The 188th meeting of the National Advisory Allergy and Infectious Diseases Council (NAAIDC) convened at 10:30 a.m. on Monday, January 29, 2018, in Conference Rooms E1/E2, Building 45, National Institutes of Health. Dr. Anthony S. Fauci, director, National Institute of Allergy and Infectious Diseases (NIAID) presided as chair.
In accordance with the provisions of Public Law 92-463, the meeting was open to the public from 10:30 a.m. to 11:45 a.m. and from 1:00 p.m. to 4:30 p.m. The meeting was closed to the public from 8:30 a.m. to 10:15 a.m. and from 11:45 a.m. to 12 noon for review and consideration of individual grant applications. Notice of the meeting was published in the Federal Register.
Meeting Attendees
Council Members Present: Council Members Absent:
Dr. Raul Andino Dr. Karen Nelson
Dr. Aftab Ansari
Dr. Wendy Book NIAID Senior Staff Present:
Dr. Amanda Castel Dr. Hugh Auchincloss
Dr. Anita Chong Dr. Carl Dieffenbach
Dr. Mark Feinberg Dr. Emily Erbelding
Dr. Stephen Galli Dr. Matthew Fenton
Dr. John Guatelli Dr. John McGowan
Dr. Sally Hodder Dr. Daniel Rotrosen
Dr. Gurjit Khurana Hershey
Dr. Stanley Lemon
Dr. Robin Patel
Dr. Larry Schlesinger
Dr. Arlene Sharpe
Dr. Cara Wilson
Dr. Christopher Wilson
Ex Officio Members Present:
Dr. Victoria Davey
Dr. Anthony Fauci
Dr. Rima Khabbaz
Ad Hoc Members Present:
Dr. Rafi Ahmed
Dr. James Crowe, Jr.
Table of Contents
I. Review of Grant Applications
II. Remarks of the Director, NIAID—Anthony S. Fauci, M.D.
III. Report of the Allergy, Immunology, and Transplantation Subcommittee—Daniel Rotrosen, M.D., director, DAIT
IV. Report of the Microbiology and Infectious Diseases Subcommittee—Emily Erbelding, M.D., M.P.H., director, DMID
V. Joint Meeting of the AIDS Subcommittee and AIDS Research Advisory Committee (ARAC)–Carl Dieffenbach, Ph.D., director, DAIDS
VI. Adjournment
I. Review of Grant Applications
The National Advisory Allergy and Infectious Diseases Council convened in closed session to consider applications in allergy and immunology, microbiology and infectious diseases, and AIDS.
Funding Actions: The Council reviewed 4,471 research and training applications with primary assignment to NIAID for a requested amount of $1,506,558,868 in first-year direct costs and recommended approval of 2,258 applications with $641,670,154 in first-year direct costs.
II. Remarks of the Director, NIAID—Anthony S. Fauci, M.D.
Dr. Fauci opened the Council session by welcoming visitors to the meeting. He introduced three new Council members: Drs. Stanley Lemon, Mark Feinberg, and Robin Patel, and thanked them for their patience as we awaited final approval of their appointments.
He introduced two ad hoc Council members: Dr. Rafi Ahmed, Charles Howard Candler Professor of Microbiology and Immunology and director of the Emory Vaccine Center, and Dr. James Crowe, Jr., professor of pediatrics and pathology, microbiology and immunology, and director of the Vanderbilt Vaccine Center.
Council member Karen Nelson was unable to attend the meeting.
Consideration of Minutes of Previous Meeting
Council considered the minutes of the September 11, 2017 meeting and approved them as written.
Appointments and Transitions
On September 29, Dr. Tom Price resigned as HHS Secretary. President Trump selected Deputy HHS Secretary Eric Hargan to serve as acting HHS Secretary. On November 13, President Trump nominated Alex Azar as the new HHS Secretary. He was sworn in as HHS Secretary on January 29, 2018.
The Board of the Global Fund to Fight AIDS, Tuberculosis, and Malaria recently named Peter Sands as its new executive director.
The World Health Organization selected Stewart Simonson as assistant director-general for general management. Steward was instrumental in helping establish the NIAID Special Clinical Studies Unit in the NIH Clinical Center.
Staff and Organizational Changes
Dr. Seema Nayak was chosen as the new director of the Office of Clinical Research Resources in the Division of Microbiology and Infectious Diseases.
Dr. Tara Schwetz is the new chief of the Strategic Planning and Evaluation Branch in the Office of Strategic Planning, Initiative Development, and Analysis.
In the Division of Extramural Activities, Shamay Knox has been selected as the new chief of the Acquisition Management and Operations Branch in the Office of Acquisitions.
Tributes and Awards
Dr. Fauci paid tribute to former colleague Dr. Bonnie Mathieson who passed away on January 8, 2018, a little more than a week after she retired from her distinguished 43-year career at NIH. Since 1995, Dr. Mathieson had headed the HIV Vaccine Program in NIH’s Office of AIDS Research (OAR). Before joining OAR, she was a program officer for six years in the Vaccine Branch, Division of AIDS, NIAID.
Dr. John Mascola, director of the Vaccine Research Center (VRC), was elected to the National Academy of Medicine.
Dr. Steve Whitehead, senior associate scientist in the Dengue Virus Group of the Laboratory of Viral Diseases, received the 2018 American Society of Microbiology’s Maurice Hilleman Award. The Award recognizes major contributions to pathogenesis, vaccine discovery, vaccine development, or control of vaccine preventable diseases.
The American College of Rheumatology recently designated Dr. Karyl Barron as a master of the college. Dr. Barron is deputy director of the Division of Intramural Research, NIAID.
Four NIAID scientists have been elected as fellows of the American Academy of Microbiology: Dr. Michael Grigg, chief, Molecular Parasitology Section, Laboratory of Parasitic Diseases; Dr. Carole Long, chief, Molecular Immunology Section, Laboratory of Malaria and Vector Research; Dr. Paolo Lusso, chief, Viral Pathogenesis Section, Laboratory of Immunoregulation; and Dr. Joseph Marcotrigiano, chief, Structural Virology Section, Laboratory of Infectious Diseases.
Meetings and Events
Last fall on the occasion of the annual NIH William Paul Memorial Lecture, NIAID dedicated a conference room in the VRC to Dr. Paul.
On September 27, Dr. Fauci participated in The Atlantic Washington Ideas Festival on examining modern medicine.
Dr. Brenda Fitzgerald, then CDC director, visited NIH on November 2. Dr. Fauci gave her an overview of NIAID and a tour of the VRC, where she heard about research being conducted on a variety of vaccines.
On November 28, NIH welcomed then Acting HHS Secretary Eric Hargan. Dr. Francis Collins, Dr. Fauci, and several other institute directors participated in a roundtable discussion with Mr. Hargan. He also toured the Clinical Research Center and visited several laboratories.
U.S. Surgeon General Dr. Jerome Adams visited NIH on January 16. During his visit, Dr. Adams toured the NIAID Special Clinical Studies Unit in the Clinical Center.
Over the last few months, international delegations from Brazil, China, Georgia, and South Korea visited NIAID.
Budget Update
The President’s Budget for fiscal year (FY) 2019 is expected to be released on February 12.
Dr. Fauci noted that NIH continues to operate under a continuing resolution through February 8, 2018 (since extended to March 23, 2018). NIAID is cautiously optimistic that the final FY 2018 budget will at least be flat from that of FY 2017.
NIAID’s interim financial management plan for FY 2018 takes a conservative approach. Our interim R01 payline will be the 9th percentile for established investigators and the 13th percentile for new investigators. NIAID does not plan to make programmatic cuts to noncompeting and competing grants, though competing research initiatives have been cut up to 20 percent from their planned budget level. Our estimated success rates for research project grants will be between 18 and 20 percent.
Legislative Update
On September 12, Dr. Collins, Dr. Lawrence Tabak, and Dr. Fauci participated in a congressional meet and greet hosted by Representative Pete Sessions. Dr. Fauci provided updates on Zika and universal influenza vaccine research.
On November 9, Dr. Fauci briefed staff of the Senate Health, Education, Labor, and Pensions Committee on NIAID’s efforts to develop and test medical countermeasures for biodefense threats and emerging infectious diseases.
On December 21, Dr. Fauci briefed Representative Michael Burgess, chair of the Health Subcommittee of the House Energy and Commerce Committee, on the likely limited effectiveness of this season’s influenza vaccine and research being done to develop a universal influenza vaccine. Representative Burgess then invited Dr. Fauci to brief members of the House Energy and Commerce Committee on this topic on January 9.
Other Information Items
Dr. Fauci began by citing global HIV/AIDS statistics from the UNAIDS Data 2017 update. He then presented selected accomplishments of the President’s Emergency Plan for AIDS Relief (PEPFAR), which is celebrating its 15th anniversary—more than 13 million people on antiretroviral therapy, over 2 million perinatal HIV infections averted, more than 85 million people received HIV testing services in FY 2017, and a 25 to 40 percent decline in new HIV diagnoses among adolescent girls and young women through comprehensive HIV prevention interventions. Dr. Fauci also highlighted several of NIAID’s HIV trials that are underway.
He continued with a recap of some recent activities related to pandemic preparedness and an update on Zika research.
Dr. Fauci outlined some of the challenges of seasonal and pandemic influenza, showing data for this influenza season in comparison to previous seasons and noting that NIAID has created a strategic plan for universal influenza vaccine research.
He concluded by giving brief updates on gain-of-function research, neglected tropical diseases, malaria, tuberculosis, and stem-cell transplantation for severe scleroderma.
III. Report of the Allergy, Immunology, and Transplantation Subcommittee—Daniel Rotrosen, M.D., director, DAIT
Dr. Rotrosen welcomed the Subcommittee members to the 188th meeting of the National Advisory Allergy and Infectious Diseases Subcommittee meeting:
Dr. Rotrosen presented the following scientific and Division activities:
Staff and Organizational Changes
Kelly Stone, M.D., Ph.D. Dr. Stone joined the Asthma, Allergy, and Airway Biology Branch (AAABB) in September 2017, as a medical officer. He joins under detail from the NIAID Division of Intramural Research, where he maintains responsibility as the director of the Allergy and Immunology Clinical Fellowship Program and as a senior clinician and deputy chief of the Laboratory of Allergic Diseases. He received his medical degree and Ph.D. from the University of Maryland, completed pediatric residency at the Children’s National Medical Center in Washington, DC, and completed a fellowship in Allergy/Clinical Immunology at Children’s Hospital, Boston. He held academic appointments at Harvard Medical School and the George Washington University School of Medicine and Health Sciences before joining NIH/NIAID as a staff clinician in 2007. He became director of the Allergy and Immunology Fellowship Program in 2008, director of the NIH Clinical Center Allergy and Immunology Consultation Service in 2011, and deputy chief of the NIAID Laboratory of Allergic Diseases in 2014, where he has also held the title of senior clinician since 2016. As part of AAABB, Dr. Stone will have special responsibilities for atopic dermatitis and the Atopic Dermatitis Research Network (ADRN).
Qian (Joy) Liu, M.D. Dr. Liu jointed the Basic Immunology Branch as a program officer in November 27, 2017. She received her M.D. from Southeast University in Nanjing and her Master’s in Immunology from Beijing University. Dr. Liu was a scientist in the laboratory of Dr. Philip Murphy in the Division of Intramural Research, NIAID, where she studied the pathogenesis of WHIM syndrome, including the immunological mechanism in mouse models and humans, and the efficacy and mechanism of a CXCR4 inhibitor used to treat WHIM patients. Before coming to NIAID, Dr. Liu was an assistant professor at the New Jersey Medical School, studying B and T cell responses to helminths and the immunological impact of helminth infection on autoimmune disease.
Division Activities
Allergy, Asthma, and Airway Biology Branch
2017 Annual Asthma and Allergic Disease Cooperative Research Center Face to Face Meeting (AADCRC). On November 2 and 3, 2017, NIAID sponsored the 12th annual meeting of the AADCRC investigators in Rockville, Maryland. The one-and-a-half-day meeting of principal investigators, co-investigators, students, and NIAID program staff included oral and poster presentations from the nine NIAID-funded research Centers, as well as three NIAID-funded program project grant teams, and a special session featuring the work of AADCRC-funded young investigators.
Basic Immunology Branch
Skin Immune Responses to Vector Bites-Workshop. On September 14, 2017, NIAID co-sponsored a workshop in Rockville, Maryland. The goal of the workshop was to examine how the bite from a blood-feeding arthropod affects the local immune environment at the bite site and subsequent transmission of vector-borne pathogens. Experts from disparate scientific communities, namely vector biology, skin immunology, and infectious disease research, exchanged ideas and establish collaborations. These multidisciplinary interactions were designed to provide insights into what occurs at the site of a bite from an immunological and disease transmission perspective, including how local immune responses in the skin are altered by immunomodulatory molecules in the saliva of blood-feeding arthropods. The workshop featured 17 speakers and junior investigators discussing research gaps they identified and presenting concepts to address these gaps that they developed with a senior investigator (mentor) in a complementary research area.
Molecular Mechanisms and Immune Consequences of Pathogen Reservoirs: Battling Unseen Enemies. On September 19 and 20, 2017, NIAID held a workshop in Rockville, Maryland. The goal was to bring together a multidisciplinary audience to consider shared and unique characteristics of pathogens that shield themselves from detection by the host immune system. The organizers hoped to achieve an understanding of host immune mechanisms that maintain privilege and modulate inflammatory responses. Twenty-five speakers were invited and addressed topics ranging from pathogen diagnostics, host biomarkers of infection, and common and unique mechanisms of immune privilege.
Immunity in the Elderly Annual Meeting. On September 26 and 27, 2017, the final annual meeting of the Immunity in the Elderly program was held in Rockville, Maryland. NIAID and National Institute on Aging (NIA) jointly support this program, with five projects supported by NIAID and three projects supported by NIA. The goal of the program is to understand immune mechanisms that contribute to impaired host responses during infections and in response to vaccines. Investigators presented their research findings and discussed opportunities for future collaborations among the members of this program.
Immune Epitope Database and Analysis Resource User Workshop. On October 25 and 26, 2017, the Immune Epitope Database and Analysis Resource (IEDB) held a two-day user workshop in Rockville, Maryland. The goal of the workshop was to provide instruction on the capabilities of the IEDB and review case studies and other examples so that attendees would understand how to access and fully utilize the database and analysis resource for their work. The IEDB contract supported 13 trainees and junior faculty, out of 37 total participants, to travel to and attend the workshop. The DAIDS HIV Immunology Database staff, operated by Los Alamos National Laboratory, also provided training during the workshop so that attendees could learn to use both HIV and non-HIV related epitope databases and analysis tools.
Joint Adjuvant Contractor Meeting. On November 13, 2017, NIAID held the joint annual meeting of the DAIT Vaccine Adjuvant programs in Rockville, Maryland. The program includes the Adjuvant Discovery and the Adjuvant Development contract programs, where the goal is to identify and develop new vaccine adjuvants that allow the development of stronger, more protective vaccines against infectious diseases. The meeting featured talks from seven Adjuvant Discovery contractors and four Adjuvant Development contractors, as well as presentations by FDA staff to educate investigators about the agency’s expectations for toxicity studies and the investigational new drug approval process. The contractors’ talks highlighted progress made in the past year and how their novel adjuvants were being used to improve vaccines against pathogens such as Bordetella pertussis, influenza, Zika, West Nile Virus, and Shigella sp. Two of the novel adjuvants, developed under FY 2009 adjuvant discovery projects and which are currently supported by adjuvant development contracts, are scheduled to be tested in humans for the first time in late 2018 or early 2019.
Human Immunology Project Consortium (HIPC) Subcommittee Meeting. On November 29 and 30, 2017, the HIPC Assay, Bioinformatics, and Clinical Subcommittees met to discuss ongoing activities and develop future projects. The mission of these Subcommittees is to promote HIPC program goals and foster collaboration amongst HIPC investigators. Current activities include development of data and meta-data standards to facilitate data submission to the ImmPort and ImmuneSpace websites and data reuse/mining by both HIPC investigators and the broader research community.
2017 Adaptive Immune Receptor Repertoire (AIRR) Community Meeting. From December 3 to 6, 2017, DAIT and DAIDS hosted the third annual meeting of the Adaptive Immune Receptor Repertoire (AIRR) Community in Rockville, Maryland. The goal of this meeting was to discuss scientific progress and opportunities for generation and reporting of B and T cell receptor sequence data, with a focus on associated challenges for this rapidly evolving field. The meeting covered topics such as outreach, education, and activities of the minimal standards, data repository, and tools and resources working groups. Community input was encouraged throughout, and recommendations were prepared by the extramural organizers and presented to the overall group.
Cooperative Centers on Human Immunology (CCHI). The annual meeting of the Cooperative Centers on Human Immunology was held on December 7 and 8, 2017, in Rockville, Maryland. Principal investigators and scientists from the six U19 centers presented their research updates on the molecular mechanisms by which the human immune system is activated and regulated in response to infection, vaccination against infectious disease, or administration of a vaccine adjuvant. In addition, new technologies developed to facilitate studies in humans were also presented. The CCHI Steering Committee finalized plans to fund five infrastructure and opportunity fund applications.
Immunity in Neonates and Infants Kick-off Meeting. Investigators funded under the NIAID-led Immunity in Neonates and Infants program met on December 14, 2017 in Rockville, Maryland. Fifteen projects are supported under this program that is a partnership among NIAID, National Institute of Child Health and Human Development), and National Institute of Environmental Health Sciences. The goal of this program is to better understand neonatal and infant immune regulatory mechanisms in response to commensal bacteria, allergens, infectious agents (including HIV), vaccines, or environmental pollutants. Investigators presented their project plans and recent updates to introduce their programs. The meeting provided a venue for investigators to exchange ideas and to foster collaborations within the program.
Autoimmune and Mucosal Immunology Branch
Cooperative Study Group for Autoimmune Disease Prevention Annual Meeting. On October 16 and 17, 2017, the first meeting following the recent recompetition of the Cooperative Study Group for Autoimmune Disease Prevention was held in Rockville, Maryland. Investigators from the five groups awarded under this program presented their individual projects aimed at understanding aspects of autoimmune diseases and avenues for prevention. The meeting provided a venue for investigators to exchange ideas and establish collaborations to foster advances in the program.
Development of Sample Sparing Assays Program Meeting. On December 4, 2017, the third meeting of the Development of Sample Sparing Assays was held in Rockville, Maryland. Investigators presented updates on their projects and shared views on cutting edge technology developments in their fields of study. The research funded in this Program has important implications for introduction of high resolution immune monitoring in clinical settings where only limited amounts of samples are available.
Autoimmunity Centers of Excellence (ACE), Steering Committee Meeting. On October 18 and 19, 2017, ACE steering committee members and collaborative project leaders met in Rockville, Maryland, to discuss their progress and plan the future of their shared research agenda. Their annual progress report was posted in January (autoimmunitycenters.org). ACE continues to be highly productive in supporting outstanding fundamental research into the mechanisms of autoimmunity in humans, publishing several papers in high impact journals in the past year. ACE is also supporting clinical trials with mechanistic studies of novel therapies for the autoimmune diseases systemic lupus erythematous (NCT01946880 and another opening soon), pemphigus (NCT03239470), and rheumatoid arthritis (NCT02603146), and mechanistic studies in multiple sclerosis (NCT02330965) and systemic sclerosis (NCT02161406).
Radiation and Nuclear Countermeasures Program (RNCP)
2017 Annual Update Meeting for the Centers for Medical Countermeasures Against Radiation Consortium (CMCRC). On December 5 and 6, 2017, the CMCRC Annual Meeting was held in Rockville, Maryland. CMCRC investigators and their staff from the four awarded cooperative agreements (Columbia University, Duke University, UCLA, and the University of Pittsburgh Medical Center) provided an update on the progress that has been made in their Centers over the past year. The meeting provided an opportunity for exposure of the portfolio to other federal government agency staff that were in attendance and fostered dialog and collaboration among the CMCRC investigators and program staff regarding future research and development directions. Also present were the five members of the External Advisory Board, who provided their insight into the successes and needs of the program.
Concepts Presented for Clearance
FY 2019 Research Concept Clearances
B Cell Epitope Discovery and Mechanisms of Antibody-Mediated Protection: The objective of renewing this program is to support basic research aimed at the discovery of novel B cell epitopes and to elucidate mechanisms of antibody-mediated protective immunity and/or mechanisms of antibody-mediated pathology. Data from this program has been used to predict cross-protective epitopes among related pathogens, generate therapeutic antibodies, and inform the development of epitope-based vaccine strategies. The scope of this program will be expanded to include epitope discovery for antibodies associated with either autoimmune diseases or transplant rejection.
The Subcommittee endorsed and unanimously approved this initiative.
Large-Scale T Cell Epitope Discovery: The objective of this program is to support highly interactive, multidisciplinary teams whose research efforts are focused on large-scale discovery of T cell immune epitopes associated with infectious or autoimmune diseases, commensal organisms, or alloantigen, and validation of these epitopes regarding their role in immune protection or immune-mediated pathogenesis in humans.
The Subcommittee endorsed and unanimously approved this initiative.
Collaborative Cross Mouse Model Generation and Discovery of Immunoregulatory Mechanisms: The objective of this program is to support the use of Collaborative Cross (CC) mouse lines to advance understanding of the host genetics involved in immune regulation and function and to further develop CC mouse lines that more faithfully reproduce human immune responses.
The Subcommittee endorsed and unanimously approved this initiative.
Immune Mechanisms at the Maternal-Fetal Interface: The objective of this program is to determine the roles and interactions of immune cells at the maternal-fetal interface and to elucidate the effects of infection or vaccination during pregnancy on these cells and the developing fetal immune system.
The Subcommittee endorsed and unanimously approved this initiative.
High-Priority Immunology Grants: The objective of this program is to continue set-aside support for growth in the field of fundamental immunology and emphasize the continued and long-term interest of NIAID in fundamental immunology, a major mission of NIAID among the NIH institutes and centers.
The Subcommittee endorsed and unanimously approved this initiative.
Adjuvant Development for Vaccines and for Autoimmune and Allergic Diseases: The goal of this program is to accelerate preclinical development and optimization of a single lead adjuvant candidate or a select combination-adjuvant for prevention of human disease caused by non-HIV infectious pathogens, or for autoimmune or allergic diseases.
The FY 2019 Small Business Innovation Research (SBIR) contract concept topics were posted in the Electronic Council Book (ECB) for Council access and review. The subcommittee endorsed and unanimously approved this initiative by email vote.
B Cell Receptor and T Cell Receptor Repertoire Computational Tools: The objective of this program is to support the development of computational tools to accelerate the analysis of B cell receptor and T cell receptor repertoire sequence data.
The FY 2019 SBIR contract concept topics were posted in the ECB for Council access and review. The Subcommittee endorsed and unanimously approved this initiative by email vote.
Reagents for Immunologic Analysis of Non-Mammalian and Underrepresented Mammalian Models: The objectives of this program are to develop and validate reliable antibodies and reagents for the identification and tracking of primary immune cells and/or the analysis of immune function/responses (e.g., cytokines, chemokines, intracellular signaling) in non-mammalian models and underrepresented mammalian models.
The FY 2019 SBIR contract concept topics were posted in the ECB for Council access and review. The Subcommittee endorsed and unanimously approved this initiative by email vote.
Development of Sample Sparing Assays: The objective of this proposal is to accelerate commercial development of novel, standardized sample sparing assays that improve monitoring of the immune system using limited amounts of biological sample.
The FY 2019 SBIR contract concept topics were posted in the ECB for Council access and review. The Subcommittee endorsed and unanimously approved this initiative by email vote.
Adjuvant Discovery for Vaccines and for Autoimmune and Allergic Diseases: The objective of this program is to support the screening for new adjuvant candidates for vaccines against infectious diseases or for autoimmune and allergic diseases; their characterization; and early-stage optimization.
The FY 2019 SBIR contract concept topics were posted in the ECB for Council access and review. The Subcommittee endorsed and unanimously approved this initiative by email vote.
IV. Report of the Microbiology and Infectious Diseases Subcommittee—Emily Erbelding, M.D., M.P.H., director, DMID
Director’s Report
Dr. Emily Erbelding, director of the Division of Microbiology and Infectious Diseases (DMID), chaired the NIAID Microbiology and Infectious Diseases Council Subcommittee meeting on January 29, 2018. Dr. Erbelding noted several recent senior staff changes, and introduced Dr. Seema Nayak, who has joined DMID as the director of the Office of Clinical Research Resources.
Dr. Erbelding provided several DMID research updates:
- In follow up to Dr. Fauci’s Open Session presentation, Dr. Erbelding provided further information on NIAID’s soon-to-be published Universal Influenza Strategic Plan, summarizing the three research areas included in the Plan: 1) improving the understanding of the natural history of influenza immunity and pathogenesis; 2) improving the understanding of influenza immunity and correlates of protection; and 3) supporting rational vaccine design through an iterative approach. She acknowledged the need to make strategic investments in these areas and informed the Subcommittee that they would be hearing about related concepts in the future.
- She mentioned a recent supplement that was published through the Journal of Infectious Diseases, that she edited together with Cristina Cassetti, which provides a comprehensive overview of Zika virus research activities. She noted that DMID has played a significant role stimulating research in this area since 2015.
- She described a recent DMID request for information (RFI) issued that aimed to collect information related to prospective, longitudinal cohort studies on influenza infections. The primary goal of the RFI was to gather information about existing community-based, prospective, longitudinal cohort studies of influenza, or other acute respiratory infections that may allow assessment of influenza immunity from banked samples. Also of interest are longitudinal cohort studies examining the effectiveness of influenza vaccination. DMID received more than 20 responses.
- In response to additional funding NIAID has received from Congress designated for Combatting Antibiotic Resistant Bacteria (CARB), Dr. Erbelding reported that DMID would soon release a program announcement to stimulate research focused on understanding the nature of microbial communities, how antibiotics affect them, and how they can be harnessed to prevent disease, as well as research exploring combination therapies to address the emergence of resistance.
- She informed the Subcommittee of recent legislation mandating that DHHS establish a Tick-Borne Disease Working Group, with a requirement that they have to publish a report for the Secretary by the end of 2018. This effort focuses largely upon Lyme disease, which is a significant problem in the United States. Dr. Dennis M. Dixon will serve as the NIH representative on this working group. She anticipates receiving the group’s recommendations for research in the area of tick-borne diseases by the end of the year.
- Dr. Erbelding welcomed three new DMID Subcommittee members: 1) Mark Feinberg M.D., Ph.D., president and CEO of the International AIDS Vaccine Initiative (IAVI); 2) Stanley M. Lemon, M.D., professor of medicine and microbiology and immunology at the University of North Carolina, Chapel Hill; and 3) Robin Patel, M.D., the Elizabeth P. and Robert E. Allen Professor of Individualized Medicine and professor of microbiology and medicine at Mayo Clinic in Rochester, Minnesota.
- She congratulated Dr. Patel on her appointment as President Elect of the American Society of Microbiology effective June 2018, to be followed by the role of President from July 2019 to July 2020.
- Finally, Dr. Erbelding presented three topics for inclusion in the next Small Business Innovation Research (SBIR) Contract Solicitation for the Subcommittee’s consideration:
1. Mobile Health Point-of-Care (POC) Diagnostics, to explore capabilities of smartphones to improve POC diagnostics particularly in low-resource settings.
2. Development of POC Assays to Quantify Anti-Tuberculosis Antibiotics in Blood, to develop tools to monitor antibiotic concentrations during treatment.
3. POC Diagnostic for Gonorrhea and Determination of Antimicrobial Susceptibility, to develop diagnostics capable of determining the infecting strain’s susceptibility to antibiotics.
Dr. Erbelding noted that the SBIR program is congressionally mandated and requires eligible governmental agencies such as NIH to set aside a percentage of their extramural budget to support domestic small businesses with research and development (R&D) for technology commercialization. She summarized the scientific and programmatic significance of these topics, noting that two of the topics address the urgent issue of antimicrobial resistance; described the availability/feasibility of the technology solicited by each topic; and commented on potential uses of each. One Subcommittee member encouraged consideration of other bodily fluids beyond blood in the tuberculosis POC topic. Another Subcommittee member encouraged broadening the research scope allowed under the mobile POC topic. The Subcommittee was supportive of all three topics.
Program, Scientific, and Budget Updates
Sexually Transmitted Infections Research: DMID Program Update – Dr. Carolyn Deal, chief of the Sexually Transmitted Diseases Branch, provided an overview of DMID’s current sexually transmitted infections (STIs) research portfolio. She described the global problem of STIs and discussed the public health importance of STI prevention efforts. She then focused on two major components of the DMID research portfolio: antibiotic resistance research activities, which are responsive to the National Combatting Antibiotic-Resistant Bacteria effort, and vaccine R&D.
Dr. Deal described ongoing research activities in both areas, for example she reported on DMID’s recent support of a new class of antibiotics for Neisseria gonorrhoeae, which DMID has helped in partnership with Entasis Pharmaceuticals. She also noted recent efforts to advance the development of live biotherapeutics. She then described NIAID’s STI vaccine portfolio for several leading STIs, including herpes simplex virus, Neisseria gonorrhoeae and Chlamydia trachomatis, providing details on the preclinical and clinical vaccine R&D pipeline for these diseases. She reported on NIAID’s efforts over the past several years to help develop a STI Vaccine Roadmap, in collaboration with WHO and other stakeholders, that outlines the need and prospects for new and improved STI vaccines.
Dr. Deal noted that despite diagnostic and treatment options for many STIs, epidemics of these diseases continue, and new interventions are needed. Moreover, growing concerns about antibiotic resistance, particularly for Neisseria gonorrhoeae, are further impacting treatment options.
Concepts Presented for Clearance
The following FY 2019 concepts were presented to the Subcommittee:
Sexually Transmitted Infections (STI) Cooperative Research Centers (CRC): Vaccine Development – this concept would support multidisciplinary, collaborative, synergistic approaches for the development of vaccines to control and prevent sexually transmitted infections (STIs) caused by high-priority pathogens with limited candidates in the pipeline. The presentation was well received by the Subcommittee. Subcommittee members agreed that there is a clear need for STI vaccines and noted that there appear to be enough candidates in the pipeline poised for further development. In addition, it was clarified that although this is a renewal of the STI CRC, vaccine development represents a major shift from the scope of the current program. Further discussion revolved around the types of studies the initiative would support to advance candidate vaccines along a “reasonable path to licensure.” Members commented that research efforts should be directed towards those activities that add qualities to vaccine candidates that would appeal to future development partners and that doing so may foster industrial partnerships. Program agreed and added that the initiative could provide an opportunity to support a dialogue between STI investigators and industry around this important research need. The concept was unanimously approved by the Subcommittee.
Impact of Initial Influenza Exposure on Immunity in Infants – this concept aims to help inform the design of durable, broadly protective influenza vaccines by determining how immunity, generated by the initial and subsequent influenza infections and/or vaccinations, shapes protective immunity to future influenza exposures in longitudinal human infant cohorts. Program staff outlined the critical need to establish a cohort to understand the basic immunology of infant “imprinting,” and described how studies in such a cohort could help facilitate design of a universal influenza vaccine. The Subcommittee voiced strong support for the concept, and there was consensus that the proposed initiative is important and will address research gaps in understanding the natural history of influenza immunity and pathogenesis. The Subcommittee acknowledged that the infant population is prone to high mortality from influenza. There was discussion on the overall programmatic strategy to achieve the goals of the concept, including the most suitable award mechanism, consideration of geographic and genetic distribution for cohort recruitment, collaborations between different funded research programs, and accessibility of biological samples. There was additional discussion on the importance of following this cohort for longer than five years, that is the standard NIH grant period, as well as the importance of enrolling infants over more than a single season of influenza to account for differences in circulating influenza strains. Program staff agreed that these points would all be considered. In addition, Program staff explained that this initiative is part of a larger coordinated effort for the design and development of a universal influenza vaccine. Components of other ongoing cohort studies will help to answer other questions related to influenza immunity. The concept was unanimously approved by the Subcommittee.
Elucidating the Functional Roles of Non-Coding RNAs in Viral Infectious Diseases – the overall goal of this concept is to stimulate hypothesis-driven research to uncover functional roles of non-coding RNAs (ncRNAs) in viral infectious diseases. Subcommittee members were enthusiastic about the concept not only for the translational research potential, but more importantly for the focus on basic research to understand the function of ncRNAs. They noted that although the therapeutic potential of ncRNAs is interesting, their use as biomarkers could be very beneficial to the field. One member commented that restricting the concept to dengue and influenza virus may be too limiting for the field and suggested broadening the scope to learn more across the larger infectious disease field. This member also suggested Program consider revising the scope such that while micro-RNA (miRNA) research would be included, an emphasis should be placed on long non-coding (lncRNA) research. Program responded that there is particular interest in uncovering lncRNA functions but that miRNA research is still of interest due to the potential for use as biomarkers as has been seen in fields outside of infectious disease. Other Subcommittee members agreed that pathogens beyond viruses could be considered (e.g., bacteria, fungi) but acknowledged that limited funding impacts the scope. Subcommittee members expressed support for the proposed R21 grant mechanism, stating this is the appropriate mechanism for this work based on where the infectious research field stands at this time. The concept was unanimously approved by the Subcommittee.
V. Joint Meeting of the AIDS Subcommittee and AIDS Research Advisory Committee (ARAC)–Carl Dieffenbach, Ph.D., director, DAIDS
Director’s Report and SBIR Contract Topics
Carl Dieffenbach, Ph.D.
Dr. Dieffenbach provided a budget update, a report card of how NIAID did with R01 funding during the previous, 2017, fiscal year, and introduced Kimberly Smith M.D., MPH, as a new committee member.
Budget Update
The President’s FY 2019 Budget will be released on February 12, 2018. FY 2018 began under a continuing resolution and the government is currently operating under the 4th stopgap spending bill which will fund the government through February 8, 2018. The NIAID FY 2018 interim financial management plan was outlined and included the R01 payline for new and established principal investigators. Competing research initiatives have been cut by up to 20 percent for FY 2018, giving NIAID an estimated success rate of 18 to 20 percent. Given the current structure of the way AIDS funding is going at NIH, there is movement by leadership to hold the AIDS funding level. The data and trends in NIAID payline history, success rates, NIAID AIDS success rates, AIDS 2017 success rates by select mechanisms and comparative success rates were presented. Overall, the NIAID AIDS success rate showed that more R01s than R21s were paid in 2017. DAIDS, compared to NIH’s and NIAID’s overall success rate, was slightly better in terms of grant success rate.
Q: Why are the number of R01s and similar applications going down?
A: A couple of reasons. Fewer people in the field. Also, the list previously contained more AIDS-related research. After working with OAR to tighten the definition of AIDS research, less of the lower priority research is getting funded with AIDS dollars. Younger PIs should be encouraged to apply for R01s as it is unclear if many R21s will be paid out at the end of the year.
SBIR Contract Topics
Dr. Dieffenbach explained that the SBIR program is a set-aside fraction of NIH’s total budget that is used for grants to small business entities and can also be used for contract purposes.
Topic 1: In vivo Targeted Degradation of HIV Proteins
Project goal: Support the development of reagents that specifically bind to HIV expressed proteins in an infected cell and deliver them to the proteasome for degradation.
Phase I activities:
• Design, optimize, and test strategies for both targeting HIV proteins and degrading HIV proteins through the ubiquitin proteasome system
• Perform proof-of-concept studies of HIV protein degradation in cell lines
• Evaluate off-target effects
• Perform proof-of-concept studies in an HIV animal model
Phase II activities:
• Optimize delivery to target HIV infected-cells with minimal off-target effects
• Evaluate, in nonhuman primates (NHPs), organ toxicity, immune responses/adverse events, and pharmacokinetic/pharmacodynamic parameters
• Perform IND-enabling studies in consultation with the FDA
Committee members were asked to cast their votes.
Ballot Voting Outcome:
12 Approval
0 Approval with modification(s)
0 Deferral for further information
0 Disapproval
Topic 2: Particle-Based Delivery of HIV Env Immunogens
Project goal: Design and develop novel formulated nanoparticles (NPs) to deliver HIV Env immunogens, either as protein (minimal epitope, chimeric or natural trimers, etc.) decorated on NP surfaces and/or encoded as an encapsulated nucleic acid.
Phase I activities:
• Develop NP systems capable of delivering HIV immunogens (e.g. Envs, monomers, RNA, DNA)
• Study compatibility and interactions of components (excipients, buffers, pH) and effect on antigen epitope integrity and it’s in vitro and in vivo performance
• Analyze, quantify, and characterize NP formulations through biophysical, physicochemical, binding assays and/or in vivo testing (small animal studies)
• Develop processes adaptable for scale-up studies leading to the production of cGMP grade clinical material
• Correlate in vitro-in vivo performance of NP formulations with animal studies
- Investigate the effects of route of immunization, dose, dosage form, and dose-sparing capacity on the kinetics immune response
Phase II activities:
• Develop stable and reproducible formulations(s) using optimized conditions that can be adapted to GMP manufacturing
• Conduct proof of concept studies in larger animals and NHPs as warranted, evaluating performance and toxicity
• Develop methods to evaluate compositional quality of critical components in NPs, establishing quality assurance and quality control process for reproducibility and consistency of NP formulations
• cGMP manufacturing of formulations(s)
Committee members were asked to cast their votes.
Ballot Voting Outcome:
12 Approval
0 Approval with modification(s)
0 Deferral for further information
0 Disapproval
Topic 3: Co-Delivery and Formulation of Adjuvants for HIV Vaccines
Project goal: Support advancement of preclinical development of a promising HIV antigen-adjuvant formulation or combination-adjuvant(s) for co-delivery for a preventative HIV vaccine.
Phase I activities:
• Evaluate conditions (e.g., screening compatibility of excipients, buffers, pH) to develop a stable, reproducible adjuvanted antigen formulation; evaluating formulations with immunomodulatory agents (e.g., mineral salts, cytokines, chemokines)
• Develop assays and testing methods for physicochemical, biophysical and functional/potency characterization of antigen-adjuvant formulations and their individual components, as applicable
• Develop formulation processes adaptable for scale-up studies leading to the production of cGMP grade clinical material
• Compare performance of different adjuvanted formulations in small animal models, assessing the influence of route of administration, delivery and dose-sparing capacity of HIV antigen-adjuvanted vaccines
Phase II activities:
• Develop formulation(s) using optimized, controlled conditions that can be adapted to GMP manufacturing
• Conduct proof-of-concept studies in larger animals and NHPs, as warranted, evaluating performance and toxicity
• Create Quality Assurance and Quality Control SOPs to ensure that critical quality attributes of HIV antigen-adjuvanted formulations are preserved
• Contingent on progress, develop cGMP manufacturing processes for developing adjuvanted formulations
Committee members were asked to cast their votes.
Ballot Voting Outcome:
12 Approval
0 Approval with modification(s)
0 Deferral for further information
0 Disapproval
Discussion:
Q: Topic 1 seems interesting but narrowly focused. How do you arrive at these project proposals? Are specific applicants in mind and is it the best approach for targeting applicants?
A: We have not picked out anyone specific in mind. We were brainstorming about why we have residual immune activation in HIV. One hypothesis is that there is a low level of reactivation and the HIV antigens that are produced are a result of the natural disease process. Any therapy that is only suppressive will always have this low level of activation. One strategy would be to target proteins that do not cause off-target effects. Although narrow, this targets a broader problem.
Q: Topic 3. Why limit Phase I studies to rodents only where results may not be reproducible in higher species?
A: That specific component is limited because Phase I is relatively poorly funded. We can look at that specifically, if approved, to modify it slightly so that a more appropriate animal model is used.
AIDS Vaccine Research Subcommittee (AVRS) Update
Jim Bradac, Ph.D.
Dr. Bradac’s presentation focused on summarizing the two workshops, “Early Life Immunization Strategies Against HIV Acquisition” and “Potential Importance of Cell-Associated HIV for Prevention Strategies,” that were presented at the AVRS meeting in September 2017.
The “Early Life Immunization Strategies Against HIV Acquisition” workshop was held to look for strategies to address the challenges of inducing broadly neutralizing antibodies (bnAbs) against HIV via immunization. The thought is that if immunization occurs during early childhood development, before tolerance mechanisms have had their greatest effect, it could generate bnAbs in the population. Early life immunizations are looked at because HIV-infected infants produce bnAbs faster and with less mutations than what is seen in adults. Immunizing infants results in a more durable antibody response. AIDS vaccines that have been tested in infants (PACTG 230 and HVTN 027) have shown to be immunogenic. The goals of this workshop were to discuss the scientific rationale for selectively testing relevant HIV vaccines, address the immune tolerance and other immune obstacles, identify vaccine platforms that might best benefit from testing in infants, and identify vaccines that are available for such testing. The action items that came out of this workshop were to organize a working group to further pursue strategies that address the early immunization landscape, selection of vaccines, potential of combining strategies, identification of age relevant adjuvants, and use of optimal models/tools.
The “Potential Importance of Cell-Associated HIV for Prevention Strategies” workshop had two goals: discuss the relevance of cell-associated HIV in the context of HIV vaccine and passive immunization strategies and discuss how animal models and in vitro assays measuring the blocking of cell-associated HIV transmission may provide a new dimension to better predict the efficacy of HIV vaccine candidates and antibody-based prevention therapies. This workshop was important because it is not known whether cell-free virus is the main source of transmitted virus and/or virus spread in established infections. Several publications suggest that neutralizing antibodies are less effective against cell-cell viral spread. Further, cell-free virus in vitro assays may be underestimating the problems associated with neutralizing an infectious stalk. The conclusions of this workshop were that HIV-infected cells are present in bodily fluids associated with HIV transmission but their role is not known; there remains broad disagreement within the research community as to whether cell-cell spread of HIV is an additional obstacle for prevention strategies; there is need to improve the nonhuman primate and humanized mouse models; and the in vitro data indicated that cell-associated HIV may be more difficult to neutralize than cell-free virus. It was suggested that the current AMP trial in South Africa might shed light on the role cell-associated virus plays in transmission.
Discussion:
No questions.
NIH HIV/AIDS Clinical Trials Networks Recompetition Presentations (Approval Requested)
Overview: HIV/AIDS Clinical Trials Networks Refinement for FY 2021 to FY 2028
Carl Dieffenbach, Ph.D.
Dr. Dieffenbach’s presentation provided an overview for the NIAID-NIH HIV/AIDS Clinical Trials Network refinement for FY 2021 to FY2028. Every seven years, NIAID competitively reviews and renews the HIV network funding, addressing significant changes in research priorities that have occurred since the last competition.
This presentation at the advisory committee meeting is the end of the planning stage. Awards will occur November 30th/December 1st, 2020, which is FY 2021. The five current networks, clinical trial units, and aligned clinical trial research sites will be streamlined. NIAID is proposing to streamline adolescent prevention by taking it out of the current IMPAACT Network and moving it to a prevention-centric network. The evaluation of HIV vaccines in pediatrics and adolescents will be moved into a vaccine network. Moving forward, collaborations with leadership groups and networks and the clinical research units and sites will be critical. NIAID is also proposing to streamline nonvaccine-based prevention research to a single network that will result in a single set of priorities for HIV prevention intended to speed safe and effective products to market and implement these products at scale. Addressing the challenges of adherence to all prevention tools is a priority. The development of concepts that provide systemic coverage and the development of tools that are powered to bend the curve of the epidemic by research key populations with effective products are sought. A robust preclinical/discovery pipeline of concepts that can prevent HIV acquisition is a commitment of NIH. Concepts must include strategies to address adherence challenges by using behavioral and biological strategies. NIH will continue to provide support for clinical evaluation of promising candidates that meet the priorities for prevention research in any category (microbicides, injectables, PEP) and the development of a combination vaginal ring for HIV prevention and contraception. The proposed structure for the recompetition includes four leadership and operations center FOAs – prevention; vaccine; adult therapeutics; maternal, pediatric, and adolescent therapeutics – followed by a FOA specific for statistical and data management centers, a FOA specific for laboratory centers, and a FOA for clinical units and sites. The goals of the HIV/AIDS Clinical Trials Networks are to address targeted scientific priorities, maintain domestic and international scope, preserve community involvement, increase flexibility of the network infrastructure, enable multi-disease research capacity through intra-NIAID collaborations, ensure that a transparent mechanism is in place for meritorious ideas to be considered, reviewed and supported, and work with host countries to improve the efficiency and timeliness of the research approval process.
• Laboratory Centers for the HIV/AIDS Clinical Trials Network
The Laboratory Centers (LC) for the HIV/AIDS Clinical Trials Network are to provide scientific expertise and a framework for laboratory leadership, structure and activities that contribute to the development of the Network’s research agenda and to execute the laboratory component of the Network’s clinical research. There will be two to four awards, each supporting one or more Networks, for a duration of seven years. Key elements/activities of the LC include continuing to foster innovation, discovery, and implementation of assays and methodologies to advance HIV/AIDS clinical sciences; assuring state-of-the-art laboratory-based evaluations required for the Network clinical trials; working closely with the Network Leadership Groups to contribute to the scientific agendas, and develop and review the lab components of study protocols; centralizing testing in support for one or more Network’s studies when appropriate, and harmonizing lab-related requirements between Networks; in collaboration with Data Centers, ensuring the use of appropriate, validated, and verified laboratory data capturing and specimen tracking system; ensuring, in collaboration with DAIDS-funded laboratory QA contracts, compliance with DAIDS requirements, including participation in External Quality Assurance schemes to assess ability to perform tests correctly, CLIA certification, and/or compliance with Good Clinical Laboratory Practices; ensuring reliable specimen chain of custody, addressing shipping challenges, and providing for local and centralized short- and long-term storage of study samples obtained from study participants; and in collaboration with Network Leaderships, promoting access to stored specimens for future research by the broader scientific community.
• Statistical and Data Management Centers for the HIV/AIDS Clinical Trials Networks
The Statistical and Data Management Centers (SDMC) for HIV/AIDS Clinical Trials Networks are to provide statistical expertise and data management resources for leadership, structure, and operational support for Network global multi-center clinical trials, including those when NIAID is the IND sponsor. Activities cover protocol development, trial implementation, conduct, analysis and dissemination of results. There will be two to four awards, each supporting one or more Networks, for a duration of seven years. Key elements/activities for the SDMC include providing biostatistical leadership in clinical trial design, analysis, interpretation and publication of results; contributing to network scientific agenda, and develop and review study protocols; creating new statistical methodologies to accommodate changing needs; providing and maintaining interoperable data systems compliant with NIH, U.S. federal and international standards for sponsored clinical research and clinical trials; ensuring data quality and integrity through the use of validated data capturing and tracking systems; and developing composite protocol budgets and project plans for data management operations with CTU/CRS and LC.
Discussion
Q: Regarding the modular nature of the leadership centers, a data center, and a laboratory center, does a given leadership center have to commit to relationships with a specific data center and laboratory center at the time of the application?
A: We are going to ask for alignments to be addressed within each of the applications. For example, I am writing a leadership and operations center application and I am going to affiliate with X data center and with Y laboratory. We are going to request that they affiliate and assign. This is a change that NIH forced upon us.
Q: In theory one data management center can affiliate, at the time of application, with two different competing applications for the leadership centers?
A: Yes.
Q: Regarding the governance structure for the shared statistical centers and laboratories, the diagram shown in the presentation shows a governance over the top across all four leadership groups, but nothing for between leadership groups where they are sharing.
A: In the situation of leadership groups sharing statistical centers and laboratories, the leadership groups would need to align for how they are going to share a data center or a lab. Sharing data centers and labs is an option, it is not a requirement.
Q: How independently would the lab centers function with respect to assay development or the scientific component of the developmental work? Is that internal to the lab center or is that sitting in the leadership network?
A: That is a key point and it remains a collaborative process. As research is being developed, there is a thought process that would go back and forth between a laboratory center and a leadership and operations center about what assays are needed. Money could come from protocol-specific funds or it could be embedded either in the leadership and operations center or in the laboratory.
Q: Since the maternal, adolescent, and pediatric network is getting restructured, will it be written into the FOA so that the right kind of leadership and expertise is drawn into the prevention and the vaccine network, which have not traditionally included this kind of expertise?
A: It had never been required in the past. As we move forward, and protocols continue to be developed, leadership will come from with the network, but also from people who are currently very interested in pediatric activities that can join and be a part.
Comment: A strong scientific application for a leadership group is going to be inextricably linked to a statistical center and a laboratory center. It would very likely turn out that a strong application for leadership groups will be tied to better applications for a laboratory center and a statistical center.
Q: In past competitions, how many applications have been received and what has been the turnover in the leaderships of these networks historically?
A: There has been variation in turnover in the different networks. Some networks have a very specific proposed turnover process that they follow. Other networks have never turned over their leadership.
Q: Has a network that was led by one group ever failed on recompetition?
A: No.
HIV/AIDS Clinical Trials Units
Manizhe Payton, MPH
Ms. Payton presented the HIV/AIDS Clinical Trials Units (CTU) concept. The objective of this concept is to identify CTUs and their component Clinical Research Sites (CRS) and investigators that will contribute to the development and implementation of multiple clinical trials in support of the NIAID HIV/AIDS research agenda. There will be 30 to 35 awards for a duration of 7 years. The refined CTUs will ensure availability of clinical research capacity, and scientific administrative expertise to support the research goals of the HIV/AIDS Networks; contain CRSs which will conduct clinical trials in compliance with local and national regulatory standards; preserve community education and engagement; maintain optimal authority and accountability across components; mentor the next generation of investigators; and contribute to the scientific agenda. NIAID will be seeking ‘research ready’ sites that demonstrate experience conducting IND-level clinical research and access to appropriate clinical trial participant populations. CTUs must be affiliated with at least two HIV/AIDS Networks and have between one and eight CRSs to efficiently support multiple networks. CTUs will receive two types of funding – core funds and protocol funds. Core funds are intended to provide a baseline level of infrastructure across the unit and are based on geographical location, size, and scope. Protocol funds are provided to support the execution of protocols and are negotiated with each network on a protocol-specific basis and are provided by the networks to the sites or the units directly. Reviewer comments for the CTU initiative and a draft timeline for the CTU FOA were listed.
Discussion
Q: Are you considering some way of incorporating the ability of international sites to comply with regulatory approval and transfer of specimens as a review criterion in the announcement and review process?
A: Sometimes in the international setting, the regulatory requirements are dynamic. This will be taken under consideration. Putting more specific language in the regulatory section of the FOA to speak to compliance with regulations while also meeting NIH requirements for things such as data transmission and specimen transmission will be important to achieve scientific goals.
Q: Mentorship is important; however, from experience it is hard to find good mentoring models within academic sites in the United States and the idea of mentorship in many of the international clinical trial units does not have a good model. Some CTUs do not have the capacity to provide mentorship. This is an important piece of the initiative, but it is difficult since the mentors are not necessarily there at the international sites. How will this be operationalized in the FOA?
A: Mentoring is not an entitlement and works best if it is a competitive process.
Q: Given that there will be a multitude of sites applying, how will it be determined that the best sites can fulfill the four different networks’ needs? How will a balance be achieved?
A: We work closely with our scientific program counterparts to ensure that the sites that are being selected can fulfill the scientific needs of those programs and networks. It is a highly collaborative process. There is also the possibility of surge capacity to bring on more sites if specific gaps are identified. There is the opportunity to make minor changes on an annual basis to the funded portfolio sites if there are changes to the scientific priorities in the network.
Q: Can you expand upon the thinking of going from 37 CTUs to 30-35? It is a 10 to 20 percent reduction in the number of CTUs.
A: There are some CTUs and CRSs that were over capacity and are not contributing to the level that is expected from fully funded sites. It is likely that some of the CTUs will become larger and additional sites might be added, especially in the prevention arena.
Comment: It is worth emphasizing the fact that new CTUs will be considered. It is not necessarily just reducing the current number of CTUs.
Leadership and Operations Center for HIV Prevention Clinical Trials Network
Sheryl Zwerski, DNP, CRNP
Dr. Zwerski presented the concept for the Leadership and Operations Center for HIV Prevention Clinical Trials Network. The objective of this concept is to establish a Leadership and Operations Center (LOC) to carry out the NIAID HIV prevention research related agenda domestically and internationally in conjunction with Network Laboratory and Statistical and Data Management Centers. There will be one award for a duration of seven years. Participating institutes and centers (ICs) include the National Institute of Mental Health (NIMH), the National Institute on Drug Abuse (NIDA), and the National Institute of Child Health and Human Development (NICHD). The goals of the NIAID Prevention Network are to reduce HIV incidence at a population level; provide data on a range of products and strategies to meet the needs of diverse target populations; address prevention of HIV acquisition from all potential routes without preferences for product and/or delivery systems; and establish flexibility in scientific focus and processes to address emerging HIV epidemics. To accomplish these goals, the proposed HIV Prevention Clinical Trials Network will streamline the prevention research infrastructure and consolidate to one prevention network to make efficient use of available resources, focus on HIV prevention product and strategy evaluation, and foster partnerships to evaluate products and strategies. In prevention product evaluation, adherence challenges remain a significant barrier to achieving HIV prevention goals. The streamlined Prevention Network will focus on long-acting products as well as other novel agents to address this challenge. In addition, end-user preferred characteristics will be determined using appropriate methodologies to increase prevention product uptake; desirability is the standard to meet. Required capabilities of applicants include broad research expertise to address all scientific areas; ability to conduct proof of concept through Phase IV strategy studies; efficient protocol development, resource planning and management, and clinical trials implementation processes; coordination with the SDMC and the LC to support and enhance the network’s research agenda; encourage the submission of innovative concept proposals from investigators outside the network; and mentorship and training of next generation of investigators and leaders. Requirements for the SDMC and the LC components of the HIV Prevention Clinical Trials Network were overviewed. Potential collaborations and partnerships, including with the community, were listed. Reviewer comments were presented and addressed.
Discussion
Q: It is understood that prevention of HIV is going to need various products for different people, and not everyone who could benefit from systemic antiretrovirals will want to take them. This is in alignment with some of the comments made about end-users and what they want. It has been gratifying to hear Dr. Dieffenbach’s comments and to see the inclusion of some microbicide research as well as the next generation MPT ring for continuation in the Clinical Trials Network structure. However, language related to everything being systemic is still present. Can you clarify the difference between the opening comments today and the ones just made?
A: It was not intended to say that we would not support microbicide products moving forward. We currently support the testing of a number of products and await those results to be able to determine what the next steps will be. In considering the consolidation of the prevention networks, it has not been said that the support for microbicide concepts or products would not continue. Any products, including microbicides, would need to meet standards for being safe, implementable, feasible, and to provide systemic protection moving forward. We feel that it is NIAID’s responsibility to consider information on changing sexual trends and to be able to move the science forward and make the most efficient use of the resources available.
Q: The sine qua non of microbicides is that they are not systemic. To say a topical product would provide protection from an intravenous drug exposure is probably not feasible. It should be completely clear if there is support of microbicide research, which I am pleased to hear there is. Microbicides, vaginally or rectally delivered products, are not the best way to deliver systemic drugs. If the objective is to only use systemic drugs, microbicides make no sense. If there is interest in developing products that can provide protection when delivered topically, which can work, it needs to be clear what is being proposed.
A: We are not saying that microbicide products could not continue to be developed. It is recognized that vaginally and rectally applied products would have a limited delivery and are probably not practical. However, we are currently testing several microbicide products and if these products show promise and have an effect at the population level, we would take it forward. When looking at 2020 onwards through 2027, it is imagined that the products that are developed will need to provide systemic protection.
Q: Relevant to the mentorship, you mentioned underrepresented minorities and certainly Sub-Saharan African investigators. There is another underrepresented group, which is the rural United States. This is the area in the United States where we are having emerging epidemics, where there has been in the past historically very low prevalence of HIV, and where there are few investigators. It is also areas where there is sometimes dubious interpretation of science. I would like to add to the mentorship that it is important that those investigators are focused upon.
A: We agree. We want to make sure that we include mentorship for investigators and early career investigators in the United States, particularly in underserved areas or underserved populations.
Leadership and Operations Center for Adult HIV/AIDS Therapeutics Clinical Trials Network
Sarah Read, M.D.
Dr. Read presented the concept for the Leadership and Operations Center for the Adult HIV/AIDS Therapeutics Clinical Trials Network. The objective of this network is to establish and/or support a Leadership and Operations Center (LOC) to carry out the NIAID adult therapeutics HIV related agenda in conjunction with Network Laboratory and Statistical and Data Management Centers. There will be one award for a duration of seven years. NIMH will be a participating IC. The major scientific foci of the Adult Therapeutics Network will be novel and durable interventions for treatment of HIV; ART-free remission; complications and co-infections; and tuberculosis (TB). Novel and durable interventions for treatment of HIV will continue to try to achieve durable HIV suppression for all adults, including special populations, by investigating interventions such as novel drugs and biologics, including long-acting formulations and novel combinations of biomedical and behavioral interventions. In terms of ART-free remission the identification of strategies to either eradicate HIV or sustain virologic remission will continue through immune-based interventions including therapeutic vaccines and antibodies, gene/cell therapies, and interventions that activate or suppress latent provirus. Complications and co-infections will focus on noninfectious complications and co-infections in fully suppressive antiretroviral therapy settings. These include mechanisms that lead to host cell and tissue dysfunction, including low-level HIV viral replication and persistence of viral products, will be targeted; the identification and evaluation of strategies to prevent and treat end-organ disease with other stakeholders; and the exploration of curative strategies for hepatitis B co-infection. In terms of TB, the scientific focus will be to evaluate novel drugs and combination treatments for drug-sensitive and –resistant TB, including new formulations, delivery routes, and adjunctive host-directed therapies; evaluate strategies to improve chemoprevention of TB; evaluate prognostic biomarkers and new diagnostics and conduct pathogenesis and translational research in the context of clinical trials; improve therapies for TB in the setting of co-morbidities that worsen TB outcomes with the help of other stakeholders; and partner with pediatric and maternal therapeutics network to extend clinical investigation across the lifespan. Required capabilities of applicants include broad research expertise to address all scientific areas; ability to conduct all phases of clinical trials; efficient protocol development, resource planning and management, and clinical trials implementation processes; coordination with the SDMC and the LC to support and enhance the network’s research agenda; encourage the submission of innovative concept proposals from investigators outside the network; and mentorship and training of next generation of investigators and leaders. Requirements for the SDMC and the LC components of the Adult HIV/AIDS Therapeutics Clinical Trials Network were overviewed. Potential collaborations and partnerships, including with the community, were listed. Reviewer comments were presented and addressed.
Discussion
No questions.
Leadership and Operations Center for Maternal, Adolescent, and Pediatric HIV/AIDS Therapeutics Clinical Trials Network
Sheryl Zwerski, DNP, CRNP
Dr. Zwerski presented the concept for the Leadership and Operations Center for Maternal, Adolescent, and Pediatric HIV/AIDS Therapeutics Clinical Trials Network. The object of this concept is to establish a Leadership and Operations Center to carry out the NIAID maternal, adolescent, and pediatric HIV-related agenda domestically and internationally in conjunction with Network Laboratory and Statistical and Data Management Centers. There will be one award for a duration of seven years. The participating ICs and divisions include NICHD, NIMH, and the Division of Microbiology and Infectious Diseases (DMID). The major scientific foci of this network are novel and durable interventions for treatment of HIV, ART-free remission, tuberculosis (TB), and complications and co-infections. With novel and durable interventions for HIV, the scientific focus is to accelerate the evaluation and licensure of promising antiretroviral drugs using innovative approaches for rational selection and prioritization of ARVs towards accelerated path to licensure; advance the evaluation of long-acting and novel drug delivery strategies with extended dosing intervals for HIV-infected maternal, pediatric, and adolescent populations; and with partners, demonstrate the effectiveness of these approaches as integrated behavioral, biomedical, and structural interventions with an emphasis for adolescent populations. The scientific focus for ART-free remissions is to evaluate novel therapeutic interventions and strategies to achieve ART-free remission in pediatric populations from newborns to adolescents including antibodies, therapeutic vaccines, novel strategies for early treatment in the immediate newborn period, and other approaches as the safety profile emerges in adult populations; and within the context of clinical trials, evaluate and characterize host and viral processes involved in reservoir establishment and maintenance and evaluate tools and approaches to identify, characterize, and measure HIV reservoirs. With TB, the scientific focus will be to evaluate new anti-TB drugs and regimens for treatment and prevention of drug-sensitive and drug-resistant TB disease in pediatric, adolescent, and maternal populations with and without HIV; and within the context of clinical trials or other appropriate settings, evaluate diagnostic, prognostic, or treatment response biomarkers for TB disease with a particular focus on young children, non-sputum samples, and suitability for POC platforms. The scientific focus for complications and co-infections is to investigate neuroprotective ART and other strategies for infants and children; work with partners to evaluate novel preventive and/or therapeutic approaches for high-priority diseases of importance to maternal and/or pediatric HIV-infected/affected populations; and evaluate other co-morbidities and complications of importance for pediatric, adolescent, and maternal populations with other partner institutes. Required capabilities of applicants include broad research expertise to address all scientific areas; ability to conduct proof of concept through Phase IV strategy studies; efficient protocol development, resource planning and management, and clinical trials implementation processes; coordination with the SDMC and the LC to support and enhance the network’s research agenda; encourage the submission of innovative concept proposals from investigators outside the network; and mentorship and training of next generation of investigators and leaders. Requirements for the SDMC and the LC components of the Maternal, Adolescent, and Pediatric HIV/AIDS Therapeutics Clinical Trials Network were overviewed. Potential collaborations and partnerships, including with the community, were listed. Reviewer comments were presented and addressed.
Discussion
Q: The original proposal called for only three networks instead of four with this network to be rolled into the others. Is that correct?
A: Correct. That was what was first discussed. Through feedback received, it was determined along with NICHD, that the area of maternal, adolescent, and pediatric therapeutics area would be best served by having a separate leadership group that would focus very specifically on the scientific areas that were outlined. This area is evolving, and the prevention for adolescents would largely be led by the HIV prevention trials network, and then the vaccine work would be led by the vaccine trials network.
Q: Can you explain the logic of moving the prevention of HIV in adolescents and pregnant women to a different network that does not have the same expertise?
A: We are not proposing that prevention in pregnant women would be moved to the prevention network. We are proposing that adolescent, HIV-negative, at-risk adolescent prevention be largely led by the prevention network, in collaboration with this network. The specific vaccine work will be led by the vaccine trials network. The bulk of the expertise lies here, and as far as thinking about prevention of mother-to-child transmission, we hope that this would be largely addressed by optimizing treatment for maternal population and would consider other modalities moving forward.
Leadership and Operations Center for HIV Vaccines Clinical Trials Network
Mary Marovich, M.D.
Dr. Marovich presented the concept for the Leadership and Operations Center for the HIV Vaccine Clinical Trials Network. The objective of this concept is to establish and/or support a Leadership and Operations Center to carry out the NIAID HIV vaccine-related agenda in conjunction with Network Laboratory and Statistical and Data Management Center. There will be one award for a duration of seven years. The major scientific foci of this network are to establish a comprehensive clinical research program to discover and develop an efficacious prophylactic HIV vaccine and to provide the expertise and capacity for advanced phase (≥2a) trials to develop prophylactic vaccines against other infectious diseases that impact populations burdened by HIV (TB and HCV). Applicants must include comprehensive HIV vaccine clinical research program and a description of the ability to expand to accommodate large trials of vaccines against other infectious diseases. The scientific priorities of the HIV Vaccines network are to evaluate vaccines to prevent HIV acquisition and define correlates of risk and protection across lifespans; to build partnerships to bridge from phase 2b/3 studies to licensure and market, and to address obstacles to HIV vaccine development; develop vaccination strategies for targeting youth to establish protection prior to sexual debut; advance concepts to elicit and technologies to assess B and T cell, tissues, and innate responses and integrate clinical and basic/NHP research agendas; incorporate research on behavioral and social aspects in prevention and transmission of HIV infection; and evaluate vaccines to prevent TB. Additional priorities are to establish processes to solicit and approve clinical research concepts from network and non-network members and to ensure engagement of scientists in other fields able to contribute to the HIV vaccine research agenda; collaborate with the HIV vaccine research community in developing and implementing a coherent/coordinated clinical research agenda; attract, mentor, and train early career investigators; and avail core expertise, operational infrastructure, laboratories and/or affiliated sites to conduct large clinical trials of vaccines against other diseases. Requirements for the SDMC and the LC components of the HIV Vaccines Clinical Trials Network were overviewed. Potential collaborations and partnerships, including with the community, were listed. Reviewer comments were presented and addressed.
Discussion
Comment: Nice incorporation of reviewer comments. Want to emphasize that we are changing a network in terms of its scope and it is going to be important that the FOA be written in a way that facilitates that change so that the pediatric, adolescent, pre-pubertal children, and infants are incorporated in the new vaccine network.
Q: If thinking about monoclonal antibodies in a therapeutic capacity, does that fall under the therapeutic network, and if monoclonal antibodies were used in a prevention capacity, it would fall in the vaccine group, but not in the prevention group?
A: Currently, the prevention testing of the monoclonal antibodies is jointly run by the HPTN and the HVTN and it is anticipated that that would proceed. That may change, the therapeutics would be run out of therapeutics, and the preventive monoclonal antibodies could be run out of both vaccine and the preventative networks.
Q: Is there an intentional de-emphasis of monoclonal antibodies over vaccines?
A: No, there is not.
Questions and Comments on the HIV/AIDS Clinical Trials Network Recompetition
Q: Developing a network structure is a compromise between avoiding redundancy and capturing all the expertise that reside in the differing networks. How are the budgets of the networks, as they have existed previously, going to change for the next leadership groups? How are the old budgets and new budgets going to fit into the new network structure?
A: We are going to seek limited redundancy so there is appropriate handoff. There is a group that is primarily responsible and will have the budget to drive it, but they will collaborate with others. We are conscious of making sure that we have an appropriate level, not necessarily of deliberate redundancy, but enough overlap so that there is touching and appropriate sharing of information. These are very complicated scientific agendas and these groups struggle to maintain emphasis on critical questions. Resources are limited, and it is going to become a little tighter, so everything will require additional scrutiny.
Q: Is control over what gets done in these networks at the level of the leadership groups?
A: There is daily discussion between leaders in the networks and the division about what is going on. There is significant amount of give-and-take all the time that is put into protocol development. These are cooperative agreements and a hands-on process.
Q: Is it a centrally organized activity to avoid redundancy and competition between networks?
A: It is centrally organized. To the best of our availability, we avoid redundancy and competition. We agree that redundancy is wasteful. For example, by collaborating with people like the Gates Foundation, we can merge our areas and decide to do a study together to save both the NIH, the taxpayers, and Gates. For smaller-focus studies, it is about the right concept coming forward that could have an impact. Networks spend a lot of time rejecting concepts because they are either not ready or they are not well thought-out, or they are never going to succeed. There is a lot that goes on behind the scenes before we have a Phase IIA type study.
Q: Does a leadership group have complete control over their budget? Or will NIAID oversee what that budget gets spent on? Does NIAID have veto power over redundant activities?
A: There is a process that defines what trials leadership groups will propose and then there is an evaluation. Ultimately, there is a process where the division approves requests and an amount of money to cover them. It is a negotiation and a process that occurs on a yearly basis. We do not give all the money in one aliquot in a given year. We give some, and then we see how progress is made and if additional funds are needed. NIAID does have veto power.
Q: Is a mentoring plan going to be a requirement on the applications, or is it more of a suggestion?
A: We have a couple of networks that have had reasonably good mentoring plans that have been successful. It is based on limited resources going into mentoring programs where there is competition. Not everybody that is interested in being mentored will get mentored. Networks must decide who the top candidates are.
Q: For the contribution of the other institutes, such as NIDA, contributing to the prevention network, has it been fleshed out how much these other institutes will contribute or are there limitations?
A: Every institute forms their own interest in terms of what they are seeking to achieve through the leadership groups. We reach out to them consistently and the OAR has assisted in reaching out as well. Some institutes are more interested in collaboration than others. Ultimately, it is an institute-by-institute decision on what they are willing to contribute. If NIDA only wants to contribute $1 million into adult therapeutics program, what they buy is maybe some enrollment in clinical trials of people who are actively using substances, but not necessarily a research agenda in that area. The strength of NIH is 27 institutes and centers; the weakness of the NIH is 27 institutes and centers.
Q: There is reference in the presentations from all four new networks to the idea of getting input from people external to the network and potentially funding some of their ideas. Is there going to be an attempt or has there been an attempt in the past to look at some metrics to see whether these groups are using input that is coming from others? Will there be metrics that you will look at to try to assess whether these units are doing what they should?
A: Putting metrics in place for making sure the vaccine trial group has appropriate input on pediatric and adolescent vaccines will be easier than some of the other metrics. Getting people to bring their ideas forward is difficult. A lot of investigators would rather try to get an investigator-initiated clinical trial than work within the network. The challenge we face is making the networks attractive so that people will come to the networks. This has been a perennial struggle since the beginning. As resources get more limited, it will be easier for people to realize that a quicker path to trial may be to work with the networks. Networks could do a better job assigning a partner to make sure that the idea got developed in conjunction. Ultimately, we want people with their ideas to come in and potentially play a role of protocol chair or co-chair.
Q: Will leadership groups be required to specifically address the mechanism by which they will elicit and evaluate external ideas?
A: It is in the leadership groups’ bylaws but making it more publicly available would be important.
Public Comments
Public comments were given by Jim Pickett, the senior director of prevention and gay men’s health at the AIDS Foundation of Chicago; Bob Roehr, a journalist for community and medical trade press for the last 25 years; Anna Forbes, an independent consultant; Jessica Salzwedel from AIDS Vaccine Advocacy Coalition (AVAC); and Matthew Rose, a community co-chair for the MTN and a policy and advocacy manager at the National Minority AIDS Council. These comments focused on the need to continue microbicide research, the importance of providing people with different treatment and prevention options/products, need to continue and increase engagement with communities, need to consider non-systemic drugs, and the necessity to engage younger investigators and involve them with research decisions.
Committee members were asked to cast their vote on the NIH HIV/AIDS Clinical Trials Networks Renewal.
Ballot Voting Outcome:
10 Approval
1 Approval with modification(s)
1 Deferral for further information
0 Disapproval
VI. Adjournment
The meeting of the Council adjourned at 4:30 p.m., on Monday, January 29, 2018.
We do hereby certify that, to the best of our knowledge, the foregoing minutes are accurate and complete.
Anthony S. Fauci, M.D.
Chair, National Advisory Allergy and Infectious Diseases Council
Director, National Institute of Allergy and Infectious Diseases
Date
Matthew J. Fenton, Ph.D.
Executive Secretary
National Advisory Allergy and Infectious Diseases Council
Director, Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Date
Council will formally consider these minutes at its next meeting; any corrections or notations will be incorporated in the minutes of that meeting.