Vaccine and Infectious Disease Division

Safety and immunogenicity of a DNA/adenovirus serotype 5 HIV-1 Env/Gag/Pol/Nef vaccine

A major obstacle to the development of an effective HIV vaccine is the high genetic diversity among global HIV-1 isolates, most notably in the envelope protein (Env) that makes up the virus’ outer shell. One approach to address this issue has been to include pieces from multiple diverse HIV-1 subtypes in the candidate vaccine regimen. Several HVTN clinical trials were initiated to study the safety and immunogenicity of vaccination regimens using this methodology, including HVTN protocol 204. This clinical trial evaluated immune responses to a candidate DNA plasmid prime, recombinant adenovirus serotype 5 (rAd5)-vectored boost HIV-1 vaccine developed by the National Institutes of Health Vaccine Research Center. Both parts of the vaccine regimen included inserts for the HIV-1 clade A Env, clade B Env, clade C Env, clade B Gag, clade B Pol and clade B Nef proteins. Participants received three doses of the DNA prime and one dose of the rAd5-vectored boost, or placebo, and were monitored for adverse events and immunogenicity for a total of one year. The trial was evaluated by VIDD staff scientists Drs. Cecilia Morgan and Olivier Defawe, VIDD senior staff scientists Drs. John Hural and Zoe Moodie, VIDD associate member Dr. Stephen De Rosa, VIDD co-director Dr. Julie McElrath, Center President and Director Dr. Larry Corey and colleagues.

Side effects were minimal and the vaccine was generally well tolerated and safe. T-cell responses were induced in more than 70% of vaccinees, most frequently targeting Gag and Env (~54% each). As seen in other trials, individuals with pre-existing neutralizing antibodies to the Ad5 vector were less likely to produce a T-cell response to the vaccine inserts (62% vs. 86%), but in all cases the majority of T-cell responses produced multiple cytokines, a response type that is thought to be more effective at controlling viral infection. The vaccine also induced a high frequency of binding antibody responses to Env from all three clades included in the vaccine (with response rates ranging from 84%-95% by clade). Overall the vaccine showed promise, and a similar regimen has moved on to testing in HVTN protocol 505, an ongoing large study investigating the regimen’s safety and efficacy in men who have sex with men.

Churchyard GJ, Morgan C, Adams E, Hural J, Graham BS, Moodie Z, Grove D, Gray G, Bekker LG, McElrath MJ, Tomaras GD, Goepfert P, Kalams S, Baden LR, Lally M, Dolin R, Blattner W, Kalichman A, Figueroa JP, Pape J, Schechter M, Defawe O, De Rosa SC, Montefiori DC, Nabel GJ, Corey L, Keefer MC; NIAID HIV Vaccine Trials Network.  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).  PLoS One. 2011;6(8):e21225.