ABSTRACT
SARS-CoV-2 neutralizing antibodies play a critical role in prevention and treatment of COVID-19 but are challenged by viral evolution and antibody evasion, exemplified by the highly resistant Omicron BA.1 sublineage.1-12 Importantly, the recently identified Omicron sublineages BA.2.12.1 and BA.4/5 with differing spike mutations are rapidly emerging in various countries. By determining polyclonal serum activity of 50 convalescent or vaccinated individuals against BA.1, BA.1.1, BA.2, BA.2.12.1, and BA.4/5, we reveal a further reduction of BA.4/5 susceptibility to vaccinee sera. Most notably, delineation of the sensitivity to an extended panel of 163 antibodies demonstrates pronounced antigenic differences of individual sublineages with distinct escape patterns and increased antibody resistance of BA.4/5 compared to the most prevalent BA.2 sublineage. These results suggest that the antigenic distance from BA.1 and the increased resistance compared to BA.2 may favor immune escape-mediated expansion of BA.4/5 after the first Omicron wave. Finally, while most monoclonal antibodies in clinical stages are inactive against all Omicron sublineages, we identify promising novel antibodies with high pan-Omicron neutralizing potency. Our study provides a detailed understanding of the antibody escape from the most recently emerging Omicron sublineages that can inform on effective strategies to prevent and treat COVID-19.
ABSTRACT
BackgroundCOVID-19 has so far affected more than 250 million individuals worldwide, causing more than 5 million deaths. Several risk factors for severe disease have been identified, most of which coincide with advanced age. In younger individuals, severe COVID-19 often occurs in the absence of obvious comorbidities. Guided by the finding of cytomegalovirus (CMV)-specific T cells with some cross-reactivity to SARS-CoV-2 in a COVID-19 intensive care unit (ICU) patient, we decided to investigate whether CMV seropositivity is associated with severe or critical COVID-19. MethodsNational German COVID-19 bio-sample and data banks were used to retrospectively analyze the CMV serostatus of patients who experienced mild (n=101), moderate (n=130) or severe to critical (n=80) disease by CMV IgG serology. We then investigated the relationship between disease severity and CMV serostatus via statistical models. ResultsNon-geriatric patients (< 70 years) with severe COVID-19 were found to have a very high prevalence of CMV-seropositivity, while CMV status distribution in individuals with mild disease was similar to the prevalence in the German population; interestingly, this was not detectable in older patients. Prediction models support the hypothesis that the CMV serostatus might be a strong biomarker in identifying younger individuals with a higher risk of developing severe COVID-19. ConclusionsWe identified CMV-seropositivity as a potential novel risk factor for severe COVID-19 in non-geriatric individuals in the studied cohorts. More mechanistic analyses as well as confirmation of similar findings in cohorts representing the currently most relevant SARS-CoV-2 variants should be performed shortly.
ABSTRACT
The Omicron variant of SARS-CoV-2 is causing a rapid increase in infections in various countries. This new variant of concern carries an unusually high number of mutations in key epitopes of neutralizing antibodies on the spike glycoprotein, suggesting potential immune evasion. Here we assessed serum neutralizing capacity in longitudinal cohorts of vaccinated and convalescent individuals, as well as monoclonal antibody activity against Omicron using pseudovirus neutralization assays. We report a near-complete lack of neutralizing activity against Omicron in polyclonal sera after two doses of the BNT162b2 vaccine, in convalescent individuals, as well as resistance to different monoclonal antibodies in clinical use. However, mRNA booster immunizations in vaccinated and convalescent individuals resulted in a significant increase of serum neutralizing activity against Omicron. Our study demonstrates that booster immunizations will be critical to substantially improve the humoral immune response against the Omicron variant.
ABSTRACT
Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic [~]0.9-Mb inversion polymorphism and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.
ABSTRACT
BackgroundThe investigation of antibody response to SARS-CoV-2 represents a key aspect in facing the COVID-19 pandemic. In the present study, we compared one new and four widely used commercial serological assays for the detection of antibodies targeting S (spike) and NC (nucleocapsid) protein. MethodsSerum samples from a group of apparently non-responders, from an unbiased group of convalescent patients and from a negative control group were sim-ultaneously analyzed by the LIAISON(R) SARS-CoV-2 S1/S2 IgG test, Euroimmun anti-SARS-CoV-2 S1 IgG ELISA and IDK(R) anti-SARS-CoV-2 S1 IgG assays. IgG binding NC were detected by the Abbott SARS-CoV-2 IgG assay and by the panimmunoglobulin immunoassay Elecsys(R) Anti-SARS-CoV-2. Additionally, samples were also tested by live virus and pseudovirus neutralization tests. ResultsOverall, about 50% of convalescent patients with undetectable IgG antibodies using the commercial kit by Euroimmun were identified as IgG positive by Immundiagnostik and Roche. While both assays achieved similarly high sensitivities, Immundiagnostik correlated better with serum neutralizing activity than Roche. ConclusionsAlthough the proportion of IgG seropositive individuals appears to be higher using more sensitive immunoassays, the protective ability and the potential to serve as indirect markers of other beneficial immune responses warrants for further research.
ABSTRACT
BackgroundWhile the leading symptoms during coronavirus disease 2019 (COVID-19) are acute and the majority of patients fully recover, a significant fraction of patients now increasingly experience long-term health consequences. However, most data available focus on health-related events after severe infection and hospitalization. We present a longitudinal, prospective analysis of health consequences in patients who initially presented with no or minor symptoms of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection. Hence we focus on mild COVID-19 in non-hospitalized patients. MethodsWe included 958 patients with confirmed SARS-CoV-2 infection in this study. Patients were observed for seven months from April 6th to December 2nd 2020 for long-term symptoms and SARS-CoV-2 antibodies. We identified anosmia, ageusia, fatigue or shortness of breath as most common, persisting symptoms at month 4 and 7 and summarized presence of such long-term health consequences as post-COVID syndrome (PCS). Predictors of long-term symptoms were assessed using an uni- and multivariable logistic regression model. FindingsWe observed 442 and 353 patients over four and seven months after symptom onset, respectively. Four months post SARS-CoV-2 infection, 8.6% (38/442) of patients presented with shortness of breath, 12.4% (55/442) with anosmia, 11.1% (49/442) with ageusia and 9.7% (43/442) with fatigue. At least one of these characteristic symptoms was present in 27.8% (123/442) and 34.8% (123/353) at month 4 and 7 post-infection, respectively. This corresponds to 12.8% patients with long-lasting symptoms relative to the initial total cohort (123/958). A lower baseline level of SARS-CoV-2 IgG, anosmia and diarrhea during acute COVID-19 were associated with higher risk to develop long-term symptoms. InterpretationThe on-going presence of either shortness of breath, anosmia, ageusia or fatigue as long-lasting symptoms even in non-hospitalized patients was observed at four and seven months post-infection and summarized as post-COVID syndrome (PCS). The continued assessment of patients with PCS will become a major task to define and mitigate the socioeconomic and medical long-term effects of COVID-19. FundingCOVIM:"NaFoUniMedCovid19"(FKZ: 01KX2021) Research in contextO_ST_ABSEvidence before this studyC_ST_ABSData about long-term health consequences after SARS-CoV-2 infection and COVID-19 is scarce and most available data describe health consequences in hospitalized patients during acute COVID-19. However, these studies do not take into account the vast majority of patients with a milder course of infection (WHO score1-3). Added value of this studyOur cohort consists of mostly mild COVID-19 cases that have been prospectively followed for a median time of 6.8 months. At least one trained physician critically reviewed the patients reported symptoms at each visit. We assessed SARS-CoV-2 IgG at each visit to correlate reported symptoms with serological data. At 4 months after SARS-CoV-2 infection, shortness of breath occurred in 8.6% (38/442), anosmia in 12.4% (55/442), ageusia in 11.1% (49/442), and fatigue in 9.7% (43/442) of patients. At least one characteristic symptom was present in 27.8% (123/442) and 34.8% (123/353) at months 4 and 7 post-infection, respectively. Symptoms were summarized as post-COVID syndrome (PCS). Relative to our initial total cohort (123/958), this corresponds to 12.8% patients with long-lasting symptoms. Lower baseline level of SARS-CoV-2 IgG, anosmia and diarrhea during acute COVID-19 were associated with higher risk of developing long-term symptoms. Implications of all available evidenceWe believe that our findings have important implications for the fields of infectious diseases and public health, because we show long-term health consequences may occur even after very mild COVID-19 in the outpatient setting. As up to 81% of all SARS-CoV-2 infected patients present with mild disease, it can be expected that PCS will affect a larger number of individuals than initially assumed, posing major medical, social and economic challenges.
ABSTRACT
A detailed understanding of antibody-based SARS-CoV-2 immunity has critical implications for overcoming the COVID-19 pandemic and for informing on vaccination strategies. In this study, we evaluated the dynamics of the SARS-CoV-2 antibody response in a cohort of 963 recovered individuals over a period of 10 months. Investigating a total of 2,146 samples, we detected an initial SARS-CoV-2 antibody response in 94.4% of individuals, with 82% and 79% exhibiting serum and IgG neutralization, respectively. Approximately 3% of recovered patients demonstrated exceptional SARS-CoV-2 neutralizing activity, defining them as elite neutralizers. These individuals also possessed effective cross-neutralizing IgG antibodies to SARS-CoV-1 without any known prior exposure to this virus. By applying multivariate statistical modeling, we found that sero-reactivity, age, time since disease onset, and fever are key factors predicting SARS-CoV-2 neutralizing activity in mild courses of COVID-19. Investigating longevity of the antibody response, we detected loss of anti-spike reactivity in 13% of individuals 10 months after infection. Moreover, neutralizing activity had an initial half-life of 6.7 weeks in serum versus 30.8 weeks in purified IgG samples indicating the presence of a more stable and long-term memory IgG B cell repertoire in the majority of individuals recovered from COVID-19. Our results demonstrate a broad spectrum of the initial SARS-CoV-2 neutralizing antibody response depending on clinical characteristics, with antibodies being maintained in the majority of individuals for the first 10 months after mild course of COVID-19.
ABSTRACT
The SARS-CoV-2 pandemic has unprecedented implications for public health, social life, and world economy. Since approved drugs and vaccines are not available, new options for COVID-19 treatment and prevention are highly demanded. To identify SARS-CoV-2 neutralizing antibodies, we analysed the antibody response of 12 COVID-19 patients from 8 to 69 days post diagnosis. By screening 4,313 SARS-CoV-2-reactive B cells, we isolated 255 antibodies from different time points as early as 8 days post diagnosis. Among these, 28 potently neutralized authentic SARS-CoV-2 (IC100 as low as 0.04 g/ml), showing a broad spectrum of V genes and low levels of somatic mutations. Interestingly, potential precursors were identified in naive B cell repertoires from 48 healthy individuals that were sampled before the COVID-19 pandemic. Our results demonstrate that SARS-CoV-2 neutralizing antibodies are readily generated from a diverse pool of precursors, fostering the hope of rapid induction of a protective immune response upon vaccination.
