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Abstract Monoclonal antibodies (mAbs) directed against the spike of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are effective therapeutic options to combat infections in high-risk patients. Here, we report the adaptation of SARS-CoV-2 to the mAb cocktail REGN-COV in a kidney transplant patient with hypogammaglobulinemia. Following mAb treatment, the patient did not clear the infection. During viral persistence, SARS-CoV-2 acquired three novel spike mutations. Neutralization and mouse protection analyses demonstrate a complete viral escape from REGN-COV at the expense of ACE-2 binding. Final clearance of the virus occurred upon reduction of the immunosuppressive regimen and total IgG substitution. Serology suggests that the development of highly neutralizing IgM rather than IgG substitution aids clearance. Our findings emphasise that selection pressure by mAbs on SARS-CoV-2 can lead to development of escape variants in immunocompromised patients. Thus, modification of immunosuppressive therapy, if possible, might be preferable to control and clearance of the viral infection.

IntroductionDuring the first months of the COVID pandemic it emerged that facilities where people gather or live together in cohorts, such as nursing homes or schools, were particularly at high risk for becoming hotspots of virus transmission. German political and health institutions responded with far-reaching interventions and preventive strategies to protect the population from infection with SARS-CoV-2. In this context, it remains unclear whether boarding schools for sports particularly pose a risk of infection to their residents.MethodsIn a single-center prospective cohort study, numbers of SARS-CoV-2 infections of students in sports boarding schools (n = 11) vs. students attending regular day schools (n = 22) in the region Freiburg/Hochschwarzwald in Germany were investigated over a period from October 2020 to January 2021 via regular virus and antibody screening (German Clinical Trials Register; Study ID: DRKS00021909). In addition, individual and behavioral risk factors for infection were stratified via questionnaire, which provide an indication of cohort specific risk factors for infection and the success of the implementation of hygiene concepts, as well as other infection prevention strategies, within the respective facilities.ResultsRegarding SARS-CoV-2 infection numbers, the screening detected no significant group difference between sports boarding schools vs. day schools.DiscussionThe study results provide indications that sports boarding schools did not pose an increased risk of infection, assuming that the facilities prevent virus transmissions with appropriate preventive strategies and hygiene measures. In future pandemic scenarios larger-scale and multicenter studies are necessary to achieve more comprehensive epidemiological data in this field.

Introduction Shingrix, an effective adjuvanted, recombinant herpes zoster vaccine (RZV), has been available since 2018. Immunocompromised patients are known to be predisposed to vaccine failure. In-vitro testing of immunological surrogates of vaccine protection could be instrumental for monitoring vaccination success. So far, no test procedure is available for vaccine responses to RZV that could be used on a routine basis.Methods and analysis This is a single-centre, three-arm, parallel, longitudinal cohort study aspiring to recruit a total of 308 patients (103 with a liver cirrhosis Child A/B, 103 after liver transplantation (both ≥50 years), 102 immunocompetent patients (60–70 years)). Blood samples will be taken at seven data collection points to determine varicella zoster virus (VZV) and glycoprotein E (gE)-specific IgG and T cell responses. The primary study outcome is to measure and compare responses after vaccination with RZV depending on the type and degree of immunosuppression using gE-specific antibody detection assays. As a secondary outcome, first, the gE-specific CD4+ T cell response of the three cohorts will be compared and, second, the gE-VZV antibody levels will be compared with the severity of possible vaccination reactions. The tertiary outcome is a potential association between VZV immune responses and clinical protection against shingles.Ethics and dissemination Ethical approval was issued on 07/11/2022 by the Ethics Committee Essen, Germany (number 22-10805-BO). Findings will be published in peer-reviewed open-access journals and presented at local, national and international conferences.Trial registration number German Clinical Trials Registry (number DRKS00030683).

Abstract Background and Aims Dual immune checkpoint blockade (ICB) therapy can result in immune-related-adverse events (irAE) such as ICB-hepatitis. An expansion of effector-memory (TEM) CD4 T cells associated with antiviral immunity against herpesviridae was implicated in ICB-hepatitis. Notably, these memory subsets are frequently associated with age. Here, we sought to understand baseline patient, immune and viral biomarkers associated with the development of ICB-hepatitis to identify currently lacking baseline predictors and test if an expansion of TEM or positive serology against herpesviridae can predict ICB-hepatitis. Methods A discovery (n = 39) and validation cohort (n = 67) of patients with advanced melanoma undergoing anti-PD-1&anti-CTLA4 combination therapy (total n = 106) were analyzed for baseline clinical characteristics, occurrence of irAE and oncological outcomes alongside serological status for CMV, EBV and HSV. Immune populations were profiled by high-parametric flow cytometry (n = 29). Results ICB-hepatitis occurred in 59% of patients within 100 days; 35.9% developed severe (CTCAE 3–4) hepatitis. Incidence of ICB-hepatitis was higher in the younger ( = 55y: 27.8%) age group (p = 0.0003), occured earlier in younger patients (p

Abstract Background Effective SARS-CoV-2 vaccination in patients receiving treatment with B-cell depleting agents is challenging. Information on vaccination responses in these patients are a valuable tool to develop efficient vaccination regimens. Methods In this single-center retrospective observational study, we report the humoral and cellular response in 34 patients receiving anti-CD20 antibody treatment for renal immune disease. Results After base immunization with SARS-CoV-2-vaccines, 92.0% developed a cellular, 32.4% a humoral response. Humoral immunity correlated with B-cell counts and the timespan between anti-CD20 antibody treatment and vaccination. All patients with > 21/µl B-cells, or > 197 days after treatment showed humoral response. Conclusions Adequate timing of SARS-CoV-2-vaccinations after anti-CD20 antibody treatment and CD19 measurements are crucial to generate immunity. Awaiting partial B-cell recovery by postponing regularly scheduled anti-CD20 treatment should be considered in patients with stable immune disease. Trial registration: This study has been retrospectively registered in the German Clinical Trials Register (DRKS00027049) on 29/10/2021.

During viral infections high levels of antibodies can form soluble immune complexes (sICs) with antigen and trigger Fcγ receptors (FcγR) leading to increased immunopathology. Here the authors measure FcγRs activation by sICs and consider how these may lead to excessive immunopathology during severe SARS-CoV-2 infection.

In this prospective cohort study, authors follow 328 households in Germany with at least one confirmed SARS-CoV-2 infection and find that children are more likely to seroconvert without symptoms and have higher specific antibody levels that persist longer than in adults.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread globally since its emergence in December 2019. As of March 2021, >120 million infections have been reported, and >2.7 million [...]

Resolving the role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in households with members from different generations is crucial for containing the current pandemic. We conducted a large-scale, multicenter, cross-sectional seroepidemiologic household transmission study in southwest Germany during May 11–August 1, 2020. We included 1,625 study participants from 405 households that each had ≥1 child and 1 reverse transcription PCR–confirmed SARS-CoV-2–infected index case-patient. The overall secondary attack rate was 31.6% and was significantly higher in exposed adults (37.5%) than in children (24.6%–29.2%; p = 60 years of age (72.9%; p = 0.039). Other risk factors for infectiousness of the index case-patient were SARS-CoV-2–seropositivity (odds ratio [OR] 27.8, 95% CI 8.26–93.5), fever (OR 1.93, 95% CI 1.14–3.31), and cough (OR 2.07, 95% CI 1.21–3.53). Secondary infections in household contacts generate a substantial disease burden.

Here, in a longitudinal case study, Weigang et al. demonstrate that evolution of SARS-CoV-2 within a persistently infected immunosuppressed patient can result in the emergence of novel variants with reduced sensitivity to antibody neutralization.

Summary: Background: Long COVID in children and adolescents remains poorly understood due to a lack of well-controlled studies with long-term follow-up. In particular, the impact of the family context on persistent symptoms following SARS-CoV-2 infection remains unknown. We examined long COVID symptoms in a cohort of infected children, adolescents, and adults and their exposed but non-infected household members approximately 1 year after infection and investigated clustering of persistent symptoms within households. Methods: 1267 members of 341 households (404 children aged

Tests for diagnosing infectious diseases (ID-POCT) play a special role among the available point-of-care testing (POCT) methods.

IntroductionThe SARS-CoV-2 pandemic poses extraordinary challenges in all fields of daily life. The WHO recommended social distancing guidelines and person-to-person contact was strongly discouraged to contain transmission. Team-based sports were questioned and widely debated. However, there is a lack of available evidence on the risk of in-game SARS-CoV-2 transmission. We aim to derive new insights regarding the risk of SARS-CoV2 infection during team sports and provide current opinion on how to behave during training and competition.MethodsWe report on six competitive male volleyball players (national level) of the same team who were infected with COVID-19. The mode of transmission and potential virus spreading within the team was investigated. The entire course of infection was documented by detailed medical history of the players and RT-PCR tests confirmed suspected infections. Serological testing was performed to establish the antibody status of the team.ResultsThe investigation did not show strong evidence of viral transmission within the team during sporting activities. Only two players with PCR-proven infection hat detectable antibodies in two antibody assays.ConclusionPrivate and social gatherings can spread infection into team sports. Clearly defined test strategies and strict adherence to standard COVID-19 hygiene guidelines during sports seasons cannot be overemphasized.

Emerging data indicate that SARS-CoV-2-specific CD8.sup.+ T cells targeting different viral proteins are detectable in up to 70% of convalescent individuals.sup.1-5. However, very little information is currently available about the abundance, phenotype, functional capacity and fate of pre-existing and induced SARS-CoV-2-specific CD8.sup.+ T cell responses during the natural course of SARS-CoV-2 infection. Here, we define a set of optimal and dominant SARS-CoV-2-specific CD8.sup.+ T cell epitopes. We also perform a high-resolution ex vivo analysis of pre-existing and induced SARS-CoV-2-specific CD8.sup.+ T cells, applying peptide-loaded major histocompatibility complex class I (pMHCI) tetramer technology. We observe rapid induction, prolonged contraction and emergence of heterogeneous and functionally competent cross-reactive and induced memory CD8.sup.+ T cell responses in cross-sectionally analyzed individuals with mild disease following SARS-CoV-2 infection and three individuals longitudinally assessed for their T cells pre- and post-SARS-CoV-2 infection. SARS-CoV-2-specific memory CD8.sup.+ T cells exhibited functional characteristics comparable to influenza-specific CD8.sup.+ T cells and were detectable in SARS-CoV-2 convalescent individuals who were seronegative for anti-SARS-CoV-2 antibodies targeting spike (S) and nucleoprotein (N). These results define cross-reactive and induced SARS-CoV-2-specific CD8.sup.+ T cell responses as potentially important determinants of immune protection in mild SARS-CoV-2 infection. Functionally competent memory CD8.sup.+ T cells specific for different viral epitopes are induced by SARS-CoV-2 infection and can be detected in the absence of virus-specific antibodies., Author(s): Isabel Schulien [sup.1] , Janine Kemming [sup.1] [sup.2] , Valerie Oberhardt [sup.1] [sup.2] , Katharina Wild [sup.1] [sup.3] , Lea M. Seidel [sup.1] [sup.2] [sup.4] [sup.5] , Saskia Killmer [...]

Acute neurologic complications from Varicella-Zoster-Virus reactivation occur in both immunocompromised and immunocompetent patients. In this report, we describe a case of a previously healthy immunocompetent boy who had received two doses of varicella vaccine at 1 and 4 years. At the age of 12 he developed acute aseptic meningitis caused by vaccine-type varicella-zoster-virus without concomitant skin eruptions. VZV-vaccine strain DNA was detected in the cerebrospinal fluid. The patient made a full recovery after receiving intravenous acyclovir therapy. This disease course documents another case of a VZV vaccine-associated meningitis without development of a rash, i.e., a form of VZV infection manifesting as “zoster sine herpete”.

To determine factors influencing the vaccination response against SARS-CoV-2 is of importance in recipients of allogeneic hematopoietic cell transplantation (allo-HCT) as they display an increased mortality after SARS-CoV-2 infection, an increased risk of extended viral persistence and reduced vaccination response. Real-life data on anti-SARS-CoV-2-S1-IgG titers (n = 192) and IFN-γ release (n = 110) of allo-HCT recipients were obtained using commercially available, validated assays after vaccination with either mRNA (Comirnaty™, Pfizer-BioNTech™, NY, US and Mainz, Germany or Spikevax™, Moderna™, Cambridge, Massachusetts, US) or vector-based vaccines (Vaxzevria™,AstraZeneca™, Cambridge, UK or Janssen COVID-19 vaccine™Johnson/Johnson, New Brunswick, New Jersey, US), or after a heterologous protocol (vector/mRNA). Humoral response (78% response rate) was influenced by age, time after transplantation, the usage of antithymocyte globulin (ATG) and ongoing immunosuppression, specifically corticosteroids. High counts of B cells during the vaccination period correlated with a humoral response. Only half (55%) of participants showed a cellular vaccination response. It depended on age, time after transplantation, ongoing immunosuppression with ciclosporin A, chronic graft-versus-host disease (cGvHD) and vaccination type, with vector-based protocols favoring a response. Cellular response failure correlated with a higher CD8+ count and activated/HLA-DR+ T cells one year after transplantation. Our data provide the basis to assess both humoral and cellular responses after SARS-CoV2 vaccination in daily practice, thereby opening up the possibility to identify patients at risk.

Immunosuppressive therapies increase the susceptibility of patients to infections. The current pandemic with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compels clinicians to develop recommendations for successful clinical management and surveillance of immunocompromised patients at high risk for severe disease progression. With only few case studies published on SARS-CoV-2 infection in patients with rheumatic diseases, we report a 25-year-old male who developed moderate coronavirus disease 2019 (COVID-19) with fever, mild dyspnea, and no major complications despite having received high-dose prednisolone, cyclophosphamide, and rituximab for the treatment of highly active, life-threatening eosinophilic granulomatosis with polyangiitis (EGPA).

Abstract Background Some rheumatologic disorders may initially manifest with central nervous system (CNS) affection, mimicking the clinical, magnetic resonance imaging, and cerebrospinal fluid findings of multiple sclerosis (MS). The MRZ reaction (MRZR), composed of the three respective antibody indices (AIs) against measles, rubella, and varicella zoster virus, has been found positive frequently in MS patients. However, it is unclear whether the MRZR is helpful to distinguish rheumatologic disorders with CNS involvement (RDwCNS) from MS. Methods The MRZR was evaluated in patients with RDwCNS (n = 23), MS (n = 46; age and sex matched to patients with RDwCNS), and other inflammatory autoimmune neurological diseases affecting the CNS (OIND; n = 48). Both the stringency levels that have been used in previous MRZR studies, MRZR-1 (≥ 1 of 3 AIs positive) and MRZR-2 (≥ 2 of 3 AIs positive), were applied. Results There was no statistically significant difference in the prevalence of positive MRZR between patients with RDwCNS (MRZR-1: 13.0% and MRZR-2: 8.7%, respectively) and OIND (MRZR-1: 22.9% and MRZR-2: 8.3%, respectively). Compared to these two study cohorts, the MS group exhibited significantly higher prevalences of positive MRZR (MRZR-1: 82.6%, MRZR-2: 63.0%; p

Abstract Background We previously described inflammatory cerebrospinal fluid (CSF) alterations in a subgroup of patients with schizophreniform disorders and the synthesis of polyspecific intrathecal antibodies against different neurotropic infectious pathogens in some patients with bipolar disorders. Consequently, we have measured the prevalence of a positive MRZ reaction (MRZR)—a marker for a polyspecific, antiviral, intrathecal, humoral immune response composed of three antibody indices for the neurotropic viruses of measles (M), rubella (R), and varicella zoster (Z)—in these patients. Methods We analyzed paired CSF and serum samples of 39 schizophreniform and 39 bipolar patients. For comparison, we used a group of 48 patients with other inflammatory neurological disorders (OIND) and a cohort of 203 multiple sclerosis (MS) patients. Results We found a positive MRZR in two patients with schizophreniform disorders (5.1%); both suffered from schizodepressive disorders without any other signs suggestive of MS. None of the bipolar patients (0%) and four members of the OIND group (8.3%) showed a positive MRZR. In the MS cohort, a positive MRZR was found significantly more frequently [in 99 patients (48.8%)] than in the other patient groups (p > 0.001). In summary, we did not find a positive MRZR in a relevant subgroup of patients with schizophreniform or bipolar disorders. Conclusions Our results indicate that the MRZR is highly specific to MS. Nevertheless, two schizodepressive patients also had a positive MRZR. This finding corresponds to the few MRZR-positive patients with OIND or other autoimmune disorders with central nervous involvement, implicating that the MRZR specificity for MS is high, but not 100%.

Objective: Rheumatic diseases with involvement of the central nervous system (RDwCNS) may mimic multiple sclerosis (MS). Inversely, up to 60% of MS-patients have antinuclear autoantibodies (ANAs) and may be misdiagnosed as RDwCNS. The detection of antibodies against extractable nuclear antigens (ENA) and oligoclonal bands (OCB) are established valuable diagnostic tools in the differential diagnosis of RDwCNS and MS. The MRZ-reaction (MRZR) is defined by three antibody indices (AIs) against neurotropic viruses and is frequently positive in MS. To investigate the added value of MRZR combined with testing for antibodies against ENAs and OCB detection to distinguish RDwCNS from ANA positive MS.Methods: MRZR was evaluated in RDwCNS (n = 40) and 68 ANA positive MS-patients. Two stringency levels, MRZR-1 and MRZR-2 (at least one respectively two of three AIs positive) were applied. Autoantibody testing included ANA plus ENA and anti-dsDNA antibodies, antiphospholipid antibodies, and anti-neutrophil cytoplasmic antibodies.Results: Most of the RDwCNS patients (n = 32; 80%) suffered from systemic lupus erythematosus. Within the RDwCNS group 20% had a positive MRZR-1 and 8.5% a positive MRZR-2 compared to 80.9 and 60%, respectively within the MS-group (p < 0.0001 for both comparisons). Oligoclonal bands were found in 28.6% of the RDwCNS patients and 94.3% of the MS-patients (p < 0.0001). Conversely, autoantibodies to specific nuclear antigens or phospholipids were found more frequently in RDwCNS. A positive MRZR in conjunction with the absence of ENA autoantibodies distinguished MS from RDwCNS with high specificity (97.5%).Conclusions: We suggest combining MRZR, OCBs, and specific autoantibody diagnostics to differentiate RDwCNS from MS.