Among 87 male study participants who acquired HIV infection during the Step study, there was no difference in HIV disease progression between vaccine and placebo recipients during 2 years of follow-up. HIV RNA levels, CD4+ T cell counts, time to initiation of ART, and AIDS-free survival were the same for vaccine and placebo recipients. There may have been a favorable effect of the vaccine on HIV-1 RNA levels in a subset of participants with HLA types associated with better immune control of HIV-1.
These results are consistent with the primary analysis of the Step study that was conducted when the study was halted in October 2007 [12
]. The earlier analysis found no vaccine effect on set point viral load, defined as the average log10
viral load at weeks 8 and 12 after infection. Our analysis includes the full set of additional follow-up, through October 2009, and incorporates the longitudinal viral load and CD4+ T cell count measurements, as well as time to initiation of ART and AIDS-free survival. The breadth, magnitude, or functionality of the immune response elicited by the MRKAd5 HIV-1 gag/pol/nef vaccine may not have been sufficient to affect HIV-1 viral load set point and disease progression [37
]. Furthermore, rapid HIV-1 escape from immunologic control and exhaustion of cell-mediated immunity may also explain the inability of the MRKAd5 HIV-1 gag/pol/nef vaccine to affect HIV-1 disease progression [8
The failure of MRKAd5 HIV-1 gag/pol/nef to control viremia is perplexing in light of the robust CD8+ T cell responses elicited by the vaccine [37
]. Studies of cellular immunity in elite controllers [6
] and in vaccinated and non-vaccinated non-human primates suggest that HIV-specific CD8+ T cells play a central role in maintaining effective control of viral replication. We are conducting additional studies to characterize the nature of the cellular response in Step study vaccine recipients to elucidate why it failed to control viral replication; this information may guide development of more-efficacious T cell vaccines. Results from a large trial in Thailand, RV144, which used a vaccine regimen comprising a series of 4 priming injections of recombinant canarypox vaccine accompanied by a booster injection of a recombinant bivalent (B/E) glycoprotein 120 subunit protein on the final 2 vaccination occasions, showed modest protection against HIV acquisition [45
]. The immune profile elicited by this regimen differed substantially from that seen in response to the Merck vaccine; it too was ineffective in controlling early viremia or maintaining CD4+ T cell count among infected study participants.
We found no effect of Ad5 serostatus or circumcision status on HIV disease progression. There may have been a modest effect of the MRKAd5 HIV-1 gag/pol/nef vaccine on HIV-1 RNA levels among a subset of subjects with HLA types known to be associated with lower viral load set points and a slower course of disease progression (HLA B27, B57, and B58). In a previous study of recombinant canarypox ALVAC-HIV vCP205, vaccinated healthy volunteers with HLA-B27 or –B57 developed earlier and greater magnitude CTL responses than did vaccine recipients with other class I alleles, suggesting that HLA alleles can favorably alter HIV-specific immune responses following vaccination [46
]. The number of patients was small, and the trend was modest; therefore, these data need to be interpreted with caution.
Several participants started ART during acute HIV infection, and ~30% of the participants started ART by 1 year. Of note, international HIV treatment guidelines are moving towards earlier initiation of therapy. Future HIV vaccine trials that plan to observe HIV disease progression in infected volunteers should design their studies to anticipate that a large proportion of participants will start ART within 1 year of diagnosis of HIV infection.
In HIV-infected participants in the Step study, there was no difference in HIV RNA levels, CD4+ T cell counts, time to ART initiation, and AIDS-free survival between the vaccine and placebo recipients. There may have been a favorable effect of the vaccine on HIV-1 RNA levels in a subset of participants. Additional clinical testing of vaccine candidates that aims to elicit robust cellular immunity, alone or in combination with antigens eliciting a humoral response, is warranted to build on these early findings in selecting regimens that will reduce HIV acquisition and effectively control viral replication.