Background:  Despite raising broad virus-specific immune responses, prior prime/boost vaccine regimens have not prevented infection upon virulent mucosal challenge. We evaluated HIV-1-vaccinated rhesus monkeys for an ability to resist intrarectal infection after repeated low-dose challenge by a heterologous virus. The vaccine consisted of priming with plasmid DNA and boosting with recombinant MVA, both encoding Gag-Pol-Env of an HIV-1 CRF02_AG primary isolate.

Methods:  At 0, 8, and 26 weeks, 16 rhesus monkeys were primed with 0.6 mg of DNA plasmid and followed by a 10⁸ pfu MVA boost at week 41. Monkeys were challenged at 7 or 11 months after the MVA boost by weekly intrarectal exposures to 3.8 x 10⁵ viral particles of SHIV SF162p3 (containing an R5-using HIV-1 subtype B envelope). Systemic infection was determined by plasma vRNA, PBMC-proviral DNA, and virus-specific seroconversion. Vaccine-induced immunity was evaluated by standard T-cell and serologic assays for HIV-specific and cross-HIV-1 subtype responses.

Results:  Importantly, protection of vaccinated monkeys from the establishment of systemic infection was observed after repeated SHIVSF162p3 IR challenges. Naïve monkeys (n=4) were systemically infected after an average of 3.5 intrarectal exposures in this low-dose challenge model. However, 7 of 16 (44%) vaccinated animals remained virus free after receiving 10 intrarectal exposures, and 5 of these 7 (31% of the original 16) remained virus free after receiving 18 intrarectal exposures. Cox hazard model assessment indicated that, as a group, vaccinated animals were significantly less likely to be infected than naïve control animals (p = 0.021). Because a clear separation of susceptible and protected vaccinees was observed during the course of intrarectal challenges, a preliminary evaluation for vaccine-elicited correlates of protection was undertaken. Although the DNA/MVA vaccine regimen induced significant HIV-1 A/G specific and cross-subtype CTL and humoral responses, no distinction in responses between susceptible and protected monkeys was evident.

Conclusions:  These findings provide the first evidence that a multigene HIV-1 DNA/MVA vaccine may successfully prevent transmission in a SHIV-monkey model when the challenge dose more closely mimics that in human sexual transmission. Furthermore, this system provides insight into correlates of protection that may involve subtle aspects of immunity distinct from standard vaccine-elicited T-cell and serologic responses.

Keywords: DNA/MVA vaccine; mucosal challenge; non-human primate model