Combinatorial mRNA vaccination enhances protection against SARS-CoV-2 delta variant

Abstract

Emergence of SARS-CoV-2 variants of concern (VOC), including the highly transmissible delta strain, has posed challenges to current COVID-19 vaccines that principally target the viral spike protein (S). Here, we report a nucleoside-modified mRNA vaccine that expresses the more conserved viral nucleoprotein (mRNA-N). We show that mRNA-N alone was able to induce a modest but significant control of SARS-CoV-2 in mice and hamsters. Critically, by combining mRNA-N with the clinically approved S-expressing mRNA vaccine (mRNA-S-2P), we found that combinatorial mRNA vaccination (mRNA-S+N) led to markedly enhanced protection against the SARS-CoV-2 delta variant compared to mRNA-S. In a hamster model, we demonstrated that while mRNA-S alone elicited significant control of the delta strain in the lungs (~45-fold reduction in viral loads compared to un-vaccinated control), its effectiveness in the upper respiratory tract was weak, whereas combinatorial mRNA-S+N vaccination induced markedly more robust control of the delta variant infection in the lungs (~450-fold reduction) as well as in the upper respiratory tract (~20-fold reduction). Immune analyses indicated that induction of N-specific immunity as well as augmented S-specific T-cell response and neutralizing antibody activity were collectively associated the enhanced protection against SARS-CoV-2 delta strain by combinatorial mRNA vaccination. These findings suggest that the combined effects of protection in the lungs and upper respiratory tract could both reduce the risk of severe disease as well as of infection and transmission.

Synergistic Immunity and Protection in Mice by Co-Immunization with DNA Vaccines Encoding the Spike Protein and Other Structural Proteins of SARS-CoV-2

“…The S + N group showed increased S protein-specific cellular immunity levels after three immunizations. One SARS-CoV-2 mRNA vaccine study reported that combinatorial S + N induced an augmented S-specific CD8+ T-cell response compared with S alone, which is consistent with our results [ 24 ]. Another study reported that T-cell responses to S and N antigens after dual-antigen hAd5 S + N prime vaccination alone were equivalent to those from previously SARS-CoV-2-infected patients, and in silico prediction models of T-cell epitope HLA binding suggested that T-cell responses to the hAd5 S + N vaccine will retain their efficacy against the B.1.351 variant.…”

“…Unfortunately, the reduction in virus titers cannot be specifically attributed to the M or N protein, and nAb levels were not evaluated in this study. One SARS-CoV-2 mRNA vaccine study reported that S + N co-immunization induced an augmented S-specific CD8+ T-cell response and neutralizing antibodies activity, providing better protection in the lungs against the Delta variant compared with S alone, which is consistent with the results of this study [ 24 ]. Another study reported that the N protein of transmissible gastroenteritis coronavirus promoted the synthesis of neutralizing antibodies when porcine TGEV-IMMUNE cells were stimulated with a combination of S and N proteins in vitro, and this effect might be explained by the helper T-lymphocyte response to the N protein [ 25 ].…”

De novodesign of anti-variant COVID-19 Vaccine

“…Even COVID-19 infection demonstrated that T cell response is important to generate memory response and lower severity in infected patients (14,15,16,17). Other studies concluded that nucleocapsid protein has to be included in further vaccine strategy (18,19,20,21). This can be a promising strategy to curb circulating Delta (22), Omicron variants (23) and hybrids (24) simultaneously.…”