Our goal in preparing this report is to outline the scientific and practical obstacles in the path of developing a safe, effective, globally deployable AIDS vaccine; to examine the AIDS vaccine research programs funded by the NIH -- taking 1998 as a single, comprehensive snapshot -- and to recommend methods of overcoming those obstacles in order to accelerate the discovery, development, and deployment of an effective vaccine.
It is our belief that a vaccine is most likely to emerge from a creative and rigorous synthesis of basic research in human and non-human primate immunology and in HIV virology, with animal and clinical studies of vaccine candidates, delivery routes and adjuvants. We hope that by examining the scientific issues faced in basic, animal, and clinical HIV vaccine research, we can contribute to overcoming the obstacles and thus contribute to a revitalized, accelerated, intensified vaccine effort.
We surveyed the published scientific literature in order to get a sense of the progress in the field and the unanswered questions that are facing the scientific community. We also interviewed more than two dozen leading researchers, asking them what they thought were the most pressing scientific issues in vaccine research and what practical problems might be impeding progress toward developing a vaccine for HIV infection. Finally, we pored over the listings and abstracts of grants funded with AIDS vaccine research dollars during federal fiscal year (FY) 1998. We looked at FY 1998 because that was the most recent year for which complete records were available. Whenever possible, we have tried to comment on newer projects and programs where they are relevant.
We have divided the report into three major sections: basic research, animal-based research, and clinical trials. Several major recommendations and overarching themes emerged from our analysis. These major themes include advocating for:
It is of great concern to us that our findings and recommendations echo many of those made by researchers and advocates about the NIH AIDS vaccine program in the Levine report almost four years ago. While the NIH AIDS vaccine program has grown substantially in recent years and been considerably restructured, there are lingering problems in the program that have yet to be adequately addressed.
Finding a way to control the global AIDS epidemic should be one of the world's highest public health priorities. Although behavioral interventions and public health measures such as safer sex campaigns, antiretroviral therapy initiated during pregnancy, and the surveillance of the blood supply remain our best current options, HIV vaccines may be the only cost-effective way to ultimately end transmission of HIV worldwide. Despite increased attention in the media, speeches from President Clinton, and increased budgets for HIV vaccine research, government and private investor funding for HIV vaccine research is still relatively small. Funding in 1998 to research and develop HIV vaccines by NIH and all other U.S. agencies amounted to only about 10% of overall AIDS research funding.
The $148 million spent by the NIH in 1998 for HIV vaccine research was widely distributed, supporting research through 647 grants and contracts to more than 140 institutions and easily more than 1,000 researchers. NIH funding thus encompassed an enormously broad range of researcher ideas. Although widely distributed, NIH funding wasn't randomly scattered. The 1998 NIH effort included several targeted, concerted funding initiatives to address critical research questions, refine research techniques, make new assays and reagents widely available, and support networks and collaborations.
It is our contention that the NIH AIDS vaccine research effort -- including its basic, animal, and clinical aspects -- can utilize continuing funding increases in line with those obtained in the past few years. Where will this money come from? In recent years, NIH has received unprecedented increases in its annual budget. AIDS research too has continued to grow at a robust rate. With the NIH budget set to double by 2002, additional spending on AIDS vaccine research should be possible without reducing resources devoted to other areas of research on HIV infection, or on other high priority basic and clinical research areas.
NIH needs to support additional work on antigen delivery in both primates and humans. NIH should expand access to monkeys through supporting new breeding programs and investing in the development and production of reagents for primate experiments. Study sections need to be more generous in the level of funding they will support for primate studies. Resources devoted to clinical and human immunology need to be increased, with a special emphasis on bringing young physicians into the field to study some of these unanswered questions in a clinical setting.
Given the difficulty in sustaining both antibody and cellular responses with current immunogens, NIH should invest additional resources in the study of immunological memory in humans. NIH should coordinate its non-AIDS work in this area with basic research on HIV vaccines. NIH needs to break free of the tether of outdated approaches to virus neutralization using monomeric subunit vaccines in both basic and clinical research. While several groups are working on better envelope-based immunogens, research in this area can be expedited if NIH supports fast-track testing of these new products in macaques and in humans.
Large, comparative studies of vaccines in macaques are critical to assess and optimize candidate immunogens for further testing in humans. NIH should streamline the mechanisms for initiating these trials and provide sufficient resources for their expeditious conduct so that the information gathered can be quickly integrated into decision making.
NIH needs to directly fund development of products to feed into clinical evaluation. NIH should expand direct contracting with companies to develop HIV vaccine candidates, such as newer versions of Modified Vaccinia Ankara (MVA), Venezuelan Equine Encephalitis (VEE), Adeno-Associated Virus (AAV), and attenuated salmonella vectors. The NIH should encourage optimization of current vaccine candidates and be willing to discourage work in outdated vaccine concepts that have performed poorly in preclinical, animal or early human studies.
NIH should ensure that the new HIV Vaccine Trials Network and the vaccine clinical trial activities of the Vaccine Research Center, the NIH intramural trial site, and the perinatal sites have the capacity for an adequate number of phase I, II, and III trials during the coming five years. The advancement of candidate immunogens along the vaccine clinical development pipeline has to be driven by science and not by political expediency or industry demands.
"NIH-Funded AIDS Vaccine Research: A Critical Review" can be obtained in its entirety at our website www.aidsinfonyc.org/tag or by requesting a printed copy from our office: (212) 971-9022.
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