Design, immunogenicity, and efficacy of a pan-sarbecovirus dendritic-cell targeting vaccine (preprint)

The emergence of SARS-CoV-2 variants of concern (VOCs) that escape pre-existing antibody neutralizing responses increases the need for vaccines that target conserved epitopes and induce cross-reactive B- and T-cell responses. We used a computational approach and sequence alignment analysis to design a new-generation subunit vaccine targeting conserved sarbecovirus B- and T-cell epitopes from Spike (S) and Nucleocapsid (N) to antigen-presenting cells expressing CD40 (CD40.CoV2). We demonstrate the potency of CD40.CoV2 to elicit high levels of cross-neutralizing antibodies against SARS-CoV-2, VOCs, and SARS-CoV-1 in K18-hACE2 transgenic mice, associated with improved viral control and survival after challenge. In addition, we demonstrate the potency of CD40.CoV2 in vitro to recall human multi-epitope, functional, and cytotoxic SARS-CoV-2 S- and N-specific T-cell responses that are unaffected by VOC mutations and cross-reactive with SARS-CoV-1 and, to a lesser extent, MERS epitopes. Overall, these findings provide a framework for a pan-sarbecovirus vaccine. Keywords: COVID-19, SARS-CoV-2, vaccine, pre-clinical model, sarbecoviruses

Targeting SARS-CoV-2 receptor-binding domain to cells expressing CD40 improves protection to infection in convalescent macaques (preprint)

Controlling the circulation of the recently emerged SARS-CoV-2 in the human populations requires massive vaccination campaigns. Achieving sufficient worldwide vaccination coverage will require additional approaches to first generation of approved viral vector and mRNA vaccines. Subunit vaccines have excellent safety and efficacy records and may have distinct advantages, in particular when immunizing individuals with vulnerabilities or when considering the vaccination of children and pregnant women.. We have developed a new generation of subunit vaccines with enhanced immunogenicity by the targeting of viral antigens to CD40-expressing antigen-presenting cells, thus harnessing their intrinsic immune-stimulant properties. Here, we demonstrate that targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to CD40 (αCD40.RBD) induces significant levels of specific T and B cells, with a long-term memory phenotype, in a humanized mouse model. In addition, we demonstrate that a single dose of the αCD40.RBD vaccine, injected without adjuvant, is sufficient to boost a rapid increase in neutralizing antibodies in convalescent non-human primates (NHPs) exposed six months previously to SARS-CoV-2. Such vaccination thus significantly improved protection against a new high-dose virulent challenge versus that in non-vaccinated convalescent animals. Viral dynamics modelling showed the high efficiency of the vaccine at controlling the viral dissemination.