Appendix H: Summary of HHS Research Strategy

The National Institutes of Health Revitalization Act of 1993 (Public Law 103-43) provided that the Director of the Office of AIDS Research (OAR) “shall plan, coordinate and evaluate research and other activities conducted or supported” by the NIH. The Director of OAR “shall act as the primary Federal official with responsibility for overseeing all AIDS research conducted or supported by the National Institutes of Health” and “shall establish a comprehensive plan for the conduct and support of all AIDS activities of the agencies of the National Institutes of Health...; ensure that the Plan establishes priorities among the AIDS activities that such agencies are authorized to carry out; ensure that the Plan establishes objectives regarding such activities...; and ensure that the Plan serves as a broad, binding statement of policies regarding AIDS activities of the agencies, but does not remove the responsibility of the heads of the agencies for the approval of specific programs or projects, or for other details of the daily administration of such activities, in accordance with the Plan.” The law further provides that “the Director of the OAR shall ensure that the Plan provides for basic research; provides for applied research; provides for research that is supported and conducted by the agencies; provides for proposals developed pursuant to solicitations by the agencies and for proposals developed independently of such solicitations; and provides for behavioral research and social science research.”

Highlights from the plan are provided below. More detailed information can be obtained at http://www.nih.gov/od/oar/public/public.htm#PLAN

Vaccine development
A safe and effective HIV vaccine would provide a valuable tool to prevent HIV infection. Despite years of extensive research, however, a vaccine to prevent HIV infection remains elusive. Private- and govern-ment-sponsored research continues, focusing on defining necessary vaccine components and the best means of vaccine delivery to ensure the optimal protective response.

The process of vaccine development will benefit from a strategic alliance that ensures coordination among the agencies working to identify a safe and effective HIV/AIDS vaccine, particularly as activities to evaluate promising candidate vaccines in developing countries progress. The Emergency Plan offers an unprecedented opportunity to develop interagency alliances. The Department of Health and Human Services (HHS) has created a new strategic alliance – Partners in AIDS Vaccine Evaluation (PAVE) – in which the National Institute of Allergy and Infectious Diseases (NIAID/HHS) will be joined by the NIH Office of AIDS Research, the Centers for Disease Control and Prevention (CDC), the Department of Defense (DOD), and the HIV Vaccine Trials Network. PAVE will invite participation from nongovernmental organizations that are collaborating directly with government agencies on HIV vaccine development. PAVE will serve as a forum to achieve increased efficiencies and cost-effectiveness for all vaccine evaluations under its auspices. A steering group comprising the principals from the three governmental agencies and the chair of NIH’s AIDS Vaccine Research Working Group will serve as PAVE’s principal advisory group.

PAVE will focus initially on preparing for phase III trials, which will involve:

• Developing common immunological, virological, safety, and other laboratory capabilities worldwide;

• Strengthening clinical trial site capacity in developing countries, including the development and use of common training modules and site development priorities and standards; and

• Developing shared, compatible protocols.

Strategies include:

1. Central medical centers:  Institutions suitable for hosting central medical centers to serve as hubs or referral centers for institutions conducting HIV vaccine trials will be identified. Logistical, managerial, operational, ethical, and regulatory support will be provided to ensure adequate capacity for conducting large-scale trials and to help link existing networks to future central medical centers.

2. Efficacy trials: Support will be provided to identify and advance promising candidate vaccines to efficacy trials, including trials in five to seven targeted countries. These trials will evaluate vaccine safety and efficacy against locally circulating strains of HIV.

3. Phase I/II studies: Phase I/II studies in two to three targeted countries will be conducted to evaluate the safety and immunogenicity of promising candidate vaccines; to train research staff in the conduct of HIV vaccine trials; to establish standard operating procedures for high-quality, ethically sound trials; and to ensure that appropriate reporting and oversight procedures are in place. Knowledge from clinical trials will be used to improve vaccine design and make vaccines more effective.

4. Capacity building: Health care delivery networks need to be strengthened so they have the components and capacities necessary to conduct trials of the highest caliber and integrate these activities into care and prevention programs. These components and capacities include:

• Sufficient numbers of motivated and trained medical, laboratory, and support personnel;

• Equipment to plan, conduct, and oversee quality vaccine trials;

• The capacity to follow patients for prolonged periods;

• The ability to maintain medical records according to international standards; and

• Appropriate reporting and oversight procedures to ensure the protection of human subjects, data quality, and study integrity.

The linkages among federally supported vaccine development programs need to be strengthened with emphasis on preparing sites for HIV vaccine efficacy trials.

1. Public-private partnerships: Expansion of public-private partnerships in HIV vaccine development will help engage the expertise necessary to advance candidate vaccines through the clinical pipeline. Partnerships should provide support to companies for developing manufacturing and testing processes and producing sufficient doses of the most promising candidate vaccines for efficacy trials.

Microbicide development
In the absence of a safe and effective vaccine, the options for sexually active women – particularly those who are coerced or forced to have sex – to protect themselves from HIV and other sexually transmitted infections remain minimal. A safe and effective topical microbicide (i.e., an antimicrobial product applied topically that inhibits or inactivates HIV) would offer another means of protection for women beyond condoms.

Under the Emergency Plan, HHS will continue to support a comprehensive program for discovering, developing, testing, and evaluating microbicides for HIV prevention.

NIH is the major federal sponsor of microbicide research and development, supporting microbicide design research and microbicide development and production. Under the Emergency Plan, NIH will expand the HIV Prevention Trials Network, a worldwide network for collaborative multidisciplinary, multisite clinical trials established by NIH to evaluate the safety and efficacy of non-vaccine HIV prevention interventions.

NIH has also spearheaded an effort to develop a U.S. Government strategic plan for microbicides, which incorporates the microbicide activities of agencies within HHS such as NIH, CDC, and the Food and Drug Administration, as well as USAID. This strategic plan provides a blueprint for a coordinated effort structured to address each step involved in developing and testing potential microbicides and their subsequent implementation in prevention activities.

Strategies include:

1. Basic biological and physiological research related to microbicides: This research will elucidate the basic mechanisms of HIV transmission (both virus and host factors) and other sexually transmitted infections at mucosal surfaces. Such research is important for developing and applying microbicides in diverse populations.

2. Microbicide development and preclinical studies: The Emergency Plan will support the discovery, development, and preclinical evaluation of topical microbicides alone and in combination.

3. Microbicide formulations and modes of delivery: Programs will develop and assess acceptable formulations and modes of delivery for microbicides, bridging knowledge and applications from the chemical, pharmaceutical, physical, bioengineering, and social sciences.

4. Clinical trials of microbicide products: Clinical studies of candidate microbicides will be conducted to assess their safety, acceptability, and effectiveness in reducing the transmission of HIV and other sexually transmitted infections in diverse populations in domestic and international settings.

5. Behavioral and social science research related to microbicides: Basic and applied behavioral and social science research will be conducted to enhance microbicide development, testing, acceptability, and use domestically and internationally.

6. Training and infrastructure: Infrastructure and training needs will be met to permit international and domestic microbicide research to proceed and to accelerate access to microbicidal products in diverse populations.

Therapeutics research
Considerable progress has been made in understanding how HIV attacks the immune system and how to treat it. Researchers have developed new methods to detect and measure HIV in blood and tissue and to test for antiretroviral (ARV) drug resistance. Therapeutic regimens using combinations of drugs have extended and improved the quality of life for many HIV-infected people in developed nations and have led to declines in AIDS-related mortality.

There is an urgent need today to extend these benefits to developing countries hardest hit by the disease. Research is needed to determine how best to deliver and monitor antiretroviral therapy (ART) and to manage the clinical treatment of adults and children in resource-limited settings. Additionally, research is needed to determine the spectrum of opportunistic infections and co-infections in threatened populations and their impact on HIV infection and disease progression.

Under the President’s Emergency Plan, the United States will support the expansion of preclinical drug development resources; feasibility studies and efficacy trials for ARV and antimicrobial drugs; and the provision of laboratory support for diagnostics, clinical trials, and expanded treatment delivery. As part of this effort, NIH is working with France’s Agence Nationale de Recherche sur le SIDA and the Antiretroviral Therapy Cohort Collaboration to develop a database that will collect treatment-related data from a large number of research sites in developing countries. Systematic analyses of the database may permit comparisons of the short- and long-term effectiveness of ART in these sites and developed countries. The database also will facilitate studies on other aspects of treatment-related operational research. Findings from this project may provide important models for multisite, multicountry operational research that will complement traditional clinical research models in establishing the effectiveness of antiretroviral strategies in developing countries.

Tuberculosis research
Worldwide, tuberculosis is the leading cause of death in HIV-infected persons. Research is needed to determine the incidence of TB infection and co-infection, improve diagnostic capability, and develop and deliver affordable and effective therapies to adults and children in developing countries. Important research questions include the effectiveness and tolerance of different dosing regimens and comparisons of providing concurrent TB/ARV treatment and providing TB treatment before ART.

Research is needed to:

• Determine incidence of TB infection and co-infection;

• Improve diagnostic capability, especially given the significant lower sensitivity of current methods in person infected with HIV;

• Develop and deliver affordable and effective therapies to adults and children in developing countries;

• Determine the effectiveness and tolerance of different dosing regimens and comparisons of providing concurrent TB/ARV treatment;

• Optimize timing of providing TB treatment before ART;

• Develop new drugs to combat the problem of emerging drug resistance;

• Develop and test molecular targets for tuberculosis vaccines tailored for HIV-infected persons, including those in largely BCG-vaccinated populations;

• Develop models for building community-research partnerships with local health units in ethnically diverse communities;

• Focus on the special problems of children co-infected with tuberculosis and HIV; and

• Refine cooperative strategies between tuberculosis and HIV prevention and control activities.

Malaria research
Malaria is a major cause of death and disability in Africa. The research agenda will include:

• The genome sequencing of the malaria parasite Plasmodium falciparum and of its mosquito vector Anopheles gambiae;

• Development of molecular tools to genetically manipulate the parasite and vector in studies relevant to drug and vaccine discovery;

• Pathogenesis and vector control;

• Identification of the genes mediating chloroquine and insecticide resistance and molecular techniques to characterize drug-resistant parasites from clinical isolates;

• An accelerated malaria vaccine research and development program;

• Quantification of the economic impacts of malaria in endemic countries;

• Discovery and development of new antimalarial drugs from plants, animals, and microorganisms; and

• Development of predictive models of the transmission risk for many infectious diseases, including malaria, in relation to major environmental disturbance events.

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