Antibody Response in Immunocompromised Patients With Hematologic Cancers Who Received a 3-Dose mRNA-1273 Vaccination Schedule for COVID-19

Abstract

Importance: It has become common practice to offer immunocompromised patients with hematologic cancers a third COVID-19 vaccination dose, but data substantiating this are scarce.

Objective: To assess whether a third mRNA-1273 vaccination is associated with increased neutralizing antibody concentrations in immunocompromised patients with hematologic cancers comparable to levels obtained in healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule.

Design, setting, and participants: This prospective observational cohort study was conducted at 4 university hospitals in the Netherlands and included 584 evaluable patients spanning the spectrum of hematologic cancers and 44 randomly selected age-matched adults without malignant or immunodeficient comorbidities.

Exposures: One additional mRNA-1273 vaccination 5 months after completion of the standard 2-dose mRNA-1273 vaccination schedule.

Main outcomes and measures: Serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens prior to and 4 weeks after a third mRNA-1273 vaccination, and antibody neutralization capacity of wild-type, Delta, and Omicron variants in a subgroup of patients.

Results: In this cohort of 584 immunocompromised patients with hematologic cancers (mean [SD] age, 60 [11.2] years; 216 [37.0%] women), a third mRNA-1273 vaccination was associated with median S1-IgG concentrations comparable to concentrations obtained by healthy individuals after the 2-dose mRNA-1273 schedule. The rise in S1-IgG concentration after the third vaccination was most pronounced in patients with a recovering immune system, but potent responses were also observed in patients with persistent immunodeficiencies. Specifically, patients with myeloid cancers or multiple myeloma and recipients of autologous or allogeneic hematopoietic cell transplantation (HCT) reached median S1-IgG concentrations similar to those obtained by healthy individuals after a 2-dose schedule. Patients receiving or shortly after completing anti-CD20 therapy, CD19-directed chimeric antigen receptor T-cell therapy recipients, and patients with chronic lymphocytic leukemia receiving ibrutinib were less responsive or unresponsive to the third vaccination. In the 27 patients who received cell therapy between the second and third vaccination, S1 antibodies were preserved, but a third mRNA-1273 vaccination was not associated with significantly enhanced S1-IgG concentrations except for patients with multiple myeloma receiving autologous HCT. A third vaccination was associated with significantly improved neutralization capacity per antibody.

Conclusions and relevance: Results of this cohort study support that the primary schedule for immunocompromised patients with hematologic cancers should be supplemented with a delayed third vaccination. Patients with B-cell lymphoma and allogeneic HCT recipients need to be revaccinated after treatment or transplantation.

Trial registration: EudraCT Identifier: 2021-001072-41.

Figure 1.. Included Patients, SARS-CoV-2 Antibody Concentrations, and Antibody Maturation

A, Patient inclusion. B, Spike subunit 1 (S1)-immunoglobulin G (IgG) concentration at each time point for n = 584 evaluable patients. The S1-IgG concentration of age-matched controls measured after the standard 2-dose mRNA-1273 schedule is indicated in black (eMethods in Supplement 1). Blue lines indicate seroconversion (S1-IgG > 10 BAU/mL) and S1-IgG concentration 300 BAU/mL or greater. C, Ratio of ID₅₀ to S1-IgG concentration in patients with ID₅₀ greater than 20 for SARS-CoV-2 wild type and variants of concern. ^aDetails of patients who did not receive a third vaccination during the time under study are depicted in eTable 2 in Supplement 1. ^bDetails of patients who received cell therapy between the second and third vaccination are depicted in eTable 4 in Supplement 1. ^cDetails of patients who became SARS-CoV-2 infected are depicted in eTable 3 in Supplement 1.

Figure 2.. Individual Spike Subunit 1 (S1) Binding Antibody Concentrations and B-Cell Numbers

A, The S1-immunoglobulin G (IgG) concentrations over time of previously uninfected patients. Blue lines indicate thresholds for seroconversion (S1-IgG > 10 BAU/mL) and S1-IgG concentration of 300 BAU/mL; gray lines are individual patients and thick blue lines represent median values for each cohort. Bold lines in HDM and allogeneic HCT panels indicate median values; number of BEAM or Bu/Cy autologous HCT and CAR T-cell recipients was too low for statistical analyses. B, The B-cell number at the time of third vaccination vs S1-IgG concentration 4 weeks after the third vaccination. Blue lines indicate thresholds for seroconversion (S1-IgG > 10 BAU/mL), S1-IgG concentration of 300 BAU/mL, and B-cell detection, and upper and lower limits of normal B-cell numbers. C, Patients who received cell therapy as indicated at any time during the 5 months between the second and the third mRNA-1273 vaccination. See eTable 4 in Supplement 1 for patient details. AML indicates acute myeloid leukemia; BEAM, BCNU, etoposide, cytarabine, melphalan; Bu/Cy, busulfan/cyclophosphamide; CAR, chimeric antigen receptor; cGVHD, chronic graft-vs-host disease; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; HCT, hematopoietic cell transplantation; HDM, high-dose melphalan; IMiDs, immunomodulatory imide drugs; MPN, myeloproliferative neoplasm; TKI, tyrosine kinase inhibitor.