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Abstract
Background Although vaccination against SARS-CoV-2 is recommended prior to introducing anti-CD20 therapies, limited data are available regarding the evolution of post-vaccinal immunity.
Methods This retrospective study compared anti-Spike antibody titres at 6 and 12 months from SARS-CoV-2 vaccination between patients vaccinated before switching to anti-CD20 (‘Switch’) and two control groups: (1) patients vaccinated under disease-modifying therapies (DMTs) other than fingolimod and anti-CD20 (‘Other DMTs’); (2) patients vaccinated on anti-CD20 (‘Anti-CD20’). Anti-Spike-specific T-cell responses were compared between ‘Switch’ and ‘Anti-CD20’ groups.
Results Fifty-three patients were included in the ‘Switch’ group, 54 in the ‘Other DMTs’ group and 141 in the ‘Anti-CD20’ group. At 6 months, in the subset of patients who received a booster dose, the ‘Switch’ group had lower anti-Spike titres compared with the ‘Other DMTs’ group (median 241.0 IQR (88.0; 504.0) BAU/mL vs 2034 (1155; 4634) BAU/mL, p<0.001), and less patients in the ‘Switch’ group reached the protective threshold of 264 BAU/mL. The ‘Switch’ group had higher anti-Spike titres than the ‘Anti-CD20’ group (7.5 (0.0; 62.1) BAU/mL, p=0.001). Anti-Spike titres were not different between the ‘Switch’ and ‘Other DMTs’ groups before booster administration. These results were similar at 12 months. Spike-specific T-cell positivity was similar between the ‘Switch’ and ‘Anti-CD20’ groups at 6 and 12 months (60.4% vs 61.0%, p=0.53, and 79.4% vs 87.5%, p=0.31, respectively).
Conclusions Despite a primary vaccination performed before the first anti-CD20 cycle, our results suggest weaker immune responses at 6 and 12 months and decreased booster efficacy after introducing anti-CD20. Patients vaccinated prior to anti-CD20 introduction might falsely be considered as fully protected by vaccination.
- MULTIPLE SCLEROSIS
- COVID-19
- IMMUNOLOGY
Data availability statement
Data are available upon reasonable request. The datasets used and analysed during the current study are available from the corresponding author on reasonable request.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
As anti-CD20 therapies decrease humoral immune responses, updating vaccination schemes is recommended before the first anti-CD20 infusion.
However, no data are available regarding the follow-up of this post-vaccine immunity after the anti-CD20 therapy is introduced.
WHAT THIS STUDY ADDS
Patients vaccinated against SARS-CoV-2 before an anti-CD20 therapy was introduced have decreased anti-Spike antibody titres at 6 and 12 months from the primary vaccination, compared with patients with other disease-modifying therapies, and respond poorly to booster doses.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The pre-existence of a humoral immune response before the introduction of anti-CD20 was insufficient to increase anti-Spike IgG titres after booster vaccination and to maintain sufficient long-term immune protection over time, warranting the need for serological follow-up in this population and the discussion for reinforced booster schemes.
Introduction
Treatment strategies for multiple sclerosis (MS) and related disorders (RDs) have broadened in recent years with the early introduction of high-efficacy disease-modifying therapies (DMTs).1 Managing the infectious risk induced by these immunosuppressive therapies2 is balanced by the need to reduce long-term disability and relies on individual prevention strategies and vaccination. Among DMTs, anti-CD20 antibodies are used in active forms of MS,3 neuromyelitis optica spectrum disorder (NMOSD) and myelin-oligodendrocyte glycoprotein antibody disease (MOGAD),4 5 and are associated with a risk of severe infections6 and decreased humoral responses to both infections and vaccination.7 8
With the emergence of SARS-CoV-2 vaccines reducing COVID-19-related mortality and hospitalisations,9 10 patients with immunosuppressive DMTs were targeted for high-priority vaccination. Patients with anti-CD20 have lower antibody titres,11 while being at higher risk of severe COVID-19 infection.12 13 Therefore, when possible, completing vaccination schemes before the first anti-CD20 administration is recommended, including vaccination against Streptococcus pneumoniae, hepatitis B virus and a strong recommendation for SARS-CoV-2.14–16 However, data on the evolution of post-vaccine immune responses after introduction of anti-CD20 therapies remain scarce. To date, no further serological follow-up is recommended, and patients are generally considered as protected if vaccinated before the first anti-CD20 cycle.
In 2021, the massive vaccination campaign launched to stop the COVID-19 pandemic offered an excellent opportunity to study post-vaccine immunity. Patients with MS and RD indicated for anti-CD20 initiation in 2021 were strongly advised to receive vaccination against SARS-CoV-2 before the first anti-CD20 administration,17 offering a rare opportunity to study the effect of the introduction of an anti-CD20 therapy on post-vaccine immunity at a large scale.
In this study, we aimed to address the long-term evolution of SARS-CoV-2 vaccine immune responses in patients with MS and RD vaccinated before receiving an anti-CD20 therapy. The primary objective was to assess whether these patients had a lower humoral response at 6 and 12 months compared with patients treated with other DMTs, that is, if the introduction of anti-CD20 therapies was responsible for a quicker decrease in humoral immunity. Humoral responses were also compared with a control group of patients vaccinated under anti-CD20 therapy. The secondary objectives were (1) to assess if vaccination before introducing anti-CD20 therapies helps to achieve good responses to booster doses, and (2) to compare the cellular immune responses of patients vaccinated before and during anti-CD20 therapies.
Methods
Design
We conducted a retrospective cohort study in a French reference centre (Neurology Department of Pitié Salpétrière University Hospital) on patients with MS and RD, included into three groups (figure 1):
Patients who switched from any DMT (or naïve patients) to an anti-CD20 therapy within 4 months after receiving a complete primary vaccination scheme against SARS-CoV-2 before the first anti-CD20 infusion (‘Switch’ group).
Patients vaccinated during treatment with a DMT other than rituximab, ocrelizumab or fingolimod (‘Other DMTs’ group), considered as good responders to vaccination.18 19
Patients vaccinated during treatment with an anti-CD20 therapy (‘Anti-CD20’ group), considered as poor responders to vaccination.18 19
Study design. Patients were included into three groups: (1) switch to anti-CD20 after a primary vaccination with two injections of anti-SARS-CoV-2 vaccine while on other DMTs or naïve from any DMT (‘Switch’ group); (2) primary SARS-CoV-2 vaccination during treatment with a DMT other than fingolimod or anti-CD20 (‘Other DMTs’ group) or no treatment; (3) vaccination during an anti-CD20 therapy (‘Anti-CD20’ group). Patients underwent blood draws at month 6 (M6) and month 12 (M12) after the primary vaccination to compare immune responses at the two time points. Some patients received one or two booster doses at month 6 and/or month 12. DMT, disease-modifying therapy; M6, month 6; M12, month 12.
Population and inclusion criteria
Period of interest
The first year of anti-SARS-CoV-2 vaccine availability in France from 1 January 2021 to 31 December 2021.
Population of interest
Patients with MS and RD, including relapsing MS (RMS), primary progressive MS (PP-MS), secondary progressive MS (SP-MS), NMOSD, seronegative or with anti-AQP4 antibodies, and MOGAD.
Inclusion and exclusion criteria
See online supplemental table 1 for detailed criteria. We included adults (≥18 years old), with MS or RD, who completed a two-dose or three-dose primary mRNA vaccination scheme against SARS-CoV-2, and with available serology testing 6 months after primary vaccination.
Supplemental material
‘Switch’ group: Patients admitted for a first ocrelizumab or rituximab infusion between 1 January 2021 and 31 December 2021 were screened for inclusion. Inclusion criteria were as follows: vaccination against SARS-CoV-2 with a DMT (or without treatment) before receiving a first anti-CD20 infusion within 4 months from the last injection of primary vaccination. Exclusion criteria were as follows: vaccination under fingolimod, first booster received before the first infusion of anti-CD20 and anti-CD20 infusion intervals >6 months.
‘Other DMTs’ group: Subjects were screened from two prospective studies of patients with MS vaccinated with the BNT162b2 vaccine, who had SARS-CoV-2 serology testing at 6 and 12 months after primary vaccination: the COVIVAC-ID (NCT04844489) and BioCoCo neurosciences (NCT04568707) cohort studies. For the present study, we included patients participating in COVIVAC-ID or BioCoCo Neurosciences, treated with natalizumab, dimethylfumarate, teriflunomide, glatiramer acetate, interferon or receiving no treatment. Exclusion criteria include patients receiving fingolimod.
‘Anti-CD20’ group: We included patients treated with anti-CD20 therapies in our daily hospitalisation unit, or included in COVIVAC-ID or BioCoCo-Neurosciences (see above). Inclusion criteria were as follows: SARS-CoV-2 primary vaccination administered after at least one anti-CD20 infusion. Exclusion criteria were as follows: interval between two anti-CD20 infusions of more than 6 months, administration of monoclonal antibodies against SARS-CoV-2 or intravenous immunoglobulins before serology testing.
Collected data
The following data were collected: age; neurological diagnosis; treatments received; Expanded Disability Status Scale (EDSS) at treatment onset and vaccination; primary vaccine scheme, booster doses and name of vaccine; anti-Spike (Anti-S) and anti-Nucleocapsid (anti-N) immunoglobulin G (IgG) at 6 and 12 months from the primary vaccination; CD4, CD8, total lymphocyte counts and IgG dosage at 6 and 12 months from vaccination if available; interferon γ enzyme-linked immunospot for SARS-CoV-2 data at 6 and 12 months from vaccination (data available only for the ‘Anti-CD20’ and ‘Switch’ groups as only these patients were followed in the daily hospitalisation unit where this analysis was performed). Data were collected and managed in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) Statement Checklist (https://www.strobe-statement.org/checklists/).
SARS-CoV-2 serology
Anti-N IgG detection and anti-S IgG quantification were performed using an automated chemiluminescence assay on the Abbott Alinity i platform. An IgG index ≥0.8 indicates a positive serological result for anti-N antibodies. A cut-off of 7.1 binding antibody units per millilitre (BAU/mL) was retained for anti-S positivity, as recommended by the manufacturer. A cut-off of 264 BAU/mL for anti-S was considered a good humoral response based on a vaccine efficacy of 80%.20
SARS-CoV-2-specific T-cell responses
SARS-CoV-2-specific T-cell responses were assessed by a whole blood interferon-gamma (IFN-γ) release assay (Quantiferon SARS-CoV-2, Qiagen). Briefly, venous blood samples were transferred into Quantiferon tubes containing Spike peptides, positive and negative controls. Whole blood was incubated at 37°C for 16–24 hours and centrifuged to separate plasma. IFN-γ (IU/mL) was measured in these plasma samples using QuantiFERON Human IFN-γ SARS-CoV-2 ELISA kits (Qiagen) on Dynex DS2 analyser (Qiagen). IFN-γ levels ≥0.15 IU/mL were considered as positive.
Statistical analysis
Results are expressed as counts and frequencies for categorical variables and medians (IQR) for quantitative variables. Comparisons were performed using χ2 or Fisher’s exact test for categorical variables and Wilcoxon rank-sum test for continuous variables, as appropriate. All tests were two-sided, and a p value <0.05 was considered statistically significant. Analyses were performed using R Statistical Software V.3.5.2 (R Project for statistical computing).
Results
A total of 248 patients were included: 53 patients in the ‘Switch’ group, 54 patients in the ‘Other DMTs’ group and 141 patients in the ‘Anti-CD20’ group (see Study Design in figure 1).
Patients’ characteristics
Patients’ characteristics and vaccination data are presented in table 1.
Patients’ characteristics and vaccination data
One hundred and sixty-one (64.9%) patients were female, with a median age at primary vaccination of 43.0 (IQR 33.0, 51.0) years, and a median EDSS of 2.5 (IQR 1.5, 5.0). Overall, 167 (67.3%) patients were diagnosed with RMS, 21 (8.5%) with PP-MS, 53 (21.4%) with SP-MS, 6 (2.4%) with AQP4+NMOSD and 1 (0.4%) with seronegative NMOSD. No patient had MOGAD. Thirty-nine (73.6%) patients were treated with ocrelizumab in the ‘Switch’ group and 118 (83.7%) in the ‘Anti-CD20’ group. In the ‘Other DMTs’ group, the main treatment was teriflunomide (15 (27.8%) patients), followed by natalizumab (10 (18.5%) patients), dimethyl fumarate (9 (16.7%) patients), glatiramer acetate (6 (11.1%) patients), interferon (6 (11.1%) patients) and 8 (14.8%) patients had no ongoing treatment. Lymphocyte counts and IgG dosage were similar between the three groups and are available in online supplemental table 2).
Vaccination data
In the ‘Switch’ group, the first anti-CD20 infusion was delayed relative to the treatment decision in 40 (75.5%) patients to allow time for SARS-CoV-2 vaccination. Sixty-two (44.0%) patients in the ‘Anti-CD20’ group had a three-dose primary vaccination, compared with five (9.4%) patients in the ‘Switch’ group and none in the ‘Other DMTs’ group (p<0.001). A total of 242 (97.6%) patients were vaccinated with the BNT162b2 vaccine, 194 (78.2%) received a booster dose 6 months after primary vaccination and 40 (16.1%) received a second booster dose at 12 months.
Humoral immune response at month 6 (M6) after primary vaccination
Post-vaccine follow-up data at 6 and 12 months are presented in table 2.
Post-vaccine SARS-CoV-2 humoral and cellular response at 6 and 12 months
At M6, 52 (98.1%) patients in the ‘Switch’ group had detectable anti-S IgG, compared with 54 (100.0%) in the ‘Other DMTs’ group and 75 (53.2%) in the ‘anti-CD20’ group (p<0.001). Patients in the ‘Switch’ group had a lower humoral response at M6 compared with the ‘Other DMTs’ group (219.0 (QR 78.0, 498.0) BAU/mL vs 992.9 (169.5, 2317.0) BAU/mL, p<0.001, see figure 2A) but higher than the anti-CD20 group (7.4 (0.0, 64.2) BAU/mL, p<0.001). In post hoc subgroup analyses based on SARS-CoV-2 booster dose administrations (figure 2B,C), among patients who did not receive a booster dose before M6 serology, the median anti-S IgG titres were similar between the ‘Switch’ (176.0 (IQR 63.5, 260.5) BAU/mL) and ‘Other DMTs’ groups (206.6 (103.7, 498.4) BAU/mL, p=0.25). In the subgroup of patients who received a booster dose, median anti-S IgG titres were lower in the ‘Switch’ group (241.0 (88.0, 504.0) BAU/mL; p<0.001) compared with the ‘Other DMTs’ group (2033.6 (1155.0, 4634.5) BAU/mL). In the ‘Anti-CD20’ group, the median anti-S IgG titre remained lower in the ‘Switch’ or ‘Other DMTs’ groups, regardless of booster administration (p<0.001, see figure 2B,C).
Comparison of anti-Spike IgG titres at month 6 among the three groups. (A) Comparison of anti-Spike IgG titre between ‘Other DMTs’ (n=54), ‘Switch’ (n=53) and ‘Anti-CD20’ (n=141) groups at month 6 from primary vaccination. (B) Comparison of anti-Spike IgG titre between ‘Other DMTs’ (n=28), ‘Switch’ (n=11) and ‘Anti-CD20’ (n=41) groups at month 6 from primary vaccination, in the subgroup of patients who did not receive a booster dose (‘Without booster’) prior to serology testing. (C) Comparison of anti-Spike IgG titre between ‘Other DMTs’ (n=26), ‘Switch’ (n=42) and ‘Anti-CD20’ (n=100) groups at month 6 from the primary vaccination, in the subgroup of patients who received a booster dose (‘With booster’) prior to serology testing. Significance: NS non-significant, that is, p>0.05; ***p<0.001. The positivity (ie, 7.1 BAU/mL) and protective (ie, 264 BAU/mL) thresholds are represented by blue and red dashed lines, respectively. Anti-S IgG, anti-Spike immunoglobulin G; BAU/mL, binding antibody unit per millilitre; DMT, disease-modifying therapy.
The proportion of patients reaching IgG anti-S positivity (≥7.1 BAU/mL) and protective thresholds (≥264 BAU/mL) are shown for each group in figure 3. Patients in the ‘Switch’ group were less likely to reach the protective threshold than those in the ‘Other DMTs’ group (43.4% vs 68.5%, p=0.01). In the ‘Anti-CD20’ group, 16 (11.3%) patients reached the protective threshold of anti-S humoral response (p<0.001).
Rates of patients reaching positivity (ie, ≥7.1 BAU/mL) and protective (ie, ≥264 BAU/mL) anti-Spike IgG titre thresholds at month 6. (A) Rates (%) of patients reaching the positivity threshold of ≥7.1 BAU/mL for anti-Spike IgG titre at month 6, for all patients with and without booster (left), for subgroup of patients without a booster dose (middle) and for subgroup of patients with a booster dose (right). (B) Rates of patients reaching the protective threshold of ≥264 BAU/mL for anti-Spike IgG titre at month 6, for all patients with and without booster (left), for subgroup of patients without a booster dose (middle) and for subgroup of patients with a booster dose (right). Significance: NS, non-significant, that is, p>0.05; *p=0.01; ***p<0.001. Anti-S IgG, anti-Spike immunoglobulin G; BAU/mL, binding antibody unit per millilitre; DMT, disease-modifying therapy.
A booster dose administration was associated with increased humoral response in the ‘Other DMTs’ group (206.6 (IQR 103.7, 498.4) vs 2033.6 (1155.0, 4634.5) BAU/mL, p<0.001), while it had no significant effect in the ‘Switch’ group (176.0 (63.5, 260.5) vs 241.0 (88.0, 504.0) BAU/mL, p=0.31) and in the ‘Anti-CD20’ group (7.4 (0.0, 64.2) vs 7.5 (0.0, 62.1) BAU/mL, p=0.50, see online supplemental figure 1).
Supplemental material
Sixteen patients in the ‘Switch’ group received steroids prior to primary vaccination because of an MS relapse. The median delay between steroid pulses and vaccination in these 16 patients was 16.9 (10.3, 21) weeks. In the ‘Switch’ group, anti-S IgG titres at month 6 and month 12 were not statistically different in the subgroup of patients who received steroids before vaccination and those who did not (month 6: 277 (121, 597) BAU/mL vs 115 (65.5, 273.5) BAU/mL, with and without steroids, respectively, p=0.187; month 12: 62.5 (18, 186) vs 183 (50.7, 450.7) with and without steroids, respectively, p=0.186).
Humoral immune response at month 12 (M12) after primary vaccination
At M12, anti-S IgG were detectable in 40 (95.2%) patients in the ‘Switch’ group, compared with 45 (100.0%, p=0.23) in the ‘Other DMTs’ group and 31 (44.9%, p<0.001) in the ‘Anti-CD20’ group (table 2). Anti-S IgG titres were lower in the ‘Switch’ group (148.5 (41.2, 338.5) BAU/mL) than in the ‘Other DMTs’ group (2471.5 (1180.0, 5675.0) BAU/mL, p<0.001, see figure 4A), but remained higher than in the ‘Anti-CD20’ group (3.7 (0.1, 51.0) BAU/mL, p<0.001). In line with the results at M6, a lower proportion of patients in the ‘Switch’ group reached the 264 BAU/mL protective threshold compared with the ‘Other DMTs’ group (35.7% vs 100%, p<0.001) (see figure 4B,C). Patients in the ‘Anti-CD20’ group were the least likely to reach the protective thresholds (10.1%; p<0.001). The proportion of patients reaching the protective threshold in the ‘Switch’ and ‘Anti-CD20’ groups did not differ between month 6 and month 12, while it increased in the ‘Other DMTs’ group (see online supplemental figure 2). No additional analysis per booster subgroup was performed at M12 given the low number of patients who received a second booster dose.
Supplemental material
Anti-Spike IgG titres at month 6 and month 12 between the three groups. (A) Comparison of anti-Spike IgG titre between ‘Other DMTs’ (n=45), ‘Switch’ (n=42) and ‘Anti-CD20’ (n=69) groups at month 12 from the primary vaccination. (B) Rates of patients reaching the positivity threshold of ≥7.1 BAU/mL for anti-Spike IgG titre at month 12. (C) Rates of patients reaching the protective threshold of ≥264 BAU/mL for anti-Spike IgG titre at month 12. Significance: NS, non-significant, that is, p>0.05; *p=0.01; ***p<0.001. The positivity (ie, 7.1 BAU/mL) and protective (ie, 264 BAU/mL) thresholds are represented by blue and red dashed lines, respectively. Anti-S IgG, anti-Spike immunoglobulin G; BAU/mL, binding antibody unit per millilitre; DMT, disease-modifying therapy.
Spike-specific T-cell responses at month 6 (M6) and month 12 (M12) after primary vaccination
Spike-specific T-cell responses data are represented in figure 5. The proportion of patients with a positive Spike-specific T cell response was similar between the ‘Switch’ and ‘Anti-CD20’ groups at M6 (60.4% vs 61.0%, p=0.53, figure 5A). There was no quantitative difference for the response to the two antigens (namely, antigen 1 and antigen 2) used in the assay to detect Spike-specific T-cell responses at M6 (figure 5B,C). Comparable results were obtained at M12 with a similar proportion of patients with positive T-cell responses (79.4% vs 87.5%, p=0.31; figure 5D) and similar quantitative results (figure 5E,F).
Spike-specific T-cell responses at month 6 and month 12 in the ‘Switch’ and ‘Anti-CD20’ groups. (A) Positivity rates of the Spike-specific T-cell response at M6 in the ‘Switch’ and ‘Anti-CD20’ groups. (B) Quantitative Spike-specific T-cell response for antigen 1 (one of the two tested antigens for T-cell stimulation) at M6 in the ‘Switch’ and ‘Anti-CD20’ groups. (C) Quantitative Spike-specific T-cell response for antigen 2 at M6 in the ‘Switch’ and ‘Anti-CD20’ groups. (D) Positivity rates of the Spike-specific T-cell response at M12 in the ‘Switch’ and ‘Anti-CD20’ groups. (E) Quantitative Spike-specific T-cell response for antigen 1 at M12 in the ‘Switch’ and ‘Anti-CD20’ groups. (F) Quantitative Spike-specific T-cell response for antigen 2 at M12 in the ‘Switch’ and ‘Anti-CD20’ groups. Significance: NS, non-significant, that is, p>0.05. An ‘undetermined’ result signifies that either the positive (mitogen) or negative control failed to give an appropriate response. A low T-cell response to mitogen may occur with lymphopenia, functional defect in the patient’s T lymphocytes to generate IFN-γ or improper sample handling. Ag, antigen; DMT, disease-modifying therapy; IFN, interferon; M6, month 6; M12, month 12.
Discussion
Our study focused on the follow-up of SARS-CoV-2 vaccine immune response after the initiation of anti-CD20 therapies for MS and RDs. Although the poor vaccine responses under anti-CD20 therapies have been extensively studied,11 to our knowledge, no data are available on the evolution of humoral and cellular immunity in patients vaccinated before the introduction of anti-CD20 therapies.
Vaccination is strongly advised before the first infusion of anti-CD20,14–16 and since vaccination occurs before the B lymphocytes depletion, patients are often considered as protected by vaccine immunity afterwards. However, our findings showed that patients vaccinated against SARS-CoV-2 before the first anti-CD20 cycle had lower anti-S IgG titres at 6 and 12 months compared with patients treated with other DMTs. Titres of anti-S antibodies are positively associated with protection against symptomatic SARS-CoV-2 infection.20 In our cohort, almost all patients had detectable anti-S IgG at 6 months in the ‘Switch’ group, suggesting the development of an immune response following the primary vaccination. However, unlike patients with other DMTs, less than half were reaching the protective threshold of 264 BAU/mL. This suggests that these patients may be falsely considered as fully protected by the vaccination that occurred before the first cycle of anti-CD20.
Studies have suggested the interest of a third vaccine dose in patients with a weak immune response to a two-dose SARS-CoV-2 primary vaccination.21 In our cohort, only five (9.4%) patients in the ‘Switch’ group received a three-dose primary vaccination, compared with 44% of patients in the ‘Anti-CD20’ group, which was insufficient to study the effect of this reinforced primary vaccination scheme on the evolution of anti-S IgG titres and the response to the booster doses.
When considering the subgroup of serology testing performed before the administration of a booster dose at 6 months, we found no significant differences in anti-S IgG titres between the ‘Switch’ and the ‘Other DMT’ groups. However, this could be due to a lack of power because only 11 patients in the ‘Switch’ group had available pre-booster samples at M6. Therefore, we cannot exclude that introducing an anti-CD20 might decrease anti-S IgG titres faster than the usual fading humoral response.
The booster dose increased anti-S IgG titres in the ‘Other DMTs’ group, and similar to previously published data,22 this was not the case in patients in the ‘Anti-CD20’ group. Previous studies reported that patients on anti-CD20 therapies have better chances of responding to booster doses if they had a positive response after the primary vaccination.22 However, in the ‘Switch group’, the booster dose at M6 (after the anti-CD20 therapy was started) did not significantly affect the proportion of patients reaching the protective threshold of 264 BAU/mL. Lower anti-S IgG titres in the ‘Switch’ compared with the ‘Other DMTs’ group were also observed at 12 months, despite the administration of a booster dose at 6 months in a large proportion of patients. This suggests that vaccination during treatment with anti-CD20 remains poorly effective for humoral immunity, and that the pre-existence of a humoral immune response before the introduction of anti-CD20 was insufficient to increase anti-S IgG titres after booster doses.
In the ‘Switch’ group, the first anti-CD20 cycle was delayed in more than 75% of cases to perform primary vaccination against SARS-CoV-2, at the risk of exposing patients to clinical relapses. These patients showed better immune responses at 6 and 12 months than those in the ‘Anti-CD20’ group, suggesting that vaccination before anti-CD20 stays useful in this population. The persistence of this humoral response on longer time scales is however uncertain. Especially, one could wonder if the IgG titres of the ‘Switch’ group would ultimately match those of the ‘Anti-CD20 group’, meaning the post-vaccine immune protection would only be transitory. Data from longer term, prospective studies appear necessary to assess the sustainability of immune protection over time.
Fingolimod is associated with lower anti-Spike-specific T-cell responses and anti-S IgG titres after vaccination,23 24 while patients with anti-CD20 therapies have preserved specific T-cell responses.11 Patients vaccinated during treatment with fingolimod before switching to anti-CD20 therapies were therefore excluded from our study. We showed no difference in the anti-Spike-specific T-cell response between ‘Switch’ and ‘Anti-CD20’ groups, with preserved cellular responses in 60%–80% of patients in both groups.
Our study has several limitations. First, its retrospective design did not allow a standardised protocol for blood sampling at similar time points for all patients. Out of the 248 patients with available serological data at 6 months, only 156 had available data at 12 months. Second, we could not obtain baseline serology testing following primary vaccination, nor blood samples before and after booster injections: subgroup analyses of pre-booster and post-booster anti-S IgG titres were performed in different patients. Third, as patients from ‘Other DMTs’ group were followed in the outpatient clinic and not in daily hospitalisation unit, blood sampling for anti-Spike-specific T-cell response could not be collected for this group. We also did not have reliable data on documented SARS-CoV-2 infections during the period of the study. However, with a long period of follow-up of 12 months and in a real-life context, systematically performing PCR for SARS-CoV-2 for each COVID-19 suspicion would be difficult to set up, particularly given the number of asymptomatic infections and the development of antigenic self-testing. We nevertheless report the results of anti-N IgG for our patients, but anti-CD20 therapies are known to impair the development of these antibodies.8
Our study is the first report investigating follow-up of immune responses after introducing an anti-CD20 therapy. It raises the question of long-term immunity in patients vaccinated against various infectious agents before the introduction of anti-CD20 therapies, who are often considered to be protected with vaccine immunity. Prospective studies with serological assessments at various time points are needed to extend our knowledge of long-term immunity with other types of vaccines recommended for these populations.
Conclusion
Vaccination against SARS-CoV-2 before the introduction of anti-CD20 therapy, despite allowing a detectable initial humoral immune response, did not allow conservation of a protective anti-S antibody titre at 6 and 12 months compared with other DMTs, probably partly due to decreased booster efficacy. More data from prospective studies are needed to assess the decrease in post-vaccine humoral and cellular immunity after the introduction of anti-CD20 therapies in patients who are often considered protected if vaccination is performed before anti-CD20 initiation.
Data availability statement
Data are available upon reasonable request. The datasets used and analysed during the current study are available from the corresponding author on reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
The COVIVAC-ID study was registered on ClinicalTrial.gov (NCT04844489) and approved by the ethical and scientific committee of Ile de France number 8 under the registration number IDRCB 2021-A00469-32. The BioCoCo neurosciences study was registered on ClinicalTrial.gov (NCT04568707) and approved by the ethical and scientific committee Ile de France number 3 under the registration number 2020-A02256-33. In both studies, subjects provided written informed consent for participation and for the use of clinical and biological data in further studies focusing on post-vaccine COVID-19 immunity. Patients included from our daily hospitalisation unit were informed about the objective of the study, and the collection of non-opposition to the retrospective use of medical data was carried out according to French law, good clinical practice and General Data Protection Regulation (GDPR). Participants gave informed consent to participate in the study before taking part.
Acknowledgments
The authors thank the doctors and laboratory technicians from the Immunology Department (Hôpital Pitié-Salpêtrière, 75013 Paris, France) who participated in this study; medical and nurse staff from daily MS clinic and from Neuroscience Clinical Investigation Center (Hôpital Pitié-Salpêtrière, 75013 Paris, France).
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Twitter @clouapre
Contributors CL accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
LJ participated in the study conception, collected and interpreted the data, performed statistical analysis, designed the figures and wrote the first draft of the manuscript. BA, CS and A-GM provided serology data and analyses and participated in data interpretation. DS provided specific T-cell data and analyses and participated in data interpretation. EM, YB and AH participated in major revisions of the manuscript. LB contributed to data interpretation and major revisions of the manuscript. VM participated in data interpretation and major revisions of the manuscript. CL supervised the study, participated in the study conception, data collection and interpretation. All authors contributed to critical revision of the manuscript and have read and approved its final version. CL accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
Funding Part of the data used in one of the control groups of this study was extracted from the COVIVAC-ID study that was supported by Roche and by a grant from Assistance Publique – Hôpitaux de Paris. The biological Cohort COVID-19 Neurosciences (BioCoCo Neurosciences), was funded by the generous support of the Fédération Internationale de l'Automobile (FIA) Foundation, the Fondation de France Grant No 00113315, and donors of Paris Brain Institute – ICM.
Competing interests CL has received consulting or travel fees from Biogen, Novartis, Roche, Sanofi, Teva and Merck Serono, and research grant from Biogen, none related to the present work. EM has received consulting or travel fees from Alexion, Biogen, Horizon, Janssen, Merck, Novartis, Sanofi and Teva, and research grant from Biogen, none related to the present work. VP has received consulting or travel fees from Gilead, ViiV, MSD, Biogen, Novartis, Roche and Merck Serono, none related to the present work. LJ, BA, CS, DS, YB, AH, LB and A-GM have no competing interest to declare.
Provenance and peer review Not commissioned; externally peer reviewed.
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