The trend towards an increased risk of HIV acquisition associated with prior adenovirus exposure in vaccine recipients in early follow-up from the STEP study seems to diminish over time, Susan Buchbinder told the AIDS Vaccine 2009 conference in Paris on Tuesday.
The STEP study was halted in October 2007 after it became apparent that no matter how long the trial continued, it was unlikely to show any difference in the risk of infection between vaccine recipients and placebo group.
However, subsequent analysis soon revealed that certain subgroups of vaccine recipients had a higher risk of HIV acquisition than placebo recipients.
Male vaccine recipients who were uncircumcised and who had antibodies to adenovirus-5 due to prior exposure had the highest risk of HIV acquisition (see this report on earlier findings from the study). The vaccine studied in the STEP trial, manufactured by Merck, used a common cold virus called adenovirus-5 to deliver multiple HIV sequences in order to stimulate cell-mediated immunity.
A number of theories have been put forward to explain why prior adenovirus exposure might increase the risk of infection, and scientists have been concerned that use of adenoviruses as a vector for delivering HIV sequences in vaccines might pose a risk to vaccine trial participants.
Indeed, the biggest concern was that any interaction between the vaccine vector and adenovirus antibodies in vaccine recipients might place trial participants at permanently heightened risk of HIV infection.
Consequently, investigators from the STEP study have been conducting careful follow-up to assess whether new infections are occurring disproportionately in the categories previously detected to be at higher risk.
Susan Buchbinder of San Francisco’s Department of Public Health presented results of follow-up on trial participants for the period from October 2007 to 23 January 2009.
A total of 60 new infections occurred in study participants between unblinding in October 2007 and January 2009. Twelve occurred in women (six in each group) and 48 in men (26 in the vaccine group and 22 in the placebo group). The higher rate of infections in men is explained by the fact that just over 60% of trial participants were men; the study recruited men who have sex with men and female sex workers in the United States, Latin America and Australia.
An excess risk is still evident in Ad5-seropositive men, but it is no longer trending towards significance, said Susan Buchbinder. In uncircumcised, Ad5-seropositive men the risk had declined too, although it remains of borderline statistical significance.
"So the question is, was this just noise? The other explanation is that the risk has just gone away over time," she said.
Dr Gary Nabel of the US National Institutes of Health Vaccine Research Center told the conference that a wide variety of adenovirus vectors, much less common in humans, are now being investigated, but that simian advenoviruses may prove less problematic as vaccine vectors.
Buchbinder S et al. Clinical outcomes from the STEP study. AIDS Vaccine 2009, Paris, abstract SS01-02, 2009.