The discovery and development of safe, efficacious, cost-effective vaccines to prevent HIV infection and/or disease worldwide are among the highest priorities of the NIH AIDS research program. Within the NIH, the National Institute of Allergy and Infectious Diseases (NIAID) has the primary responsibility for HIV vaccine research and development.
A. Fundamental Research Supported Through RO1s
- NIAID has an extensive portfolio of grants directed at understanding:
- Mechanism of virus binding and entry.
- Methods of virus spread during the establishment of infection.
- Studies of establishment and spread of infection.
- Structure, function studies of HIV proteins.
- Basic immunology.
- HIV antigenic and nucleic acid variation.
- The Mechanisms of AIDS Pathogenesis Program solicits hypothesis -- driven in vivo -- HIV and AIDS pathogenesis research by collaborative multidisciplinary research teams. For HIV vaccine studies, this program seeks applications that address:
- Mechanisms of establishment of viral infection, including mucosal transmission.
- Immunological and virological events controlling primary infection.
- Host and virological factors modulating latent cellular and tissue reservoirs of HIV, including compartmentalization of virus.
- Host factors that modulate viral infection and/or disease progression.
- Host and viral factors regulating interspecies transmission of HIV/SIV.
- Mechanisms of protection induced by attenuated viruses.
- Impact of vaccination on viral transmission and/or disease progression.
- Transgenic animal models for HIV infection.
The most relevant studies are expected to examine molecular and cellular biology, virology, and immunology within the context of animal models and/or well-defined human cohorts or patient samples. Studies examining HIV transmission and pathogenesis in the context of the gastrointestinal mucosal tissues are also encouraged.
B. Vaccine Discovery, Screening, and Preclinical Research
- Innovation Grant Program (IGP): the IGP fosters exploratory investigator-initiated AIDS vaccine research at the earliest stages of concept genesis and evaluation. As such, a premium is placed on high-risk, high-impact studies and those believed to have a high likelihood of advancing the field.
- HIV Research and Design: HIVRAD supports basic vaccine research and design, including concept testing in animal models, development of potential vaccine candidates and evaluation of their mechanism of action, studies of immune correlates, and animal model development. Its goal is to advance the development of vaccine concepts identified in Innovation Grant studies or in other early preclinical research.
- Integrated Preclinical/Clinical AIDS Vaccine Development Program (IPCAVD): the IPCAVD program targets research at the preclinical-clinical interface of the HIV vaccine research and development pipeline. The program supports consortia of experts in animal models, molecular biology, immunology, and early clinical trials to pursue the iterative process of vaccine development, evaluation, and refinement of specific vaccine concepts. Early human studies within the period of the award are expected.
- HIV Vaccine Design and Development Teams (HVDDT): the HVDDT consists of consortia of scientists from industry and/or academia who have identified specific promising vaccine concepts amenable to targeted, accelerated product development.
- Vaccine Development Resources: a group of HIV-1 vaccine development resources contracts aids preclinical development of promising vaccine candidates. Resources are available to accomplish three basic functions:
- Manufacture of GMP pilot lots of vaccine for testing in humans, or GLP/reagent grade vaccine for testing in non-human primates.
- Preclinical testing of GMP produced candidates (e.g., safety, immunogenicity).
- Preparation of FDA submissions leading up to human trials.
For vaccine manufacturing, resources are currently available to produce reagents (GLP) or trial (GMP) vaccines within the following categories:
- Recombinant protein subunits
- DNA Vaccines
- Poxvirus vector-based vaccines
- Whole-killed virus
- Animal Models: the Simian Vaccine Evaluation Units (SIVEUs) and Laboratories evaluate promising SIV and HIV vaccines in non-human primates in order to accelerate HIV vaccine development. The sites and laboratories include:
- Tulane Regional Primate Research Center
- Washington Regional Primate Research Center
- TSI Mason Laboratories
- Henry Jackson Research Foundation
- Advanced BioScience Laboratories
- Beth Israel Deaconess Medical Center (cellular immunology)
- Duke University Medical Center (humoral immunology)
C. Clinical Research
- HIV Vaccine Trials Network (HVTN): NIAID-supported clinical trials of preventive HIV vaccines will be centered in the HVTN. The HVTN will carry out a comprehensive program of research to identify an effective and safe vaccine to prevent HIV/AIDS by studying the safety, immunogenecity, and efficacy of candidate HIV vaccines both domestically and internationally. Directly and through collaborations with other investigators, the HVTN will also support fundamental research relevant to HIV vaccine development and pathogenesis, including clinical evaluation of the relevance of global viral and host genetic variation in vaccine immunogenicity, to better understand the fundamental scientific principles of HIV vaccine development.
It is anticipated that awards will be made to the HVTN clinical sites in May 2000. Other components of the HVTN have already been funded, including:
Core Group/Operations Center:
Fred Hutchison Cancer Research Center
Larry Corey, Principal Investigator
Kent Weinhold, Principal Investigator
Statistical and Data Coordinating Center:
Fred Hutchison Cancer Research Center
Steve Self, Principal Investigator
- The HIV Prevention Trials Network (HPTN): the HPTN will conduct multidisciplinary Phase I, II, and III trials of biomedical and behavioral interventions to prevent HIV transmission. In addition to studies involving microbicides, STD prevention and treatment, and behavioral and barrier interventions, the HPTN will conduct vaccine trials (and studies of other modalities) to prevent perinatal transmission of HIV.
It is anticipated that awards to the HPTN clinical sites will be made in July 2000. Awards have already been made to:
Core Group/Operations Center:
Family Health International
Ward Cates, Principal Investigator
Johns Hopkins University
Brooks Jackson, Principal Investigator
The Statistical and Data Coordinating Center:
Fred Hutchinson Cancer Research Center
Thomas Fleming, Principal Investigator
- The NIH Loan Repayment Program (LRP), mandated by congress under Public Law 100-607 in 1988, authorized under 42 USC 288-1 and reauthorized under Public Law 103-43, encourages health professionals to engage in AIDS-related research at NIH. Since the program enrolled the first participants in 1989, 115 professionals have been attracted to NIH as a result of loan repayment benefits, with more than half remaining longer than their contractually obligated period.
- For the past 10 years, the Fogarty International Center (FIC) has supported the AIDS International Training and Research Program (AITRP), a multidisciplinary program designed to strengthen research capacity in the epidemiology, prevention, diagnosis, and treatment of HIV/AIDS in developing countries; to facilitate the evaluation of AIDS drugs and vaccines internationally; and to provide global scientific leadership in HIV/AIDS. The AITRP is active in 100 developing countries, with activities focused in the dozen countries that have the most serious current or emerging HIV/AIDS epidemics.
- The Fogarty International Research Collaboration Award for AIDS (FIRCA) provides support for collaboration between U.S. and foreign scientists in the foreign collaborator's laboratory through grants to U.S. investigators already conducting HIV-related research.
- The HVTN also have positions available to train scientists in developing countries.
E. Other Research Resources Available for the Global Research Community
- NIH AIDS Research and Reference Reagent Program. Since 1988, the AIDS Reagent Program has served the worldwide research community by providing state-of-the-art biological and chemical materials for study of HIV and related opportunistic infections. Over 1,670 reagents are available to registered users.
- Tetramer Facility. Currently a component of the NIH AIDS Research and Reference Reagent Program, the Tetramer Facility provides custom synthesis and distribution of soluble MHC I/peptide tetramer reagents that can be used to stain antigen-specific CD8 T cells. In the future, MHC II/peptide reagents should become available for the staining of antigen-specific CD4 T cells. Tetramer reagents will be synthesized at the NIAID Tetramer Facility contract site located at Emory University.
- HIV Database and Analysis Unit. This unit, based at the Los Alamos National Laboratory in New Mexico, consists of two related databases, the HIV Molecular Immunology Database and the HIV Genetic Sequence Database.
- The HIV Molecular Immunology Database provides a comprehensive listing of defined HIV epitopes. It includes epitope alignments, maps, and reference information for the cytotoxic and helper T-cell epitopes, and antibody binding sites in HIV-1 immunologically reactive sites along with reviews pertaining to HIV Immunology.
- The Genetic Sequence Database compiles genetic information on HIV from GenBank and other international genetic databases, and then carries out in-depth analysis of this information.
- Genetic Sequence Variability of HIV-1 and Related Lentiviruses. This contract, currently held by the University of Alabama at Birmingham, carries out genetic cloning and sequencing studies. Through this contract, full-length proviruses representing clades A through H (group M subtypes), a number of subtype recombinant viruses, and several group O viruses have been cloned and sequenced in their entirety. Individual viral genes have been subcloned into expression vectors as research tools. These clones can be used to produce proteins in various expression systems, for the creation of SIV-HIV chimeric viruses (SHIV), or directly in the design of vaccines. In addition, gag, pol, env, and nef genes from clades A through H have been subcloned into shuttle vectors for generating recombinant vaccinia viruses.
- Collaboration with UNAIDS, formally known as the UNAIDS Network for HIV Isolation and Characterization, sponsors an international collaboration among more than a dozen laboratories. UNAIDS obtains patient materials from HIV-infected individuals at sites around the world and then distributes these materials to network laboratories for virological and immunological studies. NIAID provides for large-scale expansion, storage, immunological and biological characterization of virus isolates and transfer of these isolates to vaccine companies and other UNAIDS collaborating laboratories. In addition, the NIAID-supported HIV Database and Analysis Unit serves as the database for this activity. To date, close to 200 viruses have been isolated through this project.
The Dale and Betty Bumpers Vaccine Research Center.
The Dale and Betty Bumpers Vaccine Research Center (VRC) will be housed in a new building, which is still under construction, and will bring together the largest number of NIH researchers dedicated to making vaccines. The initial goal of the VRC will be to develop candidate vaccines against HIV. The building has been designed to encompass the entire spectrum of vaccine research, from basic research up through product development, and will include facilities to produce small lots of experimental vaccines suitable for clinical trials. At full capacity, the VRC will employ about 100 scientists and support staff led by Director Gary Nabel, M.D., Ph.D.