Perplexing Results of Failed HIV Vaccine Grow More Puzzling

SEATTLE, Nov. 8 -- HIV vaccine researchers remain puzzled by the results of the ill-starred STEP trial, halted in September because of a lack of efficacy.
New results just released also hint that the vaccine might have slightly increased the risk of HIV infection.
Volunteers who had a high level of pre-existing immunity to the adenovirus vector used in the vaccine seemed to be more vulnerable to HIV infection, the researchers revealed in a special forum here.
But the researchers also said the data are complex and will require more in-depth analysis before it's clear what happened.
"It will take some time before we understand why the vaccine did not work and why there was a trend toward more cases of infection in volunteers who received the vaccine," said Keith Gottesdiener, M.D., of Merck Research Laboratories, which was developing the vaccine.
The vaccine includes three viral genes delivered by an adenovirus-5 vector, and in earlier clinical trials appeared to generate a significant HIV-specific cell-mediated immune response.
It was being tested in two large phase IIb trials, STEP in North and South America, the Caribbean, and Australia and Phambili in South Africa. Both trials stopped vaccinating volunteers after the STEP data safety monitoring committee found the vaccine wasn't efficacious. (See: Hopes Dashed Again for HIV Preventive Vaccine)
But in a special open scientific meeting of the HIV Vaccine Trials Network, researchers revealed more details of the ill-fated trial.
The key finding that led to halting the trial was that among volunteers with low pre-existing immunity to the adenovirus vector who were HIV-negative at the start of the trial, 24 of the 741 who got the vaccine developed an HIV infection, compared with 21 in the 762 who got placebo.
When the researchers restricted the analysis to those who got at least two of three planned vaccinations and who remained HIV-negative for at least the first 12 weeks of the trial, they found 19 HIV infections in the 672 volunteers who got the vaccine and 11 in the 691 who got placebo.
In the whole study population, including cases recorded after the trial was stopped, there were 49 cases of HIV infection among the 914 men in the vaccine group compared with 33 cases among the 922 in the placebo group.
The vaccine also failed to achieve its secondary endpoint -- reducing the HIV viral levels among volunteers who got infected despite the vaccine.
When the trial was stopped, researchers said that the HIV RNA levels approximately eight to 12 weeks after diagnosis of infection were generally similar in the two groups -- but with a trend toward higher levels in those who got the vaccine.
HIV RNA levels in the blood were about 40,000 copies per milliliter among volunteers in the vaccine group who developed HIV infection and approximately 26,000 copies per milliliter in infected volunteers in the placebo group.
When the entire study population was taken into account, including male volunteers with both low and high levels of immunity to Ad5, the geometric means of HIV RNA levels were approximately 29,000 copies/mL for the vaccine group (based on 46 infections) and approximately 38,000 copies/mL in the placebo group (based on 30 infections).
The study wasn’t designed to look at the effect of immunity to adenovirus on HIV acquisition, but a post hoc analysis showed that HIV infection among volunteers with high Ad5 immunity was more pronounced among those who received the vaccine compared to those who received placebo.
Among the 778 male volunteers who had high levels of pre-existing immunity, there were 21 cases of HIV infection in the vaccine group and nine in the placebo group.
The researchers also said that among volunteers who had no or limited pre-existing immunity to adenovirus, there was little difference in the HIV infection rate.
Researchers outside the trial emphasized that there remain large knowledge gaps.
"We know the Merck vaccine didn't work," said Seth Berkley, M.D., president of the New York-based International AIDS Vaccine Initiative. "We don't know why."
"We know that more people who got the Merck [vaccine] candidate than got the placebo wound up becoming HIV infected," he said in a statement. "We don't know if that had anything to do with the candidate or not."
He added that the trend was not statistically significant, so "it could have been chance. And if the vaccine was a factor, we don't know why."
Dr. Berkley said many in the vaccine community were not surprised by the result.
"The failure of the Merck product to prevent HIV infection is not unexpected," he said, because the vaccine -- like nearly all of those in the pipeline -- aimed at producing cell-mediated immunity.
But T cells only attack infected cells, so that "many scientists, including those at IAVI, think T-cell vaccines are unlikely to protect individuals from becoming infected."
Likely to be more effective, Dr. Berkley said, would be vaccines aimed at producing an antibody response and thus preventing HIV particles from entering the body.