Antiviral drugs block replication of highly immune-evasive Omicron subvariants ex vivo, but fail to reduce tissue inflammation.

The identification of the SARS-CoV-2 Omicron variants BA.4/BA.5, BF.7 and BQ.1.1 immediately raised concerns regarding the efficacy of currently used monoclonal antibody therapies. Here we examined the activity of monoclonal antibody therapies and antiviral drugs against clinical specimens for SARS-CoV-2 Omicron BA.4/BA.5, BF.7 and BQ.1.1 employing an immunofluorescence neutralization assay. Further we explored treatment of BA.4/BA.5 infections with efficient antiviral drugs and monoclonal antibodies in a 3D model of primary human bronchial epithelial cells. We found that the antiviral drugs Molnupiravir, Nirmatrelvir and Remdesivir efficiently inhibit BA.4/BA.5, BF.7 and BQ.1.1 replication. In contrast, only the monoclonal antibody Cilgavimab exerted an inhibitory effect, while Tixagevimab, Regdanvimab and Sotrovimab lost their efficacy against BA.4/BA.5. We found that only the prophylactic treatment with Cilgavimab impacted on tissue inflammation by reducing intracellular complement component 3 (C3) activation following BA.4/BA.5 infection in primary human airway epithelial grown in air-liquid-interphase, which was not the case when using antiviral drugs or Cilgavimab after establishment of infection. Of note, all tested monoclonal antibodies had no neutralizing activity during infection by BF.7 and BQ.1.1 variants. Our results suggest that despite a marked reduction of viral replication, potent antiviral drugs fail to reduce tissue levels of inflammatory compounds such as C3, which can still result in tissue destruction.

Vitronectin promotes immunothrombotic dysregulation in the venular microvasculature.

Microvascular immunothrombotic dysregulation is a critical process in the pathogenesis of severe systemic inflammatory diseases. The mechanisms controlling immunothrombosis in inflamed microvessels, however, remain poorly understood. Here, we report that under systemic inflammatory conditions the matricellular glycoproteinvitronectin (VN) establishes an intravascular scaffold, supporting interactions of aggregating platelets with immune cells and the venular endothelium. Blockade of the VN receptor glycoprotein (GP)IIb/IIIa interfered with this multicellular interplay and effectively prevented microvascular clot formation. In line with these experimental data, particularly VN was found to be enriched in the pulmonary microvasculature of patients with non-infectious (pancreatitis-associated) or infectious (coronavirus disease 2019 (COVID-19)-associated) severe systemic inflammatory responses. Targeting the VN-GPIIb/IIIa axis hence appears as a promising, already feasible strategy to counteract microvascular immunothrombotic dysregulation in systemic inflammatory pathologies.

Variable detection of Omicron-BA.1 and -BA.2 by SARS-CoV-2 rapid antigen tests.

During 2022, the COVID-19 pandemic has been dominated by the variant of concern (VoC) Omicron (B.1.1.529) and its rapidly emerging subvariants, including Omicron-BA.1 and -BA.2. Rapid antigen tests (RATs) are part of national testing strategies to identify SARS-CoV-2 infections on site in a community setting or to support layman's diagnostics at home. We and others have recently demonstrated an impaired RAT detection of infections caused by Omicron-BA.1 compared to Delta. Here, we evaluated the performance of five SARS-CoV-2 RATs in a single-centre laboratory study examining a total of 140 SARS-CoV-2 PCR-positive respiratory swab samples, 70 Omicron-BA.1 and 70 Omicron-BA.2, as well as 52 SARS-CoV-2 PCR-negative swabs collected from March 8th until April 10th, 2022. One test did not meet minimal criteria for specificity. In an assessment of the analytical sensitivity in clinical specimen, the 50% limit of detection (LoD50) ranged from 4.2 × 104 to 9.2 × 105 RNA copies subjected to the RAT for Omicron-BA.1 compared to 1.3 × 105 to 1.5 × 106 for Omicron-BA.2. Overall, intra-assay differences for the detection of Omicron-BA.1-containing and Omicron-BA.2-containing samples were non-significant, while a marked overall heterogeneity among the five RATs was observed. To score positive in these point-of-care tests, up to 22-fold (LoD50) or 68-fold (LoD95) higher viral loads were required for the worst performing compared to the best performing RAT. The rates of true-positive test results for these Omicron subvariant-containing samples in the highest viral load category (Ct values < 25) ranged between 44.7 and 91.1%, while they dropped to 8.7 to 22.7% for samples with intermediate Ct values (25-30). In light of recent reports on the emergence of two novel Omicron-BA.2 subvariants, Omicron-BA.2.75 and BJ.1, awareness must be increased for the overall reduced detection rate and marked differences in RAT performance for these Omicron subvariants.

Secondary zoonotic dog-to-human transmission of SARS-CoV-2 suggested by timeline but refuted by viral genome sequencing.

PURPOSE: The risk of secondary zoonotic transmission of SARS-CoV-2 from pet animals remains unclear. Here, we report on a 44 year old Caucasian male presenting to our clinic with COVID-19 pneumonia, who reported that his dog displayed respiratory signs shortly prior to his infection. The dog tested real-time-PCR (RT-PCR) positive for SARS-CoV-2 RNA and the timeline of events suggested a transmission from the dog to the patient. METHODS: RT-PCR and serological assays were used to confirm SARS-CoV-2 infection in the nasopharyngeal tract in the dog and the patient. We performed SARS-CoV-2-targeted amplicon-based next generation sequencing of respiratory samples from the dog and patient for sequence comparisons. RESULTS: SARS-CoV-2 infection of the dog was confirmed by three independent PCR-positive pharyngeal swabs and subsequent seroconversion. Sequence analysis identified two separate SARS-CoV-2 lineages in the canine and the patient's respiratory samples. The timeline strongly suggested dog-to-human transmission, yet due to the genetic distance of the canine and the patient's samples paired-transmission was highly unlikely. CONCLUSION: The results of this case support current knowledge about the low risk of secondary zoonotic dog-to-human transmissions of SARS-CoV-2 and emphasizes the strength of genomic sequencing in deciphering viral transmission chains.

Doxycycline for the prevention of progression of COVID-19 to severe disease requiring intensive care unit (ICU) admission: A randomized, controlled, open-label, parallel group trial (DOXPREVENT.ICU).

BACKGROUND: After admission to hospital, COVID-19 progresses in a substantial proportion of patients to critical disease that requires intensive care unit (ICU) admission. METHODS: In a pragmatic, non-blinded trial, 387 patients aged 40-90 years were randomised to receive treatment with SoC plus doxycycline (n = 192) or SoC only (n = 195). The primary outcome was the need for ICU admission as judged by the attending physicians. Three types of analyses were carried out for the primary outcome: "Intention to treat" (ITT) based on randomisation; "Per protocol" (PP), excluding patients not treated according to randomisation; and "As treated" (AT), based on actual treatment received. The trial was undertaken in six hospitals in India with high-quality ICU facilities. An online application serving as the electronic case report form was developed to enable screening, randomisation and collection of outcomes data. RESULTS: Adherence to treatment per protocol was 95.1%. Among all 387 participants, 77 (19.9%) developed critical disease needing ICU admission. In all three primary outcome analyses, doxycycline was associated with a relative risk reduction (RRR) and absolute risk reduction (ARR): ITT 31.6% RRR, 7.4% ARR (P = 0.063); PP 40.7% RRR, 9.6% ARR (P = 0.017); AT 43.2% RRR, 10.8% ARR (P = 0.007), with numbers needed to treat (NTT) of 13.4 (ITT), 10.4 (PP), and 9.3 (AT), respectively. Doxycycline was well tolerated with not a single patient stopping treatment due to adverse events. CONCLUSIONS: In hospitalized COVID-19 patients, doxycycline, a safe, inexpensive, and widely available antibiotic with anti-inflammatory properties, reduces the need for ICU admission when added to SoC.

Potent high-avidity neutralizing antibodies and T cell responses after COVID-19 vaccination in individuals with B cell lymphoma and multiple myeloma.

Individuals with hematologic malignancies are at increased risk for severe coronavirus disease 2019 (COVID-19), yet profound analyses of COVID-19 vaccine-induced immunity are scarce. Here we present an observational study with expanded methodological analysis of a longitudinal, primarily BNT162b2 mRNA-vaccinated cohort of 60 infection-naive individuals with B cell lymphomas and multiple myeloma. We show that many of these individuals, despite markedly lower anti-spike IgG titers, rapidly develop potent infection neutralization capacities against several severe acute respiratory syndrome coronavirus 2 variants of concern (VoCs). The observed increased neutralization capacity per anti-spike antibody unit was paralleled by an early step increase in antibody avidity between the second and third vaccination. All individuals with hematologic malignancies, including those depleted of B cells and individuals with multiple myeloma, exhibited a robust T cell response to peptides derived from the spike protein of VoCs Delta and Omicron (BA.1). Consistently, breakthrough infections were mainly of mild to moderate severity. We conclude that COVID-19 vaccination can induce broad antiviral immunity including ultrapotent neutralizing antibodies with high avidity in different hematologic malignancies.

Vaccine-hesitant individuals accumulate additional COVID-19 risk due to divergent perception and behaviors related to SARS-CoV-2 testing: a population-based, cross-sectional study.

PURPOSE: To investigate the perception of SARS-CoV-2 detection methods, information sources, and opinions on appropriate behavior after receiving negative or positive test results. METHODS: In a questionnaire-based, cross-sectional study conducted between September 1 and November 17, 2021, epidemiological, behavioral, and COVID-19-related data were acquired from the public in Munich, Germany. RESULTS: Most of the 1388 participants obtained information from online media (82.8%) as well as state and federal authorities (80.3%). 93.4% believed in the accuracy of SARS-CoV-2 PCR testing and 41.2% in the accuracy of rapid antigen tests (RATs). However, RATs were preferred for testing (59.1%) over PCR (51.1%). 24.0% of all individuals were willing to ignore hygiene measures and 76.9% were less afraid of SARS-CoV-2 transmission after receiving a negative PCR test (5.9% and 48.8% in case of a negative RAT). 28.8% reported not to self-isolate after receiving a positive RAT. Multivariate analyses revealed that non-vaccinated individuals relied less on information from governmental authorities (p = 0.0004) and more on social media (p = 0.0216), disbelieved in the accuracy of the PCR test (p ≤ 0.0001) while displaying strong preference towards using RATs (p ≤ 0.0001), were more willing to abandon pandemic-related hygiene measures (p ≤ 0.0001), less afraid of transmitting SARS-CoV-2 after a negative RAT (p ≤ 0.0001), and less likely to isolate after a positive RAT (p ≤ 0.0001). CONCLUSION: Insights into preferred information sources as well as perception, preferences, and behavior related to SARS-CoV-2 testing and hygiene measures are key to refining public health information and surveillance campaigns. Non-vaccinated individuals' divergent believes and behaviors possibly increase their COVID-19 risk.

Quantitation of SARS-CoV-2 neutralizing antibodies with a virus-free, authentic test.

Neutralizing antibodies (NAbs), and their concentration in sera of convalescents and vaccinees are a correlate of protection from COVID-19. The antibody concentrations in clinical samples that neutralize SARS-CoV-2 are difficult and very cumbersome to assess with conventional virus neutralization tests (cVNTs), which require work with the infectious virus and biosafety level 3 containment precautions. Alternative virus neutralization tests currently in use are mostly surrogate tests based on direct or competitive enzyme immunoassays or use viral vectors with the spike protein as the single structural component of SARS-CoV-2. To overcome these obstacles, we developed a virus-free, safe and very fast (4.5 h) in vitro diagnostic test based on engineered yet authentic SARS-CoV-2 virus-like-particles (VLPs). They share all features of the original SARS-CoV-2 but lack the viral RNA genome and thus are non-infectious. NAbs induced by infection or vaccination, but also potentially neutralizing monoclonal antibodies can be reliably quantified and assessed with ease and within hours with our test, because they interfere and block the ACE2-mediated uptake of VLPs by recipient cells. Results from the VLP neutralization test (VLPNT) showed excellent specificity and sensitivity and correlated very well with a cVNT using fully infectious SARS-CoV-2. The results also demonstrated the reduced neutralizing capacity of COVID-19 vaccinee sera against variants of concern of SARS-CoV-2 including omicron B.1.1.529, BA.1.

Accumulation of mutations in antibody and CD8 T cell epitopes in a B cell depleted lymphoma patient with chronic SARS-CoV-2 infection.

Antibodies against the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can drive adaptive evolution in immunocompromised patients with chronic infection. Here we longitudinally analyze SARS-CoV-2 sequences in a B cell-depleted, lymphoma patient with chronic, ultimately fatal infection, and identify three mutations in the spike protein that dampen convalescent plasma-mediated neutralization of SARS-CoV-2. Additionally, four mutations emerge in non-spike regions encoding three CD8 T cell epitopes, including one nucleoprotein epitope affected by two mutations. Recognition of each mutant peptide by CD8 T cells from convalescent donors is reduced compared to its ancestral peptide, with additive effects resulting from double mutations. Querying public SARS-CoV-2 sequences shows that these mutations have independently emerged as homoplasies in circulating lineages. Our data thus suggest that potential impacts of CD8 T cells on SARS-CoV-2 mutations, at least in those with humoral immunodeficiency, warrant further investigation to inform on vaccine design.

Unterdrückung der SARS‐CoV‐2‐Replikation mit stabilisierten und durch Klick‐Chemie modifizierten siRNAs

Die Entstehung von leichter übertragbaren oder aggressiveren Varianten von SARS‐CoV‐2 erfordert die Entwicklung von antiviralen Medikamenten, die schnell an sich entwickelnde virale Escape‐Mutationen anpassbar sind. Hier berichten wir über die Synthese von chemisch stabilisierter small interfering RNA (siRNA) gegen SARS‐CoV‐2. Die siRNA kann mit Hilfe von CuI‐katalysierter Klick‐Chemie mit Rezeptorliganden wie Peptiden zusätzlich modifiziert werden. Wir zeigen, dass optimierte siRNAs die Viruslast und die virus‐induzierte Zytotoxizität in Zelllinien, die mit SARS‐CoV‐2 infiziert sind, um bis zu fünf Größenordnungen reduzieren können. Darüber hinaus zeigen wir, dass eine mit einem ACE2‐bindenden Peptid‐konjugierte siRNA in der Lage ist, die Virusreplikation und die virus‐induzierte Apoptose in mukoziliären 3D‐Lungenmikrogeweben zu reduzieren. Eine Änderung der siRNA‐Sequenz ermöglicht eine schnelle Anpassung ihrer antiviralen Aktivität gegen verschiedene Virusvarianten. Die Möglichkeit, die siRNA mittels Klick‐Chemie an Rezeptorliganden zu konjugieren, erleichtert die Entwicklung zielgerichteter siRNAs für eine flexible antivirale Abwehrstrategie.

Suppression of SARS-CoV-2 Replication with Stabilized and Click-Chemistry Modified siRNAs.

The emergence of more transmissible or aggressive variants of SARS-CoV-2 requires the development of antiviral medication that is quickly adjustable to evolving viral escape mutations. Here we report the synthesis of chemically stabilized small interfering RNA (siRNA) against SARS-CoV-2. The siRNA can be further modified with receptor ligands such as peptides using CuI -catalysed click-chemistry. We demonstrate that optimized siRNAs can reduce viral loads and virus-induced cytotoxicity by up to five orders of magnitude in cell lines challenged with SARS-CoV-2. Furthermore, we show that an ACE2-binding peptide-conjugated siRNA is able to reduce virus replication and virus-induced apoptosis in 3D mucociliary lung microtissues. The adjustment of the siRNA sequence allows a rapid adaptation of their antiviral activity against different variants of concern. The ability to conjugate the siRNA via click-chemistry to receptor ligands facilitates the construction of targeted siRNAs for a flexible antiviral defence strategy.

Detection of SARS-CoV-2-RNA in post-mortem samples of human eyes.

PURPOSE: To detect SARS-CoV-2 RNA in post-mortem human eyes. Ocular symptoms are common in patients with COVID-19. In some cases, they can occur before the onset of respiratory and other symptoms. Accordingly, SARS-CoV-2 RNA has been detected in conjunctival samples and tear film of patients suffering from COVID-19. However, the detection and clinical relevance of intravitreal SARS-CoV-2 RNA still remain unclear due to so far contradictory reports in the literature. METHODS: In our study 20 patients with confirmed diagnosis of COVID-19 were evaluated post-mortem to assess the conjunctival and intraocular presence of SARS-CoV-2 RNA using sterile pulmonary and conjunctival swabs as well as intravitreal biopsies (IVB) via needle puncture. SARS-CoV-2 PCR and whole genome sequencing from the samples of the deceased patients were performed. Medical history and comorbidities of all subjects were recorded and analyzed for correlations with viral data. RESULTS: SARS-CoV-2 RNA was detected in 10 conjunctival (50%) and 6 vitreal (30%) samples. SARS-CoV-2 whole genome sequencing showed the distribution of cases largely reflecting the frequency of circulating lineages in the Munich area at the time of examination with no preponderance of specific variants. Especially there was no association between the presence of SARS-CoV-2 RNA in IVBs and infection with the variant of concern (VOC) alpha. Viral load in bronchial samples correlated positively with load in conjunctiva but not the vitreous. CONCLUSION: SARS-CoV-2 RNA can be detected post mortem in conjunctival tissues and IVBs. This is relevant to the planning of ophthalmologic surgical procedures in COVID-19 patients, such as pars plana vitrectomy or corneal transplantation. Furthermore, not only during surgery but also in an outpatient setting it is important to emphasize the need for personal protection in order to avoid infection and spreading of SARS-CoV-2. Prospective studies are needed, especially to determine the clinical relevance of conjunctival and intravitreal SARS-CoV-2 detection concerning intraocular affection in active COVID-19 state and in post-COVID syndrome.

Should routine risk reduction procedures for the prevention and control of pandemics become a standard in all oncological outpatient clinics? The prospective COVID-19 cohort study: protect-CoV.

Limited knowledge exists on the effectiveness of preventive preparedness plans for the care of outpatient cancer patients during epidemics or pandemics. To ensure adequate, timely and continuous clinical care for this highly vulnerable population, we propose the establishment of preventive standard safety protocols providing effective early phase identification of outbreaks at outpatient cancer facilities and communicating adapted standards of care. The prospective cohort study Protect-CoV conducted at the LMU Klinikum from mid-March to June 2020 investigated the effectiveness of a rapid, proactive and methodical response to protect patients and interrupt SARS-CoV-2 transmission chains during the first pandemic wave. The implemented measures reduced the risk of infection of individual cancer patients and ensured safe adjunctive infusion therapy in an outpatient setting during the early COVID-19 pandemic. In addition to the immediate implementation of standard hygiene procedures, our results underscore the importance of routine PCR testing for the identification of asymptomatic or pre-symptomatic COVID-19 cases and immediate tracing of positive cases and their contacts. While more prospective controlled studies are needed to confirm these results, our study illustrates the importance of including preventative testing and tracing measures in the standard risk reduction procedures at all out patient cancer centers.

Adrenal tropism of SARS-CoV-2 and adrenal findings in a post-mortem case series of patients with severe fatal COVID-19.

Progressive respiratory failure and hyperinflammatory response is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. Despite mounting evidence of disruption of the hypothalamus-pituitary-adrenal axis in COVID-19, relatively little is known about the tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to adrenal glands and associated changes. Here we demonstrate adrenal viral tropism and replication in COVID-19 patients. Adrenal glands showed inflammation accompanied by inflammatory cell death. Histopathologic analysis revealed widespread microthrombosis and severe adrenal injury. In addition, activation of the glycerophospholipid metabolism and reduction of cortisone intensities were characteristic for COVID-19 specimens. In conclusion, our autopsy series suggests that SARS-CoV-2 facilitates the induction of adrenalitis. Given the central role of adrenal glands in immunoregulation and taking into account the significant adrenal injury observed, monitoring of developing adrenal insufficiency might be essential in acute SARS-CoV-2 infection and during recovery.

Protective immune trajectories in early viral containment of non-pneumonic SARS-CoV-2 infection.

The antiviral immune response to SARS-CoV-2 infection can limit viral spread and prevent development of pneumonic COVID-19. However, the protective immunological response associated with successful viral containment in the upper airways remains unclear. Here, we combine a multi-omics approach with longitudinal sampling to reveal temporally resolved protective immune signatures in non-pneumonic and ambulatory SARS-CoV-2 infected patients and associate specific immune trajectories with upper airway viral containment. We see a distinct systemic rather than local immune state associated with viral containment, characterized by interferon stimulated gene (ISG) upregulation across circulating immune cell subsets in non-pneumonic SARS-CoV2 infection. We report reduced cytotoxic potential of Natural Killer (NK) and T cells, and an immune-modulatory monocyte phenotype associated with protective immunity in COVID-19. Together, we show protective immune trajectories in SARS-CoV2 infection, which have important implications for patient prognosis and the development of immunomodulatory therapies.

Three exposures to the spike protein of SARS-CoV-2 by either infection or vaccination elicit superior neutralizing immunity to all variants of concern.

Infection-neutralizing antibody responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease 2019 vaccination are an essential component of antiviral immunity. Antibody-mediated protection is challenged by the emergence of SARS-CoV-2 variants of concern (VoCs) with immune escape properties, such as omicron (B.1.1.529), which is rapidly spreading worldwide. Here we report neutralizing antibody dynamics in a longitudinal cohort of coronavirus disease 2019 convalescent and infection-naive individuals vaccinated with mRNA BNT162b2 by quantifying SARS-CoV-2 spike protein antibodies and determining their avidity and neutralization capacity in serum. Using live-virus neutralization assays, we show that a superior infection-neutralizing capacity against all VoCs, including omicron, developed after either two vaccinations in convalescents or a third vaccination or breakthrough infection of twice-vaccinated, naive individuals. These three consecutive spike antigen exposures resulted in an increasing neutralization capacity per anti-spike antibody unit and were paralleled by stepwise increases in antibody avidity. We conclude that an infection-plus-vaccination-induced hybrid immunity or a triple immunization can induce high-quality antibodies with superior neutralization capacity against VoCs, including omicron.

SARS-CoV-2 variants of concern display enhanced intrinsic pathogenic properties and expanded organ tropism in mouse models.

SARS-CoV-2 variants of concern (VOCs) display enhanced transmissibility and resistance to antibody neutralization. Comparing the early 2020 isolate EU-1 to the VOCs Alpha, Beta, and Gamma in mice transgenic for human ACE2 reveals that VOCs induce a broadened scope of symptoms, expand systemic infection to the gastrointestinal tract, elicit the depletion of natural killer cells, and trigger variant-specific cytokine production patterns. Gamma infections result in accelerated disease progression associated with increased immune activation and inflammation. All four SARS-CoV-2 variants induce pDC depletion in the lungs, paralleled by reduced interferon responses. Remarkably, VOCs also use the murine ACE2 receptor for infection to replicate in the lungs of wild-type animals, which induce cellular and innate immune responses that apparently curtail the spread of overt disease. VOCs thus display distinct intrinsic pathogenic properties with broadened tissue and host range. The enhanced pathogenicity of VOCs and their potential for reverse zoonotic transmission pose challenges to clinical and pandemic management.

Rapid and sensitive identification of omicron by variant-specific PCR and nanopore sequencing: paradigm for diagnostics of emerging SARS-CoV-2 variants.

On November 26, 2021, the World Health Organization classified B.1.1.529 as a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VoC), named omicron. Spike-gene dropouts in conventional SARS-CoV-2 PCR systems have been reported over the last weeks as indirect diagnostic evidence for the identification of omicron. Here, we report the combination of PCRs specific for heavily mutated sites in the spike gene and nanopore-based full-length genome sequencing for the rapid and sensitive identification of the first four COVID-19 patients diagnosed in Germany to be infected with omicron on November 28, 2021. This study will assist the unambiguous laboratory-based diagnosis and global surveillance for this highly contagious VoC with an unprecedented degree of humoral immune escape. Moreover, we propose that specialized diagnostic laboratories should continuously update their assays for variant-specific PCRs in the spike gene of SARS-CoV-2 to readily detect and diagnose emerging variants of interest and VoCs. The combination with established nanopore sequencing procedures allows both the rapid confirmation by whole genome sequencing as well as the sensitive identification of newly emerging variants of this pandemic ß-coronavirus in years to come.

Evidence for increased SARS-CoV-2 susceptibility and COVID-19 severity related to pre-existing immunity to seasonal coronaviruses.

The importance of pre-existing immune responses to seasonal endemic coronaviruses (HCoVs) for the susceptibility to SARS-CoV-2 infection and the course of COVID-19 is the subject of an ongoing scientific debate. Recent 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. Challenging this notion, we provide evidence that pre-existing, anti-nucleocapsid antibodies against endemic α-coronaviruses and S2 domain-specific anti-spike antibodies against ß-coronavirus HCoV-OC43 are elevated in patients with COVID-19 compared to pre-pandemic donors. 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. Thus, 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.