Background: In the present non-human primate challenge study, we assessed the ability of an adenovirus type 5 (Ad5) vector vaccine, either alone or with DNA vector priming, to attenuate infection following either SIVmac239 or SHIV89.6P virus challenge.  We compared (1) the influence of the different challenge viruses, (2)the effect of  dominant MHC-I allele expression and (3) the effect of including multiple vaccine antigens. 

Methods: For the SIV challenge MamuA*01-positive and –negative monkeys were immunized with Ad5-SIV gag, alone or as an SIV gag DNA prime/Ad5-gag boost combination. For SHIV challenge MamuA*01 -negative monkeys were immunized with Ad5 vectors encoding SIV gag, homologous gp140(89.6P), heterologous gp140(jrfl), or SIV gag + gp140(jrfl).

Results: All vaccinees developed antigen-specific CD8+ and CD4+ T cells. In the intravenous SHIV89.6P infection study, all Ad5-immunized groups exhibited attenuation of acute viremia and CD4 lymphopenia. Ad5-gp140(jrfl) and Ad5-SIVgag mediated comparable effects, and the combination of the two was more effective than either one given alone. The gp140(jrfl) vectors elicited cellular immune responses that were cross-reactive with the 89.6 env, but unlike the Ad5-gp140(89.6P) vector, did not prime for anti-SHIV 89.6P neutralizing antibodies.  Set-point SHIV viremias for vaccinees were ~100-fold lower than controls (but at least 10-fold higher than in MamuA*01-positive Ad5-gag vaccinees). In contrast with many previous studies, these positive  effects were seen in the absence of a vaccine expressing an env protein closely related to the challenge virus and with animals not harboring the dominant MamuA*01 MHC-I allele.  In the SIVmac239 challenge, all animals developed viremia after intrarectal infection. The DNA/Ad5 MamuA*01⁺ vaccinees exhibited the best control of infection with approx. 10- to 35-fold lower viremia through day 136 post challenge compared to controls. Ad5 immunization alone did not suppress SIV viremia relative to controls.

Conclusions: These studies show that Ad5 vector-containing vaccines elicit attenuating cellular immune responses against both SHIV89.6P and the stringent SIVmac239 challenge viruses.  In addition, attenuation of the SHIV infection was achieved without a relevant immunodominant MHC-I allele and using a vaccine antigen that was only 85% homologous (gp140-jrfl).  The attenuating effect was also greater in animals that had been immunized against multiple viral proteins.