NEWS

AIDSVAX flop leaves field unscathed HIV vaccine researchers have known for to induce a powerful enough immune re- Although nearly everyone in the field years that VaxGen’s AIDSVAX, and oth- sponse. More recently, Harvard re- now points to a cocktail of — ers like it, have little chance of inducing searchers reported that three of four which would induce both and antibodies that can neutralize HIV. Some monkeys treated with a promising DNA the cellular immune response—as the so- have instead chosen to investigate vac- vaccine have died due to viral break- lution, there is little evidence to support cines that, rather than prevent , through. that premise. induce a cellular immune response to de- Researchers now know there are at least “Intuitively we say we need a combi- stroy infected cells. six human antibodies that can broadly nation,” says Wayne Koff, IAVI’s vice As a few of those alternatives inch to- neutralize HIV. Members of IAVI’s president for research and development, ward phase 3 trials, however, many sci- Neutralizing Consortium say but proof of that principle has yet to be entists now say that a combination of they have determined the structures of established. Asked how long an effective the two approaches offers the best shot three of those. But retracing the steps to AIDS vaccine is likely to take, researchers at preventing HIV infection. find the immunogens that can elicit still offer a now-familiar estimate: “five “The Holy Grail is a candidate that will those antibodies has been difficult, at years.” give you a robust cell-mediated response, best. Tinker Ready, Boston together with the neutralizing antibodies that can recognize and defend against a wide range of primary isolates,” says Skeptical scientists skewer VaxGen statistics , director of the US When California-based VaxGen an- justed for multi-group analysis. National Institute of Allergy and nounced in February that its HIV vaccine Key says the next step is to find a bio- Infectious Diseases (NIAID). was ineffective in a majority of trial par- logical explanation for the mixed results. Not long ago, there were so few vaccine ticipants, few researchers in the field Asked why the company went public candidates that keeping track of them were surprised. “All the animal studies with incomplete data analysis, Key says was an easy task, says Scott Hammer, pointed that way and even the phase 2 that VaxGen, a publicly traded com- http://www.nature.com/naturemedicine chief of the Division of Infectious trials…suggested that it wouldn’t work pany, was in a difficult position. Once Diseases at Columbia Presbyterian out—and it didn’t,” says Dennis Burton the data were initially unblinded, he Medical Center in New York. “Now it’s a (see page 380), professor of immunol- says, the company had to protect the in- challenge to compress [the information] ogy at Scripps Research Institute. formation from leaking out for fear it into a few minutes,” he says. The vaccine, which was directed would influence stock trading. The initial Many of the new candidates are based against the gp120 envelope protein, announcement of trial results was fol- on the prime-boost approach—a DNA or elicited neither neutralizing anti-

vector vaccine to destroy infected cells bodies (see page 380) nor a cellular Infected at Total end of trial Percentage who became infected followed by a subunit-based vaccine to immune response, Burton notes. All subjects induce antibodies. Hammer cites four “The science community is pretty 1,679 98 5.8% Placebo 3,330 191 5.7% Vaccine potential vaccines that are likely to make angry by now because I think it was White & Hispanic up the next wave of clinical trials: a pretty clear failure,” he says. 1,508 81 5.4 3,003 179 6.0 Merck’s ; a DNA vac- But with those results, VaxGen Black, Asian, other combined © Group 2003 Nature Publishing cine with a modified vaccinia Ankara also revealed the tantalizing possi- 171 17 9.9 327 12 3.7 boost, sponsored by the International bility that the vaccine conferred Black 111 9 8.1 AIDS Vaccine Initiative (IAVI); an NIAID 78% protection in African- 203 4 2.0 trial of the Aventis canarypox vaccine; Americans and 67% protection in a Source: VaxGen, Inc. and an Emory University vaccine featur- group composed of African-Americans, ing a DNA prime and a recombinant Asians and other minorities. Skeptical lowed by an immediate drop in poxvirus booster. scientists were ready with sharp pencils. VaxGen’s share price from about $10 to None of the trials are expected to Bette Korber of Los Alamos National around $4. begin before late 2003 or 2004; candi- Laboratory questions how VaxGen de- Is it possible that a vaccine could se- dates face formidable obstacles such as rived the P (significance) value for lectively protect African-Americans? viral diversity and the recently described African-Americans and the grouped mi- Human leukocyte antigen (HLA) geno- potential for superinfection. In the norities. “If you move the African types could certainly affect both the meantime, Hammer says, scientists need [Americans] out, you’re left with Asians transmission and cure of certain dis- a better way to predict which candidates and ‘others’ and [the results are] not sig- eases, says Keith Crawford, director of will prevent in humans. “It’s nificant,” she says. clinical research at Howard University’s going to be a while before we have true In response to press reports question- School of Pharmacy. But Crawford and human correlates of infection,” he says. ing its statistical analysis, the company others are reserving further judgment “It’s absolutely what we need to push the issued a statement saying, “the re- until they see a detailed analysis. vaccine forward.” sults…remain accurate as stated, and “[VaxGen] should tell people what The path to a vaccine is littered with the analysis continues.” But Jim Key, they’ve done,” says Korber. “They abandoned candidates. Last year, NIAID VaxGen’s director of communications, should explain it to us.” cancelled one phase 3 study of the now says the data have not been ad- Myrna E. Watanabe, New York ALVAC canarypox vaccine when it failed

376 NATURE MEDICINE • VOLUME 9 • NUMBER 4 • APRIL 2003