ABSTRACT
Background: SARS-CoV-2 antibody responses after COVID-19 vaccination are attenuated in people living with MS on high efficacy DMTs such as Fingolimod and Ocrelizumab. Uncertainties on how to manage vaccination schedule and DMT administration persist. Furthermore, data on effects of newer related DMTs like Siponimod and Ofatumumab are limited. Objective(s): We aimed to determine the seroprevalance of Spike antibody and the longevity of antibody mediatedimmune protection after COVID-19 vaccination in MS patients. Method(s): Spike IgG antibodies against Wuhan SARS CoV-2 were assessed in sera (n=520) of MS patients collected pre-vaccination (baseline n= 304), 1 month post second dose (n=172), 6 months post second dose (n=23) and 1 month post third dose (n=21). Demographic and clinical information including age, gender, DMT treatment and timing of COVID-19 vaccination were collected from 160 of these MS patients. Result(s): 151/172 sera at 1 month post second dose, 20/23 sera at 6 months post second dose, and 15/21 sera at 1 month post third dose were positive for Spike antibodies. Seropositive patients were treated on Alemtuzumab;n=3, Cladribine;n=32, Dimethyl fumarate;n=8, Fingolimod;n=16, IFN;n =4, Ocrelizumab;n=14, Ofatumumab;n=4, Natalizumab;n=11, Siponimod;n=1 and Teriflunomide;n=1. Out of the 21 patients who did not seroconvert at a month post second dose, treatment information was available in 12 patients. n=9 were treated by Ocrelizumab and n=2 were treated by Cladribine and n=1 was treated by Fingolimod, confirming certain DMTs prevent seroconversion. Out of the 151 patients that did seroconvert, 120 had titers that were comparable to controls (healthy general population) and 31 had reduced titres. Treatment information was available in 21/31 of these patients. Interestingly, 9/21 were on Ocrelizumab, 8/21 were on Fingolimod, 2/21 were on Ofatumumab, 1/21 was on Natalizumab and 1/21 was on Siponimod. This finding confirmed that certain DMTs such as Fingolimod, Ocrelizumab, Ofatumumab and Siponimod cause a reduction in post-vaccination Spike antibody titers in MS patients in comparison to general population. Expectedly, 304/304 sera were negative at baseline. Conclusion(s): Some High efficacy DMTs reduce Spike Ab titers or even prevent seroconversion. To maximize vaccine-mediated immune protection against COVID-19, timing of DMT administration and vaccine schedule may need intricate co-ordination in people living with MS.
ABSTRACT
Background: People with multiple sclerosis (MS) are a vulnerable group for severe COVID-19, particularly those taking immunosuppressive disease-modifying therapies (DMTs). Objective(s): To assess characteristics of COVID-19 severity in an international sample of people with MS, including hospitalisation, ICU admission, requiring artificial ventilation, and death. Method(s): Data from 12 data-sources in 28 countries were aggregated. Demographic and clinical covariates were queried, alongside COVID-19 clinical severity outcomes, hospitalisation, admission to ICU, requiring artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/ confirmed COVID-19 using multilevel mixed-effects logistic regression. Result(s): 657 (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19. Older age, progressive MS-phenotype, and higher disability associated with worse COVID-19 outcomes. Ocrelizumab and rituximab associated with hospitalisation (aOR=1.75,95%CI=1.29-2.38;aOR=2.76,95%CI=1.87-4.07) and ICU admission (aOR=2.55,95%CI=1.49-4.36;aOR=4.32, 95%CI=2.27-8.23) vs pooled-other-DMTs but only rituximab with artificial ventilation (aOR=6.15,95%CI=3.09-12.27). Similar associations seen compared to dimethyl fumarate and to natalizumab. No associations observed between DMTs and death. Conclusion(s): Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab and ocrelizumab with worse COVID-19, suggesting their use may be a risk factor for more severe COVID-19.
ABSTRACT
Background: Current SARS-CoV-2 vaccines rely on protective immunity against early clade SARS-CoV-2 and have resulted in seroconversion in a subset of MS patients receiving immunosuppressive DMTs. However, it is unknown if SARS-CoV-2 spike antibodies afford immunity against emerging variants of concern, such as Delta and Omicron. Objective(s): To determine the binding of spike antibodies to early clade, Delta, and Omicron SARS-CoV-2 in patients with MS receiving different DMTs. Method(s): Spike antibody binding to early clade SARS-CoV-2, Delta and Omicron was assessed by flow cytometry using sera collected from 58 patients one month post second dose and one patient 1 month post third dose. All patients were previously determined to be seropositive against Wuhan (early clade spike). Clinical and demographic information including DMT treatment and vaccination timing was collected. Result(s): 53 patients were seropositive for Wuhan, Delta and Omicron spike antibodies. Wuhan Spike antibody titres were high at one month post second vaccination, whereas Delta and Omicron Spike antibody titres were significantly decreased. We observed a 70% and 93% decrease of in immunoreactivity to Delta and Omicron, respectively. Although ocrelizumab and fingolimod decrease Spike antibody titres after vaccination, they did not affect immunoreactivity to variants, in comparison to other DMTS. Conclusion(s): All 53 patients were able to generate a positive antibody response following vaccination. However, there was an observable decrease in the antibody titres and immunoreactivity to the Delta and Omicron variants, in comparison to Wuhan.
ABSTRACT
Background: COVID-19 vaccination induces protective Spike antibodies. Some responses are attenuated in people with multiple sclerosis (MS) on high efficacy disease-modifying therapies (DMT).Whether antibodies afford immunity against emerging SARS-CoV-2 Variants of Concern (VoC) such as Delta and Omicron is unknown. Aim(s): To assess the longevity and breadth of Spike antibody in MS patients after COVID-19 vaccination. Objective(s): To determine seroconversion and antibody binding toVoC Spike. Method(s): Spike antibodies to Clade A SARS-CoV-2 were assessed in 535 MS sera at baseline (n=292), 1 (n=141) and 6 month (n=67) post-second dose, and 1 month post-third dose (n=35), and 489 health worker controls. When known, COVID- 19 vaccines were BNT162b2 (n= 489 controls, n=108 MS patients) and ChAdOx1-S (n=37).Spike antibody binding to VoC Delta and Omicron BA1 was assessed in 68 sera 1 month post-second dose. Demographic and DMT information was available in 269 patients. Result(s): 123/141 sera at 1 month post-second dose, 66/67 at 6 months post-second dose, and 26/35 at 1 month post-third dose were positive for Spike antibodies.Patients who did not seroconvert at 1 and 6 month post-second and 1 month post-third dose (n=28) were treated with ocrelizumab (n=22), cladribine (n=1), fingolimod (n=4), and siponimod (n=1). At 1 month post-second dose, the median and IQR Spike antibody levels were 67,224+/- 101,251 in the seroconverted MS group compared to 145,510+/- 99,669 in controls (n=489). When patient sera were assessed for binding to Clade A Spike, and VoC Delta and Omicron BA1 Spikes, most sera were able to bind the three different Spike antigens (n=61). However, Spike antibody immunoreactivity was decreased by 70% against Delta Spike and 90% for Omicron BA1 Spike compared to the original clade A Spike.As observed for Clade A Spike antibody, DMTs, such as ocrelizumab, fingolimod, and ofatumumab, decreased the antibody binding to Delta and Omicron Spike. Still, the pattern of antibody recognition was similar between the three Spikes and all DMTs analysed, i.e. alemtuzumab, natalizumab, teriflunomide, and interferons. Our data suggest that, irrespectively of DMTs, antibodies generated after vaccination did not bind Spike from recent VoCs to the same extent as the original Spike used in COVID-19 vaccines. Conclusion(s): Some DMTs reduce Spike antibody titres or prevent seroconversion. The sequence of Spike used in the first generation of vaccines may need to be updated for emerging VoC.
ABSTRACT
Background: As the COVID-19 pandemic continues, evidencebased clinical guidance for managing the care of people with multiple sclerosis (MS) is an ongoing concern. In recent months, data from cohorts of people with MS has indicated that certain demographic and clinical characteristics, including use of some disease- modifying therapies (DMTs), leads to worse outcomes from SARS-CoV-2 infection. The COVID-19 in MS global data sharing initiative, which now includes over 4,500 confirmed COVID- 19 cases in people with MS, gives the opportunity to corroborate previous findings with greater certainty. Methods: Clinician-reported data from 32 countries were aggregated into a dataset of 5,543 patients who had suspected or confirmed COVID-19. Demographic and clinical covariates were queried, alongside COVID-19 clinical severity outcomes. These outcomes (hospitalisation, admission to ICU, requiring artificial ventilation, and death) were assessed in patients with suspected/ confirmed COVID-19 using multilevel mixed-effects logistic regression. All models were corrected for age, sex, EDSS, and MS type. DMTs were individually compared to glatiramer acetate (GA), as well as to pooled other DMTs and natalizumab. Results: Of 5,543 patients in the clinician-reported dataset, 909 with suspected and 4,634 with confirmed COVID-19 were included in the analysis. Previous demographic findings were confirmed: male sex, older age, progressive MS, and higher disability were associated with worse outcomes from SARS-CoV-2 infection. Use of anti-CD20 DMTs (ocrelizumab and rituximab) was associated with worse COVID-19 outcomes. Compared to GA, ocrelizumab and rituximab were associated with increased risk of hospitalisation (aOR=1.61(95%CI=1.06-2.43);aOR=2.42(95%CI=1.54-3.81) and ICU admission (aOR=3.13(95%CI=1.22-8.00);aOR=4.46 (95%CI=1.64-12.09)). Rituximab was associated with increased risk of artificial ventilation (aOR=3.57(95%CI=1.38-9.20));ocrelizumab showed a positive trend (aOR=1.86(95%CI=0.76-4.55). Rituximab showed a positive trend with increased risk of death (aOR=2.74(95%CI=0.68-11.09). Associations persisted on restriction to confirmed COVID-19 cases. Conclusions: Analysing the largest international real world dataset of people with MS who have suspected or confirmed COVID- 19 confirms previous findings that male sex, older age, progressive MS, higher disability, the use of anti-CD20 medication (ocrelizumab and rituximab) are associated with worse COVID-19 outcomes.