Humoral and cellular immune response from first to fourth SARS-CoV-2 mRNA vaccination in anti-CD20-treated multiple sclerosis patients-a longitudinal cohort study.

Background: This study examines the humoral and cellular response in multiple sclerosis (MS) patients on anti-CD20 therapy before and after the 1st to 4th BNT162b2 mRNA SARS-CoV-2 vaccination and the relationship with breakthrough infection. Methods: Participants with McDonald 2017 MS that were treated with ocrelizumab were included. The study duration was throughout the COVID-19 pandemic until four months after fourth mRNA SARS-CoV-2 vaccination (BNT162b2). Longitudinal blood samples were analysed for: IgG antibodies of SARS-CoV-2 spike anti-receptor binding domain (anti-RBD), nucleocapsid IgG antibodies (anti-N) and activation induced marker expressing CD4+, CD8+ T-cells and concentration of ocrelizumab and anti-drug antibodies. Incidences of breakthrough infection were confirmed with SARS-CoV-2 PCR tests. Results: The rate of anti-RBD positive participants increased substantially between the third and fourth vaccination from 22.2% to 55.9% (median 54.7 BAU/mL; IQR: 14.5 - 221.2 BAU/mL and 607.7 BAU/mL; IQR: 29.4 - 784.6 BAU/mL, respectively). Within the same period 75% of participants experienced breakthrough infection. The fourth vaccination resulted in an additional increase in seropositive individuals (64.3%) (median 541.8 BAU/mL (IQR: 19.1-1007 BAU/mL). Breakthrough infection did not influence the cellular response without a significant change after the fourth vaccination. During the study period two participants had detectable anti-N, both after the fourth vaccination. No correlation was found between serum concentration of ocrelizumab and the humoral and cellular response. Discussion: Low levels or absence of specific anti-RBD following vaccination, with a significant increase after breakthrough infections and boosted by the fourth vaccination. T-cell reactivity remained sustained and unaffected by breakthrough infections.

Extended interval dosing with ocrelizumab in multiple sclerosis.

BACKGROUND: This study investigates clinical and biomarker differences between standard interval dosing (SID) and extended interval dosing (EID) of ocrelizumab therapy in multiple sclerosis (MS). METHODS: This is a prospective, double-arm, open-label, multi-center study in Denmark. Participants diagnosed with MS on ocrelizumab therapy >12 months were included (n = 184). Clinical, radiological, and blood-based biomarker outcomes were evaluated. MRI disease activity, relapses, worsening of neurostatus, and No Evidence of Disease Activity-3 (NEDA-3) were used as a combined endpoint. RESULTS: Out of 184 participants, 107 participants received EID (58.2%), whereas 77 participants received SID (41.8%). The average extension was 9 weeks with a maximum of 78 weeks. When comparing EID to SID, we found higher levels of B-cells, lower serum concentrations of ocrelizumab, and similar levels of age-adjusted NFL and GFAP in the two groups. No difference in NEDA-3 between EID and SID was demonstrated (hazard ratio: 1.174, p = 0.69). Higher levels of NFL were identified in participants with disease activity. Body mass index correlated with levels of ocrelizumab and B-cells. CONCLUSION: Extending one treatment interval of ocrelizumab on average 9 weeks and up to 78 weeks did not result in clinical, radiological, or biomarker evidence of worsening compared with SID.

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

BACKGROUND: Our study investigated the rate of breakthrough SARS-CoV-2 infection and clinical outcomes in a cohort of multiple sclerosis (MS) patients who were treated with the anti-CD20 monoclonal antibody (Ab), ocrelizumab, before first, second and third BNT162b2 mRNA vaccinations. To correlate clinical outcomes with the humoral and cellular response. METHODS: The study was a prospective non-randomised controlled multicentre trial observational study. Participants with a diagnosis of MS who were treated for at least 12 months with ocrelizumab prior to the first BNT162b2 mRNA vaccination were prospectively followed up from January 2021 to June 2022. RESULTS: Out of 54 participants, 32 (59.3%) developed a positive SARS-CoV-2 PCR test in the study period. Mild infection was observed in all infected participants. After the third vaccination, the non-infected participants had higher mean Ab levels compared to the infected participants (54.3 binding antibody unit (BAU)/mL vs 26.5 BAU/mL, p=0.030). The difference in reactivity between spike-specific CD4+ and CD8+ T lymphocytes in the two groups was not significant. CONCLUSION AND RELEVANCE: The study results demonstrate rates of 59% in breakthrough infections after the third SARS-CoV-2 mRNA vaccination in ocrelizumab-treated patients with MS, without resulting in critical disease courses. These findings suggest the need for continuous development of prophylactic treatments when proved important in the protection of severe breakthrough infection.

Persistently reduced humoral and sustained cellular immune response from first to third SARS-CoV-2 mRNA vaccination in anti-CD20-treated multiple sclerosis patients.

OBJECTIVE: To examine humoral and cellular response in multiple sclerosis patients on anti-CD20 therapy after third BNT162b2 mRNA SARS-CoV-2 vaccination. METHODS: A prospective longitudinal study design from first throughout third vaccination in Danish and American MS centers. All participants were treated with ocrelizumab. Antibody (Ab) levels were assessed before and after third vaccination using SARS-CoV-2 IgG II Quant assay (Abbott Laboratories). B- and T-lymphocytes enumeration was done with BD Multitest™6-color TBNK reagent. Spike-specific T-cell responses were measured through PBMC stimulation with spike peptide pools (JPT Peptide Technologies). RESULTS: We found that 14.0%, 37.7%, and 33.3% were seropositive after first, second and third vaccination. The median Ab-levels were 74.2 BAU/mL (range: 8.5-2427) after second vaccination, as well as 43.7 BAU/ml (range: 7.8-366.1) and 31.3 BAU/mL (range: 7.9-507.0) before and after third vaccination, respectively. No difference was found in levels after second and third vaccination (p = 0.1475). Seropositivity dropped to 25.0% of participants before the third vaccination, a relative reduction of 33.3% (p = 0.0020). No difference was found between frequencies of spike reactive CD4+and CD8+ T-cells after second (0.65 ± 0.08% and 0.95 ± 0.20%, respectively) and third vaccination (0.99 ± 0.22% and 1.3 ± 0.34%, respectively). CONCLUSION: In this longitudinal cohort we found no significant increased humoral or cellular response with administration of a third SARS-CoV-2 mRNA vaccination. These findings suggest the need for clinical strategies to include allowance of B cell reconstitution before repeat vaccination and/or provision of pre-exposure prophylactic monoclonal antibodies.

Humoral immune response following SARS-CoV-2 mRNA vaccination concomitant to anti-CD20 therapy in multiple sclerosis.

BACKGROUND: The immunogenicity of COVID-19 vaccine among patients receiving anti-CD20 monoclonal antibody (Ab) treatment has not been fully investigated. Detectable levels of SARS-CoV-2 immunoglobulin G (IgG) are believed to have a predictive value for immune protection against COVID-19 and is currently a surrogate indicator for vaccine efficacy. OBJECTIVE: To determine IgG Abs in anti-CD20 treated patients with multiple sclerosis (MS). METHOD: IgG Abs against SARS-CoV-2 spike receptor-binding domain were measured with the SARS-CoV-2 IgG II Quant assay (Abbott Laboratories) before and after vaccination (n = 60). RESULTS: 36.7% of patients mounted a positive SARS-CoV-2 spike Ab response after the second dose of vaccine. Five patients (8.3%) developed Abs >264 BAU/mL, another 12 patients (20%) developed intermediate Abs between 54 BAU/mL and 264 BAU/mL and five patients (8.3%) had low levels <54 BAU/mL. Of all seropositive patients, 63.6% converted from seronegative to seropositive after the 2nd vaccine. CONCLUSION: Our study demonstrates decreased humoral response after BNT162b2 mRNA SARS-CoV-2 vaccine in MS patients receiving B-cell depleting therapy. Clinicians should advise patients treated with anti-CD20 to avoid exposure to SARS-CoV-2. Future studies should investigate the implications of a third booster vaccine in patients with low or absent Abs after vaccination.

Poor compliance with an antibiotic directive-A call for intensified monitoring.

BACKGROUND: In April 2017, the Central Denmark Region Antibiotic Stewardship Committee issued a directive to reduce the general use of piperacillin-tazobactam and prescribe narrow-spectrum antibiotics for mild and moderate pneumonia. The directive was distributed to all regional hospital clinicians. METHODS: Electronic medical records were used to obtain de-identified details of all antibiotics administered (together with diagnosis codes) to all in-hospital patients (pre-directive and post-directive) in the nine regional hospitals. Average moving range statistical process control charts were used to analyze pre-directive and post-directive variation in antibiotic usage patterns. RESULTS: Upon the distribution of the directive, a period of decline of the overall usage of piperacillin-tazobactam ensued. Rather than benzylpenicillin, as recommended for pneumonia, the initial decline in piperacillin/tazobactam usage was accompanied by increased use of cefuroxime. CONCLUSIONS: A steward-directed reduction in piperacillin-tazobactam usage was accompanied by less desirable usage of a broad-spectrum alternative. Future antibiotic stewardship initiatives will hopefully benefit from close monitoring and timely feedback to clinicians. A dialogue with clinicians based on near real-time data is predicted to improve antibiotic stewardship actions.