NIAID Council Minutes September 13, 2021

The 199^th meeting of the National Advisory Allergy and Infectious Diseases Council (NAAIDC) convened virtually at 10:30 a.m. on Monday, September 13, 2021. 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 11:40 a.m. and from 1:00 p.m. to 3:17 p.m. The meeting was closed to the public from 8:00 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 Director, NIAID—Anthony S. Fauci, 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 4,351 research and training applications with primary assignment to NIAID for a requested amount of $1,294,640,020 in first-year direct costs and recommended approval of 2,163 applications with $736,838,093 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 new Council members: Dr. Linda Bockenstedt, the Howard W. Jockers Professor of Medicine at Yale School of Medicine, and Dr. Stephanie Taylor, professor of medicine and microbiology at Louisiana State University Health Sciences Center in New Orleans. 

Council member Dr. Harry Greenberg and ex officio Council member Dr. Jay Butler were unable to attend the meeting.

Dr. Fauci acknowledged the contributions of four retiring Council members—Kay Whalen and Drs. Michael Brenner, Ana Fernandez-Sesma, and Marc Jenkins—and thanked them for their service.

He then introduced three Division of Allergy, Immunology, and Transplantation (DAIT) ad hoc members—Dr. Andrew Adams, professor of surgery and chief of the Division of Transplantation at the University of Minnesota; Dr. Daniel Hurst, assistant professor and director of Medical Professionalism, Ethics and Humanities at the Rowan University School of Osteopathic Medicine; and Dr. Megan Sykes, Michael J. Friedlander Professor of Medicine and professor of microbiology, immunology, and surgical sciences at Columbia University.

Consideration of Minutes of Previous Meeting

Council considered the minutes of the June 7, 2021 meeting and concepts that had been presented and approved them.

Staff and Organizational Changes

Dr. Fauci announced appointments and transitions that have taken place since the last Council meeting.

In June, the White House announced that Harold Phillips had been appointed to lead the Office of National AIDS Policy. Mr. Phillips most recently served as the senior HIV advisor and chief operating officer of the Ending the HIV Epidemic initiative at HHS.

After serving 28 years, NIH Deputy Director for Intramural Research Dr. Michael Gottesman plans to step down once a replacement is found. Dr. Gottesman will return to his responsibilities as chief of the National Cancer Institute’s Laboratory of Cell Biology. 

Dr. Karin Bok has been named director of Pandemic Preparedness and Emergency Response in the Office of the Scientific Director at the Vaccine Research Center (VRC). Dr. Bok made important contributions to VRC’s COVID-19 response in her previous role as the Center’s senior advisor for Vaccine and Antibody Development.

In the Division of AIDS, Dr. Adeola Adeyeye has been chosen to lead the Clinical Prevention Research Branch in the Prevention Sciences Program.

Sam Ashe has been selected as chief of the Clinical Trials and NIH OD Grants Branch in the Division of Extramural Activities Grants Management Program.

Dr. Jim Cherry is the new chief of the Research Technologies Branch in the Division of Intramural Research (DIR).

Dr. Wilbert Van Panhuis has been chosen as director of NIAID’s Office of Data Science and Emerging Technologies.

Michelle Grifka has been named chief of the Biodefense and Emerging Infectious Diseases Budget and Financial Management Branch in the Office of Mission Integration and Financial Management.

Tributes and Awards

Dr. Barney Graham, former deputy director of VRC and chief of the Viral Pathogenesis Laboratory, retired at the end of August after more than 20 years as an investigator at VRC. Dr. Graham led the development efforts for COVID-19 vaccines and universal influenza vaccines.

Dr. Fauci paid tribute to Dr. Leonard “Pug” Evans, chief of the Retroviral Molecular Biology Section at NIAID’s Rocky Mountain Labs, who passed away unexpectedly on June 24, 2021.

Meetings and Events

Dr. Fauci reported on virtual meetings that have been held with international delegations and health officials, including UK’s Chief Medical Officer, the President of Chile, the WHO regional director for Europe, the minister of health for Gabon, and the Prime Minister of Israel.

Budget Update

Dr. Fauci began by summarizing the President’s budget request for fiscal year (FY) 2022, which proposes a 21 percent increase for NIH, or $9 billion over the FY 2021 enacted level. This increase includes $6.5 billion to establish the Advanced Research Projects Agency for Health (ARPA-H), an initiative to speed transformational innovation in health research and the application and implementation of health breakthroughs. The remaining $2.5 billion increase is allocated among NIH’s 27 institutes and centers (ICs) and the Office of the Director, and emphasizes national priorities, including fighting the opioid epidemic, addressing health disparities, and researching the impacts of climate change on human health.

The House passed a spending package proposal in July that provides NIH with an overall increase of 15.1 percent, with most ICs receiving increases between 5 and 8 percent. NIAID’s budget would increase by 8 percent, which includes increases of $30 million for universal influenza vaccine research, $10 million for the Institute’s Centers for AIDS Research, $50 million to advance rapid vaccine platform technologies, and $6 million for the Consortium of Food Allergy Research. 

The Senate had not completed its work on the budget. NIH will start FY 2022 under a continuing resolution.

Dr. Fauci presented NIAID’s interim FY 2022 financial management plan. Taking a conservative funding approach, our interim R01 paylines are the 10 percentile for established principal investigators (PIs) and the 14 percentile for new PIs. NIAID does not plan to make programmatic cuts to noncompeting and competing grants. Competing research initiatives will be cut up to 20 percent from their planned budget levels. Our estimated success rates for research project grants will be 21 to 23 percent.

He also provided an update on the funding NIAID and NIH received through supplemental appropriations to respond to the COVID-19 pandemic and coronaviruses, as well as how the Institute and NIH allocated the funds.

Legislative Update

On July 20, Dr. Fauci testified at a Senate Health, Education, Labor, and Pensions Committee hearing about the ongoing federal response to the COVID-19 pandemic, the role NIAID has played in the response, and the safety and effectiveness of available COVID-19 vaccines. 

Throughout the summer, Dr. Fauci participated in several COVID-19 Congressional briefings and updated members of Congress on the safety and effectiveness of COVID-19 vaccines and efforts to address emerging SARS-CoV-2 variants of concern, most notably the Delta variant. 

On August 12, Dr. Fauci and Representative Bennie Thompson, chair of the House Committee on Homeland Security, participated in a Congressional Black Caucus Institute event focused on the impact of COVID-19 on African American populations and discussed ways to address underlying concerns that lead to vaccine hesitancy.

At a Congressional HIV Caucus event on June 14 commemorating the 40^th anniversary of the historic Morbidity and Mortality Weekly Report that described the first cases of what came to be known as AIDS, Dr. Fauci discussed HIV-related issues with Representative Barbara Lee. He highlighted the progress that has been made since the early days of HIV.

Dr. Fauci thanked NIAID staff who participated in many Congressional briefings on his behalf.

Other Information Items

Dr. Fauci presented the most recent statistics on HIV/AIDS from UNAIDS. In 2020, 37.7 million people were living with HIV, and there were 1.5 million new infections and 680,000 deaths. 

He then continued with a COVID-19 update, summarizing the number of COVID-19 cases and deaths globally and in the United States. As of September 8, 2021, there were over 223 million cases and 4.6 million deaths globally, with more than 40 million of those cases and almost 650,000 deaths in the United States.

The United States has experienced multiple surges in reported cases, with different variants playing an important role in the dynamics of the outbreak. The current dominant variant, the Delta variant, is at least two times more transmissible than the previously dominant Alpha variant, and people who get infected with the Delta variant have viral loads up to 1,000 times greater than with the Alpha variant.

Dr. Fauci noted that for fully vaccinated people the risk of disease incidence is 8-fold less than for unvaccinated people, and hospitalizations and deaths are 25-fold less. He provided some vaccination statistics—73 percent of the U.S. population 12 years of age and older have received one vaccine dose and 62 percent are fully vaccinated. 

The clinical trial results of the Novavax vaccine showed it was safe and 90.4 percent efficacious in preventing symptomatic disease and provides 100 percent protection against moderate and severe disease. 

Dr. Fauci also summarized results from a study evaluating the mRNA-1273 SARS-CoV-2 vaccine in adolescents and mentioned studies being conducted of COVID-19 vaccination during pregnancy and postpartum, a third COVID-19 vaccine dose in kidney transplant recipients, and an extra COVID-19 vaccine dose in people with autoimmune disease. 

FDA approved the Pfizer-BioNTech vaccine, Comirnaty, for prevention of COVID-19 in people 16 years of age and older. Emergency use authorization continues to be available for adolescents from 12 to 15 years old, along with a third dose in certain immunocompromised individuals. 

Dr. Fauci provided information on booster shots for SARS-CoV-2 vaccines, clinical trials being done to evaluate the mix and match approach to various booster regimens, and therapeutics available to treat COVID-19. He noted NIH made the first infrastructure awards to support research on post-COVID conditions, and NIAID and Children’s National Hospital launched a large study on the long-term impact of COVID-19 and multisystem inflammatory syndrome in children. 

The Biden Administration has invested $3.2 billion from the American Rescue Plan as part of the COVID-19 Antiviral Development Strategy and announced a 10-Year Pandemic Preparedness Plan.

Dr. Fauci concluded with updates on malaria vaccine and monoclonal antibody trials, and a trial NIH launched of a universal influenza vaccine candidate developed by NIAID scientists.

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

Dr. Holland began by explaining that NIAID’s intramural programs are in Bethesda and at the Rocky Mountain Laboratories in Montana, along with programs around the world meeting infectious disease adversaries where they live. 

He reviewed DIR’s priorities, which are:

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

Dr. Holland gave an overview of DIR’s activities over the last year, which included over 1,000 publications and more than 200 clinical studies that have been published. COVID-19 funding supported 80 PIs and/or branches, which resulted in 266 published COVID papers.

Dr. Holland also paid tribute to Dr. Leonard “Pug” Evans, who died in June. He mentioned DIR leadership changes that have occurred over the last year, along with personnel changes, including upcoming retirements, searches for new lab chiefs, new hires, and new tenure-track investigators.

Recent honors received by DIR staff include the following: Dr. Heinz Feldman was elected to the National Academy of Medicine and American Academy of Microbiology; Dr. Marshall Bloom was named to the Montana BioScience Alliance Hall of Fame; Drs. Emmie de Wit, Vincent Munster, Kizzmekia Corbett, and Barney Graham received Golden Goose Awards; and Dr. Yasmine Belkaid was selected as a 2020 Paul Allen Institute Distinguished Investigator. 

Dr. Holland concluded by highlighting some of DIR’s scientific research on COVID-19 vaccine reactions and responses, long COVID syndrome, SARS-CoV-2 infections, drugs that inhibit COVID-19, infectious mammalian prions, mucosal fungal infections, and the microbiome. 

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

Charles Hackett, Ph.D., on behalf of Daniel Rotrosen, M.D., director

Dr. Hackett welcomed the subcommittee members to the 199^th meeting of the National Advisory Allergy and Infectious Diseases Subcommittee meeting. 

Dr. Hackett presented the following scientific and Division activities:

Staff and Organizational Changes

None

Selected Funding Opportunities

NIAID

Notice of Special Interest (NOSI): Somatic Cell Gene Editing Therapies To Improve Transplantation Outcomes NOT-AI-21-067: Published on August 6, 2021, the goal of the NOSI is to encourage submission of R01 and R21 applications (clinical trial not allowed) that apply progress made in somatic cell gene editing approaches to transplantation research. Research funded by this NOSI may utilize various models, including human tissues or organs excluded from clinical use and/or rodent, porcine, or nonhuman primate models, and should address unmet needs in vascularized composite allotransplantation (VCA), islet, or organ allotransplantation.

Inviting Comments and Suggestions on the Impact of Radiation Exposure From a Radiological or Nuclear Incident on the Microbiome and the Development of Targeted Therapeutics NOT-AI-21-055: Request for Information (RFI): Released May 21, 2021, this RFI from the Radiation Nuclear Countermeasures Program (RNCP) is intended to solicit input from the radiation biology and microbiome research communities regarding the state of the science of the interplay between radiation exposure and the microbiome, including impact of radiation on the known microbiome niches in the human body, microbiome signatures to predict susceptibility to radiation injury, and/or microbiota-based or microbiota-targeted radiation medical countermeasures (MCMs).

Division Activities

Allergy, Asthma, and Airway Biology Branch

Epithelial Determinants of Host Response to Respiratory Viral Infections. On May 17, 2021, as part of the annual meeting of the American Thoracic Society (ATS), NIAID organized a virtual session entitled “Epithelial Determinants of Host Response to Respiratory Viral Infections.” The session highlighted new work performed by investigators from the NIAID-funded Asthma and Allergic Diseases Cooperative Research Centers (AADCRC). Three experts in the field discussed rhinovirus-C/receptor interactions and the layered epithelial response to infection, Type-2 inflammation in asthma and the role of IL-13 in modulating host response to respiratory infections including influenza and SARS-CoV-2, and differential host-specific airway epithelial response to viruses from human rhinovirus to SARS-CoV-2.

T Cell Reagent Research for the Study of Allergic Diseases. On June 29, 2021, DAIT sponsored a virtual update meeting of the NIAID-funded T Cell Reagent Research for the Study of Allergic Diseases program. Investigators from Centers at La Jolla Institute for Immunology, Benaroya Research Institute, and Stanford University gave updates on their research related to the characterization of epitope-specific T cells and phenotypes in allergic disease, and T cell reagent research for monitoring T cells in food allergy.

EAACI-NIH Joint Symposium: COVID-19 and Allergy. On July 10, 2021, NIAID organized a virtual Sister Symposium presentation at the annual European Academy of Allergy and Clinical Immunology (EAACI) meeting. Three experts in the field discussed the influence of Type 2 mucosal inflammation on susceptibility to SARS-CoV-2, the HEROS study (a prospective household cohort investigation of differences between allergic and non-allergic children in SARS-CoV-2 infection and disease), and how inhibiting Type 2 inflammation in atopic dermatitis modulates COVID-19 responses. 

Basic Immunology Branch

Secondary Effects of Antigen Specific Vaccines Workshop. From July 27 to 29, 2021, NIAID convened a workshop on secondary vaccine effects (SVEs). SVE’s, also known as off-target effects, are defined as either positive or negative outcomes of antigen-specific vaccines that are distinct from the intended vaccine target, such as a decrease in all-cause mortality in children given BCG vaccine at birth compared to children who did not receive BCG. This workshop was jointly developed by staff from DAIT and the Division of Microbiology and Infectious Diseases (DMID), with the goal of further exploring 1) possible immunologic mechanisms associated with and 2) public health implications of secondary vaccine effects.

Collaborative Influenza Vaccine Innovation Centers (CIVICs) Annual Program Progress Meeting. From August 8 to 11, 2021, NIAID hosted the annual meeting of the CIVICs investigators as a mixed in-person and web-based platform. The purpose of the CIVICs contract program, which is jointly managed by DAIT and DMID, is to develop improved influenza vaccines that are both efficacious and broadly protective, as outlined in NIAID’s universal influenza vaccine strategic plan. The CIVICs program is generating novel vaccine candidates, performing preclinical testing and validation of candidates, and manufacturing and testing candidate vaccines in clinical trials, including human challenge studies. Detailed immunologic analyses are being conducted on the preclinical and clinical samples to further improve the vaccines and identify correlates of immune protection. Data from the program is being managed by a statistical and data management coordination center. The meeting enabled the principal investigators to describe recent progress and continue developing collaborations initiated in the first two years of funding.

Transplantation Branch

Clinical Trials in Organ Transplantation in Children and Adults (CTOT-CA). On April 22, 2021, applications in response to the CTOT-CA request for applications (RFA) were reviewed and awards were made to seven highly competitive applicants. This research consortium is a renewal and merger of the Clinical Trials in Organ Transplantation and Clinical Trials in Organ Transplantation in Children initiatives. The CTOT-CA investigators will continue to focus on clinical trials with associated studies of immune mechanisms in adult and pediatric organ transplant recipients. A new feature for this funding cycle is collaboration with the DMID, supporting an increased focus on transplant infectious disease. The initial steering committee meeting of the new awardees is scheduled for late September.

Protection Against COVID-19 in Organ Transplant Recipients. Transplant recipients are known to respond poorly to vaccines against SARS-CoV-2, generating no or very low levels of protective antibody; at the same time, they are at increased risk for severe COVID-19 disease because of pharmacologic immunosuppression and a high prevalence of co-morbidities such as obesity, hypertension, diabetes and cardiovascular disease. On August 10, 2021, a pilot trial, “COVID Protection After Transplantation,” (CPAT) was launched at Johns Hopkins University. The open-label single arm study will evaluate the impact of a third dose of Moderna or Pfizer vaccine on the development of anti-COVID antibodies in kidney transplant recipients, and the determinants of that response. Initial results of this trial are anticipated in September or October of 2021. Shortly after that, NIAID will launch a multi-center adaptive trial, “Interventions to Augment the Antibody Response to Vaccination against SARS-CoV-2 in Organ Transplant Recipients,” in which a broader transplant population will be enrolled. The impact of same-platform vs. different-platform booster doses will be evaluated, and, in addition, a selected subgroup of stable kidney and liver recipients will undergo a temporary reduction in their maintenance immunosuppressive regimen to promote an enhanced vaccine response.

Nonhuman Primate MHC and KIR Allele Discovery and Typing Technology Development. On August 12, 2021, a kick-off meeting was held for the contract award to the University of Wisconsin-Madison (UWM). The meeting was attended by NIAID staff and contract personnel and included presentations by representatives from the University of Wisconsin-Madison, Baylor College of Medicine, and the Biomedical Primate Research Centre in the Netherlands. Diversity in the MHC region drives allogeneic responses in transplant recipients and influences immune responses in many immune-mediated and infectious diseases; a full understanding of this diversity will enable more rigorous experimental design, hypothesis generation, and data interpretation. This contract renewal continues support for UWM’s efforts to sequence and curate the nonhuman primate (NHP) major histocompatibility complex (MHC) genomic region in species and subspecies commonly used in research; define allelic variations and frequencies present in domestic NHP breeding colonies; and make curated and validated sequency data and information on the technological approaches developed and used publicly available.

Autoimmunity and Mucosal Immunology Branch

COVID‐19 Booster Vaccine in Autoimmune Disease Non‐Responders. On August 24, 2021, the NIAID-funded Autoimmunity Centers of Excellence began a clinical trial to assess the antibody response to an extra dose of an authorized or approved COVID-19 vaccine in people with autoimmune disease who did not respond to an original COVID-19 vaccine regimen. The trial also will investigate whether pausing immunosuppressive therapy around the time of vaccination improves the antibody response at four weeks to an extra dose of a COVID-19 vaccine in this population. The trial will initially include people with one of five autoimmune diseases: multiple sclerosis, pemphigus, rheumatoid arthritis, systemic lupus erythematosus or systemic sclerosis. Participants also must be taking one of three immunosuppressive therapies: mycophenolate mofetil (MMF) or mycophenolic acid (MPA); methotrexate (MTX); or B cell- depleting drugs. Preliminary data suggests these immunosuppressive therapies have been associated with poor immune responses to the COVID vaccines. Approximately 600 participants ages 18 years and older will be enrolled at 15 to 20 sites nationwide. Participants must have had a negative or suboptimal antibody response to two doses of the Moderna COVID-19 vaccine, two doses of the Pfizer-BioNTech COVID-19 vaccine, or one dose of the Johnson & Johnson COVID-19 vaccine, all received prior to enrollment. An estimated 8 percent of the American population has autoimmune disease including a disproportionate number of people in minority communities. People with autoimmune disease are more severely affected by COVID-19 and many do not respond adequately to the initial COVID vaccine regimen.

Mucosal Immunology Studies Team (MIST). From June 21 to 23, 2021, the final annual meeting of the second round of the MIST cooperative agreement research program was held as a virtual meeting. MIST is composed of 11 U01 cooperative agreement awardees who focus on discovery of novel immune mechanisms, cells, mediators, and pathways operating at the mucosal surface; exploration of innovative hypotheses; and tackling difficult unsolved questions in mucosal immunity. The MIST awardees presented their progress and discussed new ideas and tools and progress on their projects, provided constructive advice on ongoing projects, facilitated sharing of ideas and of newly developed tools, and reported on the progress of informal collaborations among the MIST awardees. The meeting also provided the awardees of the MIST Scholar Award the opportunity to present progress on their pilot projects and receive feedback and advice from MIST members. MIST awardees reviewed the achievements of the group and the value of the program (https://mucosal.org/).

Radiation and Nuclear Countermeasures Program (RNCP)

FirstString Contract Kickoff Meeting. On April 26, 2021, the RNCP conducted a virtual kickoff meeting for the contract titled “Granexin® as a Topical Therapeutic to Mitigate Cutaneous Radiation Injury.” FirstString has developed a topical gel that contains the anti-inflammatory peptide aCT1 and the company plans to test efficacy of the applied gel, which is already in clinical trials, in an animal model of cutaneous radiation injury. The meeting was attended by science and business personnel from FirstString and NIAID staff.

ChromoLogic Contract Kickoff Meeting. On April 30, 2021, the RNCP conducted a virtual kickoff meeting for the contract titled “Development of Second-Generation Probiotics as Radiation Mitigators.” ChromoLogic is partnering with the University of Pittsburgh to use their Lactobacillus reuteri platform to express the cytokines IL-22 or IFN-β and plans to test the efficacy of the orally administered, engineered bacteria in animal models of Gastrointestinal Acute Radiation Syndrome (GI-ARS). The meeting provided for an exchange of ideas and was attended by science and business personnel from ChromoLogic, collaborators from the University of Pittsburgh, and NIAID staff. 

ARS Action Team Meeting With FDA Office of Counterterrorism and Emerging Threats (OCET). On May 11, 2021, the RNCP met with the OCET Acute Radiation Syndrome (ARS) Action Team to discuss research activities on GI-ARS. GI-ARS is of particular concern since there are currently no licensed products for this indication. An assessment of data from GI-ARS product testing throughout the RNCP portfolio was discussed. The challenges and impact of radiation sources used in GI-ARS animal studies within the radiation research community also were considered.

FY 2023 Research Concept Clearances Presented to Division Advisory Council

The subcommittee endorsed and unanimously approved the following three research concept clearances:

1. Asthma and Allergic Disease Cooperative Research Centers (U19, Clinical Trial Optional)
   This initiative will support NIAID's unique and long-standing Asthma and Allergic Diseases Cooperative Research Centers (AADCRC) program. This program funds research centers across the United States to conduct interdisciplinary and translational research in asthma and allergic diseases.
    
2. Development of Radiation/Nuclear Medical Countermeasures (MCMs) and Biodosimetry Devices 
   This broad agency announcement serves as the RNCP’s only mechanism to solicit investigator-initiated mid-stage research directed to investigational new drug (IND) application or investigational use only (IUO)-enabling efforts for the development of countermeasures to treat acute radiation syndrome (ARS), and/or delayed effects of acute radiation exposure (DEARE).
    
3. Immune Drivers of Autoimmune Diseases (U01, UM1, Clinical Trial Not Allowed)
   This initiative will enable the unbiased definition, at the molecular level, of the immunologic events underlying two key events in autoimmune disease. These two key events are 1) the transition from apparent health to clinical autoimmune disease and 2) the initiation and resolution of disease flares.

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

Director’s Report

Dr. Cristina Cassetti, deputy director of the Division of Microbiology and Infectious Diseases (DMID), chaired the NIAID Microbiology and Infectious Diseases Council Subcommittee meeting on September 13, 2021. She welcomed two new members to DMID’s Subcommittee, Drs. Linda Bockenstedt and Stephanie Taylor, who were formally introduced during the NIAID Open Session of Council earlier in the day. She also provided a DMID personnel update, recognizing new staff appointments made in the Division since the last Council meeting, including Nita Basu and Kate Bradford in the Respiratory Diseases Branch; Amir Zeituni in the Enteric and Sexually Transmitted Infections Branch; Ashish Pathak in the Office of Biodefense, Research Resources and Translational Research (OBRRTR); and Jomy George in the Office of Regulatory Affairs. She also reported that Dr. Lawrence Wolfraim has been selected to serve as the Vaccine Section Chief in OBRRTR.

Following staff introductions, Dr. Cassetti reported on several activities, including:

• The launch of the Antiviral Program for Pandemics (APP), a five-year program which focuses on seven virus families of pandemic potential to accelerate development of direct-acting antivirals from discovery to early development, as a complement to vaccines, neutralizing antibodies, and other therapeutic options. Dr. Cassetti described the specific criteria required for a candidate to be within scope of the APP program. She also updated the Subcommittee on the status of the funding opportunity announcement to establish the Antiviral Drug Discovery Centers, which was presented to the Subcommittee in June and is a component of APP. Applications for this program are due in late October 2021.
• COVID-19 Research Updates:
  • Results are expected soon from a Phase 1/2 clinical trial in which adult volunteers who have been fully vaccinated against COVID-19 will receive booster doses of different COVID-19 vaccines to determine the safety and immunogenicity of mixed boosted regimens. The study is being conducted through NIAID’s Infectious Diseases Clinical Research Consortium.
  • An NIAID-supported research team developed chimeric spike mRNA vaccines that produce high levels of broadly protective neutralizing antibodies.
  • A research team partially funded by DMID discovered a potent, stem helix neutralizing monoclonal antibody (mAb) that reduces viral burden in hamsters challenged with SARS-CoV-2 through viral neutralization and Fc-mediated effector functions.
  •  A study assessing the durability of mRNA-1273 vaccine-induced antibodies against SARS-CoV-2 variants found study subjects had responses to all variants at the peak of response to the second vaccine dose.
  • A Phase 3 trial found that the administration of subcutaneous REGEN-COV prevented symptomatic COVID-19 and asymptomatic SARS-CoV-2 infection in uninfected household contacts of infected individuals.
• Promising therapeutic approaches against alphaviruses from investigators supported by the NIAID Centers of Excellence for Translational Research, which are relevant to broader pandemic preparedness research efforts.
• The recent FDA clearance/Clinical Laboratory Improvement Amendments (CLIA) waiver for Visby’s single-use polymerase chain reaction (PCR) platform to diagnose sexually transmitted infections (N. gonorrhea, C. trachomatous, and T. vaginalis) in less than 30 minutes, noting that NIAID provided significant support for early-stage research efforts.

FY 2023 Concepts Presented for Clearance

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

Diagnostics Preclinical Services Program–This concept would support essential services to facilitate the development of diagnostics. The program would include the following services: clinical specimen acquisition, especially for novel or rare emerging infectious diseases; clinical isolates, especially novel or antimicrobial resistant strains; assay services, such as recombinant protein or antibody reagent development to accelerate assay development; cell-line development and cell-based assays for assay modeling and surrogate testing; and product development processes (regulatory strategies, quality systems compliance) to support program maturity and reduce risk for securing advanced development funding. Subcommittee members agreed that there was a compelling need for such a program to facilitate the development of in vitro diagnostic (IVD) products. In considering whether this concept is meant to be more responsive or proactive, the members agreed that it needs to be both: available to support aggressive timelines to complete development for an ongoing threat, and also proactive to anticipate the needs of new developers ahead of unknown, future emerging threats. Subcommittee members recognized the potential benefit for such preclinical services outside of an ongoing outbreak, for example, supporting developers who intend for their product to be useful for infectious disease surveillance or epidemiology studies.

Biological and Emerging Infections Research Resources Program (BEI-RRP)–This concept is a renewal and would continue to provide research and reference reagents from a single source for NIAID priority pathogens that are generally not available elsewhere for critical research activities. Specific activities include the acquisition, authentication, production, preservation, storage and distribution of research and reference reagents to support the infectious disease research community. The Subcommittee members were very supportive of the concept, observing the need for a smooth transition of the DAIDS HIV Repository Program (HRP) into BEI-RRP. Program noted that NIAID successfully transitioned smaller repositories during the previous contract period and anticipates the transition of the HRP to be smooth. Program addressed questions from the Subcommittee regarding the registration process and how to request reagents. The Subcommittee members mentioned the need for and the importance of sustainability of this research resource. Program reiterated the need for continued vetting of deposits and thoughtful deaccessioning to maintain a successful program. Related, the topic of listing deaccessioned items on the website was discussed, which would allow interested researchers an avenue to reach out to the original depositor to possibly gain access to these materials. Lastly, the Subcommittee members also mentioned the importance of program acknowledgement and shared some thoughts on ways to capture citations.

Preclinical Services for Biopharmaceutical Product Development–This concept is a renewal and would maintain an NIAID resource that provides a suite of product development services for biopharmaceutical products that are intended for the treatment of infectious diseases. The biopharmaceutical products include therapeutic antibodies, cell lines, proteins, peptides, natural products, bacteriophages and nucleic acid-based materials (such as siRNA, oligonucleotides, genes or plasmids), and live entities and their derivatives. The Subcommittee members noted the need for the program, which provides valuable support for development of biopharmaceutical products to address medically important needs and emerging threats. Program staff also noted growing interest from drug research and development communities for the services. The Subcommittee members also supported the proposed renewal plan, which they think is thoughtful and includes: an assessment of needs and the availability of service providers; a plan for engaging potential contractors, particularly small businesses and academic institutions with the goal of expanding the contractor pool; and a plan to increase the awareness of the services in academia and industry.

Partnerships for Rapid Diagnostics and Phenotypic Antibacterial Susceptibility Testing for Bacteremia or Hospital Acquired Pneumonia (HAP)–This concept would advance the development of diagnostics that permit rapid differential species identification, and corresponding phenotypic antibacterial susceptibility profiles. The primary goal of such diagnostics is to facilitate antibacterial stewardship, thereby reducing selective pressure and improving patient outcomes. The Subcommittee members expressed strong support for the concept, noting the need for better, rapid, therapy-informing tools for these two clinical problems. The Subcommittee members asked about phenotypic vs. genotypic assays and where the final product would be used (e.g., near-patient, primarily in hospitals). One member recommended clarifying the types of HAP samples needed to address this topic in the planned funding opportunity announcement.

Improved Drug Susceptibility Testing (DST) for Tuberculosis–This concept aims to further develop new diagnostic technologies for tuberculosis (TB) DST with an emphasis on rapid, point-of-care, low complexity assays. The Subcommittee members expressed strong support for the concept, recognizing the critical need for improved DST for TB, particularly tests that are rapid and used at the point-of-care. Subcommittee members noted that improved TB DST is needed in the United States as well as endemic settings, as treatment regimens may be chosen empirically and DST may only be conducted when treatment fails. Even with available DST, repeat sputum tests may be needed; rapid point-of-care DST would reduce the burden of patient isolation while waiting to see if they respond to therapy. Ideally, DST would be simple and be a CLIA waived assay. Subcommittee members appreciated the synergy of this concept with the NIAID-supported Feasibility of Novel Diagnostics for TB diagnostic consortium, which could provide clinical evaluation of new DSTs, and asked about the availability of clinical resources for samples. Program staff also described other programs that may be able to provide reagents and clinical resources, including RePORT International and the BEI-RRP.

Biocontainment Laboratory Support for Pandemic Preparedness–This concept would provide support for biocontainment (BSL-3 and BSL-4) facilities and related core research services to further the goals of U.S. pandemic preparedness research and the Antiviral Program for Pandemics. The Subcommittee members expressed support for the concept to provide funding to BSL-3 and BSL-4 biocontainment laboratories to maintain facilities and the key capabilities necessary to conduct medical countermeasure (MCM) research for preparedness against viruses with pandemic potential. One Subcommittee member asked whether the initiative would support research towards the development of standardized reagents, animal models, and/or assays that will be used to facilitate MCM development. It was clarified that this was not the intent, that the goal of this concept is to ensure that the BSL-3/4 labs have the infrastructure, core competencies, and scientific/technical expertise to facilitate the research. In response to another Subcommittee question, program staff clarified that influenza is not a focus of the Antiviral Program for Pandemics. Related, while influenza expertise may be considered by reviewers for applications submitted in response to this concept, applicants would also need to demonstrate the ability to work with other viruses with pandemic potential; influenza expertise alone will not be sufficient.

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

Director’s Report

Carl Dieffenbach, Ph.D.

Dr. Dieffenbach thanked Kimberly Y. Smith M.D., M.P.H, senior vice-president in charge of research and development at ViiV Healthcare for her service and commitment to the NIAID mission and HIV/AIDS research as she will be rotating off the ARAC in November. Also mentioned were David Burns, M.D., who will retire as chief of the Clinical Prevention Research Branch in the DAIDS Prevention Sciences Program. Adeola Adeyeye, M.D., was introduced as the new branch chief. 

Budget Update

For FY 2022, the average proposed budget increase across NIH overall is approximately 21 percent with a large proportion going to ARPA-H. The FY 2022 Presidential budget proposal has not been finalized. However, on July 29, the House passed the 2022 spending package that funds many departments including HHS which has less money for ARPA-H and more for the Institute. It is anticipated that the new fiscal year will start under a continuing resolution. 

We will begin the fiscal year at a conservative level. The NIAID FY 2022 interim financial management plan for the R01 paylines would be at the 10^th and 14^th percentiles for established investigators and new PIs respectively. No adjustments will be made to noncompeting and competing grants. There will be a cut in competing research initiatives of up to 20 percent and the estimated success rates across the Institute is expected between 21 and 23 percent.

COVID-19 response emergency supplemental funding (2020-2021) was described and covered how specific amounts were allocated to NIH ($4.8B total including $1.5 billion to NIAID and $3.3 billion to other NIH institutes) and the HHS Office of the Secretary [$4.9 billion total including $1.7 billion to heavily fund the efficacy trials that NIAID has participated in with COVID-19 Prevention Network (CoVPN) and funding for ACTIV, and $3.2 billion allocated for the Antiviral Program for Pandemics (APP)]. 

Scientific and Programmatic Updates

HVTN 705/HPX2008-Imbokodo

This trial, launched in 2017, evaluated an Ad26-vectored mosaic vaccine with an HIV clade C gp140 boost in 2,637 sub-Saharan African women at high risk of acquiring HIV. However, this vaccine candidate did not sufficiently protect women against HIV infection and did not meet the “go criteria” for advancing to the next stage. This was certainly not the study outcome we were seeking, and we will apply the knowledge learned from the Imbokodo trial to continue efforts to find a vaccine that will be protective against HIV. Importantly, the investigational vaccine was found to be safe with no serious adverse events among trial participants.

HVTN 706/HPX3002-Mosaico

A parallel study, launched in 2019, will evaluate an Ad26-vectored mosaic vaccine with a bivalent HIV clade C and mosaic gp140 in 3,800 MSM and transgender individuals in the Americas and Europe. This study has recently completed enrollment and it is our intention to continue the study.

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)

The current statuses of the six ACTIV groups were briefly reviewed and summarized, with ACTIV-2 and ACTIV-3 primarily driven by NIAID. Importantly, within the ACTIV-2 protocol using the Brii Biosciences antibody combination, there were positive findings reported from its Phase 3 trial that showed a 78 percent reduction in hospitalization and deaths.

SARS-CoV-2 Monoclonal Antibody (mAb) Landscape

The current SARS-CoV-2 antibody landscape and range of vaccine candidates being evaluated through the ACTIV program were briefly updated. Emergency Use Authorizations (EUAs) for mAbs (Lilly, Regeneron, Vir) have all occurred and other Abs continue to be advanced. An important point is that the AstraZeneca combination has shown efficacy as post-exposure prophylaxis.

Update on the Efficacy Testing of COVID-19 Vaccine Candidates

The COVID-19 vaccine candidates continue to evolve. The need for boosts is still being debated with data supporting such a requirement coming from Israeli studies. The FDA will rule on the EUAs then Advisory Committee on Immunization Practices will make recommendations going forward. EUAs are lacking submission for the AstraZeneca product and other candidates including Novavax. Sanofi Phase 3 is enrolling.

Antiviral Program for Pandemics (APP)

This five-year program, announced by the Biden administration in June, is a whole of NIH approach that has a $3.2 billion investment from the American Rescue Plan. The purpose of this program is to catalyze the development of new medicines to combat coronavirus disease and prepare the United States to respond to future virus threats. 

This currently is a two-pronged approach of discovery (to build a sustainable platform to discover new antivirals) and development (to accelerate clinical testing of promising antiviral candidates) to catalyze the development of a robust pipeline of antivirals. The NIH is currently working closely with BARDA to advance three or four candidates, the first of which is Merck’s molnupiravir.

Additionally, NIAID recently published the Antiviral Drug Discovery (AViDD) RFA. This very large grant program will support comprehensive multidisciplinary research Centers focused on innovative antiviral drug development targeting coronaviruses, emphasizing SARS-CoV-2, and one or more select RNA viruses with pandemic potential.

Candidates for APP must meet specific criteria. What is in scope and out of scope was listed and had involved much discussion. Small molecules or biotherapeutics are being sought so a pill or patch or something that can be inhaled is considered in scope, but injections or infusions are out of scope.

Discussion:

Q: Elaborate on molnupiravir and the public/private partnership around that drug.
A: There will be some presentations from Merck about the drug dose selection. Merck intends to file for an EUA and will move forward with an arrangement with BARDA depending on what the trial data shows to make that drug available within Q4 of 2021. But this all depends on whether it is successful (anti-viral activity) in the trial.

Q: Is there anything specific and targeted by the government to address vaccine hesitancy in the United States? Also, how does this work with the flu shots?
A: The government has tried persuasion and now will focus on mandatory requirement. There needs to be more discussion within NIH to deal with vaccine hesitancy and the behaviors around it. We really need behavioral and social scientists to study this. We are working towards coordinated strategic efforts to try to advance factual scientific information. We must continue to promote the truth. Vaccine hesitancy is not a new thing. This is a continual battle. The annual flu shots are still needed.

Office of AIDS Research Advisory Council (OARAC) Update

Tricia H. Burdo, Ph.D.

Highlights of the 57^th OARAC meeting held on June 24, 2021, were presented. This included the OAR Director’s Report; NIH UNITE initiative, updates from the OARAC HIV Clinical Guidelines Working Groups (HIV Antiretroviral and OI Guidelines); “Pharmacogenetics of Antiretrovirals and the Importance of Inclusivity in Science”; and remarks from Harold Phillips (director, Office of National AIDS Policy).

OAR Director’s Report

This covered COVID-related research resources, CDC surveillance data, OAR engagements and recent listening sessions in Nebraska, San Diego, and New Orleans. The listening sessions comprised expert panel consultation to discuss strategies to support, retain, and expand the pool of early career HIV investigators.

HIV Funding and Budget Update

The President’s proposed FY 2022 budget includes $3.1 billion for NIH HIV research. Additional information is found in the FY 2022 Congressional Justification which is posted on the OAR website. It was noted that the NIH HIV/AIDS portfolio is now almost 100 percent aligned with the overarching OAR research priorities. It was noted that HIV research funding for NIH has only increased moderately over the past 20 years. Recent budget increases have lagged behind the increasing costs associated with conducting this critical research.

HIV Antiretroviral and Opportunistic Infections (OI) Guidelines Working Groups of OARAC

Updates from the clinical guidelines panel included the adult adolescent guidelines that were updated in June. The pediatric guidelines panel is reviewing new data and implications for dosing of neonates and infants and the use of some drugs in adults. The perinatal guidelines group continues efforts to incorporate more inclusive language and to address the care of transgender and non-binary people who are pregnant or trying to conceive.

Other Highlights

NIH UNITE Initiative Overview

There were two presentations on the UNITE initiative, which was established to identify and address structural racism within NIH and the greater scientific community. The UNITE “E” committee is charged with performing a broad systematic evaluation of NIH extramural policies and procedures to identify changes in practices and structures that perpetuate lack of inclusivity and diversity within the extramural research program. This includes developing strategies to address funding disparities and increase applications that would support individuals from underrepresented groups. 

There was a presentation by Namandjé N. Bumpus, Ph.D., on her work involving pharmacogenetics of antiretrovirals and the importance of inclusivity in science. 

White House Office of National AIDS Policy (ONAP)

There was a presentation by Harold J. Phillips, newly appointed director of the ONAP who discussed the progress in HIV/AIDS research since it was first described 40 years ago.

Next OARAC meeting: October 28, 2021 (Virtual Meeting).

NIAID/DAIDS FY 2023 Proposed Concepts Presented for ARAC Approval

A Multi-omics Approach to Immune Responses in HIV Vaccination and Intervention

Amy Palin, Ph.D.

This new P01 initiative is intended to support integration of bioinformatics and hypothesis-driven experimental approaches to define signatures of outcomes of HIV/SIV vaccination or intervention. This concept was developed after a workshop and involves interrogating samples from clinical trials, nonhuman primates, or whole animal models, with various omics platforms and omics approaches, then performing computational analyses. Several knowledge gaps identified from the workshop included the ability to predict the efficacy and safety of vaccines and other interventions. Factors contributing to the gaps include the high degree of immune heterogeneity at the population and cellular levels. Validation and application of computationally generated hypotheses will help to generate biologically meaningful insights from big data. Some correlates of protection may not be mechanistic; therefore, it is important to improve the predictive value of models. Examples of research that are being sought to support were described. This included the Ad26 mosaic HIV vaccine platform, the trivalent influenza vaccine (TIV) platform and the RhCMV/SIV vaccine platform. The omics approach is being supported because it is relatively unbiased.

Application requirements comprise two or more projects plus an administrative core, preliminary data for vaccine, therapeutic, or cure intervention, use of at least two omics approaches, an experimental component (human samples, animal models, or in vitro models), and a bioinformatics/statistical component. Clinical trial applications will be excluded.

The reviewers were supportive of this concept. Their comments and suggestions were summarized and responses to them were discussed.

Discussion:

Q: Would a small clinical study be useful?
A: Combination of two things: (i) concern that a clinical study may use too much of the budget and (ii) want to use existing resources that are already available.

Q: Is this initiative to define outcomes of response?
A: We were interested in data mining existing trials that have already occurred to see what can be learned and to use that knowledge to improve the next generation.

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

Molecular Dynamics of HIV

David McDonald, Ph.D.

The purpose of this initiative is to fund innovative R01s that support computational dynamic modeling of molecular complexes regulating the HIV life cycle, immune responses, and therapeutic interventions using existing and new HIV/host structural datasets. Addition of the dimension of time to the three-dimensional structures already studied by structural biologists is expected to facilitate novel insights into their function.

Molecular dynamics (MD) is a computer computational approach to simulate the movement of atoms and molecules over time, providing testable models of complex molecular behavior. MD can be used to animate static structures, such as an electron micrograph of the HIV capsid, to understand how they interact with other structures. Examples of advances in computational science were highlighted as these have enabled protein structure prediction. Highly accurate predictions from DNA and amino acid sequences by an AlphaFold AI system was recently reported. Quantum computing is speculated to be 1,000 times faster than regular computing and will further accelerate structural modeling processes.

The initiative will leverage the growing number of high-resolution HIV/host cell biomolecular structures by directly funding MD simulation research and incentivizing computational specialists to collaborate with HIV researchers.

The importance of this initiative shown by the NIH investment in HIV structural biology has increased the number of atomic-resolution structures of HIV and HIV-host complexes; however, these are only static images which provides an incomplete picture of their function. MD can use these images to provide real-time simulations of complex interactions and generate hypotheses for functional testing to see how they work in real life. 

The scope of this initiative covered research objectives such as HIV capsid interactions with cytoplasmic and nuclear transport machinery. Applications not supported by this initiative include those which only involve theoretical modeling or do not include functional analysis of the modeling simulations. Research teams are expected to include structural dynamics modelers along with appropriate structural, virologic, immunologic, and/or cell biological expertise.

The reviewers were supportive of this concept. The reviewers’ comments and suggestions were summarized and responses to them were discussed.

Discussion: None

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

Limited Interaction Targeted Epidemiology: Viral Suppression (LITE-VS)

Gerald B. Sharp, DrPH

The purpose of this new milestone-driven initiative is to define individual and contextual risk factors in people living with HIV-1 (PLWH) that are associated with inadequate viral suppression using methods that maximize outreach to unsuppressed PLWH, and to use the findings to design and conduct pilot studies to improve viral suppression and other study outcomes. This is important because suppression of HIV among people with HIV in the United States is essential for patient care and prevention of HIV transmission.

Viral suppression data in the United States from CDC in 2019 was reviewed as background and it was highlighted that this data is slightly behind the current epidemic and COVID has affected HIV testing and viral suppression. Other factors affecting viral suppression rates include race, age, gender, and individuals who inject drugs.

Digital approaches used to study the epidemic were summarized including various platforms (e.g., social media tools, game theory and other technologies) to provide information on ways to achieve consistent and stable viral suppression. These approaches are useful as they can be performed to obtain real-time data, unlike CDC data which can be a year old or more. 

LITE-VS will build upon previous successful approaches to enroll and retain large (i.e., > 1,000 participants) electronic cohorts in the United States. LITE-VS will focus on PLWH of all ages, sexes, and genders who are not consistently viral suppressed, with a requirement that at least 50 percent of participants have minority status. Investigators will be expected to enroll large, electronically generated cohorts in the first two years of the award and meet negotiated milestones in terms of total, minority, and adolescent enrollment of non-suppressed PLWH in the United States. Grantees meeting milestones in the first two years of the award will be eligible to transition to the second phase and receive up to three additional years of funding. In Phase 2, awardees may conduct epidemiologic research comparing suppressed and non-suppressed participants, investigate the predictors and mediators of viral suppression over time, and, optionally, address methodological questions about how best to enroll and retain participants or to pilot digital interventions designed to improve levels of suppression.

The reviewers were supportive of this initiative. Their comments and suggestions were summarized and responses to them were discussed.

Discussion:

Q: How will you address homeless and marginalized individuals?
A: This will be up to investigators to figure out how to do this, but structural factors are important. We might list the homeless as a target group, but it is unclear how to use social media to reach them.

Comment: We now have previously unavailable long-acting drugs as a tool that can be used in an aggressive way to target certain groups like the homeless. We should use creative ways and initiatives, and pair them with these long-acting therapies in collaborative partnerships to reach out and treat these groups. Numbers are trending worse particularly in poorer communities and COVID may make these numbers worse. Virtual clinic visits are not realistic if the internet is not available. This is an important initiative that needs to be amped up. 

Q: There is still a digital divide from marginalized populations. Please comment.
A: Agreed. But I think many people have phones and maybe even some of these people are homeless. So many people can be reached by phones for this study. Maybe some assistance can be requested in the budget to provide for those individuals without phones.

Comment: Economic disadvantaged people, especially transgender people of color and those in rural areas, are overlooked and data not obtained.

Q: We need something that is more intensive for people who are not suppressed that clinical services cannot provide. We need more services for medical health and substance abuse. Not sure if they will be reached with this approach.
A: We think these people can be reached. There are ways but not sure how the clinical trial part will work. One option is to get those individuals into a program that can be found for them.

A: This is a very important conversation and the points are well taken. The point of this initiative is research and not for delivery of care long term. We see it as a strategy to test if something works and will treat it as a starting point. It can be tweaked later for treatment approaches. If many great applications are received, then more can be funded. The question is: does this research need to be done? And the answer seems to be a resounding yes.

Comment: For those without access to the internet or a phone, maybe the RFA could encourage partnerships with libraries or community organizations or something innovative where people can drop in and use a computer at a kiosk.

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

Enhancing HIV Reservoir Susceptibility to Elimination

Diane Lawrence, Ph.D.

The purpose of this new R01 initiative is to support basic research focused on understanding why some HIV reservoir cells are resistant to virus- or immune-mediated cell death despite potent reactivation and specific immunologic responses. It will also support translational research to sensitize these cells to death or killing, either by the immune system or by therapeutic interventions.

The primary objectives of this initiative are to 1) elucidate cellular and molecular mechanisms within persistently infected HIV reservoir cells that impact their susceptibility to death, 2) identify novel therapeutic targets within persistently infected cells that will increase their sensitivity to cell death, and 3) explore synergistic approaches to combine enhancement of cell death with latency reversal and/or immunotherapeutic strategies. These studies will inform efforts to develop more effective interventions for an HIV cure.

There are major barriers to overcome to eradicate HIV such as: what drives reservoir formation, maintenance and decay, how the reservoir changes over time, and mechanisms of spontaneous reactivation in lately infected cells. There is evidence that clonal proliferation plays a major role in counteracting HIV reservoir decay, but it's unclear which drivers of proliferation may be most involved. HIV reservoirs and tissue compartments are difficult to access and are thought to be protected from immune clearance. Residual or defective virus production may be recognized by the immune system, so it may serve as a decoy and contribute to chronic immune activation. Together with viral escape mutations and exhaustion of effector cells, this can result in a failure of immune clearance.

One major approach to overcome these barriers and eliminate the HIV reservoir is the “kick and kill”, which involves reactivating the latent HIV (the kick) followed by enhancing the HIV-specific immune effector function (the kill). This involves a search for ways to overcome epigenetic and transcriptional silencing mechanisms to stimulate HIV RNA and antigen production, as well as antibody based or cellular immune therapeutic strategies to improve immune targeting and function. The goal of these strategies would be to induce selected death of persistently infected cells either by virus induced cytotoxicity, or immune mediated clearance. This strategy however has had only limited success possibly because of the host environment allowing formation or stabilization of a longer-lived reservoir, variable survival of HIV-infected cells and inconsistent effect of immune checkpoint inhibitors that reverse HIV latency and enhance CTL function. Other approaches may therefore be needed. It is known that several HIV proteins can either up- or downregulate pro- and anti-apoptosis pathways which may explain survival and proliferation of these reservoirs. It is unknown how the balance of these pathways may differ in primary infection versus persistently infected cells in different reservoir cell subtypes or following spontaneous reactivation versus stimulation with latency reactivation agents.

Key scientific questions included what cellular mechanisms impacts susceptibility of these reservoirs to either virus or immune mediated cell death upon either spontaneous reactivation or deliberate therapeutic intervention to reactivate the reservoirs and how do epigenetic factors and transcriptional regulation impact the response to death signals in various blood and tissue reservoir cells and cell subtypes?

The scope of the initiative was summarized and included defining the contribution of apoptosis pathways to survival, longevity, or expansion of blood and tissue HIV reservoirs.

The reviewers were supportive of this initiative. Their comments and suggestions for this initiative were summarized and responses to them were discussed.

Discussion:

Comment: This is timely and could be very insightful in reaching the goal of HIV cure.

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

Public Comments: None

Future ARAC Meetings

January 31, 2022 (Virtual)
June 6, 2022
September 12, 2022
January 30, 2023
June 5, 2023
September 11, 2023

Adjournment

Dr. Freedberg commented that the range shown in the four presentations is remarkable - from the atomic and molecular level to the availability of usable apps, and the breadth of scientific expertise within NIAID and DAIDS. Dr. Dieffenbach mentioned the daily challenge of not having a safe, effective durable HIV vaccine and that partnerships are required to solve such problems. Drs. Freedberg and Dieffenbach thanked the ARAC and DAIDS staff and adjourned the meeting.

VI. Adjournment

The meeting of the Council adjourned at 3:17 p.m., on Monday, September 13, 2021.

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.