Priming immunization with DNA augments immunogenicity of recombinant adenoviral vectors for both HIV-1 specific antibody and T-cell responses
Richard A Koup, Mario Roederer, Laurie Lamoreaux, Jennifer Fischer, Laura Novik, Martha C Nason, Brenda D Larkin, Mary E Enama, Julie E Ledgerwood, Robert T Bailer, John R Mascola, Gary J Nabel, Barney S Graham, VRC 009 Study Team, VRC 010 Study Team, Margaret McCluskey, Sarah Hubka, Lasonji Holman, Ingelise Gordon, Pamela Edmonds, Steve Rucker, Joseph Casazza, Andrew Catanzaro, Alan Fix, Richard A Koup, Mario Roederer, Laurie Lamoreaux, Jennifer Fischer, Laura Novik, Martha C Nason, Brenda D Larkin, Mary E Enama, Julie E Ledgerwood, Robert T Bailer, John R Mascola, Gary J Nabel, Barney S Graham, VRC 009 Study Team, VRC 010 Study Team, Margaret McCluskey, Sarah Hubka, Lasonji Holman, Ingelise Gordon, Pamela Edmonds, Steve Rucker, Joseph Casazza, Andrew Catanzaro, Alan Fix
Abstract
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.
Trial registration: ClinicalTrials.gov NCT00102089, NCT00108654.
Conflict of interest statement
Competing Interests: Gary J. Nabel is named on patent applications for the DNA and adenovirus vector components of this vaccine concept (patent #s E-173-2004/0-US-01, E-335-2003/0-US-01, and E-267-2004/0). This does not alter the authors' ability to adhere to all the PLoS ONE policies on sharing data and materials.
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