American Foundation for AIDS Research, July 2003
Kristen Kresge

If it weren't for the spectacular mountain scenery, vaccine researchers gathered at the recent Keystone Symposia in the Canadian Rockies may have come away a little depressed. One after another, the obstacles to finding an effective HIV vaccine were illuminated. These arise from the virus's enormous genetic variation.

Undue Optimism
David Weiner of the University of Pennsylvania Medical School began his talk by apologizing for his inherent optimism - what he called a faux pas in an HIV vaccine talk.

Weiner's remark directly pertained to the most anticipated vaccine talk. In that presentation VaxGen updated the results for its phase III study of AIDSVAX. Although this HIV vaccine that was unable overall to prevent infection or slow disease progression in a 5,000-person trial, VaxGen's attempts to cast the results in more favorable light has generated considerable controversy. The company announced in March that a subanalysis indicated that AIDSVAX did exhibit a protective effect in the African-American trial participants. But that conclusion pivoted on four black women who acquired HIV while participating in the trial's placebo arm.

"It's highly unlikely that their story about the vaccine working in blacks is correct," Dr. Dennis Burton (Scripps Research Institute, San Diego) said at Keystone. "You can see all sorts of effects in small numbers."

To bolster its argument, VaxGen promised a Keystone presentation on AIDSVAX-induced antibody production. The new results did not satisfy the critics: measured antibody levels were higher in black vaccine recipients than in the corresponding white males. Yet black men had equivalent HIV infection rates whether they received the vaccine or the placebo.

VaxGen also reported that women had higher antibody responses to AIDSVAX than men, regardless of race. But in non-black women, there were no new infections in the placebo group and one in the vaccine group. It does not appear from these results that antibody levels accurately indicate the extent to which a vaccine can protect against HIV.

Other presentations on antibody-eliciting vaccines also were discouraging. Researchers are now realizing that a strong antibody response may be a necessity for an effective HIV vaccine. But reports at Keystone underscored the difficulty of finding antibodies able to neutralize the wily virus.

Dr. Douglas Richman, a virologist and physician at Veterans Affairs San Diego Healthcare System, painted a bleak picture. Richman followed 19 HIV-infected volunteers for over 39 months after they contracted the virus. He found that most patients develop a strong antibody response soon after infection. But at every step along the way, the virus dodges the antibodies through its ability to mutate and escape detection. The mutations arise very quickly. Antibodies extracted from blood samples were unable to neutralize virus isolated from the same person only one month later.

"The virus is escaping much more readily than anyone has realized," said John Eldridge, Vice President of Immunology at Wyeth.

Moving Forward
With effective antibodies elusive, attention returned to the vaccine candidates that rely on cellular immunity (killer T-cells that attack HIV-infected cells). Merck announced that it is going forward with its viral vector (MRKAd5, an adenovirus containing three HIV genes - gag, pol and nef). This vector, which creates a self-limiting mock HIV infection, looks more effective in animal studies than the company's nonviral "naked" DNA construct, either alone or in combination with MRKAd5.

Dr. Emilio Emini, Senior Vice President of Vaccine Research at Merck, talked about the collaboration between Merck and Aventis Pasteur to combine an adenovirus-based vaccine with Aventis' HIV vaccine that utilizes a canary pox vector (ALVAC vCP205). Participants in Merck's viral vaccine study that have already received the adenovirus vaccination will be rolled over into this new study and receive a booster vaccination of the canarypox vaccine.

In monkey studies, the combination of these two vaccine constructs induced a better immune response than when either was given alone. The clinical trial will begin soon, and Emini is hopeful that human volunteers will evince a similarly enhanced immune response.

While Merck sets aside its nonviral naked DNA vaccine, Wyeth is moving its DNA vaccine forward into human clinical trials. The trial will combine the DNA vaccine with the protein interleukin 12 (IL-12; a cytokine secreted by macrophages that enhances cellular immunity) and a viral vector boost (using a vesicular stomatitis virus with inserted HIV genes).

The human trial will begin early next year, and according to Eldridge, "The difference is going to be the cytokine." In animal studies, the addition of IL-12 protein triggered a greater antibody response, as well as a four- to sixfold enhancement in cellular immunity.

Despite the obstacles encountered by HIV vaccine researchers, Emini remains confident of a successful outcome - though maybe not in the next five years. He remarked, "Everything is difficult until it's done."

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