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. 2024 Apr 1;7(4):e246345.
doi: 10.1001/jamanetworkopen.2024.6345.

Vaccine Safety and Immunogenicity in Patients With Multiple Sclerosis Treated With Natalizumab

René Carvajal  1 , Ana Zabalza  1 , Pere Carbonell-Mirabent  1 , Xavier Martínez-Gómez  2 , Juliana Esperalba  3   4 , Agustín Pappolla  1 , Ariadna Rando  3 , Alvaro Cobo-Calvo  1 , Carmen Tur  1 , Marta Rodriguez  1 , Jordi Río  1 , Manuel Comabella  1 , Joaquín Castilló  1 , José Ángel Rodrigo-Pendás  2 , Nathane Braga  1 , Neus Mongay-Ochoa  1 , Claudia Guío-Sánchez  1 , Ángela Vidal-Jordana  1 , Georgina Arrambide  1 , Breogán Rodríguez-Acevedo  1 , Luciana Midaglia  1 , Blanca Borras-Bermejo  2 , Ingrid Galán  1 , Jaume Sastre-Garriga  1 , Xavier Montalban  1   5 , Susana Otero-Romero  1   2 , Mar Tintoré  1   5
Affiliations

Vaccine Safety and Immunogenicity in Patients With Multiple Sclerosis Treated With Natalizumab

René Carvajal et al. JAMA Netw Open. .

Abstract

Importance: Vaccination in patients with highly active multiple sclerosis (MS) requiring prompt treatment initiation may result in impaired vaccine responses and/or treatment delay.

Objective: To assess the immunogenicity and safety of inactivated vaccines administered during natalizumab treatment.

Design, setting, and participants: This self-controlled, prospective cohort study followed adult patients with MS from 1 study center in Spain from September 2016 to February 2022. Eligible participants included adults with MS who completed immunization for hepatitis B virus (HBV), hepatitis A virus (HAV), and COVID-19 during natalizumab therapy. Data analysis was conducted from November 2022 to February 2023.

Exposures: Patients were categorized according to their time receiving natalizumab treatment at the time of vaccine administration as short-term (≤1 year) or long-term (>1 year).

Main outcomes and measures: Demographic, clinical, and radiological characteristics were collected during the year before vaccination (prevaccination period) and the year after vaccination (postvaccination period). Seroprotection rates and postvaccination immunoglobulin G titers were determined for each vaccine within both periods. Additionally, differences in annualized relapse rate (ARR), new T2 lesions (NT2L), Expanded Disability Status Scale (EDSS) scores, and John Cunningham virus (JCV) serostatus between the 2 periods were assessed.

Results: Sixty patients with MS (mean [SD] age, 43.2 [9.4] years; 44 female [73.3%]; 16 male [26.7%]; mean [SD] disease duration, 17.0 [8.7] years) completed HBV, HAV, and mRNA COVID-19 immunization during natalizumab treatment, with 12 patients in the short-term group and 48 patients in the long-term group. The global seroprotection rate was 93% (95% CI, 86%-98%), with individual vaccine rates of 92% for HAV (95% CI, 73%-99%), 93% for HBV (95% CI, 76%-99%), and 100% for the COVID-19 messenger RNA vaccine (95% CI, 84%-100%). Between the prevaccination and postvaccination periods there was a significant reduction in the mean (SD) ARR (0.28 [0.66] vs 0.01 [0.12]; P = .004) and median (IQR) NT2L (5.00 [2.00-10.00] vs 0.81 [0.00-0.50]; P = .01). No changes in disability accumulation were detected (median [IQR] EDSS score 3.5 [2.0-6.0] vs 3.5 [2.0-6.0]; P = .62). No differences in safety and immunogenicity were observed for all vaccines concerning the duration of natalizumab treatment.

Conclusions and relevance: The findings of this cohort study suggest that immunization with inactivated vaccines during natalizumab therapy was both safe and immunogenic, regardless of the treatment duration. Natalizumab may be a valuable option for proper immunization, averting treatment delays in patients with highly active MS; however, this strategy needs to be formally evaluated.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Carvajal reported receiving grants from the Vall d’Hebron Institut de Recerca and European Committee for Treatment and Research in Multiple Sclerosis; honoraria from Roche, Novartis, BIIB-Colombia, Merck, and Sanofi outside the submitted work. Dr Zabalza reported receiving grants from Rio Hortega, Instituto de Salud Carlos III, Spain (grant No. CM22/00237), and Novartis; personal fees from Biogen-Idec, Merck-Serono, and Novartis; and honoraria from Eisai outside the submitted work. Mr Carbonell reported receiving a grant from Biogen to Fundació Privada Cemcat for statistical analysis outside the submitted work. Dr Martínez-Gómez reported receiving personal fees from GlaxoSmithKline, Sanofi Pasteur and Merck, Statens Serum Institut, and Janssen outside the submitted work. Dr Pappolla reported receiving personal fees from Roche; honoraria from Novartis; and grants from the European Committee for Treatment and Research in Multiple Sclerosis Clinical Training Fellowship Program and the Multiple Sclerosis International Foundation/The Scientific Committee of the French Multiple Sclerosis Research Support Foundation Fellowship Program outside the submitted work. Dr Cobo-Calvo reported receiving grants from the Instituto de Salud Carlos III, Spain (grant No. JR19/0000D7) outside the submitted work. Dr Tur reported receiving grants from the Junior Leader La Caixa Fellowship (grant No. LCF/BQ/PI20/11760008) awarded by the la Caixa Foundation (ID 100010434) and Fundación Merck Salud (the 2021 Merck Award for Investigation in Multiple Sclerosis), the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación de España (grant No. PI21/01860), European Committee for Treatment and Research in Multiple Sclerosis (postdoctoral research fellowship), and the UK Multiple Sclerosis Society; being a member of the Editorial Board of Neurology and Multiple Sclerosis Journal, a steering committee member of the O’HAND trial, and a steering committee member and of the Consensus group; and receiving honoraria from Roche and Novartis outside the submitted work. Dr Río reported receiving honoraria and personal fees for participating on advisory boards from Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Teva, Roche, and Sanofi-Aventis outside the submitted work. Dr Comabella reported receiving personal fees and honoraria from Bayer Schering Pharma, Merck-Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, and Novartis outside the submitted work. Dr Rodigo-Pendás reported receiving research support fees from GlaxoSmithKline, Sanofi Pasteur and Merck, Statens Serum Institut, Janssen, Prevention B.V. and Spanish Clinical Research Network; and travel expense fees from Sanofi Pasteur and Merck outside the submitted work. Dr Braga reported receiving personal fees and honoraria from Roche, Novartis, Biogen, and Merck outside the submitted work. Dr Mongay-Ochoa reported receiving grants from Rio Hortega and the Instituto de Salud Carlos III (grant No. CM21/00018); and personal fees and honoraria from Merck and Roche outside the submitted work. Dr Guío-Sánchez reported receiving grants from the European Committee for Treatment and Research in Multiple Sclerosis (clinical fellowship awardee 2022-2023); personal fees from Sanofi-Genzyme, Merck, Novartis, Roche, and Biogen-Idec outside the submitted work. Dr Vidal-Jordana reported receiving honoraria for consulting and/or participating as a speaker in events organized by Roche, Novartis, Merck, and Sanofi outside the submitted work. Dr Arrambide reported receiving honoraria for consulting services and participating in advisory boards for Sanofi, Merck, Roche, and Horizon Therapeutics; personal fees from Novartis and Roche; and grants from the European Committee for Treatment and Research in Multiple Sclerosis outside the submitted work. Dr Rodríguez-Acevedo reported receiving honoraria from Merck and Novartis outside the submitted work. Dr Borras-Bermejo reported receiving personal fees from GlaxoSmithKline outside the submitted work. Dr Sastre-Garriga reported serving as coeditor for Europe on the editorial board of the Multiple Sclerosis Journal and as Editor-in-Chief in Revista de Neurología; receiving research support from Fondo de Investigaciones Sanitarias (19/950); and receiving personal fees from Biogen, Celgene, Bristol Meyers Squibb, Sanofi, Novartis, and Merck outside the submitted work. Dr Montalbán reported receiving honoraria and personal fees, being a steering committee member of clinical trials, and participating on advisory boards of clinical trials with Abbvie, Actelion, Alexion, Biogen, Bristol-Myers Squibb, Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, Medday, Merck, Mylan, Nervgen, Novartis, Sandoz, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, Multiple Sclerosis International Foundation, and the National Multiple Sclerosis Society outside the submitted work. Dr Otero-Romero reported receiving honoraria from Genzyme, Biogen-Idec, Novartis, Roche, Excemed, Merck Sharp & Dohme, and GlaxoSmithKline; and research support from Novartis outside the submitted work. Dr Tintoré reported receiving personal fees and honoraria from Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio, and Teva Pharmaceuticals; and serving on the Data Safety Monitoring Board for Parexel and UCB Biopharma outside the submitted work.

Figures

Figure 1.
Figure 1.. Patient Flow Diagram
MS indicates multiple sclerosis. aCriteria included at least the first 3 doses of the hepatitis B primovaccination schedule (0, 1, 2, and 6-12 months); at least the first dose of the hepatitis A vaccination schedule (0 and 6-12 months); 2 doses of the COVID-19 primovaccination schedule (BNT162b2 and mRNA-1273, 0 and 1 months; ChAdOx1-S, 0 and 3 months).
Figure 2.
Figure 2.. Immunogenicity of Vaccination in Patients With Multiple Sclerosis Treated with Natalizumab
The figure shows immunoglobulin G (IgG) titers according to type of vaccine for hepatitis vaccines (A) and COVID-19 vaccines (B). Each dot in panels A and B represents a different participant. Cutoff values for antibody positivity are indicated by a dotted line. Panel C displays seroprotection rates for the hepatitis A, hepatitis B, and COVID-19 vaccines after vaccination. AU indicates antibody units; BAU, binding antibody units; mrNA, messenger RNA.
Figure 3.
Figure 3.. Disease Paths, Relapses, Natalizumab Exposure, and Differences Between Prevaccination and Postvaccination Periods
Each line illustrates a patient’s journey from symptom onset to the latest follow-up. The line turns red during natalizumab treatment. Blue dots symbolize relapses. The shaded gray region marks the year before and after vaccination, corresponding to prevaccination and postvacciantion periods.
Figure 4.
Figure 4.. Proposed Algorithm for Immunizations in Patients With Highly Active Multiple Sclerosis Who Require Prompt Initiation of High Efficacy Disease Modifying Therapy,
AHSCT indicates autologous hematopoietic stem cell transplantation; DMT, disease-modifying therapy; JCV, John Cunningham virus; MAbs, monoclonal antibodies. aAccording to the patients’ characteristics, background history of infections and vaccinations, serological tests, and past or future immunosuppressive therapies.,, bFor measles and varicella zoster virus.
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