NIAID Council Minutes—June 3, 2019

The 192nd meeting of the National Advisory Allergy and Infectious Diseases Council (NAAIDC) convened at 10:30 a.m. on Monday, June 3, 2019, in Conference Rooms E1/E2, Building 45, National Institutes of Health. Dr. Anthony S. Fauci, director, National Institute of Allergy and Infectious Diseases (NIAID) presided as chair.

In accordance with the provisions of Public Law 92-463, the meeting was open to the public from 10:00 a.m. to 11:45 a.m. and from 1:00 p.m. to 4:35 p.m. The meeting was closed to the public from 8:00 a.m. to 9:45 a.m. and from 11:45 a.m. to 12:00 noon for review and consideration of individual grant applications. Notice of the meeting was published in the Federal Register.

Meeting Attendees

Council Members Present:

Dr. Raul Andino
Dr. Michael Brenner
Dr. Amanda Castel
Dr. Mark Feinberg
Dr. Ana Fernandez-Sesma
Dr. Sally Hodder
Dr. Marc Jenkins
Dr. Stanley Lemon
Dr. Anuradha Ray
Ms. Kay Whalen
Dr. Cara Wilson

Ex Officio Members Present:

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

Ad Hoc Members Present:

Dr. Jeremy Boss
Dr. Amita Gupta
Dr. John Harley
Dr. Gwendalyn Randolph

Council Members Absent:

Dr. Karen Nelson
Dr. Robin Patel

Ex Officio Members Absent:

Lt. Col. Wendy Sammons-Jackson

NIAID Senior Staff Present:

Dr. Hugh Auchincloss
Dr. Carl Dieffenbach
Dr. Emily Erbelding
Dr. Matthew Fenton
Dr. Jill Harper
Dr. Daniel Rotrosen

Table of Contents

I. Review of Grant Applications
II. Remarks of the Director, NIAID—Anthony S. Fauci, M.D.
III. Guest Speaker—John R. Mascola, M.D., director, Vaccine Research Center
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 4,469 research and training applications with primary assignment to NIAID for a requested amount of $1,669,460,119 in first-year direct costs and recommended approval of 2,260 applications with $705,003,093 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 four ad hoc Council members: Dr. John Harley, director of the Cincinnati Children's Hospital Center for Autoimmune Genomics and Etiology; Dr. Jeremy Boss, professor and chair of the Department of Microbiology and Immunology at Emory University; Dr. Gwendalyn Randolph, professor in the Department of Pathology and Immunology at Washington University School of Medicine; and Dr. Amita Gupta, deputy director of the Johns Hopkins Center for Clinical Global Health Education and associate professor of infectious diseases at the Johns Hopkins School of Medicine.

Council members Drs. Robin Patel and Karen Nelson were unable to attend the meeting.

Consideration of Minutes of Previous Meeting

Council considered the minutes of the January 28, 2019 meeting and approved them as written.

Staff and Organizational Changes

In March, HHS Secretary Alex Azar announced that Dr. Ned Sharpless would serve as FDA acting commissioner after Dr. Scott Gottlieb resigned as FDA commissioner. Dr. Douglas Lowy, the National Cancer Institute (NCI) deputy director, agreed to serve as the acting director of NCI.

Dr. Noni Byrnes is the new director of NIH’s Center for Scientific Review.

NIH Director Dr. Francis Collins announced the selection of Dr. Debara Tucci as the director of the National Institute on Deafness and Other Communication Disorders.

Dr. Andrea Lerner recently joined Dr. Fauci’s office as a clinical associate in the Immediate Office of the Director.

In the Division of Microbiology and Infectious Diseases (DMID), Dr. Irene Glowinski retired after 30 years with NIH, including the last 12 as deputy director of DMID. Dr. Cristina Cassetti has been chosen to succeed Dr. Glowinski as DMID’s new deputy director.

In the Division of AIDS (DAIDS), Dr. Jui Shah has been selected as the new chief of the Protection of Participants, Evaluation, and Policy Branch.

Dr. Fauci announced two new appointments in NIAID’s Office of Administrative Services. Kristie Gehlhaus is the new director, and Karen Zlotnick-Solomon is the new deputy director.

Meetings and Events

On April 30, Dr. Diane Havlir delivered the 2019 James C. Hill Memorial Lecture, “Ending AIDS: The Wild West.” Dr. Havlir examined strategies being employed to control the HIV epidemic in San Francisco, as well as in rural Uganda and Kenya, highlighting insights learned from each setting.

On April 18, Dr. Kelvin Droegemeier, director of the Office of Science and Technology Policy, visited NIH. During his visit, he met with NIH senior leadership and toured NIAID’s Special Clinical Studies Unit in the NIH Clinical Center.

In early April, Dr. Fauci attended a reception at Japanese Ambassador Sugiyama’s residence in Washington, D.C., to celebrate the tent exhibition developed for the Cherry Blossom Festival. The exhibition featured examples of innovation that have emerged from more than 50 years of U.S.-Japan scientific collaborations.

Several high-level delegations visited NIH and met with NIAID senior leadership to discuss scientific topics of mutual interest. On April 11, Dr. Fauci gave Dr. Takeshi Kasai, director of the Western Pacific Regional Office of the World Health Organization, an overview of NIAID and spoke to him about influenza, dengue, HIV/AIDS, and tuberculosis. On May 2, Dr. Fauci and Dr. Cliff Lane met with Dr. Siswanto, director general of the Indonesian National Institute for Health Research and Development. They discussed the importance of continued collaboration for research on emerging and re-emerging diseases to enhance response readiness to disease outbreaks.

Budget Update

Dr. Fauci began by comparing the fiscal year (FY) 2019 enacted budget with the FY 2018 final budget. Most institutes received about a 3.4 percent increase in their FY 2019 budget. NIAID received a 5.7 percent increase over FY 2018, which included an additional $40 million for developing a universal influenza vaccine and a $37 million increase for antibiotic resistance research for activities related to the President’s National Strategy for Combating Antibiotic-Resistant Bacteria (CARB).

The FY 2019 budget also includes a $44 million realignment of the National Institute of General Medical Sciences (NIGMS) AIDS basic research portfolio to NIAID. The transfer initiated and made in collaboration with NIGMS will improve scientific coordination, better leverage existing resources, and maximize collaboration.

Dr. Fauci summarized NIAID’s FY 2019 financial management plan. Our R01 payline is set at the 14 percentile for established principal investigators (PIs) and the 18 percentile for new PIs. No programmatic adjustments will be made to competing unsolicited awards, as well as noncompeting grants and research and development awards. Competing research initiatives were cut up to 15 percent. Our estimated overall success rate will be 21 to 23 percent.

On March 11, the President released his FY 2020 budget request, “A Budget for a Better America,” which includes an overall decrease to NIH of 12.6 percent or $4.9 billion below the FY 2019 enacted level. Dr. Fauci noted that most institutes received reductions of about 13.9 percent. However, Congress is deliberating the FY 2020 budget, and ultimately, it is responsible for authorizing appropriations.

NIAID will maintain a conservative funding approach for FY 2020 until a final budget is passed.

Legislative Update

On February 26, Dr. Fauci participated in a Congressional briefing on influenza vaccine research hosted by Senator Edward Markey and Representative Rosa DeLauro, two strong supporters of NIAID research in this area. Dr. Fauci also attended the annual Congressional reception for the NIH Children’s Inn.

On February 27, Dr. Fauci testified before the House Energy and Commerce Subcommittee on Oversight Investigations at a hearing on the measles outbreak in the United States. This hearing was an opportunity to reassure Congress and the public that the measles vaccine is safe and highly effective.

During March, Dr. Fauci held several briefings for Congressional members and staff on the HHS Plan to End the HIV Epidemic in the United States.

On March 14, Dr. Fauci testified before the Senate Labor, HHS Appropriations Subcommittee at a hearing on Ebola and other emergency health threats.

On April 2, Dr. Fauci briefed the House Energy and Commerce Oversight and Investigations Subcommittee on the ongoing Ebola outbreak in the Democratic Republic of the Congo (DRC) and NIAID’s research efforts.

On April 2 and 11, Dr. Collins, accompanied by Dr. Fauci and several other institute directors, testified before the House Labor, HHS Appropriations Subcommittee on the President’s FY 2020 budget for NIH.

On May 7, Dr. Fauci attended the Congressional reception hosted by the ACT for NIH Foundation, which highlighted the important medical advances made possible by NIAID and NIH research.

Since the last Council meeting, NIAID leadership and staff have participated in Congressional briefings on Valley fever, Ebola vaccine development, the Plan to End the HIV Epidemic in the U.S., Lyme and tick-borne disease, acute flaccid myelitis, and global health security.

Other Information Items

On February 5, 2019, in the State of the Union Address, President Trump announced the goal of ending the HIV/AIDS epidemic by the end of the next decade. Dr. Fauci noted several papers that he’s written on this topic and that we have the tools to end the epidemic.

Dr. Fauci and representatives from other HHS agencies presented the idea for ending the HIV/AIDS epidemic to HHS Secretary Alex Azar. They then developed a plan, which focused on incidence “Hot Spots”—demographic hot spots and geographic hot spots. Dr. Fauci summarized the plan, with the goal of decreasing infections by 75 percent in 5 years and 90 percent in 10 years. It’s a multi-agency effort, with each agency having its own role. NIH’s role is mostly implementation science to collect and disseminate data on the effectiveness of the approaches used in the initiative and to inform its partners on best practices.

He provided statistics on the number of confirmed cases and deaths related to the Ebola outbreak in the DRC and gave a brief overview of the randomized, controlled trial of four Ebola therapeutics that NIAID is helping to conduct.

Dr. Fauci concluded by giving brief updates on influenza, tuberculosis, measles, acute flaccid myelitis, opioids and infectious diseases, and gene therapy in severe combined immunodeficiency.

III. Guest Speaker—John R. Mascola, M.D., director, Vaccine Research Center

Dr. John Mascola began by noting that the Vaccine Research Center (VRC) was founded as an HIV vaccine research center and much of what VRC has done emerged from its work on HIV. VRC’s vaccine development pathway begins with basic research and has the ability to do first-in-human studies.

Over the last five years, VRC has doubled its capacity for manufacturing and to conduct clinical trials. VRC can make four or five products a year in its pilot plant and conduct four or five Phase I studies a year.

One of VRC’s major areas of focus is structure-based vaccine design, which includes work on respiratory syncytial virus (RSV) and influenza virus vaccines.

Dr. Mascola summarized encouraging data from a recent RSV study using the structure-based vaccine design. VRC is working with pharmaceutical partners that are moving this into their own development pathway to do Phase II and Phase III studies.

He concluded by giving an update on VRC’s influenza vaccine work, which is now the second largest program at the Center behind HIV. Dr. Mascola highlighted two Phase I studies using the nanoparticle platform.

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

Dr. Rotrosen welcomed the subcommittee members to the 192nd meeting of the National Advisory Allergy and Infectious Diseases Subcommittee meeting.

Dr. Rotrosen presented the following scientific and Division activities:

Staff and Organizational Changes

Nancy Vazquez-Maldonado, Ph.D. Dr. Vazquez-Maldonado joined the Basic Immunology Branch on May 13, 2019, as a program officer. She received her Ph.D. in microbiology and immunology from Temple University, Philadelphia and joined the NIH as an IRTA fellow in 1997. She continued her postdoctoral training at the FDA and returned to the NIH (NIDCR) as a research biologist in 2000. Her most recent laboratory research included the investigation of host-pathogen interactions (Mycobacterium and HIV) and the factors that regulate monocyte/macrophage and T cell responses to infection and inflammation. She identified the mechanism by which a synthetic triterpenoid interfered with HIV replication and characterized the immunological defects of macrophages infected with Mycobacterium avium. Dr. Vazquez-Maldonado will oversee the innate immunity portfolio within the Branch.

Selected Funding Opportunities

NIAID

Atopic Dermatitis Research Network Leadership Center (UM1 Clinical Trial Required) (RFA-AI-19-014): The purpose of this FOA is to solicit applications for the NIAID Atopic Dermatitis Research Network Leadership Center (ADRN-LC) for the NIAID ADRN. The ADRN-LC will provide the overall scientific strategy and organizational structure to the ADRN and will interact closely with the ADRN Clinical Research Centers (ADRN-CRCs), to support the conduct of multi-site clinical studies and trials under the ADRN.

Atopic Dermatitis Research Network-Clinical Research Centers (U01 Clinical Trial Optional) (RFA-AI-19-015): The purpose of this FOA is to solicit applications for the NIAID Atopic Dermatitis Research Network Clinical Research Centers (ADRN-CRCs). The ADRN-CRCs will conduct the ADRN network-wide clinical research projects under the leadership of the ADRN Leadership Center (ADRN-LC). In parallel, each ADRN-CRC will pursue its own clinical research program in support of the scientific goals of the ADRN. To achieve the ADRN objectives, the ADRN-CRCs will work closely with the ADRN-LC.

Division Activities

Allergy, Asthma, and Airway Biology Branch

Single Cell Analysis in Human Disease: Lessons Learned from the Asthma and Allergic Diseases Cooperative Research Centers. On February 22, 2019, as part of the annual meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI), in San Francisco, CA, the NIAID funded Asthma and Allergic Diseases Cooperative Research Centers (AADCRCs) organized a course entitled “Single Cell Analysis in Human Disease: Lessons Learned from the Asthma and Allergic Diseases Cooperative Research Centers” Six experts in the field presented lectures on topics including single cell analysis in nasal polyposis, single cell analysis as a window to airway epithelium cell function and diversity, single cell analysis to reveal immune cell heterogeneity, discovery of Th2A cells by single cell analysis, transcriptional profiling of eosinophilic esophagitis, and single cell RNA profiling of human lung and immune cells.

Early Life Environmental Exposures Regulate Host Allergic Immune Responses: Lessons Learned from the Asthma and Allergic Diseases Cooperative Research Center Birth Cohorts. On February 22, 2019, as part of the annual meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI), in San Francisco, CA, the NIAID funded Asthma and Allergic Diseases Cooperative Research Centers (AADCRCs) organized a Symposium entitled “Early Life Environmental Exposures Regulate Host Allergic Immune Responses: Lessons Learned from the Asthma and Allergic Diseases Cooperative Research Center Birth Cohorts.” Three experts in the field presented lectures on topics including effects of the farming environment on immune development and respiratory illnesses, identifying asthma-causing RSV strains in RSV mediated asthma development, and traffic related air pollution and childhood asthma.

National Institute of Allergy and Infectious Diseases: Allergic Sensitization and the March to Allergic Diseases. On February 23, 2019, as part of the annual meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI), in San Francisco, CA, the NIAID funded Asthma and Allergic Diseases Cooperative Research Centers (AADCRCs) organized a Symposium entitled “National Institute of Allergy and Infectious Diseases: Allergic Sensitization and the March to Allergic Diseases.” Three experts in the field presented lectures on topics including phenotypes of specific allergic sensitization, allergic sensitization and the development of allergic disease in the first 10 years of life, and sensitization to allergen components and the relationship to the phenotype of allergic disease.

Interferons Contribute to Allergic Disease: Lessons Learned from the Asthma and Allergic Diseases Cooperative Research Center. On February 24, 2019, as part of the annual meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI), in San Francisco, CA, the NIAID funded Asthma and Allergic Diseases Cooperative Research Centers (AADCRCs) organized a Symposium entitled “Interferons Contribute to Allergic Disease: Lessons Learned from the Asthma and Allergic Diseases Cooperative Research Center.” Three experts in the field presented lectures on topics including high interferon-gamma marks in severe asthma, interferon responses by bronchial epithelial cells and contribution to airway disease, and regulation of interferon-gamma production by innate and adaptive lymphocytes.

Basic Immunology Branch

Human Immunology Project Consortium II (HIPC II) Annual Meeting. On March 27-28, 2019, the annual meeting of this renewed cooperative agreement research program was held in Rockville, MD. The HIPC II program (http://www.immuneprofiling.org/) is composed of nine U19 cooperative agreement awardees, and is designed to characterize molecular profiles of human immune responses to infection or vaccination using systems immunology approaches. All of the data generated by the HIPC investigators are being made available to the broader research community through ImmPort (http://www.immport.org) and ImmuneSpace (https://www.immunespace.org/), a powerful data management and analysis engine for the exploration and analysis of HIPC-generated datasets using state-of-the-art computational tools. The HIPC II program is co-administered by DAIT and co-funded by NIAID.

Accelerating Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). On April 4-5, 2019, a research conference was held in the Masur Auditorium at the NIH Clinical Center. NIAID, NINDS, and NCATS all supported speakers who presented the latest findings from their ME/CFS work to their colleagues within the scientific community and to patients in attendance. The conference also was videocast and archived for future use. Scientific progress is being made in this very challenging disease, and important research areas are emerging such as neuroimaging to further study inflammation and a deeper analysis of connections between metabolism and immune response.

Systems Immunology Program. On April 11, 2019, the annual programmatic meeting of the DAIT Systems Immunology U19 Cooperative Agreement program was held in Rockville, MD. The overall goal of the program is to identify new genes, pathways and mechanisms which are critical for initiating, maintaining, and controlling immune responses to pathogens, adjuvants, or vaccines. The three awardees (Harvard University: Arlene Sharpe; University of North Carolina: Ralph Baric and Mark Heise; The Scripps Research Institute: Richard Ulevitch) and their group members presented their progress, which included:  identification of new quantitative trait loci (QTLs); validation of novel genes and pathways; and the development of innovative technologies, such as CODEX, the MiniMUGA platform, and CHIME. The scientific meeting was followed by a Steering Committee meeting, which involved the principal investigators from each U19 group and NIAID staff, to discuss the awardees plans for the coming year and new collaborations between the three centers.

Skin Tissue-Resident Memory T Cells in Homeostasis, Infection and Immune-Mediated Disease. On April 22-23, 2019, DAIT hosted the “Skin Tissue-Resident Memory T Cells in Homeostasis, Infection and Immune-Mediated Disease” workshop in Rockville, MD. The workshop objectives were to share existing knowledge and resources in the field of skin tissue-resident memory T cells, to define the knowledge gaps, and to improve communication and collaborations between investigators to promote progress in this research area. Investigators presented their recent findings on the development, maintenance, migration, function, and manipulation of skin resident memory T cells in homeostasis, infection, autoimmune diseases, graft vs. host disease, and delayed onset drug reactions. Workshop participants discussed knowledge gaps, nomenclature, available resources, existing obstacles and potential therapeutics in the skin tissue-resident memory T cell research area. 

Imaging Tissue Specific Immunity. On May 10, 2019, a meeting was held at the Immunology 2019 meeting in San Diego, CA. Four invited speakers discussed their respective approaches using contemporary and increasingly powerful technology to examine functional immunity in the context of tissue and cellular architecture. Presentations included imaging of both innate and adaptive components of the immune response in several model systems.

Concepts Presented for Clearance

FY 2020 Research Concept Clearance

Investigations on Primary Immunodeficiency Diseases/Inborn Errors of Immunity (R03, R21 Clinical Trial Not Allowed)
This initiative is to support the discovery and characterization of primary immunodeficiency diseases, also referred to as inborn errors of immunity, to understand the causes and mechanisms of disease, to enable early detection and molecular diagnosis, and to support the development of strategies to treat and eventually cure these disorders.

The subcommittee endorsed and unanimously approved this initiative.

FY 2021 Research Concept Clearance

Collaborative Network for Clinical Research on Immune Tolerance (UM1 Clinical Trials Required)
This initiative is to renew NIAID’s successful Immune Tolerance Network (ITN). This initiative will enhance understanding of the underlying mechanisms of the induction, maintenance and loss of immune tolerance in humans, and to develop improved tolerogenic interventions for the prevention and treatment of immune system mediated diseases (including transplant rejection, autoimmune diseases, and asthma and allergic diseases).

The subcommittee endorsed and unanimously approved this initiative.

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

Director’s Report

Dr. Emily Erbelding, Director of the Division of Microbiology and Infectious Diseases (DMID), chaired the NIAID Microbiology and Infectious Diseases Council Subcommittee meeting on June 3, 2019. Dr. Erbelding provided a personnel update, noting that Dr. Cristina Cassetti had been appointed the DMID Deputy Director following Dr. Irene Glowinski’s recent retirement. She noted that Cristina’s ability to form relationships across NIAID divisions and NIH institutes will serve DMID well as the Division continues to address emerging infectious disease challenges. She also recognized new staff and personnel appointments throughout the Division, including: Chidi Obasi, a Scientific/Clinical Project Manager in the Bacteriology and Mycology Branch; Jorge Mejia-Galvis, a medical monitor in the Office of Clinical Research Activities; Ranjodh Gill, a nurse consultant in the Office of Clinical Research Resources; Mark Challberg, who is serving as the Acting Branch Chief of the Virology Branch; Lakshmi Ramachandra, Chief of the TB and Other Mycobacterial Disease Section in the Respiratory Diseases Branch (RDB); Susana Mendez, a Program Officer in the TB and Other Mycobacterial Diseases Section, RDB; Christine Oshansky, an HSA-Scientific Lead in the Respiratory Pathogens Clinical Research Section, RDB; and Elizabeth Rodriguez, a Health Specialist in the Office of Scientific Coordination and Program Operations.

Following staff introductions, Dr. Erbelding reported on several recent DMID scientific activities. She noted that DMID made awards under a new program, Impact of Initial Influenza Exposure on Immunity in Infants, which was established to examine how young children’s immune systems respond over multiple years to their initial influenza infection and their first vaccination. She noted that these types of longitudinal cohort studies are an important component of NIAID’s plan to advance the development of a universal influenza vaccine. Awards were made to Cincinnati Children’s Hospital and St. Jude Children’s Research Hospital. She also announced that the FDA had recently cleared the first diagnostic for extragenital testing for gonorrhea and chlamydia, noting that the DMID-supported Antibacterial Resistance Leadership Group supported these studies. Dr. Erbelding also reported on a recent NIAID trip to meet with scientists in Poland to learn about their phage therapy clinical research efforts. Dr. Erbelding noted that this is an area of research NIAID hopes to further catalyze in the coming years as an effective tool against antibacterial resistant infections. She also informed the Subcommittee that she represented NIAID at a Congressional Valley Fever Task Force Roundtable with the CDC and the NIH. The event was organized by Representative Kevin McCarthy to brief Members of Congress and their staff on Valley Fever and why there needs to be further action on this issue. She also provided a brief update on the DMID-supported Valley Fever prospective observational study. She also reported that DMID recently organized a workshop focused on Hepatitis C vaccine development. During the workshop, participants discussed what new knowledge is needed in order to design an effective vaccine against hepatitis C, and what types of vaccine-induced immune responses would be most likely to be efficacious. Related to this topic, Dr. Erbelding reported that a DMID-supported clinical trial to evaluate an experimental vaccine was not found to be effective at preventing chronic hepatitis C virus (HCV) infection in adults. Finally, she reported that DMID would sponsor a workshop in the Fall 2019, focused on antivirals for measles.

TB Update – Dr. Alan Embry, chief, Respiratory Diseases Branch, DMID

Dr. Embry provided a broad overview of tuberculosis research activities supported by NIAID and other funders, noting that all three NIAID extramural divisions support significant TB research efforts. He stated that a concept to renew the Tuberculosis Research Units program, DMID’s flagship TB effort, would be presented during today’s meeting.

Dr. Embry noted that NIAID released a strategic plan for tuberculosis research in 2018 that aligns with the World Health Organization’s End TB Strategy and other U.S. supported efforts. He described select science advances in several areas addressed by the plan, with an emphasis on diagnostics and vaccines. In summary, he stated that going forward in 2019 and beyond, NIAID will build upon recent results from the TB vaccine clinical trials described earlier in the presentation. These efforts will include fundamental research of tuberculosis, better understanding the pathogenesis, the heterogeneity of disease, immune responses that mediate the progression to active disease, and the development of improved biomarkers and diagnostics to be able to better test and treat people who are infected. He noted that multidisciplinary collaboration and coordination would be a critical component of these efforts.

Concepts Presented for Clearance

The following FY 2021 concepts were presented to the Subcommittee:

Tuberculosis Research Units–this concept would support the establishment of up to four TB Research Units (TBRUs) to advance our understanding of TB. TBRUs will operate as a collaborative network with expertise in clinical research, animal modeling, microbiology and other disciplines. The Subcommittee members agreed that the concept was important and timely. The concept addresses knowledge gaps in characterization of bacterial factors contributing to disease latency and persistence, among other factors contributing to disease progression. Clarification was sought on whether a focus on host immune responses would be allowed as part of the proposed renewal of the TBRU. Program staff explained that studies of the immune response in the context of host-pathogen interactions will be included. However, programs/studies that solely focus on the immune response or that may overlap with the aims of the soon-to-be-awarded FY 2019 NIAID IMPAc-TB initiative (e.g., correlates of protection, analysis of immune response to vaccine candidates) will be discouraged. Council members also advocated for a holistic approach to understanding TB disease and suggested connecting the investigators supported under IMPAc-TB with the TBRU community. Program staff was appreciative of these suggestions and anticipates potential joint meetings and/or webinars between investigators of these large research programs.

Centers of Excellence for Influenza Research and Response (CEIRR)–this concept would support the conduct of integrated basic and clinical research to advance knowledge of host and viral factors that determine influenza emergence, transmission and protection against influenza to accelerate development of new and improved control measures, including vaccines and therapeutics. The Subcommittee members were in agreement that the concept, which would establish a program to replace the current Centers of Excellence for Influenza Research and Surveillance (CEIRS) program, addresses significant influenza research questions. The CEIRS was described as a model network that produces high-quality science, training and resources for the influenza research community. Subcommittee members mentioned that it was important to continue to publicize program-generated reagents and resources to the broader scientific community and that the stated goal of bringing scientists from other fields into the CEIRR program was important. Subcommittee members also emphasized that the CEIRS have been collaborative with other NIAID-funded programs, such as the Human Immunology Project Consortium, and that continuing to integrate and coordinate with other programs should be an important component of the CEIRR program as well.

Influenza Data Processing and Communication Center (iDPCC)–this concept would support the collection and processing of the diverse influenza data sets generated by NIAID’s CEIRR to facilitate the management and transfer to other appropriate databases. Subcommittee members agreed that this program will have a critical role in supporting the CEIRR, which, as noted above, is proposed to replace the current CEIRS program. In addition to supporting the data needs of the CEIRRs, Subcommittee members noted other important roles for the iDPCC, including expanding awareness of the NIAID universal influenza vaccine programs and providing information about NIAID-generated resources to the broad scientific community. Program staff appreciated the comment made by a Subcommittee member that the iDPCC should integrate with other NIAID influenza programs to ensure synergy and avoid duplication of effort.

Multidisciplinary Studies to Improve Understanding of Influenza Transmission–this concept would support coordinated, multidisciplinary research to better understand the dynamics and drivers of influenza transmission between humans. The Subcommittee members were supportive of the concept, citing the importance of the research, significant knowledge gaps, and need to connect knowledge and data across disciplines. One Subcommittee member noted that there are some existing efforts to study human-to-human influenza transmission, but the scope of those projects is limited, whereas the larger scope of this concept will allow multidisciplinary groups to work together to move the field forward. Subcommittee members stressed the importance of defining the specific questions best addressed by the proposed program given the complicated nature of studying influenza transmission. Program staff acknowledged the feedback and will ensure that the scope is clearly defined and addresses gaps identified by the scientific community.

Partnerships for Countermeasures Against Select Pathogens–this concept would support milestone-driven projects focused on advancement of candidate therapeutics and vaccines against select pathogens. The Subcommittee expressed support for the ongoing DMID Partnerships Program, noting that it has been successful in supporting translational and preclinical product-related research and development efforts that address evolving programmatic priorities. There is appreciation for the role of the program in expanding the product development pipeline for development of countermeasures against targeted pathogens, stimulating innovation, generating and vetting candidate products and leveraging resources within academic and industrial communities. One member requested insight on the relationship of the noted therapeutics priority to the FY 2016 initiative: Non-Traditional Therapeutics that Limit Antibacterial Resistance (R21/R33). Program pointed out that the initiative dovetails the earlier discovery-based effort by providing potential support for continued development of promising candidate therapeutics. One member queried the extent of program-required industrial participation in supported projects. Program noted that examples of acceptable industrial commitment are provided in the funding opportunity announcement and that for most competitive projects, the industrial partner is actively engaged in a significant portion of supported activities throughout the project period. One member requested additional information on Partnerships program accomplishments. Program pointed out that program accomplishments are periodically evaluated externally using multiple metrics including marketed products, candidate products in late-stage development, candidate products in preclinical development, adaptation of new technologies/platforms, subsequent funding for continued development of a candidate, industrial participation, awardee feedback and publications. Program briefly summarized some results from the 2014 external evaluation, highlighting successes in meeting stated goals, metrics of technology transfer and regulatory milestone achievement, and examples of products either licensed or under late-stage clinical evaluation. One member asked for more information about the review of Partnerships applications. Program responded that the applications are reviewed by NIAID Special Emphasis Panels composed of academic and industrial experts. One member commented that it would be helpful to learn how Partnerships activities align with and complement countermeasure development objectives of associate enterprises (BARDA, DoD, Pharma, etc.). Program responded that DMID works closely with BARDA to align product development-related objectives and coordinate hand-off of targeted candidate products for continued late-stage development.

Partnerships for the Development of Universal Influenza Vaccines–this concept would support early preclinical studies to advance the development of universal influenza vaccines that protect against both influenza A and B viruses. The Subcommittee expressed support for this concept as part of the DMID Partnerships Program with one member noting the Partnerships Program could add timely and significant support to the influenza community currently working on influenza B viruses. The member further noted that the inclusion of influenza B is an important part of the community’s strategy for achieving more broadly protective influenza vaccines. A second member noted that the definition of universal influenza vaccines is still debated in the community. Program appreciated the comment and responded that NIAID acknowledges an iterative approach is likely needed to achieve a universal vaccine and that all vaccine strategies targeting greater durability and breadth of protection over seasonal influenza vaccines are of interest. One member queried the role of program staff in the R21/R33 transition evaluation process that selects R21s to transition to the R33 phase. Program responded that two panels of nonconflicted staff members with appropriate subject matter expertise evaluate and rank the R21s on set metrics; the top one-half of the ranked R21s are recommended for transition. Several members stated that there were many new and ongoing initiatives to support the implementation of NIAID’s Strategic Plan for Universal Influenza Vaccine Development and that ongoing communication regarding synergies between these programs is important. Program agreed and further presented how the Partnerships concept and other initiatives supported by NIAID were complementary and holistic to those efforts.

Statistical and Data Coordinating Center (SDCC) for Clinical Research in Infectious Diseases–this concept would support a program to provide comprehensive and consistent statistical and data management support for DMID clinical research studies and trials spanning a wide range of infectious diseases and candidate products, including vaccines, diagnostics, biologics, devices, and therapeutics. The Subcommittee members were enthusiastically supportive of the Statistical and Data Coordinating Center (SDCC) concept and confirmed that it is an essential component of DMID’s clinical trials infrastructure. One member stated the SDCC was necessary for all IND studies. The Subcommittee asked for clarification on the types of programs that utilize the current SDCC; Program staff reported that the SDCC currently supports several DMID clinical trials programs as well as individual contracts and grants spanning all of the DMID branches and offices.

All concepts were unanimously approved.

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

Dr. Wilson welcomed everyone and the ARAC members approved the minutes of the January 2019 meeting.

Director’s Report

Carl Dieffenbach, Ph.D.

Dr. Dieffenbach introduced a new ARAC member, Amita Gupta, M.D., who is serving as an ad-hoc member for the June meeting. He then introduced the new Chief of Protection of Participants, Evaluation, and Policy at DAIDS, Jui Shah, Ph.D.

Budget Update

On May 13th, a series of blog posts, one from NIAID and one from the National Institute for General Medical Sciences (NIGMS), were published that discussed the transfer of the NIGMS AIDS research portfolio, en masse, to NIAID as part of the fiscal year (FY) 2019 budget. NIGMS has historically fostered fundamental HIV research, and in recent years the portfolio has focused heavily on structural biology. Further, as NIGMS has excelled at this research for 37 years, it was a perceived honor to be able to pick up this grant portfolio. Concurrently, a notice to the investigator community was published in the NIH Guide by NIGMS that effective immediately all grants and associated funds in the portfolio were transferred to NIAID. The transfer was coordinated by the Office of AIDS Research (OAR), with a goal toward improving scientific coordination, prioritization, and efficiency of utilizing and managing HIV/AIDS dollars traditionally allocated to NIGMS. With this transfer, the criteria for grant assignments also fundamentally changed such that NIGMS is no longer listed anywhere in the AIDS portfolio as receiving AIDS applications. Anything that previously would have gone to NIGMS is now assigned to NIAID. The NIH budget comparison by Institute/Center for FY 2018 (Final), 2019 (Enacted) showed a 5.7 percent increase for the NIAID. A part of this increase was due to the transfer of the NIGMS money. The NIAID FY 2019 financial management plan keeps the payline at the 14th percentile for established PIs and at the 18th percentile for new PIs. No adjusts were made to competing and noncompeting grants. Money is trimmed out of the research initiative budget every year in order to support payline, giving an estimated success rate of 21-23 percent. The President’s budget arrived in March 2019 and this will be discussed by Congress before a final budget is passed.

Timeline for the Clinical Trials Networks Recompetition

For the NIAID HIV/AIDS Clinical Trials Network Recompetition, the FOAs were published on schedule and the receipt dates are set. Leadership, statistical and data management centers, and laboratory applications are all due August 1st. The CTU applications are due November 18th. Everything is on track for funding in December 2020.

Ending the HIV Epidemic: A Plan for America

The Ending the HIV Epidemic: A Plan for America, is a presidential initiative that was announced at the State of the Union address. Currently, there is significant data that indicates there is a possibility of success for this initiative as we have the right tools and the right leadership at the Centers for Disease Control and Prevention (CDC), at Health Resources and Services Administration (HRSA), and here at NIH. The epidemiology indicates that new infections are clustered in a limited number of counties and in a limited number of populations. An extensive surveillance infrastructure is in place, but a potential challenge may be in the long run data quality and the rapidity with which data can be generated and applied to a detect and respond strategy. Improvements are needed as much of the data that built this model of Ending the Epidemic is still 2016 data from the CDC. Other tools now available include highly effective antiretroviral therapy that not just saves lives, but also prevents sexual transmission; models of care and prevention; tremendous strides made by the VA in treating their populations; and, availability of pre-exposure prophylaxis (PrEP). To achieve the Plan for America goals, five pillars were proposed - diagnose, treat, protect, respond, and help to create an HIV workforce that is more than just boots on the ground. The goal is to achieve a 75 percent reduction of HIV infections in 5 years, with an ultimate target of 90 percent reduction in 10 years. This initiative was originally conceived as an HHS activity involving CDC, NIH, HRSA, and the Indian Health Service. At the insistence of NIH and CDC, Substance Abuse and Mental Health Services Administration (SAMHSA) was added because of the many epidemics that are co-occurring in the U.S, such as for opioid epidemic. By partnering with SAMHSA, we are able to build relationships here at NIH with National Institute of Mental Health (NIMH), OAR, and National Institute on Drug Abuse (NIDA) to help tackle opioid use in rural South and in other areas. The implementation plan involves an initial focused effort to target 48 counties, DC, and San Juan, which account for 50 percent of new infections, and 7 states with substantial rural HIV burden. The next phase will expand efforts across the Nation, followed by intensive case management to maintain the number of new infections at fewer than 3,000 per year. The approach taken to operationalize the pillars to achieve the Plan for America was described. In part, this involved partnering with NIMH to form a consortium between the two types of AIDS centers here at NIH, the Centers for AIDS Research (CFARs) and the AIDS Research Centers (ARC) as a significant concentration of the centers are located in the South where much of the epidemic is located. It is thought that some activities, we could be jumpstarted in FY 2019. CFARs and ARCs can provide shovel-ready, experienced investigators that know how to partner with health departments, the CDC, and with HRSA grantees to address implementation questions. Both centers' programs are nimble and flexible, allowing centers to respond quickly at the local level to meet local needs. Supplements have been requested that will be competitively reviewed from the centers’ programs. These supplements will help get activities started in FY 2019 that will assist with building information that will inform local partners on best practices in state-of-the-art biomedical research that can help be implemented to improve the implementation of activities along the cascade from testing to continuums of care, to treatment, to rollout of PrEP. Dr. Dieffenbach concluded by saying that based on what has been started with the CFARS, over the next several years, there will be activities able to be expanded so that all necessary participants can work together to help tackle the important “Whole-of-Society” initiative. Future ARAC and AVRS meeting dates were mentioned before addressing questions from the Committee.

Questions:

Q: Is there any discussions about including other Federal agencies, such as the Department for Housing and Urban Development, for example? While there is discussion about the administration’s End the AIDS Epidemic, there's pullback on healthcare coverage. How do we meet the goal without expanding access to healthcare?
A: There is agreement on the point regarding the concern about the lack of expanding healthcare. Congress will help to define the true scope of activities like healthcare. In parallel to the Ending the Epidemic initiative, there is the National HIV Strategy, which covers all the Cabinet Secretaries. Housing, Labor, and all the legal civil rights groups' protections are aligning at that level. There are also parallel tracks on a national strategy for hepatitis C; one is being developed for sexually transmitted infections, and the CDC is also working with one domestically for tuberculosis.

Q: The CFARs traditionally have been given the task of coordinating and promoting synergy of HIV research within an institution or multiple institutions. Can you summarize how the implementation and rollout of the Ending the AIDS Epidemic strategy has been received?
A: The CFARs played a major role in a CDC activity. The CFARs had a great partnership with CDC from 2011 to 2017 during a 12 Cities Program that was to improve the continuum of care and talk about linkage of it to health departments and CDC activities in these 12 cities. The Ending the Epidemic initiative will further build upon this relationship between the research community and the health department so that the health department can help guide the research questions to become very implementation focused.

Q: There are many people that can perform implementation science without being in a CFAR. How can others, not a part of a CFAR, do implementation science?
A: There is currently no budget yet for FY 2020. We are waiting to see how much money will be specifically tailored for the Ending the Epidemic. There are discussions about increase in FY 2021 and beyond. Funding will have to grow as tackling this epidemic cannot be done on a flat budget. We want to grow a pipeline of discovery while also tackling this epidemic and the implementation.

Q: Some of the PrEP pillar challenges were mentioned. Is there discussion at state level for programs to assist with providing PrEP to those who need it?
A: This has become a HRSA and CDC discussion. Gilead recently announced a significant contribution of PrEP over the next 11 years, ~20 percent of what is needed. There is much that needs to be worked through. But, the short answer is no, not yet.

AIDS Vaccine Research Subcommittee (AVRS) Update
Alan Schultz, Ph.D.

The January 29th AVRS meeting focused on nonhuman primate (NHP) work, specifically the consortia for Innovative Research in Nonhuman Primates. This initiative was created in 2010 as part of the Back to Basics push after the STEP trial because of the many protected nonhuman primates that had resisted infection without neutralizing antibodies. The consortia were funded to determine what was causing this protection. In 2016, it was recompeted and at this AVRS meeting, the Vaccine Research Program wanted to show what the investment in the consortia was producing. Updates from four vaccine platforms representing various stages of development were shown. These platforms are rhCMV, Ad26/gp145, SOSIP BG505.664 in Alum, and SOSIP BG505.664 PLUS three vectors expressing SIVgag only. Significant results from these platforms were summarized.

rhCMV platform: Key data from Louis Picker’s CMV vector work showed an overall viral clearance efficacy of 55 percent from over 40 vaccinated and challenged Rhesus macaques. All traces of infection disappear after approximately 1 to 2 years. The mechanism involves early viral replication arrest and protection appears binary with either complete protection or none at all. Ab responses, as well as Env inserts, are not required for protection. Established protection is not abrogated by depleting CD4 or CD8/NK cells, and it is nonclassical and unconventional MHC-E responses that are a major factor in these protective responses. However, while all vaccinated animals were shown to present MHC-E, only 50 percent of these animals clear the infection. To try and explain this difference, a complementary transcriptomics study was set up to perform RNA sequencing of whole blood from the NHP. Differences in gene expression between the protected and unprotected animals were determined and revealed that upregulation of IL-15 signaling seems to be important for rhCMV mediated viral clearance in NHP. The current hypothesis now is that sustained IL-15 signaling is necessary for the functional MHC-E anti-viral effector programs. Experiments expressing IL-15 in CMV are currently being done in NHP to try and raise the protection number above 50 percent. Whether these data will translate into humans is a big question and a first-in-human trial to answer this may start within a year.

Ad26/gp145 platform: This Jansen platform is currently being used in the large HVTN 705 trial. The standard NHP experiment trial data here came from is a 12-month vaccination, prime and boost, a 6-month wait, and then a challenge. The best prime/boost vaccine combination showed 66 percent protection from acquisition. Despite the protection, this series of animals was unable to neutralize the Tier 2 challenge virus and this group provided a large pool of protected and unprotected animal for correlates of protection analyses by systems serology. This approach takes sera from individual animals, through a battery of assays with various different effector cells in vitro. Multiparametric analysis are then done similar to transcriptomics. Published data from these analyses showed Fc-based properties of antibodies that seem to protect even when the sera do not neutralize the challenge virus. To move from statistical correlates to mechanisms of protection a new strategy was used that involved an immunization with the Ad26 platform in the SIV system, rank ordering the animals by systems serology, collection of large volumes of plasma, and purification of polyclonal IgG for adoptive transfer into naïve rhesus monkeys. The overall conclusion from prospective NHP studies so far has shown that non-neutralizing antibodies, if they have the right character, can contribute to protecting infection.

SOSIP study platform: The SOSIP trimer is a clade A protein that can induce type-specific neutralizing antibody against the Tier 2 challenge virus. The study design uses four inoculations of the SOSIPs in the 3M-052 adjuvant followed 4 weeks later by repeat vaginal exposure. Results showed that approximately 50 percent of vaccinated animals had significant protection from infection compared with controls. BG505 antibody neutralization titers were used as correlates of protection. Animals with titers generally above 300 were protected from viral challenge and this indicated a strong correlate of neutralization. Another study was performed on the 50 percent of animals that were not protected following vaccination. This attempted to recruit T cells using the strongest T cell inducing viral vectors: unattenuated VSV, wild-type vaccinia, and Ad5. While T cells were induced in these studies, generally there was no enhanced protection. What distinguishes the non-protected animals from the protected animals is still unknown.

A schematic diagram of the synergistic effects of cellular and humoral immunity in mediating protection was presented to help describe the potential mechanism. Dr. Schultz concluded by briefly mentioned three talks about reagents that might be useful in deconvoluting which is going on among all the players in the tissues using multicolored probes for both prevention and cure.

Office of AIDS Research Advisory Committee Update
Richard Chaisson, M.D.

Dr. Chiasson presented highlights of the 50th Office of AIDS Research Advisory Committee (OARAC) meeting. Covered in the Director’s Report was an update on OAR staff and budget, strategic planning, portfolio review, Ending the Epidemic in the U.S., and the Presidential Advisory Committee on HIV/AIDS. Also discussed at the meeting was the transition to a 5-year NIH Strategic Plan which is now under process and development after a request for input closed in April. The congressional justification budget, which defends the President’s budget, and the professional judgment budget, which is a report on what it will actually take to meet NIH strategic goals, were briefly covered. The portfolio review, annually done by OAR of projects that are up for recompetition to see how they align with the NIH priorities for HIV, was covered. This review showed that the proportion of projects that now align with the NIH priorities has grown from approximately 80 percent to over 90 percent both in terms of dollars and number of projects. At the OARAC meeting, there were presentations from a number of the HHS HIV/AIDS treatment and prevention guidelines working groups. Deputy Director of the NIH, James Anderson, talked about the new Office of Sexual and Gender Minority Research and its mission, the Helping End Addiction Long-Term, HEAL initiative, which has $850 million targeted in the coming year, and a couple of new Common Fund projects. Dr. Anderson spent most of his presentation talking about the ill-fated Moderate Alcohol and Cardiovascular Health (MACH) trial and some of the outcomes that the trial within the NIH, including an NIH Director’s Review that cancelled the MACH trial and recommendations of the process of developing trials with ties to industry. The National Center for Complementary and Integrative Health (NCCIH) Strategic priorities related to resilience and health restoration was presented by Helene Langevin, the new Director of the NCCIH. This covered NCCIH HIV grants that look at resilience and at inflammation. Dr. Langevin talked about her own work on inflammation which included a set of experiments with rats that were trained to do yoga which reduced inflammation in their muscle tissue. David Goff presented the National Heart, Lung, and Blood Institute’s (NHLBI) growing portfolio, covering the Institutes focus on comorbidities, including the Multicenter AIDS Cohort Study, a new initiative looking at HIV cure using stem cell transplantation, and some expanded strategic investments for the coming years in transplantation, stem cell transplantation and comorbidities. The REPRIEVE study that involves the statin study for reducing cardiovascular events in people with HIV is now fully enrolled. It enrolled a population that was at lower risk for cardiovascular disease than originally intended, causing the sample size to be increased from 6,500 to 7,500. Results will be available in 2023. Carl Schmid, the co-chair of the Presidential Advisory Council on HIV/AIDS, spoke about the reinstated council and discussed the Ending the HIV Epidemic. Kendall Bryant from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) spoke about alcohol and HIV extensively. The portfolio at NIAAA of HIV-related projects contains six major platform and center projects. The Institute has a large number of collaborations on alcohol and HIV that they are sponsoring.

Concept Review (Approval Requested)

Basic Sciences Program (BSP)

NIH Centers for AIDS Research and Developmental Centers for AIDS Research
Candice Beaubien, M.P.H.

The Centers for AIDS Research (CFAR) and the Developmental Centers for AIDS Research (D-CFAR) concepts were presented for renewal. The main purpose of these concepts is to foster high-quality HIV/AIDS research by increasing collaborations and multidisciplinary research within an institution, between institutions, and by enhancing translation of basic research findings into vaccine, therapeutic, prevention, and HIV cure concepts in a synergistic and cost-effective manner. The duration of the initiatives will be 5 years and it is estimated that there will be one to six awards made for a first-year total cost of $1.5 million, by NIAID, for these initiatives. The CFARs were established in 1988 and provide infrastructure support to institutions with significant NIH HIV/AIDS-related funding and ongoing research activity.  The program is co-funded by 12 NIH Institutes and there are currently 19 CFARs located throughout the United States. The overarching CFAR mission is to support multidisciplinary research aimed at reducing the burden of HIV both in the U.S. and around the globe by providing scientific leadership and institutional infrastructure dedicated to HIV/AIDS research; stimulating scientific collaboration in interdisciplinary and translational research, through facilitating research collaborations; supporting basic, translational, implementation and health policy research to facilitate application of research findings to HIV/AIDS prevention and care; developing the next generation of scientific leaders in HIV/AIDS research through focused mentoring, career development and funding support to early career investigators; and promoting knowledge of CFAR research findings and the importance of HIV/AIDS research through community outreach. Both CFARs and D-CFARs are eligible institutions that have substantial NIH-funded HIV research and have shared infrastructure support that is not available through research grant mechanisms. They should be multidisciplinary and a major focus is scientific and fiscal flexibility. Additionally, D-CFARs have a nucleus of HIV/AIDS researchers but not the critical mass for a full CFAR and will provide funding to build and strengthen a program competitive for a full CFAR. Key components of the program include promoting local control by allowing scientific and fiscal flexibility, a nimble structure that allows for quick response to emerging priorities, adding value to HIV/AIDS research, providing economies of scale, creating synergy and collaboration, and supporting early career investigators through pilot studies and mentoring. The basic required structure for the programs is an administrative core, at least one basic science core, at least one clinical core with infrastructure support for human subject studies, a developmental core and between one and three scientific working groups. Proposed changes for the renewal include increasing the D-CFAR funding level from $750 thousand to $1 million, increasing emphasis on innovative technologies in basic science research, including a microgrant component as an option for the Developmental Core, strengthening language that Scientific Working Groups should be focused on a scientific area that is important for the field but not already a strength of the CFAR, and requiring a community engagement plan in the application. The current CFARs provided data on their pilot awards with resulting grants. This data showed that between 2009 and 2018, the return investment for every dollar spent was $5.65 and about a third of pilots have resulting grants.

The role of the CFARs, and the NIMH AIDS Research Centers, involvement in Ending the HIV Epidemic Initiative was briefly discussed. These programs already have an established relationship with the CDC and HRSA-funded partners, are nimble and flexible, and the CFARs have started creating Implementation Science Cores and Implementation Science scientific working groups. The CFARs will serve as research platforms to support implementation science, collaborate with federally funded partners to implement locally relevant approached, inform local partners on best practices based on state-of-the-art biomedical research findings, and will collect and disseminate data on the effectiveness of approaches. There are two supplement opportunities specifically for FY 2019, that were established to strengthen partnerships around the Ending the HIV Epidemic goals - implementation science planning applications and applications focused on HIV-related health disparities for racial and ethnic minority communities. While there are no specific plans for FY 2020, the plan is to coordinate and align with HHS partners, scale up successful FY 2019 projects, and support a collaborators meeting for key stakeholders.

Reviewers’ comments were presented and addressed and the ARAC committee cast their votes.

Questions:

Q: Have you thought about having an established CFAR partner with an interested institution in an area lacking a CFAR to help support them to apply as a Developmental CFAR and support them to become competent?
A: A lot of the applicants do reach out to the established CFARs, and they form a scientific review committee that comes and gives them feedback for their application.

Q: Should there be these rigid requirements, particularly in basic sciences? And if you remove those, would that enable CFARs to spring up in places in the country where there are not already?
A: There is some flexibility. We are starting to see some of the CFARs involve and have innovative technologies, imaging cores, and next-generation sequencing. But we do need to keep these multiple core structures. We have looked at whether the types of cores that are currently required still work for the program.

Ballot Voting Outcome (NIH Centers for AIDS Research)
7 Approval
0 Approval with modification(s)
0 Deferral for further information
0 Disapproval

Ballot Voting Outcome (Developmental Centers for AIDS Research)
7 Approval
0 Approval with modification(s)
0 Deferral for further information
0 Disapproval

Martin Delaney Collaboratories for HIV Cure Research &
Martin Delaney Collaboratory for Pediatric HIV Cure Research

Karl Salzwedel, Ph.D.

Two concepts were presented; the first was a reissue of the Martin Delaney Collaboratories (MDC) for HIV Cure Research Program and the second was to establish a new Martin Delaney Collaboratory focused specifically on pediatric HIV cure research.

The purpose of the MDC for HIV Cure Research Program is to foster dynamic multidisciplinary collaborations between basic, applied, and clinical researchers by establishing partnerships across academia, industry, government, and community, with a goal of leveraging common resources to accelerate the pace of HIV cure research and engage the next generation of HIV cure researchers. This reissued grant concept will have a duration of 5 years with an anticipated 4 to 6 awards. The first-year cost for the initiative by NIAID will be $27.5 million. Potential co-funding partners include the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Mental Health (NIMH), National Institute for Drug Abuse (NIDA), and the National Institute of Neurological Disorders and Stroke (NINDS). There is a need for an HIV cure with over 37 million individuals currently living with HIV, all of which require life-long ART to prevent transmission and disease. Curative therapies would curb transmission, reduce comorbidities and side-effects, combat stigma, eliminate the treatment cascade, and relieve cost burden of lifelong ART. In the absence of an effective prophylactic vaccine, a cure will be necessary to the end HIV epidemic globally. The scope of research includes basic and clinical research to characterize persistent HIV reservoirs, developing and testing therapeutic strategies for eradicating or controlling residual virus in in vitro, ex vivo, and animal models, and drafting clinical trial protocols to test safety, tolerability, and initial proof-of-concept. The location of the parent institutions for the six existing MDC and an overview of some of the therapeutic approaches being pursued by these six collaboratories were shown. These approaches can be divided into five general categories – immune modulators, cell-based therapeutics, vaccines, antibody-based therapeutics, and transcriptional regulation. Key accomplishments of the MDCs include a cumulative total of over 600 publications in 7 years, increased collaboration across the field, twelve clinical trial protocols developed, and actively engaging community in HIV cure research. Some of the key scientific advances include the discovery of the Intact Proviral DNA Assay (IPDA), that CD32 is not a marker for reservoir cells, and that TLR7 agonist + PGT121 controls viral rebound in NHP. Because funding is spread thinly, many of these projects leverage other grants and grant programs; the MDC grant is the glue that ties these independent projects together toward a common goal of developing combination therapies for HIV cure. A third-party evaluation of the MDC program from 2011 to January 2019 was recently commissioned by DAIDS and found that unique coauthor connections increased greater than threefold between the first 3 years of the program and the subsequent 3 years of the program; unique industry connections increased over sevenfold; 14 percent of publications overall involved more than 1 MDC; and papers were cited about 3 times more often than average for the field over the same period. The rationale for the reissue is that MDCs greatly broadened participation in HIV cure research, have accelerated the pace of HIV cure research by facilitating critical advances that benefit from broad collaboration, and the reissue will stimulate innovation by creating opportunities to restructure/refocus the most productive existing collaborations and encourage new partnerships to form. Key features of the current MDC program include the dynamic structure of UM1 enhances innovation, accommodates high-risk/high-reward studies; the limit of years to encourage innovation and competition; budgets capped at $3.5 million direct costs, basic and clinical research required; multiple industry partners; and community engagement. A “Back to Basics” theme to the changes of the renewal propose to shift the focus more towards basic research to maintain an innovative pipeline of cure strategies. Clinical trials will be shifted to DAIDS networks and other mechanisms to ensure sufficient resources and timeline. Reviewers’ comments were presented and addressed and the ARAC committee casted their votes.

The purpose of the Martin Delaney Collaboratory for Pediatric HIV Cure Research is to establish an MDC with similar structure and scientific scope tailored specifically toward addressing the unique biological opportunities and challenges associated with HIV cure research in pediatric populations. This new concept will have a duration of 5 years with one anticipated award. The first-year total cost by NIAID for this initiative is $3.5 million. Potential co-funding partners include the National Institute of Child Health and Human Development (NICHD) and National Institute of Mental Health (NIMH). The scope of research is to advance development of pediatric-targeted cure strategies by leveraging uniqueness of infants’ immune system; to study differences in viral reservoir resulting from timing and mode of HIV acquisition, timing and duration of treatment, and anatomical location; developing specialized tools, assays, imaging, and animal models tailored to pediatric studies; and engaging community stakeholders unique to these populations. The unique considerations for pediatric HIV cure research, as compared to adult, are that the neonate immune system is naïve when exposed to HIV, children respond better to vaccines than adults, and it is hypothesized that because pediatrics received early treatment, it is expected that the reservoir will be smaller and more homogeneous, and may be easier to control or eliminate. Reviewers’ comments were presented and addressed and the ARAC committee casted their votes.

Questions:

Q: What does “more structured community input” mean? Is there any formal connection between the Martin Delany initiatives and End the Epidemic?
A: There is no formal connections with Ending the Epidemic at this time. There may be opportunities in the future. The main concern in the community was that PIs felt the community engagement plans were not as well organized and structured as they could have been. There is the thought to put more language in that will model what is in the RFA for the Clinical Trial Networks, for example, to be more clear of what DAIDS’ expectations are for community engagement.

Q: What are you going to do to ensure that coordination with the ACTG, in particular, or with IMPAACT for actually conducting trials that might come out of the collaboratories is going to work?
A: It is our expectation to be very involved in helping to prioritize these trials and to make it clear that the most meritorious trials should be accommodated by the networks. But it might be healthy for some filter that forces clinical trials to rise to a certain level to justify the investment in carrying out the trial.

Ballot Voting Outcome (Martin Delaney Collaboratories for HIV Cure Research)
7 Approval
0 Approval with modification(s)
0 Deferral for further information
0 Disapproval

Ballot Voting Outcome (Martin Delaney Collaboratory for Pediatric HIV Cure Research)
7 Approval
0 Approval with modification(s)
0 Deferral for further information
0 Disapproval

Limited Competition: International Epidemiologic Database to Evaluate AIDS (IeDEA)
Carolyn Williams, Ph.D.

The International Epidemiology Databases to Evaluate AIDS (IeDEA) is being reissued for the fourth time as a closed competition of the existing regional data centers to study questions on HIV and AIDS with a new emphasis on tuberculosis (TB). The objective of IeDEA is to advance knowledge about HIV and TB by combining data for questions that cannot be answered by individual studies; address local, national and global questions on morbidity and mortality and to provide data to international partners to provide actionable evidence for program implementation; build research infrastructure in clinical research, data management, data science and data analysis that supports clinicians and scientists; and improve the quality of data, and inferences from these data. This reissued initiative will have a duration of 5 years with 7 anticipated awards for a first-year total cost of $7.9 million, with an additional $2 million to study TB, by NIAID. There are nine additional partner Institutes, including NIMH, NICHD, and the National Cancer Institute (NCI). IeDEA brings in data from about 1.7 million patients from around the world. Principle investigators have remained relatively steady over each reissue; however, now many of the cohorts have co-PIs. The success of PIs from IeDEA sites from specific regions in competing for subsequent grant was overviewed. Each IeDEA region is responsible for the data within their region. A table was shown that listed IeDEA enrollment for each global region and data for each of those regions. This reflected the epidemic within that region with Eastern and Southern Africa having the largest databases. The IeDEA working structure, data exchange standard and publications, broken down into regions, were discussed. Some scientific data slides were shown and included a 6-country regression discontinuity analysis dataset from the effect of “Treat All” on rapid ART initiation in sub-Saharan Africa. An important element of IeDEA is that the data are incredibly dense as there are so many participants and several covariates. Improving data presentation to quickly give the visual impact is one issue that the North American group has been working on. Several things have been learned from the three iterations of IeDEA were listed including data systems are weak and are weakening in some countries, HIV Care is becoming more distributed, non-HIV outcomes are crucial, and not all data are of equal importance. Changes from the previous initiative was listed, including the key change with TB. IeDEA is being expanded to take on the epidemiology in TB RePORT and IeDEA sites will incorporate the cohorts at TB RePORT epidemiology sites. The other key change is using funds from OAR to add several new institutes, NIDDK, NIAAA, and NHLBI, which will co-fund a Sentinel Research Network where data will be collected specific to disease of interest to those ICs. Other changes are that NICHD and NCI were able to receive additional finding. NCI will be able to do a study on treatment outcomes for cervical cancer patients and NICHD will be enrolling a cohort of pregnant women and conducting a pharmacovigilance study to look at the pregnant women and their children. Also, the National Library of Medicine (NLM) has joined the consortium and will bring their bioinformatics expertise for the development of the data standards for the Sentinel Research Network and the creation of an All-Africa Data dashboard. Finally, Fogarty received funding for a training program that will focus on D34s. Reviewers’ comments were mentioned the ARAC committee casted their votes.

Questions:

Q: Eastern Europe and the former Soviet Union, where people who inject drugs are driving the epidemic, is an area where there is great epidemiology going on. Can you speak about whether there may be a way to incorporate some of those people in an IeDEA-D, similar to the CFAR-D concept?
A: NIAAA does fund a project that extends across the U.S. and across Europe, and we have been talking with them about that cohort and whether there might be opportunities there. I think we will be collaborating with NIAAA more formally. Not having Europe is a big gap in IeDEA, but there are strong collaborators there.

Q: Why a closed and not an open competition?
A: At this point, it would be exceedingly difficult for another group to compete with the existing IeDEA regions with their many years of data and experience. If we wanted to add additional regions and have an open competition in other regions, it would come down to an economic question of what would be the value of bringing in a North African or Eastern European region.

Q: With the integration of TB and RePORT into IeDEA, how are you going to incorporate all of the specimen collection and archiving and curating the specimens?
A: This is not intended to be the data specimens and the basic science element of TB RePORT. That will remain TB RePORT and will stay under the bilateral agreement. This is intended to give some stability and longitudinal strength to the clinical cohorts that either exist within those regions already or adding new regions to add those countries to the consortium of epidemiology research. It was felt that the opportunity in IeDEA was to be able to collect more clinical data. If we were going to collect clinical data, then the thought was why not use a standard that is already being used by a significant portion of the research community under RePORT.

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

NIAID Specimen Repository
Lori Zimand, M.P.H.

The objective of this contract is to continue a contract resource for processing, storage, management, and distribution of biospecimens from HIV positive and negative subjects enrolled in clinical studies. This is a renewal of a contract with an award duration of 7 years. The NIAID Specimen Repository currently stores over 8 million specimens and provides high quality specimens to investigators to support clinical and epidemiologic research. Currently, the repository receives specimens from the MACS/WIHS Combined Cohort Study and the HIV Vaccine Trials Network. Charts presented showed the steady increase in specimen inventory over the last 10 years by study. The current repository contains peripheral blood mononuclear cells (PBMCs), serum, plasma, tissue specimen, other bodily fluids or substances, such as CVL, semen, saliva, urine, feces, autopsy, and biopsy material. Other charts summarized the total vials received, and total vials requested and shipped. The number of publications was highlighted, including almost 150 biomarker publications from the MACS related to specimens from 2012 to 2019, with selected papers briefly discussed. It was noted that the HVTN has conducted over 75 trials across 4 continents and is committed to making specimens and data available to investigators around the world. Advantages of the central repository are that it enables research using longitudinally collected specimens from HIV+ subjects and controls at all stages of disease in the pre- and post-HAART eras, provides specimens at no cost to investigators, ensures high quality specimens under uniform preparation and storage conditions, and increases efficiency and cost effectiveness of sample storage/distribution from/to multiple sites. The repositories are required to receive daily shipments of specimens, store as appropriate in -80 freezers or liquid nitrogen, aliquot as requested by researchers, ship specimens, provide a database to inventory specimens and track utilization, maintain effective QA/QC program, and communicate regularly with NIAID and repository users. Reviewers’ comments were mentioned and the ARAC committee casted their votes.

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

Therapeutics Research Program (TRP)

Preclinical Services for AIDS Therapeutics (PSAT)
Joseph Fitzgibbon, Ph.D.

The objective of this contract is to provide preclinical services to support the discovery and development of chemical compounds or biologicals for research on HIV infection and other infectious diseases (i.e. TB, hepatitis B and C) and advancement of products towards regulatory submission and clinical trials. This is a new contract that brings together six technical areas that are currently in separate contracts. The duration will be 7 years and it is estimated that there will be multiple awards made. The development of new therapies for HIV and related infected remains a high priority for NIAID; however, investigators often lack the resources to conduct the types of preclinical work that is required to advance products to clinical testing. Investigators may submit a request to NIAID for the services provided by the contract mechanism. These contracts do not provide funding to investigators, they only provide services to investigators at the direction of NIAID. This new contract will bring six technical areas currently under separate contracts under one umbrella contract mechanism, indefinite delivery/indefinite quantity (ID/IQ), that will have the flexibility to easily provide funding to each technical area according to needs and priorities. The six technical areas covered are the reagent program for HIV and other infectious diseases, in vitro testing and screening, chemical synthesis, small animal model testing for HIV and related infections, formulation development and manufacture of dosage forms, and preclinical pharmacology/toxicology. The reagent program for HIV and other infectious diseases will acquire, maintain, produce, expand, and distribute state-of-the-art standardized reagents for basic and preclinical research on HIV and other infectious disease research; support authentication and characterization of biological reagents following quality control and quality assurance procedures; provide support of technology transfer and execution of material transfer agreements; and provide reagent technical information through program website. In vitro testing and screening will adapt relevant cell- or target-based assays for evaluation of activity; conduct evaluations for in vitro efficacy in cell- or target-based assays; adapt assays to a high-throughput format and perform high-throughput screening of chemical compound libraries; perform “hit-to-lead” progression studies on promising compounds; and conduct lead optimization and mechanism of action studies on candidate compounds. Chemical synthesis will synthesize chemical agents for testing in in vitro screens, animals, or early Phase I clinical studies and adhere to FDA Good Manufacturing Practice (GMP) when required. Small animal model testing for HIV and related infections will use small animal models to evaluate candidate chemicals or biologicals; develop assays to determine the efficacy of the candidate molecules in animal models; and improve or adapt small animal models for HIV, HBV, HCV and TB developed elsewhere. Formulation development and manufacturing of dosage forms will develop new formulations and manufacture dosage form for clinical use; develop and perform analytical assays in compliance with applicable regulations; manufacture and release, package, label, store, and ship pharmaceutical products in compliance with cGMP regulations; and conduct product stability studies in compliance with cGMP. Preclinical pharmacology and toxicology services will conduct preclinical IND-enabling studies to assess pharmacological properties in vitro and in animals, safety pharmacology, acute, repeated dose and chronic toxicity, and immunotoxicity, carcinogenicity, genotoxicity and reproductive toxicity; develop bioanalytical methods and perform bioanalytical testing to support the studies described above; and perform in vitro preclinical toxicology assays, such as mitochondrial toxicity screening. The process that investigators can use for accessing these contracts was discussed. Finally, accomplishments of the current six contracts was overviewed and included the reagent program’s fulfillment of requests from 886 laboratories in 38 countries over the 2017-2018 project year; the in vitro screening program supported the development of 14 new assays and adapted 8 standard assays from sponsors to a high-throughput platform; over 200 different compounds have been synthesized in the last 5 years for enzymatic, in vitro, and in vivo studies; and the formulation/manufacturing program provided manufacturing of two clinical dosage forms tested in clinical trials and conducted multi-year drug stability studies. Reviewers’ comments were presented and addressed and the ARAC committee casted their votes.

Question:

Q: What is the rationale for bringing all these different activities under a single contract?
A: A single contract provides the flexibility to easily move funding between the different areas, if needed. Under this contract mechanism, we don't have to put money into a service unless it is needed.

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

Immunology Quality Assessment Program (IQA)
Daniella Livnat, B.Sc.

The objective of the Immunology Quality Assessment Program (IQA) is to provide a critical resource to evaluate and enhance the ability of laboratories to participate in NIAID-funded collaborative trials by monitoring the ability to reliably perform study-specified immunological tests, freeze viable PBMCs, and process leukopaks; facilitating the optimization, standardization, and validation of immunological assay methodologies, and with a focus of laboratory-developed-tests for implementation in NIAID-supported studies; and helping laboratories meet sponsor and regulatory requirements for good clinical laboratory practices. This contract is a renewal with an award duration of 7 years. The aims of the contract are to achieve participant safety, reliability of study data, and accountability to regulatory agencies (i.e. FDA, EMA). Key elements of the laboratory quality management system are test reliability, monitored by external quality assurance/proficiency testing; appropriate level of assay characterization to meet regulatory-required “fit for purpose”, as described in the FDA guidelines; and laboratory operations according to good clinical laboratory practices. IQA contract is one piece of the DAIDS clinical laboratory QA toolbox, which also includes SMILE, VQA, and TBQA. There are three key tasks of the IQA contract – Proficiency Assessment, Assay Characterizations, and GLCP, IQA Resources. The proficiency assessment will monitor the ability of non-U.S. labs to reliably perform CD4 enumeration and will monitor the ability of labs to reliably freeze viable PBMC or process leukopaks. The assay characterizations will provide guidance and support to select, specialized, central-testing labs for characterization of study-specified immunological LDTs that may be included in a regulatory submission in support of product licensure. The GCLP, IQA resources will help PBMC freezing labs and specialized immunology labs achieve CGLP; provide guidance and training vial mail and phone communications, interactive web conferences, presentations at meetings and training events; and visits of various durations to labs; and maintain a web-based information repository and searchable resource library. Key accomplishments of the IQA are that it has continued to monitor the quality of study-specified CD4 testing and viable PBMC freezing in DAIDS labs; implemented a novel program to evaluate the ability of labs to reliably perform leukapheresis, a process incorporated into HIV trials focused on the cure; in collaboration with the ACTG immunology specialty lab, developed and evaluated a multi-plex Luminex assay to help harmonize inflammatory biomarker research across interventional trials aimed at reducing inflammation in virologically-controlled study participants; and acquired ISO 17043 accreditation needed for proficiency testing providers, as well as maintained CAP, CLIA, and GCLP standards. Reviewers’ comments were presented and addressed and the ARAC committee casted their votes.

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

Advancing Vaccine Science for Improving TB Treatment Outcomes in HIV Infection
Daniel Frank, Ph.D.

The purpose of this concept is to advance development of an effective therapeutic vaccine to improve outcomes of active tuberculosis (TB) disease in the setting of HIV co-infection. TB immunotherapies may be especially important for drug-resistant TB in people living with HIV. This is a new initiative with a duration of five years. It is estimated that there will be two to three awards and the first-year total cost for the initiative is $4.0 million. Having a history of active TB increases the risk of TB recurrence and this risk of recurrence is further increased in HIV-infected patients. It has been noted that a therapeutic vaccine may shorten TB antibiotic therapy and/or prevent recurrence, and along with the continued rise of MDR-TB has increased interest in developing new TB immunotherapies. A number of research gaps in the field include the immune correlates of protection from recurrence remain to be determined; few current/new vaccine candidates are being tested in a therapeutic setting, and even fewer in the HIV co-infection environment; the use of adjuvants or host-directed therapy drugs to target host signaling pathways/effectors to potentiate therapeutic vaccination remains unexplored; and the lack of research to guide development of vaccine strategies to improve treatment outcomes of active TB. An overview of the current vaccine candidates was shown, and it was highlighted that all of the candidates were originally developed as preventive TB vaccines. A few of the vaccine candidates have shown interesting preclinical results in the therapeutic setting in both guinea pigs and in nonhuman primates. Areas of research interest include correlating changes in host immune cell regulation and function associated with Mycobacterium tuberculosis (Mtb) proliferation versus control during active disease and/or recurrence; evaluating the impact of Mtb strain variation and host genetic/epigenetic factors on immune responses to candidate therapeutic vaccines and adjuvants and modulation of disease outcomes; evaluating current and novel candidate TB vaccines/adjuvants with antimicrobial chemotherapy (including for DS/MDR-TB and, as appropriate, HIV ART) for decreasing recurrence and/or treatment shortening strategies; assessing the role of underlying HIV-associated immune dysfunction in generating anti-TB immunity; and identifying correlates of protection from TB recurrence and potentially a biosignature for protection status. Responsive applications should include studies of candidate and novel TB vaccines/adjuvant combinations to improve treatment outcomes during or immediately following antimicrobial therapy; studies with appropriate animal models, and human cells/tissues from both HIV-infected and uninfected individuals; animal model adaption/improvement and development of novel functional assays for correlating changes in immune functions with treatment effects is encouraged, but cannot be a primary focus of the application; and highly collaborative multidisciplinary research teams incorporating expertise in infectious diseases, vaccinology, and immunology and utilizing novel research tools to probe molecular targets and alterations in specific host defense mechanisms triggered by vaccines/adjuvants in the presence of TB disease. Non-responsive applications include those with a primary focus on analysis of cytokines, chemokines, eicosanoids, and immune cell subset enumeration without a focus on understanding fundamental immune cell mechanisms associated with enhanced antimicrobial restriction, treatment shortening, or protection against recurrence and those which propose clinical trials or the establishment of patient cohorts. Reviewers’ comments were presented and addressed and the ARAC committee casted their votes.

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

Prevention Sciences Program (PSP)

Immunopathogenesis and Biomarkers of Latent and Incipient TB in Children
Patrick Jean-Phillipe, M.D.

The purpose of this concept is to support multidisciplinary research to elucidate immuno-pathogenesis of latent and incipient TB and stimulate discovery of novel biomarkers for rapid, sputum-independent diagnosis of latent and incipient TB and prediction of progression to active TB disease in both HIV-infected and uninfected children. This is a new RFA with a duration of 5 years with NICHD as a potential co-funding partner. The first-year total cost for this initiative is $5 million and it is anticipated that there will be 2 to 3 awards. The need for this new program is partly due to a shift in the focus on biomarker discovery, poor understanding of disease progression in children, and current tests (TST and IGRA) that perform sub-optimally. Thus, this new concept, in contrast with other related awards (RFS-AI-17-039 and RFA-AI-19-036), focuses on biomarker discovery for active TB disease and progression of TB disease in children. NHP and other animal models are showing promise in studying TB as there has been concordant transcriptional signatures detected between human and NHP models. This raises the hope that some of those observations can also be made in children and that an increased understanding of TB immunopathogenesis will advance discovery and development of simple, accurate, rapid tests for diagnosis of latent/incipient TB and reliable correlate of risk for progression to TB disease. Some background into TB transmission was discussed in detail which involved risk and TB exposure via various means such as from outside the household. Characteristics that favor implementation and scale-up of a diagnostic tool for TB progression in children include being simple to use, particularly decentralized use; in settings such as lower health care; require only a minimally trained health worker; rapid point of care applications; and eligible matrices including serum, urine, stools, or other non-sputum matrices. Applications require at least two distinct scientific projects and one core resource. Required scientific projects include the discovery and validation of novel biomarkers for latent/incipient TB and correlate of risks for progression to TB disease, targeted TB immunopathogenesis research to uncover relevant biologic mechanisms and pathways to extend/complement biomarker discovery activities, and a collaborative and integrated research environment. The required core resource will be an administrative core to oversee and manage projects and resources. Target populations will be HIV-infected and uninfected children that are < 5 years of age; older children/adult populations will be allowed with a strong justification. A summary of key differences between this concept and other similar concepts was listed.  Differences included the stage of TB that is targeted, the phase of diagnostic development, the research strategy, and the implementation vision. Reviewers’ comments were presented and addressed and the ARAC committee casted their votes.

Questions/Discussion:

Q: I share the reviewers' concerns that this is not that distinct from RFAs that have been previously approved.  All three concepts sort of overlapping to some degree.
A: The overlap is not substantial. Different phases of TB are targeted, which means that different populations will be targeted as well as different stages of the development cycle.

Q: Why label this concept as a U19 while the other two are R01s?
A: We wanted to not just focus on the biomarker discovery, but also be able to have a targeted immunopathogenesis approach. Having two separate projects components that are going to call on different expertise yet are going to feed from each other so that there is a sort of cross-fertilizations was thought to be well suited for a U19 mechanism.

Q: What would be the cohort for this study? Would you be looking at kids who are in daycare, not known exposure, and then assessing them to see if they develop TB versus an exposed cohort that has a known TB case and then trying to see what their disease state it?
A: There are epidemiological cohort that have followed children and infants, for instance, in settings and that have highlighted how the extent of TB exposure and TB disease in the absence of documented exposure. We also know that there are cohorts that follow the children who are exposed for outcomes. We hope that both of these cohorts can be used in a way that the diagnostic test or biomarkers can be compared between them.

Q: Is idea to take a multi-omics approach and look for a diagnostic like a parsimonious protein signature; a parsimonious gene signature that could tell you who's at the highest risk of progression in this age?
A: Yes, that would be on pathogenesis side. But from the human cohort side, we know this has worked and have provided some really validated biomarkers like the GCS-16. There is high value in terms of being able to encounter a child that is less than 5, either in the setting of contact tracing or in the settings of where there is significant high risk of progression to TB disease or high burdens, and being able to apply a simple test that is going to predict the risk of this child to progress to TB in the next 1 year or 2. We think that this is highly valuable, and that there is a cohort out there that will allow this type of research.

Comment: The challenge will be that kids under 5 are not ideal in terms of prophylaxis.  It will be challenging to take a look at this in a meaningful way to get at the cohorts. Also, the number of under 5 kids being HIV infected is becoming fewer and fewer. It would obviously be a focus on HIV uninfected largely in the under 5 if you're doing prospective cohorts.

Comment: It sounds like we should consider, when voting, that one of the options is deferral.  Vote your conscience, and if deferral wins, we will bring this back in September with focus in a way that is a little clearer and considers the realities of exactly what we are seeking to get to. You have heard from the two reviewers that they feel that the concept is different from previous initiatives. The question is, is do you as a committee want to see this again? Even if you vote to pass this concept, you could also ask for an update at the next committee meeting.

Ballot Voting Outcome
2 Approval
2 Approval with modification(s)
2 Deferral for further information
1 Disapproval

This concept has been deferred and is being reconsidered. It will not be presented in September.

VII.  Adjournment

The meeting of the Council adjourned at 4:35 p.m., on Monday, June 3, 2019.

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

 

-s-

Anthony S. Fauci, M.D.

Chair, National Advisory Allergy and Infectious Diseases Council

Director, National Institute of Allergy and Infectious Diseases

09/06/2019

Date

 
-s-

Matthew J. Fenton, Ph.D.

Executive Secretary

National Advisory Allergy and Infectious Diseases Council

Director, Division of Extramural Activities

National Institute of Allergy and Infectious Diseases

09/06/2019

Date

 

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

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