Methods: We examined the CD8 T cell cross-reactivity in recipients of two prior preventative HIV-1 vaccine studies, both of which used adenovirus serotype 5 (Ad5) vectors: HVTN 502 (MRKAd5) and HVTN 505 (VRC DNA with Ad5 boost). We measured the responses to vaccine-encoded epitopes and their common variants using IFNγ ELISpot assays. We also quantified the antigen sensitivities by measuring the IFNγ responses to log fold serial peptide dilutions.
Results: Overall, CD8 responses to variant epitopes had a lower magnitude and decreased antigen sensitivity than those targeting vaccine-encoded epitopes (p<0.0001 and p=0.014). A greater number of mutations, less conservative amino acid substitutions, and HLA-I driven mutations negatively affect the immunogenicity of cross-reactive responses (p<0.0001, p=0.0003, and p<0.0001, respectively). Additionally, cross-reactive responses had a higher magnitude in MRKAd5 recipients with low pre-existing Ad5 titers than those with high pre-existing titers (p=0.0230). Among that former MRKAd5 group, cross-reactive responses were decreased in magnitude and proportion in comparison with cross-reactive responses of VRC DNA/Ad5 recipients (p=0.0052, p=0.0488), even though both groups’ responses to vaccine-encoded epitopes had similar magnitudes.
Conclusion: Our data shows that cross-reactive responses are frequently elicited by vaccination and that this cross-reactivity is affected by the vaccine regimen and by pre-existing Ad5 titers. Future work will focus on analyzing the TCR clonotype repertoire responsible for these CD8 T cell responses and establishing the biologic and clinical significance of these vaccine-induced cross-reactive CD8 T cells.
K. Qin, None
A. Bansal, None
P. Goepfert, None