A modified vaccinia Ankara vaccine expressing spike and nucleocapsid protects rhesus macaques against SARS-CoV-2 Delta infection

Abstract

SARS-CoV-2 vaccines should induce broadly cross-reactive humoral and T cell responses to protect against emerging variants of concern (VOCs). Here, we inactivated the furin-cleavage site (FCS) of spike expressed by a modified vaccinia Ankara (MVA) virus vaccine (MVA/SdFCS) and found that FCS inactivation markedly increased spike binding to human ACE2. Following vaccination of mice, the MVA/SdFCS vaccine induced 8-fold higher neutralizing antibodies compared to MVA/S, which expressed spike without FCS inactivation, and protected against the beta variant. We next added nucleocapsid to the MVA/SdFCS vaccine (MVA/SdFCS-N) and tested its immunogenicity and efficacy via intramuscular (IM), buccal (BU) or sublingual (SL) routes in rhesus macaques. IM vaccination induced spike-specific IgG in serum and mucosae (nose, throat, lung, rectum) which neutralized the homologous (WA-1/2020) and heterologous VOCs, including delta, with minimal loss (<2-fold) of activity. IM vaccination also induced both S and N specific CD4 and CD8 T cell responses in the blood. In contrast, the SL and BU vaccinations induced less spike-specific IgG in secretions and lower levels of polyfunctional IgG in serum compared to IM vaccination. Following challenge with SARS-CoV-2 delta variant, the IM route induced robust protection, BU moderate protection and the SL no protection. Vaccine-induced neutralizing and non-neutralizing antibody effector functions positively correlated with protection, but only the effector functions correlated with early protection. Thus, IM vaccination with MVA/SdFCS-N vaccine elicited cross-reactive antibody and T cell responses, protecting against heterologous SARS-CoV-2 VOC more effectively than other routes of vaccination.

Dual spike and nucleocapsid mRNA vaccination confer protection against SARS-CoV-2 Omicron and Delta variants in preclinical models

“…The emergence of SARS-CoV-2 VOCs has posed challenges to the current S-targeting vaccines ( 4 – 8 ), and next-generation vaccine strategies may benefit from multivalency ( 46 ). Several studies have tested multivalent SARS-CoV-2 candidate vaccines that include the N protein, including adenoviral ( 23 , 47 ) and modified vaccinia Ankara ( 48 , 49 ) vectors. These studies did not compare efficacy with the current, clinically proven S-targeting vaccines.…”

Pre-clinical models to define correlates of protection for SARS-CoV-2

“…A higher magnitude of serum and mucosal IgG, and functional Abdependent cellular activity was observed in the IM-vaccinated RhMs. Nasal anti-RBD IgG and NAbs, as well as serum ADCD, ADCP and ADNKA, were found to inversely correlate with viral load, providing further evidence for the collaborative efforts of neutralising and non-neutralising antibody to protect against SARS-CoV-2 challenge (101). T cell responses were comparable between the IM and buccal administration routes, hence they may contribute to protection also (101).…”

Next-Generation Vaccines against COVID-19 Variants: Beyond the Spike Protein

“…The vaccine has been evaluated in a phase I clinical trial, which has indicated that the vaccine is well tolerated and elicits S-and N-specific immune responses in healthy participants [87]. Similarly, another independent study has investigated the effect of a recombinant MVA vaccine expressing S and N proteins (MVA/SdFCS-N) in NHPs against the SARS-CoV-2 Delta variant [88]. Among the different routes of administration, MVA/ SdFCS-N administration via an intramuscular route has been found to better protection against the Delta variant than other routes [88].…”

“…Similarly, another independent study has investigated the effect of a recombinant MVA vaccine expressing S and N proteins (MVA/SdFCS-N) in NHPs against the SARS-CoV-2 Delta variant [88]. Among the different routes of administration, MVA/ SdFCS-N administration via an intramuscular route has been found to better protection against the Delta variant than other routes [88].…”