Comparative Study of Two Vaccination Schedules for the Subunit Herpes Zoster Vaccine in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disease Patients Treated With Anti-CD20 Therapy: an Open-label Randomised Controlled Trial

Shingles, caused by reactivation of varicella zoster virus (VZV), is a common condition in immunocompromised people. Its prevention, which has long remained a medical need unmet among these patients, was improved thanks to the availability of the recombinant glycoprotein-based VZV vaccine E (gE). Based on demonstrated clinical efficacy and safety profile in the general population as well as in immunocompromised patients, this vaccine is recommended in France according to a two-person schedule doses spaced two months apart in immunocompromised patients aged ≥ 18 years. However, further studies are needed in order to optimize vaccination strategies according to the different types of immunosuppression.

Patients with MS or NMOSD, who are at increased risk of herpes zoster, are extensively treated with anti-CD20 monoclonal antibodies, which are known to significantly alter immune responses to vaccines, in particular when vaccination is carried out early after the infusion of anti-CD20.

We hypothesize that in patients with MS or NMOSD treated with anti-CD20 administered every six months, a two-dose M0-M6 vaccination schedule, consisting of deferring the second dose to six months after the first, that is, five months after the anti-CD20 infusion, could improve vaccine immunogenicity and, consequently, the effectiveness of the vaccine.

In this phase IV randomized, controlled, open-label, parallel-group trial, we will compare, within a homogeneous population of patients with MS or NMOSD receiving antiCD20, the humoral response induced by a two-dose vaccination schedule administered at 2 months (M0-M2, "2-month" or standard group) or 6 months (M0-M6, "6-month" or experimental group). After the screening and inclusion phase, patients randomized to the M0-M2 (standard) and M0-M6 (experimental) groups will receive a first dose of recombinant herpes zoster vaccine (RZV) one month before the next scheduled infusion of anti-CD20 monoclonal antibodies (M1). The second dose of RZV will be given at either 2 months ("2-month group", M2) or 6 months ("6-month group", M6). Patients will receive their usual anti-CD20 monoclonal antibody infusions at the appropriate time M1, M7 and M13. The primary outcome will be evaluated one month after the second vaccine dose (M3 for the "2 months" group and M7 for the "6 months" group). The kinetics, intensity, and persistence of humoral and cellular immune responses, as well as safety, will be analyzed as criteria for secondary judgments during the scheduled follow-up visits until M13.

• Two-dose M0-M2 vaccination schedule (Biological): Patients randomized to the "2 months" vaccination group will receive their first dose of RZV vaccine one month before the next scheduled infusion anti-CD20 monoclonal antibody (M0 corresponding to the visit during the first dose of vaccine, M1 at the time of scheduled anti-CD20 infusion). The second dose of RZV vaccine will be administered 2 months later. Patients will receive their regular anti-CD20 infusions at times M1, M7, and M13.
• Two-dose M0-M6 vaccination schedule (Biological): Patients randomized to the "6 months" vaccination group will receive their first dose of RZV vaccine one month before the next scheduled infusion anti-CD20 monoclonal antibody (M0 corresponding to the visit during the first dose of vaccine, M1 at the time of scheduled anti-CD20 infusion). The second dose of RZV vaccine will be administered 6 months later. Patients will receive their regular anti-CD20 infusions at times M1, M7, and M13.

Primary outcomes

• Humoral vaccine response rate for IgG anti-VZV gE response [3 months for the " 2 months " group and 7 months for the " 6 months " group]: It will be defined as the proportion of patients with at least a 4-fold increase in anti-VZV gE antibody titers (measured by ELISA) at 1 month after the 2nd vaccine dose compared to baseline (M0), or seroconversion for those who were seronegative at M0.

Secondary outcomes

• The humoral response in terms of Geometric Mean Titer (GMT) at 1 month after the 2nd vaccine dose. [3 months for the " 2 months " group and 7 months for the " 6 months " group]: It will be assessed by the ratio (M0-M6 versus M0-M2 groups) of the adjusted Geometric Mean Titer (GMT) of anti-VZV gE IgG at 1 month after the 2nd vaccine dose. The adjusted GMT will correspond to the GMT at 1 month after the 2nd vaccine dose conditionally to the means of the log transformed GMT before vaccination at baseline (M0) calculated across the treatment groups.
• Composite criteria of the humoral response up to M13 [13 months]: The kinetics, intensity and persistance will be assessed by the Geometric Mean Titer (GMT) of anti-VZV gE IgG measured at baseline (M0) and up to M13: before the 2nd vaccine dose, 1 month after the 2nd vaccine dose, and prior to the next anti CD20 infusions at M7 and M13.
• Composite criteria of the cellular response at 1 month after the 2nd vaccine dose [3 months for the " 2 months " group and 7 months for the " 6 months " group]: It will be assessed by the cellular vaccine response rate for gE-specific CD4\[AIM+\] T response measured 1 month after the 2nd vaccine dose. The cellular VRR is defined as the proportion of patients with a proportion of gE-specific CD4\[AIM+\] T cells at least 2 times above the cutoff after vaccination. The proportion of gE-specific CD4\[AIM+\] T cells among CD4 T cells is defined by the proportion of CD4 T cells expressing at least one Activation-Induced Marker (AIM), as detected by flow cytometry, following in vitro stimulation with a peptide pool covering the entire ectodomain of gE. The AIM include CD69, CD25, OX40, CD40L, and CD137. We will determine the cut-off of gE-specific CD4\[AIM+\] T cells by assessing cellular immune responses across a range of non-vaccinated, healthy individuals.
• Composite criteria of the cellular response at M13 [13 months]: The kinetics, intensity and persistance of the cellular response up to M13 will be assessed by the proportion of gE-specific CD4\[AIM+\] T cells among CD4 T cells measured at baseline (M0) and up to M13 : before the 2nd vaccine dose, 1 month after the 2nd vaccine dose, and prior to the next anti-CD20 infusions at M7 and M13.
• The vaccine safety [from M0 to month 13]: The safety will be assessed by the adverse events including serious adverse events collected during the study.

Other outcomes

• Composite criteria of the predicted humoral response at M20 [20 months]: Predicted humoral vaccine response rate will be assessed by the predicted humoral vaccine response rates at M20 of the M0-M6 RZV vaccine schedule ("6 months" group) and the M0-M2 RZV vaccine schedule ("2 months" group). Anti-VZV gE IgG at M20 will be assessed by the adjusted Geometric Mean Titers of anti-VZV gE IgG at M20 of the M0-M6 RZV vaccine schedule ("6 months" group) and the M0-M2 RZV vaccine schedule ("2 months" group).
• The overall predicted humoral exposure from M0 to M20 [20 months]: It will be assessed by the areas under the curve (AUC) of anti-VZV gE IgG titers between M0 and M20 of the M0-M6 RZV vaccine schedule ("6 months" group) and the M0-M2 RZV vaccine schedule ("2 months" group).
• The predicted cellular response at M20 [20 months]: It will be assessed by the predicted cellular vaccine rate response proportions of gE specific CD4\[AIM+\] T cells among CD4 T cells of the M0-M6 RZV vaccine schedule ("6 months" group) and the M0-M2 RZV vaccine schedule ("2 months" group).
• The overall predicted cellular exposure from M0 to M20 [20 months]: It will be assessed by the areas under the curve (AUC) of gE-specific CD4\[AIM+\] T cells among CD4 T cells between M0 and M20 of the M0-M6 RZV vaccine schedule ("6 months" group) and the M0-M2 RZV vaccine schedule ("2 months" group).
• Composite criteria of the associated factors with early and persistent, humoral and cellular vaccine responses [20 months]: The factors which will be studied are : age, sex, number of prior anti-CD20 infusions, type of latest DMT before anti-CD20 therapy, albumin and gammaglobulin levels, Ig G levels, leukocyte counts, T and B cell immunophenotyping, and immune exhaustion and immunosenescence markers throughout the study.
• The correlation between the titers of anti-VZV gE IgG by ELISA and the titers of total IgG anti-VZV by the commercial Diasorin serological test. [20 months]: It will be assessed by the correlation between ELISA gE titer and the total anti-VZV glycoproteins IgG measured by the Liaison XL® Diasorin serological test.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Patients with Multiple Sclerosis (any clinical form) or Neuromyelitis optica spectrum disease seropositive for aquaporin-4 antibodies (AQP4+)
* Aged 18 years or more
* Treated with anti-CD20 mAbs (Rituximab IV or Ocrelizumab IV or SC) since < 2 years with dosing intervals of 6 months (and for Rituximab, treated with 1g per infusion)
* Planned to receive the same anti-CD20 mAbs with dosing intervals of 6 months during the 13 months of the study (and for Rituximab, planned to receive 1g per infusion)
* Known history in the medical file of varicella, or VZV IgG serology known to evidence a prior infection
* Affiliated or beneficiary of a social security scheme
* Written and informed consent
* Understands and agrees to comply with the study procedures

Exclusion Criteria:

* Temporary contraindication to vaccination (concurrent episode of acute fever >38.5°C)
* Shingles in the last 12 months or VZV vaccination in the last 5 years
* Patients already treated or supposed to be treated with Ofatumumab (another anti-CD20 mAbs but delivered with a monthly subcutaneous injection)
* Patients who received high dose corticosteroids (methylprednisolone at a dose of ≥ 500 mg, administered over 1 to 5 days) in the 3 months prior to inclusion
* Patients who have been exposed to Cladribine in the prior 12 months
* Patients who received or were scheduled to receive any vaccination, except for influenza and SARS-CoV-2 vaccines during the epidemic season, within 2 weeks prior to the 2 RZV injections and up to 4 weeks after the second RZV injection
* Hypersensitivity to the active substance or to one of the excipients
* Patient protected by the law (guardianship, curatorship)
* Pregnancy or breast-feeding
* Women of childbearing potential (WOCBP) without effective contraception throughout the duration of the trial
* Criteria related to the use of ancillary anti-CD20 treatments (Rituximab and Ocrelizumab):

Hypersensitivity to the active substance or to any of the excipients Severe, active infections Severe immunodeficiency Severe heart failure or severe uncontrolled heart disease Known progressive malignancies

• Jonathan Ciron, MD, Principal investigator, University Hospital, Toulouse

NIH grants: 2025