Protection against Mucosal SHIV Challenge by Peptide and Helper-Dependent Adenovirus Vaccines

Abstract

Groups of rhesus macaques that had previously been immunized with HIV-1 envelope (env) peptides and first generation adenovirus serotype 5 (FG-Ad5) vaccines expressing the same peptides were immunized intramuscularly three times with helper-dependent adenovirus (HD-Ad) vaccines expressing only the HIV-1 envelope from JRFL. No gag, pol, or other SHIV genes were used for vaccination. One group of the FG-Ad5-immune animals was immunized three times with HD-Ad5 expressing env. One group was immunized by serotype-switching with HD-Ad6, HD-Ad1, and HD-Ad2 expressing env. Previous work demonstrated that serum antibody levels against env were significantly higher in the serotype-switched group than in the HD-Ad5 group. In this study, neutralizing antibody and T cell responses were compared between the groups before and after rectal challenge with CCR5-tropic SHIV-SF162P3. When serum samples were assayed for neutralizing antibodies, only weak activity was observed. T cell responses against env epitopes were higher in the serotype-switched group. When these animals were challenged rectally with SHIV-SF162P3, both the Ad5 and serotype-switch groups significantly reduced peak viral loads 2 to 10-fold 2 weeks after infection. Peak viral loads were significantly lower for the serotype-switched group as compared to the HD-Ad5-immunized group. Viral loads declined over 18 weeks after infection with some animals viremia reducing nearly 4 logs from the peak. These data demonstrate significant mucosal vaccine effects after immunization with only env antigens. These data also demonstrate HD-Ad vectors are a robust platform for vaccination.

High‐capacity adenoviral vectors circumvent the limitations of ΔE1 and ΔE1/ΔE3 adenovirus vectors to induce multispecific transgene product‐directed CD8 T‐cell responses

“…They showed that HC-Ad vectors induced stronger immune responses than ΔE1 vectors against GFP and luciferase but equal responses against HIV-env. These vectors were further successfully used in a prime-boost vaccination approach followed by simian HIV (SHIV) challenge in rhesus macaques pre-immunized with HIV envelope peptides or ΔE1Ad vectors [37]. Although these studies suggest a high potency of this vector type as a genetic vaccine, the reasons for the promising performance of HC-Ad vectors in these studies have so far not been addressed.…”

Characterization of species C human adenovirus serotype 6 (Ad6)

“…Recently, Ad6 has been tested as a lower seroprevalence vector for gene-based vaccines and oncolytic virotherapy (Capone et al, 2006; Senac et al, ; Shashkova, May, and Barry, 2009; Weaver et al, 2009a; Weaver et al, 2009b). In these applications, Ad6 appears nearly as potent as Ad5 for vaccine (Weaver et al, 2009a) and is as good or better than Ad5 for solid tumor cell killing (Shashkova, May, and Barry, 2009).…”

Generation and Evaluation of Clade C Simian-Human Immunodeficiency Virus Challenge Stocks

“…Such SHIVs are widely used for preclinical testing of candidate vaccines and therapeutics, but the majority of currently available SHIVs have been constructed with chronic clade B env genes (4)(5)(6)(7). Transmission of HIV-1 across an intact mucosal barrier is relatively inefficient, and in most cases a single or a small number of transmitted/founder viruses are responsible for establishing infection (8)(9)(10).…”