This proposal is designed to extend our ongoing studies by investigating immunization approaches aimed at maximizing immune responses to oral or intestinal SIV vaccination in primates. As a source of viral antigen during vaccination, we will use a SIV construct previously used in our SIV and SHIV vaccine studies: a genetically inactivated proviral genome that produces non-infectious viral particles. We achieved significant systemic and mucosal cellular responses with a SIV DNA-rMVA approach after oral cavity and intestinal immunizations. These immunizations had two important impacts on SIV exposure and infection: 1. the intestinal immunization provided significant protection from infection but no protection from disease progression;2. the oral cavity immunization provided significant protection from disease with no AIDS development observed during the post-challenge follow up and with more than 50% of the animals controlling virus replication to undetectable blood levels after experiencing a peak of viremia, and apparently clearing the infection. The goals of this proposal are: 1. to evaluate whether an immunization consisting of SIVvaxmac/sm and cytokine DNA, matched rMVA, and gp140 SIVsmE543-3 Env administered in the oral cavity or intestinally, leads to persistent anti-Env IgG and IgA titers at mucosal sites of HIV exposure in humans and whether this addition improves protection from heterologous SIVmac251 infection and disease in Indian RM. 2. to more extensively evaluate the correlates of protection from infection and disease previously observed with the DNA+MVA oral and intestinal vaccinations;3. to evaluate whether the best regimen identified in Aim 1 that protects after vaginal SIV exposure also provides a similar protection after rectal viral exposure in both male and female animals.
This proposal is designed to extend our studies and investigate immunization approaches aimed at improving the oral vaccination regimens already explored that showed very promising partial protection of infection and significant disease delay in the infected animals, to further improve prevention of infection and disease progression. They also investigate whether the protection provided is different when virus exposure occurs via different routes, as HIV infects humans via multiple routes of exposure. The experiments described in this proposal are critical to continue the evaluation of qualitative aspects of the antiviral immune responses that have not been systematically explored during preclinical vaccine trials and during the clinical HIV trials conducted so far. Our approach, which includes vaccines similar to those of the human RV144 trial that showed partial protection of infection and in its previously tested version has already achieved better results than those observed in macaques with the corresponding RV144 vaccine, follows exactly the accepted philosophy that this vaccine modality should be further investigated and improved.
