Natalizumab treatment shows no clinically meaningful effects on immunization responses in patients with relapsing-remitting multiple sclerosis

https://doi.org/10.1016/j.jns.2014.03.035Get rights and content

Highlights

  • We immunized MS patients who were randomized to natalizumab or control groups.

  • Tetanus toxoid [TT] was the recall antigen.

  • Keyhole limpet hemocyanin (KLH) was the neoantigen.

  • Immunization responses were similar in natalizumab-treated and control groups.

  • Findings suggest no meaningful effect of natalizumab on immunization response.

Abstract

Natalizumab is an immunomodulatory drug approved for the treatment of multiple sclerosis. This randomized, multicenter, open-label study evaluated natalizumab's effects on immunization responses to a recall antigen (tetanus toxoid [TT]) and a neoantigen (keyhole limpet hemocyanin [KLH]) in patients with relapsing forms of multiple sclerosis (MS). Natalizumab-naive relapsing MS patients were randomized (1:1; n = 30 per group) to receive TT and KLH immunizations either without natalizumab treatment (control) or after 6 months of natalizumab treatment (natalizumab group). An adequate response to immunization was defined as an increase to at least twofold in specific serum immunoglobulin G (IgG) 28 days after the first immunization. All evaluable patients achieved protective levels of anti-TT IgG antibodies, and the proportion of responders to this recall antigen, as well as to primary immunization with KLH, was similar in the presence and absence of natalizumab. This indicates that natalizumab treatment does not appear to affect responses to primary or secondary immunization in a clinically meaningful way.

Introduction

Understanding immune responses with immunomodulatory therapy is important for the management of multiple sclerosis (MS) patients in clinical practice. Interferon beta-1a (Rebif®, EMD Serono Rockland, MA, USA) and teriflunomide (Aubagio®, Genzyme, Cambridge, MA, USA) do not appear to have an effect on immunization responses [1], [2]. In contrast, fingolimod (Gilenya®, Novartis, East Hanover, NJ, USA) appeared to decrease the response to a pneumococcal vaccine, while responses to keyhole limpet hemocyanin (KLH) and influenza vaccines in patients treated with fingolimod were similar to or lower than responses in patients who received placebo [3], [4], [5]. In a small pilot study of patients treated with alemtuzumab (Lemtrada™, Genzyme, Cambridge, MA, USA) [6], humoral responses to recall antigens (pneumococcal vaccine and diphtheria, tetanus, and poliomyelitis vaccine) and a novel antigen (Haemophilus influenza type b and meningococcal group C conjugate vaccine) were consistent with historical controls. However, compared with patients who were vaccinated at least 6 months after alemtuzumab treatment, response was achieved in a smaller proportion of patients who were vaccinated within 6 months of treatment [7]. To our knowledge, no immunization data are currently available for glatiramer acetate (Copaxone®, Teva Neuroscience, Kansas City, MO, USA), mitoxantrone (Novantrone®, EMD Serono, Inc, Darmstadt, Germany), or dimethyl fumarate (Tecfidera™, Biogen Idec, Cambridge, MA, USA). With respect to natalizumab (Tysabri®, Biogen Idec, Cambridge, MA, USA), one report showed no decrease in the response to influenza vaccination [8].

Natalizumab, an established therapy for MS and Crohn's disease, is a recombinant humanized monoclonal antibody (Ab) that inhibits binding of the α4 subunit of the α4β1 and α4β7 integrins on mononuclear leukocytes to their endothelial receptors and prevents trafficking of mononuclear leukocytes across vascular endothelium [9], [10], [11]. Treatment with natalizumab has been associated with herpes infections as well as with progressive multifocal leukoencephalopathy [9], [12], [13], [14].

Both de novo Ab responses to neoantigens (primary responses) and recall responses to memory antigens (secondary responses) involve activation of antigen-specific T and B cells in secondary lymphoid tissues [15]. While human and animal studies have shown that natalizumab increases the number of circulating lymphocytes, possibly due to trafficking effects [12], [16], [17], [18], [19], [20], animal studies have not shown a significant effect of α4-integrin blockade on T and B cell trafficking into most lymphoid tissues [21]. Nonhuman primate studies have shown no significant effect of natalizumab on primary or secondary Ab responses [20]; however, it is important to evaluate its effects on primary and secondary immune responses in patients.

Owing to the potential effects of α4-integrin blockade by natalizumab on lymphocyte trafficking through primary and secondary lymphoid organs, it is important to provide additional data on the impact of natalizumab therapy on vaccination response in MS patients [21].

The objective of this study was to evaluate the effect of natalizumab on T-cell-dependent Ab responses to a recall antigen (tetanus toxoid [TT]) and to a neoantigen (keyhole limpet hemocyanin [KLH]) in patients with relapsing forms of MS. TT was used in this United States (US) study to assess recall Ab responses, as the majority of the US population receive childhood TT immunizations [22]. KLH, a strongly immunogenic protein isolated from the giant keyhole limpet, was used to assess primary immunization responses [23].

Section snippets

Study design

 In this phase 4, randomized, multi center, open-label study, eligible MS patients, naive to natalizumab, were randomized (1:1) to receive TT and KLH immunizations either 2 months prior to natalizumab treatment or after 6 months of natalizumab treatment (Fig. 1). Patients enrolling in the study agreed to delay treatment with natalizumab for approximately 2 months if randomized to the control/immunization-only group. All nine US sites used an interactive voice response system to randomize patients

Patient disposition

Planned enrollment was approximately 46 patients — 23 patients per group. Per protocol, it was possible to replace patients who withdrew. This was done by increasing the total number of patients randomized rather than by recruiting patients to the required pre-specified groups. The number of eligible patients and the amount of eligible data were reduced further as a result of protocol deviations concerning the administration of KLH and TT. Therefore, in order to ensure sufficient patient

Discussion

Natalizumab has proven efficacy in reducing central nervous system inflammation in MS [9]; however, its effects on primary and secondary humoral immune responses have not been well studied.

This study was not designed to detect small differences between treatment arms, but to investigate whether there is a clinically relevant alteration of the immune response with natalizumab treatment. The proportions of responders to recall antigen (TT) and neoantigen (KLH) immunization were similar in control

Funding

This study was funded by Biogen Idec Inc.

Conflict of interest statement

Dr. Kaufman has received honoraria and research support from Biogen Idec, has received financial support from Bayer, EMD Serono, Novartis, and Teva, and is a consultant for Department of Defense. Dr. Pardo has received consulting fees from Acorda, Biogen Idec, Novartis, and Teva; he has received compensation for speaking from Acorda, Bayer HealthCare, Biogen Idec, EMD Serono, Novartis, Pfizer, and Teva. Dr. Rossman has no financial relationships to disclose. Drs. Sweetser and Duda and Ms.

Acknowledgments

Biogen Idec provided funding for editorial support in the development of this manuscript; Britt Anderson, PhD, from Infusion Communications wrote the first draft of the manuscript based on input from authors, and Jackie Cannon from Infusion Communications copyedited and styled the manuscript per journal requirements. Biogen Idec reviewed and provided feedback on the manuscript to the authors. The authors had full editorial control of the manuscript and provided their final approval of all

References (28)

  • M. Vågberg et al.

    Humoral immune response to influenza vaccine in natalizumab-treated MS patients

    Neurol Res

    (Sep 2012)
  • C.H. Polman et al.

    A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis

    N Engl J Med

    (Mar 2 2006)
  • W.J. Sandborn et al.

    Natalizumab induction and maintenance therapy for Crohn's disease

    N Engl J Med

    (Nov 3 2005)
  • T.A. Yednock et al.

    Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin

    Nature

    (Mar 5 1992)
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