SARS-CoV-2 natural infection, but not vaccine-induced immunity, elicits cross-reactive immunity to OC43

Background: The recent SARS-CoV-2 pandemic renewed interest toward other non-severe acute respiratory syndrome human coronaviruses. Among these, OC43 is a seasonal human coronavirus widely diffused in the population (90 % seroprevalence in adults) which is responsible for mild respiratory symptoms. As OC43 protective immunity is short lasting, we investigated whether humoral immunity to SARS-CoV-2, induced by vaccination or spontaneous infection, protects against OC43 re-infection at either systemic or mucosal level. Methods: A neutralization assay was conducted against “wild type" SARS-CoV-2 lineage B.1 (EU) and OC43 in VeroE6 cell lines using plasma and saliva samples from 49 subjects who were never infected and received three BNT162b2 RNA vaccine doses (SARS-CoV-2-vaccinated: SV) and from 25 SARS-CoV-2-infected and vaccinated subjects (SIV). The assays were performed right before (T0), fifteen days (T1) and three months (T2) after the third dose administration (SV) or post- infection (SIV). Results: After the third vaccination dose was administered, SARS-CoV-2-specific neutralizing ac- tivity (NA) significantly augmented in SV saliva (p < 0.05) and plasma (p < 0.0001); yet, this NA was not protective against OC43. Conversely, in SIV, at T1, natural infection significantly increased NA against both SARS-CoV-2 (p < 0.01) and OC43 (p < 0.05) at systemic as well as mucosal level; still, this cross-reactivity vanished at T2. Of note, NA against SARS-CoV-2 and OC43 was shown to be higher in SIV compared to SV in plasma and saliva, as well; though, statistically significant differences were evident only in the oral mucosa at T1 (p < 0.05). Conclusions: Our findings show that SARS-CoV-2 spontaneous infection triggers a more compre- hensive and cross-reactive immunity than vaccine-induced immunity, protecting against OC43 at the systemic and mucosal levels. These results support the development of a pan-coronavirus vaccine able to prompt cross-reactive immunity even against seasonal coronaviruses, which could have enormous economic and health benefits globally.