The very bad news about the Merck HIV vaccine trial (STEP/HVTN 502) that emerged today at the HVTN meeting in Seattle is that there were significantly more HIV infections among male vaccine recipients in the second 1,500-person cohort of the trial compared to placebo recipients (21 infections vs. 9 infections). The second cohort consisted of individuals with higher levels of antibodies (titers over 1:200) against adenovirus serotype 5 (Ad5), the virus used - in weakened form - as a vehicle or vector for the vaccine components. Ad5 in its natural form causes bad colds, so many people are exposed to it during their lives and develop anti-Ad5 antibodies as a result. The STEP results suggest that the Ad5 vaccine somehow enhanced susceptibility to HIV infection in people with high levels of anti-Ad5 antibodies, as the difference in infection rates between vaccine and placebo recipients increased in parallel with levels of anti-Ad5 antibodies. However, it was also the case that placebo recipients with high levels of anti-Ad5 antibodies had a very low incidence of HIV infection compared to the rest of the STEP cohort, raising the possibility of as yet unexplained confounding effects.
| Anti-Ad5 antibody titer | # of infections (vaccine) | # of infections (placebo) |
| less than 1:18 | 20 | 20 |
| 1:18-1:200 | 8 | 4 |
| 1:200-1:1000 | 14 | 7 |
| over 1:1000 | 7 | 2 |
| Anti-Ad5 antibody titer | HIV incidence (vaccine) | HIV incidence (placebo) |
| less than 1:18 | 4% | 4% |
| 1:18-1:200 | 4.4% | 2.2% |
| 1:200-1:1000 | 6.1% | 3% |
| over 1:1000 | 4.4% | 1.2% |
These data were not part of the initial review by the DSMB that caused immunizations in the trial to be stopped back in September. Because no women vaccine recipients became infected (only one of the 1,150 women in the trial was infected, a placebo recipient) all of these infections occurred among men. Looking at all of the 1,850 men in both the first and second STEP cohorts, there were 49 infections among the 914 in the vaccine group, compared with 33 out of the 922 in the placebo group. Although this was not a pre-planned analysis, the differences are significant and cause for extreme concern. For the individuals with post-infection viral loads available, there were no significant differences between 46 vaccine recipients (29,109 copies) and 30 placebo recipients (38,416 copies).
As outlined in a whirlwind talk by Juliana McElrath, researchers from the HVTN and Merck have been working around the clock to look at the factors that might account for these observed differences. Some preliminary data indicates that participants with higher anti-Ad5 antibody titers also had higher levels of CD4 T cell activation at week 30 of the study, but this held true in both vaccine and placebo recipients. Whether the kinetics of CD4 T cell activation over time was altered by the vaccine remains to be determined; one hypothesis that has been put forward is that the activation of CD4 T cell responses to Ad5 itself (which would be expected to be of higher magnitude in individuals with higher anti-Ad5 antibody levels) may have contributed to the outcome. McElrath outlined an enormous and comprehensive plan that will look at these and other possible biological mechanisms that might explain the trial results. The plan will involve an expanded version of HVTN’s laboratory science committee (chaired by Bruce Walker) whose task is to further develop and refine the agenda for investigating biological explanations for the STEP results; HTVN will also solicit applications from independent investigators via their website.
In parallel, Susan Buchbinder is evaluating potential behavioral or other non-biological differences between vaccine and placebo recipients in the second STEP cohort. So far, no differences in risk have emerged, although there are some complicated associations with circumcision status; the evidence of enhancement in the trial appears to be skewed toward uncircumcised men but the relevance of this observation, if any, is still unclear.
Researchers at the HVTN meeting are currently discussing how to proceed with follow-up to ascertain whether the increased incidence among vaccine recipients with high anti-Ad5 antibody titers persists over time; 65 of the 82 infections in the trial occurred within a year of the first immunization and those that have occurred since week 52 are roughly evenly split between vaccine and placebo.
TAG will report on the STEP trial results in more detail in the coming days. A number of articles and statements have been issued about today’s announcements:
AVAC on the STEP study: comprehensive links, statement & Q&A
Wall Street Journal article
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