Increasing Breadth of Immune Response by Single-Dose Influenza Vaccines

PROJECT SUMMARY / ABSTRACT Vaccines have been very effective at protecting against infectious diseases that pose serious threats to human health, but they can also be limited if the pathogens demonstrate antigenic drift, as is the case for influenza. This genetic drift causes mismatches between antigens in the vaccines vs. in the circulating strains, resulting in vaccines that lose neutralization potency against the new variants. Recent studies have shown that the release kinetics of vaccines can be important in establishing lasting and efficacious immunity. In particular, extending the exposure time to antigens can result in higher antibody titers and increase the breadth of neutralizing antibodies that target a broader range of epitopes (relative to conventional bolus vaccination). This can prevent the concern of low vaccine potency after viral mutations. To develop a single-administration vaccine platform based on these premises, we use a H5N1 avian influenza virus model, a pathogen for which the human population currently does not have existing immunity. We have shown that combining the effects of nanoparticles to effectively present H5 hemagglutinin antigen, together with slow release from a thermo-responsive PLGA- PEG-PLGA polymer depot to give extended antigen exposure, will elicit increased durability of the immune response, a broader cross-reactivity for viral variants, and protection from H5N1 infection. Many questions still remain, however, regarding the mechanisms by which this is accomplished and the optimization of this nanoparticle-hydrogel vaccine platform. Our specific aims are to: (1) determine optimized conditions for a nanoparticle-hydrogel vaccine platform and understand the contributing factors of their immune effects, (2) broaden cross-reactivity by incorporating antigens into nanoparticle-hydrogel vaccines that will generate homosubtypic and heterosubtypic responses, and (3) evaluate the cross-reactive and protective effects of combined, optimized vaccine elements. Because these vaccines are modular, and different antigens can be exchanged in a relatively straightforward approach, the successful implementation of this proposed strategy would have wider applicability towards the development of vaccines for other infectious pathogens and for universal flu vaccines.