The effect of rituximab on vaccine responses in patients with immune thrombocytopenia

Abstract

B-cell depletion may impair vaccine responses and increase infection risk in patients with immune thrombocytopenia (ITP). We investigated the effects of rituximab on antibody and cellular responses to Streptococcus pneumoniae polysaccharide and Haemophilus influenzae type b (Hib) vaccines in ITP patients. Of 60 patients in the main trial, 24 patients received both vaccines 6 months after rituximab (n = 17) or placebo (n = 7). Among 20 evaluable patients, 3 of 14 (21%) in the rituximab group and 4 of 6 (67%) in the placebo group achieved a fourfold increase in anti-pneumococcal antibodies (P = .12). For anti-Hib antibodies, 4 of 14 (29%) and 5 of 6 (83%), respectively, achieved a fourfold increase (P < .05). Fewer patients in the rituximab group demonstrated Hib killing (2 of 14 [14%], 5 of 6 [83%], P < .05). Three of 14 rituximab-treated patients failed to respond to vaccines by any criteria. After vaccinations, preplasma cell blasts and interferon-γ-secreting T cells were reduced in rituximab-treated patients. Antibody responses were impaired for at least 6 months after rituximab. Cellular immunity was reduced in parallel with depleted B-cell pools. These findings have implications for the timing of vaccinations and the mechanism of infection after rituximab in ITP patients.

Figure 1. Antibody response to vaccinations

IgG specific antibodies to S. pneumoniae antibodies (A) and H. influenzae type b (Hib) (B) detected in the first month after the pneumococcal polysaccharide vaccine and the conjugate Hib vaccine. Patients had immune thrombocytopenia (ITP) and had been treated with rituximab (n=14) or placebo (n=6) 6 months before vaccinations. Vaccine responders were defined as patients who achieved at least a 4-fold increase in antibody titer compared with baseline values.

Figure 2. Serum bactericidal activity against H. influenzae type b

A) Titer (reciprocal of the serum dilution capable of killing 50% of bacterial cells compared to complement controls) of serum bactericidal activity against H. influenzae type b (Hib) post vaccination in ITP patients treated with rituximab (n=14) or placebo (n=6) (*p<0.05; bars represent standard error of the mean). B) Vaccine responders, defined as patients who achieved a 4-fold increase in functional Hib bacteria cell killing in the first month after vaccination.

Figure 3. Effect of rituximab on peripheral blood B-cell subsets

(A) Naïve B-cells (CD19⁺CD27⁻); (B) resting memory B-cells (CD19⁺CD27⁺CD38^−/low); and (C) pre-plasma cell blasts (CD19⁻CD27⁺CD38^hi) expressed as percentage of total CD19⁺ cells (*p<0.05; bars represent standard error of the mean). Rituximab (n=17) or placebo (n=7) was administered at time 0; S. pneumoniae and H. influenzae type B vaccines were administered on week 24.

Figure 4. Pre-plasma cell blasts before and after vaccinations

Absolute cell counts of peripheral blood pre-plasma cell blasts in patients with immune thrombocytopenia who received rituximab (n=4) or placebo (n=5) 6 months earlier. All patients received vaccinations with S. pneumoniae and H. influenzae type b vaccines.

Figure 5. Effect of rituximab on T-cell function after vaccinations

IFN-γ secreting cells were determined by ELISPOT at 0, 1, 4, and 24 weeks after vaccination with S. pneumoniae and H. influenzae type B vaccines in patients with immune thrombocytopenia who received rituximab (n=17) or placebo (n=6) 6 months earlier (*p<0.05; bars represent standard error of the mean).