Abstract Immune responses in people with multiple sclerosis (pwMS) on disease-modifying therapies (DMTs) have been of significant interest throughout the COVID-19 pandemic. Lymphocyte-targeting immunotherapies including anti-CD20 treatments and sphingosine-1-phosphate receptor (S1PR) modulators attenuate antibody responses after vaccination. Evaluation of cellular responses after vaccination is therefore of particular importance in these populations. In this study, we analysed CD4 and CD8 T cell functional responses to SARS-CoV-2 spike peptides in healthy controls and pwMS on five different DMTs by flow cytometry. Although pwMS on anti-CD20 and S1PR therapies had low antibody responses after both 2 and 3 vaccine doses, T cell responses in pwMS on anti-CD20 therapies were preserved after a third vaccination, even when additional anti-CD20 treatment was administered between vaccine doses 2 and 3. PwMS taking S1PR modulators had low detectable T cell responses in peripheral blood. CD4 and CD8 T cell responses to SARS-CoV-2 variants of concern Delta and Omicron were lower than to the ancestral Wuhan-Hu-1 variant. Our results indicate the importance of assessing both cellular and humoral responses after vaccination and suggest that even in the absence of robust antibody responses vaccination can generate immune responses in pwMS.
Abstract Diagnostic assays currently used to monitor the efficacy of COVID-19 vaccines measure levels of antibodies to the receptor-binding domain of ancestral SARS-CoV-2 (RBDwt). However, the predictive value for protection against new variants of concern (VOCs) has not been firmly established. Here, we used bead-based arrays and flow cytometry to measure binding of antibodies to spike proteins and receptor-binding domains (RBDs) from VOCs in 12,000 sera. Effects of sera on RBD-ACE2 interactions were measured as a proxy for neutralizing antibodies. The samples were obtained from healthy individuals or patients on immunosuppressive therapy who had received two to four doses of COVID-19 vaccines and from COVID-19 convalescents. The results show that anti-RBDwt titers correlate with the levels of binding- and neutralizing antibodies against the Alpha, Beta, Gamma, Delta, Epsilon and Omicron variants. The benefit of multiplexed analysis lies in the ability to measure a wide range of anti-RBD titers using a single dilution of serum for each assay. The reactivity patterns also yield an internal reference for neutralizing activity and binding antibody units per milliliter (BAU/ml). Results obtained with sera from vaccinated healthy individuals and patients confirmed and extended results from previous studies on time-dependent waning of antibody levels and effects of immunosuppressive agents. We conclude that anti-RBDwt titers correlate with levels of neutralizing antibodies against VOCs and propose that our method may be implemented to enhance the precision and throughput of immunomonitoring.
Background: Understanding cellular responses to SARS-CoV-2 immunisations is important for informing vaccine recommendations in patients with inflammatory bowel disease (IBD) and other vulnerable patients on immunosuppressive therapies. This study investigated the magnitude and quality of T cell responses after multiple SARS-CoV-2 vaccine doses and COVID-19 breakthrough infection. Methods: This prospective, observational study included patients with IBD and arthritis on tumour necrosis factor inhibitors (TNFi) receiving up to four SARS-CoV-2 vaccine doses. T cell responses to SARS-CoV-2 peptides were measured by flow cytometry before and 2-4 weeks following vaccinations and breakthrough infection to assess the frequency and polyfunctionality of responding cells, along with receptor binding domain (anti-RBD) antibodies. Findings: Between March 2, 2021, and December 20, 2022, 143 patients (118 IBD, 25 arthritis) and 21 healthy controls were included. In both IBD and arthritis patients, humoral immunity was attenuated compared to healthy controls (median anti-RBD levels 3391 vs. 6280 BAU/ml, p=0·008) after three SARS-CoV-2 vaccine doses. IBD patients had a comparable quantity (median CD4 0·11% vs. 0·11%, p=0·26, CD8 0·031% vs. 0·047%, p=0·33) and quality (polyfunctionality score: 0·403 vs. 0·371, p=0·39; 0·105 vs. 0·101, p=0·87) of spike-specific T cells to healthy controls. Arthritis patients had lower frequency, but comparable quality, of responding T cells to controls and IBD patients. Breakthrough infection increased spike-specific CD8 T cell quality and T cell responses against non-spike peptides. Interpretation: IBD patients on TNFi have T cell responses comparable to healthy controls despite attenuated humoral responses following three vaccine doses. Repeated vaccination and breakthrough infection increased the quality and breadth of T cell responses. Our results indicate that IBD patients on TNFi treatment may follow the same COVID-19 vaccine recommendations as the healthy population in future. Funding: South-Eastern Norway Regional Health Authority, Coalition for Epidemic Preparedness Innovations (CEPI), Norwegian Institute of Public Health, Akershus University Hospital, Diakonhjemmet Hospital.Declaration of Interest: KHB reports funding from Akershus University Hospital and speaker bureaus for Janssen-Cilag. TKK reports grants from AbbVie, BMS, Galapagos, Novartis, Pfizer, UCB, speakers’ bureaus from Grünenthal, Janssen, Sandoz, consultant fees from AbbVie, Gilead, Janssen, Novartis, Pfizer, Sandoz, UCB, and participation on advisory board for AbbVie. JJ reports grants from Boehringer-Ingelheim, speakers bureaus from AbbVie/Abbott, Bristol-Myers, Squibb, Galapagos, Gilead, Janssen, Pfizer, Roche, Sandoz, Takeda, consultant fees from AbbVie/Abbott, Pfizer, and participation in advisory board for AbbVie/Abbott, Bristol-Myers Squibb, Galapagos, Gilead, Janssen, Pfizer, Roche, Sandoz, Takeda. LAM reports funding from KG Jebsen foundation, support for infrastructure and biobanking from the university of Oslo and Oslo University Hospital, grants from the Coalition of Epidemic Preparedness Innovations (CEPI), speakers bureaus from Incyte, Janssen, and expert testimony for Norwegian Medicines Agency. EAH reports speakers’ bureaus from Pfizer, UCB, Novartis, and consulting fees from Abbvie, Pfizer, Eli Lilly. GG reports speaker bureaus from AbbVie/Abbott, Galapagos, Pfizer, UCB, participation in advisory board from AstraZeneca, Janssen, Moderna, Seqirus. and consulting fees from The Norwegian System of Patient Injury Compensation. JTV reports grant from CEPI. FLJ reports funding from South-East Health Authorities in Norway, CEPI and Oslo University Hospital. GLG reports speakers’ bureaus from AbbVie/Abbott, Galapagos, Pfizer, UCB, and participation in advisory board from AbbVie/Abbott, Galapagos, Pfizer, UCB, Novartis. KKJ reports speakers’ bureaus from Bristol-Myers Squibb and Janssen, and participation in advisory board for AstraZeneca and IPSEN. SWS reports participation in advisory board for AstraZeneca. ASW, HSØ, SB, GS, IFK, IJ, UCN, ABK, IEC, SEJ, KPL, AC, ATT, JS, SAP, HK, and SM report nothing to disclose.Ethical Approval: The study was approved by the Norwegian Regional Committees for Medical and Health Research Ethics (reference numbers 235424 and 135924). Written informed consent was obtained from all the patients.
Abstract Background One year into the COVID‐19 pandemic, the cumulative number of confirmed COVID‐19 cases in Norway was still low. In January 2021, when the Norwegian COVID‐19 vaccination campaign started, the national seroprevalence estimate of SARS‐CoV‐2 antibodies was 3.2%. We have conducted a nationwide cross‐sectional study in August 2021 to investigate the overall prevalence of SARS‐CoV‐2 antibodies in Norway after 8 months of COVID‐19 mass vaccination and a third wave of SARS‐CoV‐2 infection. Methods Residual sera were collected from laboratories across Norway in August 2021. In IgG antibodies against the spike protein, the spike receptor binding domain (RBD) and the nucleocapsid protein of SARS‐CoV‐2 were measured by a bead‐based flow cytometric assay. Results In total, 1926 residual sera were collected from individuals aged 0–98 years; 55.1% were from women. The overall national estimated seroprevalence from vaccination and/or infection was 62.6% (credible interval [CrI] 60.1%–65.2%) based on having antibodies against both spike and RBD. Estimated seroprevalence increased with age. Among all samples, 11.7% had antibodies against nucleocapsid. For unvaccinated children <12 years, the seroprevalence estimate due to SARS‐CoV‐2 infection was 12.5% (95% CrI 9.3%–16.1%). Of seropositive samples from the unvaccinated children, 31.9% lacked anti‐nucleocapsid antibodies. Conclusions The high overall SARS‐CoV‐2 seroprevalence estimates are in line with Norwegian registry data. Vaccination, not infection, contributed the most to the high seroprevalence in August 2021. Lack of antibodies against nucleocapsid should not automatically be interpreted as absence of previous infection as this could lead to underestimation of COVID‐19 cases in seroprevalence studies.
COPCORD population surveys (Stage I) have reported the prevalence of MSK pain and rheumatic disorders in several countries. A crude point prevalence rate of 18.2% for MSK pain (adult) was reported by the maiden COPCORD India survey (1996) in rural Bhigwan (Pune) and was continued to date with a free-of-cost local rheumatology clinic and a health education program. Several other factors (development, environment, Chikungunya epidemic 2006, Covid pandemic 2019) are likely to impact the epidemiology of MSK disorders and thus we carried out a resurvey in Bhigwan from April to July 2022. We present early results of MSK pain and related factors.
Objectives
To describe and measure the current MSK pain and rheumatic disorders in Bhigwan rural population and further assess the transformation over time (1996 to 2022).
Methods
The resurvey (Stage I) was carried out using the methods of the previous survey (Bhigwan COPCORD model 1996). Trained voluntary health workers (HW) completed a house-to-house cross-sectional survey (Phase 1) of the adult population(≥ 18 years) and identified current and/or past MSK pain respondents. Pain due to recent trauma (< 3 months) was excluded. Concurrently, the respondents were also evaluated (Phase 2) for pain descriptors and other relevant issues. Rheumatologists examined (Phase 3) the respondents to make a clinical diagnosis, order relevant investigations, and begin treatment. A follow-up was scheduled. The target population was estimated at 8117 (Government records). The database was created using an indigenous software program. Standard population analysis was carried out. Crude point prevalence rates (95% confidence intervals) are presented. Further analysis is being done.
Results
6970 population (85.9% response, 50% males) was surveyed. The age-gender distribution pattern was comparable with the India rural census 2011; 63% in 18-44 years age groups (Bhigwan). Paradoxically, only 7.6% current population in sharp contrast to about 55% in 1996 admitted working (physically) in fields; now dependent upon temporary migrant labor (not in the survey). 32% population possessed mobile phones. Five hundred eighty-six pain respondents (women 69%) were identified; 46% belonged to the 45-64 years age group. The MSK pain prevalence was 8.2% (7.5%, 8.8 %); male 2.5 (2.2 %,2.9%). female 5.6% (5.1, 6.2). 14.2% population used tobacco in some form, mostly oral; 36.3% of MSK pain respondents (58% women). Hypertension in 7.9%, diabetes in 4.7%, thyroid disorders in 1.6%, and rectal hemorrhoids in 1% was self-reported in the population; correspondingly 25%, 12%, 2.5%, and 3% were reported by the MSK pain cohort. Past history of Chikungunya in 5.7% and COVID-19 in 7.4% of the total population was reported. On univariate analysis, MSK pain was significantly associated (p < 0.0001, Chi-square) with Chikungunya, COVID-19, tobacco use, fieldwork, and low education status. Prevalence rates for disease groups were 1.38% (1.12. 1.68) for inflammatory arthritis, 3.66% (3.23, 4.13) for degenerative arthritis and 2.87 % (2.49, 3.29) for non-specific rheumatism/arthritis. Self-reported data, subject recall, and limited investigations were important concerns.
Conclusion
The current COPCORD survey shows that despite a substantial reduction from 1996, MSK pain continues to be a predominant and important self-reported illness in the Bhigwan rural community. Undoubtedly, the lives and livelihoods of the Bhigwan people and their MSK landscape have been transformed substantially. Interestingly, the burden of other non-communicable diseases seems increased. Further research studies will be required to unravel the role of Chikungunya and COVID-19, and other risk factors in MSK disorders.
References
[1]Joshi, Chopra. (COPCORD Bhigwan Model Surveys). J Rheumatol 2009;36:614-22 [2]Chopra A. (COPCORD World). Rheumatol 2013; 52(11):1925-8 [3]Chopra et al. (Bhigwan survey 1996).J Rheumatol 2002; 29: 614-621.
Acknowledgements
Funded by an ILAR grant 2022 and ARCF-Centre for Rheumatic Diseases (CRD) Pune India, CRD personnel, Bhigwan Administration, leaders and population.
Abstract Diagnostic assays currently used to monitor the efficacy of COVID-19 vaccines measure levels of antibodies to the receptor-binding domain of ancestral SARS-CoV-2 (RBDwt). However, the predictive value for protection against new variants of concern (VOCs) has not been firmly established. Here, we used bead-based arrays and flow cytometry to measure binding of antibodies to spike proteins and receptor-binding domains (RBDs) from VOCs in 12,000 sera. Effects of sera on RBD-ACE2 interactions were measured as a proxy for neutralizing antibodies. The samples were obtained from healthy individuals or patients on immunosuppressive therapy who had received two to four doses of COVID-19 vaccines and from COVID-19 convalescents. The results show that anti-RBDwt titers correlate with the levels of binding- and neutralizing antibodies against the Alpha, Beta, Gamma, Delta, Epsilon and Omicron variants. The benefit of multiplexed analysis lies in the ability to measure a wide range of anti-RBD titers using a single dilution of serum for each assay. The reactivity patterns also yield an internal reference for neutralizing activity and binding antibody units per milliliter (BAU/ml). Results obtained with sera from vaccinated healthy individuals and patients confirmed and extended results from previous studies on time-dependent waning of antibody levels and effects of immunosuppressive agents. We conclude that anti-RBDwt titers correlate with levels of neutralizing antibodies against VOCs and propose that our method may be implemented to enhance the precision and throughput of immunomonitoring.
Disease activity indices (DAI) are used to guide immunosuppressive therapy in rheumatoid arthritis (RA). The inclusion of patient global assessment (PGA) in these indices has been questioned as it conveys mainly disease impact rather than disease activity.
Objectives
To determine the influence of PGA on patient disease states and to determine PGA correlations with inflammatory parameters, disease impact, demographic, clinical and contextual factors.
Methods
The METEOR international database was used, namely data from patients9 first available visit with no missing values on PGA, tender and swollen joint counts (TJC28, SJC28) and C-reactive protein (CRP). Remission rates were compared according to the DAS28CRP3v vs 4v and ACR/EULAR Boolean remission vs near-remission (failing 1 of the 4 criteria) definition. We assessed the correlation of PGA with (predominantly) inflammatory (TJC28, SJC28, CRP) and disease impact (pain and HAQ) factors. We used hierarchical modelling to explain PGA by 4 blocks (B) of independent variables (B1: gender, age, disease duration; B2: biologic DMARD, Gross National Income; B3: pain, HAQ; and B4: TJC28, SJC28, CRP).
Results
Among the 18280 patients analysed, 1930 (10.6%) were in DAS28CRP4v remission, and 2197 (12.0%) in DAS28CRP3v remission. According to the Boolean definition, 1207 (6.6%) patients were in remission. PGA was the main obstacle to Boolean remission: 2090 (79.0%) of the 2645 near-remission patients (Table 1). A considerable proportion of patients with low inflammation perceived high PGA (Figure 1). PGA correlated better with Pain (rp=.79) and HAQ (rp=.55) than with TJC28 (rp=.45), SJC28 (rp=.36) or CRP (rp=.25). In the entire dataset, 60.2% of PGA variance was explained by Pain and HAQ, 1.8% by B1 and B2 of covariates and only 1.3% by B4 (TJC28, SJC28, CRP) (Table 2). In near-remission patients, B4 did not contribute significantly to changes in the model.
Conclusions
Two thirds of patients that achieve TJC28, SJC28, and CRP≤1 still perceive high PGA despite disease “inflammatory” control. The weight of PGA in DAI could lead to immunosuppressive overtreatment. In these patients, disease impact management, including non-pharmacological treatments delivered by Health Care Professionals, are more likely to be effective.
Disclosure of Interest
R. Ferreira Grant/research support from: MERIT foundation, M. Ndosi: None declared, C. Duarte: None declared, P. Carvalho: None declared, A. Chopra: None declared, K. Salomon-Escoto: None declared, D. Vega: None declared, D. van der Heijde: None declared, P. Machado: None declared, J. da Silva: None declared
'%3e%3ccircle r='20' fill='%23008'/%3e%3ccircle r='17.5' fill='%23fff'/%3e%3ccircle r='3.5' fill='%23008'/%3e%3cg id='d'%3e%3cg id='c'%3e%3cg id='b'%3e%3cg id='a' fill='%23008'%3e%3ccircle r='.875' transform='rotate(7.5 -8.75 133.5)'/%3e%3cpath d='M0 17.5.6 7 0 2l-.6 5L0 17.5z'/%3e%3c/g%3e%3cuse xlink:href='%23a' transform='rotate(15)'/%3e%3c/g%3e%3cuse xlink:href='%23b' transform='rotate(30)'/%3e%3c/g%3e%3cuse xlink:href='%23c' transform='rotate(60)'/%3e%3c/g%3e%3cuse xlink:href='%23d' transform='rotate(120)'/%3e%3cuse xlink:href='%23d' transform='rotate(-120)'/%3e%3c/g%3e%3c/svg%3e)