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1.
Annals of the Rheumatic Diseases ; 81:367-368, 2022.
Article in English | EMBASE | ID: covidwho-2008923

ABSTRACT

Background: Rheumatic musculoskeletal diseases (RMD) are pathological conditions characterized by an impaired immunological system that is determinant both in the pathogenesis and in the inadequate response to infections. The use of disease-modifying anti-rheumatic drugs (DMARDs), which include conventional synthetic (cs) or biologic and targeted synthetic (b/ts) DMARDs, contribute to compromise immunological reactivity. Objectives: To analyze the immune response to SARS-CoV-2 in patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA) receiving treatment with DMARDs and to investigate the effect of the different classes of drugs on humoral and cellular response. Methods: Patients were tested for anti-SARS-CoV-2 IgG, IgM and IgA antibodies to nucleoprotein (N) and receptor-binding domain (RBD) through ELISA and neutralization assays. Then, we performed a fow cytometry analysis of monocytes, NK cells, B and T lymphocytes from PBMCs of serologically positive patients. We also included a cohort of non-RMD individuals recovered from COVID-19 as a reference group of non-immunosuppressed subjects. A frst recruitment occurred in May-June 2020 (T1) and a second recruitment, 3-4 months after (T2), allowed to evaluate the persistence of the antibody response over time and to investigate the cellular immune response to SARS-CoV-2 in RMD patients having resolved the infection. Results: During T1, 358 patients with RA (n=200) or SpA (n=158) were recruited. Mean age was 52.8, 64% were female. All patients were treated with DMARDs, 299 with b/tsDMARDs and 59 received csDMARDs alone. One third was also receiving corticosteroids (CS). At T2, 36 subjects were recruited. We found a seroprevalence rate of 18.4%, which did not signifcantly differ between RA and SpA groups, and between patients treated with b/ts-DMARD or csDMARDs, either alone or in combination with CS (Table 1). Antibody levels of RMD patients were lower than non-RMD individuals (Figure 1), with CTLA4-Ig-treated patients having the lowest IgG levels. This difference was less marked in symptomatic RMD patients. 72% of seropositive patients elicited neutralizing sera. Despite an overall decrease in anti-RBD and anti-N titers, more than two-third of patients maintained antibodies titers above positivity threshold at T2. Concerning cellular response, we found that CD8+ T-cells frequency was overall comparable between RMD and non-RMD convalescents, and did not differ in b-or cs-DMARD treated ones. Conversely, CD4+ T-cell frequencies were signifcantly lower in RMD patients, especially those treated with anti-IL6R and CTLA4-Ig. B-cell subpopulations (class-switched, memory, and IgG+ memory B-cells) had sustained frequencies in anti-TNFα treated patients, while they had a trend of reduction in patients treated with anti-IL6R and CTLA4-Ig. Conclusion: Our data provide a comprehensive picture of the humoral and cellular immune responses to SARS-CoV-2 infection in RMD patients. We showed that DMARDs treatments did not alter a successful antibody response to the virus and did not hamper the antibody neutralizing ability. However, the magnitude of antibody response was slightly reduced compared to non-RMD individuals, especially in patients receiving CTLA4-Ig. We did not observe marked differences in the B-and T-cell populations between RMD patients compared to non-RMD individuals. However, in patients receiving anti-TNFα we found a higher relative abundance of effector adaptive population compared to other bDMARDs.

3.
Embase;
Preprint in English | EMBASE | ID: ppcovidwho-326896

ABSTRACT

Numerous safe and effective COVID-19 vaccines have been developed that utilize various delivery technologies and engineering strategies. The influence of the SARS-CoV2 spike (S) glycoprotein conformation on antibody responses induced by vaccination or infection in humans remains unknown. To address this question, we compared plasma antibodies elicited by six globally-distributed vaccines or infection and observed markedly higher binding titers for vaccines encoding a prefusion-stabilized S relative to other groups. Prefusion S binding titers positively correlated with plasma neutralizing activity, indicating that physical stabilization of the prefusion conformation enhances protection against SARS-CoV-2. We show that almost all plasma neutralizing activity is directed to prefusion S, in particular the S1 subunit, and that variant cross-neutralization is mediated solely by RBD-specific antibodies. Our data provide a quantitative framework for guiding future S engineering efforts to develop vaccines with higher resilience to the emergence of variants and longer durability than current technologies.

4.
Embase;
Preprint in English | EMBASE | ID: ppcovidwho-326798

ABSTRACT

The recently emerged SARS-CoV-2 Omicron variant harbors 37 amino acid substitutions in the spike (S) protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody therapeutics. Here, we show that the Omicron RBD binds to human ACE2 with enhanced affinity relative to the Wuhan-Hu-1 RBD and acquires binding to mouse ACE2. Severe reductions of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for vaccinated and convalescent individuals. Most (26 out of 29) receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only three mAbs, including the ACE2-mimicking S2K146 mAb1, retaining unaltered potency. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs recognizing antigenic sites outside the RBM, including sotrovimab2, S2X2593and S2H974, neutralized Omicron. The magnitude of Omicron-mediated immune evasion and the acquisition of binding to mouse ACE2 mark a major SARS-CoV-2 mutational shift. Broadly neutralizing sarbecovirus mAbs recognizing epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.

5.
Annals of the Rheumatic Diseases ; 80(SUPPL 1):229, 2021.
Article in English | EMBASE | ID: covidwho-1358667

ABSTRACT

Background: Emerging observational data have shown that rheumatic patients seem not to be more susceptible to SARS-CoV-2 infection neither to worse outcomes. However, the true prevalence of COVID19 is still unknown due to the high proportion of subclinical infection. In this scenario, measuring the seroprevalence of SARS-CoV-2 may be crucial to improve the knowledge about the impact of COVID19 in rheumatic patients. Objectives: To estimate in a COVID19 high-endemic area (Lombardy, Italy) the prevalence of anti-SARS-CoV-2 antibodies in a large cohort of patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA) treated with biologic (b-) or targeted synthetic (ts-) disease modifying drugs (DMARDs). Methods: A seroprevalence cross-sectional study was conducted in the period between 4th May and 16th June 2020, including patients with confirmed RA or SpA treated with b-or tsDMARDs. Patients were tested for anti-SARS-CoV-2 IgG, IgM and IgA antibodies against main viral antigens (nucleoprotein [N], spike 1 [S1], receptor-binding domain [RBD]) using ELISA. These data were compared with those observed in the healthy population in the same period and region. Patients also answered a questionnaire on history of symptoms consistent with COVID19, risk factors and comorbidities. Serological response to RBD was evaluated according to symptom severity (asymptomatic, minor, or major [respiratory and fever >37.5°C] symptoms). Results: The study population included 300 patients (62% females, mean age 53 years, 20% over 65 years old) diagnosed with RA (56%), psoriatic arthritis (23%), or ankylosing spondylitis (21%), treated with anti-TNF (57%), abatacept (20%), anti-IL6 (11%), or JAK inhibitors (5%). Four patients (1.3%) referred a prior diagnosis of COVID19 defined by nasopharyngeal swab. Immunoglobulin titers were evaluated resulting in 9%, 13.6%, and 13.3% positive patients for IgG, IgM and IgA, respectively (Table 1), with no significant difference to the healthy population. Among seropositive patients, 55.3% were asymptomatic, 16% had minor and 19.6% major symptoms, 7.1% were hospitalized. No deaths or admission to intensive care units occurred. IgM, IgG and IgA titers to RBD were higher in patients with both minor and major symptoms compared with asymptomatic ones (Figure 1). No differences were found between seronegative and seropositive patients in relation to age, sex, rheumatic diagnosis, and treatments with b-or tsDMARDs. A relative lower risk of seropositivity was observed in patients receiving concomitant methotrexate (RR 0.49, 95% CI 0.25-0.94;p 0.04), while an increased risk was associated with obesity (RR 2.33, 95% CI 1.26-3.79;p 0.019) and presence of at least 2 comorbidities (RR 1.94, 95% CI 1.11-3.15;p 0.037). Corticosteroids use was numerically more frequent in seropositive than seronegative patients (18% vs 14%). Conclusion: This study confirms that, even in a cohort of rheumatic patients, the spread of SARS-CoV-2 infection is much greater than that observed by capturing only swab-diagnosed COVID19 cases. The underlying rheumatic disease and ongoing therapy with b/ts-DMARDs do not seem to impact SARS-CoV-2 antibody positivity, which conversely seems to be proportional to the intensity of COVID19 symptoms and less frequent in patients receiving concomitant methotrexate. The project was co-financed by Lombardy Region 2014-2020 Regional Operational Programme under the European Regional Development Fund.

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