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1.
J Exp Med ; 221(10)2024 Oct 07.
Article in English | MEDLINE | ID: mdl-39316018

ABSTRACT

Tick-borne encephalitis (TBE) virus (TBEV) is transmitted to humans via tick bites. Infection is benign in >90% of the cases but can cause mild (<5%), moderate (<4%), or severe (<1%) encephalitis. We show here that ∼10% of patients hospitalized for severe TBE in cohorts from Austria, Czech Republic, and France carry auto-Abs neutralizing IFN-α2, -ß, and/or -ω at the onset of disease, contrasting with only ∼1% of patients with moderate and mild TBE. These auto-Abs were found in two of eight patients who died and none of 13 with silent infection. The odds ratios (OR) for severe TBE in individuals with these auto-Abs relative to those without them in the general population were 4.9 (95% CI: 1.5-15.9, P < 0.0001) for the neutralization of only 100 pg/ml IFN-α2 and/or -ω, and 20.8 (95% CI: 4.5-97.4, P < 0.0001) for the neutralization of 10 ng/ml IFN-α2 and -ω. Auto-Abs neutralizing type I IFNs accounted for ∼10% of severe TBE cases in these three European cohorts.


Subject(s)
Antibodies, Neutralizing , Autoantibodies , Encephalitis, Tick-Borne , Interferon Type I , Humans , Encephalitis, Tick-Borne/immunology , Interferon Type I/immunology , Autoantibodies/immunology , Female , Male , Antibodies, Neutralizing/immunology , Middle Aged , Adult , Encephalitis Viruses, Tick-Borne/immunology , Aged , Austria/epidemiology , Czech Republic
2.
Front Immunol ; 15: 1447980, 2024.
Article in English | MEDLINE | ID: mdl-39295866

ABSTRACT

The ubiquitous Torque teno virus (TTV) establishes a chronically persistent infection in the human host. TTV has not been associated with any apparent disease, but, as part of the human virome, it may confer a regulatory imprint on the human immune system with as yet unclear consequences. However, so far, only few studies have characterized the TTV-specific immune responses or the overall immunological imprints by TTV. Here, we reveal that TTV infection leads to a highly exhausted TTV-specific CD8+ T-cell response, hallmarked by decreased IFN-γ production and the expression of the inhibitory NKG2A-receptor. On a functional level, we identified a panel of highly polymorphic TTV-encoded peptides that lead to an expansion of regulatory NKG2A+ natural killer, NKG2A+CD4+, and NKG2A+CD8+ T cells via the stabilization of the non-classical HLA-E molecule. Our results thus demonstrate that TTV leads to a distinct imprint on the human immune system that may further regulate overall human immune responses in infectious, autoimmune, and malignant diseases.


Subject(s)
CD8-Positive T-Lymphocytes , DNA Virus Infections , HLA-E Antigens , Histocompatibility Antigens Class I , NK Cell Lectin-Like Receptor Subfamily C , Torque teno virus , Humans , Torque teno virus/immunology , NK Cell Lectin-Like Receptor Subfamily C/metabolism , NK Cell Lectin-Like Receptor Subfamily C/immunology , CD8-Positive T-Lymphocytes/immunology , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class I/metabolism , DNA Virus Infections/immunology , Interferon-gamma/metabolism , Interferon-gamma/immunology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Male
3.
Proc Natl Acad Sci U S A ; 121(33): e2323016121, 2024 Aug 13.
Article in English | MEDLINE | ID: mdl-39088388

ABSTRACT

Blood plasma viscosity (PV) is an established biomarker for numerous diseases. Measurement of the shear PV using conventional rheological techniques is, however, time consuming and requires significant plasma volumes. Here, we show that Brillouin light scattering (BLS) and angle-resolved spectroscopy measurements of the longitudinal PV from microliter-sized plasma volumes can serve as a proxy for the shear PV measured using conventional viscometers. This is not trivial given the distinct frequency regime probed and the longitudinal viscosity, a combination of the shear and bulk viscosity, representing a unique material property on account of the latter. We demonstrate this for plasma from healthy persons and patients suffering from different severities of COVID-19 (CoV), which has been associated with an increased shear PV. We further show that the additional information contained in the BLS-measured effective longitudinal PV and its temperature scaling can provide unique insight into the chemical constituents and physical properties of plasma that can be of diagnostic value. In particular, we find that changes in the effective longitudinal viscosity are consistent with an increased suspension concentration in CoV patient samples at elevated temperatures that is correlated with disease severity and progression. This is supported by results from rapid BLS spatial-mapping, angle-resolved BLS measurements, changes in the elastic scattering, and anomalies in the temperature scaling of the shear viscosity. Finally, we introduce a compact BLS probe to rapidly perform measurements in plastic transport tubes. Our results open a broad avenue for PV diagnostics based on the high-frequency effective longitudinal PV and show that BLS can provide a means for its implementation.


Subject(s)
Blood Viscosity , COVID-19 , Humans , Blood Viscosity/physiology , COVID-19/blood , COVID-19/diagnosis , SARS-CoV-2 , Scattering, Radiation , Plasma/chemistry , Light , Rheology/methods , Male
4.
J Med Virol ; 96(7): e29801, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38988204

ABSTRACT

SARS-CoV-2 Omicron lineages continue to emerge and evolve into new sublineages, causing infection waves throughout 2022 and 2023, which has been attributed to immune escape. We examined neutralizing antibody responses to the recently emerged SARS-CoV-2 JN.1 variant in comparison to ancestral D614G and Omicron BA.1, BA.2, BA.5, and XBB.1.5 variants. We tested 79 human sera from cohorts with different combinations of vaccinations and infections, including 23 individuals who had been repeatedly exposed to Omicron. Individuals with a monovalent XBB.1.5 vaccine booster or XBB.1.5 breakthrough infection had robust antibody levels against all variants tested; however, JN.1 evaded antibodies in individuals after single Omicron BA.1, BA.2 or BA.5 breakthrough infections. Moreover, in the non-vaccinated cohort, serum antibodies demonstrated almost no cross-neutralization activities against D614G, XBB.1.5 and JN.1. after infections with earlier Omicron variants. These findings show that SARS-CoV-2-immunity is heterogeneous, depending on different combinations of vaccinations and infections, and emphasize the importance of considering different immune-backgrounds when evaluating novel variants.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , COVID-19 , Immunization, Secondary , SARS-CoV-2 , Humans , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , Antibodies, Viral/blood , SARS-CoV-2/immunology , SARS-CoV-2/genetics , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , Female , Male , Adult , Middle Aged , Vaccination , Neutralization Tests , Aged
5.
Diagnostics (Basel) ; 14(8)2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38667468

ABSTRACT

While neutralizing antibodies (nAbs) induced by monovalent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations are primarily directed against the wildtype (WT), subsequent exposure to the Omicron variants may increase the breadth of the antibodies' cross-neutralizing activity. Here, we analyzed the impact of an Omicron breakthrough infection (BTI) or a fourth monovalent mRNA vaccination on nAb profiles in people living with human immunodeficiency virus (PLWH). Using a multivariant surrogate virus neutralization test (sVNT), we quantified nAbs in 36 three-times vaccinated PLWH, of whom 9 acquired a serologically confirmed Omicron BTI, 8 received a fourth vaccine dose, and 19 were neither infected nor additionally vaccinated. While nAbs against WT and Delta increased after the BTI and a fourth vaccination, a significant increase against BA.1, BA.2, and BA.5 was only observed after the BTI. However, there was no significant difference in nAb concentrations between the samples obtained after the BTI and fourth vaccination. In contrast, nAb levels were significantly lower in PLWH, who were neither infected nor additionally vaccinated after three vaccinations. Thus, our study demonstrates the suitability of a multivariant sVNT to assess hybrid humoral immunity after Omicron BTIs in PLWH vaccinated against SARS-CoV-2.

6.
Vaccines (Basel) ; 12(1)2024 Jan 18.
Article in English | MEDLINE | ID: mdl-38250907

ABSTRACT

The capability of antibodies to neutralize different SARS-CoV-2 variants varies among individuals depending on the previous exposure to wild-type or Omicron-specific immunogens by mono- or bivalent vaccinations or infections. Such profiles of neutralizing antibodies (nAbs) usually have to be assessed via laborious live-virus neutralization tests (NTs). We therefore analyzed whether a novel multivariant surrogate-virus neutralization test (sVNT) (adapted from a commercial microarray) that quantifies the antibody-mediated inhibition between the receptor angiotensin-converting enzyme 2 (ACE2) and variant-specific receptor-binding domains (RBDs) can assess the neutralizing activity against the SARS-CoV-2 wild-type, and Delta Omicron BA.1, BA.2, and BA.5 subvariants after a booster with Omicron-adapted bivalent vaccines in a manner similar to live-virus NTs. Indeed, by using the live-virus NTs as a reference, we found a significant correlation between the variant-specific NT titers and levels of ACE2-RBD binding inhibition (p < 0.0001, r ≤ 0.78 respectively). Furthermore, the sVNTs identified higher inhibition values against BA.5 and BA.1 in individuals vaccinated with Omicron-adapted vaccines than in those with monovalent wild-type vaccines. Our data thus demonstrate the ability of sVNTs to detect variant-specific nAbs following a booster with bivalent vaccines.

8.
J Med Virol ; 95(11): e29245, 2023 11.
Article in English | MEDLINE | ID: mdl-38009693

ABSTRACT

Arthropod-borne flaviviruses include a number of medically relevant human pathogens such as the mosquito-borne dengue (DEN), Zika, and yellow fever (YF) viruses as well as tick-borne encephalitis virus (TBEV). All flaviviruses are antigenically related and anamnestic responses due to prior immunity can modulate antibody specificities in subsequent infections or vaccinations. In our study, we analyzed the induction of broadly flavivirus cross-reactive antibodies in tick-borne encephalitis (TBE) and DEN patients without or with prior flavivirus exposure through TBE and/or YF vaccination, and determined the contribution of these antibodies to TBE and dengue virus (DENV) neutralization. In addition, we investigated the formation of cross-reactive antibodies in TBE-vaccination breakthroughs (VBTs). A TBEV infection without prior YF or TBE vaccination induced predominantly type-specific antibodies. In contrast, high levels of broadly cross-reactive antibodies were found in samples from TBE patients prevaccinated against YF as well as in DEN patients prevaccinated against TBE and/or YF. While these cross-reactive antibodies did not neutralize TBEV, they were effective in neutralizing DENV. This discrepancy points to structural differences between the two viruses and indicates that broadly cross-reactive epitopes are less accessible in TBEV than in DENV. In TBE VBT infections, type-specific antibodies dominated the antibody response, thus revealing no difference from that of unvaccinated TBE patients. Our results emphasize significant differences in the structural properties of different flaviviruses that have an impact on the induction of broadly cross-reactive antibodies and their functional activities in virus neutralization.


Subject(s)
Dengue , Encephalitis Viruses, Tick-Borne , Encephalitis, Tick-Borne , Flavivirus Infections , Zika Virus Infection , Zika Virus , Animals , Humans , Encephalitis, Tick-Borne/prevention & control , Antibody Formation , Antibodies, Viral , Flavivirus Infections/prevention & control , Vaccination , Dengue/prevention & control
9.
iScience ; 26(11): 108146, 2023 Nov 17.
Article in English | MEDLINE | ID: mdl-37867935

ABSTRACT

Despite the similar clinical outcomes after renin-angiotensin system (RAS) inhibitor (RASi) continuation or withdrawal in COVID-19, the effects on angiotensin-converting enzyme 2 (ACE2) and RAS metabolites remain unclear. In a substudy of the randomized controlled Austrian Corona Virus Adaptive Clinical Trial (ACOVACT), patients with hypertension and COVID-19 were randomized 1:1 to either RASi continuation (n = 30) or switch to a non-RASi medication (n = 29). RAS metabolites were analyzed using a mixed linear regression model (n = 30). Time to a sustained clinical improvement was equal and ACE2 did not differ between the groups but increased over time in both. Overall ACE2 was higher with severe COVID-19. ACE-S and Ang II levels increased as expected with ACE inhibitor discontinuation. These data support the safety of RASi continuation in COVID-19, although RASi were frequently discontinued in our post hoc analysis. The study was not powered to draw definite conclusions on clinical outcomes using small sample sizes.

10.
J Autoimmun ; 140: 103118, 2023 Oct 10.
Article in English | MEDLINE | ID: mdl-37826919

ABSTRACT

BACKGROUND: The role of autoreactive T cells on the course of Coronavirus disease-19 (COVID-19) remains elusive. Type II pneumocytes represent the main target cells of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Autoimmune responses against antigens highly expressed in type II pneumocytes may influence the severity of COVID-19 disease. OBJECTIVE: The aim of this study was to investigate autoreactive T cell responses against self-antigens highly expressed in type II pneumocytes in the blood of COVID-19 patients with severe and non-severe disease. METHODS: We collected blood samples of COVID-19 patients with varying degrees of disease severity and of pre-pandemic controls. T cell stimulation assays with peptide pools of type II pneumocyte antigens were performed in two independent cohorts to analyze the autoimmune T cell responses in patients with non-severe and severe COVID-19 disease. Target cell lysis assays were performed with lung cancer cell lines to determine the extent of cell killing by type II PAA-specific T cells. RESULTS: We identified autoreactive T cell responses against four recently described self-antigens highly expressed in type II pneumocytes, known as surfactant protein A, surfactant protein B, surfactant protein C and napsin A, in the blood of COVID-19 patients. These antigens were termed type II pneumocyte-associated antigens (type II PAAs). We found that patients with non-severe COVID-19 disease showed a significantly higher frequency of type II PAA-specific autoreactive T cells in the blood when compared to severely ill patients. The presence of high frequencies of type II PAA-specific T cells in the blood of non-severe COVID-19 patients was independent of their age. We also found that napsin A-specific T cells from convalescent COVID-19 patients could kill lung cancer cells, demonstrating the functional and cytotoxic role of these T cells. CONCLUSIONS: Our data suggest that autoreactive type II PAA-specific T cells have a protective role in SARS-CoV-2 infections and the presence of high frequencies of these autoreactive T cells indicates effective viral control in COVID-19 patients. Type II-PAA-specific T cells may therefore promote the killing of infected type II pneumocytes and viral clearance.

11.
Biochemistry ; 62(17): 2517-2529, 2023 09 05.
Article in English | MEDLINE | ID: mdl-37554055

ABSTRACT

Antigen conformation shapes CD4+ T-cell specificity through mechanisms of antigen processing, and the consequences for immunity may rival those from conformational effects on antibody specificity. CD4+ T cells initiate and control immunity to pathogens and cancer and are at least partly responsible for immunopathology associated with infection, autoimmunity, and allergy. The primary trigger for CD4+ T-cell maturation is the presentation of an epitope peptide in the MHC class II antigen-presenting protein (MHCII), most commonly on an activated dendritic cell, and then the T-cell responses are recalled by subsequent presentations of the epitope peptide by the same or other antigen-presenting cells. Peptide presentation depends on the proteolytic fragmentation of the antigen in an endosomal/lysosomal compartment and concomitant loading of the fragments into the MHCII, a multistep mechanism called antigen processing and presentation. Although the role of peptide affinity for MHCII has been well studied, the role of proteolytic fragmentation has received less attention. In this Perspective, we will briefly summarize evidence that antigen resistance to unfolding and proteolytic fragmentation shapes the specificity of the CD4+ T-cell response to selected viral envelope proteins, identify several remarkable examples in which the immunodominant CD4+ epitopes most likely depend on the interaction of processing machinery with antigen conformation, and outline how knowledge of antigen conformation can inform future efforts to design vaccines.


Subject(s)
CD4-Positive T-Lymphocytes , Epitopes, T-Lymphocyte , CD4-Positive T-Lymphocytes/metabolism , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/metabolism , Viral Fusion Proteins/metabolism , Histocompatibility Antigens Class II/metabolism , Antigen Presentation , Immunodominant Epitopes/chemistry , Immunodominant Epitopes/metabolism
12.
NPJ Vaccines ; 8(1): 110, 2023 Aug 04.
Article in English | MEDLINE | ID: mdl-37542025

ABSTRACT

We report SARS-CoV-2 neutralizing antibody titers in sera of triple-vaccinated individuals who received a booster dose of an original monovalent or a bivalent BA.1- or BA.4/BA.5-adapted vaccine or had a breakthrough infection with Omicron variants BA.1, BA.2 or BA.4/BA.5. A bivalent BA.4/BA.5 booster or Omicron-breakthrough infection induced increased Omicron-neutralization titers compared with the monovalent booster. The XBB.1.5 variant effectively evaded neutralizing-antibody responses elicited by current vaccines and/or infection with previous variants.

13.
Diagnostics (Basel) ; 13(13)2023 Jul 05.
Article in English | MEDLINE | ID: mdl-37443672

ABSTRACT

Primary infection with the Omicron variant of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) can be serologically identified with distinct profiles of neutralizing antibodies (nAbs), as indicated by high titers against the Omicron variant and low titers against the ancestral wild-type (WT). Here, we evaluated whether a novel surrogate virus neutralization assay (sVNT) that simultaneously quantifies the binding inhibition of angiotensin-converting enzyme 2 (ACE2) to the proteins of the WT- and Omicron-specific receptor-binding domains (RBDs) can identify nAb profiles after primary Omicron infection with accuracy similar to that of variant-specific live-virus neutralization tests (NTs). Therefore, we comparatively tested 205 samples from individuals after primary infection with the Omicron variant and the WT, and vaccinated subjects with or without Omicron breakthrough infections. Indeed, variant-specific RBD-ACE2 binding inhibition levels significantly correlated with respective NT titers (p < 0.0001, Spearman's r = 0.92 and r = 0.80 for WT and Omicron, respectively). In addition, samples from individuals after primary Omicron infection were securely identified with the sVNT according to their distinctive nAb profiles (area under the curve = 0.99; sensitivity: 97.2%; specificity: 97.84%). Thus, when laborious live-virus NTs are not feasible, the novel sVNT we evaluated in this study may serve as an acceptable substitute for the serological identification of individuals with primary Omicron infection.

14.
J Med Virol ; 95(6): e28830, 2023 06.
Article in English | MEDLINE | ID: mdl-37282809

ABSTRACT

In 2022, Austria experienced a severe respiratory syncytial virus (RSV) epidemic with an earlier-than-usual start (Weeks 35/2021-45/2022) and increased numbers of pediatric patients in emergency departments. This surge came 2 years after a season with no cases detected as a result of coronavirus disease 2019 nonpharmaceutical interventions. We analyzed epidemiologic patterns and the phylodynamics of RSV based on approximately 30 800 respiratory specimens collected year-round over 10 years from ambulatory and hospitalized patients from 248 locations in Austria. Genomic surveillance and phylogenetic analysis of 186 RSV-A and 187 RSV-B partial glycoprotein sequences collected from 2018 to 2022 revealed that the 2022/2023 surge was driven by RSV-B in contrast to the surge in the 2021/2022 season that was driven by RSV-A. Whole-genome sequencing and phylodynamic analysis indicated that the RSV-B strain GB5.0.6a was the predominant genotype in the 2022/2023 season and emerged in late 2019. The results provide insight into RSV evolution and epidemiology that will be applicable to future monitoring efforts with the advent of novel vaccines and therapeutics.


Subject(s)
COVID-19 , Respiratory Syncytial Virus Infections , Respiratory Syncytial Viruses , Child , Humans , Austria/epidemiology , COVID-19/epidemiology , Epidemiological Monitoring , Evolution, Molecular , Genotyping Techniques , Molecular Epidemiology , Phylogeny , Respiratory Syncytial Virus Infections/epidemiology , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Viruses/classification , Respiratory Syncytial Viruses/genetics , Respiratory Syncytial Viruses/isolation & purification , Whole Genome Sequencing
15.
Microbiol Spectr ; 11(1): e0231422, 2023 02 14.
Article in English | MEDLINE | ID: mdl-36622205

ABSTRACT

Neutralizing antibodies (nAbs) are considered a valuable marker for measuring humoral immunity against SARS-CoV-2. However, live-virus neutralization tests (NTs) require high-biosafety-level laboratories and are time-consuming. Therefore, surrogate virus neutralization tests (sVNTs) have been widely applied, but unlike most anti-spike (S) antibody assays, NTs and sVNTs are not harmonized, requiring further evaluation and comparative analyses. This study compared seven commercial sVNTs and anti-S-antibody assays with a live-virus NT as a reference, using a panel of 720 single and longitudinal serum samples from 666 convalescent patients after SARS-CoV-2 infection. The sensitivity of these assays for detecting antibodies ranged from 48 to 94% after PCR-confirmed infection and from 56% to 100% relative to positivity in the in-house live-virus NT. Furthermore, we performed receiver operating characteristic (ROC) curve analyses to determine which immunoassays were most suitable for assessing nAb titers exceeding a specific cutoff (NT titer, ≥80) and found that the NeutraLISA and the cPass assays reached the highest area under the curve (AUC), exceeding 0.91. In addition, when the assays were compared for their correlation with nAb kinetics over time in a set of longitudinal samples, the extent of the measured decrease of nAbs after infection varied widely among the evaluated immunoassays. Finally, in vaccinated convalescent patients, high titers of nAbs exceeded the upper limit of the evaluated assays' quantification ranges. Based on data from this study, we conclude that commercial immunoassays are acceptable substitutes for live-virus NTs, particularly when additional adapted cutoffs are employed to detect nAbs beyond a specific threshold titer. IMPORTANCE While the measurement of neutralizing antibodies is considered a valuable tool in assessing protection against SARS-CoV-2, neutralization tests employ live-virus isolates and cell culture, requiring advanced laboratory biosafety levels. Including a large sample panel (over 700 samples), this study provides adapted cutoff values calculated for seven commercial immunoassays (including four surrogate neutralization assays and a protein-based microarray) that robustly correlate with specific titers of neutralizing antibodies.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , COVID-19/diagnosis , Antibodies, Neutralizing , Neutralization Tests , Immunoglobulin G , Antibodies, Viral
16.
Ann Rheum Dis ; 82(2): 292-300, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36109141

ABSTRACT

OBJECTIVES: A third COVID-19 vaccination is recommended for immunosuppressed patients. However, data on immunogenicity and safety of a third COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMIDs) are sparse and therefore addressed within this clinical trial. METHODS: 60 immunosuppressed patients and 48 healthy controls (HCs) received a third vaccination with an mRNA vaccine. The primary endpoint was defined as the presence of antibody levels against the receptor-binding domain (RBD)>1500 BAU/mL in patients with IMIDs versus HCs. Further endpoints included differences in neutralising antibodies and cellular immune responses after the third vaccination. Reactogenicity was recorded for 7 days, and safety was evaluated until week 4. RESULTS: Rate of individuals with anti-RBD antibodies>1500 BAU/mL was not significantly different after the third vaccination between patients with IMIDs and HCs (91% vs 100% p=0.101). Anti-RBD and neutralising antibody levels were significantly lower in patients with IMIDs after the third vaccination than in HCs (p=0.002 and p=0.016, respectively). In contrast, fold increase in antibody levels between week 0 and 4 was higher in patients with IMIDs. Treatment with biological (b) disease-modifying anti-rheumatic drugs (DMARD) or combination of bDMARDs and conventional synthetic DMARDs was associated with reduced antibody levels. Enhanced cellular immune response to wild type and Omicron peptide stimulation was observed after the third vaccination. No serious adverse event was attributed to the third vaccination. CONCLUSION: Our clinical trial data support the immunogenicity and safety of a third COVID-19 vaccination in patients with IMIDs. However, effects of DMARD therapy on immunogenicity should be considered. TRIAL REGISTRATION NUMBER: EudraCT No: 2021-002693-10.


Subject(s)
COVID-19 Vaccines , Humans , Antibodies, Viral , Antirheumatic Agents , COVID-19 , COVID-19 Vaccines/adverse effects , Immunogenicity, Vaccine , Immunomodulating Agents , Vaccination
17.
Sci Rep ; 12(1): 20117, 2022 11 22.
Article in English | MEDLINE | ID: mdl-36418458

ABSTRACT

SARS-CoV-2 gains cell entry via angiotensin-converting enzyme (ACE) 2, a membrane-bound enzyme of the "alternative" (alt) renin-angiotensin system (RAS). ACE2 counteracts angiotensin II by converting it to potentially protective angiotensin 1-7. Using mass spectrometry, we assessed key metabolites of the classical RAS (angiotensins I-II) and alt-RAS (angiotensins 1-7 and 1-5) pathways as well as ACE and ACE2 concentrations in 159 patients hospitalized with COVID-19, stratified by disease severity (severe, n = 76; non-severe: n = 83). Plasma renin activity (PRA-S) was calculated as the sum of RAS metabolites. We estimated ACE activity using the angiotensin II:I ratio (ACE-S) and estimated systemic alt-RAS activation using the ratio of alt-RAS axis metabolites to PRA-S (ALT-S). We applied mixed linear models to assess how PRA-S and ACE/ACE2 concentrations affected ALT-S, ACE-S, and angiotensins II and 1-7. Median angiotensin I and II levels were higher with severe versus non-severe COVID-19 (angiotensin I: 86 versus 30 pmol/L, p < 0.01; angiotensin II: 114 versus 58 pmol/L, p < 0.05), demonstrating activation of classical RAS. The difference disappeared with analysis limited to patients not taking a RAS inhibitor (angiotensin I: 40 versus 31 pmol/L, p = 0.251; angiotensin II: 76 versus 99 pmol/L, p = 0.833). ALT-S in severe COVID-19 increased with time (days 1-6: 0.12; days 11-16: 0.22) and correlated with ACE2 concentration (r = 0.831). ACE-S was lower in severe versus non-severe COVID-19 (1.6 versus 2.6; p < 0.001), but ACE concentrations were similar between groups and correlated weakly with ACE-S (r = 0.232). ACE2 and ACE-S trajectories in severe COVID-19, however, did not differ between survivors and non-survivors. Overall RAS alteration in severe COVID-19 resembled severity of disease-matched patients with influenza. In mixed linear models, renin activity most strongly predicted angiotensin II and 1-7 levels. ACE2 also predicted angiotensin 1-7 levels and ALT-S. No single factor or the combined model, however, could fully explain ACE-S. ACE2 and ACE-S trajectories in severe COVID-19 did not differ between survivors and non-survivors. In conclusion, angiotensin II was elevated in severe COVID-19 but was markedly influenced by RAS inhibitors and driven by overall RAS activation. ACE-S was significantly lower with severe COVID-19 and did not correlate with ACE concentrations. A shift to the alt-RAS axis because of increased ACE2 could partially explain the relative reduction in angiotensin II levels.


Subject(s)
COVID-19 , Peptide Hormones , Humans , Angiotensin-Converting Enzyme 2 , Renin-Angiotensin System , Angiotensin I , Angiotensin II , SARS-CoV-2 , Renin , Antihypertensive Agents
19.
Nat Commun ; 13(1): 5362, 2022 09 12.
Article in English | MEDLINE | ID: mdl-36097029

ABSTRACT

Impaired response to COVID-19 vaccination is of particular concern in immunosuppressed patients. To determine the best vaccination strategy for this vulnerable group we performed a single center, 1:1 randomized blinded clinical trial. Patients who failed to seroconvert upon two mRNA vaccinations (BNT162b2 or mRNA-1273) are randomized to receive either a third dose of the same mRNA or the vector vaccine ChAdOx1 nCoV-19. Primary endpoint is the difference in SARS-CoV-2 spike antibody seroconversion rate between vector and mRNA vaccinated patients four weeks after the third dose. Secondary outcomes include cellular immune responses. Seroconversion rates at week four are significantly higher in the mRNA (homologous vaccination, 15/24, 63%) as compared to the vector vaccine group (heterologous vaccination, 4/22, 18%). SARS-CoV-2-specific T-cell responses are reduced but could be increased after a third dose of either vector or mRNA vaccine. In a multivariable logistic regression analysis, patient age and vaccine type are associated with seroconversion. No serious adverse event is attributed to COVID-19 booster vaccination. Efficacy and safety data underline the importance of a booster vaccination and support the use of a homologous mRNA booster vaccination in immunosuppressed patients.Trial registration: EudraCT No.: 2021-002693-10.


Subject(s)
BNT162 Vaccine , COVID-19 Vaccines , COVID-19 , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , ChAdOx1 nCoV-19 , Humans , Immunization, Secondary , RNA, Messenger , SARS-CoV-2/genetics , Vaccination , Vaccines, Synthetic , mRNA Vaccines
20.
Front Immunol ; 13: 946318, 2022.
Article in English | MEDLINE | ID: mdl-35928813

ABSTRACT

Background and Methods: The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Omicron (B.1.1.529) variant is the antigenically most distinct variant to date. As the heavily mutated spike protein enables neutralization escape, we studied serum-neutralizing activities of naïve and vaccinated individuals after Omicron BA.1 or BA.2 sub-lineage infections in live virus neutralization tests with Omicron BA.1, Omicron BA.2, wildtype (WT, B1.1), and Delta (B.1.617.2) strains. Serum samples obtained after WT infections and three-dose mRNA vaccinations with and without prior infection were included as controls. Results: Primary BA.1 infections yielded reduced neutralizing antibody levels against WT, Delta, and Omicron BA.2, while samples from BA.2-infected individuals showed almost no cross-neutralization against the other variants. Serum neutralization of Omicron BA.1 and BA.2 variants was detectable after three-dose mRNA vaccinations, but with reduced titers. Vaccination-breakthrough infections with either Omicron BA.1 or BA.2, however, generated equal cross-neutralizing antibody levels against all SARS-CoV-2 variants tested. Conclusions: Our study demonstrates that although Omicron variants are able to enhance cross-neutralizing antibody levels in pre-immune individuals, primary infections with BA.1 or BA.2 induced mostly variant-specific neutralizing antibodies, emphasizing the differently shaped humoral immunity induced by the two Omicron variants. These data thus contribute substantially to the understanding of antibody responses induced by primary Omicron infections or multiple exposures to different SARS-CoV-2 variants and are of particular importance for developing vaccination strategies in the light of future emerging variants.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , Broadly Neutralizing Antibodies , Humans , Membrane Glycoproteins , Neutralization Tests , RNA, Messenger , Spike Glycoprotein, Coronavirus/genetics , Viral Envelope Proteins
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