SARS-CoV-2 vaccination in the first year after hematopoietic cell transplant or chimeric antigen receptor T cell therapy: A prospective, multicenter, observational study (BMT CTN 2101)

Abstract

Background: The optimal timing of vaccination with SARS-CoV-2 vaccines after cellular therapy is incompletely understood.

Objective: To describe humoral and cellular responses after SARS-CoV-2 vaccination initiated <4 months versus 4-12 months after cellular therapy.

Design: Multicenter prospective observational study.

Setting: 34 centers in the United States.

Participants: 466 allogeneic hematopoietic cell transplant (HCT; n=231), autologous HCT (n=170), or chimeric antigen receptor T cell (CAR-T cell) therapy (n=65) recipients enrolled between April 2021 and June 2022.

Interventions: SARS-CoV-2 vaccination as part of routine care.

Measurements: We obtained blood prior to and after vaccinations at up to five 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 (TCRs), in a subgroup.

Results: Anti-S IgG and neutralizing antibody responses increased with vaccination in HCT recipients irrespective of vaccine initiation timing but were unchanged in CAR-T cell recipients initiating vaccines within 4 months. Anti-S IgG ^≥2,500 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. Humoral and cellular responses did not significantly differ among participants initiating vaccinations <4 months vs 4-12 months after cellular therapy. Pre-cellular therapy SARS-CoV-2 infection or vaccination were key predictors of post-cellular therapy anti-S IgG levels.

Limitations: The majority of participants were adults and received mRNA vaccines.

Conclusions: These data support starting mRNA SARS-CoV-2 vaccination three to four months after allogeneic HCT, autologous HCT, and CAR-T cell therapy.

Funding: National Marrow Donor Program, Leukemia and Lymphoma Society, Multiple Myeloma Research Foundation, Novartis, LabCorp, American Society for Transplantation and Cellular Therapy, Adaptive Biotechnologies, and the National Institutes of Health.

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

Figure 1.

Longitudinal SARS-CoV-2 anti-Spike 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 line indicates the threshold for a positive response, defined as anti-S IgG >2,500 U/mL as determined from a ROC curve analysis; this was also the upper limit of quantitation for the assay. B) SARS-CoV-2 neutralizing antibody titers (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%. The horizontal dotted line shows the median neutralizing antibody level (5,274 ID50) achieved in a healthy cohort vaccinated with two 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’ (green squares) indicates data in the first two 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.

Figure 2.

Propensity score-adjusted antibody response rates (anti-Spike IgG >2,500 U/mL) after two 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 <4 months versus 4–12 months after cellular therapy, who had a positive anti-Spike IgG value (defined as 2,500 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 <4-month timing subgroup were constructed using stepwise variable selection with a criterion of a p-value ≤0.05 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 (IPW) were constructed from these propensity scores for all patients according to their timing groups. These were used to obtain adjusted response rate estimates and confidence intervals using IPW proportions and their standard errors. Wald 99% confidence intervals (CI) are shown. Comparisons used a Wald test to compare IPW weighted proportions. Patients who received tixagevimab-cilgavimab (Evusheld) within the prior six months were excluded.

Figure 3.

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). 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 timepoint 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 timepoint in categories of negative, any detectable, or positive (>2,500 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. NS indicates not significant; *, ≤0.05; **, ≤0.01; ***, ≤0.001.