators, who provided updates on their research programs and collaborative supplements and discussed potential future collaborative projects to leverage available resources and complementary expertise.

Immunity in Neonates and Infants Annual Meeting. Investigators awarded under the Immunity in Neonates and Infants program met on December 5 and 6, 2018, in Rockville, Maryland. Fifteen projects are supported under this program that is a partnership among NIAID, National Institute of Child Health and Human Development (NICHD), and National Institute of Environmental Health Sciences (NIEHS). The goal of this program is to better understand neonatal and infant immune regulatory mechanisms in response to commensal bacteria, allergens, infectious agents (including HIV), vaccines, or environmental pollutants. Investigators reported current progress on their projects and recent updates on new collaborations that were initiated during the year. The meeting provided a venue for investigators to exchange ideas, foster collaborations, and leverage resources and expertise to advance the field.

Cooperative Centers on Human Immunology (CCHI): The annual meeting of the Cooperative Centers on Human Immunology was held on December 11, 2018, in Rockville, Maryland. Principal investigators and research scientists from the six U19 centers presented their research findings on the molecular mechanisms by which the human immune system is activated and regulated in response to infection and/or vaccination and the new technologies developed to facilitate studies in humans.

Human Immunology Project Consortium (HIPC) Subcommittee Meeting. On December 12 and 13, 2018, the HIPC Assay, Bioinformatics, and Clinical Subcommittees met to discuss ongoing activities and develop future projects. The mission of these Subcommittees is to promote HIPC program goals and foster collaboration amongst HIPC investigators. Current activities include development of data and meta-data standards to facilitate date submission to the ImmPort and ImmuneSpace websites and date reuse/mining by both HIPC investigators and the broader research community.

Recent Advances and Opportunities in the Development and Use of Humanized Immune System Mouse Models. On December 18, 2018, NIAID organized a workshop in Rockville, Maryland, to discuss progress made in development and use of mouse models containing reconstituted humanized immune systems. The workshop addressed features of humanized mouse models utilizing fetal and non-fetal tissue sources, as well as the challenges, limitations, strategies, and alternatives to optimize current and emerging humanized immune system models.

Radiation and Nuclear Countermeasures Program (RNCP)

U01 Cellular Therapies Kickoff Meeting. On October 3, 2018, NIAID/RNCP held a kickoff meeting for seven new U01 awards made under RFA-AI-17-001: Cellular Therapies for Treatment of Radiation Injuries. The RNCP released this new funding opportunity on February 8, 2018, to support studies to evaluate candidate cellular therapies to treat radiation-induced injuries in appropriate in vivo models, when the therapy is administered 24 hours or later post-irradiation. The intent of the funding is to support research that will be aimed toward the eventual approval of candidate cellular therapies under the U.S. FDA Animal Rule licensure pathway.

Policies and Regulatory Pathways to FDA Licensure: Radiation Countermeasures and Biodosimetry Devices. On October 9 and 10, 2018, NIAID/RNCP organized a workshop in Rockville, Maryland. The goal was to understand the current policies in preclinical research that facilitate advancing medical countermeasure (MCM) agents and biodosimetry devices towards licensure for use in the event of a mass radiation casualty incident. In addition, we hosted a poster session focused on helping MCM developers understand the technology readiness level of their MCM or biodosimetry devices. The meeting included MCM developers, regulatory experts, and government product managers. It was attended by government personnel, researchers, industry, and academia. A meeting report on this workshop is in preparation.

A Poly-Pharmacy Approach to Mitigate Acute Radiation Syndrome. On October 25, 2018, NIAID/RNCP organized a workshop in Rockville, Maryland. The goal was to elucidate the complexities of using multiple MCMs to treat this multi-systemic insult in a mass casualty scenario. The meeting included MCM developers, regulatory experts, and experts that manage the strategic national stockpile. It was attended by government personnel, researchers, industry, and academia.

2018 Annual Update Meeting for the Centers for Medical Countermeasures Against Radiation Consortium (CMCRC). On December 5 and 6, 2018, the CMCRC annual meeting was held in Rockville, Maryland. CMCRC investigators and their staff from the four cooperative agreements (Columbia University, Duke University, UCLA, and the University of Pittsburgh Medical Center) provided an update on the progress that has been made in their Centers over the past year. The meeting provided an opportunity for an exchange of ideas with other federal government agencies and fostered collaboration among the CMCRC participants. Five members of the External Advisory Board also attended and provided feedback on the successes and future directions of the consortium.

FY 2020 SBIR Contract Topics Discussed at Council

  • Adjuvant Discovery for Vaccines Against Infectious or Immune-Mediated Diseases
  • Adjuvant Development for Vaccines Against Infectious or Immune-Mediated Diseases
  • Production of Adjuvants
  • Reagents for Immunologic Analysis of Non-mammalian or Underrepresented Mammalian Models

Concepts Presented for Clearance

FY 2020 Research Concept Clearances

Development of Sample Sparing Assays for Monitoring Immune Responses

The objective of this initiative is to accelerate development of sample sparing assays that will broaden availability of well-characterized tools for monitoring immune responses in basic and clinical research.

The subcommittee endorsed and unanimously approved this initiative.

Human Leukocyte Antigen (HLA) and Killer-Cell Immunoglobulin-Like Receptor (KIR) Regions Genomics in Immune-Mediated Diseases (U01, U19 Clinical Trial Not Allowed)

The goal of the HLA and KIR Region Genomics in Immune-Mediated Diseases program is to define the association between variations in human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptor (KIR) genetic regions and immune-mediated diseases, including risk, progression, and severity of or protection from disease, and organ, tissue, and cell transplantation outcomes.

The subcommittee endorsed and unanimously approved this initiative.

Immunobiology of Xenotransplantation Cooperative Research Program

This initiative will support new or competing renewal proposals focused on: 1) development or optimization of genetically-modified models of pig to nonhuman primate xenotransplantation of pancreatic islet, kidney, heart, lung, or liver, including optimal combinations of genetic modifications and improved surgical techniques; and 2) defining and ultimately resolving the physiological and immunological barriers of successful xenograft application in clinic.

The subcommittee endorsed and unanimously approved this initiative.

Radiation/Nuclear Countermeasure Product Development Support Services Contract

This initiative will provide additional funds to continue and expand nonclinical and clinical efforts for product development or radiation/nuclear medical countermeasure candidate drugs and biodosimetry devices for inclusion in the Strategic National Stockpile for use during a radiation emergency.

The subcommittee endorsed and unanimously approved this initiative.

RNCP-Wide Dosimetry Guidance and Monitoring of Source and Irradiation Protocols

This initiative will support the development of an RNCP-Wide Dosimetry Guidance and Monitoring of Sources and Irradiation Protocols Core.

The subcommittee endorsed and unanimously approved this initiative.

Development of Vaccines for the Treatment of Opioid Use Disorder

This program will support foundational vaccine development activities, including adjuvant screening, immunogen design, and elucidation of fundamental immune mechanisms required to induce protective anti-opioid antibodies.

The subcommittee endorsed and unanimously approved this initiative.

Characterizing and Improving Humanized Immune System (HIS) Mouse Models

The objective of this initiative is to more fully characterize and further develop HIS mouse models and conduct direct comparisons of HIS mice derived from fetal versus non-fetal human tissue sources.

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 January 28, 2019. Dr. Erbelding provided a personnel update, noting that the DMID Deputy Director Irene Glowinski was planning to retire in March, and thanking her for her service. She also recognized new staff and personnel appointments, including: Judy Hewitt, deputy director of the Office of Biodefense Research Resources and Translational Research (OBRRTR); William Dowling, research resource section chief in OBRRTR; Robert Jurao, nurse consultant, Office of Clinical Research Resources; Carmelle T. Norice-Tra, medical officer, Bacteriology and Mycology Branch; and Chris Beisel, chief, Basic Research Section, Virology Branch. She also noted that Maria Giovanni has retired, and that Alison Yao will serve as acting director of the Office of Genomics and Advanced Technologies until a new director is appointed.

Dr. Erbelding provided further details about the CDC-led Acute Flaccid Myelitis (AFM) Task Force, in follow up to Dr. Fauci’s remarks at the Open Session. Dr. Erbelding serves as a member of the Task Force and stated that the objectives of this group are to develop a research agenda to further characterize the pathogenesis of AFM and to develop hypotheses about potential etiologies. The group is also charged with reviewing and updating clinical guidance on the management of patients with AFM. Related, Dr. Erbelding reported that DMID is currently developing a research protocol for a natural history study of AFM in children.

In addition, Dr. Erbelding provided an update on the HHS Tick-borne Disease Working Group, which was established in response to the 21st Century Cures Act. In 2018, Working Group members reviewed HHS efforts related to tick-borne diseases to help ensure interagency coordination, minimize overlap between the agency efforts, and examine research priorities. Drs. Dennis Dixon, Sam Perdue, and Maliha Ilias participated in this effort and helped prepare a report summarizing agency activities, which was provided to the HHS Secretary and Congress on November 14, 2018. This effort will continue, with the next report due in 2020; Dr. Dixon will continue to serve as a federal member of the Working Group.

Dr. Erbelding also reported that DMID-supported researchers have engineered a subunit vaccine that was found to be effective against both anthrax and plague in animal models. The hope is that a single vaccine could be used to vaccinate against multiple Category A pathogens.

Finally, Dr. Erbelding presented three topics for inclusion in the FY 2020 Small Business Innovation Research (SBIR) Contract Solicitation for the Subcommittee’s consideration. Before introducing the topics, Dr. Erbelding informed the Subcommittee that new guidance was provided in the Electronic Council Book about voting for contracts. She described the elements the Subcommittee should consider in weighing the merit of a proposed concept, including scientific, technical, or program significance of the goals of the proposed research and development activity, and availability of the technology and other resources necessary to achieve the required goals. She then briefly described the DMID topics.

DMID proposed SBIR contract topics include:

  • Development of Rapid Fungal Diagnostics for Select Endemic dimorphic Fungi – to support the development of rapid, sensitive, specific, simple, and cost-effective diagnostics for primary health-care settings to detect invasive fungal diseases.
  • Antiviral Drugs to Cure Chronic Hepatitis B Virus (HBV) Infection – to support preclinical development of anti-HBV candidate therapeutics designed to lead to functional cure of HBV infection.
  • Broad Spectrum Antibody Against Human Enteroviruses – to develop broad spectrum prophylactic and therapeutic monoclonal antibody therapeutics against human enteroviruses.

All topics were approved.

Special Report–Why don’t we have a Hepatitis C Virus (HCV) vaccine? Dr. Stanley Lemon, DMID Subcommittee member and professor of medicine, microbiology and immunology, University of North Carolina at Chapel Hill, provided an update on the state of HCV vaccine development. Dr. Lemon described various scientific and other challenges associated with developing HCV vaccines, for example, critical immune correlates of protection are not known, and clinical trials to assess vaccine efficacy are extremely daunting and lengthy, complicated by difficulty accessing at-risk populations. He outlined a compelling case for the need for an HCV vaccine, noting that HCV-related deaths have exceeded deaths from HIV/AIDS within the United States since 2007, and that the current opioid epidemic has profoundly altered the epidemiology of HCV, increasing the rates of new infection. He described current research activities and outlined a number of activities that could be pursued to accelerate HCV vaccine development efforts.

Concepts Presented for Clearance

The following FY 2020 concept was presented to the Subcommittee:

Feasibility of Novel Diagnostics for Tuberculosis (TB) in Endemic Countries (FEND for TB)–the objective of this concept is to support the evaluation of early stage diagnostics and novel diagnostic strategies for TB in the context of existing clinical diagnostic algorithms in TB endemic countries. The Subcommittee members were in agreement that the concept for establishing a consortium to evaluate TB diagnostics in TB endemic countries, as described in the concept, is important and timely. The Subcommittee members recognized the need for improved diagnosis for TB, particularly in special populations, including children, and the need for point-of-care diagnostics. Subcommittee members recommended that the scope of diagnostics being targeted by the concept needs to be better defined, particularly with regard to how far along in development they are anticipated to be and what would be considered an early stage diagnostic.

It was suggested that this effort target TB specifically, not non-tuberculous mycobacteria (NTMs), and could also include Mycobacterium bovis, a newly recognized public health concern, by limiting the scope to the Mycobacterium tuberculosis complex. Questions were raised about the structure of the proposed consortium, particularly with regard to the role of an Expert Advisory Committee to ensure that the most relevant diagnostics are evaluated. There was a question about which countries would be best suited to conduct evaluations of TB diagnostics. Subcommittee members noted that it is important to ensure the backing of in-country TB control programs and clinical personnel to move forward effectively. Several Subcommittee members noted the need to extend point-of-care drug susceptibility testing beyond Rifampicin and to distinguish between infected individuals and vaccinated individuals. A question was raised about whether the diagnostics would target specific stage(s) of disease, or if they would span the full spectrum of disease. Program staff was appreciative of the specific suggestions. The concept was unanimously approved.

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

Welcome and Approval of Minutes

Cara Wilson, M.D., Chair, ARAC

Dr. Wilson welcomed everyone, and the ARAC members approved the minutes of the September 17, 2018 meeting.

Director’s Report and SBIR Contract Topics

Carl Dieffenbach, Ph.D., Director, DAIDS

Dr. Dieffenbach presented a memorial to William T. Shearer, M.D., Ph.D., a titan in the field of pediatric HIV research. He then introduced two new members to the ARAC Committee, Melinda Turner, M.S.W., M.P.A., and Kenneth Freedberg, M.D., M.Sc.

Budget Update

A budget update was summarized that covered NIH funding for FY 2019. The President’s budget request for FY 2020 is set to be released on February 4, 2019 but could be delayed due to the recent shutdown. NIH was a part of the spending bill, H.R. 6157 that was passed and signed into law in late September 2018, giving NIH a $2 billion increase. The overall average increase across the NIH was 5.4 percent and the majority of the NIAID increase was focused on universal flu vaccines and antimicrobial resistance. The NIAID FY 2019 financial management plan was summarized. The payline is currently set at the 14th percentile for established PIs and at the 18th percentile for new PIs. No adjustments will be made to the noncompeting and competing awards and competing research initiatives have been cut up to 15 percent. The estimated success rate for FY 2019 is 21 to 24 percent, but this rate will depend on the number of applications that are submitted for review. The NIAID/DAIDS report card for FY 2018 showed what was funded through solicited and unsolicited by grant mechanism. Recent NIAID payline history and success rates for research project grants, R01s, P01s, and R21s were discussed. The troubling fall-off of applications to AIDS and AIDS-related research project grants since 2016 was noted, including the continual fall in R01 and R21 applications. Dr. Dieffenbach stated that if application numbers continue to drop that AIDS coordinators across the institutes may want to look globally across the spectrum of AIDS research and monitor the issue.

Questions/Discussion

Comment: It seems that less people are coming into the basic HIV-1 field and there is the sense that some investigators are replacing their funding by becoming part of larger initiatives related to cure and the structural biology initiatives.

Q: What is responsible for the drop-off in the project program grant (PPG) applications? Have program staff noticed less interest?
A: When there are a large number of applications, usually it is because they are solicited and there is specific money that is set aside for these applications. This year where there was no set-asides, all of the applications that came in were unsolicited, and they did not score well.

Comment: The decrease in the number of applications that is being seen is more universal and prompted the reorganization and consolidation of the study sections in CSR.

Q: With 100 to 150 fewer grants, where is money going?
A: The money is adjusted by the budget office and is allocated based on the success rate. The budget office tries to maintain paylines and success rate that are relatively close across the Institute.

Q: What year did policy for resubmission change—are you counting the number of applications differently?
A: Unsure as to the year, but applications are not being counted differently.

Comment: What might help reverse this trend is to broaden the spectrum of RFAs that are put out. Many of the RFAs are focused in a narrow range of areas really related to cure research and vaccines, with relatively little attention given to the basic scientists in terms of more fundamental issues.

  • There is movement in the program to collaborate on some broader topic areas.

Comment: At an NIAID T32 directors meeting, we were seeing the same decrease in applicants to the T32. The competitiveness of the applicants or the number of applicants is decreasing similarly to what is shown for the NIAID/DAIDS R01 numbers. It is possibly a pipeline problem that also precedes this.

Q: Are K awards increasing? Are there any thoughts to increase pilot programs for young investigators?
A: The Institute has a program of some plans that are in development that will launch soon to deal with where we are on the training. Those have been worked through since the beginning part of this fiscal year and are about to come out.

Comment: Universities are seeing fewer people going into infectious diseases who want to do HIV/AIDS research. This has been seen with fellow applicants. This is a big concern in the field right now.

Q: For those at academic centers, are you not hiring in this area or not getting applicants?
A: Problem might be bigger than just AIDS-related research as fewer infectious disease fellows seem to actually want to do research of any sort. Success rates of grants over the last 5 to 10 years have made people nervous about going into research and dedicating their life to a field where it is difficult to be successful. There are similar problems recruiting in the clinical center at NIH. Economics is a factor given the compensation in infectious diseases compared to other subspecialties.

NIAID HIV/AIDS Clinical Trials Network Recompetition Update

The FOAs for the Leadership and Operations Centers (LOCs), Statistical and Data Management Center (SDMC), and Laboratory Center (LC) were released on Thursday, January 24, 2019. The receipt date will be early August of 2019, with reviews completed sometime in April 2020 with a December 2020 award date. The Clinical Trials Units (CTU) FOAs will not be published until April 2019, with a receipt date in November 2019. Collaborating institutes were listed along with which FOAs they have signed on to. These institutes include the National Institute of Mental Health (NIMH), the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Child Health and Human Development (NICHD), the National Institute on Drug Abuse (NIDA), and the National Institute of Dental and Craniofacial Research (NIDCR). A high-level picture of what is being solicited in the FOAs was overviewed and included the scientific foci for prevention, adult therapeutics, maternal, adolescent and pediatric therapeutics, and vaccines.

Questions

Q: What is the official position of DAIDS regarding microbicides?
A: Microbicides could be covered within the prevention network. It is up to the applicant to decide what they choose to write. We have built into the FOA the ability to take any product or strategy that appears to be compelling and meets a public health need and take that product forward. Multipurpose prevention technologies (MPT) are an important focus in the FOA, and we want to see them move forward. These could include HIV prevention and potentially contraception, as well as prevention of other sexually transmitted infections of importance.

Q: Is there any emphasis on rural populations considering the changing character of the epidemic?
A: This is a Clinical Trials Network program; it is not an implementation science program. There are other ways we intend to deal with the rural epidemic.

Small Business Innovation Research (SBIR) Contract Proposals:

The SBIR contracts complement the grant SBIR funding mechanism and help DAIDS achieve its scientific mission by encouraging scientific and technical innovation in specifically identified areas. Two new topics were presented and voted upon by the committee, and two re-issued topics from the January 2018 ARAC were presented briefly – “Co-delivery and Formulation of Adjuvants for HIV Vaccine Development” and “Particle-based Co-delivery of HIV Immunogens as Next-Generation HIV Vaccines.”

The first new topic presented, “Small Molecule Targeting of HIV RNA,” has the goal of supporting the discovery and design of RNA-targeted small molecules which specifically bind to HIV RNA transcripts to prevent RNA processing and translation into protein. Phase I actives may include designing, optimizing, and testing strategies for the targeting of small molecules to key sites on HIV RNA; performing proof-of-concept studies to demonstrate that small molecules binding to HIV RNA can prevent processing and translation into proteins in relevant cell lines and primary cells; evaluating off-target effects; and performing proof-of-concept studies in an HIV animal model. Phase II activities may include optimizing delivery to target HIV-infected cells with minimal off-target effects; evaluating organ toxicity, immune responses/adverse events, and pharmacokinetic/pharmacodynamic parameters in nonhuman primates; and performing investigational new drug-enabling studies in consultation with the FDA.

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

The second new topic presented was “Sequenced-Based Assay To Quantify the Replication-Competent HIV Reservoir.” The objective of this topic is to design an assay as an analytical tool to monitor the size of the replication-competent HIV reservoir in clinical research settings or prospective clinical trials. It is to have essential characteristics for commercially applicable HIV reservoir assays are reproducibility, low labor intensity, medium-to-high throughput performance, and correlation with the replication-competent HIV reservoir. When designing the assay, internal sequence deletions, lethal mutagenesis, such as G-A hypermutations, stop codons within the HIV open reading frames, and nonfunctional LTR promoters need to be considered. Applicants will need to provide a plan for how their assay correlates with the Quantitative Viral Outgrowth Assay and other recently developed HIV reservoir assays. Phase I activities may include developing medium medium-to-high throughput sequence-based assays that accurately reflect the size of the replication-competent reservoir; developing standardized controls for the sequence-based assays; confirming that the sequences detected correspond to full-length HIV proviruses; and determining the following assay parameters: Specificity, Sensitivity, Interference, Robustness, and Accuracy. Phase II activities may include testing clinical samples from diverse cohorts of HIV+ individuals with varying levels of residual viral reservoirs; validating the developed assays under CLIA and ICH harmonized Good Clinical Practices; determining assay performance for different HIV subtypes and drug-resistant strains; determining assay performance in tissues versus blood; and demonstrating that the assay can reliably measure changes in the size of the latent HIV reservoir if used in an intervention.

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

Office of AIDS Research Advisory Committee Update

Roy Gulick, M.D., M.P.H.

Dr. Gulick gave a summary of the Office of AIDS Research Advisory Committee (OARAC) meeting held on November 15, 2018. The meeting began by reminding the committee of the Office of AIDS Research (OAR) vision, mission statement, the NIH priorities for HIV and HIV-related research for FY 2016 – FY 2020, and the strategic planning framework for the OAR. Budget and science accomplishments of OAR for 2018 were reviewed and included restructuring the planning and budget processes, developing cost-sharing process and pilot projects, continued alignment of NIH Portfolio with high priorities, addressing emerging needs for increasing the sample size for the REPRIEVE clinical trial and increasing funding for dolutegravir research, and combining the MACS/WIHS cohorts. The key activities for 2019 were overviewed and included the 2020 budget planning, a 2020 review of the portfolio of HIV/AIDS research, and more long-range research priorities. Updates from the five HIV/AIDS Treatment guidelines panels were shared. It was noted that the guideline page views continue to experience an increase in web traffic highlighting their popularity and wide usage in the community. Brief versions of each of the guidelines were released this past year after discussion and focus groups with guideline users. Updates to adult, opportunistic infections (OI), and pediatric guidelines were reviewed. Key updates to the adult guidelines included information on dolutegravir (DTG) and its potential association with neural tube defects, three new drugs that were approved by the FDA, new ARV fixed dose combinations that were approved, and data was incorporated from the GEMINI study. The perinatal updates centered on DTG and does not recommend its use for pregnant women before 12 weeks of gestation. Dr. Gulick then presented updates from the NIH Advisory Council Representatives that presented at OARAC. Dr. Rohan Hazra presented NICHD updates at the OARAC meeting and focused on the issue of DTG and neural tube defects using data from the Tsepamo study in Botswana which NICHD obtained innovation funds from OAR to supplement the study. Dr. Raab-Traub, from the National Cancer Advisory Board, reviewed the Cancer Moonshot initiatives and emphasized the use of immune-based therapies and the possible applications to HIV cure research. Dr. Alan Greenberg reviewed the National Advisory Mental Health Council meeting and discussed the two HIV-related concepts, one looking at mechanisms of neuropsychiatric side effects and neurological toxicities of ART and the other focusing on PEPFAR, that were approved. Dr. Carlie Williams, of DAIDS, provided an update on the status of the IeDEA cohort, regional and globally relevant research databases based on clinical records with novel statistics and strong epidemiology. The National Institute on Aging presented their HIV priorities and reviewed a FOA that funded eight studies that looked to study the commonalities and difference between Alzheimer’s disease and HIV-related dementia, specifically focused on Alzheimer’s related proteinopathies. Finally, Dr. Sheri Hild, from the Office of Research Infrastructure Programs, reviewed the nonhuman primate (NHP) evaluation and analysis. NHPs are used most frequently by HIV/AIDS researchers.

Questions

Q: What does it mean to combine WIHS and MACS studies? Is that combining budgets or an analysis?
A: The cohorts have been moved over to the National Heart, Lung, and Blood Institute (NHLBI) to continue their evolution. They were originally set up to look at viral endpoints, and as time has gone on and therapy has gotten better, the questions have changed to more comorbidity related. By moving to NHLBI and through collaborations with other ICs including NIAID, they can focus more on the comorbidities. Since the cohorts have been combined, the sites are the same.  For instance, women's sites in the South will be able to enroll MSM.

Programmatic Overview: Key Accomplishments and Future Directions

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

The PSP’s mission is to deliver products and strategies to reduce HIV incidence at a population level, improve material and pediatric HIV treatment options, work towards an HIV cure in the pediatric population, and deliver products and strategies to improve maternal and pediatric TB diagnosis, prevention and treatment. The area of HIV prevention was put into perspective by showing data of the continuing HIV pandemic. It was noted that between 2015 and 2017, there has been an increase in the number of individuals receiving treatment. This increase has only slightly outpaced new infections per year. Main areas of focus for HIV prevention in PSP include continuing to expand prevention product choices to meet needs of key populations – long-acting formulations with systemic coverage that specifically focus on the needs of adolescent men and women; improving biological and behavioral understanding of key populations, including transgender people; improving understanding of how to create desire for prevention products and strategies; fostering innovative prevention trial design methodologies; improving HIV incidence assays; and partnering to improve integrated prevention strategies. Currently PSP has four major types of long-acting prevention that are in the works – the intravaginal ring, implants, injectables, and antibodies. The importance of understanding biological differences and behavioral difference and needs of key populations, specifically transgender persons, was highlighted. There are 25 million transgender persons worldwide and data from studies in 15 countries have shown a 49-fold increase in risk of HIV infection compared to all other reproductive-aged adults. Ethnographic work targeting young women in South Africa has been started to understand how to make prevention desirable. This has involved in-depth interviews, focus groups, detailed surveys, and in-home and out-of-home observations. Data analysis presented at IAS and R4P identified six psychographic typologies based on attributed and aspirations of the young women, as well as social media usage. An initial consultation has been held and next steps are being planned. Maternal and pediatric HIV treatment and cure were addressed. This included the challenges of having suitable formulations for various populations and the need to determine dosing strategies in different populations. Approaches to interventions for treatment include accelerating evaluation and licensure of promising antiretroviral drugs, advancing evaluation of long acting and novel drug delivery strategies with extended dosing intervals, and with partners, demonstrating effectiveness of these approaches as integrated behavioral, biomedical, and structural interventions with an emphasis for adolescent populations. Maternal and pediatric tuberculosis and other comorbidities were described, including the TB burden in children. Diagnosis in children is challenging due to its paucibacillary nature and non-specific manifestations with up to 2/3 of cases undiagnosed. The stages along the continuum of TB disease spectrum are poorly characterized in children and a significant proportion of morbidity and mortality occurs in children without known TB exposure. The presentation concluded with the accomplishments and highlights of the program over the last year. The preclinical group issued and received application for sustained release and multipurpose prevention FOAs, the DREAM Integrated Preclinical/Clinical Program award completed the first clinical trial of a rectal enema for use as an HIV prevention product, and PSP staff presented results of PK/PD studies in macaques to support validation of an ex vivo biopsy virus challenge model at R4P. The clinical microbicide group completed the HOPE open label study of Dapivirine intravaginal ring, initiated a multipurpose prevention technology intravaginal ring study of Dapivirine and LNG in collaboration with the Contraceptive Clinical Trials Network funded by NICHD, and completed two Phase I studies of rectal microbicide products. The clinical prevention group held the Methods for Prevention Package Program meeting, launched the Engaging Men in HIV Testing, Prevention, and Care PA along with a publication in the Lancet, and completed the HPTN 071 (PopART) study. The maternal, adolescent, and pediatric group held the Framework for HIV Cure Studies in HIV-infected Children Workshop, issued the Long Acting Drug Delivery Systems for Treatment Optimization in HIV-infected Children FOA, and started enrolling in IMPAACT 2010.

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

Dr. Finzi presented an overview of the BSP whose overarching goal is to find the virus and stop transmission (human-to-human and cell-to-cell). The grants and programs of each of the three branches (epidemiology, pathogenesis and basic research, and targeted interventions) within the Program were overviewed. Dr. Finzi highlighted a number of programs/grants within BSP, beginning with IeDEA, the International epidemiological Database to Evaluate AIDS. IeDEA is an international consortium with sites in over 130 countries and collects and analyzes data from over 1.7 million people. The program addresses local, national, and global questions about the natural and treated history of HIV infection. Due to the tremendous capacity and potential for expansion within IeDEA, it has generated pathogen libraries that can be shared, and in 2019 a Sentinel Research Network was launched at key sites within each of the seven regions. Next, a domestic program, the Center for AIDS Research (CFARs) Southern Initiative was discussed. There are eight CFARs located in the southern states where the highest burden of HIV infection is found. This initiative will leverage existing relationships with local, state, and federal agencies and community organizations to improve the implementation of existing tools for HIV prevention and care. BSP’s Limited Interaction Targeted Epidemiology (LITE) grants work to understand the dynamics of spread of HIV between individuals by showing proof of concept that high-risk populations in rural and urban settings can be reached though computers and cell phones. These grants, which are co-funded by NIAID, NIMH, and NICHD, fund four large-scale digital cohort studies of MSM and transgender women in the United States. Though these studies are still ongoing, they have shown the potential future opportunities to test digital prevention interventions. Dr. Finzi then briefly touched on the significant push to support studies that aim at being able to self-detect virus by coming up with a device that would be analogous to the glucose meters for diabetes that would allow one to self-test for virus as well as monitor one’s own viral load. BSP continues to maintain a healthy and wide base of basic science grants in area including basic immunology, cellular biology and imaging, and in structural studies. This includes the Martin Delaney Collaboratories for HIV Cure Research which support coordinated basic, translational, and clinical research focused on developing strategies for a cure. Each Collaboratory includes a private sector partner in order to facilitate rapid translation as Collaboratories are expected to carry out preclinical and clinical studies to test new single or combination strategies for HIV cure. The BELIEVE Collaboratory has shown that the human IL-15 superagonist ALT-083 directs SIV-specific CD8+ T cells into B-cell follicles, thereby reducing HIV-infected cells from making more virus. Other biological molecules that BSP continues to support include chimeric antigen receptor T-cells (CAR-T cells), dual affinity re-targeting molecules (DARTs), and eCD4Ig. Several recent important discoveries between the host and viral proteins on a subcellular level were discussed. These included the discovery that inositol phosphates, which are present in all mammalian cells, are assembly co-factors for HIV-1, and an assay that can accurately and easily count the number of cells that comprise the HIV reservoir, including latent virus infected cells. Dr. Finzi ended by discussing the future directions of each branch within BSP.

Questions

Q: Regarding the LITE cohorts, are you seeing a high zero incidence in the population and are you learning anything new about transmission?
A: Incidence was between 2 and 4 percent. There were people who wanted to be included and needed to be excluded causing the percentage to be considerably higher. We are learning new things about transmission, such as perception, but it is still early.

Q: We heard earlier about the declining number of R01, R21 applications. Do you have a sense that is particularly the case in basic science or less so as a general trend compared to the other areas?
A: I think there's a little bit of a decline, but it is hard to say. In terms of basic science questions, we have unsolicited grants and there is a broad base of questions that come in through unsolicited applications. It is a bit of a constant battle to try to solicit for things that our Director thinks should come in under unsolicited because there is such a broad possibility there.

Comment: There are areas in HIV basic science which could use a kick to bring in new people to research. The issue is discovery of new drug targets. The notion that long-acting therapies are going to be widely used requires the availability of agents with high potency that agents against the traditional drug targets rarely have. It is encouraged that DAIDS pushes the barrier to find a new target. An example is the capsid inhibitors that have remarkably high potency and look like they are going to be very good long-acting drugs. Obviously, predicting where the new targets are going to be is tricky, but it is important to keep a wide range of fundamental science in this area well supported.

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

Dr. Marovich began by sharing the priorities in HIV vaccine research and development – priorities of vaccine design are to discover immunogens that protect in challenge models and to understand protective responses; priorities of vaccine development are to translate research to clinical trial material and to evaluate safety, immunogenicity and efficacy. Advances in broadly neutralizing antibodies (bNAbs) were detailed and included more than 200 bNAbs have been described that recognize five main epitopic areas on the envelope surface. These bNAbs are isolated under conditions of natural infection and still need to be studied to understand how these antibodies develop in vivo. It was discussed how the program proposes to induce bNAbs through vaccination using schematic diagrams. In brief, the vaccine design methods involve three approaches: lineage-based, germline-based, and epitope-based. Selection criteria for immunogen selection was presented and included unmutated ancestor affinity measurements, ability to induce Ca++ flux in B cell lines, ability to expand B cell precursors in knock in (KI) mice, ability to induce nAbs in KI mice, and ability to act as bait and pull out bNAb precursor B cells. A list of the HIV vaccine bNAbs immunogens that are near term clinical testing from 2017 to 2019 was shown and divided the immunogens based on the design method. Candidate vaccine platforms that protect NHP that do not involve bNAbs were described. These included an Ad26 priming with an Ad26 gp140 boost that protected two-thirds of the animals and is now in efficacy testing in a small proof of concept study called HVTN 705, and a Rhesus CMV vector containing gag and non-envelops inserts, the Picker model. Data from the CMV vector studies consistently showed that approximately 50 percent of animals can clear SIV infection and that the mechanism involves HLA-E. However, the CMV virus is very species-specific, and it is unknown if this vector data will be repeated in humans, though the human CMV vectors are in GMP production. Translating promising vaccines to humans was discussed with the aid of a table showing HIV vaccine candidates, including a broad range of gp120s, Chimp Ads, plasma DNA, and replication-competent Ad4, that moved into clinical testing in 2018. Access to adjuvants is still a problem so this past year VRP helped develop the 2018 NIAID Strategic Plan for Research on Vaccine Adjuvants and worked with suppliers to improve adjuvant access, immunogenicity, and durability of HIV vaccine candidate. The bNAb immunogen portfolio of what is in testing now or will be in testing by 2020 was shown including CH505 protein that is being tested in the HVTN 115. Current clinical HIV vaccine approaches include an empirical approach, which takes the RV114 Thai trial and trying to improve upon the protection and durability of the non-neutralizing anti-Env V1V2 antibodies. This approach has led to the HVTN 702 Phase 2b/3 Clade C ALVAC + gp120 in MF59 trial and the HVTN 705 Phase 2b Mosaic Ad26 +gp140 trial. The other HIV approach is the theoretical approach to design vaccines that induce bNAbs, which has led to numerous Phase I trials, and the immunoprophylaxis with bNAbs which led to the AMP study (HVTN 703 and HVTN 704) using the VRC01. Dr. Marovich concluded by noting the HIV vaccine development challenges. One key point was even if a vaccine shows 40 to 50 percent efficacy and will not be advanced, immune correlates still need to be identified as they can be used to advance vaccine candidates without having to do large efficacy trials each time a new vaccine needs to be tested. This could incentivize or de-risk industry involvement and increase the capacity and efficiency of manufacturing if industry is involved to bring promising vaccines forward for prequalification and registration and marketing.

Public Comments

Three individuals spoke on issues important to them:

1. Manju Chatani-Gada: Works with AVAC.

  • Welcomed the language in FOA for the Prevention Network that non-systemic and other products can be considered in a case-by-case basis and depending on the public health need. But hopes that community advocates can be involved in the discussion of deciding what those public health needs are.
  • Happy to note the prioritization of MPTs and the population focus to include cis and transgender women of U.S. minorities and pregnant women.
  • There is hope that the applicants to the FOA will also choose to describe ways to hand off to implementation scientists after developing successful products to ensure there is rapid and uninterrupted progression from research to rollout and to ensure all the investment being made here really bears fruit quicker than later.

2. Jim Pickett: Advocate representing the AIDS Foundation of Chicago and the International Rectal Microbicide Advocates (IRMA).

  • Pleased to see language in the FOA that will allow researchers to explore modalities that do not have systemic protection because we believe, and many others believe right along with us, there is need for user-controlled, on-demand options.
  • Believes community advocates, and not just researchers, need to be part of the assessment regarding the agreed-upon compelling specific public health.
  • Very pleased to see early-stage acceptability and desirability research called out.

3. Anna Forbes: Public policy director at the American Academy of HIV Medicine (AAHIVM).

  • Appreciates the acknowledgment of the importance of desire when it comes to prevention options.
  • Asks that the development of both systemic and user-controlled non-systemic HIV prevention methods are written into the budgets. More options means more protection and fewer new HIV infections.
  • Now is a good time to increase our investment in user-controlled HIV prevention.

VII.  Adjournment

The meeting of the Council adjourned at 4:00 p.m., on Monday, January 28, 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

04/19/2019

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

04/10/2019

Date

 

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

Content last reviewed on April 29, 2019