Optimizing Vaccines by Targeting Dendritic Cells with IFNa and IFNb Inducing Adjuvants

DESCRIPTION provided by applicant There is a critical need for a safe and effective vaccine against HIV Decades of work have been invested in understanding the immune response to infection and different approaches have been taken to develop vaccines that are effective in preventing and treating the disease While effective in animal models none have been as effective in humans The immune response in humans to the virus is complex with the latter demonstrating remarkable evasion mechanisms Nevertheless in one large clinical trial over of vaccinated individuals were protected from infection and immunity correlated with IgG antibodies Abs against specific viral antigens With the further identification of viral neutralizing Abs against the conserved epitopes on the HIV envelope glycoproteins there are renewed efforts in developing vaccines that stimulate a protective immune response in humans Improvement of dendritic cell DC activation is critical to the development of more efficacious HIV vaccines where strong CD and CD responses are necessary to induce both antibody and cell mediated immunity We have previously shown that constitutively active IPS is a potent molecular adjuvant that induces a robust IFN a b response and both activates and matures human and mouse dendritic cells Constitutively active IPS formulated using a novel approach induced a robust NF kB response high levels of IFN a b expression DC activation maturation and the secretion of key cytokines involved in generating an adaptive immune response including IL p and TNF a Here we propose nano fabrication of a targeted vaccine construct that maximally leverages this IPS adjuvant The Parabon r Essemblix tm Drug Development Platform is an innovative combination of computer aided design CAD software the Parabon inS quio tm Design Studio and self assembling DNA nano fabrication technology that can be used to design and create multifunctional DNA nanostructures i e DNA origami We propose to design and manufacture a DNA origami vaccine that contains a gene cassette for two HIV antigens Ags HIV Gag and HIV gp Env Foldon To target DCs the vaccine construct will be decorated with CpG ODN which binds to DEC the endocytosis mediating receptor on DC The efficacy of the construct for DC activation and transfection will be evaluated in vitro in several cell culture models and in vivo in murine models for immune stimulation and protection against a vaccinia gag challenge PUBLIC HEALTH RELEVANCE This NIH Phase I project will extend the field of computational vaccinology by employing the Parabon Essemblix tm Drug Development Platform to design and create a novel defined DNA origami complex that includes CpG targeting elements for dendritic cells a transfection plasmid for HIV Gag antigen and a constitutively active form of the adapter protein IPS a DC adjuvant Efforts will include developing methods for production and construct validation in vitro assays for dendritic cell and T cell responses and in vivo studies n a murine model to evaluate immunity and protection against a vaccinia gag challenge