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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-336909

ABSTRACT

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.

2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-336206

ABSTRACT

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.

3.
J Clin Immunol ; 2022 May 05.
Article in English | MEDLINE | ID: covidwho-1820957

ABSTRACT

PURPOSE: Six to 19% of critically ill COVID-19 patients display circulating auto-antibodies against type I interferons (IFN-AABs). Here, we establish a clinically applicable strategy for early identification of IFN-AAB-positive patients for potential subsequent clinical interventions. METHODS: We analyzed sera of 430 COVID-19 patients from four hospitals for presence of IFN-AABs by ELISA. Binding specificity and neutralizing activity were evaluated via competition assay and virus-infection-based neutralization assay. We defined clinical parameters associated with IFN-AAB positivity. In a subgroup of critically ill patients, we analyzed effects of therapeutic plasma exchange (TPE) on the levels of IFN-AABs, SARS-CoV-2 antibodies and clinical outcome. RESULTS: The prevalence of neutralizing AABs to IFN-α and IFN-ω in COVID-19 patients from all cohorts was 4.2% (18/430), while being undetectable in an uninfected control cohort. Neutralizing IFN-AABs were detectable exclusively in critically affected (max. WHO score 6-8), predominantly male (83%) patients (7.6%, 18/237 for IFN-α-AABs and 4.6%, 11/237 for IFN-ω-AABs in 237 patients with critical COVID-19). IFN-AABs were present early post-symptom onset and at the peak of disease. Fever and oxygen requirement at hospital admission co-presented with neutralizing IFN-AAB positivity. IFN-AABs were associated with lower probability of survival (7.7% versus 80.9% in patients without IFN-AABs). TPE reduced levels of IFN-AABs in three of five patients and may increase survival of IFN-AAB-positive patients compared to those not undergoing TPE. CONCLUSION: IFN-AABs may serve as early biomarker for the development of severe COVID-19. We propose to implement routine screening of hospitalized COVID-19 patients for rapid identification of patients with IFN-AABs who most likely benefit from specific therapies.

4.
BMC Rheumatol ; 5(1): 60, 2021 Dec 28.
Article in English | MEDLINE | ID: covidwho-1817296

ABSTRACT

BACKGROUND: Adult-onset Still's disease (AOSD) is an autoinflammatory multi-systemic syndrome. Macrophage activation syndrome (MAS) is a potentially life-threatening complication of AOSD with a mortality rate of 10-20%. Especially viral infection is thought to be a common trigger for development of MAS. On the other hand, the occurrence of MAS following vaccinations is extremely rare and has been described in a few cases after measles or influenza vaccinations and more recently after ChAdOx1 nCoV-19 (COVID-19 viral vector vaccine, Oxford-AZ). CASE PRESENTATION: We report the case of a twenty-year-old female with adult-onset Still's disease (AOSD), who developed a MAS six days after receiving her first COVID-19 vaccine dose of BNT162b2 (mRNA vaccine, BioNTech/Pfizer) with ferritin levels of 136,680 µg/l (ref.: 13-150 µg/l). CONCLUSIONS: To the best of our knowledge, this is the first case report of development of MAS in a patient with preexisting AOSD after vaccination in general, and SARS-CoV-2 vaccination in particular. The new mRNA vaccines have generally shown a reassuring safety profile, but it has been shown that nucleic acids in general, including mRNA can act as pathogen-associated molecular patterns that activate toll-like receptors with extensive production of pro-inflammatory cytokines and further activation of immune cells. Proving an interferon 1 response in our patient directly after vaccination, we think that in this particular case the vaccination might have acted as trigger for the development of MAS. Even if it remains difficult to establish causality in the case of rare adverse events, especially in patients with autoimmune or autoinflammatory conditions, these complications are important to monitor and register, but do not at all diminish the overwhelming positive benefit-risk ratio of licensed COVID-19 vaccines.

5.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-333041

ABSTRACT

Abstract: Patients with COVID-19 can have a variety of neurological symptoms, but the pathomechanism of CNS involvement in COVD-19 remains unclear. While routine cerebrospinal fluid (CSF) analyses in patients with neurological manifestations of COVID-19 generally show no or only mild inflammation, more detailed data on inflammatory mediators in the CSF of patients with COVID-19 are scarce. Here, we used mass spectrometry to study the proteome, Enzym-linkend immunoassays, semiquantitative cytokine arrays, autoantibody screening, and RNA profiling to study the neuroinflammation. We study the inflammatory response in paired CSF and serum samples of patients with COVID-19 (n=38). Patients with herpes simplex virus encephalitis (HSVE, n=10) and patients with non-inflammatory, non-neurodegenerative neurological diseases (n=28) served as controls. Proteomics on single protein level and subsequent pathway analysis showed similar yet strongly attenuated inflammatory changes in the CSF of COVID-19 patients compared to HSVE patients. CSF/serum indices of interleukin-6, interleukin-16 and CXCL10 together point at an origin from these inflammatory proteins from outside the central nervous system. When stratifying COVID-19 patients into those with and without bacterial superinfection as indicated by elevated procalcitonin levels, inflammatory markers were significantly higher in those with concomitant bacterial superinfection. RNA sequencing in the CSF revealed 101 linear RNAs comprising messenger RNAs, micro RNAs and t-RNA fragments being significantly differentially expressed in COVID-19 than in HSVE or controls. Our findings may explain the absence of signs of intrathecal inflammation upon routine CSF testing despite the presence of SARS-CoV2 infection-associated neurological symptoms. The relevance of blood-derived mediators of inflammation in the CSF for neurological post-COVID-19 symptoms deserves further investigation.

6.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-332881

ABSTRACT

Summary 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.

7.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-331621

ABSTRACT

Post-acute lung sequelae of COVID-19 are challenging many survivors across the world, yet the mechanisms behind are poorly understood. Our results delineate an inflammatory cascade of events occurring along disease progression within fibrovascular niches. It is initiated by endothelial dysfunction, followed by heme scavenging of CD163+ macrophages and production of CCL18. This chemokine synergizes with local CCL21 upregulation to influence the stromal composition favoring endothelial to mesenchymal transition. The local immune response is further modulated via recruitment of CCR7+ T cells into the expanding fibrovascular niche and imprinting an exhausted, T follicular helper like phenotype in these cells. Eventually, this culminates in the formation of tertiary lymphoid structures, further perpetuating chronic inflammation. Thus, our work presents misdirected immune-stromal interaction mechanisms promoting a self-sustained and non-resolving local immune response that extends beyond active viral infection and leads to profound tissue repurposing and chronic inflammation.

8.
Emerg Infect Dis ; 28(5): 1050-1052, 2022 05.
Article in English | MEDLINE | ID: covidwho-1731731

ABSTRACT

To determine neutralizing activity against the severe acute respiratory syndrome coronavirus 2 ancestral strain and 4 variants of concern, we tested serum from 30 persons with breakthrough infection after 2-dose vaccination. Cross-variant neutralizing activity was comparable to that after 3-dose vaccination. Shorter intervals between vaccination and breakthrough infection correlated with lower neutralizing titers.


Subject(s)
COVID-19 , Antibodies, Neutralizing , Antibodies, Viral , Humans , SARS-CoV-2 , Vaccination
9.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327374

ABSTRACT

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 anti-Omicron activity and provides critical information on vaccine response durability in the highly vulnerable elderly population.

10.
Cell Host Microbe ; 30(1): 69-82.e10, 2022 01 12.
Article in English | MEDLINE | ID: covidwho-1638702

ABSTRACT

A fraction of COVID-19 convalescent individuals mount a potent antibody response to SARS-CoV-2 with cross-reactivity to SARS-CoV-1. To uncover their humoral response in detail, we performed single B cell analysis from 10 SARS-CoV-2 elite neutralizers. We isolated and analyzed 126 monoclonal antibodies, many of which were sarbecovirus cross-reactive, with some displaying merbecovirus- and embecovirus-reactivity. Several isolated broadly neutralizing antibodies were effective against B.1.1.7, B.1.351, B.1.429, B.1.617, and B.1.617.2 variants and 19 prominent potential escape sites. Furthermore, assembly of 716,806 SARS-CoV-2 sequences predicted emerging escape variants, which were also effectively neutralized. One of these broadly neutralizing potent antibodies, R40-1G8, is a IGHV3-53 RBD-class-1 antibody. Remarkably, cryo-EM analysis revealed that R40-1G8 has a flexible binding mode, targeting both "up" and "down" conformations of the RBD. Given the threat of emerging SARS-CoV-2 variants, we demonstrate that elite neutralizers are a valuable source for isolating ultrapotent antibody candidates to prevent and treat SARS-CoV-2 infection.


Subject(s)
Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/immunology , COVID-19/virology , Cells, Cultured , Chlorocebus aethiops , Cross Reactions/immunology , Female , HEK293 Cells , Humans , Male , Middle Aged , Neutralization Tests/methods , Spike Glycoprotein, Coronavirus/immunology , Vero Cells
11.
Nature ; 600(7888): 295-301, 2021 12.
Article in English | MEDLINE | ID: covidwho-1626235

ABSTRACT

SARS-CoV-2 is a single-stranded RNA virus that causes COVID-19. Given its acute and often self-limiting course, it is likely that components of the innate immune system play a central part in controlling virus replication and determining clinical outcome. Natural killer (NK) cells are innate lymphocytes with notable activity against a broad range of viruses, including RNA viruses1,2. NK cell function may be altered during COVID-19 despite increased representation of NK cells with an activated and adaptive phenotype3,4. Here we show that a decline in viral load in COVID-19 correlates with NK cell status and that NK cells can control SARS-CoV-2 replication by recognizing infected target cells. In severe COVID-19, NK cells show defects in virus control, cytokine production and cell-mediated cytotoxicity despite high expression of cytotoxic effector molecules. Single-cell RNA sequencing of NK cells over the time course of the COVID-19 disease spectrum reveals a distinct gene expression signature. Transcriptional networks of interferon-driven NK cell activation are superimposed by a dominant transforming growth factor-ß (TGFß) response signature, with reduced expression of genes related to cell-cell adhesion, granule exocytosis and cell-mediated cytotoxicity. In severe COVID-19, serum levels of TGFß peak during the first two weeks of infection, and serum obtained from these patients severely inhibits NK cell function in a TGFß-dependent manner. Our data reveal that an untimely production of TGFß is a hallmark of severe COVID-19 and may inhibit NK cell function and early control of the virus.


Subject(s)
COVID-19/immunology , Killer Cells, Natural/immunology , SARS-CoV-2/immunology , Transforming Growth Factor beta/immunology , Atlases as Topic , Gene Expression Regulation/immunology , Humans , Immunity, Innate , Influenza, Human/immunology , Killer Cells, Natural/pathology , RNA-Seq , Single-Cell Analysis , Time Factors , Transforming Growth Factor beta/blood , Viral Load/immunology , Virus Replication/immunology
12.
Lancet Respir Med ; 9(11): 1255-1265, 2021 11.
Article in English | MEDLINE | ID: covidwho-1594095

ABSTRACT

BACKGROUND: Heterologous vaccine regimens have been widely discussed as a way to mitigate intermittent supply shortages and to improve immunogenicity and safety of COVID-19 vaccines. We aimed to assess the reactogenicity and immunogenicity of heterologous immunisations with ChAdOx1 nCov-19 (AstraZeneca, Cambridge, UK) and BNT162b2 (Pfizer-BioNtech, Mainz, Germany) compared with homologous BNT162b2 and ChAdOx1 nCov-19 immunisation. METHODS: This is an interim analysis of a prospective observational cohort study enrolling health-care workers in Berlin (Germany) who received either homologous ChAdOx1 nCov-19 or heterologous ChAdOx1 nCov-19-BNT162b2 vaccination with a 10-12-week vaccine interval or homologous BNT162b2 vaccination with a 3-week vaccine interval. We assessed reactogenicity after the first and second vaccination by use of electronic questionnaires on days 1, 3, 5, and 7. Immunogenicity was measured by the presence of SARS-CoV-2-specific antibodies (full spike-IgG, S1-IgG, and RBD-IgG), by an RBD-ACE2 binding inhibition assay (surrogate SARS-CoV-2 virus neutralisation test), a pseudovirus neutralisation assay against two variants of concerns (alpha [B.1.1.7] and beta [B.1.351]), and anti-S1-IgG avidity. T-cell reactivity was measured by IFN-γ release assay. FINDINGS: Between Dec 27, 2020, and June 14, 2021, 380 participants were enrolled in the study, with 174 receiving homologous BNT162b2 vaccination, 38 receiving homologous ChAdOx1 nCov-19 vaccination, and 104 receiving ChAdOx1 nCov-19-BNT162b2 vaccination. Systemic symptoms were reported by 103 (65%, 95% CI 57·1-71·8) of 159 recipients of homologous BNT162b2, 14 (39%, 24·8-55·1) of 36 recipients of homologous ChAdOx1 nCov-19, and 51 (49%, 39·6-58·5) of 104 recipients of ChAdOx1 nCov-19-BNT162b2 after the booster immunisation. Median anti-RBD IgG levels 3 weeks after boost immunisation were 5·4 signal to cutoff ratio (S/co; IQR 4·8-5·9) in recipients of homologous BNT162b2, 4·9 S/co (4·3-5·6) in recipients of homologous ChAdOx1 nCov-19, and 5·6 S/co (5·1-6·1) in recipients of ChAdOx1 nCov-19- BNT162b2. Geometric mean of 50% inhibitory dose against alpha and beta variants were highest in recipients of ChAdOx1 nCov-19-BNT162b2 (956·6, 95% CI 835·6-1095, against alpha and 417·1, 349·3-498·2, against beta) compared with those in recipients of homologous ChAdOx1 nCov-19 (212·5, 131·2-344·4, against alpha and 48·5, 28·4-82·8, against beta; both p<0·0001) or homologous BNT162b2 (369·2, 310·7-438·6, against alpha and 72·4, 60·5-86·5, against beta; both p<0·0001). SARS-CoV-2 S1 T-cell reactivity 3 weeks after boost immunisation was highest in recipients of ChAdOx1 nCov-19-BNT162b2 (median IFN-γ concentration 4762 mIU/mL, IQR 2723-8403) compared with that in recipients of homologous ChAdOx1 nCov-19 (1061 mIU/mL, 599-2274, p<0·0001) and homologous BNT162b2 (2026 mIU/mL, 1459-4621, p=0·0008) vaccination. INTERPRETATION: The heterologous ChAdOx1 nCov-19-BNT162b2 immunisation with 10-12-week interval, recommended in Germany, is well tolerated and improves immunogenicity compared with homologous ChAdOx1 nCov-19 vaccination with 10-12-week interval and BNT162b2 vaccination with 3-week interval. Heterologous prime-boost immunisation strategies for COVID-19 might be generally applicable. FUNDING: Forschungsnetzwerk der Universitätsmedizin zu COVID-19, the German Ministry of Education and Research, Zalando SE.


Subject(s)
/immunology , COVID-19 , Immunogenicity, Vaccine , Antibodies, Viral/blood , COVID-19/prevention & control , Germany , Health Personnel , Humans , Immunoglobulin G/blood , Neutralization Tests , Prospective Studies , SARS-CoV-2 , Vaccination
13.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-296695

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.

14.
Respir Med ; 191: 106709, 2022 01.
Article in English | MEDLINE | ID: covidwho-1556145

ABSTRACT

INTRODUCTION: Prospective and longitudinal data on pulmonary injury over one year after acute coronavirus disease 2019 (COVID-19) are sparse. We aim to determine reductions in pulmonary function and respiratory related quality of life up to 12 months after acute COVID-19. METHODS: Patients with acute COVID-19 were enrolled into an ongoing single-centre, prospective observational study and prospectively examined 6 weeks, 3, 6 and 12 months after onset of COVID-19 symptoms. Chest CT-scans, pulmonary function and symptoms assessed by St. Georges Respiratory Questionnaire were used to evaluate respiratory limitations. Patients were stratified according to severity of acute COVID-19. RESULTS: Median age of all patients was 57 years, 37.8% were female. Higher age, male sex and higher BMI were associated with acute-COVID-19 severity (p < 0.0001, 0.001 and 0.004 respectively). Also, pulmonary restriction and reduced carbon monoxide diffusion capacity was associated with disease severity. In patients with restriction and impaired diffusion capacity, FVC improved over 12 months from 61.32 to 71.82, TLC from 68.92 to 76.95, DLCO from 60.18 to 68.98 and KCO from 81.28 to 87.80 (percent predicted values; p = 0.002, 0.045, 0.0002 and 0.0005). The CT-score of lung involvement in the acute phase was associated with restriction and reduction in diffusion capacity in follow-up. Respiratory symptoms improved for patients in higher severity groups during follow-up, but not for patients with initially mild disease. CONCLUSION: Severity of respiratory failure during COVID-19 correlates with the degree of pulmonary function impairment and respiratory quality of life in the year after acute infection.


Subject(s)
COVID-19/complications , COVID-19/physiopathology , Lung/physiopathology , Quality of Life , Respiratory Insufficiency/physiopathology , Adult , Aged , COVID-19/diagnostic imaging , COVID-19/therapy , Extracorporeal Membrane Oxygenation , Female , Forced Expiratory Volume/physiology , Hospitalization , Humans , Longitudinal Studies , Lung/diagnostic imaging , Male , Middle Aged , Oxygen Inhalation Therapy , Pulmonary Diffusing Capacity/physiology , Recovery of Function , Respiration, Artificial , Respiratory Function Tests , Respiratory Insufficiency/diagnostic imaging , Respiratory Insufficiency/therapy , SARS-CoV-2 , Severity of Illness Index , Surveys and Questionnaires , Tomography, X-Ray Computed , Total Lung Capacity/physiology , Vital Capacity/physiology
15.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-295758

ABSTRACT

In this position paper, a large group of interdisciplinary experts outlines response strategies against the spread of SARS-CoV-2 in the winter of 2021/2022 in Germany. We review the current state of the COVID-19 pandemic, from incidence and vaccination efficacy to hospital capacity. Building on this situation assessment, we illustrate various possible scenarios for the winter, and detail the mechanisms and effectiveness of the non-pharmaceutical interventions, vaccination, and booster. With this assessment, we want to provide orientation for decision makers about the progress and mitigation of COVID-19.

16.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-294933

ABSTRACT

Objective to assess reactogenicity and immunogenicity of heterologous prime-boost immunisations of ChAdOx1-nCoV19 (Vaxzevria, ChAdOx) followed by BNT162b2 (Comirnaty, BNT) compared to homologous BNT/BNT immunisation. Design prospective, observational cohort study. Setting unicenter study in a cohort of health care workers at a tertiary care center in Berlin, Germany. Participants 340 health care workers immunised between 27 December 2020 and 21 May 2021 at Charité - Universitätsmedizin Berlin, Germany Main outcome measures the main outcomes were reactogenicity assessed on days one, three, five and seven post prime and boost vaccination, and immunogenicity measured by serum SARS-CoV-2 full spike-, spike S1-, and spike RBD-IgG, virus neutralisation capacity, anti-S1-IgG avidity, and T cell reactivity measured by Interferon gamma release assay at 3-4 weeks post prime and boost immunisation. Results Heterologous ChAdOx/BNT booster vaccination was overall well-tolerated and reactogenicity was largely comparable to homologous BNT/BNT vaccination. Systemic reactions were most frequent after prime immunisation with ChAdOx (86%, 95CI: 79-91), and less frequent after homologous BNT/BNT (65%, 95CI: 56-72), or heterologous ChAdOx/BNT booster vaccination (48%, 95CI: 36-59). Serum antibody responses and T cell reactivity were strongly increased after both homologous and heterologous boost, and immunogenicity was overall robust, and comparable between both regimens in this cohort, with slightly increased S1-IgG avidity and T cell responses following heterologous booster immunisation. Conclusions Evidence of rare thrombotic events associated with ChAdOx has led to recommendation of a heterologous booster with mRNA vaccines for certain age groups in several European countries, despite a lack of robust safety and immunogenicity data for this vaccine regimen. This interim analysis provides evidence that the currently recommended heterologous ChAdOx/BNT immunisation regimen with 10-12 week vaccine intervals is well tolerated and slightly more immunogenic compared to homologous BNT/BNT vaccination with three week vaccine intervals. Heterologous prime-boost immunisation for COVID-19 may be generally applicable to optimise logistics and improve immunogenicity and to mitigate potential intermittent supply shortages for individual vaccines.

18.
Viruses ; 13(11)2021 11 16.
Article in English | MEDLINE | ID: covidwho-1524173

ABSTRACT

With the exception of inactivated vaccines, all SARS-CoV-2 vaccines currently used for clinical application focus on the spike envelope glycoprotein as a virus-specific antigen. Compared to other SARS-CoV-2 genes, mutations in the spike protein gene are more rapidly selected and spread within the population, which carries the risk of impairing the efficacy of spike-based vaccines. It is unclear to what extent the loss of neutralizing antibody epitopes can be compensated by cellular immune responses, and whether the use of other SARS-CoV-2 antigens might cause a more diverse immune response and better long-term protection, particularly in light of the continued evolution towards new SARS-CoV-2 variants. To address this question, we explored immunogenicity and protective effects of adenoviral vectors encoding either the full-length spike protein (S), the nucleocapsid protein (N), the receptor binding domain (RBD) or a hybrid construct of RBD and the membrane protein (M) in a highly susceptible COVID-19 hamster model. All adenoviral vaccines provided life-saving protection against SARS-CoV-2-infection. The most efficient protection was achieved after exposure to full-length spike. However, the nucleocapsid protein, which triggered a robust T-cell response but did not facilitate the formation of neutralizing antibodies, controlled early virus replication efficiently and prevented severe pneumonia. Although the full-length spike protein is an excellent target for vaccines, it does not appear to be the only option for future vaccine design.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Immunity, Cellular , Immunity, Humoral , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Antigens, Viral/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/pathology , COVID-19/prevention & control , COVID-19/virology , Coronavirus Nucleocapsid Proteins/genetics , Coronavirus Nucleocapsid Proteins/immunology , Cricetinae , Female , Inflammation , Lung/pathology , Lung/virology , Male , Mice, Inbred C57BL , Phosphoproteins/genetics , Phosphoproteins/immunology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Viral Matrix Proteins/genetics , Viral Matrix Proteins/immunology
19.
Nature ; 600(7888): 295-301, 2021 12.
Article in English | MEDLINE | ID: covidwho-1483137

ABSTRACT

SARS-CoV-2 is a single-stranded RNA virus that causes COVID-19. Given its acute and often self-limiting course, it is likely that components of the innate immune system play a central part in controlling virus replication and determining clinical outcome. Natural killer (NK) cells are innate lymphocytes with notable activity against a broad range of viruses, including RNA viruses1,2. NK cell function may be altered during COVID-19 despite increased representation of NK cells with an activated and adaptive phenotype3,4. Here we show that a decline in viral load in COVID-19 correlates with NK cell status and that NK cells can control SARS-CoV-2 replication by recognizing infected target cells. In severe COVID-19, NK cells show defects in virus control, cytokine production and cell-mediated cytotoxicity despite high expression of cytotoxic effector molecules. Single-cell RNA sequencing of NK cells over the time course of the COVID-19 disease spectrum reveals a distinct gene expression signature. Transcriptional networks of interferon-driven NK cell activation are superimposed by a dominant transforming growth factor-ß (TGFß) response signature, with reduced expression of genes related to cell-cell adhesion, granule exocytosis and cell-mediated cytotoxicity. In severe COVID-19, serum levels of TGFß peak during the first two weeks of infection, and serum obtained from these patients severely inhibits NK cell function in a TGFß-dependent manner. Our data reveal that an untimely production of TGFß is a hallmark of severe COVID-19 and may inhibit NK cell function and early control of the virus.


Subject(s)
COVID-19/immunology , Killer Cells, Natural/immunology , SARS-CoV-2/immunology , Transforming Growth Factor beta/immunology , Atlases as Topic , Gene Expression Regulation/immunology , Humans , Immunity, Innate , Influenza, Human/immunology , Killer Cells, Natural/pathology , RNA-Seq , Single-Cell Analysis , Time Factors , Transforming Growth Factor beta/blood , Viral Load/immunology , Virus Replication/immunology
20.
Science ; 374(6564): eabh1823, 2021 Oct 08.
Article in English | MEDLINE | ID: covidwho-1381146

ABSTRACT

The functional relevance of preexisting cross-immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a subject of intense debate. Here, we show that human endemic coronavirus (HCoV)­reactive and SARS-CoV-2­cross-reactive CD4+ T cells are ubiquitous but decrease with age. We identified a universal immunodominant coronavirus-specific spike peptide (S816-830) and demonstrate that preexisting spike- and S816-830­reactive T cells were recruited into immune responses to SARS-CoV-2 infection and their frequency correlated with anti­SARS-CoV-2-S1-IgG antibodies. Spike­cross-reactive T cells were also activated after primary BNT162b2 COVID-19 messenger RNA vaccination and displayed kinetics similar to those of secondary immune responses. Our results highlight the functional contribution of preexisting spike­cross-reactive T cells in SARS-CoV-2 infection and vaccination. Cross-reactive immunity may account for the unexpectedly rapid induction of immunity after primary SARS-CoV-2 immunization and the high rate of asymptomatic or mild COVID-19 disease courses.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Adult , Age Factors , Aged , Aged, 80 and over , Asymptomatic Diseases , CD3 Complex/immunology , COVID-19 Vaccines/immunology , Cross Reactions , Female , Humans , Immunity , Immunodominant Epitopes/immunology , Male , Middle Aged , Open Reading Frames , Peptide Fragments/immunology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccination , Young Adult
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