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

NEWS

HIV vaccine researchers have known foryears that VaxGen’s AIDSVAX, and oth-ers like it, have little chance of inducingantibodies that can neutralize HIV. Somehave instead chosen to investigate vac-cines that, rather than prevent infection,induce a cellular immune response to de-stroy infected cells.

As a few of those alternatives inch to-ward phase 3 trials, however, many sci-entists now say that a combination ofthe two approaches offers the best shotat preventing HIV infection.

“The Holy Grail is a candidate that willgive you a robust cell-mediated response,together with the neutralizing antibodiesthat can recognize and defend against awide range of primary isolates,” saysAnthony Fauci, director of the USNational Institute of Allergy andInfectious Diseases (NIAID).

Not long ago, there were so few vaccinecandidates that keeping track of themwas an easy task, says Scott Hammer,chief of the Division of InfectiousDiseases at Columbia PresbyterianMedical Center in New York. “Now it’s achallenge to compress [the information]into a few minutes,” he says.

Many of the new candidates are basedon the prime-boost approach—a DNA orvector vaccine to destroy infected cellsfollowed by a subunit-based vaccine toinduce antibodies. Hammer cites fourpotential vaccines that are likely to makeup the next wave of clinical trials:Merck’s adenovirus vaccine; a DNA vac-cine with a modified vaccinia Ankaraboost, sponsored by the InternationalAIDS Vaccine Initiative (IAVI); an NIAIDtrial of the Aventis canarypox vaccine;and an Emory University vaccine featur-ing a DNA prime and a recombinantpoxvirus booster.

None of the trials are expected tobegin before late 2003 or 2004; candi-dates face formidable obstacles such asviral diversity and the recently describedpotential for superinfection. In themeantime, Hammer says, scientists needa better way to predict which candidateswill prevent infections in humans. “It’sgoing to be a while before we have truehuman correlates of infection,” he says.“It’s absolutely what we need to push thevaccine forward.”

The path to a vaccine is littered withabandoned candidates. Last year, NIAIDcancelled one phase 3 study of theALVAC canarypox vaccine when it failed

to induce a powerful enough immune re-sponse. More recently, Harvard re-searchers reported that three of fourmonkeys treated with a promising DNAvaccine have died due to viral break-through.

Researchers now know there are at leastsix human antibodies that can broadlyneutralize HIV. Members of IAVI’sNeutralizing Antibody Consortium saythey have determined the structures ofthree of those. But retracing the steps tofind the immunogens that can elicitthose antibodies has been difficult, atbest.

Although nearly everyone in the fieldnow points to a cocktail of vaccines—which would induce both antibodies andthe cellular immune response—as the so-lution, there is little evidence to supportthat premise.

“Intuitively we say we need a combi-nation,” says Wayne Koff, IAVI’s vicepresident for research and development,but proof of that principle has yet to beestablished. Asked how long an effectiveAIDS vaccine is likely to take, researchersstill offer a now-familiar estimate: “fiveyears.”

Tinker Ready, Boston

When California-based VaxGen an-nounced in February that its HIV vaccinewas ineffective in a majority of trial par-ticipants, few researchers in the fieldwere surprised. “All the animal studiespointed that way and even the phase 2trials…suggested that it wouldn’t workout—and it didn’t,” says Dennis Burton(see page 380), professor of immunol-ogy at Scripps Research Institute.

The vaccine, which was directedagainst the gp120 envelope protein,elicited neither neutralizing anti-bodies (see page 380) nor a cellularimmune response, Burton notes.“The science community is prettyangry by now because I think it wasa pretty clear failure,” he says.

But with those results, VaxGenalso revealed the tantalizing possi-bility that the vaccine conferred78% protection in African-Americans and 67% protection in agroup composed of African-Americans,Asians and other minorities. Skepticalscientists were ready with sharp pencils.

Bette Korber of Los Alamos NationalLaboratory questions how VaxGen de-rived the P (significance) value forAfrican-Americans and the grouped mi-norities. “If you move the African[Americans] out, you’re left with Asiansand ‘others’ and [the results are] not sig-nificant,” she says.

In response to press reports question-ing its statistical analysis, the companyissued a statement saying, “the re-sults…remain accurate as stated, andthe analysis continues.” But Jim Key,VaxGen’s director of communications,now says the data have not been ad-

justed for multi-group analysis.Key says the next step is to find a bio-

logical explanation for the mixed results.Asked why the company went publicwith incomplete data analysis, Key saysthat VaxGen, a publicly traded com-pany, was in a difficult position. Oncethe data were initially unblinded, hesays, the company had to protect the in-formation from leaking out for fear itwould influence stock trading. The initialannouncement of trial results was fol-

lowed by an immediate drop inVaxGen’s share price from about $10 toaround $4.

Is it possible that a vaccine could se-lectively protect African-Americans?Human leukocyte antigen (HLA) geno-types could certainly affect both thetransmission and cure of certain dis-eases, says Keith Crawford, director ofclinical research at Howard University’sSchool of Pharmacy. But Crawford andothers are reserving further judgmentuntil they see a detailed analysis.“[VaxGen] should tell people whatthey’ve done,” says Korber. “Theyshould explain it to us.”

Myrna E. Watanabe, New York

All subjects

White & Hispanic

Black, Asian,other combined

Black

TotalInfected atend of trial Percentage who became infected

1,6793,330

1,5083,003

171327

111203

98191

81179

1712

94

5.8%5.7%

Placebo

Vaccine

5.46.0

9.93.7

8.12.0

AIDSVAX flop leaves vaccine field unscathed

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Skeptical scientists skewer VaxGen statistics

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