At the peak of an immune responses against a natural infection, a host can generate pathogen-specific T cell responses that comprise 20-50% of the hosts total T cell pool. We have now identified a vaccination strategy that is able to generate a similar level of T cell expansion from a purely molecular based vaccine, a result not possible with previously developed vaccine strategies. These high levels of CD8+ T cell expansion can be achieved by the vaccination of a host with antigen in combination with agonists for both the Toll-Like Receptor (TLR) and CD40 pathways (combined TLR/CD40-agonist immunization). Importantly, we have also determined the success of this vaccine successfully generating primary and memory CD8+ T cell responses even in CD4 deficient hosts. This is a feature unique to this vaccination method (in comparison to other published methods) and is a necessary component for a vaccination to be successful in treating HIV infected individuals where CD4 T cell function is so heavily compromised. All studies conducted up until now using this vaccination technique have required the separate injection of the antigen, the TLR agonist, and the CD40 agonist; this constitutes a complication in the effort to move this vaccination method into a clinical setting. For the purpose of simplifying vaccine production and clinical implementation, we will producing a vaccine in which all three components were contained within a single molecular entity; ie. a combined TLR/CD40-agonist conjugate vaccine. Following production of the vaccine, we will evaluate the induction of protective immunity against both systemic and mucosal viral challenge. These are likely necessary components of a successful vaccine against a virus such as HIV which produces a systemic infection following transmission via the genital mucosa. These studies will result in the development of a novel vaccination strategy capable of inducing potent cellular immunity and which holds significant promise for rapid humanization and investigation for prophylactic and/or therapeutic efficacy against HIV. ? ? ?
| Oh, Jason Z; Kurche, Jonathan S; Burchill, Matthew A et al. (2011) TLR7 enables cross-presentation by multiple dendritic cell subsets through a type I IFN-dependent pathway. Blood 118:3028-38 |
| Oh, Jason Z; Kedl, Ross M (2010) The capacity to induce cross-presentation dictates the success of a TLR7 agonist-conjugate vaccine for eliciting cellular immunity. J Immunol 185:4602-8 |
| Sanchez, Phillip J; McWilliams, Jennifer A; Haluszczak, Catherine et al. (2007) Combined TLR/CD40 stimulation mediates potent cellular immunity by regulating dendritic cell expression of CD70 in vivo. J Immunol 178:1564-72 |
