Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection

Abstract

SUMMARYSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread within the human population. Although SARS-CoV-2 is a novel coronavirus, most humans had been previously exposed to other antigenically distinct common seasonal human coronaviruses (hCoVs) before the COVID-19 pandemic. Here, we quantified levels of SARS-CoV-2-reactive antibodies and hCoV-reactive antibodies in serum samples collected from 204 humans before the COVID-19 pandemic. We then quantified pre-pandemic antibody levels in serum from a separate cohort of 252 individuals who became PCR-confirmed infected with SARS-CoV-2. Finally, we longitudinally measured hCoV and SARS-CoV-2 antibodies in the serum of hospitalized COVID-19 patients. Our studies indicate that most individuals possessed hCoV-reactive antibodies before the COVID-19 pandemic. We determined that ∼23% of these individuals possessed non-neutralizing antibodies that cross-reacted with SARS-CoV-2 spike and nucleocapsid proteins. These antibodies were not associated with protection against SARS-CoV-2 infections or hospitalizations, but paradoxically these hCoV cross-reactive antibodies were boosted upon SARS-CoV-2 infection.

Humoral Responses and Serological Assays in SARS-CoV-2 Infections

“…While it is expected that IgM immunoglobulins are the first class detected following infection by SARS-CoV-2, as supported by a number of studies (37,39,40,111), others have paradoxically demonstrated IgG responses that precede the IgM response (38,(112)(113)(114)(115). This surprising discrepancy is likely related to cross-reactivity with pre-existing immunity to sCoVs (40,111,(116)(117)(118). Nevertheless, the largest body of evidence suggests that nearly all SARS-CoV-2 infected individuals begin to produce IgM, IgA, and then IgG by 1 to 2 weeks PSO ( Figure 1) (39,90,114,119,120).…”

“…Several serological studies have demonstrated cross-reactivity of SARS-CoV-2 S protein with SARS-CoV, MERS, and sCoVs (43,53,116,118,165,(173)(174)(175). The spike S2 domain is believed to be primarily responsible for this cross-recognition given its slightly higher level of sequence similarity than the other S domains (118).…”

“…While the high abundance of the N protein otherwise makes it a promising candidate for diagnostic serological assays, the potential for poor specificity due to cross-reactivity with prevalent sCoVs may be a critical limitation to its use. Indeed, in a pre-print manuscript, Anderson et al demonstrated in a cohort of 207 pre-pandemic samples that 5% reacted to the SARS-CoV-2 S proteins, 2% against the RBD, and 19% against N (116). A closer analysis of these samples revealed that most had antibodies against OC43, 229E, and NL63 but these were non-neutralizing.…”

“…This hypothesis, however, remains to be tested in a well-designed randomized clinical trial. However, mounting evidence support that few to no crossneutralizing sCoV antibodies do in fact exist (116,117). Nevertheless, one must be cognizant that most neutralizing assays utilize spike-pseudotyped viruses or surrogate (virusfree) assays with purified antigen.…”

“…Such responses have been shown for influenza and dengue virus and are associated with poor virus neutralization and can have profound consequences on vaccine efficacy (190)(191)(192)(193). For SARS-CoV-2 infections, a number of studies have now reported back-boosting of non-neutralizing sCoV antibody production (116,118,167,194,195). These antibodies appear to be most prominently targeted against conserved epitopes in OC43 and HKU1, both betacoronaviruses (194,195).…”