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March 03, 2015; 84 (9) Article

Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis

Ludwig Kappos, Matthias Mehling, Rafael Arroyo, Guillermo Izquierdo, Krzysztof Selmaj, Valentina Curovic-Perisic, Astrid Keil, Mahendra Bijarnia, Arun Singh, Philipp von Rosenstiel
First published January 30, 2015, DOI: https://doi.org/10.1212/WNL.0000000000001302
Ludwig Kappos
From the University Hospital Basel (L.K., M.M.), Basel, Switzerland; Hospital Clínico San Carlos (R.A.), Madrid, Spain; Virgen Macarena Hospital (G.I.), Seville, Spain; Medical University of Lodz (K.S.), Lodz, Poland; Novartis Pharmaceuticals Corporation (V.C.-P.), Hanover, NJ; Novartis Pharma AG (A.K., P.v.R.), Basel, Switzerland; and Novartis Healthcare Pvt. Ltd. (M.B., A.S.), Hyderabad, India.
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Matthias Mehling
From the University Hospital Basel (L.K., M.M.), Basel, Switzerland; Hospital Clínico San Carlos (R.A.), Madrid, Spain; Virgen Macarena Hospital (G.I.), Seville, Spain; Medical University of Lodz (K.S.), Lodz, Poland; Novartis Pharmaceuticals Corporation (V.C.-P.), Hanover, NJ; Novartis Pharma AG (A.K., P.v.R.), Basel, Switzerland; and Novartis Healthcare Pvt. Ltd. (M.B., A.S.), Hyderabad, India.
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Rafael Arroyo
From the University Hospital Basel (L.K., M.M.), Basel, Switzerland; Hospital Clínico San Carlos (R.A.), Madrid, Spain; Virgen Macarena Hospital (G.I.), Seville, Spain; Medical University of Lodz (K.S.), Lodz, Poland; Novartis Pharmaceuticals Corporation (V.C.-P.), Hanover, NJ; Novartis Pharma AG (A.K., P.v.R.), Basel, Switzerland; and Novartis Healthcare Pvt. Ltd. (M.B., A.S.), Hyderabad, India.
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Guillermo Izquierdo
From the University Hospital Basel (L.K., M.M.), Basel, Switzerland; Hospital Clínico San Carlos (R.A.), Madrid, Spain; Virgen Macarena Hospital (G.I.), Seville, Spain; Medical University of Lodz (K.S.), Lodz, Poland; Novartis Pharmaceuticals Corporation (V.C.-P.), Hanover, NJ; Novartis Pharma AG (A.K., P.v.R.), Basel, Switzerland; and Novartis Healthcare Pvt. Ltd. (M.B., A.S.), Hyderabad, India.
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Krzysztof Selmaj
From the University Hospital Basel (L.K., M.M.), Basel, Switzerland; Hospital Clínico San Carlos (R.A.), Madrid, Spain; Virgen Macarena Hospital (G.I.), Seville, Spain; Medical University of Lodz (K.S.), Lodz, Poland; Novartis Pharmaceuticals Corporation (V.C.-P.), Hanover, NJ; Novartis Pharma AG (A.K., P.v.R.), Basel, Switzerland; and Novartis Healthcare Pvt. Ltd. (M.B., A.S.), Hyderabad, India.
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Valentina Curovic-Perisic
From the University Hospital Basel (L.K., M.M.), Basel, Switzerland; Hospital Clínico San Carlos (R.A.), Madrid, Spain; Virgen Macarena Hospital (G.I.), Seville, Spain; Medical University of Lodz (K.S.), Lodz, Poland; Novartis Pharmaceuticals Corporation (V.C.-P.), Hanover, NJ; Novartis Pharma AG (A.K., P.v.R.), Basel, Switzerland; and Novartis Healthcare Pvt. Ltd. (M.B., A.S.), Hyderabad, India.
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Astrid Keil
From the University Hospital Basel (L.K., M.M.), Basel, Switzerland; Hospital Clínico San Carlos (R.A.), Madrid, Spain; Virgen Macarena Hospital (G.I.), Seville, Spain; Medical University of Lodz (K.S.), Lodz, Poland; Novartis Pharmaceuticals Corporation (V.C.-P.), Hanover, NJ; Novartis Pharma AG (A.K., P.v.R.), Basel, Switzerland; and Novartis Healthcare Pvt. Ltd. (M.B., A.S.), Hyderabad, India.
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Mahendra Bijarnia
From the University Hospital Basel (L.K., M.M.), Basel, Switzerland; Hospital Clínico San Carlos (R.A.), Madrid, Spain; Virgen Macarena Hospital (G.I.), Seville, Spain; Medical University of Lodz (K.S.), Lodz, Poland; Novartis Pharmaceuticals Corporation (V.C.-P.), Hanover, NJ; Novartis Pharma AG (A.K., P.v.R.), Basel, Switzerland; and Novartis Healthcare Pvt. Ltd. (M.B., A.S.), Hyderabad, India.
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Arun Singh
From the University Hospital Basel (L.K., M.M.), Basel, Switzerland; Hospital Clínico San Carlos (R.A.), Madrid, Spain; Virgen Macarena Hospital (G.I.), Seville, Spain; Medical University of Lodz (K.S.), Lodz, Poland; Novartis Pharmaceuticals Corporation (V.C.-P.), Hanover, NJ; Novartis Pharma AG (A.K., P.v.R.), Basel, Switzerland; and Novartis Healthcare Pvt. Ltd. (M.B., A.S.), Hyderabad, India.
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Philipp von Rosenstiel
From the University Hospital Basel (L.K., M.M.), Basel, Switzerland; Hospital Clínico San Carlos (R.A.), Madrid, Spain; Virgen Macarena Hospital (G.I.), Seville, Spain; Medical University of Lodz (K.S.), Lodz, Poland; Novartis Pharmaceuticals Corporation (V.C.-P.), Hanover, NJ; Novartis Pharma AG (A.K., P.v.R.), Basel, Switzerland; and Novartis Healthcare Pvt. Ltd. (M.B., A.S.), Hyderabad, India.
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Citation
Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis
Ludwig Kappos, Matthias Mehling, Rafael Arroyo, Guillermo Izquierdo, Krzysztof Selmaj, Valentina Curovic-Perisic, Astrid Keil, Mahendra Bijarnia, Arun Singh, Philipp von Rosenstiel
Neurology Mar 2015, 84 (9) 872-879; DOI: 10.1212/WNL.0000000000001302

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Abstract

Objective: To evaluate immune responses in fingolimod-treated patients with multiple sclerosis (MS) against influenza vaccine (to test for responses against anticipated novel antigens in seronegative patients) and recall (tetanus toxoid [TT] booster dose) antigens.

Methods: This was a blinded, randomized, multicenter, placebo-controlled study. Patients aged 18 to 55 years with relapsing MS were randomized (2:1) to fingolimod 0.5 mg or placebo for 12 weeks. At week 6, patients received seasonal influenza vaccine (containing antigens of California, Perth, and Brisbane virus strains) and TT booster dose. Antibody titers against influenza and TT were estimated at baseline (prevaccination) and 3 and 6 weeks postvaccination. The primary efficacy variable was responder rate (proportion of patients showing seroconversion or significant increase [≥4-fold] in antibody titers against at least one influenza virus strain) at 3 weeks postvaccination and vs placebo.

Results: Of 138 randomized patients (fingolimod 95, placebo 43), 136 completed the study (2 discontinued in fingolimod group). The responder rates (odds ratio; 95% confidence interval) for influenza vaccine (fingolimod vs placebo) were 54% vs 85% (0.21; 0.08–0.54) at 3 weeks and 43% vs 75% (0.25; 0.11–0.57) at 6 weeks postvaccination. For TT, responder rates were 40% vs 61% (0.43; 0.20–0.92) at 3 weeks and 38% vs 49% (0.62; 0.29–1.33) at 6 weeks postvaccination. Adverse events were reported in 86.3% and 79.1% of patients receiving fingolimod and placebo, respectively.

Conclusion: Most fingolimod-treated patients with MS were able to mount immune responses against novel and recall antigens and the majority met regulatory criteria indicating seroprotection. However, response rates were reduced compared with placebo-treated patients. This should be kept in mind when vaccinating patients on fingolimod.

Classification of evidence: This study provides Class I evidence that in some patients with MS receiving immunizations, concurrent fingolimod treatment in comparison to placebo decreases vaccination-induced immune responses.

GLOSSARY

CCR7=
C-C chemokine receptor 7;
CI=
confidence interval;
HAI=
hemagglutination inhibition;
Ig=
immunoglobulin;
KLH=
keyhole limpet hemocyanin;
MS=
multiple sclerosis;
OR=
odds ratio;
PPV-23=
23-valent pneumococcal polysaccharides vaccine;
S1P=
sphingosine 1-phosphate;
TT=
tetanus toxoid

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Editorial, page 864

  • Supplemental data at Neurology.org

  • Received January 21, 2014.
  • Accepted in final form October 13, 2014.
  • © 2015 American Academy of Neurology
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