Immunogenicity and protective efficacy on non-adjuvanted CD40-targeting SARS-CoV-2 vaccines in non-human primates

BACKGROUND: The emergence of antigenically distinct SARS-CoV-2 variants increases the risk of immune escape and requires continually updated vaccines. In addition, short-lived specific immunity is a limitation faced by current COVID-19 mRNA vaccines against Sarbecoviruses. This underscores the need for new vaccine approaches providing lasting immunity against SARS-CoV-2. METHODS: Here, we demonstrate the capacity of two non-adjuvanted subunit vaccines to induce long-lasting and protective immunity against SARS-CoV-2 variants in macaques. We designed antibody-mediated vaccines (AMV) leveraging an anti-CD40 monoclonal antibody to enhance immune responses by targeting selected antigens to antigen-presenting cells through the CD40 receptor. The CD40.RBDv vaccine targets sequences from the original Wuhan RBD and a mutated RBD, while CD40.Pan.CoV incorporates a conserved nucleocapsid sequence and a mutated RBD region. FINDINGS: We show that both adjuvant-free vaccines induce robust and durable systemic and mucosal anti-RBD antibody responses that neutralise multiple SARS-CoV-2 variants in naive and SARS-CoV-2 convalescent animals, including recent variants such as XFG. In convalescents, mathematical modelling predicted persistence of vaccine-induced antibody for decades. Additionally, the vaccines boost immune responses in mRNA-vaccinated animals, demonstrating the efficiency of CD40-based vaccines as boosters. Both vaccines protect animals against B.1.617.2 Delta and BA.1 Omicron challenges. Viral control correlates with vaccine-induced systemic and mucosal antibody levels and T-cell responses. INTERPRETATION: These findings support the ability of AMV targeting CD40 to induce strong, long-lasting responses against adapted antigens and broad protection against evolving SARS-CoV-2 variants without requiring adjuvant. These two vaccine candidates are currently under clinical testing.