Important note: Information in this article was accurate in 2009. The state of the art may have changed since the publication date.
Wall Street Journal - October 20, 2009
Gautam Naik
NEW YORK - A deeper analysis of the results of an HIV vaccine tested in Thailand suggests that the vaccine may not have been as effective as originally indicated.
When first publicly disclosing the outcome of the Thai trial in September, researchers said the vaccine had lowered the risk of infection by about 31%. That result was modest but statistically significant, meaning it wasn't the result of a fluke. That announcement, coming after two decades of failed HIV vaccine trials, garnered headlines around the world.
Now, two other analyses of the trial data suggest that the results could have been due to pure chance, and therefore the vaccine may not have conferred protection to people after all. The additional data are published Tuesday in the New England Journal of Medicine and will be more fully discussed by researchers attending an AIDS meeting in Paris.
Details of the secondary analysis were first disclosed in The Wall Street Journal on Oct. 12. In an interview at the time, Jerome Kim of the U.S. Army and principal investigator for the trial, acknowledged that he and other scientists knew about the secondary analyses when the first result was publicly disclosed. He said his team had decided not to provide the results of all three analyses because the contradictory results could have confused the public.
The results initially announced were based on a "modified intent to treat analysis," which includes virtually everyone who enrolled in the study, regardless of whether they ended up getting the full course of the vaccine. It is a good reflection of the real world, where people don't always follow instructions properly.
By this measure, the vaccine tested in Thailand reduced by 31% the chance of infection with HIV, the AIDS-causing immunodeficiency virus. Statistical calculations showed there was a 4% probability that chance accounted for the difference. In drug and vaccine trials, anything above a 5% probability of a chance result is deemed statistically insignificant.
Observers noted that the result was derived from a small number of actual HIV cases. New infections occurred in 51 of the 8,197 people who got the vaccine, compared with 74 of the 8,198 volunteers who got placebo shots.
The two additional analyses now officially published by the peer-reviewed New England Journal of Medicine, are known as "intention to treat" and "per protocol" analysis. Both are routinely used in large-scale drug and vaccine trials. In this case, each offers a more nuanced conclusion about the vaccine's effectiveness.
"Per protocol" adheres strictly to how the trial was designed by only including study volunteers who got the full regimen of vaccine shots at the right time. Because it excludes study participants who didn't get the full vaccine regimen, it usually provides corroboration to the "intention to treat" findings.
A per-protocol analysis of the Thai trial included 12,542 subjects and showed a vaccine efficacy of 26.2%. But there was about a 16% probability the result was due to chance -- a lot higher than the 5% cut-off.
A broader intention-to-treat analysis included all 16,402 healthy Thai men and women who received either the vaccine or a placebo. In this case the vaccine was 26.4% effective but there was roughly an 8% probability the result was due to chance, according to the NEJM paper.
"Taken together, these data are consistent with a modest protective effect of vaccine in this study," the authors conclude.
In an accompanying NEJM editorial, Raphael Dolin of Harvard Medical School adds: "The possible vaccine efficacy observed was modest and indicates that the vaccine regimen studied is unlikely to be a public health control measure for HIV-1 infection, as the authors themselves acknowledge." However, Dr. Dolin said the findings, though mixed, "raise a number of questions that have important implications for future directions in vaccine research."
Write to Gautam Naik at gautam.naik@wsj.com
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