Priming Immunization with DNA Augments Immunogenicity of Recombinant Adenoviral Vectors for Both HIV-1 Specific Antibody and T-Cell Responses

Abstract

BackgroundInduction 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.MethodsThe 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.ResultsrAd5 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.ConclusionHeterologous prime-boost using vector-based gene delivery of vaccine antigens is a potent immunization strategy for inducing both antibody and T-cell responses.Trial RegistrationClinicalTrails.gov NCT00102089, NCT00108654

Potential To Streamline Heterologous DNA Prime and NYVAC/Protein Boost HIV Vaccine Regimens in Rhesus Macaques by Employing Improved Antigens

“…This outcome was predicted by previous mouse immunogenicity studies of our redesigned antigens and is likely related to the increased expression levels, especially of Gag (27,32). Similar observations were made in cynomolgus monkeys and humans after splitting of a differently designed Gag-Pol-Nef fusion protein into three parts which were subsequently delivered as a mixture of three plasmids rather than one (16,28,29).…”

“…Immunogenicity analyses in mice clearly showed superiority of this three-plasmid configuration over the parental EuroVacc vaccines regarding both the magnitude of antigen-specific T cells and the balance toward the different antigens (27). Improved responses after splitting of a different Gag-Pol-Nef antigen into separate parts were also observed in humans in clinical phase I trials (16,28). For the immunological assessment of our next-generation antigens in rhesus macaques, the plasmid backbone was also changed to VRC-8400 (29) from the pORT constructs (30) to further increase expression of the antigens.…”

“…Both the proportion of responders and the number of HIV-specific T cells, as measured by enzymelinked immunosorbent spot (ELISpot) analysis of gamma interferon (IFN-␥)-secreting cells, increased 2-to 4-fold (12,15). Other studies have shown even better augmentation (16). The T cell responses were mainly of the CD4 ϩ phenotype and directed against Env, although a balanced response against all antigens and a balanced ratio of CD4 ϩ and CD8 ϩ responses might be desirable, especially against Gag, as CD8 T cell responses against this antigen are associated with long-term disease control in some patients (17,18).…”

Superior Induction of T Cell Responses to Conserved HIV-1 Regions by Electroporated Alphavirus Replicon DNA Compared to That with Conventional Plasmid DNA Vaccine

“…This maximizes the induction of transgene-specific responses while avoiding buildup of antivector immunity (43). While simple vaccine mo-dalities are better for priming, more complex vectors such as poxviruses (12-14, 29, 41) and adenoviruses (22) excel in boosting. Currently, numerous prime-boost regimens are in both preclinical and clinical development.…”

HIV-1 vaccines

“…Aiming at inducing both functional antibodies and cellmediated responses, 44 a regimen with DNA vaccine prime composed of DNA plasmids encoding Gag, Pol, and Nef from HIV-1 subtype B and Env from subtypes A, B, and C and replicationdefective rAd5-HIV-1 vaccine boost containing a mixture of 4 rAd5 vectors encoding the HIV-1 subtype B Gag-Pol and Env matching the DNA Env components was tested in Phase I [45][46][47] and IIa 48 clinical trials. As opposed to the MRKAd5 HIV-1 vaccine that did not contain an envelope gene, the HVTN 505 vaccine contained 3 envelope genes.…”