key: cord-0927435-5h838aq8
authors: Dugas, Martin; Grote-Westrick, Tanja; Vollenberg, Richard; Lorentzen, Eva; Brix, Tobias; Schmidt, Hartmut; Tepasse, Phil-Robin; Kühn, Joachim
title: Less severe course of COVID-19 is associated with elevated levels of antibodies against seasonal human coronaviruses OC43 and HKU1 (HCoV OC43, HCoV HKU1)
date: 2021-02-23
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.02.085
sha: 8e9ab21ca4ed1c93b28e4c00cbdc7cdd6859bccc
doc_id: 927435
cord_uid: 5h838aq8

The clinical course of COVID-19 is very heterogeneous: Most infected individuals can be managed in an outpatient setting, but a substantial proportion of patients requires intensive care, resulting in a high rate of fatalities. We performed a biomarker study to assess the impact of prior infections with seasonal coronaviruses on COVID-19 severity. 60 patients with confirmed COVID-19 infections were included (age 30 - 82 years; 52 males, 8 females): 19 inpatients with critical disease, 16 inpatients with severe or moderate disease and 25 outpatients. Patients with critical disease had significantly lower levels of anti-HCoV OC43-NP (p = 0.016) and HCoV HKU1-NP (p = 0.023) antibodies at the first encounter compared to other COVID-19 patients. Our results indicate that prior infections with seasonal coronaviruses might protect against a severe course of disease.

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At present, approximately 10 to 20 percent of COVID-19 patients need medical treatment in hospitals and about 5% need long-term treatment on intensive care units (ICU) . In contrast, the majority of COVID-19 patients can be managed in an outpatient setting. Known important risk factors are age, male gender, high body mass index and pre-existing chronic conditions (Jordan et al., 2020) . However, also young and seemingly healthy individuals are at risk to die from COVID-19 infections. At present, this heterogeneity of the disease course is not well understood. Partial immunity against SARS-CoV-2 might contribute to this phenomenon, as recently discussed in reports about cross-reactivity against SARS-CoV-2: T cell responses to SARS-CoV-2 in unexposed human individuals were described (Grifoni et al., 2020; Le Bert et al., 2020; Mateus et al., 2020) . In a recent survey, patients with mild course of COVID-19 reported frequent contact to small children (Dugas et al. 2020) ; therefore, exposure to childhood-related infections might modify the disease severity of COVID-19. This corresponds to the low incidence of severe COVID-19 infections in small children (Ludvigsson 2020) . Seasonal coronaviruses mainly cause mild respiratory tract infections and are frequently found in children. Like SARS-CoV-2, those viruses belong to the subfamily of Orthocoronavirinae. Hence, the objective of this work is to assess if prior infections with a seasonal coronavirusas indicated by antibody levelsmodify the disease course of COVID-19.

Serum samples from 60 Patients with COVID-19 infections confirmed by RT-qPCR were analyzed in the context of the Coronaplasma Project (local ethics committee approval: AZ 2020-220-f-S) and COVID-19 biomarker study (local ethics committee approval: AZ 2020-210-f-S) at the University Hospital of Münster, Germany. Median age of patients was 58 years (range 30 -82 years). 52 males and 8 females were included. Outpatients were manually selected to match age and gender of inpatients. After informed consent, serum was collected at the first patient contact.

Median age was 58 years for outpatients (22 male, 3 female), 58 years for inpatients with critical disease (ICU group: 17 male, 2 female) and 55 years for inpatients with severe or moderate disease (non-ICU group: 13 male, 3 female), respectively. Critical disease was defined by invasive ventilation or ECMO therapy; severe disease by oxygen insufflation; moderate disease by hospitalization for other reasons without oxygen treatment. Median length of stay (LoS) for all inpatients was 10 days (range 2 -55); 3 fatalities occurred.

Antibodies against seasonal coronaviruses and SARS-CoV-2 were measured with the immunostrip assay recomLine SARS-CoV-2 IgG from Mikrogen GmbH, Neuried, Germany.

Regarding seasonal coronaviruses, this assay measures IgG antibodies directed against the nucleocapsid protein (NP) of HCoV 229E, NL63, OC43 and HKU1. With respect to SARS-CoV-2, NP-specific and spike protein (S)-specific antibodies directed against the S1 subunit and the Regarding antibody levels of HCoV OC43 and HKU1 there was no evidence for a change over time (supplemental figure 1), therefore these laboratory parameters are not biased by back boosting (Shrock et al. 2020) . Similar results were obtained by densitometric antibody levels (supplemental figure 2).

To further assess potential clinical implications of antibodies against endemic coronaviruses for COVID-19 patients, correlation of LoS and antibody levels against HCoVs OC43 as well as HKU1, respectively, was analyzed ( Figure 2 ). Long hospitalization periods were predominantly seen in patients with low antibody levels.

Supplemental figure 3 presents results from SARS-CoV-2 IgG antibody measurements at first encounter. In general, patients with critical disease had higher SARS-CoV-2 IgG antibody levels compared to moderate/severe inpatients and outpatients.

CoV-2 in unexposed individuals (Grifoni et al., 2020; Le Bert et al., 2020; Mateus et al., 2020) . This biomarker study assessed a potential relationship between prior infections with seasonal coronavirusesmeasured as antibody levelsand the severity of COVID-19 disease. It was shown that elevated antibody levels for HCoVs OC43 and HKU1 were associated with less need for intensive care therapy. In addition, a trend towards a reduced length of hospital stay was observed. Our findings are concordant with a recent study based on data from electronic medical records (Sagar et al. 2020). One might argue that higher levels of antibodies against seasonal coronaviruses are merely a surrogate marker for a more active immune system. However, HCoVs OC43 and HKU1 are betacoronaviruses and therefore closer related to SARS-CoV-2 than HCoVs 229E or NL63. This is in line with our data that prior exposure to HCoVs OC43 and HKU1 has a stronger association with severity of COVID-19 than HCoV 229E or NL63 infections in the past. A possible explanation might be that prior exposure to seasonal betacoronaviruses facilitates T-cell based immune response to SARS CoV-2. Further research is needed to assess the molecular mechanism behind our findings.

Regarding SARS-CoV-2 antibodies, an inverse pattern was detected: inpatients with critical disease demonstrated higher median antibody levels for NP, RBD and S1 of SARS CoV-2 J o u r n a l P r e -p r o o f compared to other patients. Similar results were reported recently (Kowitdamrong et al. 2020) .

Hence, there is no evidence for a general bias regarding antibody levels and the ability to mount a humoral immune response between the three groups (outpatient, non-ICU, ICU) in our cohort.

This study has limitations: It is a retrospective single-site study with a limited number of cases and association is not causation. However, it is remarkable that the effect of HCoV OC43 and HKU1specific antibody levels reached statistical significance regarding the need for intensive care therapy with only 60 patients. Therefore, these findings should be validated in other sites with larger patient collectives. In a prospective setting (e.g. for risk groups with contacts to many persons like employees of hospitals or supermarkets) it should be tested if the absence of HCoV OC43 and HKU1-specific antibody levels can identify persons at risk for a severe course of COVID-19. Identification of vulnerable individuals is a key priority in the current stage of the pandemic to guide protective measures and to design vaccination strategies.

Elevated levels of pre-existing antibodies against seasonal coronaviruses, specifically HCoV OC43 and HKU1, are associated with less severe course of COVID-19. Further studies should validate this finding and explore the potential to identify persons at risk for severe disease course before a SARS-CoV-2 infection. COVID-19 patients with critical disease present low antibody levels more frequently than patients without critical disease. This difference is significant for OC43 and HKU1. Figure 2 : Correlation of length of stay with OC43 (a) and HKU1 (b) antibody levels. A trend is visible, but not significant p=0.068; p=0.083) . Crosses denote fatal cases. Higher antibody levels are associated with reduced duration of hospitalization.

Association of contact to small children with mild course of COVID-19

Targets of T Cell Responses to SARS-CoV-2

Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals

Covid-19: risk factors for severe disease and death

Antibody responses to SARS-CoV-2 in patients with differing severities of coronavirus disease 2019

SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls

Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults

Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans

Viral epitope profiling of COVID-19 patients reveals cross-reactivity and correlates of severity

Supported by a grant from BMBF (HiGHmed 01ZZ1802V, Use Case Infection Control).J o u r n a l P r e -p r o o f