Cross-reactive serum and memory B cell responses to spike protein in SARS-CoV-2 and endemic coronavirus infection

Abstract

Pre-existing immune responses to seasonal endemic coronaviruses could have profound consequences for antibody responses to SARS-CoV-2, either induced in natural infection or through vaccination. Such consequences are well established in the influenza and flavivirus fields. A first step to establish whether pre-existing responses can impact SARS-CoV-2 infection is to understand the nature and extent of cross-reactivity in humans to coronaviruses. We compared serum antibody and memory B cell responses to coronavirus spike (S) proteins from pre-pandemic and SARS-CoV-2 convalescent donors using a series of binding and functional assays. We found weak evidence of pre-existing SARS-CoV-2 cross-reactive serum antibodies in pre-pandemic donors. However, we found stronger evidence of pre-existing cross-reactive memory B cells that were activated on SARS-CoV-2 infection. Monoclonal antibodies (mAbs) isolated from the donors showed varying degrees of cross-reactivity with betacoronaviruses, including SARS and endemic coronaviruses. None of the cross-reactive mAbs were neutralizing except for one that targeted the S2 subunit of the S protein. The results suggest that pre-existing immunity to endemic coronaviruses should be considered in evaluating antibody responses to SARS-CoV-2.

Absence of Severe Acute Respiratory Syndrome Coronavirus 2 Neutralizing Activity in Prepandemic Sera From Individuals With Recent Seasonal Coronavirus Infection

“…Although other groups have reported the existence of SARS-CoV-2 cross-reactive neutralizing antibodies in sera from individuals who were not infected with SARS-CoV-2, the neutralization activity observed appears low [ 11 , 12 ]. Unlike other reports, the prepandemic sera used in our study that have undetectable neutralization activity against SARS-CoV-2 can neutralize seasonal HCoVs, in some cases quite potently.…”

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

“…Furthermore, non-RBD S1 as well as S2binding neutralizing antibodies have been identified for both SARS-CoV and SARS-CoV-2 (92,165,(180)(181)(182). As of this moment, two studies have shown evidence that the presence of sCoV antibodies is associated with less severe COVID-19 symptoms (183,184), while two more have shown some neutralizing activity in pre-pandemic samples (118,165).…”

“…A significant challenge in developing a specific SARS-CoV-2 serological assay is the potential for cross-reactivity of SARS-CoV-2 capture antigens with antibodies against other human CoVs (163). SARS-CoV-2 shares amino acid sequences and antigenic T and B cell epitopes with the highly prevalent sCoVs that cause the common cold including 229E, OC43, NL63, and HKU1, and also with the now rare MERS and extinct SARS-CoV that both cause severe and fatal respiratory disease ( Figure 2) (62,(164)(165)(166)(167)(168). A recent prevalence survey of the sCoVs using RT-PCR revealed that OC43 is the most prevalent sCoV followed by NL63, HKU1, and finally 229E (169).…”

“…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 most neutralizing antibodies target the RBD to disrupt binding to the host-expressed ACE2 receptor (61,178,179), cross-reactive sCoVs primarily target the S2 domain of the SARS-CoV-2 spike protein (118,167). Furthermore, non-RBD S1 as well as S2binding neutralizing antibodies have been identified for both SARS-CoV and SARS-CoV-2 (92,165,(180)(181)(182). As of this moment, two studies have shown evidence that the presence of sCoV antibodies is associated with less severe COVID-19 symptoms (183,184), while two more have shown some neutralizing activity in pre-pandemic samples (118,165).…”