Human adenovirus-specific T cells modulate HIV-specific T cell responses to an Ad5-vectored HIV-1 vaccine
Nicole Frahm, Allan C. DeCamp, David P. Friedrich, Donald K. Carter, Olivier D. Defawe, James G. Kublin, Danilo R. Casimiro, Ann Duerr, Michael N. Robertson, Susan P. Buchbinder, Yunda Huang, Gregory A. Spies, Stephen C. De Rosa, M. Juliana McElrath
Nicole Frahm, Allan C. DeCamp, David P. Friedrich, Donald K. Carter, Olivier D. Defawe, James G. Kublin, Danilo R. Casimiro, Ann Duerr, Michael N. Robertson, Susan P. Buchbinder, Yunda Huang, Gregory A. Spies, Stephen C. De Rosa, M. Juliana McElrath
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Research Article

Human adenovirus-specific T cells modulate HIV-specific T cell responses to an Ad5-vectored HIV-1 vaccine

Abstract

Recombinant viruses hold promise as vectors for vaccines to prevent infectious diseases with significant global health impacts. One of their major limitations is that preexisting anti-vector neutralizing antibodies can reduce T cell responses to the insert antigens; however, the impact of vector-specific cellular immunity on subsequent insert-specific T cell responses has not been assessed in humans. Here, we have identified and compared adenovirus-specific and HIV-specific T cell responses in subjects participating in two HIV-1 vaccine trials using a vaccine vectored by adenovirus serotype 5 (Ad5). Higher frequencies of pre-immunization adenovirus-specific CD4+ T cells were associated with substantially decreased magnitude of HIV-specific CD4+ T cell responses and decreased breadth of HIV-specific CD8+ T cell responses in vaccine recipients, independent of type-specific preexisting Ad5-specific neutralizing antibody titers. Further, epitopes recognized by adenovirus-specific T cells were commonly conserved across many adenovirus serotypes, suggesting that cross-reactivity of preexisting adenovirus-specific T cells can extend to adenovirus vectors derived from rare serotypes. These findings provide what we believe to be a new understanding of how preexisting viral immunity may impact the efficacy of vaccines under current evaluation for prevention of HIV, tuberculosis, and malaria.

Authors

Nicole Frahm, Allan C. DeCamp, David P. Friedrich, Donald K. Carter, Olivier D. Defawe, James G. Kublin, Danilo R. Casimiro, Ann Duerr, Michael N. Robertson, Susan P. Buchbinder, Yunda Huang, Gregory A. Spies, Stephen C. De Rosa, M. Juliana McElrath

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Figure 3

Rates and magnitudes of Ad5 peptide pool–specific T cell responses in Step study participants at 4 weeks (week 30) after final immunization.

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Rates and magnitudes of Ad5 peptide pool–specific T cell responses in St...
(A) Percentage of CD4+ T cells producing IFN-γ and/or IL-2 after stimulation with Ad5 peptide pools in 96 participants. (B) Percentage of CD8+ T cells producing IFN-γ and/or IL-2 after stimulation with Ad5 peptide pools in 102 participants. Red symbols represent positive responses; blue symbols represent responses below the positivity threshold. Box plots represent positive responses only and show medians, IQR, and whiskers extending to the furthest point within 1.5 times the IQR from the upper or lower quartile. Subjects are grouped by treatment (placebo or vaccine) and baseline Ad5 nAb titers (≤18 or >18) as indicated. Numbers above each panel show response rates. Participants with high background cytokine production (>0.1%) by CD4+ T cells were excluded from analysis, resulting in reduced numbers compared with CD8+ T cell responses. The peptide pools are described in Supplemental Table 1. DBP, ssDNA binding protein; pol, polymerase; pTP, preterminal protein.