Immunocompromised individuals, such as patients with multiple sclerosis (MS) or diseases of the neuromyelitis optica spectrum (NMOSD) treated with an anti-CD20 monoclonal antibody, present an increased risk of shingles. The immunogenicity - and therefore the clinical effectiveness - of the recombinant vaccine against the varicella zoster virus based on glycoprotein E, recently recommended according to two-dose schedule two months apart in immunocompromised patients aged ≥ 18 years, could be significantly decreased when administered one month before and one month 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 six months after the first infusion, that is, five months after the anti-CD20 infusion, could improve vaccine immunogenicity and, consequently, the effectiveness of the vaccine.
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)
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
Parallel
Two-dose M0-M2 vaccination schedule
Biological/VaccinePatients 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/VaccinePatients 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.
Humoral vaccine response rate for IgG anti-VZV gE response
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.
The humoral response in terms of Geometric Mean Titer (GMT) at 1 month after the 2nd vaccine dose.
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
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
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
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.
Composite criteria of the predicted humoral response at M20
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
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
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
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).
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