Priming Immunization with DNA Augments Immunogenicity of Recombinant Adenoviral Vectors for Both HIV-1 Specific Antibody and T-cell Responses
Year of Publication
Koup, RA; Roederer, M; Lamoreaux, L; Fischer, J; Novik, L; Nason, MC; Larkin, BD; Enama, ME; Ledgerwood, JE; Bailer, RT; Mascola, JR; Nabel, GJ; Graham, BS; The VRC 010 Study Team
Adenoviridae; AIDS Vaccines; Antibodies; CD8-Positive; Enzyme-Linked Immunosorbent Assay; Genetic Vectors; HIV Infections; HIV-1/genetics; immunization; Interferon-gamma/metabolism; Secondary Immunophenotyping; T-Lymphocytes; Viral/immunology
BACKGROUND: Induction of HIV-1-specific T-cell responses relevant to diverse subtypes is a major goal of HIV vaccine development. Prime-boost regimens using heterologous gene-based vaccine vectors have induced potent, polyfunctional T cell responses in preclinical studies. METHODS: The first opportunity to evaluate the immunogenicity of DNA priming followed by recombinant adenovirus serotype 5 (rAd5) boosting was as open-label rollover trials in subjects who had been enrolled in prior studies of HIV-1 specific DNA vaccines. All subjects underwent apheresis before and after rAd5 boosting to characterize in depth the T cell and antibody response induced by the heterologous DNA/rAd5 prime-boost combination. RESULTS: rAd5 boosting was well-tolerated with no serious adverse events. Compared to DNA or rAd5 vaccine alone, sequential DNA/rAd5 administration induced 7-fold higher magnitude Env-biased HIV-1-specific CD8(+) T-cell responses and 100-fold greater antibody titers measured by ELISA. There was no significant neutralizing antibody activity against primary isolates. Vaccine-elicited CD4(+) and CD8(+) T-cells expressed multiple functions and were predominantly long-term (CD127(+)) central or effector memory T cells and that persisted in blood for >6 months. Epitopes mapped in Gag and Env demonstrated partial cross-clade recognition. CONCLUSION: Heterologous prime-boost using vector-based gene delivery of vaccine antigens is a potent immunization strategy for inducing both antibody and T-cell responses.