Hookworm Treatment for Relapsing Multiple Sclerosis

Abstract

IMPORTANCEStudies suggest gut worms induce immune responses that can protect against multiple sclerosis (MS). To our knowledge, there are no controlled treatment trials with helminth in MS.OBJECTIVE To determine whether hookworm treatment has effects on magnetic resonance imaging (MRI) activity and T regulatory cells in relapsing MS.DESIGN, SETTING, AND PARTICIPANTS This 9-month double-blind, randomized, placebo-controlled trial was conducted between September 2012 and March 2016 in a modified intention-to-treat population (the data were analyzed June 2018) at the University of Nottingham, Queen's Medical Centre, a single tertiary referral center. Patients aged 18 to 61 years with relapsing MS without disease-modifying treatment were recruited from the MS clinic. Seventy-three patients were screened; of these, 71 were recruited (2 ineligible/ declined).INTERVENTIONS Patients were randomized (1:1) to receive either 25 Necator americanus larvae transcutaneously or placebo. The MRI scans were performed monthly during months 3 to 9 and 3 months posttreatment. MAIN OUTCOMES AND MEASURESThe primary end point was the cumulative number of new/enlarging T2/new enhancing T1 lesions at month 9. The secondary end point was the percentage of cluster of differentiation (CD) 4+CD25 high CD127 neg T regulatory cells in peripheral blood.RESULTS Patients (mean [SD] age, 45 [9.5] years; 50 women [71%]) were randomized to receive hookworm (35 [49.3%]) or placebo (36 [50.7%]). Sixty-six patients (93.0%) completed the trial. The median cumulative numbers of new/enlarging/enhancing lesions were not significantly different between the groups by preplanned Mann-Whitney U tests, which lose power with tied data (high number of zeroactivity MRIs in the hookworm group, 18/35 [51.4%] vs 10/36 [27.8%] in the placebo group). The percentage of CD4+CD25 high CD127 neg T cells increased at month 9 in the hookworm group (hookworm, 32 [4.4%]; placebo, 34 [3.9%]; P = .01). No patients withdrew because of adverse effects. There were no differences in adverse events between groups except more application-site skin discomfort in the hookworm group (82% vs 28%). There were 5 relapses (14.3%) in the hookworm group vs 11 (30.6%) receiving placebo.CONCLUSIONS AND RELEVANCE Treatment with hookworm was safe and well tolerated. The primary outcome did not reach significance, likely because of a low level of disease activity. Hookworm infection increased T regulatory cells, suggesting an immunobiological effect of hookworm. It appears that a living organism can precipitate immunoregulatory changes that may affect MS disease activity.

An Absence of Epstein–Barr Virus Reactivation and Associations with Disease Activity in People with Multiple Sclerosis Undergoing Therapeutic Hookworm Vaccination

“…There were no serious clinical adverse events directly attributable to EBV during the trial. Infection with N. americanus was confirmed using molecular methods in 23 of 35 PwMS who underwent therapeutic infection [20].…”

“…PwMS meeting the McDonald criteria [21] for relapsing and remitting multiple sclerosis were included together with secondary multiple sclerosis patients with superimposed relapse, subject to specific clinical criteria. Exclusion criteria (for details, see supplementary section Tanasescu et al [20]) included prior or present evidence of parasitic infection and prior treatment with anti-helminthic drugs in the preceding six years. PwMS entered into the trial had not received immunosuppressive drugs 12 weeks prior to enrolment, were immunocompetent, and had not been treated with interferon or glatiramer acetate within 8 weeks of enrolment.…”

“…PwMS entered into the trial had not received immunosuppressive drugs 12 weeks prior to enrolment, were immunocompetent, and had not been treated with interferon or glatiramer acetate within 8 weeks of enrolment. N. americanus infection was confirmed using real-time polymerase chain reaction and amplicon sequencing [20]. Adequate serum samples were available from 51 study participants: 26 treated with hookworm and 25 given placebo.…”

“…The Nottingham Worms for Immune Regulation in Multiple Sclerosis (WIRMS) study [20] commenced on 2012 and was a randomized, double-blinded, placebo-controlled clinical trial in which 35 patients were infected with 25 larvae of Necator americanus and 36 were given placebo. Samples collected from this study afforded the opportunity to measure selected EBV antibody levels over a period of 12 months, enabling the impact of hookworm therapy on EBV reactivation and other parameters to be assessed.…”

The Worm-Specific Immune Response in Multiple Sclerosis Patients Receiving Controlled Trichuris suis Ova Immunotherapy

“…Until now, four clinical phase 1 and phase 2 trials investigating treatment effects of either oral inoculation of TSO or intradermal application of Necator americanus (hookworm) larvae in MS patients have been completed [ 11 , 12 , 13 , 14 ]. While all studies demonstrate the safety of controlled administration of both T. suis and N. americanus , none of them reported strong therapeutic efficacy, expressed in radiological or clinical disease activity [ 11 , 12 , 13 , 14 ]. Immunological results of the HINT-2 study demonstrated that TSO given at a dose of 2500 TSO every 2 weeks over 10 months resulted in mild eosinophilia and T. suis -specific antibodies [ 13 ].…”