NIH Research Goals
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Goal #4 To conduct and support basic, preclinical, and clinical research to develop a safe and effective preventive HIV vaccine.
Objective #1

Increase scientific knowledge of host defense mechanisms leading to protection against HIV infection and disease.


More basic knowledge is needed to define protective immune responses to HIV in order to facilitate the development of vaccines and other immunologic strategies to prevent and control HIV infection.

Action Steps
  1. Develop animal models that are practical and as much as possible are representative of the spectrum of HIV infections and AIDS; models should be amenable to use in evaluating protection by vaccines and, where this can be demonstrated, determining the correlates of protective immunity.
  2. Determine the mechanisms of immunologically mediated control of infection with HIV and other related retroviruses, including the role of specific and nonspecific immunity in inhibiting viral replication.
  3. Additional basic knowledge is needed to determine: o factors, including persistence of antigens, that favor establishment of memory and development of long-term protective immunity;
    • the heterogeneity of specific responses to an immunogen within distinct compartments of the immune system;
    • factors that promote development of particular effector cell types;
    • mechanisms resulting from exposure to HIV that interfere with induction or propagation of vaccine-induced effector responses;
    • mechanisms of virus neutralization.
  4. Study acutely infected individuals, exposed/uninfected humans (and other primates), and rapid/nonprogressors to determine viral and host factors that impact amounts of circulating virus and disease course; ensure that plasma, PBMC, biopsy, autopsy, and other key patient and animal samples, including CNS samples, are accessible to qualified laboratories.
  5. Define and characterize viral B cell and T cell epitopes that induce protective immunity; understand their structure and antigenicity and determine whether and how their immunogenicity can be exploited in vaccine development; and define epitopes in which substitutions cannot be tolerated by the virus.
  6. Determine whether infection with one strain of HIV or related retroviruses confers protection against subsequent infection with a second strain; determine the protective mechanism and timing.
  7. Understand how and why HIV and related lentiviruses evade or escape from humoral and cellular arms of the immune response.
  8. Explore strategies to elucidate the obligate mechanisms for protective immunity against HIV, including amplification of selected responses by passive transfer of Ab or immune cells and subtraction by deletion of selected components of the immune system.
  9. Study chronic infection with attenuated viruses, such as SIV variants shown to induce strong protection against virulent SIV strains in macaques, to understand what properties of the virus and the immune system are responsible for lack of disease induction and protection from challenge with wild-type virus.
  10. Explore the molecular epidemiology and serology of HIV-1 populations relevant to vaccine trials and collect clinical material from these populations for scientific analysis.
  11. Acquire epidemiological information to assist in interpretation of these analyses.
  12. Develop quantitative measures of HIV concentration in bodily fluids to determine whether there is a relationship between HIV concentration and transmission and to determine the effect of concurrent STDs on HIV shedding.


Objective #2

Apply findings from basic, epidemiologic, and clinical research to the design and evaluation of vaccine strategies in laboratory studies and animal models, and foster collaboration with industry in the research and development of candidate vaccines.


The identification of viral antigens and vaccine delivery methods that elicit long-lasting protective immune responses against a broad range of HIV isolates will facilitate development of effective vaccines.

Action Steps
  1. Support the design and development of potential vaccines, including vaccines composed of:
    • whole-killed HIV and genetically engineered, noninfectious HIV mutants that lack the viral RNA genome or have a defect in a critical gene necessary for replication but contain an array of HIV genes for expression of antigenic proteins;
    • live, recombinant viral and bacterial vectors engineered to express one or more HIV proteins;
    • naturally occurring and genetically engineered, live-attenuated strains of HIV;
    • synthetic peptide candidates capable of inducing and boosting both cellular and humoral immunity;
    • DNA coding for viral proteins; o agents that stimulate mucosal immune responses;
    • a combination of the above agents and preparations;
    • other novel agents and preparations.
  2. Evaluate the efficacy of vaccine strategies in animal models of HIV and related lentiviruses. To accomplish this:
    • test vaccine strategies in animal models that most closely mimic the HIV infection in humans;
    • determine the effect of vaccine formulation and regimen as well as the nature, timing, and route of vaccine challenge on the characteristics and effectiveness of the vaccine-induced immune response;
    • define the impact of different vaccine approaches on kinetics of immune responses, kinetics and localization of viral replication, disease progression, and biologic characteristics of breakthrough virus including transmissibility;
    • conduct long-term follow-up of vaccinated animals that become chronically infected to determine the impact of vaccination on disease progression;
    • develop assays to distinguish between infection and serological responses due to immunization.
  3. Support design and development of methods to improve or modulate immune responses (qualitatively or quantitatively), including:
    • novel adjuvants and presentation methods;
    • vaccines incorporating cytokines or other biologically active molecules;
    • establishment of physical or biological reservoirs for long-term antigen presentation;
    • other novel strategies.
  4. Encourage development of candidate vaccines of suitable antigenic types and possessing stability and route of administration characteristics appropriate for international as well as domestic use.
  5. Characterize and evaluate the potential negative side effects of candidate vaccines, including production antibodies enhancing neurotoxicity and oncogenicity.
  6. Develop better in vitro methodologies to measure immune responses to primary viral isolates.
  7. Develop infrastructure, and address scientific, legal, and regulatory issues to foster and encourage participation by, and collaboration with, industry and other agencies in the research, development, production, and clinical testing of candidate vaccines.
Objective #3

Select candidate vaccines or concepts suitable for Phase I and Phase II trials and conduct these trials.


Suitable candidate vaccines need to be selected and evaluated in Phase I and Phase II trials to determine safety and immunogenicity.

Action Steps
  1. Support the conduct of Phase I and Phase II coordinated clinical trial that will determine long-term and short-term safety and compare immunologic responses to preventive vaccine candidates; include a broad range of humoral, cell-mediated, and mucosal immune parameters.
  2. Develop a mechanism to evaluate the suitability of vaccine candidates for entry into Phase I and Phase II trials; evaluation criteria should include originality and intrinsic value of the concept and animal model data.
  3. Develop strategies at the local and national levels to reduce social and economic risk to volunteers in Phase I and Phase II trials to facilitate broad participation.
  4. Design and conduct Phase II trials using promising HIV vaccines that are also genetically or immunologically related to HIV isolates circulating in the proposed trial population and of an appropriate size to facilitate decisions regarding efficacy trials.
  5. Analyze immune responses in vaccines and appropriate controls.
  6. Isolate and characterize virus and follow clinical course and immune responses of vaccines who become HIV-infected.
  7. Study viral isolates from participants in HIV vaccine trials and selected controls to explore the possible effects of vaccination on the characteristics of transmitted viruses.
  8. Conduct behavioral research on trial participants to establish whether their risk behavior has been influenced by participation in a vaccine trial, with emphasis on individuals who become infected while participating.
  9. Closely coordinate the evaluation of research findings on prophylactic AIDS vaccines with preclinical research and immunotherapeutic interventions.


Objective #4

Identify mechanisms of protective immunity to HIV in newborns and infants and support the development of safe and effective immunologic strategies for preventing or controlling HIV infection in this population.


Distinct approaches and infrastructure are needed to achieve protection of newborns and infants because of the unique nature of their immune responses and modes of exposure to HIV.

Action Steps
  1. Determine what viral, immunologic, and non-immunologic host factors influence transmission of HIV-1 from mother to infant;
    • Compare virus isolates that are and are not transmitted from mother to infant;
    • Seek maternal and infant immune responses that might prevent transmission to infants.
  2. Develop and maintain domestic and international infrastructure necessary to enroll mothers and infants in prospective long-term follow-up vaccine trials and other interventions.
  3. Determine the safety and immunogenicity of various HIV vaccines and adjuvants in relevant animal models of maternal-fetal and maternal-infant transmission to evaluate safety, immunogenicity, and efficacy of candidate vaccines.
  4. Select and evaluate antibody and/or cellular preparations in passive or passive/active HIV prevention studies.
  5. Establish criteria for advancement of candidates in Phase I, Phase II, and Phase III clinical trials in children.
  6. Conduct Phase I, Phase II, and Phase III clinical trials in children for the most promising candidates that meet established criteria.
Objective #5

Identify appropriate domestic and international population and develop infrastructure and collaborations with government, communities, and industry necessary for ensuring adequate performance of Phase III efficacy trials.


Preparation for HIV vaccine efficacy trials requires development of an infrastructure and a series of studies and planning activities to ensure their feasibility.

Action Steps
  1. Develop domestic and international sites with access to populations at high risk for acquiring HIV infection, where vaccine or other prevention research activities may be feasible.
  2. Establish linkages with communities or community organizations where efficacy trials might be conducted to optimize education, recruitment, and follow-up activities and to help address community concerns related to AIDS vaccine efficacy trials.
  3. For international trials, work closely with national (host) governmental and regulatory authorities, collaborating institutions, vaccine manufacturer(s), and the World Health Organization to plan and conduct vaccine efficacy trials adhering to the highest ethical and scientific standards.
  4. Carry out appropriate epidemiologic studies that determine the risk profiles and infection rates of various populations in the United States and worldwide in order to identify those groups most likely to be the participants in vaccine trials.
  5. Maintain the necessary laboratory infrastructure at designated sites for conducting domestic and international vaccine efficacy trials.
  6. Acquire and analyze HIV isolates from recent seroconverters representative of potential efficacy trial populations so that genetic and antigenic information about virus circulating in the population can be obtained.
  7. Evaluate other biomedical and behavioral interventions that could prove of benefit in decreasing the incidence of HIV infection in the populations identified for future vaccine efficacy trials and assess their potential impact on the evaluation of vaccine efficacy.
  8. Conduct behavioral research in populations at high risk for HIV infection to determine, for example, appropriate risk-reduction interventions and to estimate risk behavior and recruitment, adherence, and retention strategies pertinent to the design and execution of a successful efficacy trial, especially for populations that have been historically underrepresented in clinical trials.
  9. Determine possible adverse social, economic, or legal consequences of participation in clinical trials, and develop strategies for mitigating potential harm.
  10. Determine optimal methods of achieving informed consent for vaccine efficacy trials.
  11. Prepare for adequate long-term follow-up of individuals participating in vaccine clinical trials where it will be necessary to determine the longevity of immune response, the correlates of immune protection, long-term safety, the impact of participation on risk-taking behavior, and the possible positive or negative effects of vaccine immunization against disease progression and HIV transmission.
  12. Encourage linkage between vaccine preparedness studies in high-risk populations and other research activities including research on TB and STDs; and integrate research on vaccines against opportunistic infections as appropriate.
Objective #6

Select suitable vaccine candidates and support efficacy trials when appropriate criteria are met.


Conduct HIV vaccine efficacy trials of the most promising candidate vaccines in well-characterized, high-risk populations to identify effective vaccines for the control of HIV infection.

Action Steps
  1. Establish criteria with concurrence of an advisory group that has the requisite scientific, public health, government and community expertise.
  2. Conduct large-scale efficacy trials of preventive vaccine candidates that have proven promising, safe, and immunogenic in Phase II trials and that meet appropriate criteria;
    • Evaluate HIV vaccine candidate efficacy against infection and disease;
    • Evaluate additional virologic, immunologic, and behavioral outcomes, particularly correlates of protective immunity;
    • Ensure that trials are conducted with the highest regard for social and ethical standards.
$ 100.4 million
$ 109.5 million
$ 116.1 million

All populations.


Researchers, clinicians, community and patient representatives, and NIH-affiliated advisory councils and committees.



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