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

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JAMA Oncology

Published Online: August 11, 2022

Brief Report

Article Information and Disclosures

Sabine Haggenburg, MD^1,2;

Quincy Hofsink, MD^1,2;

Birgit I. Lissenberg-Witte, PhD³;

Annoek E. C. Broers, MD, PhD⁴;

Jaap A. van Doesum, MD⁵;

Rob S. van Binnendijk, PhD⁶;

Gerco den Hartog, PhD⁶;

Michel S. Bhoekhan, BSc^1,2;

Nienke J. E. Haverkate, BSc^2,7;

Judith A. Burger, BSc⁸;

Joey H. Bouhuijs, BSc⁸;

Gaby P. Smits, MSc⁶;

Dorine Wouters, PhD⁹;

Ester M. M. van Leeuwen, PhD^2,7;

Hetty J. Bontkes, PhD¹⁰;

Neeltje A. Kootstra, PhD^2,7;

Sonja Zweegman, MD, PhD^11,12;

Arnon P. Kater, MD, PhD^1,12;

Mirjam H. M. Heemskerk, PhD¹³;

Kaz Groen, MD¹¹;

Tom van Meerten, MD, PhD⁵;

Pim G. N. J. Mutsaers, MD⁴;

Tim Beaumont, PhD⁸;

Marit J. van Gils, PhD⁸;

Abraham Goorhuis, MD, PhD¹⁴;

Caroline E. Rutten, MD, PhD¹;

Mette D. Hazenberg, MD, PhD^1,2,12,15;

Inger S. Nijhof, MD, PhD^11,16;

for the COBRA KAI Study Team

Author Affiliations

¹Department of Hematology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
²Amsterdam Institute for Infection and Immunity, Amsterdam UMC, Amsterdam, the Netherlands
³Department of Epidemiology and Data Science, Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands
⁴Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
⁵Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
⁶Centre for Immunology of Infectious Diseases and Vaccines, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
⁷Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
⁸Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
⁹Central Diagnostic Laboratory, Amsterdam UMC, Amsterdam, the Netherlands
¹⁰Laboratory Medical Immunology, Amsterdam UMC, Amsterdam, the Netherlands
¹¹Department of Hematology, Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands
¹²Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands
¹³Department of Hematology, Leiden UMC, Leiden, the Netherlands
¹⁴Department of Infectious Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
¹⁵Department of Hematopoiesis, Sanquin Research, Amsterdam, the Netherlands
¹⁶Department of Internal Medicine-Hematology, St Antonius Hospital, Nieuwegein, the Netherlands

COBRA KAI Study Teamfor the

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Key Points

Question Is a third mRNA-1273 vaccination associated with SARS-CoV-2 antibody concentration levels in immunocompromised patients with hematologic cancers similar to levels in healthy adults after the standard 2-dose mRNA-1273 schedule?

Findings In this cohort study that included 584 immunocompromised patients with hematologic cancers, a third mRNA-1273 vaccination was associated with significantly improved SARS-CoV-2 antibody concentrations comparable to those obtained by healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. The neutralizing capacity of these antibodies against wild-type SARS-CoV-2 virus and variants of concern also improved.

Meaning The primary COVID-19 vaccination schedule for immunocompromised patients with hematologic cancers should be supplemented with a delayed third vaccination.

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

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Article Information

Accepted for Publication: June 7, 2022.

Published Online: August 11, 2022. doi:10.1001/jamaoncol.2022.3227

Corresponding Author: Mette D. Hazenberg, MD, PhD, Department of Hematology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands (m.d.hazenberg@amsterdamumc.nl).

Author Contributions: Drs Hazenberg and Nijhof had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Haggenburg, Hofsink, Goorhuis, Rutten, Hazenberg, and Nijhof contributed equally.

Concept and design: Lissenberg-Witte, van Doesum, Zweegman, Kater, Heemskerk, Groen, Mutsaers, Goorhuis, Rutten, Hazenberg, Nijhof.

Acquisition, analysis, or interpretation of data: Haggenburg, Hofsink, Lissenberg-Witte, Broers, van Doesum, van Binnendijk, den Hartog, Bhoekhan, Haverkate, Burger, Bouhuijs, Smits, Wouters, van Leeuwen, Bontkes, Kootstra, Kater, Groen, van Meerten, Beaumont, van Gils, Goorhuis, Rutten, Hazenberg, Nijhof.

Drafting of the manuscript: Haggenburg, Hofsink, Lissenberg-Witte, Bouhuijs, Smits, Groen, Goorhuis, Hazenberg, Nijhof.

Critical revision of the manuscript for important intellectual content: Lissenberg-Witte, Broers, van Doesum, van Binnendijk, den Hartog, Bhoekhan, Haverkate, Burger, Wouters, van Leeuwen, Bontkes, Kootstra, Zweegman, Kater, Heemskerk, van Meerten, Mutsaers, Beaumont, van Gils, Goorhuis, Rutten, Hazenberg, Nijhof.

Statistical analysis: Haggenburg, Hofsink, Lissenberg-Witte, van Binnendijk, Nijhof.

Obtained funding: van Doesum, Kater, Goorhuis, Hazenberg, Nijhof.

Administrative, technical, or material support: Haggenburg, Hofsink, van Doesum, van Binnendijk, den Hartog, Bhoekhan, Haverkate, Smits, Wouters, Bontkes, Kootstra, Zweegman, Groen, van Meerten, Mutsaers, Beaumont, van Gils, Goorhuis, Rutten, Nijhof.

Supervision: Lissenberg-Witte, Broers, van Doesum, Heemskerk, Beaumont, van Gils, Goorhuis, Hazenberg, Nijhof.

Conflict of Interest Disclosures: Dr Zweegman reported other from Janssen (research funding, participation in advisory board), Takeda (research funding, participation in advisory board), Sanofi (participation in advisory board), Bristol Myers Squibb (BMS) (participation in advisory board), and Oncopeptides (participation in advisory board) outside the submitted work. Dr Kater reported grants and participation in advisory boards from Janssen, AbbVie, Roche/Genentech, and BMS outside the submitted work; in addition, Dr Kater had a patent for Janssen pending and a patent for LAVA issued. Dr van Meerten reported research grants from Genentech, Celgene/BMS; personal fees from Kite/Gilead and Janssen (advisory boards); and honoraria from Celgene/BMS outside the submitted work. Dr Nijhof reported education from Janssen and BMS/Celgene outside the submitted work. No other disclosures were reported.

Funding/Support: This study was financially supported by the Dutch Research Council (NWO ZonMW, grant 10430072010009) and Amsterdam UMC.

Role of the Funder/Sponsor: ZonMW or Amsterdam UMC were not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript or decision to submit the manuscript for publication.

Group Information: The COBRA KAI Study Team members are listed in Supplement 2.

Additional Contributions: The authors would like to extend their deepest gratitude to all patients, colleagues, students, and volunteers from participating institutes, the Netherlands Cancer Registry, and the National Institute for Public Health and the Environment who made this study possible.

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