key: cord-0688032-6hnts5l2
authors: Dugas, M.; Grote-Westrick, T.; Vollenberg, R.; Lorentzen, E.; Brix, T.; Schmidt, H.; Tepasse, P.-R.; Kuehn, J.
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: 2020-10-14
journal: nan
DOI: 10.1101/2020.10.12.20211599
sha: c10d6ae10c66c31547d1bd71f0e3f561a2f67a47
doc_id: 688032
cord_uid: 6hnts5l2

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. Recently, an association between contact to small children and mild course of COVID-19 was reported. We performed an observational study to assess the impact of previous 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 (age and gender matched to inpatients). Patients with critical disease had significantly lower levels of HCoV OC43- (p=0.016) and HCoV HKU1-specific (p=0.023) antibodies at the first encounter compared to other COVID-19 patients. Our results indicate that previous infections with seasonal coronaviruses might protect against a severe course of disease. This finding should be validated in other settings and could contribute to identify persons at risk before an infection.

At present, approximately 10 to 20 percent of COVID-19 patients need medical treatment in hospitals and 23 about 5% need long-term treatment on intensive care units (ICU). In contrast, the majority of COVID-19 24 patients can be managed in an outpatient setting. Known important risk factors are age, male gender, high 25 body mass index and pre-existing chronic conditions [1] . However, also young and seemingly healthy 26 individuals are at risk to die from COVID-19 infections. At present, this heterogeneity of the disease course 27

is not well understood. Partial immunity against SARS-CoV-2 might contribute to this phenomenon, as 28

recently discussed in reports about cross-reactivity against SARS-CoV-2: Grifoni [2] and Le Bert [3] 29 described T cell responses to SARS-CoV-2 in unexposed human individuals. In a recent survey, patients 30 with mild course of COVID-19 reported frequent contact to small children [4] ; therefore, exposure to 31 childhood-related infections might modify the disease severity of COVID-19. This corresponds to the low 32 incidence of severe is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 14, 2020. . disease was defined by invasive ventilation or ECMO therapy; severe disease by oxygen insufflation; 47 moderate disease by hospitalization for other reasons without oxygen treatment. Median length of stay 48 (LoS) for all inpatients was 10 days (range 2 -55); 3 fatalities occurred. 49 Antibody measurement 50

Antibodies against seasonal coronaviruses and SARS-CoV-2 were measured with the immunostrip assay 51 recomLine SARS-CoV-2 IgG from Mikrogen GmbH, Neuried, Germany. Regarding seasonal coronaviruses, 52 this assay measures IgG antibodies directed against the nucleocapsid protein (NP) of HCoV 229E, NL63, 53 OC43 and HKU1. With respect to SARS-CoV-2, NP-specific and spike protein (S)-specific antibodies 54 directed against the S1 subunit and the receptor binding domain (RBD) were determined. Measurements 55

were performed at the Institute of Virology/Department of Clinical Virology of the University Hospital 56

Münster according to the guidelines of the manufacturer. To test precision and reliability, a dilution series 57 and repetitive antibody measurements were performed. Negative and positive controls were analyzed. 58

Data processing and analysis 59

Antibody levels were visually determined according to the guidelines of the manufacturer as ordinal values 60 using the cutoff band of immunstrips as internal reference. Results of individual coronavirus-specific bands 61

were rated on an ordinal scale as non-detectable (-), below cutoff (+/-), with cutoff intensity (+), above cutoff 62 (++), and very strong intensity (+++). In addition, relative antibody levels were quantitatively determined 63

with is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 14, 2020. . https://doi.org/10.1101/2020.10.12.20211599 doi: medRxiv preprint with critical disease (ICU group) present lower values than other groups. This difference is higher for OC43 87 and HKU1 than for 229E and NL63. 88

To further assess potential clinical implications of antibodies against endemic coronaviruses for COVID-19 89 patients, correlation of LoS and antibody levels against HCoVs OC43 as well as HKU1, respectively, was 90 analyzed (Figure 3 ). Long hospitalization periods were predominantly seen in patients with low antibody 91 levels, but this correlation was not significant. 92 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 14, 2020. . https://doi.org/10.1101/2020.10.12.20211599 doi: medRxiv preprint severe course of disease could be identified before a SARS-CoV-2 infection and appropriate protective 13 measures could be taken. Of note, this might also be relevant for vaccination strategies. 14 This observational study assessed a potential relationship between previous infections with seasonal 15 coronaviruses -measured as antibody levels -and the severity of COVID-19 disease. It was shown that 16 elevated antibody levels for HCoVs OC43 and HKU1 were associated with less need for intensive care 17

therapy. In addition, a clear trend towards a reduced length of hospital stay was observed. One might argue 18 that higher levels of antibodies against seasonal coronaviruses are merely a surrogate marker for a more 19

active immune system. However, HCoVs OC43 and HKU1 are betacoronaviruses and therefore closer 20 related to SARS-CoV-2 than HCoVs 229E or NL63. This is in line with our data that previous exposure to 21

HCoVs OC43 and HKU1 has a stronger association with severity of COVID-19 than HCoV 229E or NL63 22

infections in the past. A possible explanation might be that previous exposure to seasonal 23 betacoronaviruses facilitates immune response to SARS CoV-2. Further research is needed to assess the 24 molecular mechanism behind our findings. Of note, cross-reactivity between HCoV OC43 and SARS-CoV 25 was already described in 2006 [7] . Kissler is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted October 14, 2020. . https://doi.org/10.1101/2020.10.12.20211599 doi: medRxiv preprint should be tested if the absence of HCoV OC43 and HKU1-specific antibody levels can identify persons at 40 risk for a severe course of COVID-19. Identification of vulnerable individuals is a key priority in the current 41 stage of the pandemic to guide protective measures and to design vaccination strategies. 42

Elevated levels of pre-existing antibodies against seasonal coronaviruses, specifically HCoV OC43 and 44 HKU1, are associated with less severe course of COVID-19. Further studies should validate this finding 45 and explore the potential to identify persons at risk for severe disease course before a SARS-CoV-2 46

infection.

Supported by a grant from BMBF (HiGHmed 01ZZ1802V, Use Case Infection Control). 49

Due to data protection regulations, personal identifiable data cannot be published. 51

Code availability statement 52 R code is available on request from the authors. 53

Covid-19: risk factors for severe disease and death

Targets of T Cell Responses to SARS-CoV-2 Coronavirus in 57 Humans with COVID-19 Disease and Unexposed Individuals

SARS-CoV-2-specific T cell immunity in cases of COVID-19 60 and SARS, and uninfected controls

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

Systematic review of COVID-19 in children shows milder cases and a better prognosis 65 than adults

Brunham 70 RC. An Outbreak of Human Coronavirus OC43 Infection and Serological

Projecting the transmission dynamics of 73 SARS-CoV-2 through the postpandemic period

Antibody 76 responses to SARS-CoV-2 in patients with differing severities of coronavirus disease 2019