The 174th meeting of the National Advisory Allergy and Infectious Diseases Council (NAAIDC) convened at 10:30 a.m. on Monday, June 3, 2013, in Conference Rooms E1/E2, Building 45, National Institutes of Health. Dr. Anthony S. Fauci, director, National Institute of Allergy and Infectious Diseases (NIAID) presided as chair.
In accordance with the provisions of Public Law 92-463, the meeting was open to the public from 10:30 a.m. to 11:45 a.m. and from 1:00 p.m. to 4:35 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:
Ex Officio Members Present:
Ad Hoc Members Present:
Council Members Absent:
Ex Officio Members Absent:
Dr. Rima Khabbaz
NIAID Senior Staff Present:
Table of Contents
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 3,464 research and training applications with primary assignment to NIAID for a requested amount of $1,412,391,162 in first-year direct costs and recommended approval of 1,242 applications with $420,462,539 in first-year direct costs.
Dr. Fauci opened the Council session by welcoming visitors to the meeting. He introduced two new Council members who were unable to attend the February meeting, Ms. Maria Acebal and Brigadier General Joseph Carvalho. Ms. Acebal is a consultant, attorney, and former CEO of the Food Allergy and Anaphylaxis Network, and Brigadier General Joseph Carvalho is commander of the U.S. Army Medical Research and Materiel Command at Fort Detrick, a physician, and ex officio Council member representing the Department of Defense.
Dr. Fauci welcomed three ad hoc Council members, Dr. Olaf Schneewind, chair, Department of Microbiology, University of Chicago; Dr. Alan Magill, director of Global Health, Bill and Melinda Gates Foundation; and Dr. David Cooper, professor of surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh.
Four Council members, Drs. Belshe, Bond, Scantlebury, and Siber, were unable to attend the meeting.
Council considered the minutes of the February 4, 2013, meeting and approved them as written.
Dr. Daiwai Lind has been appointed as the associate director for bioinformatics, DAIT.
In the Vaccine Research Program, DAIDS, Dr. Libby Adams was selected as chief of the Clinical Research Branch and Dr. Michael Pensiero was named chief of the Translational Research Branch.
Dr. Fauci announced two new appointments in the Office of the Director, Division of Extramural Activities. Dr. Mario Cerritelli is director of the Office of Knowledge and Educational Resources and David Alperin is the director of the Office of Committee Management.
The Office of Science Management Operations has two new branch chiefs. Melinda Haskins is chief of the Legislative and Correspondence Management Branch, Office of Communications and Government Relations, and Jennifer Gibbons is chief of the Extramural Administrative Management Branch, Office of Administrative Services.
Dr. Jon Lorsch was selected as the new director of the National Institute of General Medical Sciences.
Dr. Fauci paid tribute to four prominent scientists who recently passed away. Dr. C. Everett Koop, who served as the 13th Surgeon General of the United States from 1982 to 1989, died in February. Dr. Sheldon Cohen died in March. From 1977 to 1988, he led the NIAID Immunology, Allergic, and Immunologic Diseases extramural program, which is now known as DAIT. Dr. Kuan-Teh Jeang, chief of the Molecular Virology Section, Laboratory of Molecular Microbiology, passed away suddenly in January. Dr. Paul Black, a program officer in the Targeted Intervention Branch, DAIDS, died in March.
Dr. Fauci acknowledged four NIAID scientists who have been elected as fellows of the American Academy of Microbiology, Drs. Cliff Lane, Marshall Bloom, Phil Murphy, and Steve Holland.
In March, the U.S.-Japan Cooperative Medical Science Program held its 15th International Conference on Emerging Infectious Diseases in the Pacific Rim in Singapore. Council member Dr. Diane Griffin chaired the scientific committee that organized the conference.
NIAID joined in a memorandum of understanding with the World Health Organization and the Bill and Melinda Gates Foundation to cooperate on activities related to the Decade of Vaccine Collaboration.
On April 11, Dr. Wafaa El-Sadr delivered the 2013 James C. Hill memorial lecture entitled “The Global Response to the HIV Epidemic: Lessons Learned, Lasting Legacy.”
On March 14, Dr. Fauci joined other NIH institute directors in a panel discussion on global health at the fourth annual meeting of the Consortium of Universities for Global Health, held in Washington, D.C.
On May 21 at the Institut Pasteur, Dr. Fauci gave the opening lecture entitled “Thirty Years of HIV Science: Imagine the Future,” which celebrated the 30-year anniversary of the discovery of HIV by scientists at the Institut Pasteur.
The President signed into law the FY 2013 budget on March 26, 2013. NIH received an overall budget decrease of 5.5 percent.
Dr. Fauci summarized NIAID’s financial management plan for FY 2013. NIAID will support a payline to the 8 percentile for established investigators and the 12 percentile for new and early-stage investigators. NIAID plans to cut competing, unsolicited awards by an average of 6 percent, competing research initiatives by up to 20 percent, and noncompeting grants and research and development contracts by an average of 6 percent. NIAID’s estimated success rate will be between 19 and 21 percent.
On April 10, 2013, the President presented his FY 2014 budget request to Congress, which includes a compromise that replaces the across-the-board spending cuts with a combination of program reductions and new revenues. Because the FY 2013 budget was late and uncertain, the President’s FY 2014 budget request used FY 2012 as the comparable budget. The FY 2014 budget request provides NIH with a 1.5 percent increase over FY 2012. NIAID would receive a 2.2 percent increase over FY 2012 primarily because of the shift of approximately $27 million from NIMH to expand collaborative efforts for integrating behavioral research more effectively into biomedical approaches to enhance prevention and treatment.
Then Dr. Fauci compared the enacted FY 2013 budget with the FY 2014 President’s budget request. This comparison provides NIH with a 7.5 percent increase and NIAID with an 8.2 percent increase over the FY 2013 enacted level.
On February 8, Dr. Francis Collins, Dr. Fauci, and other NIH leaders met with Senator Ben Cardin during his visit to NIH to discuss budget issues and their impact. On February 20, Senator Barbara Mikulski held a press conference at the NIH Clinical Center and afterwards met with Dr. Collins, Dr. Fauci, and other NIH institute and center directors to express her support.
On March 18, Dr. Collins, Dr. Fauci, and other NIH leaders met with Representative Andy Harris to discuss the long-term implications of budget issues on NIH research priorities.
On May 7, Dr. Collins and Dr. Fauci met with House Majority Whip Kevin McCarthy to discuss valley fever research.
On May 9, House Majority Leader Eric Cantor and a bipartisan Congressional delegation visited the NIH Clinical Center and met with Dr. Collins, Dr. Fauci, and other NIH institute directors to discuss the importance of continued investment in NIH research.
On February 19, minority staff to the House Committee on Energy and Commerce toured the NIH Clinical Center and NIAID Vaccine Research Center to learn more about our research on HIV/AIDS, including vaccine development.
On February 26, Dr. Fauci participated in a Congressional staff briefing with Ambassador Eric Goosby, U.S. global AIDS coordinator. They discussed NIH research on HIV/AIDS and its role in the “PEPFAR Blueprint: Creating an AIDS-Free Generation.”
On April 30, Dr. Fauci joined Dr. Gail Cassell and Dr. John Gallin in an American Society for Microbiology Congressional briefing on the perpetual challenge of emerging and reemerging infectious diseases.
Dr. Collins testified on May 15 before the Senate Labor-HHS Appropriations Subcommittee on the President’s FY 2014 budget request. Dr. Fauci also testified along with several other institute directors.
Dr. Fauci recognized other NIAID staff members who participated in Congressional activities over the last several months.
Dr. Fauci explained how a baby born of an HIV-infected mother who did not receive any prenatal care or treatment was treated and “cured” of HIV infection. He also summarized results of several other HIV/AIDS studies, some with promising results and some with disappointing results.
In January, NIH hosted a meeting to discuss the framework for decision making about research with highly pathogenic avian H5N1. The framework was published in the March 1 issue of Science. Also, an HHS group will now review all research related to highly pathogenic avian H5N1.
Other areas that Dr. Fauci gave brief updates on include the MERS-Coronavirus, H7N9 influenza, universal influenza vaccine, antimicrobial resistance, malaria, tuberculosis, RSV, and rotavirus.
Dr. John Mascola presented an overview of the Vaccine Research Center’s (VRC) main scientific priorities, HIV-1 vaccine to prevent infection, vaccines for emerging diseases or diseases of public health interest, and vaccine platforms to induce immunity.
He summarized the results of the HVTN 505 study and explained why NIAID discontinued the study. The VRC plans to reemphasize efforts on newer vaccines designed to induce cross-reactive neutralizing antibodies.
Dr. Mascola also gave brief updates on VRC’s influenza vaccine effort and respiratory syncytial virus.
Dr. Rotrosen welcomed all of our recurring and new subcommittee members of the National Advisory Allergy and Infectious Diseases Council. Dr. Rotrosen announced that Dr. Dawei Lin joined DAIT as associate director for bioinformatics. Prior to coming to NIH, Dr. Lin was the founding director of the Bioinformatics Core at the University of California Davis Genome Center.
Dr. Rotrosen noted that Dr. Nasrin Nabavi, program officer in the Transplantation Immunobiology Branch would present an overview on the “Immunobiology of Xenotransplantation Program.” In addition, Dr. Rotrosen took the opportunity to inform the subcommittee members that it was a pleasure to have Dr. David Cooper, M.D., Ph. D., professor of surgery at the Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, present on “Progress Toward Fulfilling the Immense Potential of Xenotransplantation.”
Following the presentations, Dr. Rotrosen announced there were three research concept clearances for review and approval by the subcommittee.
Immunobiology of Xenotransplantation: This initiative will support new or competing renewal proposals focused on: (1) development or optimization of models of porcine to nonhuman primate xenotransplantation of islet, kidney, heart, lung, or liver and (2) defining and ultimately resolving the physiological and immunological barriers of successful xenograft application in clinic. The research focus is the development of pre-clinical porcine to nonhuman primate (NHP) models of islet, kidney, heart, lung, or liver xenotransplantation. The long-term goal of this program is to develop novel and effective strategies for application of xenotransplantation in the clinic.
The subcommittee endorsed and unanimously approved this initiative.
Resources to Assist Investigations in Primary Immunodeficiency Diseases: The purpose of this initiative is to provide resources to support investigators performing research into primary immunodeficiency diseases. The resources provided by the U24 fall into the following broad categories: a registry of individuals with primary immunodeficiency disease; a repository of reagents and other materials to aid primary immunodeficiency disease research; and educational resources to provide training, disseminate information, and encourage collaborative research on primary immunodeficiency disease.
Development of Sample Sparing Assays for Monitoring Immune Responses: The objective of this initiative is to accelerate development of sample sparing assays that will broaden availability of well-characterized tools for monitoring immune responses in basic and clinical research. The newly developed assays would be valuable for gaining further insights into the fundamental understanding of the immune system, but would be equally important for immune monitoring in healthy as well disease conditions such as allergy, asthma, autoimmunity, primary immunodeficiency, transplantation, and infection.
This program will solicit applications with the potential to support immunological research to develop innovative and validated sample sparing assays that lead to the maximum use of the sampled material and/or a significant reduction in the amount of sample required. Assays that will be supported could include, but are not limited to, novel approaches for monitoring antigen specific responses and various cell populations, assessments of T and B regulatory cells, cytokine and signaling networks, gene function/expression studies, and proteomics. Techniques that integrate multiple measurements might be especially valuable for a sample-sparing concept and will be encouraged. Integration of many datasets obtained from the same sample could lead to a better understanding of immune function and at the same time reduce the amount of sample material needed for analysis.
Dr. Carole Heilman, director of the Division of Microbiology and Infectious Diseases (DMID), chaired the NIAID Microbiology and Infectious Diseases Subcommittee meeting on June 3, 2013. She reported that staff would present additional FY 2015 concepts for clearance at today’s meeting, including several partnerships concepts and two international research concepts. She informed the subcommittee that the partnerships program would soon undergo an assessment to look at the program’s impact, and that she would keep the subcommittee apprised of the outcome. She also elaborated on a report provided by Dr. Fauci in the open session, further describing DMID’s long-term role as part of a public/private collaboration that developed and tested the ROTAVAC vaccine, a new rotavirus vaccine that consists of a strain of the virus that was isolated, manufactured, and tested in India. The ROTAVAC trial represents a significant victory for India’s scientific community.
Dr. Heilman also reported on two recent workshops exploring new, exciting areas of science. First, DMID staff helped organize the “In Vitro Tissue Models for Infectious Diseases” workshop, which brought together the infectious disease and tissue engineering scientific communities to discuss the study, development, and implementation of new in vitro models for infectious diseases. Second, DMID collaborated with FDA’s Center for Biologics Evaluation and Research to provide a forum for the exchange of information, knowledge, and experience between CBER, NIAID, and the scientific-medical community regarding clinical development issues for fecal microbiota transplantation. Reports of both workshops will be posted on the NIAID Web site in the coming months.
Dr. Heilman provided further details on the newly-awarded NIAID Antibacterial Resistance Leadership Group to Duke University, a collaborative effort under the guidance of Dr. Vance Fowler at Duke and Dr. Chip Chambers at UCSF. In addition to the co-principal investigators, the program supports a consortium of scientists around the country with demonstrated expertise addressing the problem of antibacterial resistance. A meeting with the investigators is scheduled later this month to discuss structure and processes of this new network.
Finally, Dr. Heilman reported that Dr. Lee Hall would provide an update on DMID’s malaria portfolio, and Dr. Maria Giovanni would discuss NIAID and NIH Big Data efforts; both reports are in keeping with DMID’s commitment to provide regular programmatic updates to the subcommittee.
Following her remarks, Dr. Heilman introduced today’s two ad hoc members, Dr. Alan Magill, director of the malaria program at the Bill and Melinda Gates Foundation, and Dr. Olaf Schneewind, Louis Block Professor and Chairman, Department of Microbiology, University of Chicago. Dr. Schneewind also serves as director of the NIAID Great Lakes Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases Program. She then referred to the branch chiefs and office directors to introduce new staff in their respective programs. Dr. Michael Kurilla, director of DMID’s Office of Biodefense, Research Resources, and Translational Research, introduced new staff members who have recently joined DMID as part of the Concept Acceleration Program, or CAP. CAP was created as a result of the Department of Health and Human Services Medical Countermeasure Review to move forward novel concepts for new medical interventions, including vaccines, therapeutics, and diagnostics.
Dr. Lee Hall, chief of DMID’s Parasitology and International Programs Branch, provided a brief global malaria situation analysis, described the key objectives and priorities of DMID’s malaria program, and reported on several recent and notable activities and selected scientific advances. He noted that the objectives of the program are to improve the understanding of malaria pathogenesis, epidemiology, and transmission while at the same time identifying and developing interventions to reduce the burden of malaria with the goal of controlling, eliminating, and eventually eradicating the disease. Dr. Hall described DMID’s International Centers of Excellence for Malaria Research program, which was established in 2010 and supports multidisciplinary research centers spanning all of the major malaria endemic areas of the world. In closing, he noted that the landscape for malaria research and development has changed substantially as a result of recent progress in malaria control, and that NIAID will maintain a robust and flexible malaria research portfolio to address evolving scientific opportunities, biomedical research needs, and global public health concerns.
Dr. Maria Giovanni described DMID’s bioinformatics efforts, noting the division’s long-term commitment to the establishment and support of bioinformatics capacity infrastructure, which includes data management, data analysis, and tools development. She reported that bioinformatics activities are incorporated and ongoing in all DMID genomics programs, and are supported in many other DMID-funded programs, such as the NIAID Centers of Excellence for Influenza Research and Surveillance and International Centers of Excellence for Malaria Research networks. Dr. Giovanni also described NIH’s new Big Data to Knowledge (BD2K) initiative, which spans all ICs and is designed to maximize the value of biomedical data by making it accessible and useful for the entire biomedical research community. The term ‘Big Data’ is meant to capture the opportunities and challenges facing all biomedical researchers in accessing, managing, analyzing, and integrating datasets of diverse data types.
Concept Clearance: Three distinct partnerships concepts were presented:
The subcommittee strongly supports the DMID Partnerships Program, noting that it provides an important mechanism to assist the academic and industrial communities in translational and preclinical product-related research and development efforts. Additionally, the program is viewed as critical in stimulating innovation in translational efforts, vetting of candidate products, and leveraging resources within the industrial community. Moreover, the subcommittee appreciates the dual mechanism approach to support early-stage and later-stage partnerships activities: the R21/R33 mechanism for high-risk early-stage translational activities and the milestone-driven R01 mechanism for later-stage preclinical and product development activities. The subcommittee favored the requirement for substantive investment by an industrial partner in R01 partnerships projects.
One subcommittee member asked about coordination of DMID product development-focused activities with related and/or parallel objectives supported by other federal programs. Program staff explained that multiple conduits of interagency communication are maintained and that relevant program staff play a role to ensure integration in overarching efforts. Another subcommittee member asked how resources and objectives are partitioned between the partnerships and SBIR/STTR programs. Program staff explained that the two programs differ significantly in terms of applicant eligibility, scope, and budget. The partnerships program was described as complementary to the SBIR/STTR program and open to a broader community including foreign researchers/institutions ineligible for SBIR/STTR support.
The subcommittee strongly supported the prioritized research foci of the individual partnerships concepts. The three concepts were unanimously approved.
Concept Clearance: International Research in ID and AIDS (IRID-A)–This program aims to support the development of local scientific expertise and to increase research capacity at NIAID international sites in resource-constrained countries. The subcommittee recognized the importance of the IRIDA program in the DMID international portfolio. The IRIDA program provides a discrete funding opportunity for foreign scientists from resource-constrained countries. Members commented on the productivity of awardees as noted by the number of publications, and on the role of the program in developing scientific expertise in difficult settings. One subcommittee member noted that “the feet on the ground” investigators are the best ones to identify the research questions that are most important locally. Another subcommittee member asked if the program has been highlighted for the Department’s Office of Global Health as an example of health diplomacy. Program responded that the Department is aware of the program and that IRIDA grantees are regularly included as potential sites for Secretarial visits.
Concept Clearance: International Collaborations in Infectious Disease Research (ICIDR)--The ICIDR program, which promotes collaborative research between U.S. and international investigators on infectious diseases that are endemic in resource-constrained international settings, was recognized by the subcommittee as a long-standing and central piece of DMID’s international program. Members noted that the ICIDR sites have been very productive over a long time span, and that the high-profile program has contributed greatly to the development of international research capacity and capabilities. One subcommittee member asked how DMID/NIAID deals with political instability that may occur at an international site. Program responded that the Institute works with each situation on a case-by-case basis and that in most cases successful solutions have been found to enable continuation of the research (sometimes at another site).
The AIDS Research Advisory Committee (ARAC) met on Monday, June 3, 2013, from 1:00 p.m. to 4:35 p.m., at the Natcher Conference Center on the NIH campus in Bethesda, Maryland.
Participating members were Connie Celum (Chair), Dazon Diallo, Adaora Adimora, Georgia Tomaras, Dave O’Connor, Susan Swindells, Stephen Mason, Jonathan Karn, Mitchell Warren, and Jerome Zack. Ex officio members in attendance were: Vicky Davey, Henry Masur, and Nelson Michael, and Office of AIDS Research Advisory Council Committee (OARAC) Liaison, Judith Wasserheit. NIAID representatives included Carl Dieffenbach, Mary Marovich, Manizhe Payton, Sheryl Zwerski, Sarah Read, Emily Erbelding, Diana Finzi, and Mark Mueller. Rona Siskind served as executive secretary.
Connie Celum, M.D., Chair, ARAC
Dr. Celum welcomed the ARAC members, DAIDS representatives, and guests. She presented the minutes of the February 4, 2013, ARAC meeting, and the members approved them with no changes by a hand vote.
Carl W. Dieffenbach, Ph.D., Director, DAIDS
Dr. Carl Dieffenbach welcomed the ARAC members, attending DAIDS and NIAID representatives, and other guests.
Dr. Dieffenbach reported updates in DAIDS staff:
Elizabeth “Libby” Adams, M.D., is the new chief of the Vaccine Clinical Research Branch (VCRB) in the Vaccine Research Program (VRP). Dr. Libby Adams first came to DAIDS in July 1998 as a medical officer in the Therapeutics Research Program and then transferred to vaccines in 2006. She is trained as an internist, immunologist, and rheumatologist and has extensive phase I-IV clinical research experience. Dr. Adams facilitated planning for the HIV Vaccine Trials Network (HVTN) 505 trial and its predecessor PAVE 100. She is presently working on the phase IIb/III (follow-up to RV144) studies to be launched in South Africa as part of the Pox Protein Public Private Partnership or P-5.
Michael Pensiero, Ph.D., is the new chief of a nascent branch in the VRP, the Vaccine Translational Research Branch (VTRB). Dr. Michael Pensiero joined DAIDS in 2000 and has managed several large grants and contracts. In his new role, he will expedite the translation of novel HIV/AIDS prophylactic vaccine discoveries into investigational vaccine candidates. A major focus of the new Branch will be building the infrastructure for clinical testing of HIV Env protein prime-boost combinations leading to the elicitation of broad and potent neutralizing antibodies.
Dr. Dieffenbach noted the recent death of Kuan-Teh Jeang, M.D., Ph.D. (1958-2013), chief of the Molecular Virology Section in the NIAID Laboratory of Molecular Microbiology. He was also the editor-in-chief of the journal, Retrovirology, in addition to having editorial duties with several other journals. Dr. Dieffenbach also reflected on the death of Paul Black, Ph.D. (1947-2013). Dr. Black worked as a microbiologist/program officer in the Targeted Interventions Branch of the DAIDS Basic Sciences Program. Dr. Black helped to advance the mouse model for therapeutic evaluation during his tenure in DAIDS.
The actual money allocated directly to NIAID for research was relatively constant in 2010 through 2011. The apparent FY 2012 decrease is because the $300 million appropriation for the Global Fund no longer passes through the NIAID budget. The data for FY 2013 reflect the enacted budget that includes post-sequestration reductions for NIAID. The FY 2014 amount reflects the President’s budget request.
The President signed into law the FY 2013 budget on March 26, 2013, one day before the continuing resolution expired. The overall NIH budget was cut 5.5 percent as compared with FY 2012 levels. NIAID and most of the institutes and centers received similar cuts of 5.7 percent. According to the bill, $69 million provided to the NIH Office of the Director (OD) will support Alzheimer’s disease research and other high-priority projects, thus resulting in only a 1.6 percent budget reduction for the NIH OD.
In light of the post-sequester FY2013 budget, the goal of NIAID is to maintain a balanced research portfolio while addressing emerging scientific needs and opportunities. The paylines for established and new principal investigators are the 8th and 12th percentiles, respectively. Competing, unsolicited awards will be cut an average of 6.0 percent, and competing research initiatives will be cut up to 20 percent. Noncompeting grants and research and development contracts will be cut an average of 6.0 percent. Based on this plan, the estimated success rate should be in the range of 19 to 21 percent.
On April 10, 2013, President Obama presented his FY 2014 budget request to Congress. It includes a compromise offer that replaces the across-the-board spending cuts, or sequester, with a combination of program reductions and new revenues. Due to the lateness and uncertainty associated with appropriating the FY 2013 budget, the President’s FY 2014 budget request was based on using FY 2012 as the comparable budget. This request provides the NIH with a 1.5 percent budget increase over FY 2012. NIAID fared a little better than most ICs, primarily due to the shift of $27 million from the National Institute of Mental Health (NIMH) to expand collaborative efforts for the ultimate enhancement of HIV prevention and treatment.
If NIH receives the President’s budget level in FY 2014, which essentially ignores the sequester from FY 2013, the overall NIH increase would be 7.5 percent compared with FY 2013 enacted level. However, passage of the President’s budget request may be problematic in the current politically charged climate.
At the Conference on Retroviruses and Opportunistic Infections (CROI) in March, one of the major stories was the functional cure of an HIV-infected baby in rural Mississippi. ARAC member, Dr. Deborah Persaud from the Johns Hopkins Children’s Center presented the case along with Dr. Katherine Luzuriaga from the University of Massachusetts Medical School.
The functional cure from HIV followed the administration of antiretroviral therapy (ART) such that viral replication was undetectable and no disease progression occurred in the absence of drugs.
Researchers suggest that the baby’s functional cure resulted from intensive treatment shortly after birth: three antiviral drugs in combination, twice daily. Experts speculate the infant had not yet developed memory T cells; thus, no latent viral reservoir was established, allowing complete elimination of HIV from the body. This case represents the first well-documented functional cure in an HIV-positive child. It raises a number of questions, including: 1) how does T-cell memory develop in children? 2) what are the implications for the reservoir in children? 3) how many days after birth could beginning treatment make a difference? 4) in what ways could this result be applicable to adults? and 5) the ethics of taking people off therapy.
The results of the VOICE study (MTN 003) were also presented at CROI. The VOICE study found that none of the three daily regimens--tenofovir gel, oral tenofovir, and oral Truvada (emtricitabine/tenofovir disoproxil fumarate) were effective, and poor adherence was a primary factor. The study was designed to evaluate the safety and efficacy of these three HIV prevention strategies compared to placebo. It was conducted among 5,029 sexually active women, 18 to 45 years of age, at 15 sites in South Africa, Uganda, and Zimbabwe. Nearly half were under the age of 25, and most were unmarried (79 percent).
The majority of study participants were unable to use their assigned approaches daily as directed. Moreover, single women 25 years of age and younger were the least likely to use the investigational products, and the most likely to become infected with HIV. The rate of new HIV infections among these young women was nearly ten percent at some of the study sites in South Africa, reflecting a very high incidence of HIV infection among young women in these communities. In order to better understand the factors that impact risk perception and adherence, two behavioral studies have been initiated involving VOICE participants. The results of those two ongoing studies may explain the use or nonuse of the investigational products and are expected later this year.
In April, following a Data Safety and Monitoring Board (DSMB) interim review, HVTN 505 was stopped due to lack of efficacy. The decision came just days after full enrollment was reached at 2,504 trial participants. Based on the data reviewed, the vaccine clearly did not prevent infection (vaccine efficacy) or reduce viral load (viral setpoint) in those who became infected. Some of the key points from HVTN 505 are summarized below:
NIAID will continue to move forward in HIV vaccine research and will convene a meeting, most likely in the early fall, to discuss the critical scientific questions raised by HVTN 505, including questions about vectored vaccine platforms. Community education activities will continue to ensure that the general public understands the importance of clinical trials, even with disappointing results.
Dr. Dieffenbach announced that after this meeting, Mark Mueller will take over executive secretary responsibilities for the ARAC. He thanked Rona Siskind for her many years of service as executive secretary.
Judith N. Wasserheit, M.D., M.P.H., OARAC Liaison
Dr. Wasserheit reviewed the April 11, 2013, meeting of the Office of AIDS Research Advisory Council (OARAC), which focused on HIV-associated neurological manifestations and disorders. The introductory remarks by Drs. Igor Grant (UC San Diego) and David Clifford (Washington University) highlighted the under-researched and unappreciated neurological aspects of HIV infection. The meeting included:
To better understand and address HANDS, OARAC meeting participants suggested that priority research include the following:
During the ARAC discussion, emphasis was placed on the consistent shift toward more subtle HIV-related neurological deficits in the era of combination antiretroviral therapy. Since the availability of highly active antiretroviral therapy (HAART), the flagrant dementias and overt neurological disorders that occurred along with HIV-associated opportunistic infections are rarely seen. Now patients are presenting with asymptomatic neurocognitive impairment found on testing. These neurological manifestations cause decreased function and loss of independence, as well as decreased ART adherence that may go undetected.
It was noted that a debate surrounds the etiology of neurological deficits: is it due specifically to HIV or due to multiple risk factors? The HIV-infected population is often afflicted with many challenges such as substance abuse and mental illness. Researchers are trying to sort out the functional role of HIV and its importance in concomitant neurological disorders. Toward this end, funding has been allotted for a shared project among the NIAID, the National Institute of Mental Health (NIMH), the National Institute of Neurological Disorders and Stroke (NINDS), and other potential partners. The study will include a population in the District of Columbia with multitude co-morbidities compared to a population in the military with little co-morbidity. The objective is to find answers related to the magnitude and HIV-dependency of cognitive deficits and PN.
Georgia Tomaras, Ph.D., NIAID Council AIDS Subcommittee
Dr. Georgia Tomaras reviewed activities of the AIDS Vaccine Research Subcommittee (AVRS), which held its most recent meeting on February 6, 2013, in Bethesda, MD. The February AVRS meeting focused on the work of the newly funded Duke and Scripps Centers for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID). The CHAVI-ID consortiums are dedicated to addressing the primary scientific barriers that hinder HIV vaccine design and development. The two CHAVI-ID are located at the Scripps Research Institute led by Dennis Burton, Ph.D., and Duke University led by Barton Haynes, M.D.
The goal of the Duke CHAVI-ID is to design a preventive HIV-1 vaccine that will induce protective antibodies, especially broadly neutralizing antibodies (bNAbs) as well as T cell immunity. The Duke CHAVI-ID presentations provided an overview of the program and addressed a range of topics, from candidate vaccines employing conserved or mosaic antigens for the induction of T cell responses to the utility of humanized mouse models.
The overall mission of the Scripps CHAVI-ID is to define immunogens and immunization regimens that induce HIV cross-protective B cell and CD4 T cell responses in pre-clinical models. The Scripps presentations included its work concerning the structure and modulation of broadly neutralizing antibodies (bNAbs); and CD4 T cell memory along with the role of a phenotypic and functionally distinct CD4 T cell subset, B follicular helper T (Tfh) cells.
In summary, each group is working toward a better understanding of the immunogens needed to elicit neutralizing antibody and T cell responses. The immunogen concepts are centered on immune focusing versus eliciting a diversity of potentially distracting responses. CHAVI-ID Scripps discussed the need for additional high throughput methodology to facilitate iterative testing and design of multiple immunogens. CHAVI-ID Duke discussed the need for increased modular capacities in the GMP production of pharmaceutical-grade proteins. The areas of research are numerous and distinct between the CHAVI-IDs, but together they are actively integrating expertise for critical problem solving.
During the Q&A, Dr. Tomaras noted that the CHAVI-IDs may collaborate more on bNAb research than T cell work; however, the consortia are partnering to effectively address overlapping issues. Both groups are interested in the contribution of innate immune pathways to advance vaccine immunogenicity, for example, in the context of viral biology and T/F viruses. Although a formal process is not yet in place to share data/samples between the CHAVI-IDs, the teams collaborate with samples going back and forth. The CHAVI-IDs also work with HVTN on components central to vaccine development such as in follow-up to HVTN 505 and various adenovirus vectors.
Concepts Presented for Clearance (approval requested)
Dr. Dieffenbach commented this meeting is organized differently with concepts grouped by research area rather than by program.
Jim A. Turpin, Ph.D., Branch Chief, Preclinical Microbicides and Prevention Research Branch, Prevention Sciences Program
The objective of this initiative is to develop a pipeline of sustained release formulations for HIV treatment and non-vaccine biomedical prevention (microbicides, PrEP). This is a new initiative, which will be supported by a request for application (RFA) UM1 cooperative agreement mechanism. The duration of the award is for five years, with two or three awards expected. The total cost of the first year will be $7.98 million. Dr. Turpin elaborated on the need for the initiative, noting the challenges of strict compliance, particularly among certain vulnerable populations; the convenience of delivery systems with a longer window of therapeutic exposure or protection; and the current limited pipeline of sustained release injectable products.
Dr. Turpin noted the acceptable types of sustained release products, such as formulations that contain only a single drug or combination of drugs as well as formulations that deliver effective drug levels to relevant target tissues. The initiative fits in with DAIDS long-range scientific priorities, including those of the Therapeutics Research Program (TRP) and the Prevention Sciences Program (PRP).
The ARAC reviewers (Swindells and Warren) noted the program is complex and requires the dual cooperation of industry and academic groups. They suggested that the initiative clarify whether applications proposing development of current vs. novel agents will be considered responsive. ARAC members suggested that applicants may be more inclined to propose use of new delivery systems and/or devices, taking advantage of strategies being utilized for other diseases. There was discussion of the clinical trial requirement of the initiative, but it was noted the expectation would be for small, short-term studies that would not require a great amount of infrastructure. In addition, needed resources and support might be available through DAIDS. Committee members were specifically concerned about the requirement for applicants to propose three parallel products/projects for the initial funding period. Some felt this approach may dilute resources and focus. To address this concern, the committee approved the concept with the modification that applicants could propose up to three products/delivery systems and that three parallel projects would not be a minimum requirement.
Karl Salzwedel, Ph.D., Program Officer, Pathogenesis and Basic Research Branch, Basic Sciences Program
Dr. Salzwedel introduced the first two cure-related research concepts. The Q-VOA is the most accurate and best characterized assay available today to measure latent virus in HIV-infected individuals whose viral load (VL) has been suppressed by ART. The assay quantifies resting CD4 T cells under conditions that reverse latency and induce replication of HIV. The Q-VOA measurements require large volumes of blood, are expensive, tedious, and labor intensive and thus, not the assay of choice for many laboratories conducting HIV eradication research.
This initiative aims to perform the Q-VOA as a service to the HIV eradication research community; it will foster the development of standardized Q-VOA measurements so that unbiased comparisons between different eradication strategies can be achieved. A cure for HIV disease, whether functional or sterilizing, is an important DAIDS scientific priority, and requires identification and control of the latent reservoir of HIV. Widespread use of the Q-VOA will raise the standards for latent HIV detection and will limit the use of surrogate, less accurate assays, presently used by some laboratories. This concept is for a new contract (request for proposals) RFP/N01 and would have one award of five-year duration.
The ARAC reviewers (Persaud and Karn) felt this service, which will perform the Q-VOA assay for the HIV cure research community (including grants, Collaboratories, and Networks) will meet a critical need by providing a centralized, standardized approach. One reviewer noted that, as currently worded, the contract would not serve as a resource for the pediatric community and the ability to process pediatric samples will be made a requirement. In response to a question, it was explained that one of the Collaboratories received a supplement to pilot this idea and it was favorably received. With regard to capacity, the Q-VOA will primarily serve as a resource for smaller pilot studies but because there is training component, it might help extend/increase capacity to larger trials.
The ARAC and NIAID Council AIDS subcommittee voted to approve the concept for this initiative.
The objective of this initiative would be to develop innovative approaches to quantify latent, replication-competent HIV that are more efficient than the Q-VOA. The initiative is new and will use the RFA/R21 mechanism in FY 14 and an R01 mechanism in FY 15. For the R21 mechanism, the duration is two years with a first year cost of $1.4 million, and the estimated number of awards is four to six. For the R01 mechanism, the duration is up to five years, with a first year cost of $1.5 million for two to four estimated awards. Dr. Salzwedel noted that new, more efficient assays are needed because: 1) PCR quantification of HIV DNA alone does not correlate with Q-VOA readout; and 2) emerging evidence suggests that even the Q-VOA may underestimate the reservoir size. Simpler assays would increase the number of global labs quantifying replication-competent reservoirs; the higher throughput would allow the collection and analysis of more data points.
During the ARAC discussion, Dr. Salzwedel stated that to pilot these concepts, the program supplemented (one year supplement) selected Centers for AIDS Research (CFARs), in collaboration with the Martin Delaney Collaboratories, to initiate exploratory studies. The response was very positive. The two initiatives being presented (an R21 in FY 14 and an R01 in FY 15) will provide sustained resources for moving concepts forward towards proof of concept. Currently, the Q-VOA is the closest to a gold standard available for measuring viral persistence and will serve as a good reference assay for benchmarking the accuracy of new assays developed under these initiatives. These initiatives are intended to “cast a broad net” to attract novel ideas for overcoming the need for improved assays.
The reviewers (Persaud and Karn) commented that it is important for this initiative to run in parallel with the Q-VOA initiative and extending the assay approaches to cells obtained from tissue biopsies would be of enormous benefit. In addition, it was noted that applicants to the Q-VOA contract could also apply to this initiative.
The ARAC members voted to approve the concept for both initiatives (the R21 in FY 14 and R01 in FY 15).
Alan Embry, Ph.D., Program Officer, Pathogenesis and Basic Research Branch, Basic Sciences Program
The objective of this initiative is to advance the understanding of mechanisms or approaches that could be harnessed to selectively eliminate HIV-1 latently-infected cells without depending on reactivation. This is a new initiative supported by the R01 mechanism with a first year total cost of $3 million. The duration of the award is up to five years, and the estimated number of awards is five to seven.
Dr. Embry noted that latently-infected cells persist in spite of prolonged HAART and present a major barrier to a cure. Since little or no viral protein is produced, latently-infected CD4 T cells avoid both viral cytopathic effects and host immune clearance. Reactivation alone may not be sufficient to eliminate latently-infected cells and likely requires the success of as yet unproven approaches. The RFA will solicit basic research in areas including biomarkers of latently-infected cells, novel approaches to kill latently-infected cells that do not require reactivation and approaches to permanently inactivate integrated HIV provirus.
The ARAC reviewers (Mason and Zack) commented that several of the proposed areas of study were likely to overly broaden the goals of the initiative and could dilute the original intent. These topics were removed, and relevant wording will be carefully considered in any future RFA. They were also concerned that the request to target latently infected cells without reactivation would be very challenging and only a select few groups may be responsive. Staff acknowledged the difficulty but noted that the goal is to encourage many approaches and also cross-disciplinary collaborations that could increase the applicant pool. In addition, the recommendations to allow potential reservoirs other than resting memory CD4+ T cells to be responsive and to encourage applicants to study latently-infected cells from a variety of tissues will both be emphasized in the RFA.
During the discussion, Dr. Dieffenbach noted this initiative brings programmatic balance to DAIDS portfolio. Dr. Embry stated that the concept fills a gap in the pipeline for refined solutions or highly technology-driven products for which investigators may be more inclined to apply through the R01 mechanism.
The ARAC members expressed support for the concept for this initiative and voted approval.
Sandra Bridges, Ph.D., Chief, Targeted Interventions Branch, Basic Sciences Program
The objective of this concept is to support the development of innovative approaches to improve on the current treatment paradigm for HIV that requires a lifetime commitment to combination drug therapy. Among the approaches of interest are: cell therapies, including those based on hematopoietic stem cells; non-traditional anti-viral strategies (miRNAs, siRNAs, gene-editing enzymes) and delivery of same; and novel gene therapy approaches. The concept is for a new initiative using the U19 multi-project mechanism. First year total cost of $11 million will be met by matching commitments of $5.5 million from NIAID and NIH Heart, Lung and Blood Institute (NHLBI). The duration of the award is five years, and the estimated number of awards is three to four.
Dr. Bridges noted that the initiative comprises strategies focusing on control of virus infection (functional cure) and complete elimination of all virus (eradication). It would exclude areas of research already funded and strategies that rely on frequent (e.g., daily) dosing. The reviewers (Cohen and Zack) strongly endorsed the concept noting that it encourages collaborative involvement with corporate partners and among institutions. Depending on the stage of research, the translational part of each grant may lead to animal or pilot clinical studies.
In discussion it was noted that while the Seattle Collaboratory is doing similar work, their work is focused on one specific area of study (zinc finger nucleases and hematopoietic stem cells). This initiative is much broader and includes opportunities to explore other kinds of cell therapies, non-traditional antiviral strategies (miRNAs, siRNAs, and other gene editing enzyme systems) and delivery of same and novel gene therapy approaches. The issue of funding for clinical trial follow-up was raised, but it was pointed out that typically the investigators address participant follow-up in “roll-over” studies, usually funded by the academic institution. During the discussion, Dr. Bridges also mentioned the initiative would be more like a Program Project grant (P01) where a group of several investigators with differing areas of expertise can collaborate around a central theme. As compared to a Collaboratory, one of which has more than 15 projects, this program would have four to five projects focusing on an HIV cure. The ARAC members expressed support for the concept and voted approval.
Katy Godfrey, M.D., FRACP, Medical Officer, Therapeutics Research Program
The purpose of this proposed FY 15 initiative is to support exploratory clinical trials designed to evaluate the effect of an intervention on the reduction of latently infected reservoir cells in HIV infected individuals successfully suppressed on long term ART. This concept represents a new initiative that would be supported by a RFA U01 of five-year duration. Two or three awards are anticipated and the first year total cost is $4 million.
Dr. Godfrey indicated this initiative supports proof-of-concept, single-site studies, designed to evaluate interventions that enhance the elimination of latently infected cells. It is anticipated that these trials will lead to an increased understanding of the mechanism involved in cell killing and eradication of the reservoir. Trials will be conducted at sites in the United States although foreign collaboration is allowed. The initiative is intended to complement ongoing and future programs aimed at eradicating the virus.
The reviewers (Swindells and Warren) were in support of the concept but had some recommendations. The suggested further clarification on the: 1) the scope of the initiative; 2) the time for the overall report (currently too short for regulatory input); 3) the focus, which should be on substantially reducing the reservoir rather than complete eradication; and 4) the small sample size, which may limit the ability to detect a positive signal. These issues were satisfactorily addressed in the presentation, including extending the timing between the call for submission to implementation from three months to six months and modifying the purpose of the initiative.
The reviewers noted the importance of the initiative given its potential for bridging the gap between the basic/translational work of the Collaboratories and the adult therapeutic networks. In response to questions about what happens after the small trial is conducted, it was explained that the five year funding either could end or be used for follow-on studies.
For these grants, the program will support the regulatory aspects but will not hold the investigational new drug (IND) application. It is understood that early preclinical development of a new drug may be long and moving forward in the regulatory process is encouraged. The best patient population and the justification for a particular intervention is all part of the grant proposal review.
During the ARAC discussion, the importance of investigating subtype variation was also noted, particularly subtype C, and the effect on progression rates as it relates to reducing the HIV-1 reservoir. Subtype C is different in its known parameters, for example, the female genital tract viral load (GTVL) is higher in those infected with subtype C, serving as a potential reservoir for persistent HIV-1.
The ARAC members expressed support and voted to approve the concept for this initiative.
Ann Namkung Lee, M.P.H., Health Specialist, Pathogenesis and Basic Research Branch, Basic Sciences Program
The objective of this initiative is to support a multidisciplinary, collaborative environment that promotes basic, clinical, behavioral, and translational research in the prevention, detection, and treatment of HIV infection and AIDS. The initiative is a renewal and will use the NIH Center Core Grants (P30) award mechanism. The duration of the award is five years, and the first year total cost is $4 million for NIAID.
The CFAR program provides resources and core facilities to foster HIV/AIDS research at institutions with a critical number of NIH-funded HIV/AIDS investigators. All CFARs must have an administrative core that supports the management and operations of the CFAR, a developmental core, and at least one clinical and one basic core. In the next program announcement, the minimum amount of NIH AIDS research funding required for eligibility to apply for a CFAR or D-CFAR will be increased. D-CFARs have a nucleus of HIV/AIDS researchers but not the critical mass for a full CFAR.
Ms. Lee noted the hallmark of CFARs is sponsoring new and early stage investigators through several efforts, including pilot projects, mentoring, grant writing, and training in study design/analysis. Currently, there are 18 CFARs and three D-CFARs located at academic and research institutions in the U.S. The CFAR program is now co-funded by nine NIH institutes.
The reviewers (Celum and O’Connor) recommended approval and acknowledged that they have effectively leveraged trans-NIH investments and stimulated scientific collaborations; serve a vital role for new AIDS investigators and junior faculty; and are cost-effective by centralizing research resources. There was discussion about the role of the developmental CFAR vs. a standard CFAR (they are important in helping an institution move up to becoming a standard CFAR and help keep the program highly competitive); whether or not funding for pilot grants should be increased (this is left to local control and institutional support is encouraged); and whether host institutions should have a required resource commitment (which is strongly encouraged). The committee was pleased that the program remains competitive and to learn that some CFARs have not been refunded. CFARs are also preparing for targeted repositories; achieving inter-CFAR collaborations; and providing a forum for engagement on emerging scientific topics of interest.
During the ARAC discussion, Ms. Lee remarked that some CFARs have not been refunded due to the inability to demonstrate added value. It was noted that if a CFAR fails to successfully compete, it is given half its amount of funding for one year in order to regroup. Approximately, 50 percent of such situations result in revision of the strategic plan and go on to successfully compete. As a result, the CFAR program overall has remained fresh and very competitive.
In discussion, ARAC members noted that the upcoming changes in healthcare (Affordable Healthcare Act) may affect HIV prevention/treatment, and comments ensued about the role of CFARs and ICs in assessing the breadth of possible problems. Dr. Dieffenbach replied that understanding the effects of healthcare changes is not necessarily a part of the NIH core mission although the treatment cascade is relevant to many DAIDS programs. He responded to this call for NIH involvement by stating that he would initiate discussions and look into the options within the broader NIH community (including NIMH and OAR) and will report back to the ARAC.
Hao Zhang, M.D., COR, Drug Development and Clinical Sciences Branch, Therapeutics Research Program
The objective of this initiative is to provide infrastructure to ensure the quality and validity of pharmacology data generated in international and domestic laboratories participating in NIAID-funded and collaborative clinical trials. This is a renewal, supported by the N01 contract mechanism and the award is for seven years.
Dr. Zhang noted that clinical pharmacology investigations require highly sensitive and selective methods to quantify drugs and metabolites in plasma and a variety of other biological matrices. These assay methods typically are not provided by the pharmaceutical industry for clinical testing purposes nor are they always approved by the FDA for clinical use. Pharmacology laboratories participating in NIAID-affiliated clinical trials must often develop, validate, and implement their own analytical methods.
The key contract activities of this initiative include:
The reviewers (Adimora and Cohen) were supportive but inquired about the role of CPQA in evaluating completely new assays and assay validation reports (AVRs) in the absence of expertise and experience. In response, it was noted that the CPQA acts as a centralized quality assurance (QA) unit for the network and non-network Labs for their new assay validation; the CPQA will keep a pool of experts and consultants for AVR review, coming from academia and industry who have demonstrated experience in review of AVRs.
In response to a question, it was noted that the statement of work will include external quality assessment (EQA) and support for assay validation for biological drug products (e.g., broadly neutralizing antibodies) used in prevention, therapeutic, and vaccine trials will be described as an option that will be activated should the need arise and funding become available.
No public comment.
Before the conclusion of the meeting, Dr. Dieffenbach talked about the September ARAC meeting and noted that there will be very limited to no discussion of the recompetition of the clinical trials networks. However, in January, when all of the details are public, he suggested that each of the newly funded Network leaders be invited to present their updated scientific agendas and future plans, and thought this may require a two-day meeting. Dr. Dieffenbach requested another mid-point teleconference with ARAC members to provide an update about the budget and to discuss the September agenda. Dr. Celum suggested that during the call ARAC could discuss the best structure and goals for the September meeting.
The meeting of the Council adjourned at 4:35 p.m., on Monday, June 3, 2013.
We do hereby certify that, to the best of our knowledge, the foregoing minutes are accurate and complete.
Anthony S. Fauci, M.D.
Chair, National Advisory Allergy and Infectious Diseases Council
Director, National Institute of Allergy and Infectious Diseases
Matthew Fenton, Ph.D.
National Advisory Allergy and Infectious Diseases Council
Director, Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Anthony S. Fauci, M.D.
Chair, National Advisory Allergy and Infectious Diseases Council
Director, National Institute of Allergy and Infectious Diseases
Matthew Fenton, Ph.D.
National Advisory Allergy and Infectious Diseases Council
Director, Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
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 August 15, 2013