Distinct trajectories of humoral immune responses after SARS-CoV-2 mRNA vaccination in autoimmune inflammatory rheumatic diseases: A group-based trajectory analysis

Yuta Yamaguchi; Saori Amiya; Shoichiro Inokuchi; Sayaka Nagao; Kazuma Kosaka; Shinichiro Nameki; Teruaki Murakami; Yuko Yoshimine; Yasutaka Okita; Takahiro Kawasaki; Takayoshi Morita; Kohei Tsujimoto; Jun Fujimoto; Masayuki Nishide; Sumiyuki Nishida; Masashi Narazaki; Yasuhiro Kato; Atsushi Kumanogoh

doi:10.1016/j.vaccine.2025.127771

Distinct trajectories of humoral immune responses after SARS-CoV-2 mRNA vaccination in autoimmune inflammatory rheumatic diseases: A group-based trajectory analysis

Vaccine. 2025 Nov 14:66:127771. doi: 10.1016/j.vaccine.2025.127771. Epub 2025 Oct 12.

Authors

Yuta Yamaguchi¹, Saori Amiya², Shoichiro Inokuchi³, Sayaka Nagao⁴, Kazuma Kosaka⁵, Shinichiro Nameki⁶, Teruaki Murakami⁷, Yuko Yoshimine⁵, Yasutaka Okita⁵, Takahiro Kawasaki⁸, Takayoshi Morita⁹, Kohei Tsujimoto¹⁰, Jun Fujimoto¹¹, Masayuki Nishide⁵, Sumiyuki Nishida¹², Masashi Narazaki¹³, Yasuhiro Kato¹⁴, Atsushi Kumanogoh¹⁵

Affiliations

¹ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Division of Pharmacology, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe City, Hyogo 650-0017, Japan; Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), The University of Osaka, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Pharmacology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-Ku, Tokyo 113-8519, Japan.
² Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Center for Infectious Diseases for Education and Research (CiDER), The University of Osaka, 1-10 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), The University of Osaka, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Respiratory Medicine, Ikeda City Hospital, 3-1-18 Jonan, Ikeda, Osaka, 563-8510, Japan.
³ Real World Evidence Division, Pharmaceutical Business Unit, JMDC Inc., 12th Floor, Sumitomo Shiba Daimon Building, 2-5-5 Shiba Daimon, Minato-ku, Tokyo 105-0012, Japan.
⁴ Center for Infectious Diseases for Education and Research (CiDER), The University of Osaka, 1-10 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁵ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), The University of Osaka, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁶ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), The University of Osaka, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Division of Rheumatology and Allergy, Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-ku, Osaka, 558-8558, Japan.
⁷ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), The University of Osaka, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Respiratory Medicine and Clinical Immunology, Nippon Life Hospital, 2-1-54 Enokojima, Nishi-ku, Osaka, 550-0006, Japan.
⁸ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), The University of Osaka, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Division of Rheumatology and Clinical Immunology, University of Pittsburgh, 3500 Terrace Street, Pittsburgh, PA 15261, USA.
⁹ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; The Center for Rheumatic Disease, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
¹⁰ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), The University of Osaka, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Center for Advanced Modalities and Drug Delivery Systems (CAMaD), The University of Osaka, 2-8 Yamadaoka, Suita, Osaka 565-0871, Japan.
¹¹ Department of Clinical Immunology, Osaka International Medical & Science Center, 2-6-40 Karasugatsuji, Tennoji-ku, Osaka 543-8922, Japan.
¹² Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Center for Advanced Modalities and Drug Delivery Systems (CAMaD), The University of Osaka, 2-8 Yamadaoka, Suita, Osaka 565-0871, Japan; Strategic Global Partnership & X (Cross)-Innovation Initiative, Graduate School of Medicine, The University of Osaka and The University of Osaka Hospital, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
¹³ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Advanced Clinical and Translational Immunology, Graduate School of Medicine, The University of Osaka, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
¹⁴ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), The University of Osaka, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Center for Advanced Modalities and Drug Delivery Systems (CAMaD), The University of Osaka, 2-8 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: kato@imed3.med.osaka-u.ac.jp.
¹⁵ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Center for Infectious Diseases for Education and Research (CiDER), The University of Osaka, 1-10 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), The University of Osaka, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Center for Advanced Modalities and Drug Delivery Systems (CAMaD), The University of Osaka, 2-8 Yamadaoka, Suita, Osaka 565-0871, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), The University of Osaka, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), The University of Osaka, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.

PMID: 41083320
DOI: 10.1016/j.vaccine.2025.127771

Abstract

Background: Patients with autoimmune inflammatory rheumatic diseases (AIRDs) are at a high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Data on the effects of multiple (>3) vaccine doses and their influencing factors are limited. Understanding antibody dynamics after repeated vaccinations is essential for optimising vaccination strategies. Therefore, this study characterised the antibody response trajectories against SARS-CoV-2 and explored key clinical and immunological determinants.

Methods: This single-centre retrospective cohort study included patients with AIRDs who received SARS-CoV-2 vaccinations between 1 February and 6 December 2021. Serum neutralising antibody titres from the first to fifth vaccinations were analysed using group-based trajectory modelling (GBTM). The clinical characteristics and serum cytokine levels were compared between the response groups.

Results: The study included 293 patients with AIRDs. Three response trajectories were identified via GBTM: low responders (n = 13, 4·4%), middle responders (n = 122, 41·6%), and high responders (n = 158, 54·0%). Abatacept use was the strongest predictor of a low response (odds ratio 11·55, [95% confidence interval 2·27-58·82], p = 0·0032) but was also associated with a middle response (3·82, [1·18-12·29], p = 0·025). A middle response was also linked to older age (2·31 [1·38-3·85], p = 0·0014), mycophenolate mofetil use (3·03 [1·02-8·97], p = 0·045), anti-neutrophil cytoplasmic autoantibody-associated vasculitis (3·26 [1·29-8·19], p = 0·012), and rheumatoid arthritis (1·62 [1·02-8·97], p = 0·048), while systemic lupus erythematosus was inversely associated (0·49 [0·26-0·95], p = 0·035). Low responders exhibited elevated inflammatory mediators, including interleukin-6 and B-cell activating factor.

Conclusion: We identified distinct antibody response trajectories in patients with AIRDs, including a subgroup with persistently low humoral immune responses despite repeated vaccinations. This study highlights the need for personalised vaccination strategies that consider individual clinical and immunological factors to optimise protection in this vulnerable populations.

Keywords: Coronavirus disease 2019; Group-based trajectory modelling; Multiple mRNA vaccination; Severe acute respiratory syndrome coronavirus 2.

MeSH terms

Adult
Aged
Antibodies, Neutralizing / blood
Antibodies, Neutralizing / immunology
Antibodies, Viral / blood
Antibodies, Viral / immunology
Autoimmune Diseases* / immunology
COVID-19 Vaccines* / administration & dosage
COVID-19 Vaccines* / immunology
COVID-19* / immunology
COVID-19* / prevention & control
Cytokines / blood
Female
Humans
Immunity, Humoral*
Male
Middle Aged
Retrospective Studies
Rheumatic Diseases* / immunology
SARS-CoV-2* / immunology
Vaccination

Substances

Antibodies, Viral
COVID-19 Vaccines
Antibodies, Neutralizing
Cytokines