Reply.

We appreciate the comments from Dr. Evangelatos and colleagues on our study of SARS–CoV‐2 vaccine responses in RTX‐treated patients. The authors briefly reviewed current evidence on the reduced rates of response to SARS–CoV‐2 vaccines among patients undergoing B cell depletion therapy with RTX and provided novel data on this topic. In a series of 11 patients with immune‐mediated inflammatory diseases treated with RTX, only 2 patients developed detectable levels of IgG antibodies against SARS–CoV‐2 spike protein after vaccination with the BNT162b2 mRNA SARS–CoV‐2 vaccine. This finding supports observations from other studies (1, 2), including our own, in which we showed that humoral but not T cell–mediated responses to SARS–CoV‐2 vaccination are reduced in patients treated with RTX.

These findings are highly relevant to the estimated 700,000 patients with hematologic malignancies (3) and 900,000 patients with immune‐mediated inflammatory diseases (4) treated with RTX worldwide. Of note, RTX‐treated patients show an increased risk of severe COVID‐19 (5). Therefore, in light of the impaired humoral immune response to SARS–CoV‐2 vaccination, new vaccination strategies and careful monitoring of vaccine efficacy are needed for this patient population, as urged by Evangelatos et al. For RTX‐treated patients who have not been vaccinated, RTX therapy and vaccination regimens should be aligned. Thus, RTX administration can be time‐adjusted, as also recommended in the American College of Rheumatology guidelines (vaccination 4 weeks before RTX administration [6]), or it could be administered depending on the grade of repopulation of peripheral B cells. The latter approach is reasonable, since adequate humoral immune responses are more likely if at least some B cells are detectable in the peripheral blood (1). However, further studies are needed to determine the effect of B cell repopulation and the best timing of vaccination.

Of note, T cell responses to SARS–CoV‐2 vaccination have been shown to be intact in RTX‐treated patients, and they have also been shown to support defense against infection and the development of severe COVID‐19 (1). Therefore, patients treated with RTX should receive SARS–CoV‐2 vaccination even in the absence of B cells. Furthermore, humoral immune responses should be assessed in RTX‐treated patients who have received a full SARS–CoV‐2 vaccination regimen. Fully vaccinated individuals who do not respond could benefit from additional boosters to achieve a protective humoral response (7). In this context, the observation that SARS–CoV‐2 infection can mobilize tissue B cells and trigger protective antibody formation in RTX‐treated patients without peripheral B cells is interesting and may support the use of booster vaccinations. When the standard vaccination regimen has failed, a humoral immune response may be mobilized by the timely administration of booster vaccines and by cross‐vaccinating with different vaccine agents.