Abstract
The impressive amount of data generated by experimental HIV/SIV vaccines has led to the realization
that protection will most likely requires 2 levels of barriers, the initial one at the mucosal port of entry and if
breached, a second set of systemic defenses. The capacity of humoral and cellular immune responses in
mucosal tissues to block or contain replication at the initial stage of virus transmission may have a profound
impact on the ability of a vaccinated host to resist infection, even in the case when virus progresses beyond
the port of entry, allowing the systemic response more time to control or eradicate the incoming pathogen.
We hypothesized that there are two necessary features for a successful vaccine: 1) A prolonged if not
life-long stimulation of the immune system with viral antigens to maintain “alert” immune responses; and 2) a
targeted immune response at the site of primary replication of HIV. A vaccine approach that simultaneously
addresses these two issues would have the potential to achieve solid, long-term active protection. To fulfill
these requirements, we have developed an original strategy to successfully deliver a vaccine to mucosal sites
that provide antigen stimuli at recurrent intervals and elicit protective mucosal immune responses. Our
strategy leverages epithelial stem cells as permanent but non-expressing source of viral antigen while their
differentiated offspring express and present antigen to the local immune system, along the reproductive cycle.
Using a single cycle SIV (SIVsc) approach, which has been shown to be safe compared to traditional
attenuated vaccines, we have cloned the SIVsc genome under the control of the involucrin promoter (pINV-
SIVsc), a terminally differentiated keratinocyte specific promoter. When administered, the vaccine targets and
transduces basal epithelial stem cells from vaginal tissues. These then proliferate and differentiate into mature
epithelial cells, triggering SIV antigen expression via the promoter and leading to both direct and cross priming.
For this project, we propose: 1) To confirm and further improve the efficacy and safety profile of the
pINV-SIVsc vaccine in female macaques; 2) To visualize and optimize vaccine delivery, and investigate the
mechanisms of action underlying protection; and, 3) Using our best optimized vaccine strategy, demonstrate
protection from virus acquisition and/or viral replication in vivo and determine the correlates of protection or
control against repeated low-dose vaginal challenges with heterologous SIV.