Safety and Immunogenicity of a Replication-Defective Adenovirus Type 5 HIV Vaccine in Ad5-Seronegative Persons: A Randomized Clinical Trial (HVTN 054)

Abstract

BackgroundIndividuals without prior immunity to a vaccine vector may be more sensitive to reactions following injection, but may also show optimal immune responses to vaccine antigens. To assess safety and maximal tolerated dose of an adenoviral vaccine vector in volunteers without prior immunity, we evaluated a recombinant replication-defective adenovirus type 5 (rAd5) vaccine expressing HIV-1 Gag, Pol, and multiclade Env proteins, VRC-HIVADV014-00-VP, in a randomized, double-blind, dose-escalation, multicenter trial (HVTN study 054) in HIV-1-seronegative participants without detectable neutralizing antibodies (nAb) to the vector. As secondary outcomes, we also assessed T-cell and antibody responses.Methodology/Principal FindingsVolunteers received one dose of vaccine at either 1010 or 1011 adenovector particle units, or placebo. T-cell responses were measured against pools of global potential T-cell epitope peptides. HIV-1 binding and neutralizing antibodies were assessed. Systemic reactogenicity was greater at the higher dose, but the vaccine was well tolerated at both doses. Although no HIV infections occurred, commercial diagnostic assays were positive in 87% of vaccinees one year after vaccination. More than 85% of vaccinees developed HIV-1-specific T-cell responses detected by IFN-γ ELISpot and ICS assays at day 28. T-cell responses were: CD8-biased; evenly distributed across the three HIV-1 antigens; not substantially increased at the higher dose; and detected at similar frequencies one year following injection. The vaccine induced binding antibodies against at least one HIV-1 Env antigen in all recipients.Conclusions/SignificanceThis vaccine appeared safe and was highly immunogenic following a single dose in human volunteers without prior nAb against the vector.Trial RegistrationClinicalTrials.gov NCT00119873

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

“…While the order of vector administration had only minor effects on the magnitude of the IgG response, increasing priming doses of rAd5 led to significantly higher response rates of binding Env-specific IgG after the NYVAC-B boost for consensus A Env gp140 (P = 0.0013), consensus C Env gp140 (P < 0.0001), ConS gp140 (P < 0.0001), A244 gp120 (P = 0.0005), and p24 NYVAC group had 2 participants with erythema and/or induration of greater than 9 cm in diameter after receipt of the fourth vaccination. Overall, the reactogenicity profile was similar to that observed in prior studies of the NYVAC and rAd5 vaccines used in this study (11,12,21).…”

“…Both rAd5 and NYVAC-B had previously been tested in humans and have been shown to elicit both humoral and cellular responses (21,25), but the combination of an adenoviral vector with a poxvirus vector had only been tested in NHPs, in which it showed superior protection from acquisition compared with that of homologous poxvirus vectors (20). The rAd5 vaccine used in Interestingly, we found that Env-specific IgA production was mainly restricted to NYVAC/Ad5 hi ( Figure 3D for clade B gp140, P = 0.003 for response rates in NYVAC/Ad5 hi vs. Ad5 hi /NYVAC; Supplemental Figure 4 for clades A and C as well as ConS gp140).…”

“…Here, we present human cellular and humoral immunogenicity data of such a combination approach in a randomized, double-blind preventive HIV Vaccine Trials Network trial (HVTN 078). Using previously tested rAd5 (21) and NYVAC (11) vectors, we show not only that the vaccines induce strong cellular and humoral responses, but also that both the order of administration and the priming dose significantly influence the ensuing immune response. Considering the lack of efficacy in the HVTN 505 trial, in which a heterologous DNA prime-rAd5 boost was evaluated (22), optimization of the dose and regimen of future candidate vaccines based on gene delivery with vector combinations will be imperative before advancing to phase IIb clinical trials.…”

Is Prime Boost Strategy a Promising Approach in HIV Vaccine Development?

“…This could be because of development of immune tolerance at such high doses. Similar results were also observed when only Ad5 based strategy was evaluated in a clinical trial [54].…”

Recombinant Adenovirus Serotype 26 (Ad26) and Ad35 Vaccine Vectors Bypass Immunity to Ad5 and Protect Nonhuman Primates against Ebolavirus Challenge

“…Since it has been shown for EBOV and other pathogens, in both nonhuman and human subjects, that heterologous prime-boost vaccination can elicit more potent immunity than single-shot immunization (10,18,39,46) we asked whether rAd26-GP immune responses could be boosted with a heterologous vector to improve protection against EBOV infection. We chose a vaccine dose of 10 11 particles with an eye toward potential clinical testing, as studies have shown this dose of related vectors to be tolerated in human subjects (3,32). Four cynomolgus macaques were inoculated with 10 11 particles (each) of rAd26-GP(Z) and -GP(S/G).…”