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Attenuated response to fourth dose SARS-CoV-2 vaccination in patients with autoimmune disease: a case series
  1. Mayan Teles1,
  2. Caoilfhionn M Connolly2,
  3. Sarah Frey3,
  4. Teresa Po-Yu Chiang3,
  5. Jennifer J Alejo3,
  6. Brian J Boyarsky1,
  7. Ami A Shah2,
  8. Jemima Albayda2,
  9. Lisa Christopher-Stine2,
  10. William A Werbel4,
  11. Dorry L Segev1,5,
  12. Julie J Paik2
  1. 1 Surgery, Johns Hopkins, Baltimore, Maryland, USA
  2. 2 Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  3. 3 Surgery, Johns Hopkins University, Baltimore, Maryland, USA
  4. 4 Infectious Diseases, Johns Hopkins University, Baltimore, Maryland, USA
  5. 5 Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
  1. Correspondence to Dr Dorry L Segev, Surgery, Johns Hopkins, Baltimore, MD 21205, USA; dorry{at}

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Severe, occasionally fatal breakthrough COVID-19 infections despite vaccination have been reported in patients with autoimmune disease,1 bringing vaccine efficacy in this population into question. Recently, the Food and Drug Administration authorised a third vaccine dose in immunocompromised patients who previously received two mRNA vaccines. We previously reported augmented antibody titers in 89% of patients with autoimmune disease after third SARS-CoV-2 vaccination dose2; herein, we describe antibody response in patients who received two additional SARS-CoV-2 vaccine doses after completion of initial series.

Patients with autoimmune diseases were recruited for our observational study as previously reported.3 We identified 18 patients ≥18 years of age who completed initial SARS-CoV-2 vaccine series (mRNA or adenovirus vector) and subsequently obtained two additional doses (AD) of SARS-CoV-2 vaccine between 30 April 2021 and 8 July 2021, six of whom were included in a previous report on response after three dose-vaccination.2 Participants with prior COVID-19 infection were excluded. Serial semiquantitative SARS-CoV-2 antibody testing was completed on the Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay, which measures total antibody to the SARS-CoV-2 S-receptor binding domain protein (positive ≥0.8 U/mL) and a consistent correlate of plasma neutralising capacity.4 Participants provided informed consent electronically.

Thirteen participants were female, with a median (IQR) age of 56 (52–66) years (table 1). The most common autoimmune diagnoses included inflammatory arthritis (n=4), myositis (n=3) and overlap connective tissue disease (n=3). Participants completed initial vaccine series with two doses of Pfizer (n=11), Moderna (n=2) or single dose of Janssen/Johnson and Johnson (J&J) (n=5). Mycophenolate was the most common immunosuppressive therapy (13/18) with median (IQR) daily dose of 2500 mg (1125, 3000 mg). All participants reported continuation of immunosuppression without interruption or modification during the initial vaccine series.

Table 1

Vaccines administered, autoimmune diagnoses, immunosuppressive regimens and perivaccination management with serial antispike antibody responses

There were 16/18 participants with negative anti-spike antibody response at a median of 84 (31–90) days after initial vaccine series. Participants reported the following additional vaccinations: AD 1 (AD1): Pfizer (n=11), Moderna (n=5), J&J (n=2), followed by AD 2 (AD2) of Pfizer (n=11) or Moderna (n=6) or J&J (n=1). Most participants (11/18) reported temporarily withholding of immunosuppressive therapy in the period surrounding the AD. Among those who completed antibody testing after AD1 (12/18), antispike antibodies increased above the threshold of positivity in eight participants and remained negative in two participants at a median (IQR) of 24 (14–31) days. Antibody testing was performed at a median (IQR) of 32 (28–34) days after AD2 in all participants, with median (IQR) antispike antibody titre of 1750 U/mL (26–2500). Both participants with persistently negative response reported use of mycophenolate and did not undergo perivaccination interruption of therapy.

This study has several limitations including small sample size, convenience sampling and lack of data on cellular response. Furthermore, most participants continued immunosuppressive therapy during initial vaccine series but modulated therapy around the time of AD which confounds results and limits interpretation of our findings; larger studies are required for systematic evaluation. We cannot exclude asymptomatic COVID-19 infection as we did not complete antinucleocapsid testing. Participants who initially received the J&J vaccine received a total of three doses while those who initially received mRNA vaccine received a total of four doses, which limits comparability. We did not routinely collect baseline disease activity or severity and the reason for participants receiving two AD, as opposed to a single AD, is unknown.

This is the first case series describing antibody responses to two AD of SARS-CoV-2 vaccines in patients with autoimmune disease on immunosuppression. While most patients demonstrated an augmented antibody response, our findings suggest that a subset of patients who do not withhold immunosuppression continue to have an impaired vaccine response despite four vaccine doses; this is similar to findings in other immunosuppressed populations.5 Both non-responders reported use of mycophenolate and continued therapy during the peri-vaccination period, which is consistent with findings that temporary interruption in immunosuppression can augment the humoral response,2 6 although, a recent case report demonstrated seroconversion following four vaccine doses without interruption of immunosuppression.7 More studies are needed to identify patients who may benefit from antibody monitoring, refinement in vaccination schedule, adjustment of perivaccination immunosuppression, or other strategies such as prophylactic therapies to better protect this vulnerable population.

Ethics statements

Patient consent for publication

Ethics approval

This study was approved by the Johns Hopkins Institutional Review Board (IRB00248540).


We would like to acknowledge the contributions of: Jake A. Ruddy BS, Allan B. Massie PhD, and Jacqueline M. Garonzik-Wang MD PhD.



  • DLS and JJP are joint senior authors.

  • Handling editor Josef S Smolen

  • Twitter @CaoilfhionnMD, @JenLAlejo

  • MT and CMC contributed equally.

  • Contributors Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work. MT, CMC, SF, BJB, JA, TP-YC, AAS, JA, LC-S, WAW, DLS and JJP. Drafting the work or revising it critically for important intellectual content. MT, CMC, SF, BJB, JA, TP-YC, AAS, JA, LC-S, WAW, DLS and JJP. Final approval of the version to be published MT, CMC, SF, BJB, JA, TP-YC, AAS, JA, LCS, WAW, DLS and JJP. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. CMC, MT, JA, DLS and JJP.

  • Funding This work was made possible by the generous support of the Ben Dov family. This work was supported by grant number F32DK124941 (Boyarsky), T32DK007713 (Alejo) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), K24AI144954 (Segev), U01AI138897 and K23AI157893 (Werbel) from National Institute of Allergy and Infectious Diseases (NIAID), K23AR073927 (Paik) from National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).

  • Disclaimer The analyses described here are the responsibility of the authors alone and do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organisations imply endorsement by the US Government.

  • Competing interests DLS has the following financial disclosures: consulting and speaking honoraria from Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallincrodt, Thermo Fisher Scientific. LC-S has the following financial disclosures: consultant fees from Janssen, Boehringer-Ingelheim, Mallinckrodt, EMD-Serono, Allogene and ArgenX. The other authors of this manuscript have no financial disclosures or completing interest to disclose as described by Annals of the Rheumatic Diseases.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.