SARS-CoV-2 Vaccination in the First Year After Hematopoietic Cell Transplant or Chimeric Antigen Receptor T-Cell Therapy: A Prospective, Multicenter, Observational Study

Abstract

Background: The optimal timing of vaccination with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines after cellular therapy is incompletely understood. The objectives of this study are to determine whether humoral and cellular responses after SARS-CoV-2 vaccination differ if initiated <4 months versus 4-12 months after cellular therapy.

Methods: We conducted a multicenter, prospective, observational study at 30 cancer centers in the United States. SARS-CoV-2 vaccination was administered as part of routine care. We obtained blood prior to and after vaccinations at up to 5 time points and tested for SARS-CoV-2 spike (anti-S) IgG in all participants and neutralizing antibodies for Wuhan D614G, Delta B.1.617.2, and Omicron B.1.1.529 strains, as well as SARS-CoV-2-specific T-cell receptors, in a subgroup.

Results: We enrolled 466 allogeneic hematopoietic cell transplantation (HCT) (n = 231), autologous HCT (n = 170), and chimeric antigen receptor T-cell (CAR-T-cell) therapy (n = 65) recipients between April 2021 and June 2022. Humoral and cellular responses did not significantly differ among participants initiating vaccinations <4 months versus 4-12 months after cellular therapy. Anti-S IgG ≥2500 U/mL was correlated with high neutralizing antibody titers and attained by the last time point in 70%, 69%, and 34% of allogeneic HCT, autologous HCT, and CAR-T-cell recipients, respectively. SARS-CoV-2-specific T-cell responses were attained in 57%, 83%, and 58%, respectively. Pre-cellular therapy SARS-CoV-2 infection or vaccination and baseline B-cell count were key predictors of post-cellular therapy immunity.

Conclusions: These data support mRNA SARS-CoV-2 vaccination prior to, and reinitiation 3 to 4 months after, cellular therapies with allogeneic HCT, autologous HCT, and CAR-T-cell therapy.

Keywords: COVID-19; SARS-CoV-2; hematopoietic cell transplant; transplant; vaccine.

Figure 1.

CONSORT diagram. Abbreviations: alloHCT, allogeneic hematopoietic cell transplant; autoHCT, autologous hematopoietic cell transplant; CAR-T, chimeric antigen receptor T-cell; CONSORT, Consolidated Standards of Reporting Trials.

Figure 2.

Longitudinal SARS-CoV-2 anti-spike (-S) IgG titers and neutralizing antibody titers stratified by cellular therapy cohort and vaccine initiation timing. A, SARS-CoV-2 anti-S IgG titers per time point. The horizontal dotted lines indicate the threshold for a positive response, defined as anti-S IgG >2500 U/mL as determined from an ROC curve analysis; this was also the upper limit of quantitation for the assay. Significant differences are indicated; other comparisons are shown in Supplementary Tables 4 and 5. B, SARS-CoV-2 neutralizing antibody titers (inhibitory dose [ID50]) in a subgroup of 151 participants; ID50 is defined as the reciprocal of the sample dilution required to reduce relative luminescence units by 50%. Statistical comparisons are shown in Supplementary Tables 3 and 4. The horizontal dotted lines show the median neutralizing antibody level (5274 ID50) achieved in a healthy cohort vaccinated with 2 doses of mRNA-1273 (Moderna) in a clinical trial and tested with the same assay and defined here as a positive response. In panels A and B, “Prior COVID Exposure” (squares) indicates data in the first 2 time points from participants with a known prior SARS-CoV-2 infection, prior SARS-CoV-2 vaccination in the participant or hematopoietic cell donor, or positive anti-N IgG assay at baseline. Results are depicted on a log₁₀ scale. Time points tested within 6 months of receipt of tixagevimab-cilgavimab (Evusheld) were excluded. The horizontal bar indicates the median and the boxes indicate the interquartile range. Abbreviations: AlloHCT, allogeneic hematopoietic cell transplantation; AutoHCT, autologous hematopoietic cell transplantation; CAR T, chimeric antigen receptor T-cell; COVID, coronavirus disease 2019; IgG, immunoglobulin G; N, nucleocapsid; ROC, receiver operating characteristic; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; V1, first vaccination; V2, second vaccination.

Figure 3.

Propensity score–adjusted antibody response rates (anti-spike IgG >2500 U/mL) after 2 or more vaccine doses stratified by cellular therapy cohort and vaccine initiation timing. Forest plots of the proportion of individuals at each time point, stratified by vaccine initiation within 4 months versus 4–12 months after cellular therapy, who had a positive anti-spike IgG value (defined as >2500 U/mL). The allogeneic HCT, autologous HCT, and CAR-T-cell therapy cohorts are depicted in panels A, B, and C, respectively. Propensity scores of being in the within-4-month timing subgroup were constructed using stepwise variable selection with a criterion of a P value ≤.05 in the model to determine which variables were included in the final model. Potential interactions were evaluated between covariates. Cell therapy type, lymphocyte count, and calendar time of enrollment were included in the final model. Inverse probability weights (IPWs) were constructed from these propensity scores for all patients according to their timing groups. These were used to obtain adjusted response rate estimates and CIs using IPW proportions and their standard errors. Wald 99% CIs are shown. Comparisons used a Wald test to compare inverse probability–weighted proportions. Patients who received tixagevimab-cilgavimab (Evusheld) within the prior 6 months were excluded. Abbreviations: CAR-T cell, chimeric antigen receptor T-cell; CI, confidence interval; HCT, hematopoietic cell transplantation; IgG, immunoglobulin; V1, first vaccination; V2, second vaccination; V3, third vaccination.

Figure 4.

SARS-CoV-2–specific T-cell receptor (TCR) variable beta-chain sequencing results in a subgroup of 151 participants. A, Qualitative results indicating a positive, negative, or indeterminate (“No Call”) result for the presence of SARS-CoV-2–specific TCRs based on the T-Detect ImmunoSEQ Assay classifier (Adaptive Biotechnologies, Seattle, WA, USA). Each row indicates a unique participant clustered by allogeneic HCT recipients at the top of the panel, autologous HCT recipients in the middle, and CAR-T-cell therapy recipients at the bottom of the panel. Unfilled cells at the end-of-study time point indicate that no sample was available for testing. B, The proportion of participants with a positive T-Detect at the post-V2 time point stratified by cellular therapy cohort and vaccine initiation timing subgroup. Participants with a positive test at baseline were excluded from these analyses. C, The proportion of participants with a positive T-Detect at the post-V2 time point in categories of negative, any detectable, or positive (>2500 U/mL) SARS-CoV-2 anti-S IgG titers. Any detectable antibody was based on a threshold determined to be predictive of detection of neutralizing antibodies at any level. In panels B and C, individuals with a positive T-Detect at the pre-V1 time point were excluded. D, Quantitative values at each time point indicating the SARS-CoV-2 TCR breadth, defined as the proportion of total unique TCRs associated with SARS-CoV-2, and depth, defined as the extent to which SARS-CoV-2-associated TCRs expand. *P ≤ .05; **P ≤ .01; ***P ≤ .001. Abbreviations: alloHCT, allogeneic hematopoietic cell transplantation; autoHCT, autologous hematopoietic cell transplantation; CAR-T, chimeric antigen receptor T-cell; HCT, hematopoietic cell transplantation; IgG, immunoglobulin G; NEG, negative; NS, significant; POS, positive; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; V1, first vaccination; V2, second vaccination.