Background/Purpose: Patients receiving glucocorticoids plus rituximab (RTX) show an increased risk of infection, especially invasive pneumococcal infections. Vaccine responses to influenza, Streptococcus pneumoniae and SARS-CoV-2 under RTX therapy are strongly impaired. In patients with autoimmune diseases receiving such treatments, especially those with ANCA-associated vasculitides (AAV), there is thus a need to develop enhanced anti-pneumococcal vaccine strategies to increase immune response and protection.

Methods: This multicenter randomized, open label, phase 2 trial, compared two innovative “reinforced” anti-pneumococcal vaccine strategies to the standard regimen in patients with AAV receiving RTX therapy. Adult patients with newly diagnosed or relapsing AAV, with an active disease (BVAS ≥3) and planned to receive RTX as induction therapy were randomized in a 1:1:1 ratio to three parallel arms: standard regimen combining a dose of PCV13 at day 0 followed by a dose of PPV23 at month 5 (M5) (arm 1); double dose of PCV13 at day 0 and day 7 followed by a dose of PPV23 atM5 (arm 2); or 4 doses of PCV13 at day 0 followed by a dose of PPV23 at M5 (arm 3). The primary endpoint was the immune response at M6 against the 12 pneumococcal serotypes common to the PCV13 and PPV23 vaccines, according to four ordered categories of ELISA response: positive antibody response to 0-3, 4-6, 7-9, or 10-12 serotypes. The primary endpoint was analyzed in a proportional odds logistic regression model with a Bonferroni correction for the 2 innovative arms. Secondary end points were local and systemic solicited reactions 7 days following each vaccination and any adverse event related or possibly related to vaccine immunization.

Results: A total of 95 participants were analyzed in the modified intention-to-treat population, with 30 assigned in arm 1, 32 in arm 2 and 33 in arm 3.

At M6, immune response to 0-3, 4-6, 7-9, or 10-12 serotypes was observed in 83.3%, 13.3%, 3.3% and 0% in arm 1; 56.3%, 28.1%, 15.6% and 0% in arm 2; and 60.6%, 33.3%, 6.1% and 0% in arm 3. Patients in arm 2 were significantly more likely to be in any higher response categories compared to the standard regimen after adjustment on age, with a proportional odds ratio (pOR) of 4.1 (97.5% CI 1.1-15.9, p=0.018), while the second innovative regimen only tended to improve vaccine responses (pOR 3.1, 97.5% CI 0.8-11.9, p=0.062).

Local and/or systemic solicited reactions 7 days following each vaccination and any adverse event related or possibly related to vaccine immunization during the first 6 months occurred at higher numbers after the reinforced first vaccinations but were mainly grade 1 or 2 local reactions. No severe adverse events related to vaccination was observed.

During follow-up, 8 vasculitis flares occurred in 6 patients, in median 87 days after the last vaccination: one patient in arm 1, 2 in arm 2, and 3 in arm 3.

Conclusion: In patients with AAV receiving RTX therapy, an innovative reinforced anti-pneumococcal vaccine strategy based on double dose of PCV13 at day 0 and day 7 followed by a single dose of PPV23 at M5 significantly improved the antibody responses against Streptococcus pneumoniae compared to the standard regimen.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/innovative-anti-pneumococcal-vaccine-strategies-versus-standard-vaccination-regimen-in-patients-with-anca-associated-vasculitides-receiving-rituximab-therapy-a-multicenter-randomized-controlled-trial/