HIV Vaccine Experiment Ignites Press Interest: But Scientists Ask, 'Will It Work In Humans?'

On Jan. 14, the day before Science published an article on a formalin-fixed fused immunogen that induced neutralizing antibodies to HIV-1 envelope glycoproteins,1 Jack Nunberg's telephone rang endlessly. Nunberg, head of the Montana Biotechnology Center at University of Montana, Missoula, is senior author of the paper, coauthored by his former graduate student Rachel LaCasse (now at University of Alabama, Birmingham), colleagues at University of Montana, and two scientists at New York University Medical Center. The press brouhaha points to the dearth of much other encouraging news on the HIV vaccine front. "I guess this just goes to show how desperate everybody is for anything that could be realistically construed as positive in the HIV vaccine field," notes HIV-vaccine researcher John Moore of the Aaron Diamond AIDS Research Center in New York. That's not to say that the work was not good. "There was no breakthrough technology involved and the experimental rationale was based on well-known facts and straight logic," says Yichen Lu, an HIV-vaccine researcher at Avant Immunotherapeutics Inc., in Needham, Mass. "The result, however, was surprisingly good." And, Lu points out, there is no extant HIV vaccine that can raise this kind of immune response: "...none of the existing vaccine candidates can match this unbelievably crude immunogen ...." In an accompanying commentary on the research, David Montefiori of Duke University Medical Center in Durham, N.C., and Moore explicate the process LaCasse et al. used to produce the immunogen.2 They combined recombinant simian fibroblast cells that express the primary HIV-1 isolate envelope protein (gp41 transmembrane protein and gp120 surface protein), with recombinant human neuroblastoma cells expressing human CD4 and CCR5 receptor and coreceptor, respectively for HIV-1. After mixing, the receptors and coreceptors bound to the envelope protein. But the binding process led to many intermediates during fusion. Nunberg and his colleagues froze these cells during fusion by exposing them to formalin. This means that new epitopes on the gp41 and gp120 proteins had then probably been formed. As Nunberg explains to The Scientist, "Obviously, a lot is occurring on the molecular level" during this period of fusion. The researchers then tested the immunogenicity of antibodies raised to these fused protein-receptor conglomerates in mice against primary isolates of human HIV-infected serum. The antibodies neutralized primary isolates containing HIV-1 in clades (subtypes) A through E. Nunberg credits his early work on gp120 vaccines--at Genentech in the early 1990s--with the nut of the idea for the recent study. He states, "Back in '93, when we and other labs were demonstrating the inability of gp120 vaccine antibodies to neutralize primary isolates, we were struck and puzzled, in contrast, by the ability of sera from infected individuals to neutralize primary isolates. It sort of crystallized with the discovery of coreceptors in '96-'97 and the recognition that there were multiple steps and multiple conformational changes" that the envelope protein underwent during fusion with the receptor. Does stimulating neutralizing antibody production mean that an HIV vaccine will provide effective, sterilizing protection against infection with HIV? This is debatable, according to researchers in the field. Phillip Berman, chief scientific officer of VaxGen Inc., points out that Jack Nunberg of University of Montana and colleagues were inaccurate in stating that gp120 vaccines don't neutralize primary isolates of HIV (see reference 1). He states that VaxGen's new bivalent vaccines are effective in neutralizing primary isolates (see reference 3). Nunberg defends his paper's statement: "Although the new claims of primary virus neutralization by VaxGen are, of course, worth follow-up in independent assays, the activity that Berman has presented in no way approaches the broad and potent neutralization observed using fusion-competent envelope protein immunogens." John Moore of the Aaron Diamond AIDS Research Center says, "The gp120 subunit vaccines that are currently in clinical trials are inadequate to protect against HIV infection. With this sort of vaccine, researchers rarely obtain 50 percent neutralization of heterologous, representative primary isolates, let alone 90 or 100 percent neutralization--the latter percentage being unheard of." In passive protection studies, antibodies of known activity against HIV are injected into the bloodstream of an uninfected animal, which is then challenged with HIV, says Moore. Moore explains that no one knows exactly what will happen in vivo when HIV-1 is introduced (via sexual relations) into the mucosal tissues of an individual who is producing such antibodies in the blood as a result of vaccination. Notes VaxGen's Donald Francis: "That is exactly why we need clinical trials to evaluate the vaccine in a real-life setting."--Myrna E. Watanabe Does this mean we have a potential HIV vaccine? Far from it. VaxGen Inc., a spinoff of Genentech located in Brisbane, Calif., has a recombinant bivalent gp120 HIV vaccine in Phase III clinical trials in the United States and soon in Thailand. Its president, Donald Francis, points out, "We don't know if any laboratory assay can predict protection of humans by vaccine. Everyone understands that there is no known correlate of protection to these assays; at least the primary isolate assay clearly does not predict protection in chimpanzees, which is the model that I think is most reliable to predict protection in humans," Francis remarks. He adds, "This study is in mice, and mice have been very poor predictors of efficacy in humans." Montefiori and Moore point out in their commentary that the antibodies may be directed against the altered receptors and coreceptors, and not to the virus envelope proteins. "There are huge unknowns whether the response is really against viral proteins or against cellular proteins," notes Phillip Berman, VaxGen's chief scientific officer and author of a recent paper illustrating that the company's bivalent recombinant gp120 vaccines against HIV-1 stimulate production of neutralizing antibodies.3 (Nunberg worked on the earliest versions of the vaccine.) Lu points out, "The immunogen used in this experiment can't be a vaccine. It's a mixture of engineered tumor cells." As Moore explains, "The FDA [U.S. Food and Drug Administration] doesn't like experiments with cancer cells." Moore adds, "It's unlikely in the extreme that you will make a vaccine by injecting people with formalin-fixed cells." Moore observes that many in the HIV research community were skeptical about the findings when they were first reported publicly at scientific meetings. He notes that people asked, "Does this really work?" (He adds, however, "The paper answers most of those initial concerns.") And the difficulty of convincing people that it would work may have led to the research being supported by the American Foundation for AIDS Research (AmFAR), not the National Institutes of Health. "One can only imagine the difficulty of proposing this type of experiment to apply for an R01 [investigator-initiated proposal to NIH for funding] type of grant," says Lu. Nunberg is continuing the work, but he understands the limitations of the current vaccine formulation. Now, with NIH funding, he and his colleagues are pursuing three projects "to come up with an immunogen that's worthy to bring to clinical study." They are studying the molecular structure of the fusion intermediates on binding. They also are working with Therion Biologics Corp. in Cambridge, Mass., to develop a Vaccinia virus-based vaccine incorporating the recombinant immunogens. The third logical step with the vaccine is to determine if it is efficacious in monkeys; this research will be carried out with the NIH Division of AIDS Research. "I think its reproducibility in monkeys will be the acid test, as always," states Moore. Myrna Watanabe (mew@99main.com) is a freelance science writer based in Patterson, N.Y. R.A. LaCasse et al., "Fusion-competent vaccines: broad neutralization of primary isolates of HIV," Science, 283:357-62, Jan. 15, 1999. D.C. Montefiori, J.P. Moore, "Magic of the occult?" Science, 283:336-7, Jan. 15, 1999. P.W. Berman, "Development of bivalent rgp120 vaccines to prevent HIV type 1 infection," AIDS Research and Human Retroviruses 14 (Suppl. 3):S277-89, 1998.

HIV Vaccine Experiment Ignites Press Interest: But Scientists Ask, 'Will It Work In Humans?'

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