Grant: Operating Grant: Emerging COVID-19 Research Gaps and Priorities - Vaccines

The COVID-19 pandemic, caused by SARS-CoV-2, is being fuelled by emerging variants such as the ones first detected in the United Kingdom (B.1.1.7), South Africa (B.1.351) and Brazil (P.1) and now more recently in California (B.1.427/B.1.429). These variants have mutations in the receptor binding domain (RBD) of the spike protein (S protein) and they are spreading rapidly in many countries, including Canada. A recent human study of the Pfizer mRNA vaccine found that it was significantly less effective (neutralizing antibody titer reduced by two thirds) at neutralizing the B.1.351 variant. This suggests that the currently approved vaccines may not be effective against these variants of concern (VOCs). The goal of our work is to develop multivalent vaccines capable of combating more than one variant simultaneously. Using a helper-dependent adenoviral vector (HD-Ad), we have successfully developed in the past two highly effective COVID-19 vaccines: one expressing the SARS-CoV-2 RBD and the other expressing the full-length S protein. Since HD-Ad vectors are devoid of adenoviral coding sequences, they have a superior safety profile and a large cloning capacity for transgenes. These features make HD-Ad an excellent vaccine platform and one that is ideal for the construction of multivalent vaccines simultaneously targeting multiple VOCs. In this work, we will construct two HD-Ad based multivalent vaccines and examine their immunogenicity and protective efficacy in animal models. These two multivalent vaccines will be representative of the main SARS-CoV-2 variants currently circulating in the human population. We anticipate that intranasal delivery of HD-Ad based multivalent vaccines targeting SARS-CoV-2 and the VOCs will be highly effective in controlling the current and future waves of this pandemic. Significance: The development of multivalent vaccines capable of combating SARS-CoV-2 and the three main VOCs will greatly facilitate efforts to control this pandemic.