Comparison of Immune Responses Elicited by SARS-CoV-2 mRNA and Recombinant Protein Vaccine Candidates.

After the outbreak of COVID-19, billions of vaccines with different types have been administrated, including recombinant protein vaccines and mRNA vaccines. Although both types of SARS-CoV-2 vaccine can protect people from viral infection, their differences in humoral and cellular immune responses are still not clearly understood. In this study, we made a head-to-head comparison between an mRNA vaccine candidate and a recombinant protein vaccine we developed previously. Results demonstrated that both vaccine candidates could elicit high specific binding and neutralizing antibody titers in BALB/c mice, but with bias towards different IgG subtypes. Besides, the mRNA vaccine candidate induces higher cellular immune responses than the recombinant protein vaccine. To date, this is the first reported study to directly compare the immune responses of both arms between SARS-CoV-2 mRNA and recombinant vaccines.

A high-throughput single cell-based antibody discovery approach against the full-length SARS-CoV-2 spike protein suggests a lack of neutralizing antibodies targeting the highly conserved S2 domain.

Coronavirus disease 2019 pandemic continues globally with a growing number of infections, but there are currently no effective antibody drugs against the virus. In addition, 90% amino acid sequence identity between the S2 subunit of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV S proteins attracts us to examine S2-targeted cross-neutralizing antibodies that are not yet well defined. We therefore immunized RenMab mice with the full-length S protein and constructed a high-throughput antibody discovery method based on single-cell sequencing technology to isolate SARS-CoV-2 S-targeted neutralizing antibodies and cross-neutralizing antibodies against the S2 region of SARS-CoV-2/SARS-CoV S. Diversity of antibody sequences in RenMab mice and consistency in B-cell immune responses between RenMab mice and humans enabled screening of fully human virus-neutralizing antibodies. From all the frequency >1 paired clonotypes obtained from single-cell V(D)J sequencing, 215 antibodies with binding affinities were identified and primarily bound S2. However, only two receptor-binding domain-targeted clonotypes had neutralizing activity against SARS-CoV-2. Moreover, 5' single-cell RNA sequencing indicated that these sorted splenic B cells are mainly plasmablasts, germinal center (GC)-dependent memory B-cells and GC B-cells. Among them, plasmablasts and GC-dependent memory B-cells were considered the most significant possibility of producing virus-specific antibodies. Altogether, using a high-throughput single cell-based antibody discovery approach, our study highlighted the challenges of developing S2-binding neutralizing antibodies against SARS-CoV-2 and provided a novel direction for the enrichment of antigen-specific B-cells.