German Study Shockingly Discovers Pre-Existing Immunity To Seasonal Coronaviruses Increases SARS-CoV-2 Susceptibility And COVID-19 Severity!

Coronavirus Research: 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 contradict all previous rubbish that were fed to us by sub-standard researchers who had claimed earlier that having antibodies or reactive T cells due to previous human coronaviruses associated with common colds conferred a certain degree of protection and prevented disease severity when infected with the SARS-CoV-2 coronavirus.

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


 Graphical Abstract.

Past sub-standard studies postulate that immune responses to previous HCoV infections can either have a slightly protective or no effect on SARS-CoV-2 pathogenesis and, consequently, be neglected for COVID-19 risk stratification. Some of these studies claimed that pre-existing immunity to seasonal coronaviruses prevented COVID-19 disease severity.
https://pubmed.ncbi.nlm.nih.gov/32726801/
 
https://pubmed.ncbi.nlm.nih.gov/32997649/
 
https://pubmed.ncbi.nlm.nih.gov/33296686/
 
https://pubmed.ncbi.nlm.nih.gov/34465633/
 
Another study had actually shown that there were no correlations between previous HCoV infections and COVID-19 disease severity.
https://pubmed.ncbi.nlm.nih.gov/33631096/
 
However, this new Coronavirus Research is the first study to show that previous HCoV infections actually makes things worse when infected with the SARS-CoV-2 coronavirus.
 
The study team prov ide evidence that pre-existing, anti-nucleocapsid antibodies against endemic α-coronaviruses and S2 domain-specific anti-spike antibodies against β-coronavirus HCoV-OC43 are elevated in patients with COVID-19 compared to pre-pandemic donors.
 
Interestingly, this finding is particularly pronounced in males and in critically ill patients. Longitudinal evaluation reveals that antibody cross-reactivity or polyclonal stimulation by SARS-CoV-2 infection are unlikely to be confounders. Hence it was concluded that specific pre-existing immunity to seasonal coronaviruses may increase susceptibility to SARS-CoV-2 and predispose individuals to an adverse COVID-19 outcome, guiding risk management and supporting the development of universal coronavirus vaccines.
 
The mode of action underlying these findings is unclear but the study team hypothesizes 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.
https://pubmed.ncbi.nlm.nih.gov/34290717/
 
It is also conceivable that 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.
 
Interestingly during the validation of the MultiCoV-Ab assay, 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. https://pubmed.ncbi.nlm.nih.gov/33608538/
 
A 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. https://pubmed.ncbi.nlm.nih.gov/34362897/
 
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%; 99.2%), whereas this current study had a substantially lower proportion of mildly affected patients with COVID-19 (26.0%,).
 
The study findings 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.
 
In addition, the study findings indicate that SARS-CoV-2 susceptibility is enhanced by pre-existing antibodies targeting the spike antigen of HCoV-OC43.
 
As for humoral responses to seasonal coronavirus spike protein, several studies observed elevated antibody levels against HCoV-OC43 in patients with COVID-19 and vaccinees compared to uninfected, non-vaccinated individuals, corroborating the study findings.
https://pubmed.ncbi.nlm.nih.gov/33015650/
 
https://pubmed.ncbi.nlm.nih.gov/33631096/
 
https://pubmed.ncbi.nlm.nih.gov/34133950/
 
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 or vaccination, and mainly mediated by antibodies targeting the S2 domain of the viral spike. In line with these findings, the new study findings 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. The 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.
 
Another study 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. https://pubmed.ncbi.nlm.nih.gov/33571429/
 
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 yet another study. https://pubmed.ncbi.nlm.nih.gov/32929268/
 
When comparing antibody responses against seasonal coronavirus in patients with COVID-19 with additional health record data the study team 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, the study team found IL-6 levels, especially those measured at admission, to correlate with disease severity, in line with recent studies. https://www.sciencedirect.com/science/article/pii/S2213260020304045
 
Contradicting all previous notions, the study team provided 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.
 
The study team proposes 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.
 
The study 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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