Low protection from breakthrough SARS-CoV-2 infection and mild disease course in ocrelizumab-treated patients with multiple sclerosis after three mRNA vaccine doses

Novak, Frederik; Bajwa, Hamza Mahmood; Coia, John; Nilsson, Anna Christine; Nielsen, Christian; Holm, Dorte Kinggaard; Østergaard, Kamilla; Hvidt, Mathilde Vilhelmine Miller; Byg, Keld-Erik; Johansen, Işık Somuncu; Mittl, Kristen; Rowles, William; Zamvil, Scott S.; Bove, Riley; Sabatino, Joseph J.; Sejbæk, Tobias

doi:10.1136/jnnp-2022-330757

Cited by 7 publications

(4 citation statements)

References 13 publications

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“…However, as no severe form of COVID-19 was observed in our cohort, whether this reinforced vaccination scheme would clinically benefit patients with MS on anti-CD20 to prevent severe COVID-19 could not be assessed. A recent study by Novak et al [27] found that 59% of patients on anti-CD20 developed breakthrough non-severe COVID-19 after three injections of SARS-CoV-2 mRNA vaccine. Another study by van Kempen et al [28] found that patients on anti-CD20 and S1PRM had a higher breakthrough COVID-19 rate compared to patients on other treatments, but most infections were mild.…”

Section: Discussionmentioning

confidence: 99%

Three to four mRNA COVID‐19 vaccines in multiple sclerosis patients on immunosuppressive drugs: Seroconversion and variant neutralization

Louapre¹,

Belin

Marot

et al. 2023

Euro J of Neurology

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Background and purpose An enhanced severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccine regimen could improve humoral vaccine response in patients with multiple sclerosis (MS) treated by anti‐CD20. The aim was to evaluate the serological response and the neutralizing activity after BNT162b2 primary and booster vaccination in MS patients, including patients on anti‐CD20 receiving a primary vaccine regimen enhanced with three injections. Methods In this prospective longitudinal cohort study of 90 patients (47 on anti‐CD20, 10 on fingolimod, 33 on natalizumab, dimethylfumarate or teriflunomide), anti‐SARS‐CoV‐2 receptor binding domain (RBD) immunoglobulin G antibodies were quantified and their neutralization capacity was evaluated by enzyme‐linked immunosorbent assay (GenScript) and a virus neutralization test against B.1 historical strain, Delta and Omicron variants, before and after three to four BNT162b2 injections. Results After the primary vaccination scheme, the anti‐RBD positivity rate was strongly decreased in patients on anti‐CD20 (28% [15%; 44%] after two shots, 45% [29%; 62%] after three shots) and fingolimod (50% [16%; 84%]) compared to other treatments (100% [90%; 100%]). Neutralization activity was also decreased in patients on anti‐CD20 and fingolimod, and notably low for the Omicron variant in all patients (0%–22%). Delayed booster vaccination was performed in 54 patients, leading to a mild increase of anti‐RBD seropositivity in patients on anti‐CD20 although it was still lower compared to other treatments (65% [43%; 84%] vs. 100% [87%; 100%] respectively). After a booster, Omicron neutralization activity remained low on anti‐CD20 and fingolimod treated patients but was strongly increased in patients on other treatments (91% [72%; 99%]). Discussion In MS patients on anti‐CD20, an enhanced primary vaccination scheme moderately increased anti‐RBD seropositivity and anti‐RBD antibody titre, but neutralization activity remained modest even after a fourth booster injection. Trial registration information COVIVAC‐ID, NCT04844489, first patient included on 20 April 2021.

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Section: Discussionmentioning

confidence: 99%

Three to four mRNA COVID‐19 vaccines in multiple sclerosis patients on immunosuppressive drugs: Seroconversion and variant neutralization

Louapre¹,

Belin

Marot

et al. 2023

Euro J of Neurology

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“…Previous studies have confirmed a greater risk of a breakthrough infection with lower anti-SARS-CoV-2-specific antibody levels and under certain disease-modifying therapies (DMTs) [ 13 , 14 , 15 , 16 ]. Especially under anti-CD20, the COVID-19 disease course was shown to remain more severe even after initial immunisation [ 15 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Long-Term Observation of SARS-CoV-2 Vaccination Response upon High Efficacy Treatment in Multiple Sclerosis—A Real-World Scenario

Schraad,

Runkel,

Hitzler

et al. 2024

Vaccines

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Immunomodulatory and immunosuppressive therapy is needed in people with a chronic neuroinflammatory disease of the central nervous system such as multiple sclerosis (MS). Therefore, MS requires monitoring for and preventing against infectious diseases like SARS-CoV-2. Vaccination and anti-viral treatments are, in particular, recommended for elderly people and people at risk of a severe course of infection and of MS. Here, we asked whether repetitive infection or vaccination influenced responses upon receiving high efficacy treatments, namely sphingosine-1-phosphate receptor modulator (S1P) or anti-CD20 B cell antibody (anti-CD20) treatments. We performed a prospective real-world study of people with MS (pwMS) under S1P or anti-CD20 with repetitive exposure to the SARS-CoV-2 virus or vaccine. The measurement of anti-SARS-CoV-2 antibody titres was performed by two independent immunoassays after initial immunisation and after booster vaccination or infection. Other laboratory and clinical parameters were included in the analysis of influencing factors. As secondary outcomes, lymphocyte and immunoglobulin levels were observed longitudinally under intravenous and subcutaneous anti-CD20 treatment. In a long-term real-world cohort of 201 pwMS, we found that despite lymphopenia upon S1P drugs, the SARS-CoV-2 immunisation response increased both in selective and non-selective S1P (100% and 88% seroconversion, respectively), whereas those under anti-CD20 therapies merely exhibited a slight long-term increase in antibody titres (52% seroconversion). The latter was independent of immunoglobulin or total lymphocyte levels, which mostly remained stable. If the individual was immunised prior to therapy initiation, their levels of SARS-CoV-2 antibodies remained high under treatment. PwMS under non-selective S1P benefit from repetitive vaccination. The risk of an insufficient vaccination response mirrored by lower SARS-CoV-2 antibodies remains in pwMS receiving anti-CD20 treatment, even after repetitive exposure to the vaccine or virus. Due to the compromised vaccination response in CD20-depleting drugs, prompt antiviral treatment might be necessary.

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“…Recent studies have identified seroconversion rates by pwMS on B cell-depleting therapies as ∼50% following three COVID-19 vaccine doses, amongst the lowest of any group, with antibody titres in those who do seroconvert inferior to healthy individuals. 5–8, 10, 12, 13 As such, it has been difficult to interpret the level of protection afforded these patients, particularly against antibody-escape variants such as omicron BA.5, and for clinicians and policy makers to make informed decisions with respect to booster dosing and existing and emerging prophylactic measures.…”

Section: Introductionmentioning

confidence: 99%

“…Common DMTs include the B cell-depleting anti-CD20 monoclonal antibody, ocrelizumab (Ocrevus), and the anti-α4integrin monoclonal antibody, natalizumab (Tysabri). B cell depleting therapies are associated with increased risk of severe COVID-19 disease [1][2][3][4][5] and impaired humoral immune response to vaccination [6][7][8][9][10] in pwMS and other patient populations. In contrast, natalizumab is nondepleting, and no impairment in vaccine response has been identified for pwMS receiving treatment with natalizumab.…”

Section: Introductionmentioning

confidence: 99%

Immune profiling of COVID-19 vaccine responses in people with multiple sclerosis on B cell-depleting therapy

Perkins,

Hope,

Chai

et al. 2023

Preprint

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Background and ObjectivePeople with multiple sclerosis (pwMS) receiving B cell-depleting therapies have impaired antibody responses to vaccination. In a proportion of individuals, repeat vaccination against COVID-19 leads to seroconversion. We sought to describe the immune phenotype of pwMS on ocrelizumab, and identify clinical and immunological determinants of an effective vaccine response.MethodsThis was a single-centre, prospective cohort study. Peripheral blood samples were collected from pwMS receiving ocrelizumab (n = 38) pre and post administration of a third dose of mRNA COVID-19 vaccine. Immunogenicity was measured by T cell IFNγ ELISpot, antibody titres, and live virus neutralisation. Humoral immunity was benchmarked against pwMS receiving natalizumab (n = 15), and against a correlate of real-world protection (50% reduction in incidence of infection) from SARS-CoV-2 ancestral and omicron BA.5 variants. The peripheral immune phenotype was comprehensively assessed by flow cytometry, and potential clinical and phenotypic determinants of response to vaccination identified.ResultsImmune cell populations relevant to disease and vaccine response were altered in pwMS receiving ocrelizumab versus natalizumab treatment, including depleted CD20-expressing B cell, T cell and NK cell populations, and elevated CD27+CD38+T cell and ‘NK8’ cell frequencies. Following a third vaccine dose, 51% of pwMS on ocrelizumab were seropositive for SARS-CoV-2 receptor-binding-domain IgG, and 25% and 14% met the threshold for effective neutralisation of live SARS-CoV-2 ancestral and omicron BA.5 virus, respectively. B cell frequency at the time of vaccination, but not time since ocrelizumab infusion, was positively correlated with antibody response, while a strong negative correlation was observed between CD56brightNK cell frequency and antibody response in the ocrelizumab group. In this exploratory cohort, CD3−CD20+B cells (% of lymphocytes; OR=3.92) and CD56brightNK cells (% of NK cells; OR=0.94) were predictive of an effective neutralising antibody response in second dose non-responders (AUC: 0.98).DiscussionOcrelizumab treatment was associated with an altered immune phenotype, including recently described T cell and NK populations with potential roles in disease pathogenesis. However, seroconversion was severely impaired by ocrelizumab, and less than half of those who seroconverted following a third vaccine dose demonstrated effective immunity against SARS-CoV-2 ancestral or omicron BA.5. B cell frequency was associated with an effective antibody response, while immunomodulatory CD56brightNK cells were identified as a potential negative determinant of response in those with inadequate B cell numbers. Immune phenotype rather than time since ocrelizumab infusion may help to stratify individuals for prophylaxis.

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Low protection from breakthrough SARS-CoV-2 infection and mild disease course in ocrelizumab-treated patients with multiple sclerosis after three mRNA vaccine doses

Cited by 7 publications

References 13 publications

Three to four mRNA COVID‐19 vaccines in multiple sclerosis patients on immunosuppressive drugs: Seroconversion and variant neutralization

Three to four mRNA COVID‐19 vaccines in multiple sclerosis patients on immunosuppressive drugs: Seroconversion and variant neutralization

Long-Term Observation of SARS-CoV-2 Vaccination Response upon High Efficacy Treatment in Multiple Sclerosis—A Real-World Scenario

Immune profiling of COVID-19 vaccine responses in people with multiple sclerosis on B cell-depleting therapy

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