Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Past failures from companies jumping on the T-cell bandwagon have borne out the complexity of the virus and prompted renewed thinking.

Significant progress has been made in the development of new drugs and drug combinations that can suppress HIV among the 33 million individuals infected worldwide. Yet new infections continue to occur—56,300 arise annually in the U.S. alone. Worldwide 7,500 people become infected with AIDS daily. The disease remains the fourth leading cause of death globally.

The economic and social burdens of HIV infection and AIDS can hardly be overstated. The obvious and realistic solution of developing a preventive vaccine, however, has evaded the most experienced and dedicated researchers and frustrated vaccine advocates.

Developers initially focused on antigen-based vaccines similar to other infectious disease vaccines to promote the production of neutralizing antibodies to HIV. When this approach failed, investigators asked whether vaccines promoting cell-based immunity would be more effective.

Merck’s HIV Vaccine Failure

Merck’s vaccine was based on the premise that cellular immunity was fundamental to promoting an effective anti-HIV immune response. It consisted of a replication-incompetent Ad5 adenovirus, or a type of common-cold virus, engineered to contain several highly conserved HIV genes. The HIV-1 gag, pol, and nef genes were previously identified as the best target antigens for broadly directed cellular immune responses.

The clinical trial, ultimately conducted in 3,000 volunteers, failed to show the vaccine’s efficacy in preventing HIV infection or in suppressing the virus after infection. Of 741 people given at least one dose of the vaccine, 24 developed infections compared with 21 infections in 762 people who received injections of the sham vaccine. The vaccine also failed to reduce HIV load. 

The results also showed that vaccine recipients with high levels of antibodies against the Ad5 adenovirus used as a vector were more likely to acquire an HIV infection than those who received the placebo.

Vaccines vs. Antiretroviral Approaches

The clinical trial failure prompted a debate among vaccine researchers, policy makers, and advocacy groups. Some encouraged further support of similarly designed vaccines, and others called for abandonment of the approach altogether. Still others suggested that money should be spent on basic research to find entirely new vaccine techniques.

“In light of over 20 years of failed AIDS vaccine research on which billions of dollars of U.S. taxpayer money have been spent,” Michael Weinstein, president of the AIDS Healthcare Foundation, said in the Los Angeles Times in 2008, “we believe it is simply unconscionable for the U.S. government to continue such wasteful funding while millions worldwide die for want of access to the AIDS research breakthrough that occurred more than 10 years ago—life-saving antiretroviral treatment.” 

The NIAID states on its website, though, that “HIV vaccines represent the best long-term hope for ending the HIV pandemic, and HIV vaccine research is a top priority for NIAID.” Anthony Fauci, M.D., the agency head, also remarked that the institute is committed to placing greater emphasis on basic research to understand the immune system and HIV infection.

On the T-cell front the NIAID is currently sponsoring randomized placebo-controlled trials to evaluate the effect on post-HIV infection viremia and the safety of a combination of two NIAID-developed HIV vaccine candidates (VRC DNA/rAd5).  The vaccines consist of a DNA phage expressing HIV gene fragments to be given three times and an inactivated Ad5, also containing HIV gene fragments, to be given once in a prime-boost strategy. Prevention of viremia in men who become infected with HIV will lend some support to the concept of T-cell-based vaccines, at least in the context of reducing viral load.

Back to B Cells

In May 2008 NIAID launched a new program to promote the study of B cells that produce HIV-neutralizing antibodies, saying, “many experts believe a successful HIV vaccine will probably need to activate both T cells and B cells; consequently, NIAID’s creation of the new B-cell research program is an important stimulus for HIV vaccine discovery.” Previously, NIAID grant recipients focused more heavily on T-cell-based approaches.

The HIV Vaccine Trials Network (HVTN) is also conducting trials on another two-component vaccine (pGA2/JS7 DNA and MVA/HIV62)  consisting of a recombinant DNA plasmid expressing HIV gag, pol, and env genes plus a recombinant modified vaccinia virus (MVA) expressing the same three genes. The vaccine is being developed by GeoVax Labs and is intended to stimulate both anti-HIV T-cell and antibody immune responses.

On August 6 the firm said that the Phase IIa study was 30% enrolled. “Of the 80 HIV-preventive vaccine protocols sponsored by the HVTN, only five have progressed to Phase II,” points out GeoVax CEO, Robert McNally, Ph.D.

What have been termed failed vaccine trials have prompted a renewed commitment to developing vaccines, either preventive or therapeutic, as well as a sobered response to the inherent difficulties. In his 2004 commentary regarding the challenges in developing an AIDS vaccine, Ronald C. Desrosiers, Ph.D., of the New England Primate Research Center, Harvard Medical School, said, “The continued testing of feeble long-shots in the clinic is inevitable (and even useful).” In view of the great challenges posed by the HIV virus, and “in the absence of answers to the major scientific questions, the iterative process will necessarily continue to rely on blind guesses.” Clearly NIAID’s current approach addresses that issue.

Patricia F. Dimond, Ph.D. ([email protected]), is a principal at BioInsight Consulting.

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