The 171st meeting of the National Advisory Allergy and Infectious Diseases Council (NAAIDC) convened at 10:30 a.m. on Monday, May 14, 2012, 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 11:40 a.m. and from 1:00 p.m. to 5:00 p.m. The meeting was closed to the public from 8:30 a.m. to 10:15 a.m. and from 11:40 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:
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 2,668 research and training applications with primary assignment to NIAID for a requested amount of $846,699,318 in first-year direct costs and recommended approval of 1,263 applications with $425,228,382 in first-year direct costs.
Dr. Fauci opened the Council session by welcoming visitors to the meeting. Three Council members, Drs. Scantlebury, Siber, and Stanley were unable to attend the meeting. Dr. Beth Bell, director, National Center for Emerging and Zoonotic Infectious Diseases, CDC, attended Council for ex officio member Dr. Rima Khabbaz.
Dr. Fauci introduced three ad hoc Council members, Dr. Henry Erlich, vice president of discovery research and director of human genetics, Roche Molecular Systems; Dr. Elizabeth Trachtenberg, research scientist and director, Clinical HLA and Immunogenetics Lab, Children’s Hospital and Research Center at Oakland; and Dr. Brett Giroir, vice chancellor for strategic initiatives, Texas A&M.
Council considered the minutes of the January 30, 2012, meeting and approved them as written.
Dr. Matthew Fenton has been officially confirmed as director of the Division of Extramural Activities.
Kevin Sullivan was selected as chief of the Intramural Administrative Management Branch. He comes from NIH’s Center for Information Technology where he served as chief of the Office of Administrative Management.
Dr. Jim Meegan returns to NIAID as the new chief of the Office of Global Research. From 1991 to 2004, Dr. Meegan served as a program officer in DMID until he left to become senior director of research and development and corporate research fellow at Life Technologies.
Dr. Fauci paid tribute to Dr. Ed Handelsman, former chief of the Maternal, Adolescent, and Pediatric Diseases Branch in the Division of AIDS, who passed away in March. While at NIAID, Dr. Handelsman was best known for his work on the Children With HIV Early Antiretroviral Therapy trial.
He noted the sudden passing of Stephanie Mercer who also worked in the Division of AIDS, primarily in the Treatment Research Branch.
Dr. Fauci recognized Drs. Joshua Farber and John Mascola for being elected members of the Association of American Physicians, a prestigious organization that recognizes physician-scientists who have made outstanding contributions to medical research through basic and clinical studies.
He also congratulated Dr. Steve Holland for receiving the American College of Physicians 2012 Award for Outstanding Work in Science as Related to Medicine.
In May, Dr. Tom Quinn received the University of Notre Dame Graduate School’s Distinguished Alumnus Award and gave the school’s commencement address.
Dr. Fauci acknowledged six NIAID intramural scientists who have been elected as 2012 fellows to the American Academy of Microbiology. He announced the appointment of Dr. Jim Yong Kim, a former NIAID grantee, as the new president of the World Bank.
For FY 2012, NIH received an overall budget increase of 0.8 percent, with NIAID receiving an increase of approximately 0.3 percent.
Dr. Fauci summarized NIAID’s financial management plan for FY 2012. NIAID will support a payline to the 10th percentile for established investigators and the 14th percentile for new and early-stage investigators. There will be no inflationary increase for noncompeting grants, and NIAID’s estimated success rate will be about 22 percent.
The FY 2012 Consolidated Appropriations Act became law on December 23, 2011, and included some policies that affect NIH grants. It does not allow for inflationary increases to future-year costs for grants awarded in FY 2012, NIH will implement a 2 percent increase at all NRSA stipend levels, and NIH will cap investigator salaries at the executive level II amount of $179,900.
The President submitted his FY 2013 budget request, which holds NIH’s budget at the FY 2012 level, to Congress. Most ICs’ budgets are close to their FY 2012 levels. However, NCATS could receive an 11.2 percent increase with the largest part of the increase going to the Cures Acceleration Network.
Dr. Fauci summarized the implications for NIAID if Congress does not develop and pass a detailed plan by January 3, 2013, to reduce the long-term U.S. deficit by $1.5 trillion or more. NIAID must have plans in place to handle budget cuts of up to 10 percent.
On March 20, Dr. Fauci accompanied Dr. Francis Collins when he testified before the House Appropriations Subcommittee on Labor, Health and Human Services, Education, and Related Agencies. Most of the discussion was about NCATS.
On March 28, Dr. Fauci accompanied Dr. Francis Collins and testified on the President’s FY 2013 NIH budget request before the Senate Appropriations Subcommittee Health and Human Services, Education, and Related Agencies.
On April 26, Dr. Fauci testified before the Senate Homeland Security and Governmental Affairs Committee about dual-use research of concern, the events surrounding it, and the Administration’s new policy regarding oversight and mitigation of risks associated with it.
On April 2, Dr. Roberta Black briefed staff from the House Appropriations Subcommittee on State Foreign Operations, and Related Programs on NIAID microbicides research. On April 25, Dr. Lee Hall spoke on advancements in malaria science at a briefing held by an advocacy organization called Malaria No More.
From April 27 to May 6, a delegation of several senators visited sites supported by CDC, State Department, and NIH in Namibia and South Africa. Dr. Fauci met with Senators Harkin and Wicker before the trip to discuss the global health importance of U.S. investment in Sub-Saharan Africa.
To celebrate its 200th anniversary, The New England Journal of Medicine is planning to publish seven special articles in 2012 to discuss important scientific advances during the last 200 years. In February, the Journal published an article by Dr. Fauci and Dr. David Morens on the “Perpetual Challenge of Infectious Diseases.”
Dr. Fauci presented statistics on the increasing burden of hepatitis C mortality in the U.S. and the status of a phase I/II clinical trial underway for a preventive vaccine.
Dr. Fauci summarized progress on stockpiling drugs for possible use in the event of bioterror attacks, challenges associated with developing a tuberculosis vaccine, and exciting results in transplantation research.
In May, an expert panel recommended that FDA approve Truvada to prevent HIV infection. Dr. Fauci gave brief updates on several HIV/AIDS publications and research advances. He also noted that in July, the International AIDS Conference would be held in Washington, D.C.
Dr. Fauci concluded by giving a detailed summary about the ongoing controversy surrounding H5N1 research. The U.S. government put together a new policy for overseeing life sciences dual-use research, and Dr. Fauci outlined the implications for institutions.
Dr. John Mascola gave an overview of the Vaccine Research Center’s (VRC) main scientific priorities over the last year as they relate to VRC’s HIV vaccine program and other emerging diseases programs.
HIV research continues to be a high priority for VRC. VRC maintains a major focus on developing vaccine immunogens for HIV that elicit neutralizing antibodies and then developing vaccine candidates and advancing them into phase I trials.
Another important research area is identifying HIV immune correlates and T-cell responses that will augment antibody responses to prevent infection. Dr. Mascola presented some of the studies that VRC is conducting in these areas.
VRC has an active interest in improving existing vaccines. Dr. Mascola summarized VRC’s efforts to improve the influenza vaccine and move toward a universal influenza vaccine.
Dr. Rotrosen announced a new staff member, Dr. Christy Sasiela who has joined the Division’s Office of Regulatory Affairs as a Regulatory Officer. Dr. Sasiela holds a Regulatory Affairs Certification through the Regulatory Affairs Professional Society.
Dr. Rotrosen then informed the subcommittee members there would be two presentations:
Following the presentation by Drs. Erlich and Trachtenberg, Dr. Rotrosen announced there were seven research concept clearances for review and approval by the Subcommittee.
National Swine Research and Resource Center: The purpose of this funding opportunity announcement (FOA) is for the continued support and advancement of the National Swine Resource and Research Center (NSRRC). The award provides support for a repository and distribution center for valuable swine models, as well as other swine resources such as reagents, cultures (cells, tissues, and organs) that serve the biomedical research community at large. The NSRRC collects, maintains, characterizes, and distributes defined strains of swine and related biological materials to biomedical researchers in a variety of research areas on a local, regional, and national basis. The overall objective of this FOA is to support the continued availability of swine to biomedical researchers in the United States. The subcommittee endorsed and unanimously approved this initiative.
Cooperative Centers on Human Immunology: This initiative will support at least two synergistic research projects focused on testing novel hypotheses about the mechanisms of immune response and regulation in the human, in the context of infection by or vaccination against NIAID emerging/re-emerging pathogens. Some animal studies will be allowed, to further explore and validate results obtained in the human system. Optional technology development projects will also be supported, together with a small education component to facilitate data sharing and to help recruit outstanding scientists to work in the human system, and a small opportunity fund component to test novel high risk/high impact ideas or to take advantage of new research opportunities. Use of the common opportunity fund will be determined by the CCHI Steering Committee, comprised of the PIs from each cooperative agreement grant. The Subcommittee endorsed and unanimously approved this initiative.
Immunity in the Elderly: This initiative will support innovative research projects in humans and relevant animal models to understand immunological mechanisms in aging hosts in the presence of infections or vaccinations. This is a renewal of initiative RFA-AI-08-012 (Rejuvenating the Aged Immune System) which focused on thymic involution and its effects on T cell development. The renewal will expand the scope to include mechanisms that are involved in innate immune protection and adaptive immunity provided by T or B cells, NK cells, or NKT cells in the course of infections and responses to vaccines. The Subcommittee endorsed and unanimously approved this initiative.
Immune Mechanisms of Virus Control: This initiative will support research focused on defining the immune response parameters to virus infection and/or vaccination that will eventually enable the development of new and better vaccines for human use. This initiative will solicit a very broad range of research questions pertaining to the innate and adaptive immune responses and how the micro-environment influences these responses. Viruses of interest will be from the NIAID Emerging and Re-emerging Diseases list. Topics of interest include:
The Subcommittee endorsed and unanimously approved this initiative.
Advanced Development of Medical Countermeasures for Platelet Regeneration and Survival Following Radiation Exposure from a Radiological/Nuclear Incident: The focus of this solicitation will be applied and translational research and development of radiation medical countermeasures that specifically target the regeneration of platelets to enhance survival after exposure. Countermeasures of interest may include novel or known drugs to mitigate and/or treat radiation damage to the bone marrow and platelet lineages when administered >24 hours after exposure. Infrastructure improvements would be limited to small equipment purchases necessary to upgrade existing laboratories. The Subcommittee endorsed and unanimously approved this initiative.
Large Scale T Cell Epitope Discovery: The goals of this program remain unchanged in the renewal and will consist of identification of immunodominant and subdominant T cell epitopes, which bind class I, class II, or non-classical MHC/HLA molecules. Epitope discovery methods must be accompanied by validation studies in appropriate animal models or using human cells to confirm the contribution of the epitopes to the generation of protective immunity. Investigators supported under this program will be required to submit their epitope data to the Immune Epitope Database (www.iedb.org). In the new initiative, prediction algorithms for MHC Class I molecules with AUC predictive scores greater than 0.9 will be excluded. The Subcommittee endorsed and unanimously approved this initiative.
B Cell Epitope Discovery and Mechanisms of Protection: This program will support the identification of B cell epitopes, coupled with basic studies to understand protective immunity mediated by antibodies and, when applicable, pathological consequences of antibody responses. Investigators may utilize recent technological advances for epitope discovery, such as genome-wide scanning, structural genomics and proteomics, phage-display libraries, and combinatorial synthetic peptide library screens; or develop new or improved technologies, including computer-based B cell epitope prediction algorithms, for the identification of novel B cell epitopes. Epitope discovery methods must be accompanied by basic studies in appropriate animal models or using human cells to validate the epitope as a target of antibody-mediated protective immunity and to understand the mechanisms by which the antibodies induce immune protection. Supported investigators will be required to attend an annual program review meeting at NIH and submit their epitope information to the Immune Epitope Database and Analysis Resource (www.immuneEPITOPE.org). The Subcommittee endorsed and unanimously approved this initiative.
After welcoming the Subcommittee, Dr. Heilman introduced Dr. Brett P. Giroir, currently Vice Chancellor for Strategic Initiatives within the Texas A&M University System and formerly at the Defense Advanced Research Projects Agency (DARPA). She then referred to the Branch Chiefs in attendance to introduce their respective new hires.
In follow up to her previous report to the Subcommittee about the Fall 2011 DMID Centers of Excellence for Influenza Research and Surveillance (CEIRS) program review, Dr. Heilman distributed a copy of the meeting report to the Subcommittee members. The report is also available on the NIAID Web site. She also noted the recent release of the Institute of Medicine’s “Ranking Vaccines: A Prioritization Framework (Phase I: Demonstration of Concept and a Software Blueprint)” report. The report describes a model that could ultimately be used to prioritize new vaccines. The Institute of Medicine Committee that developed the report is actively seeking stakeholder input, and Dr. Heilman encouraged those with an interest to provide feedback. This effort is supported by the Department of Health and Human Services (DHHS) National Vaccine Program Office.
Finally, Dr. Heilman described DMID efforts to provide regular programmatic updates to the Subcommittee over the years on the variety of infectious disease issues addressed by the Division. She noted specific topics that had been discussed in the past, e.g., antimicrobial resistance, and explained that these updates serve to provide context for the concepts that are presented to the Subcommittee for approval and pave the way for new DMID initiatives and programs. She encouraged the Subcommittee to identify topics of interest for future programmatic updates and share those with her at their convenience.
Dr. Clare Schmitt, Deputy Director of DMID’s Office of Biodefense Research Affairs, provided an update on DMID’s biodefense research activities. These activities are guided by the DHHS’ Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) Strategy, which guides biological research and other biodefense-related activities and ensures that all relevant DHHS entities work together to organize and prioritize these efforts. She noted that PHEMCE encourages a capabilities-based approach, which aligns with NIAID’s emphasis on broad spectrum technologies and platforms with multi-use potential, rather than countermeasure development for a single disease entity. She concluded by summarizing several specific DMID biodefense-related research activities that are either ongoing or have transitioned to other partners, e.g., BARDA, for further development.
The following concepts were presented to the Subcommittee for their review and approval:
Centers of Excellence for Translational Research: The goal of this concept is to support multidisciplinary translational research centers focused on generating, validating and advancing medical countermeasures to biodefense agents and emerging infectious diseases. The Subcommittee was uniformly enthusiastic about the direction of the new biodefense centers program, which builds upon NIAID’s Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases Research (RCE) program (2003-2014). DMID was encouraged to ensure coordination between these new centers and BARDA, and staff agreed this was important and would be pursued. The concept was unanimously approved.
Partnerships for Biodefense: This concept focuses on milestone-driven research to advance candidate therapeutics, vaccines, and diagnostics through the preclinical product development pathway. The Subcommittee expressed strong support for the DMID Partnerships Program, noting that it plays an important role in the Institute’s translational research objectives and provides a needed resource to assist the academic community in preclinical product-related research efforts. The Subcommittee favored the requirement for substantive investment by an industrial partner. One Subcommittee member asked about coordination of Partnerships activities and objectives with other DMID programs such as the flu vaccine effort. Program staff explained that individual efforts differ greatly with respect to needed resources and timelines, warranting multiple programmatic activities to achieve overall objectives. It was also noted that relevant program staff play a role to ensure integration of multiple activities in a particular research area to create an overarching plan. The concept was unanimously approved.
Drug Target Development and Validation for Antimicrobial Resistant Pathogens: This concept focuses on the translation of basic research findings into the very early stages of antimicrobial therapeutics discovery and development for pathogens where resistance threatens effective treatment. This earlier stage component of the DMID Partnership program was strongly supported by the Subcommittee, and they agreed that the focus on validating targets to address antibiotic resistance was timely and a high programmatic priority. There were a few questions on the process of transitioning projects to the R33 phase. Program staff explained that approximately one-half of the R21 projects would be selected for transition using an established evaluation protocol based on milestone accomplishment, programmatic priorities and available funds. The concept was unanimously approved.
Pharmacological Approaches to Evaluating Drug Regimens to Address Antimicrobial Resistance: The goal of this concept is to support efforts to apply pharmacological principles to improve understanding of the factors underlying the development of drug resistance and identify approaches for prevention and treatment in clinically relevant infectious pathogens. The Subcommittee responded enthusiastically to this concept, noting its timeliness and relevance for combating antimicrobial resistance and drug development. The Subcommittee endorsed the concept of providing funding opportunities to increase academic expertise in anti-infective (bacterial, viral, parasitic) pharmacokinetic/pharmacodynamic (PK/PD) interaction studies to better understand use of current drug regimens, and to help define new combination treatment approaches. The concept was unanimously approved.
Participating members were Connie Celum (Chair), Myron Cohen, Dazon Dixon Diallo, Karen Goldenthal, Judy Lieberman, Adaora Adimora, Jonathan Karn, Georgia Tomaras, Francine McCutchan, Susan Swindells, Mitchell Warren, and Jerome Zack. Ex officio members Victoria Davey and Nelson Michael, and Office of AIDS Research Advisory Council Committee (OARAC) Liaison, Judith Wasserheit, also participated. NIAID representatives included Emily Erbelding, Kevin Ryan, Susan Plaeger, Manizhe Payton, Scott Proestel, and Sarah Read. Rona Siskind served as executive secretary.
Connie Celum, M.D., M.P.H., Chair, ARAC
Dr. Celum welcomed the ARAC members, DAIDS representatives, and guests. She presented the minutes of the January 30, 2012, ARAC meeting, and the members approved them with no changes.
Emily Erbelding, M.D., M.P.H., Deputy Director, DAIDS
Dr. Emily Erbelding served in the place of Dr. Carl Dieffenbach who was on leave to see his daughter graduate from medical school. Dr. Erbelding welcomed the ARAC members, attending DAIDS and NIAID representatives, and other guests. She extended a special welcome to the two guest speakers: Drs. Charles Wira and Jerrold Ellner. Invited speakers have been included in the recent meeting format to help frame initiatives and highlight specific research areas.
Dr. Erbelding provided an update on leadership changes within DAIDS; specifically, Dr. Sarah Read has assumed the role of Acting Director of the Therapeutics Research Program (TRP). On behalf of Dr. Dieffenbach and DAIDS, Dr. Erbelding thanked Dr. Carla Pettinelli for her two-year of service as Acting Director of the TRP and thanked Dr. Lawrence Fox for his contributions as Acting Branch Chief of the HIV Research Branch during that time.
Dr. Erbelding noted the losses of two DAIDS staff members since the last ARAC meeting:
With Dr. Handelsman’s death, Dr. Larry Fox has agreed to serve as the Acting Chief, MAPRB.
Dr. Erbelding presented a comparison between FY 2011 and FY 2012 budgets for NIAID. NIH as a whole received a 0.8 percent increase, with several NIH Institutes and Centers (ICs), including NIAID, receiving an increase of about 0.3 percent. Congress approved elimination of the National Center for Research Resources (NCRR) in favor of the establishment of the National Center for Advancing Translational Sciences (NCATS). Several of NCRR’s large programs were realigned under NCATS.
The financial management plan for FY2012, in general, mirrors last year’s plan with projected paylines of the tenth percentile for experienced investigators and the 14th percentile for new investigators. The NIAID estimated success rate will be approximately 21 to 22 percent in FY2012. The FY2012 Consolidated Appropriations Act became law on December 23, 2011 and provides NIH a small increase. However, the Act does not allow for inflationary increases to be applied to the future-year costs for grants awarded in FY2012.
The President requested that funding for NIH in 2013 remain at the FY 2012 level. NCATS could receive an increase of 11.2 percent with the largest portion of the increase, $40 million, going to the Cures Acceleration Network (CAN). Congress received the President’s FY 2013 budget request on February 13. The Budget Control Act of 2011 requires automatic, across-the-board cuts in the federal government budget, starting in January 2013. Until Congress develops and passes a law preempting sequestering and addressing the long-term deficit, NIAID along with other federal agencies, must have plans in place to handle budget cuts of up to 10 percent.
If NIAID is forced to absorb a large budget cut in FY 2013, paylines would drop to the 8 percentile, and the amount allocated for competing initiatives would be cut by up to 20 percent. Additionally, the budgets for all non-competing grants and contracts as well as the intramural program would need to be cut by up to 10 percent. NIH is reviewing options to provide stability in funding for experienced and new investigators alike.
Two pediatric studies were presented at the CROI meeting in March. The Children with HIV Early Antiretroviral Therapy (CHER) study is a phase III randomized clinical trial in South Africa comparing different strategies for treatment HIV-infected infants less than three months of age and assessing the optimal time to begin antiretroviral (ARV) therapy. Interim data (2007) from CHER changed World Health Organization (WHO) standards for treating infants with HIV: ARV should be initiated as early as possible to infants infected with HIV under one year old.
At CROI 2012, more results from the other two arms in CHER were presented. The experimental arms evaluated whether immediate therapy in infants could be safely interrupted after either 40 or 96 weeks when the immune system is more mature. The CHER team concluded that treatment during early infancy is most critical, but it appears therapy can be safely interrupted and then followed closely later in childhood.
The Pediatric Randomized Early vs. Deferred Initiation in Cambodia and Thailand (PREDICT) trial, a phase III randomized clinical trial, examined the question of when to begin ARV therapy in children (ages 1 to 12) who were diagnosed with HIV infection after infancy. After three years of follow-up, few children in either arm had progressed to AIDS. Both groups of HIV-positive children performed poorly and had more behavioral problems compared to HIV-negative children. Taken together, CHER and PREDICT underscore the importance of identifying and treating HIV-infected infants as soon as possible to preserve the immune system and ensure healthy brain development.
The results of the RV144 correlates analysis were recently published in the New England Journal of Medicine (April 5, 2012). The findings indicate that vaccinated participants who produced high levels of IgG, which attaches to the first and second variable regions (V1V2) of the HIV outer coat, were less likely to get infected than those who did not produce the antibodies. Concomitantly, vaccinated study participants with high levels of IgA that attached to the first constant region (C1) of the virus envelope were less likely to benefit from the HIV vaccine.
Researchers will replicate the RV144 study in nonhuman primates to determine if the V1V2 antibody response directly caused the modest protective effect or was simply linked to other factors responsible for the RV144 results. The Pox virus prime boost vaccine is based on the RV144 paradigm and early phase testing will evaluate factors that encompass those correlates of risk.
The Antiviral Drugs Advisory Committee of the Food and Drug Administration (FDA) voted last week to recommend approval of Truvada for use in HIV pre-exposure prophylaxis (PrEP). The committee’s decision, representing a milestone in HIV prevention, is owed to the data generated from clinical trials sponsored by NIAID, the Gates Foundation, and the Centers for Disease Control and Prevention (CDC). The FDA is expected to make a decision by June 15. An NIAID-supported demonstration project in men who have sex with men (MSM) is being conducted in in Miami and San Francisco to examine implementation aspects of PrEP.
The funding opportunity announcement (FOA) for the NIH Clinical Trials Units (CTUs), supporting the NIAID leadership groups, was released in April and can be viewed on the NIAID Web site. Three grantsmanship workshops are planned to assist those applying for funding. The first workshop will convene in Washington, DC, July 28 to 29, 2012; the other two are scheduled to be held in Rio de Janeiro in August 2012 and Johannesburg in October 2012.
Dr. Erbelding provided an update from the joint meeting of the Strategic Working Group (SWG) and the AIDS Vaccine Research Subcommittee (AVRS) that occurred in January.
The leadership of the HIV Vaccine Trials Network (HVTN) presented their organizational structure, which has shifted from a principal investigator-focus to a more team-management approach. The HVTN presented plans in three main programs: 1) HVTN 505—investigating the safety and efficacy of a DNA/rAd5 vaccine regimen in healthy circumcised men who have sex with men (MSM) males and transgender females; 2) evaluation of Pox Prime Protein Boost in Southern Africa; and 3) exploration of new immunogens and regimens.
The leadership of the HIV Prevention Trials Network (HPTN) highlighted the HPTN 071: The PopART Study, which will test combination strategies to prevent HIV in African countries. The proposed trial sites are in Zambia and South Africa.
Judith N. Wasserheit, M.D., M.P.H., ORAC Liaison
Dr. Wasserheit presented a recap of the April 10, 2012, OARAC meeting that focused on, “New Scientific Opportunities in AIDS Vaccine Research.” The meeting covered pre-clinical research in HIV development in addition to promising HIV vaccine candidates and approaches. Key points from the meeting included the following:
During the discussion, it was noted that several projects currently funded under the Basic Sciences Program have therapeutic vaccine approaches. Therapeutic vaccines represent part of the reinvigorated interest in achieving a functional cure for HIV.
Susan F. Plaeger, Ph.D., Director, Basic Sciences Programs, NIAID/DAIDS
Dr. Plaeger introduced this session, which is devoted to the current view of the basic biology of HIV transmission in women. The invited speaker, Dr. Wira gave the scientific overview preceding the presentation of two concept reviews.
Charles R. Wira, Ph.D., Professor of Physiology; Department of Physiology and Neurobiology, The Geisel School of Medicine at Dartmouth, Lebanon, NH
Originally proposed in an article published in AIDS (Wira and Fahley, 2008 October 1) and recently validated in nonhuman primates at the Centers for Disease Control and Prevention (CDC), Dr. Wira described a “window of vulnerability” for transmission of HIV into the female reproductive tract (FRT) that occurs 7-10 days following ovulation. During this time period, aspects of innate, humoral and cell-mediated immunity are suppressed by sex hormones to facilitate the implantation of the fertilized egg. This dampened immune protection coincides with the recruitment of susceptible cells with upregulated viral coreceptors, providing greater potential for viral transmission throughout the FRT.
The FRT mucosal immune system is comprised of: 1) immune cells that migrate into the uterus, cervix and vagina as well as resident epithelial cells and stromal cells; and 2) mucus and other secretions contained in the lumen. Every cell of the immune system, both the innate and adaptive, is present in unique ways throughout the upper and lower reproductive tract. In part due to these unique defenses in the FRT, HIV viral acquisition usually begins with a small founder population of infected CD4+ cells followed by a brief period of local viral expansion before systemic dissemination occurs.
Due to the profound regulatory effects of hormones like estradiol and progesterone, every cell in the reproductive tract can be altered either by direct or indirect action. Estradiol has a direct suppressive effect on co-receptor expression (CCR5 and CXCR4) and HIV infection (intracellular p24), as well as an indirect effect on immature dendritic cells via uterine epithelial cell (UEC) secretion of TGF-β. The tissue distribution of immune cells and cell traffic significantly change as the female cycles through the proliferative secretory and post-menopausal stages. Experimental research has shown that during the “window of vulnerability,” cytotoxic T lymphocyte (CTL) activity in the uterus is completely suppressed. Although the exact mechanism is unclear, an association exists between increases in the size uterine lymphoid aggregates and CTL activity. Any vaccine designed to elicit CTL activity should take into account the formation profile of these lymphoid aggregates.
Dr. Wira noted antibody-mediated immunity is altered during the menstrual cycle as evidenced by the large decrease in IgG and IgA levels in the cervical mucosa mid-cycle and during ovulation. Estradiol also increases anti-bacterial, antiviral, and antifungal activity in UEC secretions. Much remains to be understood about the role(s) of endogenous hormones and hormonal contraceptives in regulating the FRT environment as it influences immune protection and susceptibility to HIV infection.
In discussion, Dr. Wira suggested that an area for active investigation is the effect of progesterone on fibroblasts. Similar to estradiol, progesterone apparently decreases HIV infection by acting on CD4+ T cells; however, the effect of synthetic progestins is still unclear.
Dr. Wira also stated that understanding mucosal immunity is in its infancy, and that new information in this field will further define basic biology as well as identify parameters that can be modified to protect women against HIV infection. The location(s) in the reproductive tract where HIV acquisition occurs is unclear; being aware of variability in the state of immunity during the female cycle will be helpful as clinical trials go forward.
Jim Turpin, Ph.D., Acting Branch Chief, Preclinical Microbicides and Prevention Research Branch, DAIDS
The objective of this concept is to optimize and assess safety and efficacy of microbicides, PrEP, and Multipurpose Prevention Technology (MPT) by understanding the interaction of these prevention strategies with the male and female genital and gastrointestinal (GI) mucosa. The solicitation is new, will be supported by the R01 award mechanism, with four year duration.
Rather than focusing on observational changes the initiative will require that the research focuses on the effects of prevention strategies on the mucosa and their impact on potential safety and efficacy of the strategy. Through better understanding of these interactions, the goal is to enable development of second generation non-vaccine prevention targets and strategies with less impact on the vaginal and rectal mucosa, and/or develop/optimize this interaction to enhance safety and efficacy. It will also help to identify potential new targets that are intrinsic to genital and/or GI tract function, which may either serve as standalone strategies or in combination with other candidates, provide for more targeted prevention strategies with decreased use or elimination of ARV-based prevention, thus sparing these approaches for treatment.
Reviewers (Cohen and Diallo) expressed enthusiasm for the concept and emphasized that the purpose of the concept needs to be clear. Initially, the reviewers were concerned about the inclusion of the male and female genital tracts along with the GI as concept targets because of the great differences in the mucosal tissues. Program staff explained that the intent was to seed the pipeline with formative research in prophylactic interventions directed toward novel mucosal targets. Reviewers’ comments also included suggestions that the concept look at both endogenous and exogenous hormones; program staff agreed and will have this factored into the responsive and non-responsive criteria of the RFA. These criteria will also help clarify the desire for microbiome studies that focus on understanding the role microbiome in prevention strategy efficacy and safety.
During the discussion, Dr. Turpin further clarified interest in microbiome studies to follow up data suggesting specific changes occur in the microbiome after exposure to microbicides (Saxena et al., Curr, HIV/AIDS Rep., Mar 2012). Recent work indicates defensive responses in the epithelial cells are stimulated by interactions among bacteria; interventions that perturb the normal equilibrium and explore pattern recognition in relationship to prevention will be included in the request for applications (RFAs). Dr. Turpin stated the call was not for surveys, and again reiterated that the interest in microbiome studies related to susceptibility and the safety and efficacy of prevention modalities.
The ARAC members expressed support for the concept and voted to approve.
Alan Embry, Ph.D., Program Officer, Pathogenesis and Basic Research Branch
The objective of this initiative is to discover mechanisms that mediate the induction and maintenance of effective antigen-specific memory T cells in the FRT. Solicited R01s will be funded through an RFA. The concept is new and awards will be up to five years duration.
Women account for greater than 50 percent of HIV infections, worldwide, and are predominantly infected through sexual transmission. Defining mechanisms that impact acquisition of HIV specifically in women and girls continues to be a very high priority for the Division of AIDS. The unique ability of HIV to evade the immune response and establish viral latency likely necessitates the elicitation of potent and rapid immune responses at the portal(s) of viral entry.
It is likely that an effective HIV vaccine will require both B- and T-cell responses. First, it may be advantageous to have CTLs at the mucosa to eliminate any virally-infected cells that escape innate or antibody-mediated responses. Second, previous studies show that CTLs are capable of exerting a strong selection pressure on the virus, affect viral fitness and mediate an important role in viral control. Additionally, recent work from Louis Picker’s lab using the CMV/SIV model, suggests that an HIV vaccine capable of eliciting potent effective memory T cells may be able to profoundly control or clear HIV infection.
This concept is intended to encourage basic applications that will contribute to the generation of effective and persistent memory T cell responses against mucosal pathogens relevant to HIV transmission in the FRT. The program will support cross-disciplinary collaborations and investigators new to the HIV field in areas that include but are not limited to the following:
The reviewers (Zack and Goodenow) noted that the program addresses a large gap in our current knowledge about immune responses and could lead to improved vaccine approaches. They were supportive of the idea to include non-HIV/SIV pathogens that can be explored by murine infection models. The reviewers also suggested that applications should present clear relevance and rationale for a particular model pathogen. If animal models are proposed, justification and relevance to humans is essential, and studies should be considered responsive if the influence of innate immune signals on T cells responses in the FRT is addressed. In agreement with reviewer comments, the logistics and the potential for co-funding by other agencies is being explored.
The discussion included a suggestion for broadening the program focus to other immune cells such as natural killer (NK) cells; NK cells are the initial cellular mediators, and it may be important to investigate the role of immune activation and role of NK cells in HIV acquisition. It was also suggested that long-term outcomes be tracked to assess "added-value" and success of the program. It was also noted that the male reproductive tract is also understudied, but funding limits the scope of this initiative.
The ARAC members expressed support for the concept and voted to approve it.
Sarah Read, M.D., Acting Director of the Therapeutics Research Program (TRP)
Up to one-third of the world’s population is infected with tuberculosis (TB) and about 200 million of those infected carry active TB transmittable to others. People who are co-infected with HIV and latent TB have up to 50-times greater risk of developing active TB and becoming infectious.
Dr. Read gave an overview of the Tuberculosis Clinical Research Branch, a relatively new branch in the TRP, and also introduced the invited speaker, Dr. Ellner, who provided an overview of latent TB infection (LTBI) and HIV co-infection before any concepts were presented. In its third year, the TB Clinical Research Branch is led by Dr. Richard Hafner, Acting Branch Chief. The clinical research effort in global TB has been expanded to include prospective cohorts of infected subjects and clinical trial consortia with newly established relationships in key countries such as India, Brazil, South Africa, and China. This nascent effort under DAIDS complements the ongoing TB research in NIAID funded by the Division of Microbiology and Infectious Diseases (DMID).
DAIDS’ resources for TB support the translational and clinical investigations related to individuals co-infected with HIV as well as the overall Network clinical trials agenda for TB diagnostics, therapeutics, and prevention with and without HIV co-infection and balances the overall NIAID research portfolio. The primary scientific goals for the Branch are:
Jerrold J. Ellner, M.D., Professor of Medicine; Department of Medicine, Boston University School of Medicine; Chief, Infectious Disease Section, Boston Medical Center, Boston, MA
In a household, an uninfected person exposed to TB by someone with smear-positive infectious TB has about 50 percent risk of becoming infected with TB. Innate immunity and resistance are important determinants of risk. After TB infection, one of two pathways are possible: 1) most individuals enter a period of clinical latency (asymptomatic); or 2) about five percent of individuals progress from new development to active TB (symptomatic TB), mostly within the first year. Those with greatest risk are the very young, very old, and immune-suppressed individuals.
During clinical latency, Mycobacterium tuberculosis (MTB) replication still occurs, and with HIV infection, MTB disease can reactivate. After a period of latency, which may last for years, an individual has a five percent life-time risk of reactivating TB. With HIV infection, the risk of reactivation is five percent per year. If an individual has HIV and is exposed to TB, the risk of developing active disease within 120 days is 40 percent. The accelerated time frame is the basis for explosive epidemics of TB in the context of HIV infection, usually from nosocomial spread. Additionally, in HIV infection, patients with drug-susceptible TB more often develop drug-resistant or extensively drug-resistant TB (XDR-TB) after time in the clinic or the hospital.
TB disease should be considered as a continuum rather than as discrete stages of disease. If the innate immune response is good, and an individual is exposed to TB, even in the presence of close household contacts, the organism can be eliminated without developing a T-cell mediated immune response (or infection). In such cases, immunologic memory is non-existent, and a tuberculin skin test is negative with no way to know that exposure has occurred. Alternatively, infection can ensue, but be eliminated entirely with the priming of T-cells and an acquired immune response manifesting as a positive skin test.
Continuing in the spectrum, despite good immune control, some latent non-replicating organisms may persist in quiescent infection, one component of clinical latency. An individual may proceed to active infection, nonetheless with no symptoms, or on to active disease. HIV infection drives the risk of TB and increases bacterial load. Latent MTB can reside in a range of tuberculous lesions or microenvironments, some similar to what is seen in active TB. TB, in latency and in active disease, is not static even minus chemotherapy. One latency-associated peptide stimulates interferon gamma production in patients with remote latent TB infection, but not with active tuberculosis or with recent TB infection. Thus, latency-associated peptides may be useful diagnostically.
Eighty percent of HIV-TB is in sub-Saharan Africa, where the TB incidence is the highest. Almost no one in Uganda is receiving preventive therapy in the setting of HIV infection. One of the difficulties with latent TB infection in HIV is that a (slowly) replicating infection with a moderate bacterial load is being treated with isoniazid monotherapy, which may not be the best option.
The gaps in the current knowledge about LTBI relate to:
In the discussion, Dr. Ellner noted that the DarDar Tuberculosis Vaccine Trial in HIV infected volunteers involved a study of five doses of M. vaccae and was stopped when the vaccine was judged to have shown efficacy based on a trend in protection against the primary endpoint of disseminated TB and a statistically significant reduction in the secondary endpoint of definite culture-confirmed TB. However, a study of single dose M. vaccae in Uganda showed no therapeutic effect. An ultra-short treatment course may possibly be effective. Dr. Ellner suggested that in ten years probably none of the currently used drugs will be used to treat TB, except perhaps rifamycins and fluoroquinolones.
Richard Hafner, M.D., Acting Branch Chief, TB Clinical Research Branch
The objective of this concept is to define host and microbiologic mechanisms along with interactions involved with the development, maintenance, and activation of LTBI in the context of HIV co-infection. An understanding of both the nature and characteristics of MTB’s adaptations within the host, as well as the host factors which confer either resistance or susceptibility to reactivation is fundamental to developing new diagnostics to identify those at high short-term risk of reactivation and new strategies to shorten the duration of preventive treatment, particularly with HIV co-infection. The solicitation is for R01 grants; the initiative is new, with three awards of five years duration anticipated.
One-third of the world’s population is latently infected with MTB. Isoniazid Preventive Therapy (IPT) is not used in the vast majority of high-burden countries due to cost, poor adherence/tolerance, high re-infection rates, and increasing prevalence of background resistance. More practical strategies need to be developed in addition to new paradigms and especially higher risk innovative approaches.
The unsolicited grant mechanism has not been very successful, and no significant overlap with ongoing grants exists. This initiative will build on and complement existing programs and collaborations as it seeks the following:
The reviewers (Ellner and Swindells) were very supportive of the initiative, especially in light of the gaps that may be addressed. They suggested that there be a clear focus on HIV co-infection, which there is, and that the relationship with the DMID FY14 initiative be clarified. In addition, they suggested that the initiative focus should be on TB-HIV host interactions, including immunopathology of persistence and activation, and highlight research for discovery of tools to better detect and manage latent TB in the context of co-infection. They also suggested that the inclusion pediatric populations be considered, and applications focusing on adapting/improving current assays be discouraged. Rather, new approaches and technologies should be emphasized. In discussion at the meeting, the value of focusing on biomarkers was also raised. There was also discussion about more basic scientists who will have a challenge meeting the requirement to include HIV. The discussion also included a call for ways to identify HIV-infected individuals particularly at risk for TB reactivation.
Daniella Livnat, B.Sc., Health Specialist, Drug Development and Clinical Sciences Branch
The objective of this initiative is to provide a resource that evaluates the ability of laboratories to accurately and reliably perform study-specified immunological tests and peripheral blood mononuclear cells (PBMCs) viable freezing. Additionally, the solicitation requests resources that provide advice and training when deficiencies are identified and resources to evaluate immunology-based technologies for implementation in multi-site DAIDS trials. This request is for a renewal using a contract mechanism, and is of seven year duration.
Currently, over 70 US laboratories and over 45 laboratories in 17 countries receive proficiency testing panels of coded samples with varying levels of CD4+ T cells. The labs test the samples, results are analyzed and adequacy of performance is determined. Each lab receives its own lab-specific performance report and guidance is provided when performance is lacking. It is important to monitor the quality of CD4 testing because CD4 is a marker of disease progression, used as primary and/or secondary study endpoint, and is used to correctly time prophylactic therapy for opportunistic infections. Another key activity of the IQA program is monitoring how reliably labs reliably freeze viable PBMCs. Frozen PBMCs (freezing is part of many clinical studies) are used for various purposes, including tests for identifying markers of disease progression and determining intracellular drug levels. Additionally, the IQA program evaluates new instruments and assays, helps harmonize assay protocols, and obtains and characterizes a variety of quality control materials used to support performance evaluation efforts and assay development ones.
The IQA program provides guidance and training to labs when testing and freezing proficiency is lacking, including guidance on good clinical laboratory practices and instrument and assay validation. Additionally, as new immunological assays are developed, the IQA program will be expected to prepare and distribute training materials. Guidance and training will be provided via phone, email, webinars, workshops, visits to the lab on ground, and also by hosting investigators at the IQA program’s lab.
The reviewers (Adimora and Michael) were supportive of the concept after their questions about the beneficiaries were addressed. (Namely, all DAIDS clinical trials networks and cohorts benefit from the IQA CD4 proficiency testing program. The HVTN and the Microbicide Trials Network (MTN) do not participate in the PBMC freezing proficiency program. The HVTN has its own program and the MTN is currently evaluating participation in the program. The reviewers were also assured that the appropriate evaluation criteria were in place to select a contractor with the required expertise. A question concerning why the need for this program is ongoing was answered: 1) the labs are dynamic and always in transition with personnel turnover and problems with storage of specimens and 2) the location of the laboratories will change over time so that labs will not be the same on a continual basis, which makes quality assurance critical. This may be particularly true given the restructuring of the clinical trial networks and clinical trials sites. In addition, sites do fail proficiency testing and knowledge about which labs fail and being able to address the problems is critical.
Lori Zimand, M.P.H., Contracting Officer Representative, Basic Sciences Program
This initiative is a renewal with the objective to continue storage, management, and distribution of biospecimens from HIV positive and negative subjects enrolled in cohort studies as well as those in the HVTN and the HIV Prevention Trials Network (HPTN). The contract award would be for seven year duration. The NSR has been in operation since 1988 and currently stores over six million specimens.
Advantages of a central repository include rapid answers to longitudinal questions, allowing examination of all disease stages in the pre- and post-HAART era. Other advantages include the cost-benefits of having a central repository, in terms of efficiency in storage and distribution, and providing these specimens at no cost to the scientific community. It also allows storage of high quality specimens under uniform conditions.
The reviewers (Goodenow and McCutchan) were supportive of the concept. They felt that the contract provides a valuable asset and a considerable resource that will increase in value over the years. One question was raised regarding whether NIAID might consider opening up the repository to include specimens from non-human primate trials. However, there are not enough blood and tissue samples from the non-human primate trials for a repository collection. Another concern was cost in light of continual needs for maintenance and expansion. To address this issue, the NSR is considering removing samples in the repository from studies that have been closed, and any samples rejected by the research community will be destroyed.
In the discussion, it was noted that some programs such as ACTG have their own storage systems, and the program should be as rigorous as possible in the removal of specimens that are no longer needed and consider other cost-saving measures such as consolidation of storage freezers and volume of what is collected.
The ARAC members expressed support for the concept and voted approval.
Steven Turk, Ph.D., Chemist, Drug Development and Clinical Sciences Branch, TRP
The objective of this concept is to assist academic and private sector investigators in advancing the development of their products for the treatment of HIV and its co-infections. It is a contract mechanism and will be of seven year duration. The concept combines the scientific objectives of two expiring contracts into a single solicitation with awards anticipated in 2014.
Therapeutics development overall can be characterized into three categories: discovery phase, translational research, and clinical trials. Separate contracts for analytical chemistry, formulation and dosage form manufacture, and animal pharmacology and toxicology were first awarded in 1990. The scope has been refined periodically and contracts re-competed every five to seven years. Two contracts now cover these three task areas.
Typically, investigators approach DAIDS with a formal request for services that include product details, the biological background, data to warrant advancement of the product, explanation of the intellectual property status of the product, and a proposed product development plan. DAIDS reviews the request internally and assigns approved projects to its contractors. The investigators receive no direct funding via this mechanism. The contractors, in turn, generate products and/or data which are then returned to the investigators at no cost to the investigator.
The reviewers (Karn and Zack) supported the concept and offered suggestions that included:
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
June 26, 2012
Matthew Fenton, Ph.D.
National Advisory Allergy and Infectious Diseases Council
Director, Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
June 22, 2012
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 14, 2013