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1.
researchsquare; 2022.
Preprint in English | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-2272601.v1

ABSTRACT

Background: Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressants (ISPs) may have impaired long-term humoral immune responses and increased disease activity after SARS-CoV-2 infection. We aimed to investigate long-term humoral immune responses against SARS-CoV-2 and increased disease activity after a primary SARS-CoV-2 infection in unvaccinated IMID patients on ISPs. Methods: IMID patients on active treatment with ISPs and controls (i.e. IMID patients not on ISP and healthy controls) with a confirmed SARS-CoV-2 infection before first vaccination were included from an ongoing prospective cohort study (T2B! study). Clinical data on infections and increased disease activity were registered using electronic surveys and health records. A serum sample was collected before first vaccination to measure SARS-CoV-2 anti-receptor-binding domain (RBD) antibodies. Results: In total, 193 IMID patients on ISP and 113 controls were included. Serum samples from 185 participants were available, with a median time of 173 days between infection and sample collection. The rate of seropositive IMID patients on ISPs was 78% compared to 100% in controls (p<0.001). Seropositivity rates were lowest in patients on anti-CD20 (40.0%) and anti-tumor necrosis factor (TNF) agents (60.5%), as compared to other ISPs (p<0.001 and p<0.001, respectively). Increased disease activity after infection was reported by 68 of 260 patients (26.2%; 95% CI 21.2–31.8%), leading to ISP intensification in 6 out of these 68 patients (8.8%). Conclusion: IMID patients using ISPs showed reduced long-term humoral immune responses after primary SARS-CoV-2 infection, which was mainly attributed to treatment with anti-CD20 and anti-TNF agents. Increased disease activity after SARS-CoV-2 infection was reported commonly, but was mostly mild. Trial registration NL74974.018.20, Trial ID: NL8900. Registered on 9 September 2020.

2.
biorxiv; 2022.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2022.02.14.480353

ABSTRACT

The onset of severe SARS-CoV-2 infection is characterized by the presence of afucosylated IgG1 responses against the viral spike (S) protein, which can trigger exacerbated inflammatory responses. Here, we studied IgG glycosylation after BNT162b2 SARS-CoV-2 mRNA vaccination to explore whether vaccine-induced S protein expression on host cells also generates afucosylated IgG1 responses. SARS-CoV-2 naive individuals initially showed a transient afucosylated anti-S IgG1 response after the first dose, albeit to a lower extent than severely ill COVID-19 patients. In contrast, previously infected, antigen-experienced individuals had low afucosylation levels, which slightly increased after immunization. Afucosylation levels after the first dose correlated with low fucosyltransferase 8 (FUT8) expression levels in a defined plasma cell subset. Remarkably, IgG afucosylation levels after primary vaccination correlated significantly with IgG levels after the second dose. Further studies are needed to assess efficacy, inflammatory potential, and protective capacity of afucosylated IgG responses.

3.
ssrn; 2021.
Preprint in English | PREPRINT-SSRN | ID: ppzbmed-10.2139.ssrn.3937574

ABSTRACT

Background: Research on the disease severity of COVID-19 in patients with rheumatic immune-mediated inflammatory diseases (IMIDs) has been inconclusive, and long-term prospective data on the development of SARS-CoV-2 antibodies in these patients are lacking. We conducted an investigator-driven prospective cohort study to compare the disease severity of COVID-19, and the development of SARS-CoV-2 antibodies over time between patients with rheumatic IMIDs and healthy controls.Methods: Adult patients with rheumatic IMIDs from the Amsterdam Rheumatology & immunology Center, Amsterdam were invited to participate. All patients were asked to recruit their own sex- and age-matched control subject. We developed a new platform for collecting clinical data in large patient groups with online questionnaires (at baseline, and after 1-4 and 5-9 months of follow-up). Serum samples were collected two times during follow-up; after completing the follow-up questionnaires and prior to COVID-19 vaccination. All serum samples were analyzed for the presence of SARS-CoV-2 specific antibodies with a total-antibody bridging ELISA. IgG titers were quantified in samples with a positive test result in the bridging assay. Logistic regression analyses, and linear and logistic mixed model analyses were used to compare COVID-19 related hospitalization rates, proportions of SARS-CoV-2 seropositivity and IgG antibody titers between patients and controls, and between patients stratified for major immunosuppressive drug categories (i.e. biological [b] or conventional synthetic [cs] disease modifying anti-rheumatic drugs [DMARDs]).Findings: In total, 3080 consecutive patients and 1102 healthy controls with comparable age and sex distribution were included for analyses. The incidence of COVID-19 was slightly lower in patients compared to controls (14.7% vs. 16.0% had detectable SARS-CoV-2 antibodies), but patients were more frequently hospitalized compared to controls; 23 of 347 (7%) patients vs. 1 of 134 (0.7%) controls (adjusted OR: 7.33, 95% CI: 0.96 – 55.77, P 0.055). Three (13%) of 23 patients were admitted to the intensive care unit (ICU), and one of these died. Only treatment with B-cell targeting therapy was independently associated with an increased risk of COVID-19 related hospitalization (adjusted OR: 14.62, 95% CI: 2.31 – 92.39, P 0.004). Proportions of SARS-CoV-2 seropositivity in participants with a PCR confirmed COVID-19 diagnosis were similar for patients and controls ( P 0.73), and did not significantly decrease during the first twelve months after infection ( P 0.10). IgG antibody titers were higher in hospitalized patients compared to non-hospitalized patients, and slowly declined with time (rate per month: 0.86, 95% CI: 0.81 – 0.91, P < 0.0001) in similar patterns for patients in all treatment subgroups and controls.Interpretation: We observed that patients with rheumatic IMIDs, especially those treated with B-cell targeting therapy, were more likely to be hospitalized when infected with SARS-CoV-2, although subsequent ICU admissions and/or death were infrequent. In addition, treatment with cs- or bDMARDs other than B-cell targeting agents is unlikely to have negative effects on the development of long-lasting humoral immunity against SARS-CoV-2.Funding Information: ZonMw and Reade Foundation.Declaration of Interests: None to declare. Ethics Approval Statement: The research protocol was approved by the medical ethical committee of the VU University medical center (registration number 2020.169). All participants gave written informed consent.

4.
medrxiv; 2021.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2021.01.06.20249035

ABSTRACT

The novel SARS-CoV-2 virus emerged in late 2019 and has caused a global health and economic crisis. The characterization of the human antibody response to SARS-CoV-2 infection is vital for serosurveillance purposes as well for treatment options such as transfusion with convalescent plasma or immunoglobin products derived from convalescent plasma. In this study, we measured antibody responses in 844 longitudinal samples from 151 RT-PCR positive SARS-CoV-2 convalescent adults during the first 34 weeks after onset of symptoms. All donors were seropositive at the first sampling moment and only one donor seroreverted during follow-up analysis. Anti-RBD IgG and anti-nucleocapsid IgG levels slowly declined with median half-lifes of 62 and 59 days during 2-5 months after symptom onset, respectively. The rate of decline of antibody levels diminished during extended follow-up. In addition, the magnitude of the IgG response correlated with neutralization capacity measured in a classic plaque reduction assay as well in our in-house developed competition assay. The result of this study gives valuable insight into the longitudinal response of antibodies to SARS-CoV-2.

5.
biorxiv; 2021.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2021.01.06.425544

ABSTRACT

The non-linear progression of new infection numbers in a pandemic poses challenges to the evaluation of its management. The tools of complex systems research may aid in attaining information that would be difficult to extract with other means. To study the COVID-19 pandemic, we utilize the reported new cases per day for the globe, nine countries and six US states through October 2020. Fourier and univariate wavelet analyses inform on periodicity and extent of change. Evaluating time-lagged data sets of various lag lengths, we find that the autocorrelation function, average mutual information and box counting dimension represent good quantitative readouts for the progression of new infections. Bivariate wavelet analysis and return plots give indications of containment versus exacerbation. Homogeneity or heterogeneity in the population response, uptick versus suppression, and worsening or improving trends are discernible, in part by plotting various time lags in three dimensions. The analysis of epidemic or pandemic progression with the techniques available for observed (noisy) complex data can aid decision making in the public health response.

6.
medrxiv; 2020.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2020.06.17.20133793

ABSTRACT

SARS-CoV-2 infections often cause only mild disease that may evoke relatively low antibody titers compared to patients admitted to hospitals. Generally, total antibody bridging assays combine good sensitivity with high selectivity. Therefore, we developed sensitive total antibody bridging assays for detection of SARS-CoV-2 antibodies to the receptor-binding domain (RBD) and nucleocapsid protein (NP), in addition to conventional isotype-specific assays. Antibody kinetics was assessed in PCR-confirmed hospitalized COVID-19 patients (n=41) and three populations of patients with COVID-19 symptoms not requiring hospital admission: PCR-confirmed convalescent plasmapheresis donors (n=182), PCR-confirmed hospital care workers (n=47), and a group of longitudinally sampled symptomatic individuals highly suspect of COVID-19 (n=14). In non-hospitalized patients, the antibody response to RBD is weaker but follows similar kinetics as has been observed in hospitalized patients. Across populations, the RBD bridging assay identified most patients correctly as seropositive. In 11/14 of the COVID-19-suspect cases, seroconversion in the RBD bridging assay could be demonstrated before day 12; NP antibodies emerged less consistently. Furthermore, we demonstrated the feasibility of finger prick sampling for antibody detection against SARS-CoV-2 using these assays. In conclusion, the developed bridging assays reliably detect SARS-CoV-2 antibodies in hospitalized and non-hospitalized patients, and are therefore well-suited to conduct seroprevalence studies.

7.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.06.18.159202

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic. Understanding both the immunological processes providing specific immunity and potential immunopathology underlying the pathogenesis of this disease may provide valuable insights for potential therapeutic interventions. Here, we quantified SARS-CoV-2 specific immune responses in patients with different clinical courses. Compared to individuals with a mild clinical presentation, CD4+ T cell responses were qualitatively impaired in critically ill patients. Strikingly, however, in these patients the specific IgG antibody response was remarkably strong. The observed disparate T and B cell responses could be indicative of a deregulated immune response in critically ill COVID-19 patients.

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