Pre-Existing Human Common Cold Coronavirus Antibodies Actually Negatively Impacts SARS-CoV-2 immunity

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Contrary to what has been assumed and never proven scientifically that pre-existing human common cold coronavirus antibodies can offer a certain degree of protection against the SARS-CoV-2 coronavirus, a new study by researchers from St. Jude Children’s Research Hospital Tennessee-USA and the University of Leeds-UK has found that in fact, such pre-existing human common cold coronavirus antibodies actually negatively impacts SARS-CoV-2 immunity

The SARS-CoV-2 coronavirus infection causes diverse outcomes ranging from asymptomatic infection to respiratory distress and death.
 
A key unresolved question is whether prior immunity to endemic, human common cold coronaviruses (hCCCoV) impacts susceptibility to SARS-CoV-2 infection or immunity following infection and vaccination.
 
The study team analyzed samples from the same individuals before and after SARS-CoV-2 infection or vaccination. The team found hCCCoV antibody levels increase after SARS-CoV-2 exposure, demonstrating cross-reactivity.
 
Shockingly however, a case-control study indicates baseline hCCCoV antibody levels are not associated with protection against SARS-CoV-2 infection. Rather, higher magnitudes of pre-existing betacoronavirus antibodies correlate with more SARS-CoV-2 antibodies following infection, an indicator of greater disease severity.
 
Furthermore, immunization with hCCCoV spike proteins before SARS-CoV-2 immunization impedes generation of SARS-CoV-2 neutralizing antibodies in mice.
 
The study findings hence suggest pre-existing hCCCoV antibodies hinder SARS-CoV-2 antibody-based immunity following infection and provide insight on how pre-existing coronavirus immunity impacts SARS-CoV-2 infection, which is critical considering emerging variants.
 
The study findings were published in the peer reviewed journal: Cell Host And Microbe. https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(21)00570-9

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces highly variable disease ranging from very mild or no symptoms to severe respiratory distress and death. Certain co-morbidities contribute to the diverse outcomes; however, these factors do not account for all the heterogeneity observed between infected individuals.

A major unresolved question is whether susceptibility to SARS-CoV-2 infection and disease severity after infection are impacted by immunity to human common cold coronaviruses (hCCCoV) that were circulating prior to the SARS-CoV-2 pandemic.

Four hCCCoV that are prevalent worldwide have been endemic in humans for decades and typically induce mild upper respiratory disease and account for ~30% of the “common colds” (Forni et al., 2017). HKU1 and OC43 are betacoronaviruses, as is SARS-CoV-2, which are evolutionarily distinct from the alphacoronaviruses, 229E and NL63.

Despite dramatic difference in disease severity induced by the viruses, SARS-CoV-2 and the endemic hCCCoVs share ~30% homology within the spike proteins (Hicks et al., 2021). Studies identified cross-reactive antibodies that bind both SARS-CoV-2 and hCCCoV (Ladner et al., 2020; Ng et al., 2020; Wec et al., 2020).

However, it is unclear how pre- existing hCCCoV antibodies impact the immune response against SARS-CoV-2 infection (Sealy and Hurwitz, 2021). Prior hCCCoV infections could augment SARS- CoV-2 immunity if hCCCoV antibodies are sufficiently cross-reactive with SARS-CoV-2 to be induced through immunological recall or “back-boosting” and support viral clearance (Fonville et al., 2014).

Conversely, pre-existing hCCCoV humoral immunity could hinder the generation of effective SARS-CoV-2-specific antibodies by expanding cross-reactive antibodies that do not neutralize SARS-CoV-2. Further, existing hCCCoV immunity may exacerbate disease by facilitating viral entry into FcR-expressing cells to cause antibody-dependent enhancement of disease (Arvin et al., 2020; Iwasaki and Yang, 2020).

Since hCCCoV immunity could influence the outcome of SARS-CoV-2 infection in several ways, it is critical to ascertain the impact of pre-existing hCCCoV antibodies on immunity to SARS-CoV-2 infection.

Reports investigating whether antibodies specific for hCCCoV are boosted following SARS-CoV-2 infection yielded conflicting results. Some data suggested antibodies specific for hCCCoVs were not boosted following SARS-CoV-2 infection (Dugas et al., 2020, 2021; Loos et al., 2020), while others reported a boost only in OC43-specific antibodies (Anderson et al., 2021; Guo et al., 2021; Nguyen-Contant et al., 2020; Prévost et al., 2020).

Additional studies found a boost in both HKU1 and OC43 antibodies (Aydillo et al., 2021; Cohen et al., 2021; Gouma et al., 2021; Westerhuis et al., 2020), or in antibodies specific for all four hCCCoV following SARS-CoV-2 infection (Ng et al., 2020; Shrock et al., 2020).

Yet, other reports surprisingly found a boost predominantly in antibodies specific for the alphacoronaviruses (Becker et al., 2021; Ortega et al., 2021). A major factor contributing to these inconsistencies is that prior studies did not examine the level of hCCCoV antibodies in the same individual before and after SARS-CoV-2 infection.

Assessing whether prior hCCCoV immunity impacts SARS-CoV-2 disease susceptibility has also yielded inconsistent results (Sealy and Hurwitz, 2021). While some studies reported that the levels of hCCCoV antibodies did not correlate with disease severity or likelihood of becoming infected (Anderson et al., 2021; Gombar et al., 2020; Loos et al., 2020), others concluded that higher levels of hCCCoV antibodies were associated with milder disease (Becker et al., 2021; Dugas et al., 2020, 2021; Henss et al., 2021; Ortega et al., 2021; Sagar et al., 2021; Shrock et al., 2020) or with a shorter duration of symptoms (Gouma et al., 2021).

Conversely, others found higher levels of hCCCoV antibodies correlated with increased SARS-CoV-2 disease severity (Aydillo et al., 2021; Guo et al., 2021; Prévost et al., 2020; Westerhuis et al., 2020). The health status varied greatly in the cohorts tested in the previous studies, and most of these studies did not test samples from the same individual before and after SARS-CoV-2 infection, which likely contributes to the discrepancy in conclusions.

Thus, the impact of pre-existing hCCCoV immunity on susceptibility to SARS-CoV-2 infection remains unresolved.

Here, we measured hCCCoV IgG, IgM, and IgA antibodies in samples obtained from the same individual before and after PCR-confirmed SARS-CoV-2 infection.

We observed significant increases of betacoronaviruses IgG antibodies; however, high levels of hCCCoV antibodies were not associated with protection against SARS-CoV-2 infection.

Conversely, a greater increase in hCCCoV antibodies correlated with higher antibody levels to SARS-CoV-2 following infection, which were associated with increased disease severity. Moreover, mice immunized with hCCCoV spike proteins prior to SARS-CoV-2 spike, exhibited a profound decrease in SARS-CoV-2 neutralizing antibodies relative to mice only immunized with SARS-CoV-2 spike.

Overall, these data suggest that pre-existing hCCCoV IgG antibodies may hinder the immune response to SARS-CoV-2.

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