This study represents the first truly global study of an adenovirus vector-based HIV vaccine designed to induce cell-mediated immunity. The vaccine was generally well tolerated among all subjects from all regions. Although local adverse events appeared to be dose dependent, local adverse events were not significantly affected by baseline Ad5 titer. There was an observed trend toward higher rates of fever in subjects with low baseline Ad5 titers who received the 1
vp dose, as was observed in an earlier study of the of MRKAd5 HIV-1 gag vaccine. However, the small sample size of the low and high Ad5 titer groups limits the ability to conclude that these systemic AEs occur with greater frequency in subjects with low preexisting immunity to Ad5. There were no vaccine-related serious adverse events.
The MRKAd5 HIV-1 gag vaccine was immunogenic across a diverse global population. While preexisting immunity to Ad5 dampened the immunogenicity of the vaccine in some regions, increasing the vaccine dose from 1
vp/dose generally appeared to mitigate this effect. In some cases, most notably in Caribbean and southern Africa regions, GM ELISPOT responses for low-dose vaccine recipients did not exceed that of placebo recipients, suggesting that a higher dose may be needed for a sufficiently immunogenic vaccine. The effect of baseline Ad5 titer on ELISPOT responses differed according to region as demonstrated by a statistically significant interaction between baseline Ad5 titer and region. Although in North America those with baseline Ad5 titer >200 had a lower ELISPOT response rate than those with Ad5 titer ≤200, this did not hold true for participants from Asia. There are several possible explanations for this finding. First, PBMC samples from international sites such as Asia were handled differently from those in North America. For international sites, PBMCs were isolated and frozen within 12
h of collection as opposed to U.S. sites where samples were transported at 4°C overnight and processed the following day. Data suggest that the magnitude of IFN-γ ELISPOT responses is significantly higher when PBMCs are isolated and frozen within 12
h of collection.73
Second, the geographic regions differ by human lymphocyte antigen (HLA) allele distribution, a factor known to influence disease progression in HIV infection,77
and may have an impact on response to HIV vaccination. Additional work on mapping epitope responses across the populations studied would be needed to determine whether greater ELISPOT responses were related to HLA type.
Approximately 17% of study participants had positive whole virus-based immunoassay results at week 78 but negative HIV PCR tests. Data from other phase 1 MRKAd5-vectored vaccines demonstrated that 41% of evaluable vaccine recipients had a positive ELISA but negative PCR results by week 78. In these studies, seroconversion was directly related to vaccine dose and inversely related to baseline Ad5 titer. Furthermore, among those subjects with positive ELISA results at week 78, ELISA positivity persisted through week 156 for the majority of evaluable participants who received doses containing ≥1
gag-containing Ad5 particles/dose.78
Where possible, enzyme immunoassays (such as envelope-based assays) targeting proteins not expressed in the vaccine should be the first choice for screening vaccine recipients.
There were four incident HIV infections in the current study population of low-risk adults; all had received three doses of vaccine. The proof-of-concept STEP study of the MRKAd5 trivalent vaccine showed that men who were uncircumcised and who had high levels of preexisting Ad5 neutralizing antibodyAd5 titers were more likely to become HIV infected if they had received the trivalent vaccine as opposed to placebo.67,68
In the current study four men, all of whom were in the vaccine group, became HIV infected. There was over four times the number of participants in the vaccine as compared to the placebo group (296 vs. 64). Therefore, although more infections occurred among vaccine recipients, the rate of infection in vaccinees did not differ from that in placebo recipients. Because the number of infections that occurred in this study was small and no circumcision data were collected, it is not possible to draw conclusions about increased susceptibility among vaccine recipients based on baseline Ad5 titer or circumcision. Viral loads were not followed as part of the study. Therefore, there are no data on how vaccination may have impacted viral load among study participants. Data from the STEP study showed that vaccination had no impact on viral load among vaccine as compared to placebo recipients.67,68
The data from this study provide important information on the safety and immunogenicity of an adenovirus-vectored vaccine in a diverse population including those with high baseline rates of Ad5 seropositivity. A proof-of-concept study employing the trivalent (gag, pol, nef
) MRKAd5 HIV vaccine conducted in parallel showed the trivalent vaccine to be nonefficacious. These data emphasize the challenges of developing an efficacious HIV vaccine as cell-mediated immunity did not correlate with protection from infection or lowering of the viral load in those who became infected.67,68
The results of these studies have implications for the development of other Ad5-vectored HIV vaccine candidates under development. Ad5-vectored vaccines have provided the most robust immune responses of any approach to HIV vaccination to date. Preexisting immunity to Ad5 may be partially overcome with an increase in vaccine dose and hence may not be a barrier to developing such responses; however, more data are needed to fully understand the role that preexisting immunity may have in enhancing infection. In additional, more data are needed to understand the role of alternative adenoviral vectors in HIV vaccine development.
Our results indicate that the Ad5 vector is well tolerated and immunogenic in diverse global populations and, therefore, may be a good candidate for other cell-mediated vaccine strategies. The safety of these vectors should be explored in preclinical studies and small clinical proof-of-concept studies in select populations before assessing their role in large global studies.