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NIH National Advisory Allergy and Infectious Diseases Council

Minutes of Meeting: January 27, 2014

The 176th meeting of the National Advisory Allergy and Infectious Diseases Council (NAAIDC) convened at 10:30 a.m. on Monday, January 27, 2014, in Conference Rooms E1/E2, Building 45, National Institutes of Health. Dr. Hugh Auchincloss, principal deputy director, National Institute of Allergy and Infectious Diseases (NIAID) presided as chair.

In accordance with the provisions of Public Law 92-463, the meeting was open to the public from 10:30 a.m. to 11:45 a.m. and from 1:00 p.m. to 4:25 p.m. The meeting was closed to the public from 8:30 a.m. to 10:15 a.m. and from 11:45 a.m. to 12:00 p.m. for review and consideration of individual grant applications. Notice of the meeting was published in the Federal Register.

Council Members Present:

  • Ms. Maria Acebal
  • Dr. Adaora Adimora
  • Dr. Mavis Agbandje-McKenna
  • Dr. Norman Baylor
  • Dr. Robert Belshe
  • Dr. Anita Chong
  • Ms. Dázon Diallo
  • Dr. Diane Griffin
  • Dr. Michael Holtzman
  • Dr. Jonathan Karn
  • Dr. Norma Kenyon
  • Dr. Larry Schlesinger
  • Dr. Arlene Sharpe
  • Dr. Georgia Tomaras
  • Dr. Christopher Wilson
  • Dr. Jerome Zack

Ex Officio Members Present:

  • MG Joseph Caravalho
  • Dr. Victoria Davey
  • Dr. Bruce Gellin

Ad Hoc Members Present:

  • Col. Kent Kester

Council Members Absent:

  • Dr. Enriqueta Bond
  • Dr. Velma Scantlebury

Ex Officio Members Absent:

  • Dr. Anthony Fauci
  • Dr. Rima Khabbaz

NIAID Senior Staff Present:

  • Dr. Hugh Auchincloss
  • Dr. Carl Dieffenbach
  • Dr. Susan Old
  • Dr. Charles Hackett
  • Dr. Carole Heilman
  • Dr. Clifford Lane
  • Dr. John McGowan
  • Dr. John Mascola

Table of Contents

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 4,114 research and training applications with primary assignment to NIAID for a requested amount of $1,907,798,407 in first-year direct costs and recommended approval of 1,843 applications with $746,060,889 in first-year direct costs.

II. Remarks of the Director, NIAID—Anthony S. Fauci, M.D.

Council members Drs. Enriqueta Bond and Velma Scantlebury were unable to attend the meeting.

Dr. Fauci welcomed ad hoc Council member Dr. Kent Kester of the Uniformed Services University of the Health Sciences as well as four new Council members: Dr. Anita Chong, University of Chicago; Dr. Larry Schlesinger, The Ohio State University; Dr. Arlene Sharpe, Harvard Institute of Translational Immunology; and Dr. Chris Wilson, Bill and Melinda Gates Foundation.

Consideration of Minutes of Previous Meeting

Council considered the minutes of the September 16, 2013, meeting and approved them as written.

Staff and Organizational Changes

In September, Dr. John Mascola was named director of the Vaccine Research Center (VRC). Drs. Barney Graham and Richard Koup will serve as co-deputy directors.

Dr. Julie Ledgerwood is VRC’s new chief of the Clinical Trials Program.

In the Division of Intramural Research (DIR) at the Rocky Mountain Laboratories (RML), Dr. Tom Schwan retired as chief of the Zoonotic Pathogens lab. Dr. Patricia Rosa replaces him.

The Division of AIDS has several new appointments: Dr. Alan Embry was selected as the deputy director of the Basic Sciences Program; Dr. Karl Salzwedel is now chief of the Pathogenesis and Basic Research Branch; and Dr. Devasena Gnanashanmugam is chief of the Maternal, Adolescent, and Pediatric Research Branch.

In the Division of Extramural Activities, Dr. Gregory Jarosik is the new chief of the Microbiology Review Branch in the Scientific Review Program. Pamela Nevels was named chief of the Acquisitions, Management, and Operations Branch in the Office of Acquisitions.

Tributes and Awards

Dr. Ron Germain, chief of the DIR Laboratory of Systems Biology, has been elected to the Institute of Medicine, one of the highest honors in health and medicine. His election to IOM is a testament to his many seminal contributions in the field of immunology.

Dr. Carolina Barillas-Mury, chief of the Mosquito Immunity and Vector Competence Section in the Laboratory of Malaria and Vector Research, received the 2013 Sanofi-Institut Pasteur Award for Tropical and Neglected Diseases. The award recognizes her contributions to the understanding of mosquito immune responses that affect malaria transition.

Also from the Laboratory of Malaria and Vector Research, Dr. Rick Fairhurst, chief of the Malaria Pathogenesis and Human Immunity Unit, was awarded the American Society of Tropical Medicine and Hygiene 2013 Bailey Ashford Medal. He was honored for his distinguished work on the mechanisms of malaria pathogenesis and resistance to artemisinins and other anti-malarial drugs.

Meetings and Events

On December 2, Bill Gates visited NIH. After touring NIAID's intramural BSL-3 tuberculosis lab headed by Dr. Cliff Barry, Mr. Gates delivered the David E. Barnes Global Health Lecture: Why the Future Needs Biomedical Innovation. Following his presentation, he met with NIH Director Dr. Francis Collins, Dr. Fauci, and several other institute directors to discuss several topics of mutual interest.

On December 16, Dr. Arturo Casadevall, professor and chair of the Department of Microbiology and Immunology at Albert Einstein College of Medicine of Yeshiva University, delivered the annual NIAID Kinyoun Lecture. Presenting “The Origins of Microbial Virulence,” Dr. Casadevall explored his provocative thesis that the decline of the dinosaurs and the rise of mammals may be linked to differing susceptibilities to fungal disease.

Budget Update

NIAID is waiting for guidance on the FY 2015 President’s budget, which the White House announced would be released on March 4.

The President signed the FY 2014 omnibus spending bill that allocates a little over $30 billion for NIH. Dr. Fauci pointed out that the debt ceiling is one potential roadblock that remains for the FY 2014 budget. The initial end of the debt ceiling suspension is expected to be pushed back from the originally scheduled February 7, 2014, date.

Dr. Fauci reported that NIH and most institutes received an average increase of 3.4 percent in the FY 2014 omnibus budget. NIAID's amount reflects the transfer of $27 million from National Institute of Mental Health and $10 million from the Office of AIDS Research to support cure-related HIV-AIDS research.

Dr. Fauci reported that the Institute has set paylines at levels consistent with last fiscal year, taking a conservative approach for two reasons: 1) NIAID hasn’t received guidance for the FY 2015 budget and 2) the Institute does not want to overshoot on out year commitments.

To sustain investigator-initiated awards, NIAID program initiatives remain at levels that were previously cut by up to 20 percent. Funds for R56-Bridge and selective pay awards will be unchanged from previous years.

While covering this and next fiscal year’s budgets, Dr. Fauci briefly reflected on the 16-day government shutdown at the start of FY 2014. Although most NIH operations were forced to stop, institutes were able to minimize the effect on extramural investigators until the government reopened. However, the intramural program suffered badly since all experiments and activities that didn’t involve the health and safety of patients or animals had to cease.

Legislative Update

Dr. Fauci acknowledged Representative Charles William “Bill” Young of Florida, who died in October 2013 and at the time of his death was the longest serving Republican member of Congress. Representative Young chaired the House Appropriations Committee from 1999 to 2005 and led the effort in Congress to double funding for NIH from 1998 to 2003. NIH recognized his unwavering support for biomedical research by naming Building 33 the C.W. “Bill" Young Center for Biodefense and Emerging Infectious Diseases.

On September 20, Dr. Fauci hosted a large delegation of Congressional staff from Texas who visited NIH. Staff members were accompanied by Dr. James LaDuc, director of the Galveston National Laboratory, which is supported by NIAID.

On September 23 and 24, Dr. Francis Collins, along with NIAID’s Dr. Dennis Dixon, chief of DMID’s Bacteriology and Mycology Branch, and CDC Director Dr. Tom Frieden, participated in the Congressionally-sponsored community symposium in Bakersfield, California, on coccidioidomycosis (Valley Fever). Dr. Collins announced that NIAID is partnering with CDC to implement and conduct a clinical trial to evaluate certain therapeutics for Valley Fever.

On November 6, Dr. Joseph Breen, DMID’s program officer on Lyme disease, and CDC’s Dr. Ben Beard briefed House Energy and Commerce Committee staff members on NIH and CDC Lyme disease and CDC program activities.

Also on November 6, DAIDS Director Dr. Carl Dieffenbach participated in a Congressional staff briefing on the role of HIV research in ending the HIV/AIDS pandemic, organized by the AIDS Vaccine Advocacy Coalition. He was joined by Drs. Frederick Sawe and Christina Polyak, who represented the U.S. Military HIV Research Program.

At a December 9 briefing for staff of the House and Senate Appropriations Committees, the Senate Health, Education, Labor, and Pensions Committee, and the House Energy and Commerce Committee, Dr. Mike Kurilla, director of NIAID’s Office of Biodefense Research Activities, discussed the HHS public health emergency medical countermeasures enterprise. He was joined by Dr. Robin Robinson, director of the HHS Biomedical Advanced Research and Development Authority (BARDA), and other HHS representatives.

Other Information Items

Due to the government shutdown, Dr. Fauci participated at an AIDS vaccine meeting in Barcelona, Spain, through a pretaped talk on the synergy between vaccine and nonvaccine interventions.

On November 21, Dr. Fauci took part in a digital town hall meeting in Manhattan on the topic of “Talk is Cheap: Saving Lives, Ending AIDS, and Putting Our Money Where Our Mouth Is.” The Atlantic magazine and the MAC AIDS Fund sponsored the event.

As part of World AIDS Day events at the White House on December 2, Dr. Fauci gave a presentation that linked the issue of the gaps in the care continuum with impediments to ultimately curing everyone.

NIAID recently named the leadership group of the research units for the restructured HIV/AIDS clinical trial networks, which consist of five network leadership groups and 37 clinical trial units.

Dr. Fauci pointed out some key papers on HIV vaccines before giving an update on influenza. He touched on the H7N9 virus and NIAID’s research efforts, including two clinical trials. He also reported that FDA approved the first adjuvanted H5N1 influenza vaccine for our stockpile.

The number of cases of Middle East Respiratory Syndrome Coronavirus continues to rise. So far, there has not been sustained human-to-human transmissibility.

Antibacterial resistance is getting more attention, including from President Obama. The Institute is updating the document NIAID's Antibacterial Resistance Program: Current Status and Future Directions 2014.

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

Dr. Rotrosen welcomed back all of our recurring subcommittee members of the National Advisory Allergy and Infectious Diseases Council.

Dr. Rotrosen announced that Dr. Bert Maidment, associate director for Radiation Countermeasures Research and Emergency Preparedness, would present an “Overview of the Organization and its Accomplishments.” Dr. Maidment informed the subcommittee members that it was a pleasure to have Dr. William H. McBride, University of California, Los Angeles present “Novel Paradigms Emerging from the Centers for Medical Countermeasures against Radiation.” Dr. Francesca Macchiarini, program officer, next presented “Centers for Medical Countermeasures against Radiation, Predictive Biodosimetry, and A-Bomb Survivor Studies: It Takes a Broad-based Portfolio to Grow a Medical Countermeasure against Radiation.” This presentation was followed by Dr. David Cassatt, program officer, “Focused Radiological/Nuclear Countermeasure Product Development.” Dr. Andrea DiCarlo, program officer, presented “Research on Organ-Specific Medical Countermeasures to Mitigate/Treat Radiation Injury,” and Dr. Carmen Rios presented “Radiation Nuclear Countermeasures Program Small Business Innovation Research Update.”

The presentations were followed by three research concept clearances for review and approval by the Subcommittee.

Fiscal Year 2015 Research Concept Clearance

Centers for Medical Countermeasures Against Radiation: The goal of this initiative is to maintain a network of national research centers to develop effective and comprehensive medical countermeasures applicable to all subsets of the civilian population in the event of radiological or nuclear emergencies. Multidisciplinary basic and translational research will produce new techniques and devices to measure radiation exposure in the human body and follow biomarkers of tissue damage and recovery; and will develop novel therapies to minimize tissue damage, hasten tissue recovery, restore normal physiological function, and improve survival.

The subcommittee endorsed and unanimously approved this initiative.

Development of Medical Countermeasures to Mitigate and/or Treat Radiation-Induced Lung Injury After a Radiological/Nuclear Incident: The main objective of this initiative is to invite investigator-initiated proposals for the continued development of new mitigators/therapeutics (or improvement of existing drugs) to treat or mitigate radiation-induced lung injury due to a nuclear or radiation incident. Radiation exposure type, dose level, and dose rates proposed for study would be those that would be relevant following a terrorist incident or accidental exposure.

The subcommittee endorsed and unanimously approved this initiative.

Radiation/Nuclear Medical Countermeasure Product Development Support Services: The objective of this initiative is to provide additional funds to continue and expand nonclinical and clinical efforts for product development of radiation/nuclear medical countermeasure candidate drugs and biodosimetry devices for inclusion in the Strategic National Stockpile for use during a radiation emergency.

The subcommittee endorsed and unanimously approved this initiative.

IV. Report of the Division of Microbiology and Infectious Diseases–Carole Heilman, Ph.D., Director, DMID

Dr. Carole Heilman, director of the Division of Microbiology and Infectious Diseases (DMID), chaired the NIAID Microbiology and Infectious Diseases Council Subcommittee meeting on January 27, 2014. After welcoming the Subcommittee, Dr. Heilman referred to the branch chiefs and office directors to introduce new staff in their respective programs.

Update: DMID’s Biodefense Research Activities

Dr. Kurilla provided a broad overview of the Public Health Emergency Medical Countermeasures Enterprise (PHEMCE), which is led by the Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response (ASPR). The PHEMCE coordinates federal efforts to enhance chemical, biological, radiological, and nuclear threats (CBRN) and emerging infectious diseases (EID) preparedness from a medical countermeasure (MCM) perspective. Dr. Kurilla briefly described NIH’s role in this endeavor, as well as the roles of other PHEMCE member agencies.

Dr. Kurilla also described NIAID’s specific biodefense research efforts, spanning basic research on microbiology and immunology; applied research to develop medical countermeasures; and clinical research to evaluate candidate diagnostics, therapeutics, and vaccines. He reported that NIAID coordinates with industry and PHEMCE partners to ensure that the results of NIAID-supported research can be translated rapidly into safe and effective medical countermeasures. In particular, NIAID transitions the advanced research and development of high-priority medical countermeasures to the Biomedical Advanced Research and Development Authority (BARDA) with the eventual goal of Food and Drug Administration (FDA) approval, licensure, clearance, or authorization and possible inclusion in the Strategic National Stockpile.

He also described the wide array of preclinical and clinical services DMID supports, which span basic research all the way through to product development and serve a gap-filling role by providing specialized services and critical capabilities that companies, typically small but in some cases even large companies, are not able to support or sustain. Finally, he also reported on a number of recent successes in NIAID’s biodefense program, and highlighted several ongoing efforts.

FY 2015 and FY 2016 Concepts Presented for Clearance

Microbiology and Infectious Diseases Biological Resource Repository (MID-BRR) (FY 16): The goal of this concept is to renew support for a biological resource repository to include reference reagents for current DMID/NIAID high-priority pathogens (TB, malaria, influenza, antimicrobial resistance, biodefense, etc.) and other emerging/reemerging diseases, with flexibility to respond to future priorities. Specific activities include the acquisition, authentication, production, preservation, storage, and distribution of research and reference reagents to support the infectious disease research community. The Subcommittee recognized the outstanding accomplishments of the Research Resource Repository and agreed that it was a vital resource and central to NIAID’s mission. Program staff clarified that a single award is made to operate the repository. It was also noted that reagents are deposited from multiple sources, and all qualified registrants, including those who hold NIH grants as well as those who do not, can request the reagents. The deposits are authenticated and their quality is checked prior to distribution. There was a concern expressed by one DMID Subcommittee member that adventitious agents could potentially be present in some deposits. Program staff informed the Subcommittee that each reagent includes a certificate of analysis to document what testing has been done. Finally, program staff clarified that this repository is focused on research reagents only; no clinical samples are included. Overall, the Subcommittee was supportive of the continuation of the Repository and recognized its value to the scientific community. The concept was approved by a unanimous vote.

Advanced Development of Multiplex Diagnostic Platforms (FY 15): This concept would support the advancement of multiplex diagnostics using a focused, milestone-driven development strategy, taking advantage of new FDA guidances that pave the way for the development of a rapid multiplex platform capable of detecting both common infectious disease-causing pathogens and rare, low-prevalence pathogens. Program staff confirmed that the proposed program will focus on the advanced development of multiplex diagnostic platforms designed for use in a primary health care setting, and that these diagnostic tests would have the capability to detect both common and rare infectious disease-causing pathogens. Program staff noted that the FDA has agreed to work with NIAID during the development and implementation of this initiative. A representative from the FDA addressed a question from a Subcommittee member related to the FDA clearance process for multiplex diagnostics. Another Subcommittee member recommended that NIAID staff communicate with the CDC regarding this planned activity, and program staff agreed to do that. The Subcommittee unanimously approved the concept.

Targeting Therapeutics Development to Relieve Bottlenecks in Translational Research (FY 15): This concept would support lead identification, optimization, and preclinical testing to enhance the pool of candidate small molecule therapeutics available for future clinical development. The concept was well received by the DMID Subcommittee, and they recognized that the planned initiative could help bring new lead candidate drugs to reality. A question was raised regarding the support for a candidate product where manufacturing concerns exist, and it was clarified that any offeror would have to present a reasonable approach to address Chemistry, Manufacturing, and Controls (CMC) issues. It was also pointed out that BARDA offered scale-up manufacturing support for advanced development of products that would be beyond the scope of this concept. One Subcommittee member asked if there were any restrictions on the type of company that would be eligible to receive an award, whether it be a small business or ‘large pharma,’ and it was explained that any institution could apply with the caveat that in all cases, federal regulations for contracting would apply. Finally, there was a question regarding the desired target for a candidate therapeutic and whether host-directed therapeutics would be excluded. DMID program staff responded that no Mechanism of Action will be specified in the solicitation, therefore, all targets can be considered. The concept was unanimously approved by the Subcommittee.

The meeting adjourned at 2:55 p.m.

V. Joint Meeting of the AIDS Subcommittee, National Advisory Allergy, and Infectious Diseases Council and AIDS Research Advisory Committee (ARAC)–Carl Dieffenbach, Ph.D., Director, DAIDS

The AIDS Research Advisory Committee (ARAC) met on Monday, January 27, 2014, from 12:30 p.m. to 4:15 p.m., at the Natcher Conference Center on the NIH campus in Bethesda.

Participating members included: Jerome A. Zack (Chair), Adaora Adimora, Dázon D. Diallo, Earnest C. Hopkins, Jonathan Karn, Stephen W. Mason, Francine E. McCutchan, David H. O’Connor, Deborah Persaud, William G. Powderly, Georgia D. Tomaras, Chris Wilson, and Office of AIDS Research Advisory Council Committee (OARAC) Liaison, Myron Cohen; Ex officio members, Vicky J. Davey and Colonel Nelson Michael, also participated. NIAID representatives included Carl W. Dieffenbach, Emily Erbelding, Diana Finzi, Mary Marovich, Manizhe Payton, Sarah Reed, and Sheryl Zwerski. Mark Mueller served as executive secretary.

Welcome and Approval of Minutes
Jerome Zack, Ph.D., Chair, ARAC

Dr. Zack welcomed the ARAC members, DAIDS representatives, and guests. The minutes of the September 16, 2013, ARAC meeting were approved by Dr. Connie Celum, prior to her departure as chair of ARAC in 2013.

Office of AIDS Research Advisory Council (OARAC): Update
Myron S. Cohen, M.D., OARAC Liaison

Dr. Myron S. Cohen’s first meeting as OARAC liaison (replacing Dr. Wasserheit).
November 14, 2013, Council meeting agenda reviewed.

  • OAR portfolio
  • Strategic plans
  • Stakeholder and public input
  • Additional highlights and points
  • Social and Behavioral Research Seven priorities, e.g., engagement in care and innovative methods
  • Presentations–
    • AIDS-related malignancies, seven cancers
    • Global burden of diseases/conditions related to HIV such as neuro-AIDS, structural heart disease, associated coinfections, and advanced aging
    • AIDS vaccines and Towards a cure
    • Microbicides and therapeutics

Key points raised for discussion:

  • NIH and implementation science
  • Crisis points: women in sub-Saharan Africa (SSA); black men who have sex with men (MSM) in the U.S.
  • Mediocre methods to measure HIV prevalence and incidence
  • Cost: benefit of investments; support of the highest priorities

Noted Panel leadership changes:

  • John G. Bartlett, M.D., retired cochair at end of 2013, held position since panel’s 1996 creation. He is professor emeritus of medicine in JHU School of Medicine - Division of Infectious Diseases.
  • Roy M. Gulick, M.D., M.P.H., new panel cochair. Professor of medicine and chief of the Division of Infectious Diseases at Weill Medical College of Cornell University in NY City. Served as panel member from 2002 to March 2013.
  • Martin S. Hirsch, M.D., new panel cochair. Professor of medicine at Harvard Medical School, professor of Immunology and Infectious Diseases at Harvard School of Public Health, and physician at Massachusetts General Hospital.

Director’s Report
Carl W. Dieffenbach, Ph.D., Director, DAIDS

Thanked Jerome Zack for serving as new Chair.

Introduced new members:

  • William G. Powderly, M.D.
  • Earnest Hopkins
  • Chris Wilson, M.D.

Other new positions:

  • Alan Embry new BSP deputy director
  • Karl Salzwedel new BSP chief of PBRB
  • Deborah Birx nominated as Department of State Ambassador at Large and Coordinator of U.S. Government Activities to Combat HIV/AIDS Globally

Budget

Shared annual “report card” on what NIAID funded during previous fiscal year (FY 2013), particularly grants and paylines.

FY 2013

  • R01 payline finalized at 8th percentile.
  • New principal investigators (PIs) payline set at 12th percentile.
  • Success rate of AIDS and AIDS-related research project grants (RPGs) reached 20th percentile; the success rates of RPGs and R01s in NIAID/AIDS were comparable to those in NIH and NIAID overall.
  • 6 percent of funding was lost due to sequestration.

From 2012 to 2014, NIH as a whole received about a 2.3 percent decrease. Compared to the low FY 2013 post-sequester budget, the NIH and most institutes garnered an average increase of 3.4 percent in the FY 2014 omnibus budget. NIAID’s amount reflects the transfer of $27 million from the National Institute of Mental Health (NIMH) and $10 million from the Office of AIDS Research to support cure-related HIV/AIDS research, and hence the greater increase of 3.9 percent.

With the omnibus approved, the central focus can be on executing the scientific research agenda. The debt ceiling is a potential budget roadblock for FY 2014. The initial end of the debt ceiling suspension may be pushed beyond the originally scheduled February 7 date. NIAID is taking a conservative posture since no guidance has been received for FY 2015’s budget. Thus, NIAID program initiatives remain at levels that were previously cut by up to 20 percent to sustain investigator-initiated awards. Fiscal policies will be revisited when more direction is given on the FY 2015 budget picture.

President submits his FY 2015 budget to Congress on March 4.

Question and answer period: NIAID sets a more liberal R01 payline for new and early-stage investigators to permit greater likelihood of funding. Aim is to increase number of new investigators. Payline for new investigators is determined by their ranking among all grants and thus, the payline is sometimes variable. Program project grants are funded from a separate budget, and NIAID/DAIDS is highly selective of the grants reviewed.

Programmatic Updates

Five new Leadership Awards were announced on December 9, 2013huge milestone.

  • AIDS Clinical Trials Group (ACTG)
  • HIV Prevention Trials Network (HPTN)
  • HIV Vaccine Trials Network (HVTN)
  • International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network
  • Microbicide Trials Network (MTN)

Thanked participating cofunding institutes and centers: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIMH, National Institute on Drug Abuse, National Institute of Neurological Disorders and Stroke, and the National Cancer Institute (NCI).

These awards should expand the scope of the HIV/AIDS clinical trials networks’ current activities to include treatment and prevention of other diseases, namely, tuberculosis, hepatitis, and malaria—that are of significance to people HIV infected or at risk, both domestically and internationally. Continued restructuring of the Networks is designed to increase collaboration, create transparent mechanisms for network leadership to solicit and support ideas from the research community, and develop a means for external researchers to tap into the networks’ clinical trial infrastructure and capacity. Each Network’s seven-year vision will be discussed at the joint Strategic Working Group (SWG)/ARAC meeting January 28-29.

As of this year:

  • 37 Clinical Trial Unit (CTU) awards have been made; CTUs were reduced from 72 to 37.
  • The clinical trials units and clinical research sites (CTU/CRS) are funded separately.
  • 109 CRSs in existence.

Noted overall alignment of NIH/NIAID goals and HIV/AIDS strategic goals, which are to continually develop and support research infrastructure and scientific expertise that enables innovative approaches to HIV/AIDS research such that: 1) effective preventive tactics are defined, including a preventive HIV vaccine; 2) a cure is afforded; 3) HIV-associated infections, especially TB and hepatitis are treated and prevented; and 4) partnerships are established to implement discovered scientific interventions. DAIDS works with NIH Office of AIDS Research (OAR) in these endeavors.

White House announced new NIH initiative in December 2013 to advance research for an HIV cure. NIH plans to increase investment in HIV cure research over FY 14-FY 17. AIDS research dollars will shift from lower priority areas to address nascent opportunities in cure research through solicited and unsolicited mechanisms, focusing on areas that include basic research in understanding latency and persistence, discovery of assays and biomarkers among others. Internal discussion is ongoing about developing an intramural research plan, oriented toward a “bench to bedside” strategy. A Request for Information (RFI) will be published this week to solicit feedback from the research community about how to pursue efforts in Cure research; a follow-up event is planned for early spring 2014.

Dr. Dieffenbach responded to a question about how the redirected $100 million in AIDS research funds will be spent by stating the redistribution will be mainly determined by scientific opportunity and funding flexibility will be maintained.

NIAID/DAIDS is moving to a brand new building on Fishers Lane in Rockville in April/May. NIAID extramural will be consolidated from the current three buildings into one, which will also house the NIH OAR and a portion of the Office of Human Resources.

Future meetings proposed:

  • June 2, 2014, ARAC
  • June 3-4, 2014, AVRS
  • September 15, 2014, ARAC
  • September 16-17, 2014, SWG (tentative)

Programmatic Overview: Key Accomplishments and Future Directions

Basic Sciences Program (BSP)
Diana Finzi, Ph.D., Director

Dr. Finzi gave a broad overview of the BSP, noting a large program challenge is to stay current with the HIV/AIDS epidemic and push the field toward novel discoveries. The BSP is composed of three branches, primarily centered on the early ideas or the seeds of basic research: Epidemiology (which also includes an Ethics Team), Pathogenesis and Basic Research, and Targeted Interventions (Applied Research).

The BSP oversees a large portfolio of unsolicited grants in all three areas. It also hosts the MACS and WIHS (two large cohorts of HIV infected and uninfected people), IeDEA (an international epidemiologic database that follows infected people), several contracts including the Reagent Program Contract (which provides reagents to the scientific community, free of charge), the Martin Delaney Collaboratories (NIAIDs first major investment dedicated towards cure research), and The Centers for AIDS Research (CFAR) program. The CFARs were formed to support local priorities, and thus each CFAR has a particular identity. Importantly, the CFARs have some flexibility to use pilot funds to begin new projects and serve as a developmental resource of new and young investigators, one of the great strengths of CFARs.

Dr. Finzi presented research highlights focusing first on two recent papers, outgrowths of BSP Epidemiology Branch, that demonstrate the great progress made in decreasing mortality by treating HIV disease:

  • PLOS One paper by Samji et al. Life expectancy with HIV can be the same or longer than non-infected individuals if treated before the CD4 level < 350 and healthcare is sustained.
  • Journal AIDS by Wada et al, Death rate from non-AIDS defining illnesses is similar in HIV-positive and HIV-negative individuals enrolled in the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS).

She then described the rapid growth in the restriction factor area and in the discovery of new gene editing enzymes such as the clustered regularly interspaced short palindromic repeats associated with endonuclease Cas9 (CRISPR/Cas9) system. She emphasized the need to exploit these rapidly evolving areas towards finding new ways to inhibit HIV replication.

In the area of Cure research, she emphasized the need to develop better essays to quantify latently-infected cells, citing the recent Cell paper by Dr. Robert Siliciano’s lab:

Replication-Competent Noninduced Proviruses in the Latent Reservoir Increase Barrier to HIV-1 Cure. (Volume 155, October 24, 2013)

The paper demonstrates that the current “gold standard” assay to measure Quantitative Viral Outgrowth Assay (QVOA) underestimates the frequency of latently infected cells, and that even the best “shock and kill” strategies, (largest BSP Cure research investment), may not reactivate all virus.

Dr. Finzi concluded suggesting that, in the Cure arena, the field needs: better strategies to target residual reservoirs (with particular attention focused on the problem of incomplete reactivation and proliferation of memory cells), better characterization of cells harboring latent provirus, and better targeting strategies.

Concept Review (approval requested)

Basic Research on HIV Persistence
Karl Salzwedel, Ph.D., Chief, Pathogenesis and Basic Research Branch, BSP

The objective of this concept is to address the need for more basic research to better understand the mechanisms that govern the persistence of residual HIV reservoirs during antiretroviral therapy and to identify new targets and strategies for eradicating persistent HIV reservoirs and overcoming latency. This initiative is proposed as an initial step in implementing the President’s plan to redirect funding towards HIV cure research.

  • New concept.
  • Supported by PAR (R21, R01) mechanism. Three receipt dates/year.
    • PAR is a program announcement with set aside funds wherein applications will be reviewed by a special emphasis panel.
  • Duration of award.
    • Two years for R21.
    • Up to five years for R01.
  • Estimated number of awards will be approximately eight R21s and ten R01s.
  • First year total cost for the initiative will be up to a combined $7 million.
  • Establishing set-aside funds for basic research on HIV persistence will help attract new and early-stage investigators with innovative ideas to the field.

Key questions this concept may address towards long run design strategy:

  • What are the sources of rebounding virus after removing antiretroviral therapy?
  • Is it reactivated, latent virus or a low level of ongoing HIV production?
  • What cell types does virus rebound from?
  • Are all functional proviral DNAs capable of rebound?
  • Can latency be reversed without global activation of T cells and toxicity?
  • What is required to achieve immune control of viral rebound?

Reviewers, Dr. Karn and Dr. Zack, agreed that the program is important, and is the “only initiative with a purely basic focus in the current portfolio.” At this time, they suggested focusing on R01s and R21s. They expressed enthusiastic support and approval of the concept. Dr. Karn said there is strong demand from basic scientists attracted to the cure arena. Dr. Zack said new basic scientific information is required to move the field forward if current approaches to eradicate HIV fail. During the questions and answers, Dr. Salzwedel stated that he expects a broad response to this funding opportunity announcement (FOA), much of which will be laboratory-focused and include animal models. The Division plans to publish the FOA within the next two months.

The ARAC members expressed support for the concept and marked their ballots.

Programmatic Overview: Key Accomplishments and Future Directions (Continued)

Therapeutics Research Program (TRP)
Sarah Read, MD, Director

Dr. Read gave a broad overview of the TRP and summarized the research goals as being focused on the planning, implementation, and evaluation of a scientific agenda for preclinical development and clinical testing of therapies to treat or cure HIV infection, its co-infections (e.g., tuberculosis and hepatitis C) and co-morbidities. TRP is divided into four branches: HIV Research, Drug Development and Clinical Sciences, Complications and Coinfections Research, and Tuberculosis Clinical Research.

The TRP portfolio includes 131 active grants (including ACTG and INSIGHT) and many research support contracts such as immunology quality assurance (QA), virology quality assurance, and clinical pharmacology QA and QC (quality control) contracts among others. Dr. Read reviewed activities within the research focus areas, which include novel HIV therapeutics, cure of HIV infection, comorbidities in the setting of suppressive antiretroviral therapy (ART), and coinfections, e.g., tuberculosis (TB) and hepatitis C (HCV).

Given that there are now over 30 approved antiretroviral agents, as well as fixed-dose combinations, for the treatment of HIV, a major research focus of the Program is now cure of HIV, and TRP is coordinating with BSP on this research effort including in the following areas:

  • Reactivation strategies (e.g., Vorinostat, Romidepsin)
  • Mechanisms of enhanced cell-mediated immunity
  • Broadly neutralizing antibodies
  • Cure in pediatric populations
  • Mechanisms for resistance to HIV infection (e.g., transplantation with delta-32 homozygous cord blood donor cells)

Ongoing treatment strategy trials were reviewed:

  • ARDENT (A5257)–to be presented at CROI.
  • OPTIONS (A5241)–NRTI sparing regimen is non-inferior to NRTIs for treatment of experienced patients. Long-term follow up to be presented at CROI.
  • SELECT (A5273)–trial of second line regimens, in follow up.
  • MULTI-OCTAVE (A5288)–trial of third line regimens, enrolling.
  • START–strategy trial of when to start therapy; in follow up until late 2016.

TRP is increasing focus on therapeutics with promise for extended dosing, with a goal of no more than once a month dosing. In addition, there is interest in broadly neutralizing Abs as therapeutics. TRP is working in coordination with the VRC on a number of trials withVRC01.

Chronic immune activation/inflammation has been linked to poor clinical outcomes as exemplified by comorbidities, including cardiovascular and cerebrovascular disease, osteoporosis, and other end organ and metabolic dysfunctions. TRP is supporting a number of studies examining mechanisms contributing to immune activation, as well as therapeutic trials to treat immune activation.

Also discussed was the current interest and research into HIV coinfections that extend beyond TB and HCV to other common complications like cryptococcosis, malaria, HPV, and Kaposi’s sarcoma.

During the questions and answers, Dr. Read stated that TRP works closely with other NIAID entities (e.g., DAIT, DMID) and other NIH institutes (e.g., NHLBI, NCI) to coordinate research efforts in areas of overlapping interest (e.g., TB, noninfectious comorbidities, and cancer).

Concept Review (approval requested)

Early Phase Therapeutic Vaccine and Biologically-Based Antiviral Therapy Teams
Anthony J. Conley, Ph.D., Health Scientist Administrator/Project Officer, TRP/TIB

The objective of this concept is to develop and evaluate in clinical studies, therapeutic vaccine or antibody-based products that provide new immune effector functions, for use in HIV sustained remission/eradication trials. This concept represents a new initiative to be supported by the N01 contract (Research and Development) mechanism. The duration of the award is seven years, with the estimated number of awards between two and three.

This initiative underscores the shift in thinking regarding an HIV cure, particularly toward developing interventions targeting activated HIV reservoir cells, with a goal of immune based reduction of latent infection and quiescent reservoirs. Currently, no vaccine products have been proven to elicit defined anti-HIV immune effector functions in infected humans. The initiative will support product development to fill that gap and allow critical evaluation of therapeutic vaccine products or vectored anti-HIV antibodies. In contract work toward a therapeutic product, seven years may not be sufficient, and the time may need to be extended.

The reviewers (Mason and Persaud) recommended approval and noted the initiative is “extremely timely.” During the questions and answers, Dr. Conley responded that the rationale for using the contract support mechanism was to fast-track product development and to permit careful monitoring of deliverables. The idea is to support products that may be useful as therapeutic agents.

The ARAC members expressed support for the concept and marked their ballots.

Programmatic Overview: Key Accomplishments and Future Directions (Continued)

Prevention Sciences Program (PSP)
Sheryl Zwerski, MSN, CRNP, Acting Director

Ms. Zwerski provided an orientation to PSP, focusing on Program objectives, major projects, and the future agenda. PSP has four branches: Clinical Microbicide Research; Clinical Prevention Research; Maternal, Adolescent, and Pediatric (recently joined PSP); and Preclinical Microbicide and Prevention Research. Network accomplishments were acknowledged along with notable accomplishments in the preclinical and clinical programs.

Reviewed IMPAACT, HPTN, and MTN.

IMPAACT plans major revisions to network science generation processes and improvement in the overall operational efficiency is underway. The Infant Cure Study is being developed and will open soon; robust community engagement will also continue.

The MTN-020/ASPIRE (A Study to Prevent Infection with a Ring for Extended Use)–is a Phase III safety and effectiveness trial of a vaginal ring containing the antiretroviral Dapivirine that was launched in August 2012 and will enroll about 3,476 women at 15 sites across four countries in Africa. The Dapivirine vaginal ring was developed by the International Partnership for Microbicides. Dapivirine (25 mg) is administered in a silicone elastomer vaginal matrix ring. When inserted once every four weeks, it will be evaluated for preventing HIV infection among healthy, sexually active HIV-uninfected women.

In conclusion, the future for PSP includes the following: 1) building a pipeline of sustained release products for prevention; 2) understanding better the context in which studies are being conducted, both at the macro- and micro-environmental levels; 3) integrating behavior into all study phases, including preclinical 4) improving testing strategies for those most at risk; 5) improving linkage and engagement in care for HIV-positives; 6) formulating integrated prevention strategy packages that are appropriate, acceptable, and cost-effective for target populations; 7) evaluating safety, PK/PD of ARVs for pregnant women, children, adolescents; 8) partnering to develop, support, and accelerate efforts in infant cure; 9) partnering to transform TB diagnosis, prevention, and treatment for pregnant women and children.

During the questions and answers, Ms. Zwerski noted known disparities among the U.S. population at risk for HIV infection (e.g., differences between black and white women; between white and Hispanic women) and acknowledged the dilemma in how to resolve or approach the problem. Dr. Dieffenbach suggested pulling together an internal team for discussion and ideas about the disparity problem and reporting on the outcome at a future ARAC meeting. The prevention cascade for HIV negatives remains a work in progress. Success with HIV negatives requires better understanding of appropriate assessment of who is most at risk of HIV infection and those efforts will necessitate a collaborative effort with multiple partnering organizations.

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

Dr. Marovich discussed advances in HIV-1 vaccine design and future directions of the VRP. In particular, she highlighted recent data on the HIV-1 envelope trimer structure and related immunogen design with regard to elicitation of broadly neutralizing antibodies (bNAbs) against HIV; vaccine-elicited non-neutralizing Abs; and CD8-T cell immunogens—all with regard to protection and/or control in primates.

Future Program directions encompass the following: 1) translation of protective vaccines from nonhuman primates (NHPs) to humans; 2) acceleration of HIV envelope (Env) immunogen production and testing; and 3) vaccine elicitation of balanced immune responses—favoring protection.

Three important papers published in late 2013:

Two in Science, Dec 20, 2013, by Julien et al. and Lyumkis et al, present molecular anatomical analyses of “near native” trimeric structure of HIV envelope and optimization of immunogen design to induce bNAbs.

One in Nature Apr 25, 2013. By Liao et al. reported longitudinal study of African patient, from time of infection onward, describing co-evolution of bNAbs with the founder virus.

Critical challenge in vaccine development remains the identification and translation of neutralizing epitopes into immunogens. Mapping of the immunogens must be followed by curtailing the host control mechanisms that might prevent the emergence of bNAbs. The good news is highly mutated bNAbs do develop, albeit slowly, in a subset of HIV-infected humans.

Reviewed data from Dr. Ronald Desrosiers’ laboratory concerning protective non-neutralizing antibodies. Using the closely related herpes virus of monkeys referred to as the rhesus monkey rhadinovirus (RRV) for the vector, inserts from the simian immunodeficiency virus (SIV) were cloned in—full length gp160, gag, and rev/tat/nef. Although no protection was conferred to the vaccinated NHPs upon challenge, interestingly, no Env Abs were induced either. After optimization of env expression in the RRV vector, the vaccinated NHP showed good protection against SIV239 intravenous (IV) challenge. Importantly, the NHP serum did not neutralize the challenge virus, suggesting the protection might be due to systemic nonneutralizing Abs in addition to the persistently high CD8+ T cell responses to immunodominant epitopes elicited by the redesigned RRV vaccine.

The translational research component in VRP has several products moving through the pipeline into the clinic. The Vaccine Translational Research Branch (VTRB) is exploring alternative methods to accelerate Env immunogen production. Consistent with the challenges in vaccine research, the VRP has several workshops planned for 2014 to include strategies in Ab affinity maturation, variables in NHP vaginal and mucosal HIV transmission, and glycans in immunity among others.

During the questions and answers, Dr. Marovich indicated prioritization is key to making critical choices in product development; the prioritization is influenced by NHP data, as well as the viability and stability of candidate products. Dr. Dieffenbach suggested fundamental to progress is that each set of products must be better than the previous ones, and vaccine development is built on the lessons learned from prior endeavors (e.g., phase I and II studies) that inform new directions.

Public Comment

None.

Adjournment

Dr. Zack thanked the ARAC members and other attendees and adjourned the meeting at approximately 4:45 p.m.

VI. Adjournment

The meeting of the Council adjourned at 4:45 p.m., on Monday, January 27, 2014.

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

5/6/2014
Date
-s-

Matthew Fenton, Ph.D.

Executive Secretary

National Advisory Allergy and Infectious Diseases Council

Director, Division of Extramural Activities

National Institute of Allergy and Infectious Diseases

4/17/2014
Date

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

Last Updated May 22, 2014

Last Reviewed May 22, 2014