A Phase IIA Randomized Clinical Trial of a Multiclade HIV-1 DNA Prime Followed by a Multiclade rAd5 HIV-1 Vaccine Boost in Healthy Adults (HVTN204)

Abstract

BackgroundThe safety and immunogenicity of a vaccine regimen consisting of a 6-plasmid HIV-1 DNA prime (envA, envB, envC, gagB, polB, nefB) boosted by a recombinant adenovirus serotype-5 (rAd5) HIV-1 with matching inserts was evaluated in HIV-seronegative participants from South Africa, United States, Latin America and the Caribbean.Methods480 participants were evenly randomized to receive either: DNA (4 mg IM by Biojector) at 0, 1 and 2 months, followed by rAd5 (1010 PU IM by needle/syringe) at 6 months; or placebo. Participants were monitored for reactogenicity and adverse events throughout the 12-month study. Peak and duration of HIV-specific humoral and cellular immune responses were evaluated after the prime and boost.ResultsThe vaccine was well tolerated and safe. T-cell responses, detected by interferon-γ (IFN-γ) ELISpot to global potential T-cell epitopes (PTEs) were observed in 70.8% (136/192) of vaccine recipients overall, most frequently to Gag (54.7%) and to Env (54.2%). In U.S. vaccine recipients T-cell responses were less frequent in Ad5 sero-positive versus sero-negative vaccine recipients (62.5% versus 85.7% respectively, p = 0.035). The frequency of HIV-specific CD4+ and CD8+ T-cell responses detected by intracellular cytokine staining were similar (41.8% and 47.2% respectively) and most secreted ≥2 cytokines. The vaccine induced a high frequency (83.7%–94.6%) of binding antibody responses to consensus Group M, and Clades A, B and C gp140 Env oligomers. Antibody responses to Gag were elicited in 46% of vaccine recipients.ConclusionThe vaccine regimen was well-tolerated and induced polyfunctional CD4+ and CD8+ T-cells and multi-clade anti-Env binding antibodies.Trial Registration:ClinicalTrials.gov NCT00125970

Efficacy Trials and Progress of HIV Vaccines

“…Then the involvement of many stakeholders, including the Institute of acquired immunodeficiency syndrome division (DAIDS) and the trial of members of the community site, to discuss the next steps vaccines HIV on the basis of Ad5. It was decided that the study of the system VRC DNA/rAd5 should start because of its ability to give valuable information, and safety and the results are promising immune system demonstrated in clinical trials early stage [59]. And it provided emergency, however, that the individuals who were not circumcised or have preexisting neutralizing antibodies for Ad5-who pretended to promote the acquisition of HIV virus in step would be excluded study.…”

HIV-specific humoral responses benefit from stronger prime in phase Ib clinical trial

“…The most frequently used heterologous prime-boost modality consists of a DNA prime followed by a vector boost (5,10,16), while clinical data on heterologous prime-boost strategies involving 2 vectors are sparse, even though preclinical data show that immune responses in animals primed with an adenovirus vector can be efficiently boosted with a poxvirus vector (17)(18)(19). Recent data in nonhuman primates (NHPs) also show that vaccination with an adenovirus prime-poxvirus vector boost resulted in an 83% reduction in the per-exposure probability of infection against repetitive, intrarectal challenges (20).…”

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.…”