Abstract
Background
Several studies have demonstrated reduced serological response to vaccines in patients treated with anti-CD20 agents. However, limited data exist surrounding the clinical effect of disease modifying therapy (DMT) use on vaccine efficacy.
Objectives
To investigate breakthrough coronavirus disease 2019 (COVID-19) in vaccinated people with multiple sclerosis (PwMS) on DMT.
Methods
PwMS on DMT diagnosed with COVID-19 after full vaccination were identified from an existing Cleveland Clinic COVID-19 registry, supplemented by provider-identified cases. Demographics, disease history, DMTs, comorbidities, exposures, vaccination status, and COVID-19 outcomes were confirmed by review of the electronic medical record.
Results
Thirteen (3.8%) of 344 fully vaccinated people with multiple sclerosis on disease modifying therapy were diagnosed with COVID-19 after vaccination. Ten patients (76.9%) were on an anti-CD20 therapy, the remaining 3 (23.1%) on fingolimod. Only 2 patients (15.4%), both on anti-CD20 therapy, required hospitalization and steroid treatment. Neither required Intensive Care Unit admission.
Conclusion
Patients treated with anti-CD20 agents and sphingosine 1-phosphate receptor modulators may still be at risk for COVID-19 despite vaccination. While still at risk for hospitalization, intubation and death from COVID-19 appear rare. Larger studies analyzing how this may differ in the setting of emerging variants are needed.
Keywords: COVID-19, multiple sclerosis, disease-modifying therapy
Introduction
Three vaccines for coronavirus disease 2019 (COVID-19) were approved in the United States under emergency use authorization; reported efficacies included 95% (Pfizer/BNT162b2), 94% (Moderna/mRNA-1273) and 67% (Janssen/Ad26.COV2.S) in preventing infection. 1 A systematic review of COVID-19 in people with multiple sclerosis (PwMS) estimated the pooled prevalence to be higher than the general population at 4%, with 10% of cases requiring hospitalization. 2 A separate review found that nearly half of COVID-19 cases in PwMS were in the setting of anti-CD20 therapy, raising concern for increased risk of COVID-19 in PwMS on disease-modifying therapy (DMT), and particularly in those on anti-CD20 agents. 3 Subsequent studies demonstrated a reduced serological response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in PwMS on anti-CD20 and sphingosine 1-phosphate receptor modulator (S1PR) DMTs.4–6 Given these results, questions remained regarding which factors were most important for developing immunity, and how reduced serological vaccine response translated to clinical outcomes. In this study, we investigated breakthrough COVID-19 in fully vaccinated PwMS.
Methods
PwMS diagnosed with COVID-19 after full vaccination were identified from an existing Institutional Review Board-approved Cleveland Clinic COVID-19 registry, 7 supplemented by provider-identified cases diagnosed at outside hospitals. All cases were confirmed by SARS-CoV-2 polymerase chain reaction (PCR) testing of nasal swabs. Demographics, disease history, DMT, comorbidities, vaccination status and COVID-19 outcomes were either confirmed (for existing registry patients) or abstracted (for provider-identified cases) by review of the electronic medical record.
Results
We identified 669 patients who received a full SARS-CoV-2 vaccination series; 176 (26.3%) patients received two doses of the Moderna, 456 (68.2%) received two doses of the Pfizer and 37 (5.5%) received the single dose of the Janssen vaccine. Of 669 fully vaccinated PwMS, 344 (51.4%) were on DMT at the time of vaccination. There were no breakthrough COVID-19 infections in PwMS off DMT. Of 344 PwMS on DMT, 13 (3.8%) developed confirmed COVID-19 despite full vaccination with Moderna (n = 5), Pfizer (n = 6), or Janssen (n = 2) vaccine.
Demographics of the 13 PwMS with breakthrough COVID-19 are as follows. Most were white (84.6%), female (61.5%) and had a relapsing-remitting course (84.6%). The mean age was 45.4 years. All breakthrough occurred on DMT. Ten patients (76.9%) were on an anti-CD20 therapy, and three (23.1%) were on fingolimod. There was a wide range of values for time to positive PCR after the final dose of vaccine (median 48 days; interquartile range [19–92]). The most prevalent comorbidity was hypertension (five patients; 38.5%). No patients were current smokers or had chronic obstructive pulmonary disease, coronary heart disease, heart failure or other autoimmune conditions.
Comparative demographics between those with and without breakthrough COVID-19 are summarized in Table 1. Comprehensive COVID-19 outcomes are in Table 2. Only two (15.4%) of the 13 patients required hospitalization; Both were on anti-CD20 therapy. One stayed three days, and the other stayed 13 days after the development of pneumonia. Neither required intensive care unit (ICU) admission or mechanical ventilation; both were discharged home. Both received steroid treatment, and the patient with pneumonia was additionally treated with remdesivir. Another patient, also on anti-CD20 treatment, developed pneumonia but was managed as an outpatient on inhaled corticosteroids. The three patients on fingolimod did not require COVID-targeted treatment or hospitalization. The times from last infusion to first vaccination were similar for patients on anti-CD20 therapy with breakthrough infection compared to those without, median 119 days; interquartile range (95–133) versus 137; interquartile range (95–152), respectively.
Table 1.
Demographics of fully vaccinated patients by breakthrough COVID-19 status.
| SARS-CoV-2 RNA PCR | Negative | Positive | p value |
|---|---|---|---|
| n | 656 | 13 | |
| Age (years) (median (IQR)) | 56 (47–65) | 43 (40–50) | 0.001 |
| Sex (%) | 0.068 | ||
| Male (%) | 121 (18.4) | 5 (38.5) | |
| Female (%) | 535 (81.6) | 8 (61.5) | |
| Race (%) | 0.135 | ||
| White | 541 (82.5) | 11 (84.6) | |
| Black | 84 (12.8) | 2 (15.4) | |
| Multiracial/multicultural | 14 (2.1) | 0 (0.0) | |
| Other | 4 (0.6) | 0 (0.0) | |
| Unknown | 13 (2.0) | 0 (0.0) | |
| BMI (kg/m2) (median (IQR) | 28.3 (24.3–33.3) | 30.9 (27.7–35.6) | 0.164 |
| MS course (%) | 0.602 | ||
| RRMS | 390 (59.4) | 11 (84.6) | |
| SPMS | 148 (22.6) | 1 (7.7) | |
| PPMS | 67 (10.2) | 0 (0.0) | |
| PRMS | 51 (7.8) | 1 (7.7) | |
| Years with MS (median (IQR)) | 19 (10–28) | 12 (6–18) | 0.060 |
| On DMT (%) | 335 (51.1) | 13 (100.0) | 0.001 |
| DMT name, n | |||
| azathioprine | 1 | 0 | |
| dimethyl fumarate | 66 | 0 | |
| fingolimod | 39 | 3 | |
| glatiramer acetate | 33 | 0 | |
| interferon beta-1a intramuscular | 32 | 0 | |
| interferon beta-1a subcutaneous | 2 | 0 | |
| IVIG | 1 | 0 | |
| methotrexate | 2 | 0 | |
| natalizumab | 22 | 0 | |
| ocrelizumab | 102 | 8 | |
| ozanimod | 1 | 0 | |
| PEGylated interferon beta-1a | 2 | 0 | |
| rituximab | 26 | 2 | |
| siponimod | 1 | 0 | |
| teriflunomide | 5 | 0 | |
| Diabetes (%) | 77 (11.7) | 0 (0) | 0.000 |
| Hypertension (%) | 181 (27.6) | 5 (38.5) | 0.386 |
| Coronary artery disease (%) | 45 (6.9) | 0 (0) | 0.000 |
| Known COVID-19 exposure (%) | 61 (9.3) | 4 (30.8) | 0.010 |
BMI: body mass index; MS: multiple sclerosis; RRMS: relapsing-remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis; PPMS: primary progressive multiple sclerosis; PRMS: progressive-relapsing multiple sclerosis; DMT: disease-modifying therapy; COVID-19: coronavirus disease 2019; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; PCR: polymerase chain reaction.
Table 2.
Demographics and COVID-19 outcomes per patient.
| Case | Age (years) | Race | Years since MS Onset | PDDS | DMT at time of vaccination | Smoking Status | Comorbidities | DMT to vaccine (months) a | Vaccine | Vaccine to diagnosis (days) b | CV-19 treatment | H | O2 | MV | PNA | Death |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 40 | White | 18 | 0-Normal | Ocrelizumab | NS | Sinus tachycardia | 4.5 | Moderna | 101 | No | No | No | No | No | No |
| 2 | 42 | White | 12 | 0-Normal | Fingolimod | NS | None | 0.0 | Pfizer | 26 | No | No | No | No | No | No |
| 3 | 48 | Black | 3 | 0-Normal | Rituximab | FS | Diabetes, hypertension | 4.6 | Pfizer | 27 | Steroids, remdesivir | Yes | Yes | No | Yes | No |
| 4 | 43 | White | 11 | 4-Early cane | Fingolimod | FS | Hypertension | 0.0 | Moderna | 92 | No | No | No | No | No | No |
| 5 | 55 | White | 10 | NA | Ocrelizumab | FS | None | 6.5 | Janssen | 19 | No | No | No | No | No | No |
| 6 | 35 | White | 15 | 1-Mild disability | Ocrelizumab | NS | None | 4.0 | Moderna | 110 | No | No | No | No | No | No |
| 7 | 40 | White | 6 | NA | Ocrelizumab | NS | None | 4.2 | Pfizer | 51 | No | No | No | No | No | No |
| 8 | 53 | White | 23 | 0-Normal | Ocrelizumab | NS | None | 3.1 | Janssen | 48 | No | No | No | No | No | No |
| 9 | 41 | White | 18 | 0-Normal | Fingolimod | NS | Hypertension | 0.0 | Pfizer | 13 | No | No | No | No | No | No |
| 10 | 47 | White | 18 | 6-Bilateral support | Ocrelizumab | NS | Hypertension | 3.2 | Pfizer | 11 | Steroids, remdesivir | Yes | No | No | No | No |
| 11 | 31 | White | 6 | 0-Normal | Rituximab | NS | None | 3.4 | Moderna | 79 | Inhaled cortico-steroids | No | No | No | Yes | No |
| 12 | 50 | Black | 24 | 6-Bilateral support | Ocrelizumab | NS | Hypertension | 1.7 | Pfizer | 8 | No | No | No | No | No | No |
| 13 | 65 | White | 6 | 0-Normal | Ocrelizumab | NS | Mycosis fungoides | 0.3 | Moderna | 110 | No | No | No | No | No | No |
PDDS: Patient-Determined Disease Steps; MS: multiple sclerosis; DMT: disease-modifying therapy; CV-19: coronavirus disease 2019; H: hospitalized; O2: supplemental oxygen; MV: mechanical ventilation; PNA: pneumonia; NS: never smoker; FS: former smoker; NA: not available; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; PCR: polymerase chain reaction.
Time interval from the last dose of disease-modifying therapy to the first dose of a vaccine, measured in months.
Time interval from the last dose of a vaccine to the date of the positive SARS-CoV-2 PCR result, measured in days.
Discussion
Prior pre-vaccination studies estimated the prevalence of COVID-19 in PwMS to be 4%. Although of limited sample size, our post-vaccination prevalence occurred exclusively in PwMS on DMT and was similar at 3.8%, suggesting that the 67%–95% reported vaccine efficacy may not fully apply to this population. Despite disease breakthrough, our patients had good outcomes. Most did not require hospitalization or COVID-19 treatment, none required ICU admission and none died.
In line with prior reports of reduced response to inactivated viral vaccines and higher breakthrough COVID-19 infections, particularly in those on anti-CD20 and S1PR DMTs, all observed breakthrough infections occurred in this subpopulation. However, in contrast to a report of lower humoral immunity in those on an S1PR modulator compared to anti-CD20, 22.7% and 3.8%, respectively, 6 and limited by the absence of available SARS-CoV-2 antibody titers from our patients, those requiring hospitalization in our study were all on anti-CD20 therapy. Such discrepancy highlights the range of anti-SARS-CoV-2 immune response and the remaining uncertainty surrounding which aspects of protective immunity translate to more favourable clinical outcomes – humoral versus cell-mediated processes. Recent data suggest patients on anti-CD20 have a preserved T-cell response to vaccination, albeit with shifts in lymphocyte subpopulations,8,9 yet these patients remain at higher risk for clinically significant breakthrough. Larger studies are required to analyze the range of vaccine response on DMT and if breakthrough COVID-19 outcomes differ in the setting of emerging variants. Nevertheless, PwMS on anti-CD20 and S1PR therapies appear at higher risk for breakthrough disease. Although still at risk for hospitalization, intubation and death from COVID-19 appear rare.
Acknowledgements
The authors thank our patients for participating in the registry, Mellen Center clinicians for referring patients, and Mellen Center research and intake staff for providing technical support for the study. Fellowship grant support for D.R. Rose was provided by the National MS Society, ICT-1805-311-54. Fellowship grant support for A.Z. Mahadeen was provided by the National MS Society, CF-2006-36618. Fellowship grant support for A.K. Carlson was provided by Biogen, 16696-P-FEL.
Footnotes
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: R.A. Bermel has served as a consultant for Biogen, EMD Serono, Genzyme/Sanofi, Genentech/Roche, Novartis and Viela Bio.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: S.M. Planchon received researching funding from Guthy Jackson Charitable Foundation. He receives ongoing research support directed to his institution from Biogen, Genentech and Novartis. J.A. Cohen received personal compensation for consulting for Biogen, Bristol-Myers Squibb, Convelo, Genentech, Janssen, NervGen, Novartis and PSI; speaking for H3 Communications; and serving as an Editor of Multiple Sclerosis Journal. B.P Moss has stock in Pfizer and has received consulting fees from Biogen.
ORCID iDs: Deja R Rose https://orcid.org/0000-0003-0423-0551
Sarah M Planchon https://orcid.org/0000-0002-5093-0754
Robert A Bermel https://orcid.org/0000-0003-2334-6883
Jeffrey A Cohen https://orcid.org/0000-0001-9245-9772
Brandon P Moss https://orcid.org/0000-0001-5319-5129
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