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Letters to the Editor
the induction of an anti-spike T-cell response, as assessed by IFNγ Elispot assay, irrespective of the antibody response. Elispot assays were performed, as previously reported.9
At baseline, and after one, two and three injections, the median number of SFC/106 CD3+ T cells were 0 (0-20), 112.5 (0;339), 679.0 (202;1551) and 845.0 (243; 1305), respectively. Overall, one month after V2 and V3, 17/19 patients (89%) displayed IFNγ-producing T cells reactive to S (S1+S2) peptide pools.
A significant increase in T-cell response, compared to baseline, was observed throughout the vaccination process until V2. The magnitude of T-cell response increased after the third vaccination in eight patients but appears globally unchanged for the entire cohort (Figure 1). T-cell response did not differ significantly after the complete vaccination schedule according to the type of anti-CD20 antibodies used (mean SFC/106 CD3+ T cells = 1045.0 (749; 1338) for O and 600.0 (160; 845) for R) or according to the number of anti-CD20 infusions received before vaccination (data not shown). In this cohort, no pre-existing immune memory was suggested by respons- es to other non-spike antigens in 19/20 patients. Conversely, as expected, patient n°7 displayed IFNγ-pro- ducing T cells reactive to N, M, and N7A SARS-CoV-2 proteins. Importantly, the level of T-cell response was at least equivalent to that observed in kidney-transplanted patients. We previously reported, using the same assay, a median rate of 212 SFCs /106 CD3+ T cells after two doses in responding patients (versus 679 SFCs /106 CD3+ T in the present cohort) and 330 SFC/106 CD3+ T cells after the third injection (versus 845 SFCs/106 CD3+T)(paper submitted, in revision).9 Similarly, the level of T-cell response was not below the that reported in healthy individuals, showing a median of 165 SFU/106 PBMCs 28 days after two doses (Angyal et al, Lancet 2021, in press). These comparisons suggest that T-cell response at least remains conserved in these highly immunocompromised patients.
However, there is no clear demonstration as to whether T-cell activity is sufficient to protect vaccinated patients from COVID-19 infection.10 Robust T-cell responses to the SARS-CoV-2 virus occur in most individ- uals with COVID-19.11 Furthermore, SARS-CoV-2-specif- ic T cells have been detectable in antibody-seronegative exposed family members and convalescent individuals with a history of asymptomatic and mild COVID-19, consistent with a non-redundant role of immune protec- tion against COVID-19.11 Importantly, after the third vac- cine dose, we still observed an increased interferon-γ response to the SARS-Cov-2 spike protein. This was par- ticularly visible for patient n°7, characterized by a previ- ous COVID-19 disease that occurred at the beginning of his lymphoma treatment, when only one dose of obinu- tuzumab had been delivered.
To improve the rate of seroconversion or to maintain a humoral response in elderly individuals or immunocom- promised patients, a third injection was proposed. However, the impact of such a strategy in such a case of very deep B-cell depletion is still uncertain. In the kidney transplant setting, one study has shown that a third dose of mRNA-1273 vaccine induced a serologic response in 49% of kidney transplant recipients who did not respond after two doses.12 Administration of a third dose of the BNT162b2 vaccine to solid organ transplant recipients, or to recipients of allogeneic HSCT, also significantly improved the immunogenicity of the vaccine.13,14 In our cohort characterized by complete B-cell depletion, we did not observe any improvement of the antibody response
after the third injection. The vaccination schedule could also be improved by increasing time-lapse between the second and third injection or by offering heterologous prime-boost strategies that demonstrated increased levels of neutralizing antibody titers in immunocompetent patients, as compared to homologous prime-boost strate- gies.15 Nevertheless, whether this optimization might result in an improved level of protection remains uncer- tain. REGN-COV2, a neutralizing antibody cocktail, may also be proposed as a prophylactic strategy in these immunosuppressed patients after or before SarsCov2 exposition.
The question of delaying or ceasing maintenance ther- apy is clearly raised for patients with MCL and FL in the current pandemic context. The benefit in terms of OS in MCL, contrasting with the benefit only for PFS in FL, is an important point to consider when considering the benefit-risk balance. Other points such as social context, the ability to follow physical protective measures and access to passive immunization with anti-S monoclonal antibody therapy, should be considered for each individ- ual patient in order to correctly evaluate their benefit-risk balance.
Finally, given the lack of post-vaccinal humoral response observed in our cohort, vaccination may still provide a limited but significant protection by triggering
Table 2. Population biological parameters at baseline
Biological parameter
9 Lymphocytes (10 /L)
N
median (q1;q3) min - max
T-cell (109/L) N
median (q1;q3) min - max
Reference values
1.5-4
1-2.2
Study population n=20
17
0.90 (0.7; 1.2) 0.30 ; 2.10
17
0.74 (0.6; 1.0) 0.20 ; 1.95
CD19+/CD20+ cell (109/L)
N 17
median (q1;q3) min - max
0.00 (0.0; 0.0) 0.00 - 0.00
CD4+ cell (109/L)
N 17
median (q1;q3) min - max
0.41 (0.2; 0.5) 0.11 - 1.10
CD8+ cell (109/L)
N 17
median (q1;q3) min - max
NK-cell (109/L) N
median (q1;q3) min - max
Neutrophil count (109/L) N
median (q1;q3) min - max
0.07-0.48
1.5-7
0.32 (0.1; 0.4) 0.07 - 1.10
16
0.15 (0.1; 0.2) 0.00 - 0.41
17
3.40 (2.1; 4.7) 1.80 - 5.90
Albumin (G/L)
N 16
median (q1;q3)
min - max Gammaglobulin (G/L)
41.00 (39.8; 43.2) 30.00 - 69.00
5-15
N 16
median (q1;q3) 7.00 (5.8; 8.0) min - max 3.00 - 8.00
0.11-0.57
0.53-1.4
0.33-0.92
42-50
756
haematologica | 2022; 107(3)