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. 2021 Nov;174(11):1572-1585.
doi: 10.7326/M21-1757. Epub 2021 Aug 31.

Effect of Immunosuppression on the Immunogenicity of mRNA Vaccines to SARS-CoV-2 : A Prospective Cohort Study

Parakkal Deepak  1 , Wooseob Kim  1 , Michael A Paley  1 , Monica Yang  2 , Alexander B Carvidi  2 , Emanuel G Demissie  2 , Alia A El-Qunni  1 , Alem Haile  1 , Katherine Huang  1 , Baylee Kinnett  1 , Mariel J Liebeskind  1 , Zhuoming Liu  1 , Lily E McMorrow  1 , Diana Paez  2 , Niti Pawar  2 , Dana C Perantie  1 , Rebecca E Schriefer  1 , Shannon E Sides  1 , Mahima Thapa  1 , Maté Gergely  1 , Suha Abushamma  1 , Sewuese Akuse  1 , Michael Klebert  1 , Lynne Mitchell  1 , Darren Nix  1 , Jonathan Graf  2 , Kimberly E Taylor  2 , Salim Chahin  1 , Matthew A Ciorba  1 , Patricia Katz  2 , Mehrdad Matloubian  2 , Jane A O'Halloran  1 , Rachel M Presti  1 , Gregory F Wu  1 , Sean P J Whelan  1 , William J Buchser  1 , Lianne S Gensler  3 , Mary C Nakamura  3 , Ali H Ellebedy  1 , Alfred H J Kim  1
Affiliations

Effect of Immunosuppression on the Immunogenicity of mRNA Vaccines to SARS-CoV-2 : A Prospective Cohort Study

Parakkal Deepak et al. Ann Intern Med. 2021 Nov.

Abstract

Background: Patients with chronic inflammatory disease (CID) treated with immunosuppressive medications have increased risk for severe COVID-19. Although mRNA-based SARS-CoV-2 vaccination provides protection in immunocompetent persons, immunogenicity in immunosuppressed patients with CID is unclear.

Objective: To determine the immunogenicity of mRNA-based SARS-CoV-2 vaccines in patients with CID.

Design: Prospective observational cohort study.

Setting: Two U.S. CID referral centers.

Participants: Volunteer sample of adults with confirmed CID eligible for early COVID-19 vaccination, including hospital employees of any age and patients older than 65 years. Immunocompetent participants were recruited separately from hospital employees. All participants received 2 doses of mRNA vaccine against SARS-CoV-2 between 10 December 2020 and 20 March 2021. Participants were assessed within 2 weeks before vaccination and 20 days after final vaccination.

Measurements: Anti-SARS-CoV-2 spike (S) IgG+ binding in all participants, and neutralizing antibody titers and circulating S-specific plasmablasts in a subset to assess humoral response after vaccination.

Results: Most of the 133 participants with CID (88.7%) and all 53 immunocompetent participants developed antibodies in response to mRNA-based SARS-CoV-2 vaccination, although some with CID developed numerically lower titers of anti-S IgG. Anti-S IgG antibody titers after vaccination were lower in participants with CID receiving glucocorticoids (n = 17) than in those not receiving them; the geometric mean of anti-S IgG antibodies was 357 (95% CI, 96 to 1324) for participants receiving prednisone versus 2190 (CI, 1598 to 3002) for those not receiving it. Anti-S IgG antibody titers were also lower in those receiving B-cell depletion therapy (BCDT) (n = 10). Measures of immunogenicity differed numerically between those who were and those who were not receiving antimetabolites (n = 48), tumor necrosis factor inhibitors (n = 39), and Janus kinase inhibitors (n = 11); however, 95% CIs were wide and overlapped. Neutralization titers seemed generally consistent with anti-S IgG results. Results were not adjusted for differences in baseline clinical factors, including other immunosuppressant therapies.

Limitations: Small sample that lacked demographic diversity, and residual confounding.

Conclusion: Compared with nonusers, patients with CID treated with glucocorticoids and BCDT seem to have lower SARS-CoV-2 vaccine-induced antibody responses. These preliminary findings require confirmation in a larger study.

Primary funding source: The Leona M. and Harry B. Helmsley Charitable Trust, Marcus Program in Precision Medicine Innovation, National Center for Advancing Translational Sciences, and National Institute of Arthritis and Musculoskeletal and Skin Diseases.

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Conflict of interest statement

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M21-1757.

Figures

Visual Abstract.
Visual Abstract.. Effect of Immunosuppression on Immunogenicity of mRNA SARS-CoV-2 Vaccines.
Evidence suggests that immunogenicity to mRNA-based SARS-CoV-2 vaccination in immunosuppressed patients may be reduced. This study assessed the response to 2 doses of mRNA-based SARS-CoV-2 vaccine among 133 participants with underlying chronic inflammatory disease, many of whom were receiving glucocorticoids, B-cell depletion therapy, or other immunosuppressant therapy.
Figure 1.
Figure 1.. Immunogenicity among participants with CID and immunocompetent participants.
ABA = abatacept; BCDT = B-cell depletion therapy; BLyS = B-lymphocyte stimulator; CID = chronic inflammatory disease; HCQ = hydroxychloroquine; IL23 = interleukin-23; IVIg = intravenous immunoglobulin; JAKi = Janus kinase inhibitor; LoD = limit of detection; NSAID = nonsteroidal anti-inflammatory drug; S = spike; SSZ = sulfasalazine; TCZ = tocilizumab; TNFi = tumor necrosis factor inhibitor. A. Quantification of circulating anti-S IgG for immunocompetent participants and those with CID before and after immunization. B. Neutralization of pseudotyped vesicular stomatitis virus with SARS-CoV-2 S protein by serum of immunocompetent participants and those with CID after vaccination. In panels A and B, the boxes span the 25th to 75th percentiles, lines indicate the median, and whiskers denote the 5th and 95th percentiles. Magenta circles are at the geometric means, with error bars showing the 95% CIs. Circles represent outliers. C. UpSet plot of immunomodulatory therapy combinations for participants with CID. Dots with connecting lines indicate medication combinations. Combinations with no participants are omitted.
Appendix Figure 1.
Appendix Figure 1.. Flow chart of inclusion, exclusion, and selection of participants.
ELISpot = enzyme-linked immunosorbent spot.
Appendix Figure 2.
Appendix Figure 2.. Plasmablast formation among immunocompetent participants and those with CID.
ABA = abatacept; BCDT = B-cell depletion therapy; BLyS = B-lymphocyte stimulator; CID = chronic inflammatory disease; ELISpot = enzyme-linked immunosorbent spot; HCQ = hydroxychloroquine; IL23 = interleukin-23; IVIg = intravenous immunoglobulin; JAKi = Janus kinase inhibitor; LoD = limit of detection; NSAID = nonsteroidal anti-inflammatory drug; PBMC = peripheral blood mononuclear cell; S = spike; SFU = spot-forming unit; SSZ = sulfasalazine; TCZ = tocilizumab; TNFi = tumor necrosis factor inhibitor. A. Frequency of circulating plasmablasts for immunocompetent participants and those with CID before and after immunization. Total Ig, SARS-CoV-2 S-binding Ig, and influenza virus vaccine-binding Ig are shown. B. Frequency of anti-S Ig circulating plasmablasts in participants with CID receiving or not receiving glucocorticoids (prednisone). C. Frequency of anti-S Ig circulating plasmablasts in participants with CID receiving or not receiving antimetabolites. D. Frequency of anti-S Ig circulating plasmablasts in participants with CID receiving or not receiving BCDT. In panels A through D, the boxes span the 25th to 75th percentiles, lines indicate the median, and whiskers denote the 5th and 95th percentiles. Magenta circles are at the geometric means, with error bars showing the 95% CIs. Circles represent outliers. Plasmablast frequency was measured as SFUs per 106 PBMCs via ELISpot assay. E. UpSet plot of immunomodulatory therapy combinations for participants with CID. Dots with connecting lines indicate medication combinations. Combinations with no participants are omitted.
Figure 2.
Figure 2.. Immunogenicity among participants with CID receiving glucocorticoids (prednisone).
ABA = abatacept; BCDT = B-cell depletion therapy; BLyS = B-lymphocyte stimulator; CID = chronic inflammatory disease; HCQ = hydroxychloroquine; IL23 = interleukin-23; IVIg = intravenous immunoglobulin; JAKi = Janus kinase inhibitor; LoD = limit of detection; NSAID = nonsteroidal anti-inflammatory drug; S = spike; SSZ = sulfasalazine; TCZ = tocilizumab; TNFi = tumor necrosis factor inhibitor. A. Quantification of anti–SARS-CoV-2 antibodies in participants with CID receiving or not receiving prednisone. B. Neutralization of pseudotyped vesicular stomatitis virus with SARS-CoV-2 S protein by serum for participants with CID receiving or not receiving prednisone. In panels A and B, the boxes span the 25th to 75th percentiles, lines indicate the median, and whiskers denote the 5th and 95th percentiles. Magenta circles are at the geometric means, with error bars showing the 95% CIs. Circles represent outliers. C. UpSet plot of immunomodulatory therapy combinations for participants with CID, stratified by prednisone use. Dots with connecting lines indicate medication combinations. Combinations with no participants are omitted.
Appendix Figure 3.
Appendix Figure 3.. Immunogenicity among participants with CID receiving antimetabolites.
ABA = abatacept; BCDT = B-cell depletion therapy; BLyS = B-lymphocyte stimulator; CID = chronic inflammatory disease; HCQ = hydroxychloroquine; IL23 = interleukin-23; IVIg = intravenous immunoglobulin; JAKi = Janus kinase inhibitor; LoD = limit of detection; NSAID = nonsteroidal anti-inflammatory drug; S = spike; SSZ = sulfasalazine; TCZ = tocilizumab; TNFi = tumor necrosis factor inhibitor. A. Quantification of anti–SARS-CoV-2 antibodies in participants with CID receiving or not receiving antimetabolites. B. Neutralization of pseudotyped vesicular stomatitis virus with SARS-CoV-2 S protein by serum for participants with CID receiving or not receiving antimetabolites. In panels A and B, the boxes span the 25th to 75th percentiles, lines indicate the median, and whiskers denote the 5th and 95th percentiles. Magenta circles are at the geometric means, with error bars showing the 95% CIs. Circles represent outliers. C. UpSet plot of immunomodulatory therapy combinations for participants with CID, stratified by antimetabolite use. Dots with connecting lines indicate medication combinations. Combinations with no participants are omitted.
Figure 3.
Figure 3.. Immunogenicity among participants with CID receiving TNFis.
ABA = abatacept; BCDT = B-cell depletion therapy; BLyS = B-lymphocyte stimulator; CID = chronic inflammatory disease; HCQ = hydroxychloroquine; IL23 = interleukin-23; IVIg = intravenous immunoglobulin; JAKi = Janus kinase inhibitor; LoD = limit of detection; NSAID = nonsteroidal anti-inflammatory drug; S = spike; SSZ = sulfasalazine; TCZ = tocilizumab; TNFi = tumor necrosis factor inhibitor. A. Quantification of circulating anti-S IgG for participants with CID receiving or not receiving TNFis. B. Neutralization of pseudotyped vesicular stomatitis virus with SARS-CoV-2 S protein by participants with CID receiving or not receiving TNFis. In panels A and B, the boxes span the 25th to 75th percentiles, lines indicate the median, and whiskers denote the 5th and 95th percentiles. Magenta circles are at the geometric means, with error bars showing the 95% CIs. Circles represent outliers. C. UpSet plot of immunomodulatory therapy combinations for participants with CID, stratified by TNFi use. Dots with connecting lines indicate medication combinations. Combinations with no participants are omitted.
Figure 4.
Figure 4.. Immunogenicity among participants with CID receiving JAKis.
ABA = abatacept; BCDT = B-cell depletion therapy; BLyS = B-lymphocyte stimulator; CID = chronic inflammatory disease; HCQ = hydroxychloroquine; IL23 = interleukin-23; IVIg = intravenous immunoglobulin; JAKi = Janus kinase inhibitor; LoD = limit of detection; NSAID = nonsteroidal anti-inflammatory drug; S = spike; SSZ = sulfasalazine; TCZ = tocilizumab; TNFi = tumor necrosis factor inhibitor. A. Quantification of circulating anti-S IgG for participants with CID receiving JAKis. B. Neutralization of pseudotyped vesicular stomatitis virus with SARS-CoV-2 S protein for participants with CID receiving JAKis. In panels A and B, the boxes span the 25th to 75th percentiles, lines indicate the median, and whiskers denote the 5th and 95th percentiles. Magenta circles are at the geometric means, with error bars showing the 95% CIs. Circles represent outliers. C. UpSet plot of immunomodulatory therapy combinations for participants with CID, stratified by JAKi use. Dots with connecting lines indicate medication combinations. Combinations with no participants are omitted.
Figure 5.
Figure 5.. Immunogenicity among participants with CID receiving BCDT.
ABA = abatacept; BCDT = B-cell depletion therapy; BLyS = B-lymphocyte stimulator; CID = chronic inflammatory disease; HCQ = hydroxychloroquine; IL23 = interleukin-23; IVIg = intravenous immunoglobulin; JAKi = Janus kinase inhibitor; LoD = limit of detection; NSAID = nonsteroidal anti-inflammatory drug; S = spike; SSZ = sulfasalazine; TCZ = tocilizumab; TNFi = tumor necrosis factor inhibitor. A. Quantification of circulating anti-S IgG for participants with CID receiving BCDT. B. Neutralization of pseudotyped vesicular stomatitis virus with SARS-CoV-2 S protein for participants with CID receiving BCDT. In panels A and B, the boxes span the 25th to 75th percentiles, lines indicate the median, and whiskers denote the 5th and 95th percentiles. Magenta circles are at the geometric means, with error bars showing the 95% CIs. Circles represent outliers. C. UpSet plot of immunomodulatory therapy combinations for participants with CID receiving BCDT. Dots with connecting lines indicate medication combinations. Combinations with no participants are omitted.
Appendix Figure 4.
Appendix Figure 4.. Anti-S IgG titers versus time since the last dose of B-cell depletion therapy.
Symbols represent individual participants. LoD = limit of detection; S = spike.
See this image and copyright information in PMC

Update of

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