A Tunable Nanophage Platform for Vaccine Development

PROJECT SUMMARY Newly emerging and long-standing infectious challenges, including arboviruses, Ebola virus and pandemic coronaviruses (CoVs), among others, pose serious public health concerns. Additionally, the potential use of biological agents as weapons of mass destruction poses an ongoing threat to humanity. All of these issues have in common the need for development strategies that allow for the rapid design, screening and formulation of potential vaccine candidates. We have developed a "designer nanoparticle" platform based on λ phage-like particles, or nanophages (NPs), that can display multiple antigenic biomolecules alone and in combination in rigorously defined ratios. The NPs can be rapidly modified to screen and evaluate potential vaccine candidates against newly emerging threats. Herein we propose to develop tools and technologies for rapid screening of multivalent vaccine candidates effective for current and emerging SARS-CoVs and pre- emergent SARS-like CoVs. We will engineer "second generation" nanophages (NPs) that display the spike receptor binding domain (RBD) for these pathogens, the primary target of neutralizing antibody (Ab) responses. Physiochemical and structural characterization of the preparations will be employed to ensure that they possess properties that are appropriate for a pharmaceutical preparation. We will also employ a novel atomic layer deposition technology to generate thermostable, timed-release, single-shot vaccine formulations that reduce or eliminate onerous "cold-chain" requirements for their distribution. We further propose to determine the immunogenicity and protective capacity of mosaic NPs engineered to simultaneously display multiple antigens. These studies will identify vaccine candidates that elicit potent, durable, and broad neutralizing Ab and T cell responses and protective immunity against SARS-CoV-2 variants and pre-emergent SARS-like bat CoVs. In addition to developing this powerful platform and implementing novel formulation strategies, these studies will help define mechanisms of immunogenicity and develop a platform for the rapid engineering of vaccine candidates for existing and untoward emerging biological threats. In sum, this application seeks to provide compelling evidence that the  nanophage system provides a platform for facile and rapid generation, and formulation of highly active multi-antigen presenting vaccines.