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Response to BNT162b2 vaccine in lymphoma patients
period between the last anti-CD20 administration and vaccination became longer. With a cutoff of 12 months, our findings demonstrated a significant difference in the antibody titers between patients vaccinated less than or more than 12 months after anti-CD20 therapy, while the impact of exposure to this therapy became negligible after this time point. Actually, the titers became similar to those found in naïve (untreated) lymphoma patients. A plausible explanation could be that rituximab and other anti-CD20 monoclonal antibodies commonly used for the treatment of B-cell lymphoma lead to prolonged B- cell depletion and subsequent hypogammaglobulinemia. Consistent with our results, several studies reported data suggesting lower likelihoods of developing a serological response following anti-CD20 treatment in immunocom- promised patients. For instance, patients with rheuma- toid arthritis were reported to have lower titers of anti- influenza antibodies upon treatment with rituximab compared to patients with rheumatoid arthritis not receiving such therapy.27 In another study, none of the 67 lymphoma patients vaccinated against influenza A (H1N1) within 6 months of receiving rituximab-contain- ing regimens developed an antibody-mediated response compared to 82% in the control group.28 Finally, in the recently published study including a small cohort of anti- CD20-treated chronic lymphocytic leukemia patients, none of those treated with rituximab within a year prior to vaccination developed anti-spike antibodies against SARS-CoV-2.26
Remarkably, in our study, patients receiving rituximab demonstrated an attenuated serological response to the vac- cine, whereas patients treated with obinutuzumab failed to generate any anti-spike antibodies during the study period. This could be attributed to differences in pharmacodynam- ic properties between these two agents, as observed in in vitro studies, showing enhanced direct cell death and anti- body-dependent cellular cytotoxicity for obinutuzumab compared to rituximab.29
In the present study, active disease emerged as an addi- tional factor negatively affecting the humoral response to vaccine. While this could reflect the time-wise proximity to anti-CD20 treatment in these patients, it could also be asso- ciated with the effect of chemotherapeutic agents and cor- ticosteroids commonly used during induction therapy in this clinical setting. Since humoral immunity requires func- tional T cells for the development of memory B cells and plasma cells,30,31 agents such as bendamustine and high-dose steroids, applied in lymphoma, might impede the serologi- cal response.
This study has several limitations, the lack of a control
References
1. WHO Coronavirus (COVID-19) Dashboard. Available at https://covid19.who.int/. Last accessed in June, 2021.
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group being one of them. Nevertheless, Grupper et al., uti- lizing the same assay as in our study, showed that all healthy individuals included in the control group developed a serological response to the BNT162b2 vaccine.32 In addi- tion, nucleocapsid antibody assessment was not part of the current analysis, since only patients with no documented febrile or respiratory events within months prior to vaccina- tion were included in the study. Hence, the generation of anti-spike antibodies in response to subclinical COVID-19, while being possible, was unlikely in this population of patients.
A potential relationship between a weak serological response and the true protection from clinical COVID-19 will only become evident with longer follow-up. However, these data might never mature, as presently the pandemic has significantly subsided in Israel. Moreover, there are sev- eral newly validated assays capable of examining cellular immune responses to the vaccine, which will be included in future studies aimed at better understanding the true extent of protective immunity achieved with this vaccine.
In conclusion, the current study has shown that a hetero- geneous group of lymphoma patients has developed atten- uated serological responses to the BNT621b2 vaccine. Patients recently treated with anti-CD20 monoclonal anti- bodies (<12 months since the last anti-CD20 treatment) are lesslikelytodevelopaserologicalresponsetothisvaccine.
Disclosures
No conflicts of interest to disclose.
Contributions
RG, SR-H and NAH designed and performed research, inter- preted the data, and wrote the paper. UR designed research, ana- lyzed the data, and wrote the paper. MS and HB-Z performed serology assays. GL, AG-G, CL, PR, MT-A, EJD, NH, TI, IT, NL and RF collected data. All authors approved the final version of the paper.
Aknowledgments
We would like to thank Mrs. Sonia Kamenetsky for her advice and assistance in the preparation of this manuscript.
Funding
This research was supported by grants from Janssen, Takeda, Gilead Sciences and Abbvie. The Abbot test kits were kindly pro- vided by the Israeli Ministry of Health.
Data-sharing statement:
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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