Improving the Immune Response to Nanoparticle-Based SARS-CoV-2 Vaccines

PROJECT SUMMARY / ABSTRACT Vaccines have been very effective at protecting against infectious diseases that pose serious threats to human health. However, prophylactic vaccines can also be limited, particularly if antigenic drift occurs to create variants of the pathogen; this can result in vaccines losing potency over time, needing boosters to confer protection, and lower neutralization efficacy on emerging viral variants - consequences which are observed in the current COVID-19 pandemic. Recent studies have shown that the release kinetics of vaccines can be important in establishing lasting and efficacious immunity. In particular, extending the exposure to antigens can result in higher antibody titers and increased diversity of neutralizing antibodies that target a more diverse set of epitopes, relative to immune responses from conventional bolus vaccination. Furthermore, vaccines made from protein-based nanoparticles can elicit increased antibody production, broader antigen cross-reactivity, and a more balanced Th1/Th2 response. This study tests the hypothesis that the synergy in combining the effects of nanoparticle vaccines for effective antigen presentation, together with a slower release to give a longer exposure to the vaccine, will elicit increased durability of the immune response and a broader cross-reactivity for emerging viral variants. To test this hypothesis, we propose to encapsulate protein nanoparticle vaccines with a biodegradable PLGA-PEG-PLGA (PPP)-based polymer to modulate the kinetics of its release from an in vivo vaccine depot. This extended-release vaccine strategy will then be applied towards SARS-CoV-2. We will evaluate the durability of the proposed vaccine strategy's potency and the breadth of cross-reactive immune responses toward the variants of SARS-CoV-2 and other types of coronaviruses. Our specific aims are to: (1) create controlled-release nanoparticle depot vaccines against SARS-CoV-2, and (2) determine the efficacy and immunological responses to these vaccine nanoparticles that are encapsulated by the polymeric depot. Because the design of these vaccines is modular and different antigens can be exchanged in a relatively straightforward approach, the successful implementation of this proposed strategy for coronavirus antigens could have broader applicability towards the development of vaccines for other infectious pathogens.