Dynamics of mucosal immune responses elicited by systemic prime/boost vaccination


BACKGROUND: Mucosal surfaces play a critical role in HIV-1 transmission and disease pathogenesis, hence new vaccine strategies should induce protective mucosal immune responses. Previous studies demonstrated that additional boosting of the 6 months (mo) RV144 regimen with longer boosting intervals improved/maintained immune responses. Here we assessed cellular mucosal responses elicited after the RV144 ALVAC-HIV/AIDSVAX B/E prime/boost intramuscular vaccine regimen followed by additional late boosts (RV306).
METHODS: Sigmoid biopsies were collected two weeks post the 6mo priming regimen and the 15mo and 18mo late boosts with ALVAC-HIV/AIDSVAX B/E. Dynamics of mucosal cell populations and vaccine-specific cellular immune responses were assessed by flowcytometry.
RESULTS: After the late boost at 15/18mo we observed an increase in the frequency of mucosal Ã?7highCD4+ T cells (21.5%) compared to the 6mo boost (11%, p=0.01). This was accompanied by a decrease of Ã?7highCD4+ T cells in the periphery after the 15/18mo boost to 3.85% compared to 4.65% post 6mo (p=0.04). After the 15/18mo boost, 100% of vaccine recipients developed mucosal TH023-specific CD4+ T cell TNFa responses compared to just 30% after 6mo. Correspondingly, the magnitude of those responses after 15/18mo increased to 0.92% from 0.04% post 6mo (p=0.009). A similar trend was observed for mucosal TH023-specific Th17 cells that increased to 0.11% after the 15/18mo boost while not being detectable post 6mo (p=0.04). This is in strong contrast to univariate peripheral CD4+ T cell TNFa responses that peaked post 6mo and were not augmented by late boosting, with no peripheral TH023-specific Th17 responses detected at any timepoint. We also observed an increase in mucosal IgA-producing plasmablasts upon 15/18mo boost to 17.2% compared to 8.6% after 6mo (p=0.04), however no vaccine-specific IgA was detected in rectal secretions. The frequency of peripheral plasmablasts and vaccine-specific plasma IgA did not increase after the late boosts.
CONCLUSIONS: Late boosts with ALVAC-HIV/AIDSVAX B/E induced mucosal CD4+ T cell homing and improved vaccine-specific mucosal CD4+ T cell responses including the induction of mucosal Th17 cells and increase in the frequency of IgA-producing plasmablasts. Detailed characterization of mucosal immune responses in future vaccine studies is warranted given that systemic vaccination induces differing patterns of immune response between compartments.