Role of the complement system in Long COVID (preprint)

Long COVID, or Post-Acute COVID Syndrome (PACS), may develop following SARS-CoV-2 infection, posing a substantial burden to society. Recently, PACS has been linked to a persistent activation of the complement system (CS), offering hope for both a diagnostic tool and targeted therapy. However, our findings indicate that, after adjusting proteomics data for age, body mass index and sex imbalances, the evidence of complement system activation disappears. Furthermore, proteomic analysis of two orthogonal cohorts-one addressing PACS following severe acute phase and another after a mild acute phase-fails to support the notion of persistent CS activation. Instead, we identify a proteomic signature indicative of either ongoing infections or sustained immune activation similar to that observed in acute COVID-19, particularly within the mild-PACS cohort.

The central nervous systems proteogenomic and spatial imprint upon systemic viral infections with SARS-CoV-2 (preprint)

In COVID-19 neurological alterations are noticed during the systemic viral infection. Various pathophysiological mechanisms on the central nervous system (CNS) have been suggested in the past two years, including the viral neurotropism hypothesis. Nevertheless, neurological complications can also occur independent of neurotropism and at different stages of the disease and may be persistent. Previous autopsy studies of the CNS from patients with severe COVID-19 show infiltration of macrophages and T lymphocytes, especially in the perivascular regions as well as pronounced microglial activation, but without signs of viral encephalitis. However, there is an ongoing debate about long-term changes and cytotoxic effects in the CNS due to the systemic inflammation. Here, we show the brain-specific host response during and after COVID-19. We profile single-nucleus transcriptomes and proteomes of brainstem tissue from deceased COVID-19 patients who underwent rapid autopsy. We detect a disease phase-dependent inflammatory type-I interferon response in acute COVID-19 cases. Integrating single-nucleus RNA sequencing and spatial transcriptomics, we could localize two patterns of reaction to severe systemic inflammation. One neuronal with direct focus on cranial nerve nuclei and one diffusely affecting the whole brainstem, the latter reflecting a bystander effect that spreads throughout the vascular unit and alters the transcriptional state of oligodendrocytes, microglia and astrocytes. Our results indicate that even without persistence of SARS-CoV-2 in the CNS, the tissue activates highly protective mechanisms, which also cause functional disturbances that may explain the neurological symptoms of COVID-19, triggered by strong systemic type-I IFN signatures in the periphery.

Consistency as a Data Quality Measure for German Corona Consensus items mapped from National Pandemic Cohort Network data collections (preprint)

Background As a national effort to better understand the current pandemic, three cohorts collect sociodemographic and clinical data from COVID-19 patients from different target populations within the German National Pandemic Cohort Network (NAPKON). Furthermore, the German Corona Consensus Dataset (GECCO) was introduced as a harmonized basic information model for COVID-19 patients in clinical routine. To compare the cohort data with other GECCO-based studies, data items are mapped to GECCO. As mapping from one information model to another is complex, an additional consistency evaluation of the mapped items is recommended to detect possible mapping issues or source data inconsistencies.Objectives The goal of this work is to assure high consistency of research data mapped to the GECCO data model. In particular, it aims at identifying contradictions within interdependent GECCO data items of the German national COVID-19 cohorts to allow investigation of possible reasons for identified contradictions. We furthermore aim at enabling other researchers to easily perform data quality evaluation on GECCO-based datasets and adapt to similar data models.Methods All suitable data items from each of the three NAPKON cohorts are mapped to the GECCO items. A consistency assessment tool (dqGecco) is implemented, following the design of an existing quality assessment framework, retaining their-defined consistency taxonomies, including logical and empirical contradictions. Results of the assessment are verified independently on the primary data source.Results Our consistency assessment tool helped in correcting the mapping procedure and reveals remaining contradictory value combinations within COVID-19 symptoms, vital-signs, and COVID-19 severity. Consistency rates differ between the different indicators and cohorts ranging from 95.84% up to 100%.Conclusion An efficient and portable tool capable to discover inconsistencies in the COVID-19 domain has been developed and applied to three different cohorts. As the GECCO dataset is employed in different platforms and studies, the tool can be directly applied there or adapted to similar information models.

Gut microbiota dysbiosis is associated with altered tryptophan metabolism and dysregulated inflammatory response in severe COVID-19 (preprint)

The clinical course of the 2019 coronavirus disease (COVID-19) is variable and to a substantial degree still unpredictable, especially in persons who have neither been vaccinated nor recovered from previous infection. We hypothesized that disease progression and inflammatory responses were associated with alterations in the microbiome and metabolome. To test this, we integrated metagenome, metabolome, cytokine, and transcriptome profiles of longitudinally collected samples from hospitalized COVID-19 patients at the beginning of the pandemic (before vaccines or variants of concern) and non-infected controls, and leveraged detailed clinical information and post-hoc confounder analysis to identify robust within- and cross-omics associations. Severe COVID-19 was directly associated with a depletion of potentially beneficial intestinal microbes mainly belonging to Clostridiales, whereas oropharyngeal microbiota disturbance appeared to be mainly driven by antibiotic use. COVID-19 severity was also associated with enhanced plasma concentrations of kynurenine, and reduced levels of various other tryptophan metabolites, lysophosphatidylcholines, and secondary bile acids. Decreased abundance of Clostridiales potentially mediated the observed reduction in 5-hydroxytryptophan levels. Moreover, altered plasma levels of various tryptophan metabolites and lower abundances of Clostridiales explained significant increases in the production of IL-6, IFN{gamma} and/or TNF. Collectively, our study identifies correlated microbiome and metabolome alterations as a potential contributor to inflammatory dysregulation in severe COVID-19.

Pharmacokinetics of nirmatrelvir and ritonavir in COVID-19 patients with end stage renal disease on intermittent haemodialysis (preprint)

Background: Nirmatrelvir/ritonavir is an effective therapy against SARS-CoV-2. Patients with end-stage renal disease (ESRD) are at high risk for severe COVID-19 and show impaired vaccine responses underlining the importance of antiviral therapy. However, use of nirmatrelvir/ritonavir is not recommended in these patients due to lack of clinical and pharmacokinetic data. Objective: To investigate pharmacokinetics and hepatic tolerance of nirmatrelvir/ritonavir in patients with ESRD and haemodialysis (HD). Patients and methods: Four patients diagnosed with SARS-CoV-2 infection received nirmatrelvir/ritonavir 150/100mg twice daily as recommended for renal impairment; HD ran in two- to three-day intervals. Plasma and serum samples were drawn before and after each HD during the 5-day treatment and for ensuing 3-5 days. Results: Median peak levels of nirmatrelvir obtained two hours after medication pre-HD in three patients were 7745ng/mL on day 3 and 6653ng/mL on day 5; median post-HD levels (C6h) declined to 5765ng/mL (74%) and 5521ng/mL (83%), on days 3 and 5 of treatment, respectively. Three days after end of treatment, median levels were 365ng/mL pre-HD and 30ng/mL post-HD. Measurements of the fourth patient, six hours after drug intake pre-HD showed nirmatrelvir-levels of 3704ng/mL on treatment day 3 which fell to 2308ng/mL post-HD, at one hour before intake of the next dose (Cmin). Conclusion: Use of nirmatrelvir/ritonavir in patients with ESRD results in high nirmatrelvir blood concentrations, which are still within the range known from patients without renal failure. No accumulation of nirmatrelvir took place and levels declined to zero within few days after end of treatment.

Neutralization sensitivity of the SARS-CoV-2 Omicron BA.2.75 sublineage (preprint)

The recently emerged BA.2.75 Omicron sublineage of SARS-CoV-2 identified in numerous countries is rapidly increasing in prevalence in regions of India. Compared with BA.2, the spike protein of BA.2.75 differs in nine amino acid residues. To determine the impact of the spike mutations on polyclonal and monoclonal antibody activity, we investigated the neutralization sensitivity of BA.2.75 in comparison with B.1, BA.2, BA.2.12.1, and BA.4/5. Analysis of post-boost samples from 30 vaccinated individuals revealed significantly lower serum neutralizing activity against BA.2.75 than against BA.2. However, BA.2.75 was more sensitive to serum neutralization than the widely circulating BA.4/5 sublineages. Moreover, evaluation of 17 clinical-stage monoclonal antibodies demonstrated individual differences in Omicron sublineage activity. Notably, some authorized antibodies with low activity against other Omicron sublineages demonstrated high BA.2.75 neutralizing potency. Our results indicate a less pronounced degree of antibody evasion of BA.2.75 compared with BA.4/5 and suggest that factors beyond immune evasion may be required for an expansion of BA.2.75 over BA.4/5.

The human host response to monkeypox infection: a proteomic case series study (preprint)

Monkeypox (MPX) is caused by the homonymous orthopoxvirus (MPXV) known since the 1970s to occur at low frequency in West and Central Africa. Recently, the disease has been spreading quickly in Europe and the US. The rapid rise of MPX cases outside previously endemic areas and the different clinical presentation prompt for a better understanding of the disease, including the development of clinical tests for rapid diagnosis and monitoring. Here, using Zeno SWATH MS - a latest-generation proteomic technology - we studied the plasma proteome of a group of MPX patients with a similar infection history and clinical severity typical for the current outbreak. Moreover, we compared their proteomes to those of healthy volunteers and COVID-19 patients. We report that MPX is associated with a strong and characteristic plasma proteomic response and describe MPXV infection biomarkers among nutritional and acute phase response proteins. Moreover, we report a correlation between plasma protein markers and disease severity, approximated by the degree of skin manifestation. Contrasting the MPX host response with that of COVID-19, we find a range of similarities, but also important differences. For instance, Complement factor H-related protein 1 (CFHR1) is induced in COVID-19, but suppressed in MPX, reflecting the different role of the complement system in the two infectious diseases. However, the partial overlap between MPX and COVID-19 host response proteins allowed us to explore the repurposing of a clinically applicable COVID-19 biomarker panel assay, resulting in the successful classification of MPX patients. Hence, our results provide a first proteomic characterization of the MPX human host response based on a case series. The results obtained highlight that proteomics is a promising technology for the timely identification of disease biomarkers in studies with moderate cohorts, and we reveal a thus far untapped potential for accelerating the response to disease outbreaks through the repurposing of multiplex biomarker assays.

90K/LGALS3BP Expression is Upregulated in COVID-19 but Does Not Restrict SARS-CoV-2 Infection (preprint)

Glycoprotein 90K, encoded by the interferon-stimulated gene LGALS3BP, displays broad antiviral activity. It reduces HIV-1 infectivity by interfering with Env maturation and virion incorporation, and increases survival of Influenza A virus-infected mice via antiviral innate immune signaling. Here, we analyzed the expression of 90K/LGALS3BP in 44 hospitalized COVID-19 patients. 90K protein serum levels were significantly elevated in COVID-19 patients compared to uninfected sex- and age-matched controls. Furthermore, PBMC-associated concentrations of 90K protein were overall reduced by SARS-CoV-2 infection in vivo, suggesting enhanced secretion into the extracellular space. Mining of published PBMC scRNA-seq datasets uncovered monocyte-specific induction of LGALS3BP mRNA expression in COVID-19 patients. In functional assays, neither 90K overexpression in susceptible cell lines nor exogenous addition of purified 90K consistently inhibited SARS-CoV-2 infection. Our data suggests that 90K/LGALS3BP contributes to the global type I IFN response during SARS-CoV-2 infection in vivo without displaying detectable antiviral properties.

Impaired Neutralization of SARS-CoV-2 Including Omicron Variants after COVID-19 mRNA Booster Immunization under Methotrexate Therapy (preprint)

ABSTRACT Objective To determine the immediate need for a fourth COVID-19 vaccination based on the neutralizing capacity in patients on methotrexate (MTX) therapy after mRNA booster immunization. Methods In this observational cohort study, neutralizing serum activity against SARS-CoV-2 wildtype (Wu01) and variant of concern (VOC) Omicron BA.1 and BA.2 were assessed by pseudovirus neutralization assay before, 4 and 12 weeks after mRNA booster immunization in 50 rheumatic patients on MTX, 26 of whom paused the medication. 44 non-immunosuppressed persons (NIP) served as control group. Results While the neutralizing serum activity against SARS-CoV-2 Wu01 and Omicron variants increased 67-to 73-fold in the NIP after booster vaccination, the serum activity in patients receiving MTX increased only 20-to 23-fold. As a result, significantly lower neutralizing capacities were measured in patients on MTX compared to the NIP at week 4. Patients who continued MTX treatment during vaccination had significantly lower neutralizing serum titres against all three virus strains at week 4 and 12 compared to patients who paused MTX and the control group, except for BA.2 at week 12. Patients who paused MTX reached comparably high neutralization titres as the NIP, except for Wu01 at week 12. Neutralization of omicron variants was significantly lower in comparison to wildtype in both groups. Conclusion Patients pausing MTX showed a similar vaccine response to NIP. Patients who continued MTX demonstrated an impaired booster response indicating a potential benefit of a second booster vaccination.

OxoScan-MS: Oxonium ion scanning mass spectrometry facilitates plasma glycoproteomics in large scale (preprint)

Protein glycosylation is a complex and heterogeneous post-translational modification. Specifically, the human plasma proteome is rich in glycoproteins, and as protein glycosylation is frequently dysregulated in disease, glycoproteomics is considered an underexplored resource for biomarker discovery. Here, we present OxoScan-MS, a data-independent mass spectrometric acquisition technology and data analysis software that facilitates sensitive, fast, and cost-effective glycoproteome profiling of plasma and serum samples in large cohort studies. OxoScan-MS quantifies glycosylated peptide features by exploiting a scanning quadrupole to assign precursors to oxonium ions, glycopeptide-specific fragments. OxoScan-MS reaches a high level of sensitivity and selectivity in untargeted glycopeptide profiling, such that it can be efficiently used with fast microflow chromatography without a need for experimental enrichment of glycopeptides from neat plasma. We apply OxoScan-MS to profile the plasma glycoproteomic in an inpatient cohort hospitalised due to severe COVID-19, and obtain precise quantities for 1,002 glycopeptide features. We reveal that severe COVID-19 induces differential glycosylation in disease-relevant plasma glycoproteins, including IgA, fibrinogen and alpha-1-antitrypsin. Thus, with OxoScan-MS we present a strategy for quantitatively mapping glycoproteomes that scales to hundreds and thousands of samples, and report glycoproteomic changes in severe COVID-19.

A global systematic analysis of the occurrence, severity, and recovery pattern of long COVID in 2020 and 2021 (preprint)

ImportanceWhile much of the attention on the COVID-19 pandemic was directed at the daily counts of cases and those with serious disease overwhelming health services, increasingly, reports have appeared of people who experience debilitating symptoms after the initial infection. This is popularly known as long COVID. ObjectiveTo estimate by country and territory of the number of patients affected by long COVID in 2020 and 2021, the severity of their symptoms and expected pattern of recovery DesignWe jointly analyzed ten ongoing cohort studies in ten countries for the occurrence of three major symptom clusters of long COVID among representative COVID cases. The defining symptoms of the three clusters (fatigue, cognitive problems, and shortness of breath) are explicitly mentioned in the WHO clinical case definition. For incidence of long COVID, we adopted the minimum duration after infection of three months from the WHO case definition. We pooled data from the contributing studies, two large medical record databases in the United States, and findings from 44 published studies using a Bayesian meta-regression tool. We separately estimated occurrence and pattern of recovery in patients with milder acute infections and those hospitalized. We estimated the incidence and prevalence of long COVID globally and by country in 2020 and 2021 as well as the severity-weighted prevalence using disability weights from the Global Burden of Disease study. ResultsAnalyses are based on detailed information for 1906 community infections and 10526 hospitalized patients from the ten collaborating cohorts, three of which included children. We added published data on 37262 community infections and 9540 hospitalized patients as well as ICD-coded medical record data concerning 1.3 million infections. Globally, in 2020 and 2021, 144.7 million (95% uncertainty interval [UI] 54.8-312.9) people suffered from any of the three symptom clusters of long COVID. This corresponds to 3.69% (1.38-7.96) of all infections. The fatigue, respiratory, and cognitive clusters occurred in 51.0% (16.9-92.4), 60.4% (18.9-89.1), and 35.4% (9.4-75.1) of long COVID cases, respectively. Those with milder acute COVID-19 cases had a quicker estimated recovery (median duration 3.99 months [IQR 3.84-4.20]) than those admitted for the acute infection (median duration 8.84 months [IQR 8.10-9.78]). At twelve months, 15.1% (10.3-21.1) continued to experience long COVID symptoms. Conclusions and relevanceThe occurrence of debilitating ongoing symptoms of COVID-19 is common. Knowing how many people are affected, and for how long, is important to plan for rehabilitative services and support to return to social activities, places of learning, and the workplace when symptoms start to wane. Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the extent and nature of the most common long COVID symptoms by country in 2020 and 2021? FindingsGlobally, 144.7 million people experienced one or more of three symptom clusters (fatigue; cognitive problems; and ongoing respiratory problems) of long COVID three months after infection, in 2020 and 2021. Most cases arose from milder infections. At 12 months after infection, 15.1% of these cases had not yet recovered. MeaningThe substantial number of people with long COVID are in need of rehabilitative care and support to transition back into the workplace or education when symptoms start to wane.

Extending the German Corona Consensus Dataset (GECCO) to the immunization, pediatrics, and cardiology domains (preprint)

Background The COVID-19 pandemic has spurred large-scale, inter-institutional research efforts. To enable these efforts, the German Corona Consensus (GECCO) dataset has been developed previously as a harmonized, interoperable collection of the most relevant data elements for COVID-19-related patient research. As GECCO has been developed as a compact core dataset across all medical fields, the focused research within particular medical domains demanded the definition of extension modules that include those data elements that are most relevant to the research performed in these individual medical specialties. Main body We created GECCO extension modules for the immunization, pediatrics , and cardiology domains with respect to the pandemic requests. The data elements included in each of these modules were selected in a consensus-based process by working groups of medical experts from the respective specialty to ensure that the contents are aligned with the research needs of the specialty. The selected data elements were mapped to international standardized vocabularies and data exchange specifications were created using HL7 FHIR profiles on the appropriate resources. All steps were performed in close interdisciplinary collaboration between medical domain experts, medical information scientists and FHIR developers. The profiles and vocabulary mappings were syntactically and semantically validated in a two-stage process. In that way, we defined dataset specifications for a total number of 23 ( immunization ), 59 ( pediatrics ), and 50 ( cardiology ) data elements that augment the GECCO core dataset. We created and published implementation guides and example implementations as well as dataset annotations for each extension module. Conclusions We here present extension modules for the GECCO core dataset that contain data elements most relevant to COVID-19-related patient research in immunization, pediatrics and cardiology . These extension modules were defined in an interdisciplinary, iterative, consensus-based approach that may serve as a blueprint for the development of further dataset definitions and GECCO extension modules. The here developed GECCO extension modules provide a standardized and harmonized definition of specialty-related datasets that can help to enable inter-institutional and cross-country COVID-19 research in these specialties.

Humoral immunity to SARS-CoV-2 elicited by combination COVID-19 vaccination regimens (preprint)

The SARS-CoV-2 pandemic prompted a global vaccination effort and the development of numerous COVID-19 vaccines at an unprecedented scale and pace. As a result, current COVID-19 vaccination regimens comprise diverse vaccine modalities, immunogen combinations and dosing intervals. Here, we compare vaccine-specific antibody and memory B cell responses following two-dose mRNA, single-dose Ad26.COV2.S and two-dose ChAdOx1 or combination ChAdOx1/mRNA vaccination. Plasma neutralizing activity as well as the magnitude, clonal composition and antibody maturation of the RBD-specific memory B cell compartment showed substantial differences between the vaccination regimens. While individual monoclonal antibodies derived from memory B cells exhibited similar binding affinities and neutralizing potency against Wuhan-Hu-1 SARS-CoV-2, there were significant differences in epitope specificity and neutralizing breadth against viral variants of concern. Although the ChAdOx1 vaccine was inferior to mRNA and Ad26.COV2.S in several respects, biochemical and structural analyses revealed enrichment in a subgroup of memory B cell neutralizing antibodies with distinct RBD-binding properties resulting in remarkable potency and breadth.

Delineating antibody escape from Omicron variants (preprint)

SARS-CoV-2-neutralizing antibodies play a critical role for protection and treatment of COVID-19. Viral antibody evasion therefore threatens essential prophylactic and therapeutic measures. The high number of mutations in the Omicron BA.1 sublineage results in markedly reduced neutralization susceptibility. Consistently, Omicron is associated with lower vaccine effectiveness and a high re-infection rate. Notably, newly emerging Omicron sublineages (BA.1.1, BA.2) have rapidly become dominant. Here, we determine polyclonal serum activity against BA.1, BA.1.1 and BA.2 in 50 convalescent or vaccinated individuals as well as delineate antibody sensitivities on a monoclonal level using 163 antibodies. Our study reveals a significant but comparable reduction of serum activity against Omicron sublineages which markedly increases after booster immunization. However, notable differences in sensitivity to individual antibodies demonstrate distinct escape patterns of BA.1 and BA.2 that also affect antibodies in clinical use. The results have strong implications for vaccination strategies and antibody use in prophylaxis and therapy.

Durability of Omicron-neutralizing serum activity following mRNA booster immunization in elderly individuals (preprint)

Elderly individuals are at high risk for severe COVID-19. Due to modest vaccine responses compared to younger individuals and the time elapsed since prioritized vaccinations, the emerging immune-evasive Omicron variant of SARS-CoV-2 is a particular concern for the elderly. Here we longitudinally determined SARS-CoV-2-neutralizing serum activity against different variants in a cohort of 37 individuals with a median age of 82 years. Participants were followed for 10 months after an initial two-dose BNT162b2 vaccination and up to 4.5 months after a BNT162b2 booster. Detectable Omicron-neutralizing activity was nearly absent after two vaccinations but elicited in 89% of individuals by the booster immunization. Neutralizing titers against the Wu01, Delta, and Omicron variants showed similar post-boost declines and 81% of individuals maintained detectable activity against Omicron. Our study demonstrates the mRNA booster effectiveness in inducing Omicron neutralizing activity and provides critical information on vaccine response durability in the highly vulnerable elderly population.

Functional proteomic profiling links deficient DNA clearance to mortality in patients with severe COVID-19 pneumonia (preprint)

Hyperinflammation, coagulopathy and immune dysfunction are prominent in patients with severe infections. Extracellular chromatin clearance by plasma DNases suppresses such pathologies in mice but whether severe infection interferes with these pathways is unclear. Here, we show that patients with severe SARS-CoV-2 infection or microbial sepsis exhibit low extracellular DNA clearance capacity associated with the release of the DNase inhibitor actin. Unlike naked DNA degradation (DNase), neutrophil extracellular trap degradation (NETase) was insensitive to G-actin, indicating distinct underlying mechanisms. Functional proteomic profiling of severely ill SARS-CoV-2 patient plasma revealed that patients with high NETase and DNase activities exhibited 18-fold higher survival compared to patients with low activity proteomic profiles. Remarkably, low DNA clearance capacity was also prominent in healthy individuals with chronic inflammation, suggesting that pre-existing inflammatory conditions may increase the risk for mortality upon infection. Hence, functional proteomic profiling illustrates that non-redundant DNA clearance activities protect critically ill patients from mortality, uncovering protein combinations that can accurately predict mortality in critically ill patients.

The German National Pandemic Cohort Network (NAPKON): rationale, study design and baseline characteristics. (preprint)

The German government initiated the Network University Medicine (NUM) in early 2020 to improve national research activities on the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. To this end, 36 German Academic Medical Centers started to collaborate on 13 projects, with the largest being the National Pandemic Cohort Network (NAPKON). The NAPKON’s goal is creating the most comprehensive Coronavirus Disease 2019 (COVID-19) cohort in Germany. Within NAPKON, adult and pediatric patients are observed in three complementary cohort platforms (Cross-Sectoral, High-Resolution and Population-Based) from the initial infection until up to three years of follow-up. Study procedures comprise comprehensive clinical and imaging diagnostics, quality-of-life assessment, patient-reported outcomes and biosampling. The three cohort platforms build on four infrastructure core units (Interaction, Biosampling, Epidemiology, and Integration) and collaborations with NUM projects. Key components of the data capture, regulatory, and data privacy are based on the German Centre for Cardiovascular Research. By December 01, 2021, 34 university and 34 non-university hospitals have enrolled 4,241 patients with local data quality reviews performed on 2,812 (66%). 47% were female, the median age was 53 (IQR: 38-63)) and 3 pediatric cases were included. 30% of patients were hospitalized, 11% admitted to an intensive care unit, and 4% of patients deceased while enrolled. 7,143 visits with biosampling in 3,595 patients were conducted by November 29, 2021. In this overview article, we summarize NAPKON’s design, relevant milestones including first study population characteristics, and outline the potential of NAPKON for German and international research activities.Trial registration:· https://clinicaltrials.gov/ct2/show/NCT04768998· https://clinicaltrials.gov/ct2/show/NCT04747366· https://clinicaltrials.gov/ct2/show/NCT04679584

mRNA booster immunization elicits potent neutralizing serum activity against the SARS-CoV-2 Omicron variant (preprint)

The Omicron variant of SARS-CoV-2 is causing a rapid increase in infections across the globe. This new variant of concern carries an unusually high number of mutations in key epitopes of neutralizing antibodies on the viral 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 from individuals vaccinated with two doses of the BNT162b2 COVID-19 vaccine and from 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. The presented study demonstrates that booster immunizations may be critical to substantially improve the humoral immune response against the Omicron variant.Authors Henning Gruell, Kanika Vanshylla, Florian Kurth, Leif E. Sander, and Florian Klein contributed equally to this work.

mRNA booster immunization elicits potent neutralizing serum activity against the SARS-CoV-2 Omicron variant (preprint)

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.