Original Antigenic Sin: the Downside of Immunological Memory and Implications for COVID-19

The concept of original antigenic sin (OAS) was put forth many years ago to explain how humoral memory responses generated against one set of antigens can affect the nature of antibody responses elicited to challenge infections or vaccinations containing a similar but not identical array of antigens. Here, we highlight the link between OAS and the germinal center reaction (GCR), a process unique to activated B cells undergoing somatic hypermutation and class switch recombination. It is the powerful response of activated memory B cells and the accompanying GCR that establish the foundations of OAS. We apply these concepts to the current COVID-19 pandemic and put forth several possible scenarios whereby OAS may result in either beneficial or harmful outcomes depending, hypothetically, on prior exposure to antigens shared between SARS-CoV-2 and seasonal human coronaviruses (hCoVs) that include betacoronaviruses (e.g., HCoV-OC43 and HCoV-HKU1) and alphacoronaviruses (e.g., HCoV-NL63 and HCoV-HKU1) (E. M. Anderson, E. C. Goodwin, A. Verma, C. P. Arevalo, et al., medRxiv, 2020, https://doi.org/10.1101/2020.11.06.20227215; S. M. Kissler, C. Tedijanto, E. Goldstein, Y. H. Grad, and M. Lipsitch, Science 368:860-868, 2020, https://doi.org/10.1126/science.abb5793).