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Did Merck's Failed HIV Vaccine Cause Harm?

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Science  16 Nov 2007:
Vol. 318, Issue 5853, pp. 1048-1049
DOI: 10.1126/science.318.5853.1048

SEATTLE, WASHINGTON—A common cold virus has walloped the already ailing AIDS vaccine field.

AIDS researchers, who are still staggering from the unexpected failure in September of the most promising vaccine candidate in clinical trials, met here last week to explore an even more alarming finding: The vaccine, made by Merck and Co., may actually have increased the risk of HIV infection in some study participants.

Working with the academic-based HIV Vaccine Trials Network (HVTN) and the U.S. National Institutes of Health (NIH) in Bethesda, Maryland, Merck researchers stopped the multicountry study after an interim analysis revealed that the vaccine did not work (Science, 5 October, p. 28). Now further analysis suggests that the vaccine may have helped HIV infect a subset of participants who at the trial's start had high levels of antibody to adenovirus 5 (Ad5), which causes the common cold and is also a component of the vaccine. “This is the worst possible outcome in a vaccine trial,” said AIDS researcher Eric Hunter of Emory University in Atlanta, Georgia, one of the study sites.

The finding is as befuddling as it is frightening, and its implications are far-reaching. The data presented here to some 500 attendees at an HVTN meeting on 7 November found only a “trend” toward what's called “enhancement,” leaving investigators wondering whether the elevated number of infections in vaccinees who had high Ad5 immunity was due to chance, behavior, or a vaccine-induced problem. Despite intensive investigations, no biological mechanism has emerged to explain how preexisting immunity to Ad5 could make vaccinated people more susceptible to HIV. “The data are very complex, and trying to understand what they mean has required an enormous amount of work,” said Merck's Michael Robertson, a co-chair of the study.

In the first full accounting of the trial results, Merck researchers and their partners reported that, as of 17 October, HIV had infected 83 people in the placebo-controlled trial. Of these, 49 were vaccinated and 34 received saltwater injections. This difference clearly indicates that the vaccine does not protect against HIV, but the increased infections in vaccinees have no statistical import and likely are due to chance.

Double trouble.

The vaccine clearly failed (left), but in men with high Ad5 antibodies (right), it may have increased their risk of infection. (Women were excluded from this analysis because only one became infected during the study.)


The discovery of possible enhancement in the so-called Step Study also owes something to chance. The vaccine contains three HIV genes stitched into a modified Ad5 vector that infects cells, creating HIV proteins that teach the immune system how to attack the real AIDS virus. From the outset, investigators worried that high levels of preexisting Ad5 antibodies might attack the vector and cripple the vaccine. So when Step began in December 2004, they enrolled 1500 people at high risk of becoming infected with HIV who had low Ad5 antibody levels. When data then suggested that this concern had been overblown, they doubled the trial size in July 2005 to include people with high Ad5 immunity. Most participants were men who have sex with men, although 38% were women, many of whom were sex workers.

The interim analysis in September that revealed the vaccine wasn't working looked only at the low-Ad5-antibody group. When the researchers subsequently examined the high-Ad5-antibody group, they were startled to find 21 infections in vaccinees versus nine in the placebo group.

The statistical analysis is ambiguous. Typically, researchers deem a difference as significant if it has a 95% probability of not being due to chance—a P value of less than 0.05. By these standards, the finding, with a P value of 0.029, was significant. But Steven Self, HVTN's head statistician at the University of Washington (UW), Seattle, cautioned that this comparison merits a more stringent cutoff for significance, between 0.025 and 0.0025, because the study was not designed to assess potential harm, nor did investigators plan to evaluate a subset of the study population. Still, Self said this “trend” deserves close examination.

Several researchers described their recent efforts to make sense of the trial's results. UW's Juliana McElrath, an immunologist who directs HVTN's lab program, explored what many consider the most likely explanation: that people in the high-Ad5-antibody group were more vulnerable to HIV because of “immune activation.” Specifically, HIV establishes an infection by attaching to T cells that have surface receptors known as CD4 and CCR5. Natural infection with Ad5 creates memory banks of these very T cells, which expand and direct an attack if Ad5 shows up again. Theoretically, the vaccine vector could have activated these memory cells in the same way, creating more targets for HIV. But McElrath's preliminary work found no evidence for this scenario.

Behavioral changes don't seem to provide an explanation: Study co-chair Susan Buchbinder of the San Francisco Department of Public Health said risk behaviors had decreased across the board and more so in the high-Ad5-antibody group. Buchbinder said investigators still are sorting out many variables related to HIV transmission, including circumcision, coinfection with other sexually transmitted diseases, and genetic factors.

One thing is clear: The monkey studies that suggested that the vaccine could thwart the AIDS virus, fueling much excitement, misled Merck researchers. “Mice lie, monkey sometimes lie, and humans never lie,” said Peggy Johnston, head of NIH's AIDS vaccine program. “Some monkeys have lied to us this time.” Other attendees stressed that Merck relied on a wimpy strain of the AIDS virus to “challenge” vaccinated monkeys and that challenges with stronger strains predicted that the vaccine would fail.

Although the mechanism remains elusive, researchers struggled with whether to tell trial participants if they received the vaccine or the placebo. A more recently launched study of the same vaccine in South Africa was stopped and quickly “unblinded” after learning the Step results, notifying everyone of their vaccine status (Science, 2 November, p. 729). After much debate here, Step's scientific steering committee recommended unblinding, and an oversight committee concurred on 13 November.

The specter of enhancement also affects the AIDS vaccine field's next-best hope. This NIH-made vaccine uses a similar Ad5 vector and was slated to enter a $130 million trial this fall without screening people for Ad5 immunity. “Step's results demand that we reexamine and redesign our study,” said principal investigator and Step collaborator Scott Hammer of Columbia University.

Merck's Mark Feinberg warned colleagues that “the whole field will come apart at the seams” if it doesn't properly investigate and respond to the Step results. “I've never seen more complicated data to emerge from a study,” Feinberg said. “And this one focuses on as important a question as I've ever known.”

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