Response to COVID-19 booster vaccinations in seronegative people with MS. (preprint)

Importance: Uncertainties remain about the benefit of a 3rd COVID-19 vaccine for people with attenuated response to earlier vaccines. This is of particular relevance for people with multiple sclerosis (pwMS) treated with anti-CD20 therapies and fingolimod, who have substantially reduced antibody responses to initial vaccine course. Objective: To report humoral and T-cell responses following COVID-19 vaccine 3 in pwMS who were seronegative after COVID-19 vaccines 1&2. Design, setting and participants: PwMS taking part in a seroprevalence study without a detectable IgG response following COVID-19 vaccines 1&2 were invited to participate. Participants provided a dried blood spot +/- venous blood sample 2-12 weeks following COVID-19 vaccine 3. Data on demographics, MS treatment, and COVID-19 infection/vaccine dates were derived from the medical notes. Methods: Humoral and T cell responses to SARS-CoV-2 spike protein and nucleocapsid antigen were measured. The relationship between evidence of prior COVID-19 infection and immune response to COVID-19 vaccine 3 was evaluated using Fishers exact test. Results: Of 81 participants, 79 provided a dried blood spot sample, of whom 38 also provided a whole blood sample; 2 provided only whole blood. Anti-SARS-CoV-2-spike IgG seroconversion post-COVID-19 vaccine 3 occurred in 26/79 (33%) participants; 26/40 (65%) had positive T-cell responses. Overall, 31/40 (78%) demonstrated either humoral or cellular immune response post-COVID-19 vaccine 3. There no association between laboratory evidence of prior COVID-19 infection and anti-spike seroconversion following COVID-19 vaccine 3. Conclusions: Approximately one third of pwMS who were seronegative after initial COVID-19 vaccination seroconverted after booster (third) vaccination, supporting the use of boosters in this group. Almost 8 out of 10 had a measurable immune response following 3rd COVID-19 vaccine.

Impact of mass vaccination on SARS-CoV-2 infections among the total multiple sclerosis population receiving immunomodulatory disease-modifying therapies in England (preprint)

This study aimed to understand changes in the risk of SARS-CoV-2 infection among all people with multiple sclerosis (MS) receiving immunomodulatory disease-modifying therapies (DMTs) in England, compared to the general population, following mass vaccination. Longitudinal data collected by the National Health Service (NHS) England on all MS DMT prescriptions and the UK Health Security Agency on all registered SARS-CoV-2 test results were analysed. The incidence rate ratio of SARS-CoV-2 infection among people with MS taking DMTs compared to the general population was calculated before (November 2020-January 2021) and after (July-August 2021) mass vaccination. Risk of SARS-CoV-2 infection among people on ocrelizumab or fingolimod compared to the general population increased following liberalisation of COVID-19 restrictions (during March-July 2021) despite mass vaccination. No changes were found with other DMTs. These findings converge with the impaired immune response to vaccines observed with ocrelizumab and fingolimod.

COVID-19 vaccine response in people with multiple sclerosis (preprint)

Objective: To investigate the effect of disease modifying therapies on serological response to SARS-CoV2 vaccines in people with multiple sclerosis Methods: 473 people with multiple sclerosis from 5 centres provided one or more dried blood spot samples and a questionnaire about COVID-19 and vaccine history. Information about disease and drug history was extracted from their medical records. Dried blood spots were eluted and tested for antibodies to SARS-CoV2 receptor binding domain. Seropositivity was expressed according to validated cut-off indices. Antibody titers were partitioned into tertiles using data from people on no disease modifying therapy as a reference. We calculated the odds ratio of seroconversion (Univariate logistic regression) and compared quantitative vaccine response (Kruskal Wallis) following SARS-CoV2 vaccine according to disease modifying therapy. We used regression modelling to explore the effect of factors including vaccine timing, treatment duration, age, vaccine type and lymphocyte count on vaccine response. Results: Compared to no disease modifying therapy, the use of anti-CD20 monoclonal antibodies (odds ratio 0.03; 95% confidence interval 0.01-0.06, p<0.001) and fingolimod (odds ratio 0.41; 95% confidence interval 0.01-0.12) were associated with lower seroconversion following SARS-CoV2 vaccine. All other drug groups did not differ significantly from the untreated cohort. Both time since last anti-CD20 treatment and total time on treatment were significantly related with serological response to vaccination. Vaccine type significantly predicted seroconversion, but not in those on anti-CD20 medications. Interpretation: Some disease modifying therapies carry a risk of attenuated response to SARS-CoV2 vaccination in people with MS. We provide recommendations for the practical management of this patient group.

Pre-existing anxiety, depression, and neurological disability are associated with long COVID: A prospective and longitudinal cohort study of the United Kingdom Multiple Sclerosis Register (preprint)

Objectives: To assess the prevalence of and factors associated with developing long COVID among patients with multiple sclerosis (MS), a condition which shares the neurological and psychological symptomatology of long COVID Design: Community-based prospective and longitudinal observational study Setting: The United Kingdom (UK) MS Register (UKMSR) COVID-19 study Participants: A national cohort of MS patients with COVID-19 Main outcome measures: Participants used the online questionnaire-based platform of the UKMSR to update their COVID-19 symptoms and recovery status. Questionnaires were date-stamped for estimation of COVID-19 symptom duration. The UKMSR also holds demographic and up-to-date clinical data on participants including comorbidities, MS type, date of MS diagnosis, disease-modifying therapies, web-based Expanded Disability Status Scale scores (a measure of physical disability in MS), and Hospital Anxiety and Depression Scale. The association between these factors and recovery from COVID-19 was assessed using multivariable Cox regression analysis. Results: Out of 7,977 MS patients who participated in the UKMSR COVID-19 study, 599 had COVID-19 and updated their recovery status prospectively. At least 181 participants (31.1%) had long-standing COVID-19 symptoms for [≥]4 weeks and 76 (13.1 %) for [≥]12 weeks. Participants with higher levels of pre-COVID-19 physical disability, participants with anxiety and/or depression prior to COVID-19 onset, and women were less likely to recover from COVID-19. Conclusions: Long COVID appears to affect patients with a pre-existing chronic condition, especially those with physical disabilities or mental health problems disproportionately when compared to reports in the general population. Long COVID research and the development of post-COVID-19 rehabilitation services need to be inclusive of these at-risk populations. Trial Registration: ClinicalTrials.gov: NCT04354519

Determining the risk of developing symptomatic covid-19 infection after attending hospital for radiological examinations: controlled cohort study (preprint)

OBJECTIVETo determine whether brief attendance for outpatient radiological investigations is associated with increased risk of clinically significant coronavirus disease 2019 (covid-19) infection. DESIGNObservational cohort study with a historical control. SETTING2 large UK University Hospitals located in Nottingham and Cardiff. PARTICIPANTSAll 47,340 patients who attended an outpatient radiology appointment at Nottingham University Hospitals and University Hospital of Wales during the first wave of the pandemic in 2020, and 70,655 patients that comprised the control cohort who attended for outpatient radiology the same period in 2019. MAIN OUTCOME MEASURESThe risk of developing clinically significant covid-19 infection within 28-days of attending a radiological examination. Covid-19 infection rates for the 2020 cohort were compared against a control group who attended in 2019. RESULTS84 positive SARS-CoV-2 tests were temporally associated with 47,340 radiological examinations across two hospitals in 2020. This low infection rate was higher than the 2019 control cohort; OR 2.507 (1.766 - 3.559) and equates to an approximate 1 positive covid-19 infection per 1000 radiology investigations. CONCLUSIONSOur data suggests that attending hospitals for outpatient radiological investigations during the pandemic is associated with a very small absolute risk of acquiring clinically significant covid-19 infection. It is unlikely that this risk is directly attributable to radiology attendance, considering the reasons leading individuals to attend hospitals during the pandemic, the true attributable risk will likely be even lower. TRIAL REGISTRATIONClinicalTrials.gov NCT04544176

COVID-19 is associated with multiple sclerosis exacerbations that are prevented by disease modifying therapies (preprint)

BackgroundInfections can trigger exacerbations of multiple sclerosis (MS). The effects of the coronavirus disease 2019 (COVID-19) on MS are not known. The aim of this study was to understand the impact of COVID-19 on new and pre-existing symptoms of MS. MethodsThe COVID-19 and MS study is an ongoing community-based, prospective cohort study conducted as part of the United Kingdom MS Register. People with MS and COVID-19 were invited by email to complete a questionnaire about their MS symptoms during the infection. An MS exacerbation was defined as developing new MS symptoms and/or worsening of pre-existing MS symptoms. ResultsFifty-seven percent (230/404) of participants had an MS exacerbation during their infection; 82 developed new MS symptoms, 207 experienced worsened pre-existing MS symptoms, and 59 reported both. Disease modifying therapies (DMTs) reduced the likelihood of developing new MS symptoms during the infection (OR 0.556, 95%CI 0.316-0.978). Participants with a higher pre-COVID-19 webEDSS (web-based Expanded Disability Status Scale) score (OR 1.251, 95%CI 1.060-1.478) and longer MS duration (OR 1.042, 95%CI 1.009-1.076) were more likely to experience worsening of their pre-existing MS symptoms during the infection. ConclusionCOVID-19 infection was associated with exacerbation of MS. DMTs reduced the chance of developing new MS symptoms during the infection.