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65 64 63 62 61 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 In the same issue of Nature, Letvin, Dan Barouch of Massachusetts General Hospital in Boston, and co-workers reported that similar vaccines initially protected eight monkeys against the identical SHIV strain Merck used, whereas unvaccinated control monkeys had high levels of virus and subseAs a growing number of vaccines move through the pipeline toward clinical quent disease. But 6 months later, one vactrials, experiments with monkeys are producing puzzling dataand doubts cinated monkey no longer could control the virus, and by 1 year it had developed AIDSThe first full-scale trial of an AIDS vaccine is pable of neutralizing HIV before it can es- like symptoms and died. The researchers scheduled to end in November, and the world tablish an infection. The AIDS vaccine that discovered that the SHIV had mutated its soon will learn whether it works. A second has moved furthest in human trialsa ge- way around the killer-cell response. Its an product will move into a large efficacy trial netically engineered version of HIVs sur- ominous development, Letvin thinks, bethis fall. Earlier in the pipeline, the array of face protein made by VaxGen of Brisbane, cause it threatens in time to undermine evAIDS vaccines entering human studies is Californiabanks on this concept. ery vaccine that relies on killer cells alone. more diverse than ever before (see table, p. But monkey studies with AIDS vaccines Then again, Letvin points out, seven of 2326). The pipeline is dramatically improved have completely failed to elicit antibodies the vaccinated animals are still controlling in many ways from 5 to 6 years ago, says that can neutralize the virus. I think the their SHIV infections, and even the animal Peggy Johnston, who heads the AIDS vaccine Holy Grail in the field of AIDS vaccine de- that died fared better than the unvaccinated program at the National Institute of Allergy velopment is how to generate a broad, neu- controls. Im willing to take half a loaf if and Infectious Diseases in Bethesda, Mary- tralizing antibody response, says Norman thats all we have, says Letvin. land. But, Johnston cautions, significant sci- Letvin, a primate researcher based at HarExperiments conducted by immunologist entific and operational challenges remain. vards Beth Israel Deaconess Medical Center David Watkins of the Wisconsin Primate ReForemost among those scientific chal- in Boston, but we dont know how to do it. search Center in Madison suggest that even lenges: Just what does it take for a vaccine to As a result, many have shifted their at- half a loaf might be optimistic, however. work? Almost 2 decades after HIV was identi- tention to the arm of the immune system Like the Merck team, Watkins and his colfied as the cause of AIDS, researchers are still that dispatches killer cells, tiny missiles that leagues used two vaccines debating which immune responses are likely back to back that triggered to provide the best protection against the virus. strong killer cell responses. The answer is proving elusive in part because Yet, as Watkinss team reportexperiments with monkeys are coming up ed in the April issue of the with puzzling, even contradictory, data. Were Journal of Virology, when they so much in the dark about what we would challenged the animals with a need for a protective vaccine, laments Ronald famously nasty strain of SIV Image not Desrosiers, head of Harvard Universitys New rather than SHIV, the virus available for England Regional Primate Research Center in was blunted for a time but ultionline use. Southborough, Massachusetts. mately ran wild. A growing Monkeys are the favored model for testnumber of researchers contend ing vaccine strategies. (Researchers no that this more vigorous challonger use chimps for ethical and cost realenge accurately reflects the sons.) Although HIV does not infect monway that HIV behaves in hukeys, a cousin simian virus, SIV , does: Some mans. Watkins gets better two dozen African species of monkeys are cellular immunity than Ive now known to harbor SIV in the wild, and it Immune conundrum. Sooty mangabeys have high viral loads of seen before, better than we causes them no harm. But when SIV infects SIV, yet the virus does not make them sick. can hope to get in humans, Asian monkeys, it causes an AIDS-like disand it had a modest effect, ease. In the most common type of experi- seek infected cells and obliterate them. Be- stresses Jeffrey Lifson, a virologist at SAICment, researchers vaccinate Asian rhesus cause killer cells, by definition, can do their Frederick, a company that runs the National macaques and then challenge them with thing only if an infection has already oc- Cancer Institutes AIDS Vaccine Program in either SIV or a laboratory-made hybrid of curred, the goal now is not prevention of in- Frederick, Maryland. Im very depressed fection but of disease. the simian and human viruses, called SHIV . by these studies, says Watkins. Killer cells Some monkey experiments have given by themselves, he suggests, are not going to Although some researchers question whether the monkey model truly mimics heart to those taking this approach. Re- be protective. HIV in humans, the field at large has em- searchers at Merck Research Laboratories in braced it as the best way to determine which West Point, Pennsylvania, working with Triple surprise vaccine strategies hold the most promise. Letvin, reported in the 17 January issue of African monkeys impressive ability to But a slew of recent monkey experiments Nature that two AIDS vaccines they used withstand infection by SIV might provide has raised questions about most of the vac- back to back in monkeys constrained SHIV some answers to how the immune system and protected the animals from disease by can keep the virus at bay. A few recent discine approaches now being pursued. triggering killer cell responses. The Merck coveries, however, have only made the puzHalf a loaf data have buoyed spirits among vaccine re- zle seem more complex. When HIV was first discovered, the way to searchers, and the vaccines now are in early In 1998, Lisa Chakrabarti, then at the a vaccine seemed clear: Find a part of the human trials. But other monkey studies have Pasteur Institute, and her colleagues survirus that triggers an antibody response ca- raised doubts. prised many investigators when they reportVA C C I N E S

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treating the animals the next day with tenofovir, an anti-HIV drug that also works against the monkey virus. AfVaccine Developers Location/Comment ter 28 days, they stopped all treatEfficacy trials: ment. As they reported in last Recombinant gp120 VaxGen Thailand, North America, Europe/ Novembers Journal of Virology, the Results expected in 2003 researchers could not detect SIV in the monkeys blood, and the animals Canarypox (multigenes)/rgp120 Aventis Pasteur Thailand/Late 2002 launch, U.S. and VaxGen and Thai govt. collaboration continued to control the virus once the treatment stopped. Moreover, Safety and Immunogenicity trials: when the researchers challenged the Canarypox (multigenes)/rgp120 Aventis Pasteur Caribbean, South America/Similar monkeys with the same SIV strain and VaxGen to Thai study but smaller more than a year later, they all beat Lipopeptides ANRS France/Better as boost than prime? back the challenge. DNA/modified vaccinia Ankara (MVA) Oxford and Nairobi U., U.K., Kenya/IAVIs most To further test the monkeys im(gag + CTL epitopes) International AIDS developed project munity, the researchers injected the Vaccine Initiative (IAVI) animals with antibodies that temDNA/adenovirus (gag) Merck & Co. Inc. U.S./Worked well in monkeys, porarily deplete CD8 cells, the famiinternational trial sites soon? ly from which killer cells originate. Nef-tat fusion protein +/ rgp120 GlaxoSmithKline U.S./NIAID-sponsored SIV spiked, but they quickly reDNA (gag/pol) Vaccine Research U.S./VRCs first effort established control. The investigators Center (VRC), NIAID also upped the ante, using a different SIV strain that should be much more Preclinical testing: difficult for the animals to recognize DNA/adeno (multigenes) VRC, NIAID U.S./Made from multiclades and contain. All five monkeys subDNA-IL2/IG (multigenes) VRC, NIAID U.S./Builds off monkey study stantially controlled the new virus. Adenovirus (multigenes) National Cancer U.S./Differs from other adeno Although CD8 cells appeared to Institute vaccines because it replicates play a role in the protection of some DNA/fowlpox (multigenes) U. New South Wales,Aus- Australia/Contains immunityanimals, the results perplexed many +/ cytokines tralian National U.,Virax enhancing genes. NIAID-sponsored researchers because in other vaccine MVA/fowlpox (multigenes) Therion U.S./NIAID-sponsored experiments, monkeys developed DNA/MVA (multigenes) Emory U., NIAID U.S./Worked well in monkeys more impressive immune responses DNA/MVA (multigenes) Aaron Diamond U.S./Plan to make version for but still failed to contain the chalAIDS Research Ctr. China, IAVI support lenge virus. The animals in Lifsons DNA (epitopes) Epimmune U.S., South Africa/Trying to make study, Desrosiers says, are as well one vaccine for world protected as any vaccinated monkeys on Earth. Salmonella delivering DNA vaccine Institute of Human U.S./Given orally Virology, IAVI One lesson, says Lifson, is that blunting the initial burst of virus Venezuelan equine encephalitis (gag) AlphaVax, IAVI, NIAID South Africa, U.S./Unusual vector whether by drugs or a vaccineA variety of approaches. When the search for an AIDS vaccine began, the field trained its sights on prepara- fortified immune systemis crutions that contained genetically engineered versions of HIVs surface protein. Only one of those early concepts cial, perhaps because it protects critsurvives, a gp120 made by VaxGen. The next vaccine in line, made by Aventis Pasteur, primes the immune sys- ical immune responses that othertem with a live-virus vector, canarypox, that carries HIV genes, and then boosts it with gp120. Although the wise would be lost for good. And he prime-boost concept still holds center stage, naked DNAat least for nowis the priming vector of choice, thinks this might help explain why followed by a boost with a viral vector. As time moves on, expect more exotic vectors, such as Venezuelan Watkins and others could not defeat equine encephalitis, and unusual carrying systems, such as Salmonella shuttling in a DNA vaccine. And if history SIV with their vaccines. None of these vaccines seem to give us repeats itself, you can bet that most of these vaccines will disappear before they ever make it to the finish line. enough blunting of the early viremia ed that SIV-infected sooty mangabeys main- ter, says Feinberg. We dont know enough to allow development of an immune retain terrifically high levels of the virus in to point to what are the really good immune sponse that can give a good chance of solid, their blood. If their immune system is pro- responses and which ones arent so good. prolonged protection against SIV , he says. tecting them, its not by traditional means. Two experiments that have protected Asian Given the contradictory evidence from Last year, Jonathan Allan of the Southwest monkeys also raise intriguing questions. A monkey studies, Desrosiers, the fields resiFoundation for Biomedical Research in San decade ago, Desrosierss lab reported that a dent skeptic, says he has little hope that any Antonio, Texas, and co-workers reported vaccine made from a live, weakened version of the vaccines now in human trials will that the same holds true for African green of SIV offered the best protection seen to this work. The breakthrough discovery thats monkeys. Mark Feinberg of Emory Univer- dayand he still cannot completely explain going to lead to an AIDS vaccine hasnt sity in Atlanta, Georgia, who collaborated why (Science, 18 December 1992, p. 1938). been made yet, he says. And if it happens with Allan and also has conf irmed the Another surprise has come from an exper- at all, its going to be serendipitous. Then French findings with sooty mangabeys, sug- iment that resulted in substantial protection, again, many vaccinesincluding the one gests that these monkeys might benefit from but doesnt even involve an AIDS vaccine. that eradicated smallpox from the world a sluggish immune response that keeps Lifson of SAIC-Frederick and his co-workers, went into widespread use long before humany immune cellsSIVs targetout of including Desrosiers, infected five monkeys mans had a clue how they actually worked. the line of fire. More isnt necessarily bet- with a highly lethal strain of SIV and began JON COHEN
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