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1.
Front Immunol ; 13: 863039, 2022.
Article in English | MEDLINE | ID: covidwho-1775685

ABSTRACT

Evaluating long-term protection against SARS-CoV-2 variants of concern in convalescing individuals is of high clinical relevance. In this prospective study of a cohort of 46 SARS-CoV-2 patients infected with the Wuhan strain of SARS-CoV-2 we longitudinally analyzed changes in humoral and cellular immunity upon early and late convalescence. Antibody neutralization capacity was measured by surrogate virus neutralization test and cellular responses were investigated with 31-colour spectral flow cytometry. Spike-specific, isotype-switched B cells developed already during the disease phase, showed a memory phenotype and did not decrease in numbers even during late convalescence. Otherwise, no long-lasting perturbations of the immune compartment following COVID-19 clearance were observed. During convalescence anti-Spike (S1) IgG antibodies strongly decreased in all patients. We detected neutralizing antibodies against the Wuhan strain as well as the Alpha and Delta but not against the Beta, Gamma or Omicron variants for up to 7 months post COVID-19. Furthermore, correlation analysis revealed a strong association between sera anti-S1 IgG titers and their neutralization capacity against the Wuhan strain as well as Alpha and Delta. Overall, our data suggest that even 7 month after the clearance of COVID-19 many patients possess a protective layer of immunity, indicated by the persistence of Spike-specific memory B cells and by the presence of neutralizing antibodies against the Alpha and Delta variants. However, lack of neutralizing antibodies against the Beta, Gamma and Omicron variants even during the peak response is of major concern as this indicates viral evasion of the humoral immune response.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Convalescence , Humans , Immunity, Humoral , Immunoglobulin G , Prospective Studies , Spike Glycoprotein, Coronavirus/genetics
3.
Eur J Immunol ; 52(2): 356-359, 2022 02.
Article in English | MEDLINE | ID: covidwho-1555488

ABSTRACT

Sera of vaccines were assessed by surrogate virus neutralization tests for their capacity to neutralize the SARS-CoV-2 Delta variant. Homologous prime-boost immunization with Moderna's Spikevax as well as heterologous immunization with AstraZeneca's Vaxzevria followed by Moderna's Spikevax were identified as highly potent vaccination regimens for the induction of Delta-neutralizing antibodies.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 Vaccines/administration & dosage , COVID-19/blood , SARS-CoV-2/metabolism , Vaccination , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/prevention & control , Female , Humans , Male , SARS-CoV-2/immunology
4.
Front Immunol ; 12: 772240, 2021.
Article in English | MEDLINE | ID: covidwho-1551510

ABSTRACT

Antigen-specific tissue-resident memory T cells (Trms) and neutralizing IgA antibodies provide the most effective protection of the lungs from viral infections. To induce those essential components of lung immunity against SARS-CoV-2, we tested various immunization protocols involving intranasal delivery of a novel Modified Vaccinia virus Ankara (MVA)-SARS-2-spike vaccine candidate. We show that a single intranasal MVA-SARS-CoV-2-S application in mice strongly induced pulmonary spike-specific CD8+ T cells, albeit restricted production of neutralizing antibodies. In prime-boost protocols, intranasal booster vaccine delivery proved to be crucial for a massive expansion of systemic and lung tissue-resident spike-specific CD8+ T cells and the development of Th1 - but not Th2 - CD4+ T cells. Likewise, very high titers of IgG and IgA anti-spike antibodies were present in serum and broncho-alveolar lavages that possessed high virus neutralization capacities to all current SARS-CoV-2 variants of concern. Importantly, the MVA-SARS-2-spike vaccine applied in intramuscular priming and intranasal boosting treatment regimen completely protected hamsters from developing SARS-CoV-2 lung infection and pathology. Together, these results identify intramuscular priming followed by respiratory tract boosting with MVA-SARS-2-S as a promising approach for the induction of local, respiratory as well as systemic immune responses suited to protect from SARS-CoV-2 infections.


Subject(s)
Antibodies, Viral/blood , CD8-Positive T-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Administration, Intranasal , Animals , Antibodies, Neutralizing/blood , Cell Line , Chlorocebus aethiops , Cricetinae , Genetic Vectors , Immunization, Secondary , Immunoglobulin A/blood , Immunoglobulin G/blood , Lung/immunology , Male , Mice , Mice, Inbred C57BL , Th1 Cells/immunology , Vaccination , Vaccines, Subunit/immunology , Vaccinia virus/immunology , Vero Cells , Viral Load/immunology
5.
Front Immunol ; 12: 721738, 2021.
Article in English | MEDLINE | ID: covidwho-1378191

ABSTRACT

Here, we described the case of a B cell-deficient patient after CD19 CAR-T cell therapy for refractory B cell Non-Hodgkin Lymphoma with protracted coronavirus disease 2019 (COVID-19). For weeks, this patient only inefficiently contained the virus while convalescent plasma transfusion correlated with virus clearance. Interestingly, following convalescent plasma therapy natural killer cells matured and virus-specific T cells expanded, presumably allowing virus clearance and recovery from the disease. Our findings, thus, suggest that convalescent plasma therapy can activate cellular immune responses to clear SARS-CoV-2 infections. If confirmed in larger clinical studies, these data could be of general importance for the treatment of COVID-19 patients.


Subject(s)
B-Lymphocytes , COVID-19/immunology , COVID-19/therapy , Immunologic Deficiency Syndromes/immunology , Immunotherapy, Adoptive , Killer Cells, Natural/immunology , T-Lymphocytes/immunology , B-Lymphocytes/immunology , COVID-19/complications , Female , Humans , Immunization, Passive , Immunoglobulins, Intravenous , Immunologic Deficiency Syndromes/complications , Lymphocyte Activation , Lymphopoiesis , SARS-CoV-2 , Viral Load
7.
Nat Med ; 27(9): 1525-1529, 2021 09.
Article in English | MEDLINE | ID: covidwho-1310811

ABSTRACT

Currently approved viral vector-based and mRNA-based vaccine approaches against coronavirus disease 2019 (COVID-19) consider only homologous prime-boost vaccination. After reports of thromboembolic events, several European governments recommended using AstraZeneca's ChAdOx1-nCov-19 (ChAd) only in individuals older than 60 years, leaving millions of already ChAd-primed individuals with the decision to receive either a second shot of ChAd or a heterologous boost with mRNA-based vaccines. However, such combinations have not been tested so far. We used Hannover Medical School's COVID-19 Contact Study cohort of healthcare professionals to monitor ChAd-primed immune responses before and 3 weeks after booster with ChAd (n = 32) or BioNTech/Pfizer's BNT162b2 (n = 55). Although both vaccines boosted prime-induced immunity, BNT162b2 induced significantly higher frequencies of spike-specific CD4+ and CD8+ T cells and, in particular, high titers of neutralizing antibodies against the B.1.1.7, B.1.351 and P.1 variants of concern of severe acute respiratory syndrome coronavirus 2.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , SARS-CoV-2/immunology , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Humans , Immunization, Secondary/methods , Immunogenicity, Vaccine/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination
8.
Proc Natl Acad Sci U S A ; 118(28)2021 07 13.
Article in English | MEDLINE | ID: covidwho-1284760

ABSTRACT

Severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) has emerged as the infectious agent causing the pandemic coronavirus disease 2019 (COVID-19) with dramatic consequences for global human health and economics. Previously, we reached clinical evaluation with our vector vaccine based on modified vaccinia virus Ankara (MVA) against the Middle East respiratory syndrome coronavirus (MERS-CoV), which causes an infection in humans similar to SARS and COVID-19. Here, we describe the construction and preclinical characterization of a recombinant MVA expressing full-length SARS-CoV-2 spike (S) protein (MVA-SARS-2-S). Genetic stability and growth characteristics of MVA-SARS-2-S, plus its robust expression of S protein as antigen, make it a suitable candidate vaccine for industrial-scale production. Vaccinated mice produced S-specific CD8+ T cells and serum antibodies binding to S protein that neutralized SARS-CoV-2. Prime-boost vaccination with MVA-SARS-2-S protected mice sensitized with a human ACE2-expressing adenovirus from SARS-CoV-2 infection. MVA-SARS-2-S is currently being investigated in a phase I clinical trial as aspirant for developing a safe and efficacious vaccine against COVID-19.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Spike Glycoprotein, Coronavirus/immunology , Animals , COVID-19 Vaccines/standards , Dose-Response Relationship, Immunologic , Humans , Mice , Mice, Inbred BALB C , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , T-Lymphocytes , Vaccination , Vaccinia virus
9.
Cell Mol Immunol ; 18(4): 936-944, 2021 04.
Article in English | MEDLINE | ID: covidwho-899921

ABSTRACT

Neutralizing antibodies targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into cells via surface-expressed angiotensin-converting enzyme 2 (ACE2). We used a surrogate virus neutralization test (sVNT) and SARS-CoV-2 S protein-pseudotyped vesicular stomatitis virus (VSV) vector-based neutralization assay (pVNT) to assess the degree to which serum antibodies from coronavirus disease 2019 (COVID-19) convalescent patients interfere with the binding of SARS-CoV-2 S to ACE2. Both tests revealed neutralizing anti-SARS-CoV-2 S antibodies in the sera of ~90% of mildly and 100% of severely affected COVID-19 convalescent patients. Importantly, sVNT and pVNT results correlated strongly with each other and to the levels of anti-SARS-CoV-2 S1 IgG and IgA antibodies. Moreover, levels of neutralizing antibodies correlated with the duration and severity of clinical symptoms but not with patient age. Compared to pVNT, sVNT is less sophisticated and does not require any biosafety labs. Since this assay is also much faster and cheaper, sVNT will not only be important for evaluating the prevalence of neutralizing antibodies in a population but also for identifying promising plasma donors for successful passive antibody therapy.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , Aged , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/blood , Cell Line , Convalescence , Female , Humans , Immunoglobulin A/blood , Immunoglobulin G/blood , Male , Middle Aged , Neutralization Tests/methods
10.
Infect Dis Ther ; 9(4): 837-849, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-743789

ABSTRACT

BACKGROUND: Serology testing is explored for epidemiological research and to inform individuals after suspected infection. During the coronavirus disease 2019 (COVID-19) pandemic, frontline healthcare professionals (HCP) may be at particular risk for infection. No longitudinal data on functional seroconversion in HCP in regions with low COVID-19 prevalence and low pre-test probability exist. METHODS: In a large German university hospital, we performed weekly questionnaire assessments and anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) measurements with various commercial tests, a novel surrogate virus neutralisation test, and a neutralisation assay using live SARS-CoV-2. RESULTS: From baseline to week 6, 1080 screening measurements for anti-SARS CoV-2 (S1) IgG from 217 frontline HCP (65% female) were performed. Overall, 75.6% of HCP reported at least one symptom of respiratory infection. Self-perceived infection probability declined over time (from mean 20.1% at baseline to 12.4% in week 6, p < 0.001). In sera of convalescent patients with PCR-confirmed COVID-19, we measured high anti-SARS-CoV-2 IgG levels, obtained highly concordant results from enzyme-linked immunosorbent assays (ELISA) using e.g. the spike 1 (S1) protein domain and the nucleocapsid protein (NCP) as targets, and confirmed antiviral neutralisation. However, in HCP the cumulative incidence for anti-SARS-CoV-2 (S1) IgG was 1.86% for positive and 0.93% for equivocal positive results over the study period of 6 weeks. Except for one HCP, none of the eight initial positive results were confirmed by alternative serology tests or showed in vitro neutralisation against live SARS-CoV-2. The only true seroconversion occurred without symptoms and mounted strong functional humoral immunity. Thus, the confirmed cumulative incidence for neutralizing anti-SARS-CoV-2 IgG was 0.47%. CONCLUSION: When assessing anti-SARS-CoV-2 immune status in individuals with low pre-test probability, we suggest confirming positive results from single measurements by alternative serology tests or functional assays. Our data highlight the need for a methodical serology screening approach in regions with low SARS-CoV-2 infection rates. TRIAL REGISTRATION: The study is registered at DRKS00021152.

11.
EBioMedicine ; 57: 102885, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-633885

ABSTRACT

BACKGROUND: Elucidating the role of T cell responses in COVID-19 is of utmost importance to understand the clearance of SARS-CoV-2 infection. METHODS: 30 hospitalized COVID-19 patients and 60 age- and gender-matched healthy controls (HC) participated in this study. We used two comprehensive 11-colour flow cytometric panels conforming to Good Laboratory Practice and approved for clinical diagnostics. FINDINGS: Absolute numbers of lymphocyte subsets were differentially decreased in COVID-19 patients according to clinical severity. In severe disease (SD) patients, all lymphocyte subsets were reduced, whilst in mild disease (MD) NK, NKT and γδ T cells were at the level of HC. Additionally, we provide evidence of T cell activation in MD but not SD, when compared to HC. Follow up samples revealed a marked increase in effector T cells and memory subsets in convalescing but not in non-convalescing patients. INTERPRETATION: Our data suggest that activation and expansion of innate and adaptive lymphocytes play a major role in COVID-19. Additionally, recovery is associated with formation of T cell memory as suggested by the missing formation of effector and central memory T cells in SD but not in MD. Understanding T cell-responses in the context of clinical severity might serve as foundation to overcome the lack of effective anti-viral immune response in severely affected COVID-19 patients and can offer prognostic value as biomarker for disease outcome and control. FUNDING: Funded by State of Lower Saxony grant 14-76,103-184CORONA-11/20 and German Research Foundation, Excellence Strategy - EXC2155"RESIST"-Project ID39087428, and DFG-SFB900/3-Project ID158989968, grants SFB900-B3, SFB900-B8.


Subject(s)
Betacoronavirus/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Coronavirus Infections/immunology , Lymphocyte Activation/immunology , Pneumonia, Viral/immunology , Adult , Aged , Aged, 80 and over , Biomarkers , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , COVID-19 , Female , Humans , Immunologic Memory/immunology , Lymphocyte Count , Male , Middle Aged , Pandemics , Prognosis , SARS-CoV-2 , Severity of Illness Index , Young Adult
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