Christopher Janssen

Introduction: COVID-19, the disease caused by SARS-CoV-2, is a global pandemic that has killed at least 5.7 million people and infected 385 million as of February 2022¹. Despite the successful creation and administration of 11.2 billion vaccines, antibodies generated from these vaccines have demonstrated reduced neutralization of recent variants of concern, highlighting the need for improved vaccines or other therapies². A growing body of evidence suggests that natural resistance to SARS-CoV-2 may occur from cross-reactive antibodies to conserved sequences which were generated by prior seasonal coronaviruses³. Methods: Researchers used a flow cytometry-based cell surface binding assay on COVID-19 convalescent serum with cells expressing spike proteins from several endemic coronaviruses, SARS-CoV-1, and  MERS³.  A second study involved pre-pandemic serum using a surrogate neutralizing ELISA using a lentivirus to measure spike inhibition followed by exploratory data analysis of the results⁴. Next, T-cells subtypes were isolated and their proliferation in response to S proteins from SARS-CoV-2, alpha, and beta coronaviruses measured⁵. A fourth study examined the T-cell response in further detail by culturing them and measuring their responses against truncated sequences ⁶.  Lastly, a fifth study conducted a memory B cell screen from a single patient recovered from SARS-CoV-1 to measure memory antibody binding affinity using cryo-electron microscopy. Results: The studies found evidence of recall of pre-existing cross-reactive memory B cells upon SARS-CoV-2 infection with NL63 and OC43 endemic human coronaviruses associated positively with percent neutralization of the spike protein while 229E and HKU-1 were negatively associated based on cluster analysis^3,4. Analysis of T-cell clonotypes from SARS-CoV-2 recovered individuals demonstrated proliferation in response to SARS-CoV-2 and other alpha and beta coronaviruses S proteins⁵. T-cell clonotypes proliferated in response to a 13-mer peptide S815-827 which was also highly conserved in alpha and beta coronaviruses⁶. The B cell screen from the recovered patient revealed an IgG antibody that recognized a highly conserved proteoglycan epitope on SARS-CoV-2 distinct from the receptor-binding motif which could additionally recognize clade 1,2 and 3 sarbecoronaviruses⁷. Conclusion: Analyzing both B and T cells which made cross-reactive antibodies or proliferated in response to viral proteins, respectively demonstrated the existence of conserved peptides sound across the coronaviridae family. This suggests future vaccines or other therapies based on conserved sequences could represent new treatment and prevention strategies.

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