Late last Friday seems to have seen the peak of the Merck HIV vaccine misinformation frenzy, with the Voice of America managing to get the number of infections in the STEP trial wrong (this article now seems to have disappeared) and a writer for Gay Wired headlining their story “Merck Halts Trials of AIDS Vaccine Shown to Increase Risk of Infection.” The first para of the same article also misrepresents a Seattle Times piece about the trial by claiming it suggests “the vaccine may well increase risk of infection.”
Meanwhile, it seems that it’s now OK to say that the suggestion of enhancement was not based on new data, but the STEP and Phambili DSMB’s interpreting the same data differently; the head of the HVTN, Larry Corey, is quoted to this effect in this week’s issue of Science. The Global HIV/AIDS Vaccine Enterprise has also updated their website to carry the latest news about the STEP and Phambili trials and issued an accompanying statement.
There does still appear to be some cause for concern, however, even though the cause remains unclear. On November 1, the Bay Area Reporter interviewed the STEP principal investigator Susan Buchbinder who, like Tony Fauci in the IAVI Report several weeks ago, makes reference to a “trend” toward enhancement. Since it seems unlikely that either of these individuals would refer to a p value of >0.1 as a trend, the suspicion remains that there is some kind of subgroup analysis where the difference in infections between vaccine and placebo groups comes closer to statistical significance. Things should become somewhat clearer next Wednesday morning, when the data from STEP is scheduled to be presented at a plenary session of the HVTN conference.
In the meantime, some additional details about the STEP trial are available online in a presentation by the HVTN’s Juliana McElrath from the recent IDSA meeting. The demographics of the participants are described, and some data regarding T cell responses 4 weeks after the second immunization (8 weeks into the trial) are presented. What is notable about the T cell response data is that it indicates high numbers of T cells (both CD4 and CD8 together, subsets are not presented) responding to the vaccine-encoded HIV antigens (Gag, Pol and Nef) at this timepoint (~300 spot-forming cells with some individuals >1,000). However, these are almost certainly highly activated T cells as the readout is production of the cytokine interferon-gamma, and prior studies have shown that such high numbers are not maintained at later timepoints. This strongly suggests activation-induced T cell death is still occurring at 4 weeks post-immunization and that most of the HIV-specific T cell responses have not reached a resting central memory state (see prior post on activated vs. resting T cells). CD4 T cell activation sustained for several weeks post-immunization could even be one potential mechanism of enhancement, as some researchers have reported an association between elevated levels of CD4 T cell activation and susceptibility to HIV infection. These issues relating to the phenotype and activation state of the vaccine-induced HIV-specific T cell responses are almost certainly among those that researchers will look at as they try to figure out why the Merck candidate failed.
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