The capacity of pre-existing immunity to human common coronaviruses (HCoV) to cross-protect against de novo COVID-19is yet unknown. In this work, we studied the sera of 175 COVID-19 patients, 76 healthy donors and 3 intravenous immunoglobulins (IVIG) batches. We found that most COVID-19 patients developed anti-SARS-CoV-2 IgG antibodies before IgM. Moreover, the capacity of their IgGs to react to beta-HCoV, was present in the early sera of most patients before the appearance of anti-SARS-CoV-2 IgG. This implied that a recall-type antibody response was generated. In comparison, the patients that mounted an anti-SARS-COV2 IgM response, prior to IgG responses had lower titres of anti-beta-HCoV IgG antibodies. This indicated that pre-existing immunity to beta-HCoV was conducive to the generation of memory type responses to SARS-COV-2. Finally, we also found that pre-COVID-19-era sera and IVIG cross-reacted with SARS-CoV-2 antigens without neutralising SARS-CoV-2 infectivity in vitro. Put together, these results indicate that whilst pre-existing immunity to HCoV is responsible for recall-type IgG responses to SARS-CoV-2, it does not lead to cross-protection against COVID-19.


The coronavirus disease 2019 (COVID-19) pandemic has heterogeneously impacted the diverse population groups across the world (1). Whilst some patients are at a higher risk of developing severe disease, others such as children and young adults seem to be better protected. It has thus, been hypothesised that any recent past infections due to the common alpha-coronaviruses (alpha-HCoV); HCoV-NL-63 and -229-E, or beta-HCoV-OC-43 and -HK-U1 could cross-protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (25). However, till date such cross-neutralising antibody responses have not been reported.

Following a primary infection with SARS-CoV-2, the presence of virus-specific IgM, prior to the appearance of IgG antibodies is to be expected. However, in most COVID-19 patients humoral responses directed toward SARS-CoV-2 are of the IgG isotype instead (68). We thus, decided to better delineate this link between predominant IgG or IgM antibody responses to SARS-CoV-2 antigens in COVID-19 patients and their pre-existing immunity to common alpha- and beta-HCoV. We also assessed the IgG reactivity of therapeutic intravenous immunoglobulins (IVIG) manufactured from the plasma samples of healthy donors prior to the COVID-19 outbreak. This was due to their potential capacity to demonstrate pre-existing humoral responses against HCoV infections in the general population (9).

In this work, we show that pre-existing immunity to common HCoV, especially beta-HCoV correlated with a memory-type IgG response directed toward SARS-CoV-2 antigens. This immunity however, did not confer cross-protection against subsequent infection with SARS-CoV-2.

Photonic Ring Immunoassay

The presence of serum antibodies specific for the viral antigen was determined using the Maverick SARS-CoV-2 Multi-Antigen Serology Panel (Genalyte Inc. USA). This technology uses an antigen-bound chip to detect the following antibodies for SARS-CoV-2; nucleocapsid, spike S1 RBD, full length spike S1S2, spike S2, and spike S1, as well as the those specific for the common coronavirus HCoV-NL-63; nucleocapsid, HCoV-OC-43, HCoV-229-E and HCoV-HK-U1 spike proteins (2728).. It detects and measures changes in resonance when antibodies bind to their respective antigens. All threshold values for positivity were set by the manufacturer. The raw data are shown in Supplementary Tables 14.

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