AIDS Vaccine Research Highlights
Currently, three dozen preventive HIV vaccines are being tested in small-scale clinical trials around the world. The National Institute of Allergy and Infectious Diseases (NIAID) is poised to move into large-scale efficacy trials as soon as a suitable product is identified, according to Jack Killen, M.D., director of NIAID's Division of AIDS. "NIAID believes this point will be reached most quickly," comments Dr. Killen, "through support of a balanced program that integrates both basic research and empiric development carried out in concert, neither to the exclusion of the other."
Dr. Killen will describe key aspects of NIAID's strategy for HIV vaccine research and development, with special emphasis on the government's unique role in this endeavor, at the XI International AIDS Conference in Vancouver, British Columbia. Dr. Killen will speak on Thursday, July 11, in the Waterfront Ballroom during the "Research, Development and Testing of HIV Vaccines" roundtable that begins at 1:30 p.m. Pacific Time.
"We believe that private-public sector partnerships and a vigorous level of industrial activity are pivotal to continued progress in the development of an AIDS vaccine," comments Dr. Killen. "In our view, the problem frequently alluded to as 'market failure' results directly from industry's perception of an insufficient information base for rational decision-making. We believe that the involvement of industry will increase as basic research, the source of innovation, increases knowledge, creates opportunities and lessens the perception of risk."
NIAID is addressing this problem in a number of ways, first and foremost, through its investment in basic research. Other examples include the NIAID Reference and Reagent Repository and the research of the HIVNET program, which is carrying out epidemiologic, virologic and behavioral research required to ensure the success of the efficacy trials in communities of individuals at risk of infection. Through HIVNET and other programs, NIAID is also working to build community linkages. The Institute has also provided leadership in Phase I and II clinical trials through the AIDS Vaccine Evaluation Group, and in developing better clinical trial methodology.
"Because our current state of knowledge is insufficient to predict which HIV vaccine strategy will be successful, we believe it is essential that the global HIV vaccine effort simultaneously pursue empiric development of multiple approaches in collaboration with a number of private sector sponsors," comments Dr. Killen. NIAID is therefore drafting joint development plans with individual industrial partners, as announced earlier this year by NIAID Director Anthony S. Fauci, M.D.
"The major strength of the NIH is in fundamental research and the testing of vaccine concepts, while industry's greatest strength is in product development, and appropriately, the goals of product marketing and licensure," explains Dr. Killen. "There is considerable congruence in these goals," he adds, "and it is in this congruence that we attempt to establish development plans with our industrial partners." These plans prospectively define specific scientific milestones to be met for the development and testing of the vaccine to continue.
AIDS Vaccine Evaluation Group Progress Discussed
Since 1988, more than 1,900 healthy, non-HIV-infected adults have voluntarily enrolled in 25 Phase I and II experimental AIDS vaccine trials conducted in the United States by the NIAID-sponsored AIDS Vaccine Evaluation Group (AVEG). AVEG consists of six university-based clinical testing sites, two central immunology laboratories, and a data coordinating and analysis center. Several talks describing progress in the AVEG trials will be presented on Monday, July 8, in Session 123 at 1:30 p.m. Pacific Time in Room A3 of the Vancouver Trade and Convention Centre (VTCC). Highlights include those talks mentioned below.
The AVEG trials have involved 16 experimental AIDS vaccines, 10 adjuvants (a substance that enhances the immune responses stimulated by a vaccine), and a variety of delivery vehicles and routes, dosages and schedules of immunization. A review of the last eight years of vaccine research by the AVEG program, what has been learned from these trials and AVEG's future plans will be discussed by AVEG executive committee chairman Barney S. Graham, M.D., Ph.D., of the Vanderbilt University AVEG site in Nashville, Tenn.
Initially AVEG trials focused on testing injections of first-generation subunit vaccines. These are genetically engineered copies of single HIV-1 proteins, generally the surface proteins gp160 or gp120. A three-year follow-up report on the safety, immunity and risk behavior in HIV-1-uninfected volunteers who received either of two recombinant gp120 vaccines in the only Phase II AVEG trial to date will be presented by M. Juliana McElrath, M.D., of the University of Washington AVEG site in Seattle, Wash. This trial, AVEG 201, included a diverse group of 296 heterosexuals, gay/bisexual men and injection drug users at low or high risk for HIV infection who received a recombinant gp120 vaccine made either by Genentech (South San Francisco, Calif.) or Chiron Biocine (Emeryville, Calif.).
The AVEG program has since evolved to include the testing of synthesized peptides (small compounds formed by linking two or more protein building blocks) and live vaccine vectors; novel delivery vehicles and adjuvants; and vaccines made from combinations of the highly mutable surface protein and the more conserved internal HIV proteins. Moreover, inducing cell-mediated and mucosal immune responses in addition to antibody-mediated immune responses have become goals in the design and evaluation of newer trials.
One of the most promising vaccine strategies tested by AVEG so far is the prime-boost approach, the sequential administration of a live vector vaccine and a purified subunit vaccine. The objective of this strategy is to combine the strengths of each type of vaccine. Vector-based vaccines -- which use an attenuated virus or bacterium to carry genetic copies of pieces of HIV into the body for presentation to the immune system -- primarily stimulate cell-mediated immune responses. Subunit vaccines primarily induce antibodies. To date, the prime-boost regimen has been much better than other HIV vaccine strategies at consistently inducing both HIV-1 neutralizing antibody and cytotoxic T lymphocyte (CTL) responses.
ALVAC (tradename, Pasteur-Merieux/Connaught, Swiftwater, Penn.) is a vector derived from a weakened canarypox virus used to vaccinate canaries against pox disease. ALVAC does not grow in human cells and therefore is likely to be harmless to humans. It has the capacity to carry larger quantities of HIV genes than many other vectors, and has been associated with few side effects in more than 500 people who have received experimental recombinant ALVAC vaccines against other viruses such as rabies, measles or cytomegalovirus.
ALVAC-HIV vaccines are currently being tested in four prime-boost Phase I AVEG trials. Interim results from AVEG 012, evaluating two different doses of ALVAC-HIV vCP125, the gp160 gene spliced into ALVAC, followed by boosting with Chiron Biocine's recombinant gp120 vaccine in MF-59 adjuvant, will be reported by Mary Lou Clements, M.D., M.P.H., of The Johns Hopkins University (Baltimore, Md.) AVEG unit.
Lawrence Corey, M.D., of the University of Washington AVEG unit in Seattle will report interim results from AVEG 022, which is testing a more sophisticated second-generation ALVAC-HIV vaccine, vCP205, followed by booster doses of Chiron Biocine's gp120 subunit vaccine in MF-59 adjuvant. vCP205 contains copies of genes for three pieces of HIV -- the envelope protein, the interior gag protein and the protease enzyme. The co-expression of envelope components in the same cell as gag proteins results in a gag-env interaction, followed by the enveloping of the gag particles. The particles bud from the cell membrane and are similar to HIV virions in their shape and protein content, but are genetically engineered proteins and cannot cause AIDS. However, the vaccine is designed to more closely mimic HIV and thereby stimulate both cellular and antibody responses.
Vaccine researchers hope that AVEG 022A, a similar trial testing a higher dose of vCP205 and begun just recently, will elicit even stronger immune responses. This trial also will provide more information on the safety and immunogenicity of this prime-boost regimen in an even larger group of volunteers, including individuals whose behavior puts them at higher risk for acquiring HIV.
An even newer study, AVEG 026, is testing still a more complex ALVAC-HIV construct, vCP300. vCP300 is designed to stimulate an even broader immune response than vCP205 by also incorporating into the vector fragments of HIV's pol and nef genes that can stimulate CTLs.
Anyone interested in talking to an NIAID staff member about the NIAID Division of AIDS Vaccine and Prevention Research Program can visit a poster presentation (abstract 0593) by Mary Clare Walker, Ph.D., in the Exhibit and Poster Hall of BC Place between 9:30 p.m. and 5:30 p.m. Pacific Time on Tuesday, July 9. Dr. Walker will be available to answer questions between 11:30 p.m. and 12:30 p.m. A list of prototype AIDS vaccines and vaccine approaches in development or already in clinical trials worldwide will be available on request.
NIAID, part of the National Institutes of Health (NIH), supports biomedical research to prevent, diagnose and treat illnesses such as AIDS, tuberculosis, asthma and allergies. NIH is an agency of U.S. Public Health Service, part of the U.S. Department of Health and Human Services.
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