Randomized open-label trial comparing 2-month versus 6-month schedules of adjuvanted recombinant VZV glycoprotein E vaccine in MS and NMOSD patients on anti‑CD20 therapy

The primary objective is to compare, in patients with Multiple Sclerosis or neuromyelitis optica spectrum disease receiving anti‑CD20 monoclonal antibodies, the humoral response elicited by a two‑dose recombinant zoster vaccine administered on a standard 2‑month (M0‑M2) schedule versus an experimental 6‑month (M0‑M6) schedule, with the response measured one month after the second dose. This evaluation seeks to determine the optimal timing of vaccination relative to anti‑CD20 therapy to maximize immunogenicity. Secondary objectives include:

• Comparison of the two schedules on the Geometric Mean Titer of anti‑varicella zoster antibodies one month after the second dose.
• Assessment of the kinetics and intensity of the humoral response up to month 13.
• Evaluation of the persistence of the humoral response at month 13.
• Comparison of the cellular immune response one month after the second dose (month 3 for the standard schedule and month 7 for the experimental schedule).
• Assessment of the kinetics and intensity of the cellular response through month 13.
• Evaluation of the persistence of the cellular response at month 13.
• Comparison of the two schedules regarding overall vaccine safety.

The trial enrolled adult patients (≥ 18 years) of both sexes diagnosed with Multiple Sclerosis (any clinical form) or neuromyelitis optica spectrum disorder seropositive for aquaporin‑4 antibodies, who had been receiving anti‑CD20 monoclonal antibodies (rituximab, ocrelizumab) for less than two years with six‑month dosing intervals. All participants were required to have documented prior varicella‑zoster virus exposure, be affiliated with a social security scheme, and provide written informed consent. Lifestyle factors such as diet or physical activity were not specified. The sponsor did not provide the total number of participants enrolled in the study.

The study is an open‑label, randomized, controlled trial comparing two vaccination schedules of the recombinant subunit herpes zoster vaccine in adults with multiple sclerosis or neuromyelitis optica spectrum disease receiving anti‑CD20 monoclonal antibodies (rituximab, ocrelizumab). Participants undergo a screening visit, followed by baseline (M0) where the first vaccine dose is given one month before the scheduled anti‑CD20 infusion. Subjects are randomized to a standard schedule (second dose at month 2) or an experimental schedule (second dose at month 6). Follow‑up visits occur at month 3 for the standard group, month 7 for the experimental group, and subsequently at months 7 and 13 for both groups to assess antibody titers, cellular immunity, and safety. The primary endpoint is the humoral vaccine response rate measured one month after the second dose; secondary endpoints include geometric mean titers, cellular responses, and adverse events. Participant involvement spans approximately 13 months from enrollment to the end‑of‑study visit. Early termination may occur if a participant withdraws consent, experiences a serious adverse event, fails to adhere to the vaccination or anti‑CD20 schedule, or is lost to follow‑up.

The study incorporates rituximab as a background anti‑CD20 monoclonal antibody administered by intravenous infusion at a dose of 1 g per infusion (pharmaceutical form PHF00230MIG). Doses are given every six months in accordance with the standard therapeutic schedule for patients with multiple sclerosis or neuromyelitis optica spectrum disease. Administration dates are recorded in the electronic case report form, and compliance is verified by infusion logs and periodic laboratory assessments.

ocrelizumab is also used as a background anti‑CD20 therapy. It is delivered by injection at a dose of 5 mg per administration and is scheduled on a six‑month interval, consistent with approved dosing for the indicated neurologic conditions. Dosing adherence is monitored through patient diaries and verification of injection records maintained by the study site.

The investigational product is Shingrix suspension for injection in a pre‑filled syringe, containing recombinant varicella‑zoster virus glycoprotein E. The vaccine is administered intravenously in a volume of 0.5 ml per dose. Two doses are given: the first dose is administered one month prior to the scheduled anti‑CD20 infusion, and the second dose is administered either one month later (standard 2‑month interval group) or five months later (experimental 6‑month interval group). The dosing schedule is documented for each participant, and adherence is ensured by site‑administered dosing and confirmation of receipt in the trial database. Humoral response is evaluated one month after the second vaccine dose.

Efficacy will be evaluated through both humoral and cellular immune responses to the recombinant varicella‑zoster virus glycoprotein E (gE) vaccine. The primary efficacy endpoint is the Humoral Vaccine Response Rate (VRR), measured one month after the second vaccine dose (month 3 for the 2‑month schedule and month 7 for the 6‑month schedule). VRR is defined as the proportion of participants achieving at least a four‑fold rise in anti‑VZV gE antibody titers, determined by ELISA, compared with baseline (month 0), or seroconversion in subjects who were seronegative at baseline.

Secondary efficacy assessments include:

• The ratio of the adjusted Geometric Mean Titer (GMT) of anti‑VZV gE IgG between the two vaccination schedules, evaluated one month after the second dose.
• GMT of anti‑VZV gE IgG measured at baseline (month 0) and subsequently at pre‑second‑dose, one month post‑second‑dose, and prior to the next anti‑CD20 infusion (months 7 and 13).
• Humoral VRR reassessed at month 13.
• Cellular immune response, expressed as the proportion of gE‑specific CD4[AIM+] T cells among total CD4 T cells, measured at baseline, pre‑second‑dose, one month post‑second‑dose, and before subsequent anti‑CD20 infusions (months 7 and 13).
• cellular VRR for the gE‑specific CD4[AIM+] T‑cell response, evaluated one month after the second dose and again at month 13.
• Recording of adverse events throughout the study period.

Blood samples for antibody titers and cellular assays will be collected at the specified study visits (months 0, pre‑second‑dose, 1 month post‑second‑dose, months 7 and 13). Antibody concentrations will be quantified using a validated ELISA, while cellular responses will be assessed by measuring the frequency of gE‑specific CD4[AIM+] T cells using appropriate immunophenotyping techniques.