NIAID Council Minutes June 5, 2023

The 204^th meeting of the National Advisory Allergy and Infectious Diseases Council (NAAIDC) convened virtually at 10:30 a.m. on Monday, June 5, 2023. Dr. Hugh Auchincloss, Acting 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 11:35 a.m. and from 1:00 p.m. to 4:19 p.m. The meeting was closed to the public from 8:30 a.m. to 10:30 a.m. and from 11:40 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

Table of Contents

I. Review of Grant Applications
II. Remarks of the Acting Director, NIAID-Hugh Auchincloss, M.D.
III. Guest Speaker-Steven M. 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 4,858 research and training applications with primary assignment to NIAID for a requested amount of $1,729,182,479 in first-year direct costs and recommended approval of 2,599 applications with $1,068,769,588 in first-year direct costs.

II. Remarks of the Acting Director, NIAID-Hugh Auchincloss, M.D.

Dr. Auchincloss opened the Council session by welcoming visitors to the meeting. He also introduced three ad hoc members: Dr. Lucienne Chatenoud, Hopital Necker-Enfants Malades; Dr. Kevan Herold, Yale University; and Dr. Mark Anderson, University of California, San Francisco, Diabetes Center.

Consideration of Minutes of Previous Meeting

Council considered the minutes of the January 30, 2023 meeting and concepts that had been presented and approved them as written.

Staff and Organizational Changes

Meetings and Events

On March 23, 2023, Dr. Ashish Jah, the White House COVID-19 Response Coordinator, visited the VRC, which provided an opportunity to discuss the facility's role in future vaccine studies.

Dr. Auchincloss reported on select meetings with international health officials, including Dr. Dmytro Butov, Kharkiv Medical University, Ukraine; Dr. Yoshinao Mishima, President of the Japan Agency for Medical Research and Development; Dr. Emmanuel Bonginkosi Nzimande, Minister of Higher Education, Science, and Innovation for South Africa; Dr. Rajiv Bahl, Director-General of the Indian Council of Medical Research; and Dr. Rajesh Gokhale, Secretary of the Department of Biotechnology, Government of India.

NIH recently released a Strategic Plan for Diversity, Equity, Inclusion, and Accessibility (DEIA).

Budget Update

On March 9, President Biden released his FY 2024 budget request, which includes an overall increase of 3.9 percent for NIH, or $1.9 billion above the FY 2023 enacted level. NIAID and most other institute and center (IC) budgets remain flat at the FY 2023 enacted level. However, the President's Budget does request a $1 billion increase for the Advanced Research Projects Agency for Health (ARPA-H), a 6.9 percent increase for NCI, and a 2.5 percent increase for NIH's Office of the Director.

Dr. Auchincloss summarized NIAID's FY 2023 financial management plan. Our R01 payline is set at the 12 percentile for established principal investigators (PIs) and the 16 percentile for new PIs. NIAID does not plan to make programmatic adjustments to noncompeting and competing grants. Our estimated success rate for research project grants is 18 to 22 percent.

Dr. Auch incloss gave a brief update on NIAID's COVID-19 emergency supplemental funds and the impact of the debt ceiling legislation on NIAID's budget.

Legislative Update

On January 26, Dr. Auchincloss accompanied Acting NIH Director Dr. Lawrence Tabak to a Congressional briefing with Senator Bernie Sanders to discuss the technology transfer of discoveries that arise from NIH intramural research.

On March 15, Dr. Elodie Ghedin accompanied Dr. Tabak to brief staff of the House and Senate appropriations committees to discuss coronavirus sequence analyses.

Dr. Auchincloss thanked NIAID staff who have participated in many briefings for members of Congress and their staff.

At a World Malaria Day Congressional Reception on April 26, Dr. Robert Seder from the VRC received recognition on behalf of NIH for research evaluating the safety and efficacy of a monoclonal antibody against malaria in Mali.

Other Information Items

Dr. Auchincloss provided an update on COVID-19, including the end of the COVID public health emergency, the number of daily COVID-19 deaths in the United States, and some of the lessons learned during the pandemic. He described how NIAID clinical networks combined to form the COVID-19 Prevention Network, which took advantage of existing clinical trial infrastructure to conduct Phase 3 COVID-19 vaccine trials.

The White House recently launched Project NexGen. Its goal is to accelerate the development of new coronavirus vaccines and treatments. NIAID's role is to initiate clinical trials to evaluate mucosal and broadly protective vaccines.

In April 2023, the Mucosal Vaccines for SARS-CoV-2: Scientific Gaps and Opportunities—Workshop Report published in NPJ Vaccines. The Report summarizes challenges for developing truly protective mucosal vaccines and provides recommendations for advancing the field of research. Dr. Auchincloss mentioned an ongoing activity called the STRIVE (Strategies and Treatments for Respiratory Infections & Viral Emergencies) Protocol, which is evaluating future antivirals for hospitalized adults with COVID- 19.

Next, Dr. Auchincloss gave an update on recent and current outbreaks of filoviruses. NIAID continues to conduct research on vaccine candidates. He provided statistics on the global mpox outbreak and a graph showing that incidents of mpox cases in the United States have fallen dramatically in 2023.

Dr. Auchincloss highlighted two HIV-related studies that demonstrated promising results for improving patient outcomes.

Dr. Auchincloss concluded by noting the FDA approved the first respiratory syncytial virus (RSV) vaccines for people over 60 years of age and provided background information about NIAID research that led to the development of the two RSV vaccines that were recently approved and the COVID-19 vaccines. He also gave brief updates on research on universal influenza vaccine candidates, sexually transmitted infections, discovery of a new autoinflammatory disease, and the first FDA-approved drug to delay Type 1 diabetes in at-risk patients.

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

He concluded by summarizing future priorities, such as recruiting talented diverse investigators; continuing to support outstanding basic science; fostering bench-to-bedside approaches; making Clinical Center resources available to all labs; promoting pathophysiology, innovative strategies, vaccine targets, diagnostics, and therapeutics; and encouraging extramural and international collaborations.

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

Dr. Rotrosen welcomed the subcommittee members to the 204^th meeting of the National Advisory Allergy and Infectious Diseases Subcommittee meeting.

Dr. Rotrosen presented the following scientific and Division activities:

Staff and Organizational Changes

Venera Barsaku, M.P.H., Ms. Barsaku joined the Office of Program Planning, Operations, and Scientific Information (OPPOSI) as a Program Analyst in March 2023. Prior to joining DAIT, Ms. Barsaku served as a Project Manager at DMID where she was responsible for the planning, coordinating, and implementation of activities for two international programs: the International Centers of Excellence for Malaria Research (ICEMR) Program and the Tropical Medicine Research Centers (TMRC) Program. Ms. Barsaku is a graduate of George Mason University where she received a Master's in Public Health in Epidemiology.

Selected Funding Opportunities

NIAID

Consortium for Food Allergy Research: Leadership Center (UM1, Clinical Trial Required) RFA­ AI-22-077: The purpose of this funding opportunity is to establish the Leadership Center of the NIAID Consortium for Food Allergy Research (CoFAR). The CoFAR Leadership Center (LC) will define the overall research strategy of the CoFAR including design and oversight of cutting-edge clinical trials and clinical studies to advance prevention and management strategies and to improve knowledge on the origins and the pathophysiology of IgE-mediated food allergy, Alpha-Gal Syndrome, Food Protein­ Induced Enterocolitis Syndrome, and Eosinophilic Esophagitis. To achieve its objectives, the CoFAR-LC will work closely and collaborate with the CoFAR Clinical Research Centers (CRCs) to select and implement all CoFAR network-wide clinical trials and studies. The CoFAR network-wide clinical trials and studies will be conducted by the CoFAR-CRCs.

Consortium for Food Allergy Research: Clinical Research Center (U01, Clinical Trial Required) RFA-AI-22-076: The purpose of this funding opportunity is to select the Clinical Research Centers (CRC) for the NIAID CoFAR. The CoFAR-CRCs will conduct both network-wide observational studies/clinical trials and center-specific projects with the goals to advance prevention and management strategies and to improve knowledge on the origins and the pathophysiology of IgE-mediated food allergy, Alpha-Gal Syndrome, Food Protein-induced Enterocolitis Syndrome and Eosinophilic Esophagitis. For network­ wide clinical research projects and other network functions, the CoFAR-CRCs will work closely with the CoFAR Leadership Center (CoFAR-LC).

Autoimmunity Centers of Excellence, Basic Research Program (U19, Clinical Trial Not Allowed), RFA AI-22-070: The purpose of this funding opportunity is to solicit applications to participate in the NIAID Autoimmunity Centers of Excellence (ACE), a cooperative network intended to improve the understanding, prevention, and treatment of autoimmune diseases. The ACE was founded on the premise that collaborations among basic and clinical scientists can accelerate both fundamental and applied research. The ACE combines Basic and Clinical research programs. This funding opportunity solicits applications for the Basic research program; a companion funding opportunity solicits applications for the Clinical research program. Members of the Basic research program will conduct innovative studies of human autoimmunity within Principal, Pilot, and Collaborative Projects. Members of the Basic and Clinical ACE will work together to design and conduct studies of autoimmune disease pathogenesis and mechanisms of action of immune-modulating interventions being tested in ACE clinical trials.

Autoimmunity Centers of Excellence, Clinical Research Program (UM1, Clinical Trial Required), RFA AI-22-071: The purpose of this funding opportunity is to solicit applications to participate in the NIAID Autoimmunity Centers of Excellence (ACE), a cooperative network intended to improve the understanding, prevention, and treatment of autoimmune diseases. The ACE program was founded on the premise that collaborations among basic and clinical scientists can accelerate both fundamental and applied research. The ACE combines Basic and Clinical research programs. This funding opportunity solicits applications for the Clinical research program; a companion funding opportunity solicits applications for the Basic research program. Members of the Clinical research program will conduct innovative studies of human autoimmunity within Clinical and Collaborative Projects. Members of the Basic and Clinical ACE will work together to design and conduct studies of autoimmune disease pathogenesis and mechanisms of action of immune-modulating interventions being tested in ACE clinical trials.

Broad Agency Announcement (BAA-75N93022R00021): Development of Radiation/Nuclear Medical Countermeasures (MCMs) or Biodosimetry Devices: The goal of this BAA is to solicit proposals for 1) the development of medical countermeasures (MCMs) against radiation injury or 2) biodosimetry approaches targeting radiation-specific biomarker identification and/or device development to predict acute and/or delayed damage to specific organs and tissues beyond dose assessment. This BAA is intended to support research and development of promising new approaches to mitigate or treat tissue injuries arising from unintended exposure to ionizing radiation, which may include biologics (e.g., cytokines and free radical scavengers), cellular therapies, or drugs (e.g., anti-inflammatory agents, antibiotics, and anti-fibrotics).

Request for Proposals (RFP): NIAID SPF Macaque Breeding Colonies: This RFP solicits proposals for the care, breeding, and management of government-owned specific pathogen-free (SPF) Indian-origin rhesus macaque and Mauritian cynomolgus macaque colonies. The contract requirements include provision of high-quality MHC-typed animals to support NIH-funded awards, with priority given to the NIAID Nonhuman Primate Transplantation Tolerance Cooperative Study Group (NHPCSG). The over­ arching goal of the NHPCSG is to facilitate clinical translation of safe and effective tolerance-induction protocols for long-term allograft survival.

Division Activities

Radiation and Nuclear Countermeasures Program (RNCP)

Radiation-Induced Cutaneous (CRI) and Gastrointestinal (GI) Injuries: Understanding Pathologies, Assessment, and Clinically Accepted Practices. From December 5 to 9, 2022, an in-person workshop was held at the Institut de Radioprotection et de Surete Nucleaire (IRSN), in Fontenay-aux-Roses, France. Co­sponsored by the NIAID RNCP and the IRSN (French government agency responsible for radiation protection) the meeting brought together researchers and NIAID staff from the United States and IRSN researchers, as well as scientists from local French academic institutions, to discuss topics of mutual interest to both agencies. The goals of the workshop were to examine pathophysiology and clinical interventions for radiation-induced cutaneous (CRI) and gastrointestinal (GI-ARS) injuries; explore novel assessment approaches and medical countermeasures for CRI and GI-ARS; identify existing gaps, challenges, and needs for translational application in each space; and foster collaborative connections between the U.S. and French scientists. An outcome of the meeting was the initiation of several collaborations between French and U.S. investigators. A peer-reviewed commentary is also planned.

NIAID/AFRRI Annual Meeting. On November 4, 2022, NIAID/RNCP held an annual meeting for the NIAID/AFRRI-USUHS Interagency Agreement (IAA) that was originally established in 2005. The meeting was attended by NIAID/DAIT and AFRRI/USUHS leadership and scientific staff. The IAA consists of five separate work plans that focus on small and large animal model development and testing of medical countermeasures to treat radiation-induced injuries. The scientific updates included advancements and refinement of cutaneous and multi-organ injury models and performance of drug candidates. Discussion sessions addressed future research strategies and identifying solutions to current logistical challenges.

Allergy, Asthma, and Airway Biology Branch

Early Life Environmental Exposures Regulate Host Allergic Immune Responses: Lessons Learned from the Asthma and Allergic Diseases Cooperative Research Centers (AADCRC) Birth Cohorts. On February 24, 2023, at the annual meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) in San Antonio, Texas, the NIAID-funded Asthma and Allergic Diseases Cooperative Research Centers (AADCRCs) organized a symposium entitled "Early Life Environmental Exposures Regulate Host Allergic Immune Responses: Lessons Learned from the Asthma and Allergic Diseases Cooperative Research Centers (AADCRC) Birth Cohorts." Three experts in the field presented lectures on topics including exposure to pollution and childhood asthma, early life viral infection and contributions to long term lung health, and the effects of the farming environment on immune development and childhood respiratory illnesses.

Structural Cells Support the Asthma Phenotype: Lessons Learned from the Asthma and Allergic Diseases Cooperative Research Centers (AADCRC). On February 25, 2023, at the annual meeting of the AAAAI in San Antonio, Texas, the NIAID-funded AADCRCs organized a seminar entitled "Structural Cells Support the Asthma Phenotype: Lessons Learned from the Asthma and Allergic Diseases Cooperative Research Centers (AADCRC)." Two AADCRC investigators shared their experiences on studying epithelial and other structural cells.

Immunoglobulin E Explodes!: Lessons Learned from the Asthma and Allergic Diseases Cooperative Research Centers (AADCRCs). On February 25, 2023, at the annual meeting of the AAAAI in San Antonio, Texas, the NIAID-funded AADCRCs organized a symposium entitled "Immunoglobulin E Explodes!: Lessons Learned from the Asthma and Allergic Diseases Cooperative Research Centers (AADCRCs)." Three experts in the field presented lectures on topics including Tfh in IgE development, CD23+IgG memory B cells and their association with allergic disease, and a human IgE mAB structure­ based design for the treatment of peanut allergy.

Interleukin-33 (IL-33): Gateway to Allergic Disease, Lessons Learned from the AADCRC. As part of the annual meeting of the AAAAI in San Antonio, Texas, the NIAID-funded AADCRCs organized a session entitled "Interleukin-33 (IL-33): Gateway to Allergic Disease, Lessons Learned from the AADCRC)" as a pre-recorded session. Two experts in the field presented lectures on topics including the allergen sensing apparatus that participates in the initiation of allergic disease, and the role of platelets in regulating IL-33.

New Findings on Asthma and Allergic Disease in Urban Environments. On May 22, 2023, as part of the annual meeting of the American Thoracic Society (ATS) in Washington, DC, NIAID organized a session entitled "New Findings on Asthma and Allergic Disease in Urban Environments." The session featured investigators from the NIAID-funded Childhood Asthma in Urban Settings (CAUSE) network. Researchers presented lectures on topics including interaction among allergic sensitization, lung function and wheezing in urban children, upper airway transcriptome patterns in relation to lung function in urban children with exacerbation-prone asthma, and epigenetic contributions to understanding asthma and allergic sensitization in urban children.

Airway Omics for Disease Endotyping and Management. On May 24, 2023, as part of the annual meeting of the ATS in Washington, DC, NIAID organized a session entitled "Airway Omics for Disease Endotyping and Management." The session featured investigators from three NIAID-funded programs. Researchers presented lectures on topics including using airway transcriptomics to identify pathways associated with exacerbation and responsiveness to mepolizumab therapy in children, integrated analysis of airway immune responses in severe COVID-19 (results from the IMPACC cohort), and integrated omics investigation into the mechanisms linking severe bronchiolitis during infancy and the development of asthma.

Basic Immunology Branch

Immune Development in Early Life (IDEaL) Kick-off Meeting. On February 9, 2023, investigators and their teams awarded under this program met via a virtual platform. Eight projects are supported under this program that is a partnership between the National Institute of Environmental Health Sciences (NIEHS) and the Division of AIDS (DAIDS) and the Division of Allergy, Immunology and Transplantation (DAIT) from NIAID. Two U19s and 6 U01s are part of the program. The U19 projects are from St. Jude Children's Research Hospital and from Boston Children's Hospital. The U01 projects include University of California, San Francisco, Ohio State University, University of Oxford, Columbia University, University of Massachusetts, and Johns Hopkins University. The program supports research to define the mechanisms regulating the establishment, development, and maintenance of immunity throughout childhood (from birth to less than 18 years of age). The goal of this program is to expand knowledge of immune development and functionality in children that will provide foundational information to improve immune health and vaccine efficacy in this vulnerable population. Investigators presented research plans and recent updates in each of their programs. The meeting encouraged investigators to exchange ideas and to foster collaborations within the program.

Advances in Aging, Immunity and Chronic Inflammatory Diseases Workshop. On May 9 and 10, 2023, this workshop, jointly organized by DAIT, NIAID, the National Institute on Aging (NIA), and the National Institute of Dental and Craniofacial Research (NIDCR), was held in Bethesda, Maryland. Research scientists focused on recent advances in our knowledge of immune mechanisms and function during aging, immunosenescence, and their impact on chronic disease development. Stromal degradation, metabolic and transcription factor changes, inflammation-induced neurodegeneration, and new technological approaches were some of the areas presented at the workshop. The meeting served as a forum for bringing together investigators from diverse disciplines to discuss their research advances and provide opportunities for collaboration to advance the field.

Improved Tools for Modeling Human Immunity In Vitro and In Vivo-Organoid Cultures and Novel Mouse Models. On May 12, 2023, an NIAID-sponsored symposium entitled "Improved Tools for Modeling Human Immunity In Vitro and In Vivo-Organoid Cultures and Novel Mouse Models" was hosted by DAIT at the IMMUNOLOGY 2023 meeting in Washington, DC. This meeting was chaired by Dr. Joy Liu (NIAID Program Officer) and Dr. Mark Heise (Professor at the Univ. of North Carolina, Chapel Hill), and focused on 1) recent advances in the development and application of in vitro human organoid cultures that more closely resemble the architecture and physiology of human organs and pathogen-host interactions, and 2) novel in vivo mouse models that can better "mimic" human immune responses. Five invited speakers showcased their research using innovative human organoid cultures and mouse models to advance human immunology research for different diseases. Both novel systems allow the modeling of human or human-like immunity for testing candidate vaccines and therapeutics.

Transplantation Branch

13^th CTOT-CA Mechanistic Studies in Transplantation Workshop. On March 20, 2023, an annual workshop was held by the NIAID/DAIT/Transplantation Branch. This meeting assembled clinicians and researchers with expertise in Transplantation Immunobiology, and scientists pursuing various investigative approaches to study the immune system. The major meeting focus included study of intragraft allo-immunity, novel approaches to study the immune system, infections and immunity, beyond T and B cells, and antibody biology in transplantation. The major objective was to provide a collaborative forum to define future opportunities for advancing transplantation research. The following day, on March 21, 2023, the Clinical Trials in Organ Transplantation in Children and Adults (CTOT-CA) consortium of seven large multicenter clinical networks held their biannual Steering Committee Meeting. These networks are entering year 2 of their 7-year funding period and are at various stages along the regulatory pathway of FDA clinical study protocol approval.

Autoimmunity and Mucosal Immunology Branch

Autoimmune Disease Coordinating Committee (ADCC). On December 20, 2022, NIAID convened a virtual ADCC meeting focused on fatigue in autoimmune disease. The goal was to discuss current NIH activities on fatigue in autoimmune disease, as well as needs and gaps in research. The meeting was attended by NIH members of the ADCC and representatives from autoimmune disease advocacy and professional organizations. Invited experts addressed the role of immune system dysfunction as a cause of fatigue (Mark Davis, Director of the Stanford Institute for Immunity, Transplantation and Infection and the Burt and Marion Avery Family Professor, Stanford University School of Medicine), and fatigue as a feature across diverse autoimmune disorders (Lauren Krupp, MD, Nancy Glickenhaus Pier Professor of Pediatric Neuropsychiatry, Director of the Division of Multiple Sclerosis, Department of Neurology, NYU Grossman School of Medicine). Additional presentations by representatives of autoimmune disease advocacy groups reported results of surveys to assess the frequency and severity of fatigue reported by people diagnosed with autoimmune disease.

Autoimmunity Centers of Excellence (ACE), Steering Committee. On December 8, 2022, the ACE steering committee convened a virtual meeting to discuss the progress of their shared research agenda, basic and mechanistic studies, and clinical trials. The ACE continues to be highly productive in supporting outstanding fundamental research into the mechanisms of autoimmunity in humans, and supporting clinical trials with mechanistic studies of novel therapies for autoimmune diseases, including immunoglobulin G4-related disease (NCT04918147), systemic lupus erythematous (NCT050482380, NCT05306873, NCT03093402), rheumatoid arthritis (NCT02603146), multiple sclerosis (NCT05285891), pemphigus (NCT03239470), and COVID vaccine responses in people with autoimmune disease (NCT05000216).

FY 2025 Research Concept Clearances Presented to Division Advisory Council

The subcommittee endorsed and unanimously approved the following four Research Concept Clearances:

1.  Computational Models of lnfluenza Immunity (U01, Clinical Trial Not Allowed): The objective of this program is to use computational modeling and immunologic studies to advance our understanding of the requirements for improving anti-influenza immunity, including inducing broad immune protection, and enhancing durability. This program will help inform design of universal or improved seasonal flu vaccines.
2. Development of Candidate Radiation/Nuclear Medical Countermeasures (MCMs) (U01, Clinical Trial Not Allowed): This request for applications allows the RNCP to solicit investigator-initiated research at all stages of advancement that is specifically focused on exploring efficacy of candidate MCMs to counter the damaging biological effects of radiation exposure. This funding opportunity will support the early through mid-stage research and development of radiation-relevant products and approaches that may be considered for future licensure by the U.S. FDA.
3. Fe-Dependent Mechanisms of Antibody-Mediated Killing (U01, Clinical Trial Not Allowed): This initiative will expand understanding of the role and mechanisms of action of non­neutralizing/Fc-mediated antibody functions in host protection, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent phagocytosis (ADP). Understanding these mechanisms has gained even more importance with questions surrounding current antibody therapeutics for SARS-CoV-2.
4. RNCP Portfolio-Wide Dosimetry Verification Services: This initiative will continue the harmonization of radiation dosimetry methodology across the RNCP portfolio and will lead to more reliable and reproducible data from RNCP-funded projects.

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 June 5, 2023. She provided a DMID personnel update, recognizing new staff appointments made in the Division since the last Council meeting, noting that MJ Huntsgood, Sonia Gales, and Stephen Black have all joined the Respiratory Diseases Branch. In addition, Jane Knisely is the new Pandemic Preparedness Strategy Coordinator in the DMID Office of the Director. Following staff introductions, Dr. Erbelding provided a report on recent DMID activities of note:

• The Coronavirus Variant Immunologic Landscape (COVAIL) Clinical Trial, Stage 4 (Pfizer bivalent arm) results were recently published. The randomized clinical trial compared early neutralizing antibody responses after boosting with bivalent SARS-CoV-2 mRNA vaccines based on either BA.I or BA.4/BA.5 Omicron spike protein combined with prototype spike. Responses against SARS-CoV-2 variants exhibited the greatest reduction in titers against currently circulating Omicron subvariants for both bivalent vaccines.
•  Project NextGen, a coordinated effort between the Biomedical Advanced Research and Development Authority (BARDA) and NIAID was recently established. Under this program, the federal government will work with the private sector to advance the pipeline of new, innovative vaccines and therapeutics from labs into clinical trials with the intent to transition to the private sector later stage development and potential U.S. FDA authorization. NIAID plans to leverage existing infrastructure and network sites to implement a structured program to evaluate next generation COVID-19 vaccines in Phase 1 and Phase 2 clinical trials.
• DMID launched a new clinical trial to evaluate a bacteriophage-based approach for shigella infections, which are increasingly resistant to traditional antibiotics. The study is being conducted in collaboration with a small biotech company that makes phage products, Intralytix.
•  A DMID-supported investigational universal flu vaccine candidate using the mRNA platform has entered clinical testing. The candidate, HlssF-3928 mRNA-LNP, was developed through the Collaborative Influenza Vaccine Innovation Centers (CIVICs) program and manufactured at the facilities of the Duke Human Vaccine Institute (part of the CIVICs program). A similar vaccine developed by researchers at NIAID's VRC already has shown positive results in early clinical trials.

Presentation: DMID Pandemic Preparedness Efforts - Dr. Jane Knisely, DMID's Pandemic Preparedness Strategy Coordinator, provided an overview of DMID's pandemic preparedness efforts. She shared information about NIAID's Pandemic Preparedness Plan, which was published in 2021, and described Institute efforts to systematically characterize known pathogens of pandemic concern and increase research and surveillance on novel threats before they emerge. She then described DMID's wide array of programs and activities that are focused on the themes of pandemic preparedness. For example, the Centers for Research in Emerging Infectious Diseases program and the Centers for Excellence in Influenza Research and Response are focused on pathogen discovery, tracking, and characterization. She also described ongoing efforts to develop broadly protective coronavirus and influenza vaccines through investigator-initiated awards and the DMID-supported Collaborative Influenza Vaccine Innovation Centers, a program designed to advance the development of a universal influenza vaccine, a top NIAID priority. She described the HHS-wide Antiviral Program for Pandemics (APP) announced in 2021 focused on therapeutic discovery for seven priority viral families with pandemic potential, including SARS-CoV-2, noting that NIAID awarded the Antiviral Drug Discovery Centers for Pathogens of Pandemic Concern in 2022 to advance research under the umbrella of the APP. She noted the Research and Development of Vaccines and Monoclonal Antibodies for Pandemic Preparedness Network (ReVAMPP) planned for award in FY 2024, which aims to support the development and validation of generalizable vaccine strategies for prototype viruses that can be applied to other closely related family members and advance the scientific knowledge needed to develop vaccines and monoclonal antibodies (mAbs) for prototype viruses from families with strong pandemic potential. She described DMID­supported preclinical service programs, repositories, and clinical trial infrastructure available to assist with pandemic preparedness research, and also noted that DMID issues Broad Agency Announcements on a regular basis to support later stage preclinical or early clinical development of countermeasures for pathogens with pandemic potential. Finally, Dr. Knisely recognized the many players that are critical to advancing pandemic preparedness and noted that DMID has close alliances with these groups, including other components of NIAID, e.g., DAIT, DIR, VRC, and DCR; other NIH ICs, such as the National Center for Advancing Translational Sciences and the National Institute of Biomedical Imaging and Bioengineering; and other U.S. government agencies such as BARDA and DoD. NIAID is also engaged with foundations and nongovernmental organizations, for example, CEPI and the Bill and Melinda Gates Foundation.

FY 2025 DMID Concepts Presented for Clearance

The following concepts were presented to the Subcommittee. All concepts were approved.

Research Tools for Difficult to Culture Eukaryotic Pathogens - The objective of this concept is to encourage high risk, milestone-driven approaches to develop robust culture techniques, and/or genetic and molecular tools, to better understand the biology of select eukaryotic pathogens. The DMID Subcommittee acknowledged the importance of developing research tools and culture techniques for the select eukaryotic pathogens targeted, including: Enterocytozoon bieneusi; Pneumocystis jirovecii; Plasmodium vivax; and Babesia microti. They suggested the phased funding mechanism would be appropriate to accomplish the goals of the concept and appreciated the multidisciplinary approach. The Subcommittee noted that established organoid cores could lend expertise and that this type of technology is easily transferable, underscoring the likelihood of success for the proposed initiative. One Subcommittee member inquired about the parameters of B. microti in the blood supply and chances for transfusion-related infection. Program staff responded that the risk was significant. Another Subcommittee member added that in endemic areas in the United States, transfused neonates are at significant risk for babesia infection, as well as ambulatory rheumatologic patients on immunosuppressives. Overall, the Subcommittee recognized a lack of research tools as a barrier to advancing these scientific fields. The Subcommittee approved the concept with a unanimous vote.

Centers for Research in Emerging Infectious Diseases (CREID) Network and Centers for Research in Emerging Infectious Diseases (CREID) Network Coordination Center

Two companion concepts were presented for renewal: the objective of the Centers for Research in Emerging Infectious Diseases (CREID) Network (research center component), is to bring together multidisciplinary teams of domestic and international researchers to conduct integrated research that will help formulate coordinated strategies for detecting, controlling, and preventing emergence or re­emergence of viral infectious diseases while also developing and providing novel reagents, tools, and assays, which could facilitate research in response to an infectious disease outbreak. The Centers for Research in Emerging Infectious Diseases (CREID) Network Coordination Center would play a key role in facilitating coordination, communication, and collaboration among the Network's centers and stakeholders. The DMID Subcommittee recognized the importance of the current Network and noted that these concepts will have a significant impact towards improving our understanding of emerging and re­emerging infectious diseases as well as strengthening research capabilities globally. Subcommittee members agreed that being able to conduct timely and efficient outbreak related research is critical to preventing or mitigating future outbreaks, epidemics, or pandemics and viewed it as aligning well with NIAID's mandate and pandemic preparedness strategies. The Subcommittee also noted that the scope of research for this program is extensive and serves as a critical bridge to medical countermeasure development. Furthermore, Subcommittee members noted they were supportive of the program incorporating more translational and climate change research and expanding the geographical reach within the program. Multiple members also encouraged the program to continue efforts to coordinate and work with other USG agencies or programs (such as the Centers for Disease Control and Prevention and NIH's Fogarty International Center). Subcommittee members were also very supportive of the program's efforts and plans to continue to increase data transparency and sharing as well as fostering the next generation of scientists and leaders. The Subcommittee approved the concept with a unanimous vote.

FY 2024 ODSET Concept Presented for Clearance

Finally, Dr. Wilbert Van Panhuis, Director of the NIAID Office of Data Science and Emerging Technologies, presented a FY 2024 concept to the Subcommittee for clearance titled Development of Software for Data Science Methods in Infectious and Immune-Mediated Diseases Research. Dr. Van Panhuis noted that there is a critical opportunity to (re-)use data generated through NIAID research programs effectively to discover new knowledge and understanding of pathogen transmission and evolution, pathogen-host interactions, host immune response, and infectious and immune-mediated disease pathogenesis, and to develop new and improved diagnostics, therapeutics, and vaccines. Hence, the need for innovative computational tools and software for use by the research community, ideally made available in a format compliant with Findable, Accessible, Interoperable, and Reusable (FAIR) guiding principles. The Subcommittee voiced strong support for the concept, and it was approved with a unanimous vote.

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

Welcome and Approval of Minutes
Elaine J Abrams, M.D.(Chair)

Dr. Carl Dieffenbach welcomed Dr. Elaine J. Abrams as the new ARAC Chairperson. Dr. Abrams called for a vote from the Committee to approve the minutes of the January 30, 2023 ARAC meeting. The minutes were unanimously approved.

Director’s Report

Carl Dieffenbach, Ph.D., Director, Division of AIDS (DAIDS)

Dr. Dieffenbach's presentation began with mention of the sad news of the passing of Dr. Edmund Tramont in March. Dr. Tramont was the Director of the NIAID Division of AIDS (DAIDS) from 2001- 2007.

Monica Bertagnolli, M.D., current Director of the National Cancer Institute, has been nominated to be the new NIH Director. Her nomination will require Senate confirmation.

Ted Pierson, Ph.D. has been selected as the new Director of NIAID's Dale and Betty Bumpers Vaccine Research Center.

On the DAIDS front, Janet McNicholl, M.D., is the new Chief of the Vaccine Clinical Research Branch in the Vaccine Research Program. She was previously at CDC.

Mr. Roger Ptak has been selected as Chief of the new Drug Development and Preclinical Research Branch in the Therapeutics Research Program.

Moving on to ARAC news, we welcome Elaine Abrams, M.D., as the new Chairperson of the ARAC. We welcome Cynthia Derdeyn, Ph.D., as an Ad Hoc member of the ARAC. Dr. Derdeyn is Professor and Vice Chair of Research in the Department of Laboratory Medicine and Pathology at the University of Washington.

Linda Koenig, Ph.D., is joining us today as CDC Ex-officio, representing the Division of HIV Prevention at the National Center for HIV, Viral Hepatitis, STD and TB Prevention at CDC.

We welcome Anne Neilan, M.D., M.P.H., of Mass General Hospital and the Harvard Medical School as the new OARAC liaison to the ARAC.

In other NIH news, Bill Kapogiannis, M.D., is serving as the Acting NIH Associate Director of AIDS Research and Acting Director of the Office of AIDS research (OAR) while a nationwide search for a new Director is conducted. Dr. Julio Aliberti is representing the OAR at today's ARAC meeting.

Budget Update

The President submitted the FY 2024 budget request to Congress on March 9. We are currently operating under the FY 2023 amount enacted - $6.5 billion. We are zeroed out by the President's budget, and we are also zeroed out by the passage of the Debt Ceiling Bill. For FY 2024, NIAID and most other IC budgets remain flat with the FY 2023 enacted budget. This does not include the transfers from OAR for HIV/AIDS research; if there are rearrangements in the budget, we usually stand to benefit.

NIAID FY 2023 Financial Management Plan

NIAID R01 paylines for established and new PIs are at the 12th and 16th percentiles, respectively. Competing research initiatives have been cut by up to 20 percent. We estimate that overall success rates will be 18 to 22 percent.

Debt Ceiling

We had the passage of the Debt Ceiling; the Debt Ceiling has been rescinded until January of 2025. This will not be an issue for us until we get into FY 2025. In the meantime, the sense is we will be held at zero percent increase during the intervening years of FY 2024 and into 2025.

NIAID/DAIDS FY 2022 Report Card

The payline for FY 2023 is the same as FY 2022. We've continued to see a decline in applications, and this is something that is not unique to NIAID. We've seen a reduced number of applications submitted across NIH for FY 2022. We expect numbers to increase for FY 2023 as investigators are no longer writing applications for COVID.

For FY 2022, we had a very successful year funding seven P01 program project grants (success rate=46.7 percent). The R01s have a very good success rate at 23.2 percent, and R21s have also done very well (success rate=34 percent).

Overall, NIAID AIDS funding for R01s continues to be at a higher success rate (23.2 percent) than all of NIAID (16.3 percent) and other institutes at NIH (18.9 percent).

Scientific and Programmatic Updates

Diversity, Equity, Inclusion and Accessibility (DEIA) Highlights

• NIAID is participating in the UC2 notice of funding opportunity (NOFO): "STrengthening Research Opportunities for NIH Grants (STRONG): Structured Institutional Needs Assessment and Action Plan Development for Resource Limited Institutions" (NOFO-PAR-23-144)
• NIAID Research Opportunities for New and "At-Risk" Investigators to Promote Workforce Diversity (R01, Clinical Trial Optional) (NOFO-PAR-22-241)
• CFAR Diversity, Equity, and Inclusion Pathway Initiative (CDEIPI) through 2 years: 16 CFARs, 1,085 applicants, 241 funded scholars from over 20 HBCU/MSI at the high school, undergraduate, post-bac, graduate, and post-doc levels
• New Notice of Special Interest, "Administrative Supplements to Support Collaborative HIV/AIDS Research Projects at NIMHD-Funded Research Centers in Minority Institutions (NOT-MD-23-007)

Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) Study

Dr. Dieffenbach shared the encouraging results of the completed REPRIEVE study. The clinical trial was stopped early because a daily statin medication was found to reduce the increased risk of cardiovascular disease among people living with HIV who were on antiretroviral therapy. The study found that participants who took pitavastatin calcium, a daily statin, lowered their risk of major adverse cardiovascular events by 35 percent compared with those receiving a placebo. REPRIEVE began in 2015 and enrolled 7,769 volunteers who were 40 to 75 years of age, of whom more than 30 percent were women. Study volunteers were all taking antiretroviral therapy, with CD4+ cell counts greater than 100 cells/mm³ of blood at enrollment and had low-to-moderate traditional CD risk that would not typically be considered for statin treatment.

CoVPN3008 Study

This study, a comparison of the wild-type prototype strain and bivalent in people living with HIV, has completed enrollment. This is going to be a very important study to really understand the efficacy of vaccines against COVID in people living with HIV.

Study of Tecovirimat for Human Mpox Virus (STOMP) Trial

This is an ongoing ACTG (A5418) randomized, placebo-controlled, double-blinded trial of the safety and efficacy of Tecovirimat for the treatment of persons with human Mpox virus disease. Enrollment in this Mpox trial is increasing. We have established an arrangement with the CDC for a call-in phone line to recruit those who wish to obtain access to Tecovirimat. We believe this will really help us boost enrollment. We're going to a low touch/no touch type of recruitment and the ability to enroll people wherever they are in the country.

Public Comments

No public comments were received for this meeting. Any interested person may file written comments with the Committee by forwarding the statement to the contact person listed in the Federal Register Notice at least 10 days in advance of the meeting. The statement should include the name, address, telephone number and when applicable, the business or professional affiliation of the interested person.

Future ARAC Meetings

• September 11, 2023 (hybrid)
• January 30, 2024 (virtual)
• June 3, 2024
• September 9, 2024

Question: At this morning's Council meeting there was a comment about Pandemic Preparedness and funding it out of the NIAID budget. I'm curious if that may impact HIV funding and pay lines?

Answer: It will not. HIV is a protected type of funding; we need to spend HIV money on AIDS and AIDS-related co-infections and comorbidities. The NIAID budget is made up of three budget categories: Biodefense and Emerging Infectious Diseases, Infectious and Immunologic Diseases, and HIV/AIDS. The first two will be impacted, not HIV/AIDS. There are also some other special categories of funds that the Institute has that they're tapping into that will not affect the actual budgets in those categories. HIV investigators may contribute scientifically and can apply for that funding. We have maintained a position that, in the advent of another outbreak, our clinical trials will be able to respond and be part of the response like the CoVPN did in the previous pandemic. That requires appropriated funds in the form of money coming to the Institute or the NIH to do those kinds of studies.

Comment: Meeting in-person really allows us to appreciate your enthusiasm for both the science and the initiatives. So, thank you.

NIAID/DAIDS FY 2025 Concepts Presented for ARAC Approval

Mechanisms of Inducing HIV Immunity in Early Life
DAIDS Vaccine Research Program
Anjali Singh, Ph.D.

The objective of this new grant concept is to facilitate research to define mechanisms for establishing and maintaining immunity to HIV in early life from birth to less than 12 years of age, including an impact of growth on vaccination and broadly neutralizing HIV antibodies (bNAbs) to protect against acquisition of HIV infection. The focus is on neonates, infants and pre-adolescents age groups considering that the unique, less preprogrammed immune landscape of early life may present advantages to target HIV prevention strategies for elicitation of anti-HIV immune responses.

This initiative will support basic and translational HIV immunology research to advance mechanistic understanding on how immune ontogeny and functionality in early life could be harnessed in the context of HIV prevention strategies to elicit broad, durable, and protective immunity in children exposed to or unexposed to HIV.

This initiative aims to address the unique immunological and virological challenges of developing an effective HIV vaccine, including an extensive genetic variability of HIV and the limited understanding of immune responses required to protect against HIV acquisition. Key areas of the research focus include 1) evaluation of the pediatric HIV immunization strategies to identify prime innate and adaptive pathways for the development of early and poly-specific broadly neutralizing HIV antibodies lineages, and 2) determination of the biodistribution and efficacy of prophylactic broadly neutralizing antibodies in the evolving pediatric immune landscape.

Clinical trials are not allowed, but use of clinical study samples (birth to less than 12 years of age) is acceptable.

Question: It seems to me that studying nonhuman primates might be really important for this initiative because of the limited number of cells you're going to get from archived specimens. Can you address that?

Answer: We included in one of the slides that our primary focus is to test immunogenicity and efficacy of HIV vaccines and bNAbs in the nonhuman primate (NHP) model and, in addition, the samples from the clinical trials will also be accepted for the research projects. We totally agree with your suggestions that NHP model is important to test this concept.

HIV Vaccine Research and Design (HIVRAD) Program
Bimal K. Chakrabarti, Ph.D.

The objective of this renewal P01 program project grant concept is to support multicomponent, multidisciplinary projects that address scientific questions relevant to AIDS prophylactic vaccine discovery research. Such projects have advanced past the exploratory stage addressing hypotheses crucial to the design and development and/or evaluation of a vaccine candidate. The HIVRAD Program is designed to fund projects that further address hypotheses crucial to the design of an efficacious HIV/AIDS prophylactic vaccine and extensive evaluation of vaccine concepts in nonhuman primates and innovative but appropriate small animal models (e.g., transgenic/humanized mice). Applications for up to 5 years of support include plans to further develop vaccine concept(s), sufficient preliminary data (e.g., preliminary immunogenicity data), and address potential translatability into the clinic upon successful completion.

Clinical trials and studies focused on repeating and/or expanding HIV vaccine approaches that were unsuccessful in efficacy trials are not allowed.

Question 1: Clinical trials are not allowed - correct? It's all predevelopment; what models are allowed? Animal models?

Answer 1: The funding for these grants will not support any clinical trial. However, for any immunogen that is in a clinical trial, this can be analyzed to find the correlates through the HIVRAD Program if it's supported. It will be up to the reviewers to tell us if that is important to do and then we can assess. Other than that, we have NHP models. We have the humanized mice models to test and also analyze those samples to find the correlates or find the bNAbs which can protect the animals in NHP models.

Question 2: Can you help us to understand how this P01 concept fits in with everything else? What is unique here?

Answer 2: This P01 program project grant initiative is more enhanced than an R01 grant program. The P01 grant supports an integrated, broadly based, multiproject research program that has a well-defined, central research focus or objective. The P01 includes interrelated R01-like research projects, each capable of standing on its own scientific merit but complementing one another. The P01 projects produce higher synergy and address more complex scientific questions than individuals R01s.

Comment: There's clearly a lot of great things coming out of the HIVRAD Program and I'm glad you touched on that, in terms of overall overlap and synergy with the other parts. Applications should have clear novelty in experimental approach. The tricky part will be novelty without having one part of a program compromise another if it doesn't work and so I hope the reviewers will use a very high bar for novelty.

Introduction to Support Contracts for Preclinical Evaluation of HIV/AIDS Vaccines
Cesar Boggiano, Ph.D.

An introductory overview was provided as a preamble to the detailed presentations of the four vaccine support contract concepts that DAIDS is proposing to reissue for FY 2025: Virology Core Laboratory, Humoral Immunology Core Laboratory, Functional Omics Core Laboratory, and the Resource Support Program. Last year, the ARAC approved the Cellular Immunology Core Laboratory for FY 2024. The contracts serve as a resource that is important for investigators to use in nonhuman primates. At the center of these contracts is the Simian Vaccine Evaluation Units (SVEUs). The ARAC previously approved the SVEU reissue contract for FY 2020. The SVEU provides the nonhuman primates for studies to evaluate candidate SIV or HIV vaccines. The contract conducts preliminary studies on new vaccine candidates; efficacy studies with vaccines that have already demonstrated promise; studies with passively administered products; in vivo titration of virus challenge stocks; vaccines and/or adjuvants comparative studies; and translational studies to inform Phase I clinical trials.

Virology Core Laboratory
Que Dang, Ph.D. (COR)

The reissue of the Virology Core Laboratory (VCL) contract was presented for approval. The VCL is one of the Core Laboratories that are responsible for conducting state-of-the-art assays to comprehensively evaluate immune responses and efficacy of candidate AIDS vaccines in preclinical studies critical to the progress of candidate vaccines into human clinical trials.

The VCL provides a centralized laboratory to conduct assays that quantitatively measure viral RNA levels in support of preclinical AIDS vaccine studies, ensuring standardization and comparability of data across different studies.

Specifically, the VCL conducts assays to quantitatively measure viral RNA levels in animals that have been infected/challenged with human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), or simian-human immunodeficiency virus (SHIV). The level of viral RNA in challenged animals is used to evaluate the efficacy of the candidate AIDS vaccine (or other intervention) tested. Assays are done primarily in support of preclinical vaccine studies conducted at NIAID's SVEUs or other sites identified by the contracting officer's representative (COR).

These assays conducted at the centralized laboratory ensure standardization and comparability of data across the different studies and may allow correlation of responses in nonhuman primates with those generated in human clinical trials by the same or similar vaccine candidates. Such correlations would enhance the predictive value of the nonhuman primate model.

This contract will primarily support preclinical virology assays in support of HIV/SIV/SHIV-related vaccine studies. The core laboratory will be expected to conduct validated, high throughput assays to quantitatively measure viral RNA levels using GLP-like practices. Additionally, the contract will be asked to generate large volume viral stocks that will serve as standardized reagents for the field.

Question: The current contract has assessed vaccine efficacy in preclinical studies, including SARS-CoV-2 preclinical studies. Will that be true for RSV or any other virus?

Answer: If there is a public health need, and if we were to acquire additional funds, we will have an expanded scope to work on detection of other pathogens. In case of an emerging infectious disease, the contract may be asked to support virology assays in support of other infectious diseases.

Humoral Immunology Core Laboratory for AIDS Vaccine Research and Development
Nancy Miller, Ph.D. (COR)

The reissue of the Humoral Immunology Core Laboratory for AIDS Vaccine Research and Development contract was presented for approval. The contract provides centralized support for assessment of antibody responses. The objective of this core laboratory is to assess the characteristics and functions of the SIV­ and HIV-specific antibodies generated in response to candidate AIDS vaccines, with an emphasis on supporting SVEU studies conducted in NHPs.

The Humoral Immunology Core Laboratory contract is also available to work collaboratively with AIDS researchers in non-SVEU AIDS studies to provide centralized, validated assay services for assessment of anti-HIV and anti-SIV neutralizing antibody responses in NHPs immunized with candidate AIDS vaccines or infected with SIV or SHIV viruses.

The reissue of this contract will continue to provide state-of-the art capability to assess the characteristics and function of the SIV- and HIV-specific antibodies generated in response to candidate vaccines administered to NHPs in SVEU studies and other AIDS vaccine studies, ensuring standardization and comparability of assays and evaluation of vaccines across studies.

Although the contract will focus on assessment of immune responses in NHPs, the scope of the contract will include assessment of HIV- and SIV-specific response in the sera of other animals, as appropriate to assess immunogenicity of candidate AIDS vaccines.

In the instance of a public health emergency and at the request of NIAID, contract personnel may adapt, develop, and conduct assays relating to the assessment of humoral immune responses to other viruses or pathogens. If this request is made, it is anticipated that appropriate additional funding will be provided to the contract.

Question 1: For the non-SVEU investigators, are some of them not studying NHPs or are some of them studying clinical trial specimens?

Answer 1: There is a separate mechanism, also held by Duke, that does all of the clinical trial samples; the same kinds of assays but for the human trial samples. We only run human samples if they're relevant to asking specific questions with the primate studies. It's generally not done on this contract.

Comment: Suggestion to clarify that this is for NHP investigators.

Question 2: Should there be a cellular immunity measurement?

Answer 2: That is covered in the Cellular Immunology contract that was approved last year by the ARAC for FY 2024 award.

Functional Omics Core Laboratory
Anjali Singh, Ph.D. (COR)

The reissue of the Functional Omics Core Laboratory contract was presented for approval. The objective of this contract initiative is to provide a centralized laboratory to conduct assays that evaluate functional omics approaches in support of preclinical HIV/SIV vaccine studies for the DAIDS SVEU contract and grant (investigator-initiated research programs) mechanisms, ensuring standardization, consistency, and comparability of data across studies.

The Functional Omics Core Laboratory contract aims to: apply state-of-the-art functional omics approaches to evaluate preclinical HIV/SIV vaccine-elicited immunogenicity and efficacy in NHP challenge/protection studies supported by DAIDS contracts and grant recipients; compile and analyze multi-omics data using appropriate bioinformatics and biocomputing tools to capture the systems-level state of protective immunity and infer drivers of immunity; adopt new and improved technologies and assays; optimize and validate required omics assays and protocols and develop written standard operating procedures to perform genomics, epigenomics, transcriptomics, and proteomics analysis to profile the expression of genes, modifications of DNA/histones, transcripts, and proteins, respectively; compile and maintain an electronic record of all assay results; and submit data to a public data repository.

The ultimate goal of the Functional Omics Core Laboratory contract is to identify early omics signatures to evaluate vaccine-induced adaptive and innate immune responses and determine vaccine efficacy in NHP challenge/protection studies supported by DAIDS SVEU contracts and DAIDS grant recipients, promoting standardization and consistency of data across studies.

Resource Support Program for AIDS Vaccine Development
Jon Warren, Ph.D. (COR)

The reissue of the Resource Support Program for AIDS Vaccine Development contract was presented for approval. The objective of the contract is to continue production and/or acquisition of critical reagents, assays and services required for AIDS vaccine research, including, but not limited to, viral gene products and associated peptides, adjuvants, cytokines, virus stocks, expression vectors, monoclonal/polyclonal antibodies, and unforeseen reagents and assay services.

This contract will primarily support the provision of high-quality novel and targeted reagents, NHP and other animal resources, assays and services for the NIAID SVEUs, and for other research activities by investigators engaged in AIDS vaccine-related research or vaccine research of other infectious diseases, including NIAID-funded grant recipients and contractors, other NIH-funded investigators, and researchers and investigators supported through various non-governmental organizations (NGOs). These services are provided via investigator request(s) and NIAID staff approval. Performing clinical trials is not allowed, but use of samples from, and developing reagents for, clinical trials is allowed.

Question 1: You mentioned the AIDS Research Reagent Program. Will these things that are produced in bulk, and obviously standardized, be split and shared with the program, or are they a supplier to the program?

Answer 1: Yes, we have a history of doing that. We have to consider storage issues and who has the capacity to store what. In the past, if we had critical reagents, monoclonal antibodies has been an example that have been made using this approach; we would share up to half of the amount that is produced under this contract.

Question 2: I'm just wondering about communication amongst the Cores -- I would think that there'd need to be some amount of coordination. Can you describe that?

Answer 2: Integration and central coordination is through the SVEU. The majority of these Core labs are supporting mostly SVEU studies. The SVEU provides the NHPs for studies to evaluate candidate SIV or HIV vaccines. The SVEU will immunize NHPs with the candidate vaccine and, together with the NHP Immunology laboratories, can evaluate humoral and cellular immune responses that the NHPs generate in response to the vaccines. The SVEU can also challenge the animals with SIV or SHIV virus, and with the Virology Lab, can determine the levels of replicating virus post-challenge, and will evaluate disease outcomes. The NHP Immunology and Virology Lab Core contracts will collaborate to conduct assays in support of the SVEU studies, so that approval to conduct a SVEU study is automatically accompanied by approval for access to the assay laboratories' support.

Planning for Product Development Strategy
Marina Protopopova, Ph.D.

The objective of this new R34 grant announcement is to provide support for product development planning activities to accelerate development of next-generation therapeutics for HIV and HIV-associated comorbidities, co-infections, and complications, and preventive strategies for HIV, and facilitate translation of research findings into a drug product.

This NOFO will support the development of a comprehensive and well-defined product development strategy to enable submission of an investigational new drug (IND) application to the FDA.

Investigators will be required to summarize preliminary data to demonstrate appropriateness of IND-directed activities for the stage of their program and provide strong rationale for further development that includes competitive advantage, feasibility, and potential impact of proposed technologies on the field. In the Product Development Plan, investigators shall include components in concordance with the FDA guidance for IND submission, and include product indication, route of administration and dosing, CMC strategy, pharmacology and toxicology program strategies, and clinical protocol design. The approach should also include patent position (IP filed or intentions to file), regulatory strategy, critical milestones, go/no-go decisions, and a timeline. Applicants will be strongly advised to identify potential partners, collaborators, consultants with specialized expertise that might include business professionals, clinical investigators, CROs, CMC experts, regulatory professionals, and patent consultants.

Question: It seems this could potentially be even broader than NIAID, perhaps like a Director's program or something more central that could benefit investigators across Institutes and create more bridges?

Answer: We will consider it as a pilot program within the DAIDS Therapeutics Research Program. Other DAIDS Programs are interested in working with us. We have to start somewhere.

Engineering and Preclinical Development of Biological Products that Eliminate HIV-Infected Cells
Randall Tressler, M.D.

The objective of this new biphasic grant initiative is to support the late-stage engineering and preclinical development of innovative biological products that safely and specifically kill HIV-infected cells.

Products of interest include, but are not limited to, broadly neutralizing antibodies (bNAbs), their derivatives, and other soluble, antibody-like molecules. All preclinical data needed to meet FDA requirements to move into first-in-human clinicals trials will be developed during the 5-year project period.

DAIDS and other funding organizations have supported research to identify biologics that more effectively kill HIV- and other virus-infected cells, including molecules with Fe modifications and engineered antibodies and antibody-like molecules. However, few of these enhanced biologics have been tested in people with HIV. bNAbs were initially developed to prevent HIV infection and were selected for their potency and breadth of neutralization against a representative panel of pseudoviruses. Since then, bNAbs have been engineered to enhance their potency, breadth of neutralization, pharmacokinetics (PK), and manufacturability. Clinical trials have established that bNAb administrations are safe, and they can prevent infection and maintain viral suppression in individuals with bNAb sensitive viruses. However, they have not demonstrated sufficient killing of HIV-infected cells to significantly reduce the HIV reservoir or increase the proportion of individuals able to maintain viral suppression off antiretroviral therapy once bNAb levels have waned.

IND-enabling work must use Good Laboratory Practice and product derived from the engineering run of product scale-up following FDA defined current Good Manufacturing Practice (cGMP). Examples of IND-enabling work to be conducted include: tissue cross reactivity studies and possibly a binding study against an array of human membrane bound and secreted proteins to identify the appropriate species for the toxicology studies; toxicology studies to evaluate animal PK and to identify the no observed adverse effect level and potential safety concerns; confirmatory proof-of-concept studies with human samples or in an appropriate animal model; and continued assay development to comply with FDA guidance.

Applications may not propose the discovery of new antibodies, discovery of new Fe modifications to enhance killing, toxin conjugated or radioactive antibodies, vaccines, or the scale-up and cGMP manufacture of the biologic.

The 5-year award will be provided in two phases. The UG3 phase will fund up to 3 years of hypothesis­ and milestone-driven basic technology research, assay development, generation of a pre-IND development plan consistent with FDA guidance, and completion of a meeting with the FDA appropriate for the stage of product development (see https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/otp-interact-meeting). The UH3 phase will fund up to 4 years to execute the pre-IND studies and additional activities as appropriate, such as expanded assay development, optimization, proof­ of-concept validation with human samples, and usability testing. Applications from academics must incorporate a partner from the private sector. Proposed milestones will be reviewed and negotiated prior to award.

Question 1a: You mentioned that to move from UG3 to the UH3 phase you would need an FDA­ accepted preclinical development plan. Is that through an interactive meeting and what's the mechanism?

Answer 1a: The FDA offers a preclinical consultation. A package is prepared and submitted to the FDA, and they review it with you and instruct what they believe you need to do to go forward; it's that agreement that these are the right studies that should be able to get you into the clinic.

Question 1b: That sounds like an interactive meeting, I know that FDA's pretty clear that those are nonbinding on their part and there are no minutes.

Answer 1b: You're absolutely correct. There are no minutes, and they are not binding. This is the best chance to get something moving forward.

Question 2: Are the differences in half lives in these products important at all for this?

Answer 2: The differences in half lives are really important when you get into the clinic. This portion is to identify compounds that we can move into the clinic and then once we have more compounds, we'll mix and match to find what the best dosing is or the best combination of products. Right now, we have one, two, or three compounds. We really need to move this project forward.

Multidisciplinary Research to Accelerate Hepatitis B Cure in Persons Living with HIV and HBV
Josh Radke, Ph.D.

The objective of the Multidisciplinary Research to Accelerate Hepatitis B Cure in Persons Living with HIV and HBV grant initiative is to support multisite observational cohorts to better understand the impact of host and viral heterogeneity on disease pathogenesis, persistence, and immunopathology of hepatitis B (HBV) and inform cure strategies for HBV in persons living with HIV (PLWH).

Each cohort will include a cross-disciplinary team of investigators that engages preclinical and clinical researchers in HBV and in HIV as expertise requires. Applicants are highly encouraged to include early career scientists (e.g., research track investigators, staff scientists, and assistant level professors).

Research applications are strongly encouraged to focus on the study of primary viral isolates from different genotypes and include objectives that address multiple stages of the natural life cycle of HBV in PLWH. Investigators are encouraged to develop multi-omics strategies to identify novel host and viral factors that underly disease mechanisms with an emphasis on identifying drug targets and biomarkers for HBV cure. Applications will combine at least one clinical research project and one basic or translational research project to accelerate discovery and increase clinical impact.

Cohort Components - Applicants will be required to include an Administrative Core; at least two Scientific Cores; a Shared Resource Core (biorepository); a plan for Data and Statistical Management Center; and must have established Clinical Sites and Laboratories to support and complete the work proposed in the Research Projects. Applicants will be strongly encouraged to leverage existing clinical samples and repositories from previous cohort studies as applicable.

Comment: I just think this is the time for hepatitis B cure. I would add a component that, when it's indicated, that there is a hepatitis D screening in the context of hepatitis B.

Question: I was curious about the representation of the different genotypes and how important that would be in terms of the cohorts or building new cohorts and international collaborations, making sure that you were able to see and study all the different genotypes and not be looking at just one or two.

Answer: I think one of the problems there is that unless the programs are going to propose collecting from different sites covering all of the genetic diversity, it's going to be really difficult. We hope to at least find two different programs that we can fund in different areas so that we can start the ball rolling.

Developing a Pipeline of Cell and Gene Therapies for HIV Cure
Betty Poon, Ph.D.

This new grant initiative will enable the development and advancement of gene- and cell-based approaches to achieve long-term remission or elimination of HIV that can eventually be evaluated in the clinic, rendered scalable and deliverable. Note, clinical trials are not allowed.

The scope of the research includes: novel strategies to target HIV provirus DNA with gene modifying tools to excise, inactivate, or silence the expression of the integrated viral genome; cell- or tissue­ targeting methods to enable in vivo delivery of gene therapies to sites where persistent or latent HIV­ infected cells reside; allogeneic or universal "off the shelf' cell and gene therapeutic approaches; gene modification to render cells resistant to infection and/or better able to eliminate HIV-infected cells; novel methods to enhance transplantation and engraftment, or minimize rejection, of modified cells; and test-of­ concept studies in relevant animal models.

Applicants will be required to identify one or more private sector partners to participate in their program, and to plan an INTERACT (Initial Targeted Engagement for Regulatory Advice on CBER Products (https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/otp-interact-meeting) meeting with the FDA within the first 2 years of grant award. These requirements will assist grant recipients in determining the appropriate design and conduct of preclinical test-of-concept studies and the development of their approach.

Tailoring HIV Curative Strategies to the Individual
Leia Novak, Ph.D.

The objective of this new grant initiative is to determine whether tailoring curative strategies to an individual's specific intact, rebound-competent proviral reservoir and immunologic profile might be more successful than existing, more general approaches at achieving HIV reservoir reduction and/or induction of durable control of viral rebound. The goal is to enable proof-of-concept studies to demonstrate that combination interventions can generate a cure under optimal conditions. This will help guide subsequent prioritization of translational research and optimization of approaches so that they are effective across broader populations of individuals.

This initiative will bring together multidisciplinary teams with expertise in virology, immunology, single­ cell analytics, and bioinformatics/modeling to characterize the landscapes of: intact and defective proviruses, host HLA alleles, CD4+and CD8+ T cell receptor repertoires, and autologous or heterologous neutralizing antibody specificities in virally-suppressed individuals on treatment, and use that information to design combinations of interventions specifically tailored to be effective at targeting and controlling those individuals' HIV reservoirs.

The scope of research will include basic and preclinical research, methods development and validation, analysis of clinical samples including accessible tissue samples, and testing of combinations of specifically tailored cure strategies in vitro or ex vivo. The focus should be on HIV in humans, but some testing in animal model systems will be permitted if appropriate and well justified. The strategy should be validated across a group of individuals and compared to non-tailored controls to demonstrate rigor, reproducibility, and significance of the results. The curative strategy must combine at least two different immunologic approaches that target an individual's proviral reservoir sequences - for example, combining adaptive cellular responses with humoral HIV-gene-specific targeted approaches. Non­ immunologic tailored approaches, such as gene editing of provirus or CCR5, LTR targeting, or block­ and-lock strategies will not be responsive. The research plan should also include a tailored strategy for reactivation of reservoir cells - for example, targeting based on the antigenic specificity of the reservoir cells.

Clinical trials are not allowed, but use of blood and tissue samples from clinical trials funded through separate mechanisms will be encouraged. Applications should take into account the requirements for downstream implementation of the tailored approach in future clinical trials, such as discussion of regulatory requirements for interventions and diagnostic assays and how GMP materials would be produced.

Public Comments: None

Ballot Voting Outcome:

All 11 of the DAIDS concepts presented today were unanimously approved by the voting members of the Committee.

VII. Adjournment

The meeting of the Council adjourned at 4:19 p.m., on Monday, June 5, 2023.

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

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