To the Editor,
Patients with cancer are at increased risk of adverse outcomes when infected with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV‑2) and show an impeded humoral and cellular immune response to vaccination [
1]. A fourth vaccination increased the humoral immunity against SARS-CoV‑2 including Omicron sublineages [
2]. However, data on effects of a fourth SARS-CoV‑2 vaccination on cellular immunity, particularly in relation to antibody responses, are scarce [
3].
Overall, clear signs of response on humoral, cellular, or combined humoral and cellular levels were observed in six of seven patients. However, a striking intra- and interpatient heterogeneity of immune response patterns was evident (Fig.
1b, Tables
1 and
2). Only two of seven patients (patients 4 and 6) responded with combined increases in S‑ and RBD-specific CD4
+ and CD8
+ T‑cell proliferation. All other patients showed inconsistent increases in T‑cell activity with low vaccination responses in at least one T‑cell subpopulation. Additionally, humoral response did not consistently coincide with cellular vaccine responses: Patients 4 and 6, who had no increase or only a mild increase in antibody levels showed a pronounced cellular vaccine response. Interestingly, in patient 5 increased antibody levels against S without corresponding CD4
+ responses were found. Moreover, patients with distinct antibody increases only showed mediocre vaccine responses on a cellular level (patients 1, 2, and 7). One patient (patient 3) showed severely impeded humoral and cellular vaccine responses to the fourth vaccination applied 433 days after administration of the last B‑cell targeting treatment (rituximab).
Table 1
Specific D3+CD4+ and CD3+CD8+ cell proliferations before and after vaccination
1 | S | 44.93 | 51.03 | 7.96 | 8.07 |
RBD-hu1 | 15.20 | 36.43 | 11.46 | 7.55 |
2 | S | 6.76 | 6.60 | 8.26 | 3.53 |
RBD-hu1 | 4.01 | 7.53 | 3.89 | 4.00 |
3 | S | 49.55 | 37.34 | 26.29 | 26.35 |
RBD-hu1 | 46.60 | 48.47 | 35.55 | 40.47 |
4 | S | 2.93 | 9.72 | 2.57 | 6.16 |
RBD-hu1 | 0.97 | 2.62 | 0.87 | 2.45 |
5 | S | 8.92 | 9.72 | 1.18 | 6.16 |
RBD-hu1 | 4.37 | 2.62 | 0.05 | 2.45 |
6 | S | 0.00 | 1.34 | 0.00 | 1.27 |
RBD-hu1 | 0.00 | 1.13 | 0.00 | 1.53 |
7 | S | 13.23 | 27.65 | 7.43 | 7.80 |
RBD-hu1 | 9.95 | 22.90 | 4.32 | 19.75 |
Table 2
Specific antibody response before and after vaccination
1 | 0.763 | 2.143 | 0.144 | 1.555 | 0.106 | 0.843 |
2 | 0.272 | 0.741 | 0.077 | 0.130 | 0.084 | 0.181 |
3 | 1.867 | 1.986 | 1.010 | 1.486 | 0.592 | 0.726 |
4 | 2.093 | 2.023 | 1.093 | 1.603 | 0.721 | 0.968 |
5 | 2.072 | 1.937 | 1.509 | 1.545 | 0.831 | 0.832 |
6 | 0.968 | 2.162 | 0.184 | 1.093 | 0.138 | 0.726 |
7 | 0.333 | 2.275 | 0.067 | 0.934 | 0.064 | 0.673 |
Conclusion
The most important limitation of this prospective study is its small sample size and the lack of a control group. However, we observed high intra- and interpatient heterogeneity with clear indications of humoral, cellular, or combined response to the fourth vaccine in most patients under active treatment. Of note, our observation indicates long-lasting impairment of specific immune responses for as long as 36 months after the last rituximab administration. These findings highlight the need for reliable identification of SARS-CoV‑2 vaccine non-responders.
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