Abstract
The results of the recent Step Study highlight a need to clarify the effects of pre-existing natural immunity to a vaccine vector on vaccine-induced T-cell responses. To investigate this interaction, we examined the relationship between pre-existing Ad5 immunity and T-cell cytokine response profiles in healthy, HIV-uninfected recipients of MRKAd5 HIV-1 gag vaccine (HVTN 050, ClinicalTrials.gov #NCT00849732). Participants were grouped by baseline Ad5 neutralizing antibody titer as either Ad5-seronegative (titer ≤18; n = 36) or Ad5-seropositive (titer >200; n = 34). Samples from vaccine recipients were analyzed for immune responses to either HIV-1 Gag peptide pools or Ad5 empty vector using an ex vivo assay that measures thirty cytokines in the absence of long-term culture. The overall profiles of cytokine responses to Gag and Ad5 had similar combinations of induced Th1- and Th2-type cytokines, including IFN-γ, IL-2, TNF-α, IP-10, IL-13, and IL-10, although the Ad5-specific responses were uniformly higher than the Gag-specific responses (p<0.0001 for 9 out of 11 significantly expressed analytes). At the peak response time point, PBMC from Ad5-seronegative vaccinees secreted significantly more IP-10 in response to Gag (p = 0.008), and significantly more IP-10 (p = 0.0009), IL-2 (p = 0.006) and IL-10 (p = 0.05) in response to Ad5 empty vector than PBMC from Ad5-seropositive vaccinees. Additionally, similar responses to the Ad5 vector prior to vaccination were observed in almost all subjects, regardless of Ad5 neutralizing antibody status, and the levels of secreted IFN-γ, IL-10, IL-1Ra and GM-CSF were blunted following vaccination. The cytokine response profile of Gag-specific T cells mirrored the Ad5-specific response present in all subjects before vaccination, and included a number of Th1- and Th2-associated cytokines not routinely assessed in current vaccine trials, such as IP-10, IL-10, IL-13, and GM-CSF. Together, these results suggest that vector-specific humoral responses may reduce vaccine-induced T-cell responses by previously undetected mechanisms.
Highlights
Most T-cell-targeted HIV vaccine candidates are based on vectors derived from naturally occurring human viruses, and preexisting immunity to these viruses has the potential to negatively impact the desired vaccine response
Blunting of a vaccine response due to neutralizing antibodies can be partially overcome by increasing the dose or number of inoculations [3,6], but even with such dose optimization, rates of HIV-specific IFN-c T-cell responses induced by adenovirus serotype 5 (Ad5)/HIV-1 vaccination remain higher in vaccine recipients with lower Ad5 neutralizing antibody titers [1,2]
We addressed this need in part by conducting a thorough evaluation of the insert- and vector-specific cytokine responses to an Ad5-HIV-1 Gag vaccine candidate similar to that used in the Step Study
Summary
Most T-cell-targeted HIV vaccine candidates are based on vectors derived from naturally occurring human viruses, and preexisting immunity to these viruses has the potential to negatively impact the desired vaccine response. While it has been shown that Ad5-specific antibodies blunt the desired immune response to an Ad5-based vaccine in a dose-dependent manner [2,3,4], it remains unclear how this may translate into an increased risk of HIV-1 infection. Ad5-specific antibodies limit the dose and duration of target cell exposure to Ad5-vaccine viral particles, which lower immune responses by reducing the frequency of transduced cells [3]. Such restriction is vexing because Ad5 seropositivity rates tend to be higher in populations with higher risks of HIV infection [5,6]. In vitro studies indicate that vector-specific antibodies can enhance trans infection of T cells by HIV-1 via the formation of immune complexes [7] and Ad5specific CD4+ T-cell proliferative responses correlate with increased expression of mucosal homing markers [8], but evidence for such an interaction in vivo remains to be demonstrated
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