Antigen-Specific T-Cell Repertoire Responses Following COVID-19 Vaccination Are Intact in Majority of Patients with B-Cell Lymphoid Malignancies on Active Therapy

Patients (Pts) with hematologic cancers are at increased risk for morbidity and mortality from COVID-19. Vaccination against COVID-19 has reduced morbidity and mortality, but the depth and breadth of immune responses to both vaccination and prior infection for patients with lymphoid malignancies, particularly in the context of active cancer treatment, remains incompletely understood. We previously observed impaired antibody response to a primary COVID-19 mRNA vaccination (2 dose series) in pts with lymphoma receiving B cell-depleting therapies (BCDT) (Ghione et. al., Blood 2021). These poor responses are expected to result from both intrinsic immune dysregulation from the hematologic malignancy, as well as treatment with BCDTs. However, a gap in knowledge relates to the extent that T cell responses to vaccination are intact in these patients. This question is important based on the established role of T cells in clearing virally infected cells through CTL function and driving cytokine responses.

We investigated serological and cellular responses to COVID-19 vaccination (initial and subsequent doses). Cellular responses were quantified using the T-Detect COVID Test (Adaptive Biotechnologies, Seattle, WA), which combines multiplex PCR and next-generation sequencing (NGS) to quantify T-cell receptor beta (TCRβ) sequences that are known to react to COVID-19. We collected 205 serial blood samples from 97 pts with B-cell malignancies (NHL, n=67 and CLL, n=31). 75 had received/were receiving BCDT, and 22 were either on observation or were on a treatment not including BCDT. Only 26/75 (34%) pts on treatment/previously treated with BCDT mounted a significant IgG Ab response, as opposed to 20/22 (90.9%) pts who were not receiving BCDT (p= 0.007). Vaccination was associated with an increased proportion of TCRs associated with spike protein region of the COVID-19 genome after vaccination. 43 patients out of 97 patients from this cohort were T-Detect COVID positive at all the time points sampled, while 19 patients were negative at all time points. Overall, 73/97 (75%) patients demonstrated a T-cell response to spike protein consistent with vaccine induced immunity regardless of whether the patient received BCDT. Positive T-cell responses were seen irrespective of prior BCDT. In this cohort, 19 patients demonstrated T-cell responses outside of the spike region, which is suggestive of natural infection; 10 of these appeared consistent with breakthrough infections after vaccination as they were negative at an earlier time point. Pts with breakthrough infections did not suffer from severe COVID-19 infection and recovered despite being on BCDT.

Taken together, we observed that patients with B-cell malignancies receiving BCDT have highly impaired antibody responses to COVID-19 vaccination while the majority have intact expansion of antigen-specific T cell populations. We observed no correlation between COVID-specific T-cells and COVID-specific IgG antibodies in this study population, but this may be impacted by the timing of the samples. In the setting of profound B-cell impairment, our results suggest that COVID-19 vaccination can induce potentially protective COVID-specific T-cell responses. Our findings provide rationale for additional studies of functional T cell responses to vaccination in these patients and delineating the extent that these T cell responses are associated with protection from severe COVID-19. We also note the broader application of our work to other vaccine-preventable respiratory viral infections, such as influenza and RSV.