STEP Trial: A vaccine that surprised many with increased risk of disease in vaccinees

HVTN/STEP Trial: A vaccine that surprised many with increased risk of disease in vaccinees: A Phase IIb ‘test of concept’ trial of Merck’s MRKAd5 HIV-1 gag/pol/nef trivalent vaccine based on a weakened non-replicating adenovirus (type 5 adenovirus).

This was a Randomized, double blind, placebo control study carried out in North America, South America, Caribbean and Australia

This trial enrolled 3000 adult HIV negative high-risk population from a diverse background (gay/MSM, female sex workers 18-45 years of age). The study had 62% males and 38% females. First enrolment was in Dec 2004 and the enrolment was completed in March 2007. The primary efficacy endpoints: Whether the vaccine prevented HIV infection and whether the vaccine reduced the viral load in those who were infected.

Results:

The vaccine did not prevent infection: in the 741 volunteers who received at least one dose of the three-dose vaccine series, 24 cases of HIV infection were observed and 21 cases of HIV infection were observed in the 762 participants in the placebo group.

In the subgroup who had received at least two vaccinations and who were HIV-negative for at least the first twelve weeks of the trial, 19 cases of HIV infection were observed in the 672 volunteers who received vaccine and 11 cases were observed in the 691 volunteers who received placebo.

These were interim figures: later on, when all figures were collected, it was found that there were 49 infections in patients receiving the vaccine and 33 in those receiving placebo. This 48% higher rate of infection in vaccine recipients was not statistically significant and could have been a random result.

HIV RNA levels approximately eight to twelve weeks after diagnosis of infection were similar in the vaccine and the placebo arms. The geometric means of the HIV RNA levels in the blood of infected individuals, the standard measure of ongoing HIV replication, were approximately 40,000 copies/ml in the vaccine group and approximately 37,000 copies/ml in the placebo group.

Post-hoc analysis showed that the vaccine made some participants more vulnerable to HIV, but was not statistically significant, except for a subgroup of males.

There was higher risk of infection among those who had high levels of Ad5 immunity that was 3x higher in vaccinees than in placebo group.

Uncircumcised vaccinees were 4x higher infection rates than placebo, especially through insertive anal sex.

1 female volunteer was infected.

Weak HIV-specific CD8 T cell response directed against limited T cell epitopes, particularly HIV Gag. Individuals with HLA –I (B27, b57 and B5801) had lower HIV RNA levels

Critical analysis of this study revealed that having ineffective CD8 T cells will not help in a better vaccine. The impact of having protective HLA alleles was shown on analysis of participants who had better control of viral load.

Better vaccines could be designed by deleting immunodominant epitopes restricted by non-protective alleles from the immunogens since the induction of ineffective CD8 responses will be magnified at the expense of effective CD8 response.