Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: The VELOCE study

Abstract

Objective: The phase IIIb A Study to Evaluate the Effects of Ocrelizumab on Immune Responses in Participants With Relapsing Forms of Multiple Sclerosis (VELOCE) study (NCT02545868) assessed responses to selected vaccines in ocrelizumab (OCR)-treated patients with relapsing multiple sclerosis.

Methods: Patients were randomized 2:1 into the OCR group (n = 68; OCR 600 mg) or control group (n = 34; interferon beta or no disease-modifying therapy). All received tetanus toxoid (TT)-containing vaccine, Pneumovax (23-valent pneumococcal polysaccharide vaccine [23-PPV]), and keyhole limpet hemocyanin (KLH). The OCR group was subdivided into OCR1 (n = 33) and OCR2 (n = 35) at randomization. The OCR1 group received Prevnar (13-valent conjugate pneumococcal vaccine) 4 weeks after 23-PPV; the OCR2 and control groups received influenza vaccine. Vaccinations started 12 weeks after OCR initiation (OCR group) or on day 1 (control group).

Results: Positive response rate to TT vaccine at 8 weeks was 23.9% in the OCR vs 54.5% in the control group. Positive response rate to ≥5 serotypes in 23-PPV at 4 weeks was 71.6% in the OCR and 100% in the control group. Prevnar did not enhance response to pneumococcal serotypes in common with Pneumovax. Humoral response to KLH was decreased in the OCR vs control group. Seroprotection rates at 4 weeks against 5 influenza strains ranged from 55.6% to 80.0% in the OCR2 group and 75.0% to 97.0% in the control group.

Conclusion: Peripherally B-cell-depleted OCR recipients mounted attenuated humoral responses to clinically relevant vaccines and the neoantigen KLH, suggesting that use of standard nonlive vaccines while on OCR treatment remains a consideration. For seasonal influenza vaccines, it is recommended to vaccinate patients on OCR because a potentially protective humoral response, even if attenuated, can be expected.

Classification of evidence: This study provides Class II evidence confirming that the humoral response to nonlive vaccines in patients with relapsing multiple sclerosis after OCR treatment is attenuated compared with untreated or interferon beta-treated patients, but they can still be expected to be protective.

Clinicaltrialsgov identifier: NCT02545868.

Figure 1. VELOCE study design

^aImmunization study period (ISP) duration: ocrelizumab (OCR) group (OCR1 + OCR2) 24 weeks, control group 12 weeks. DMT = disease-modifying therapy; IFN = interferon; KLH = keyhole limpet hemocyanin; LLN = lower limit of normal; 13-PCV = 13-valent pneumococcal conjugate vaccine; TT = tetanus toxoid-containing vaccine; 23-PPV = 23-valent pneumococcal polysaccharide vaccine; VELOCE = A Study to Evaluate the Effects of Ocrelizumab on Immune Responses in Participants With Relapsing Forms of Multiple Sclerosis.

Figure 2. Response (IgG) to tetanus toxoid-containing vaccine

(A) Anti-tetanus titers and (B) proportion of patients with ≥4-fold increase in tetanus antibody titer. Positive response defined as ≥4-fold increase in antibody titer measured 8 weeks after vaccination compared with prevaccination titer (if prevaccination titer was ≥0.1 IU/mL) or an antibody titer ≥0.2 IU/mL if prevaccination titer was <0.1 IU/mL. Dotted red line represents protective titer level. CI = confidence interval; DMT = disease-modifying therapy; IFN = interferon; IgG = immunoglobulin G; OCR = ocrelizumab.

Figure 3. Response (IgG) to pneumococcal vaccine

(A) Positive response to individual Streptococcus pneumoniae serotypes 4 weeks after 23-valent pneumococcal polysaccharide vaccine (23-PPV) administration and (B) positive response to number of S pneumoniae serotypes after 23-PPV administration. Positive response was defined as 2-fold increase or a >1‐μg/mL 1μg/mL rise in immunoglobulin G (IgG) level compared with prevaccination levels. DMT = disease-modifying therapy; IFN = interferon; OCR = ocrelizumab.

Figure 4. Seroprotection to individual influenza strains

Vaccination with World Health Organization Northern Hemisphere–recommended influenza vaccine, seasons 2015/2016 or 2016/2017. Seroprotection defined as a specific hemagglutination inhibition titer >40. CI = confidence interval; DMT = disease-modifying therapy; IFN = interferon; OCR = ocrelizumab.

Figure 5. Responses to KLH neoantigen

(A) Immunoglobulin (Ig) M and (B) IgG. DMT = disease-modifying therapy; IFN = interferon; KLH = keyhole limpet hemocyanin; OCR = ocrelizumab.