Pre-Existing Immunity To Seasonal Coronaviruses Increases SARS-CoV-2 Susceptibility And COVID-19 Severity

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Shocking study findings from a new research by scientists from LMU München- Germany and the University of Tübingen-Germany has found that individuals with pre-existing immunity to seasonal coronaviruses have a higher increased risk of SARS-CoV-2 susceptibility and COVID-19 severity.

The study findings were published in the peer reviewed journal: Cell Reports.
https://www.cell.com/cell-reports/fulltext/S2211-1247(21)01669-7

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Coronavirus disease 2019 (COVID-19) caused by the novel human viral pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) developed into a pandemic with more than 242.4 million confirmed cases and 4.93 million deaths thus far (Center for Systems and Science Engineering at John Hopkins University, 2020).

Defining parameters that can influence susceptibility to SARS-CoV-2 or that contribute to the high clinical variability of COVID-19 are critical to aid risk stratification, guided application of preventive measures, and COVID-19 management.

There are four species of endemic, seasonal coronaviruses (HCoVs) that typically cause mildly symptomatic respiratory tract infections in humans but are genetically dissimilar and display varying host cell tropism (Pyrc et al., 2006). Two of them, HCoV-229E and HCoV-NL63, belong to the taxonomic genus of α-coronaviruses, while the other two, HCoV-HKU1 and HCoV-OC43, belong to the genus of β-coronaviruses that includes SARS-CoV-2. HCoV infections are frequent (Killerby et al., 2018; Masse et al., 2020; Severance et al., 2008), and a longitudinal survey indicated that protective HCoV immunity may be short-lived (Edridge et al., 2020).

It has been hypothesized that previous encounters with HCoVs provide cross-protective immunity to SARS-CoV-2 (Braun et al., 2020). Corroborating this hypothesis, Sagar et al., 2021 suggested that recent HCoV infections can be associated with reduced COVID-19 severity. Moreover, a protective role of pre-existing T cells reactive to HCoVs in SARS-CoV-2 infection was suggested (Bacher et al., 2020; Loyal et al., 2021).

Anderson et al., 2021 recently reported on the potential influence of humoral HCoV immunity on the susceptibility to SARS-CoV-2 and the course of COVID-19: in pre-pandemic sera collected from individuals who became subsequently infected by SARS-CoV-2, no differences in IgG-type antibody responses to the spike protein of β-coronavirus HCoV-OC43 were observed compared to sera from individuals not infected by SARS-CoV-2.

Furthermore, there was no relationship between pre-pandemic anti-HCoV-OC43 spike antibody levels and COVID-19 severity. In patients with COVID-19, IgG antibodies reactive to the spike protein of HCoV-OC43, primarily targeting the S2 domain, were boosted in the first 7 days of hospitalization, but the magnitude of this increase was not correlated to disease severity.

The authors concluded that humoral immune responses to HCoVs are not associated with protection against SARS-CoV-2 infection and do not impact the severity of COVID-19. Contradicting this notion, our findings indicate that a genus- and antigen-specific, pre-existing immunity to HCoVs can, in fact, increase SARS-CoV-2 susceptibility and COVID-19 severity.

Discussion

In summary, our study provides evidence that specific pre-existing adaptive immunity to seasonal coronaviruses is associated with increased susceptibility to SARS-CoV-2 infection and adverse disease outcome. The mode of action underlying these findings is unclear.

We hypothesize a direct or indirect enhancement of early stages of SARS-CoV-2 infection on the nasal or oral mucosa or in the respiratory tract, or an antibody-dependent cellular cytotoxicity influencing immunopathology in lung tissue mediated by specific pre-existing antibodies against seasonal coronaviruses.

Regarding anti-nucleocapsid antibody responses, a recent study suggested that lectin pathway recognition molecules of the complement system, including the effector enzyme MASP-2, can directly bind to SARS-CoV-2 nucleocapsid protein, with subsequent activation of lectin pathway-mediated C3b and C4b deposition (Ali et al., 2021).

Conceivably, pre-existing anti-nucleocapsid antibodies against seasonal coronaviruses may cross-react with SARS-CoV-2 nucleocapsid released from infected, dying cells in the respiratory tract negatively modulating the development of thromboembolism and aggravating disease outcome.

During the validation of the MultiCoV-Ab assay (Becker et al., 2021), similar, albeit less pronounced, trends for elevated anti-nucleocapsid IgG titers against HCoV-229E and HCoV-NL63 were observed in relation to individuals’ SARS-CoV-2 serostatus. Another study conducted in healthcare workers found decreased levels of nucleocapsid-specific antibodies against seasonal coronaviruses in symptomatic individuals with COVID-19 compared to those with asymptomatic disease (Ortega et al., 2021).

Of particular note, the COVID-19 cohorts in the former studies consisted mainly of non-hospitalized patients with asymptomatic or mild disease severity (79.1%; Becker et al., 2021) (99.2%; Ortega et al., 2021), whereas our current study had a substantially lower proportion of mildly affected patients with COVID-19 (26.0%, STAR Methods).

Our data support the notion of a SARS-CoV-2 susceptibility- and COVID-19 severity-enhancing effect related to high abundance of nucleocapsid-specific antibodies against α-coronaviruses and possibly β-coronavirus HCoV-HKU1. Two other studies monitored anti-nucleocapsid responses to seasonal coronaviruses in COVID-19 cases via the recomLine assay and observed decreased anti-HCoV-OC43 antibody titers in critically ill patients compared to less severely affected (Dugas et al., 2020, Dugas et al., 2021).

Utilizing the same assay, we observed a similar albeit statistically insignificant trend toward low anti-HCoV-OC43 nucleocapsid antibody levels in critically ill patients. This result, however, could not be confirmed in the MultiCoV-Ab assay.
Furthermore, our findings indicate that SARS-CoV-2 susceptibility is enhanced by pre-existing antibodies targeting the spike antigen of HCoV-OC43.

Regarding humoral responses to seasonal coronavirus spike protein, several studies observed elevated antibody levels against HCoV-OC43 in patients with COVID-19 (Prévost et al., 2020; Anderson et al., 2021) and vaccinees (Tauzin et al., 2021) compared to uninfected, non-vaccinated individuals, corroborating our results.

However, longitudinal and cross-sectional analyses suggested that these increased anti-HCoV-OC43 spike antibody titers were likely not pre-existing, but dependent on either the COVID-19 disease course (Prévost et al., 2020; Anderson et al., 2021) or vaccination (Tauzin et al., 2021), and mainly mediated by antibodies targeting the S2 domain of the viral spike (Anderson et al., 2021).

In line with these findings, our data suggest that high anti-HCoV-OC43 spike antibody levels in COVID-19 are likely due to increased concentrations of antibodies targeting the S2 domain. Furthermore, decreased anti-spike S1 domain responses were observed in critically ill patients compared to pre-pandemic donors.

Our longitudinal assessment, on the other hand, revealed high, yet stable and COVID-19 disease course-independent antibody levels against the full-length spike antigen of HCoV-OC43 and against the nucleocapsid of seasonal α-coronaviruses, indicating that these elevated antibody concentrations were, indeed, pre-existing.

These discrepant results could be due to differences in the COVID-19 patient cohorts: the former studies included lower rates of severely and critically ill patients with COVID-19 (8.9%; Prévost et al., 2020) (14.0%; Anderson et al., 2021), whereas the percentage of such cases was more than 3-fold higher in our patient cohort (44.8%).

Thus, our findings could potentially be more applicable to severe COVID-19. Of note, Prévost et al., 2020 did not perform longitudinal antibody analyses in the same patients, but cross-sectional analyses in dissimilar patient groups. The alterations in anti-spike antibodies against HCoV-OC43 in individuals with COVID-19 observed by Prévost et al., 2020, therefore, could underlie inter-individual rather than longitudinal changes in serological responses.

Moreover, differences in the type and specificities of the assays utilized to detect anti-full-length spike antibodies against HCoV-OC43 and their cross-reactivity to anti-SARS-CoV-2 antibodies could contribute to the different results obtained by Prévost et al., 2020 and Anderson et al., 2021 compared to ours.

Unfortunately, a well-validated, broadly available anti-HCoV spike antibody assay is lacking. All studies on serological responses against these antigens currently relied on self-developed methods and the analytical performances of these are difficult to compare.

Adding to the discussion, Sokal et al., 2021 found fractions of SARS-CoV-2 spike protein-specific memory B cells that were cross-reactive for HCoV-HKU1 and HCoV-OC43 as well as B cells specific for HCoV-HKU1 or HCoV-OC3 spike protein among PBMCs from four patients with COVID-19 3 months after infection with SARS-CoV-2.

The abundance of these HCoV antigen-specific cells declined over time. However, the authors were unable to investigate the influence of SARS-CoV-2-specific, cross-reactive memory B cells on the overall serological responses against the novel coronavirus, in particular at earlier time points after infection.

Furthermore, it was not addressed in this study whether the declining numbers of HCoV-specific memory B cells were associated with SARS-CoV-2 infection itself or due to COVID-19-independent, rapid fluctuations of HCoV antibody responses as observed by Edridge et al., 2020.

Comparing antibody responses against seasonal coronavirus in patients with COVID-19 with additional health record data we found that these responses are largely independent from age, having comorbidities, the time patients spent hospitalized or on ICU, and IL-6 levels.

Interestingly, the group of male patients showed, in most instances, significantly increased anti-nucleocapsid antibody titers against seasonal coronaviruses. In multivariate analyses, we found IL-6 levels, especially those measured at admission, to correlate with disease severity, in line with recent studies (Leisman et al., 2020).

A study conducted by Sagar et al., 2021 proposed that acute HCoV infections can be associated with reduced COVID-19 severity. Data from medical records on PCR testing for acute HCoV infections were analyzed retrospectively in this investigation and not adaptive immune responses to individual HCoVs that we unveil as relevant in our study.

Anderson et al., 2021 suggested that pre-existing IgG-type antibody responses to the spike antigen of β-coronaviruses HCoV-OC43 in patient sera collected up to 7 years before SARS-CoV-2 infection do not influence susceptibility to the novel coronavirus and COVID-19 severity. However, Anderson et al., 2021 did not investigate the role of nucleocapsid-specific antibody responses to α-coronaviruses as a critical and predisposing factor for COVID-19.

Moreover, HCoV antibody titers have been reported to decay or fluctuate considerably within months after infection or re-infection (Edridge et al., 2020), questioning the validity of the interpretation of pre-existing HCoV immunity at the time of SARS-CoV-2 exposure in patient-matched reference sera, which sometimes date back many years (Anderson et al., 2021).

Based on the limited dataset that only assessed anti-HCoV-antibodies targeting the spike protein, Anderson et al., 2021 concluded that humoral adaptive immunity to seasonal coronaviruses is not associated with protection from infection or an altered disease course.

Contradicting this notion, we provide evidence that pre-existing, humoral immunity reflected by specific antibodies recognizing either the nucleocapsid of seasonal α-coronaviruses or the spike antigen of HCoV-OC43 increases SARS-CoV-2 susceptibility. We propose that seasonal coronavirus serology can serve as a marker to guide clinical risk stratification and that individuals with recently resolved seasonal coronavirus infections may benefit from advanced preventive measures against COVID-19. Our findings fuel efforts to develop a universal vaccine that mitigates the immunological crosstalk between coronaviruses of different species and its potentially negative effects on the outcome of subsequent, possibly lethal coronavirus infections.

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