A Modular Bacteriophage T4 Nanoparticle Platform Enables Rapid Design of Dual COVID-19-Flu Mucosal Vaccines

A multivalent, rapidly deployable, mucosal vaccine platform is desperately needed to prevent the acquisition and transmission of respiratory infections during epidemics and pandemics. We present one such bacteriophage T4-based platform, and design of dual COVID-19-Flu mucosal vaccines by exploiting its unique architecture. These include: T4’s natural affinity for nasal mucosa, flexible engineering to incorporate multiple antigens, and repeat and symmetric epitope presentation for enhanced B cell responses. Hundreds of SARS-CoV-2 spike trimers and nucleocapsid proteins, and influenza hemagglutinin trimers and M2e peptides, were incorporated into a single phage, creating the highest density nanoparticle presentation yet reported. Intranasal administration of adjuvant-free vaccine induced robust mucosal immunity in mice including, neutralizing antibody and secretory IgA, lung-resident CD4 + /CD8 + T cells, diverse memory B cells, and complete protection against SARS-CoV-2 and influenza challenges. The noninfectious T4 phage offers an extraordinary platform to rapidly design potent mucosal vaccines against emerging bacterial and viral threats.