[Skip to Content]
Outline
Claim CME
PDF
Vaccination

Comparison of SARS-CoV-2 Antibody Response 4 Weeks After Homologous vs Heterologous Third Vaccine Dose in Kidney Transplant RecipientsA Randomized Clinical Trial

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
JAMA Internal Medicine
Published Online: December 20, 2021
Original Investigation
Roman Reindl-Schwaighofer, MD, PhD1;
Andreas Heinzel, MSc1;
Manuel Mayrdorfer, MD1;
Rhea Jabbour, MD1;
Thomas M. Hofbauer, MD, PhD2;
Anne Merrelaar, MD3;
Michael Eder, MD1;
Florina Regele, MD1;
Konstantin Doberer, MD1;
Paul Spechtl, MD1;
Constantin Aschauer, MD1;
Maximilian Koblischke, PhD4;
Christopher Paschen, MD1;
Farsad Eskandary, MD, PhD1;
Karin Hu, MSc1;
Barbara Öhler, BSc1;
Arshdeep Bhandal, BSc1;
Sabine Kleibenböck1;
Rahel I. Jagoditsch, BSc1;
Bianca Reiskopf1;
Florian Heger, MD5;
Gregor Bond, MD, PhD1;
Georg A. Böhmig, MD1;
Robert Strassl, MD6;
Lukas Weseslindtner, MD4;
Alexander Indra, MD5,7;
Judith H. Aberle, MD4;
Michael Binder, MD8;
Rainer Oberbauer, MD, PhD1
Author Affiliations
  • 1Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
  • 2Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
  • 3Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria
  • 4Center for Virology, Medical University of Vienna, Vienna, Austria
  • 5Institute for Medical Microbiology and Hygiene, Austrian Agency for Health and Food Safety, Vienna, Austria
  • 6Division of Virology, Department of Laboratory Medicine, Medical University Vienna, Vienna, Austria
  • 7Paracelsus Medical University of Salzburg, Salzburg, Austria
  • 8Wiener Gesundheitsverbund, Vienna, Austria
Read article on JAMA Network

MOC/CME Information

editorial comment icon
Editorial
Comment
 related articles icon
Related
Articles
 author interview icon
Interviews
 multimedia icon
Multimedia
Read Article Claim CME
Key Points

Question  Does a heterologous SARS-CoV-2 vaccination strategy with the vector vaccine Ad26COVS1 result in a higher rate of antibody response compared with a homologous third dose of mRNA vaccine (mRNA-1273 or BNT162b2) in kidney transplant recipients who did not develop SARS-CoV-2 antibodies after 2 doses of an mRNA vaccine?

Findings  This randomized clinical trial found that a third dose of SARS-CoV-2 vaccine in 197 kidney transplant recipients without antibodies after 2 doses of an mRNA vaccine induced an antibody response in 35% of the homologous (mRNA) group vs 42% of the heterologous (vector) group, with no statistically significant difference.

Meaning  The findings of this randomized clinical trial show that homologous and heterologous vaccination strategies for a third SARS-CoV-2 vaccine dose in kidney transplant recipients are comparable, with both mRNA and vector vaccines achieving seroconversion in more than one-third of kidney transplant recipients. However, given the high rate of nonresponders after the third dose, additional strategies to induce an immune response in kidney transplant recipients are urgently needed.

Abstract

Importance  Fewer than 50% of kidney transplant recipients (KTRs) develop antibodies against the SARS-CoV-2 spike protein after 2 doses of an mRNA vaccine. Preliminary data suggest that a heterologous vaccination, combining mRNA and viral vector vaccines, may increase immunogenicity.

Objective  To assess the effectiveness of a third dose of an mRNA vs a vector vaccine in KTRs who did not have antibodies against the SARS-CoV-2 spike protein after 2 doses of an mRNA vaccine.

Design, Setting, and Participants  This was a single center, single-blinded, 1:1 randomized clinical trial of a third dose of vaccine against SARS-CoV-2, conducted from June 15 to August 16, 2021, in 201 KTRs who had not developed SARS-CoV-2 spike protein antibodies after 2 doses of an mRNA vaccine. Data analyses were performed from August 17 to August 31, 2021.

Interventions  mRNA (BNT162b2 or mRNA-1273) or vector (Ad26COVS1) as a third dose of a SARS-CoV-2 vaccine.

Main Outcomes and Measures  The primary study end point was seroconversion after 4 weeks (29-42 days) following the third vaccine dose. Secondary end points included neutralizing antibodies and T-cell response assessed by interferon-γ release assays (IGRA). In addition, the association of patient characteristics and vaccine response was assessed using logistic regression, and the reactogenicity of the vaccines was compared.

Results  Among the study population of 197 kidney transplant recipients (mean [SD] age, 61.2 [12.4] years; 82 [42%] women), 39% developed SARS-CoV-2 antibodies after the third vaccine. There was no statistically significant difference between groups, with an antibody response rate of 35% and 42% for the mRNA and vector vaccines, respectively. Only 22% of seroconverted patients had neutralizing antibodies. Similarly, T-cell response assessed by IGRA was low with only 17 patients showing a positive response after the third vaccination. Receiving nontriple immunosuppression (odds ratio [OR], 3.59; 95% CI, 1.33-10.75), longer time after kidney transplant (OR, 1.44; 95% CI, 1.15-1.83, per doubling of years), and torque teno virus plasma levels (OR, 0.92; 95% CI, 0.88-0.96, per doubling of levels) were associated with vaccine response. The third dose of an mRNA vaccine was associated with a higher frequency of local pain at the injection site compared with the vector vaccine, while systemic symptoms were comparable between groups.

Conclusions and Relevance  This randomized clinical trial found that 39% of KTRs without an immune response against SARS-CoV-2 after 2 doses of an mRNA vaccine developed antibodies against the SARS-CoV-2 spike protein 4 weeks after a third dose of an mRNA or a vector vaccine. The heterologous vaccination strategy with a vector-based vaccine was well tolerated and safe but not significantly better than the homologous mRNA-based strategy.

Trial Registration  EudraCT Identifier: 2021-002927-39

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 Credit(s)™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

See More About

Nephrology Surgery Transplantation Vaccination Public Health Renal Replacement Coronavirus (COVID-19)
Article Information

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Reindl-Schwaighofer R et al. JAMA Internal Medicine.

Accepted for Publication: November 1, 2021.

Published Online: December 20, 2021. doi:10.1001/jamainternmed.2021.7372

Corresponding Authors: Andreas Heinzel, MSc, and Rainer Oberbauer, MD, PhD, Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Spitalgasse 23, Vienna 1090, Austria (andreas.heinzel@meduniwien.ac.at; rainer.oberbauer@meduniwien.ac.at).

Author Contributions: Dr Reindl-Schwaighofer and Mr Heinzel had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Reindl-Schwaighofer, Heinzel, Eskandary, Jagoditsch, Bond, Binder, Oberbauer.

Acquisition, analysis, or interpretation of data: Reindl-Schwaighofer, Heinzel, Mayrdorfer, Jabbour, Hofbauer, Merrelaar, Eder, Regele, Doberer, Spechtl, Aschauer, Koblischke, Paschen, Hu, Öhler, Bhandal, Kleibenböck, Jagoditsch, Reiskopf, Heger, Bond, Böhmig, Strassl, Weseslindtner, Indra, Aberle, Binder, Oberbauer.

Drafting of the manuscript: Reindl-Schwaighofer, Heinzel, Indra, Binder, Oberbauer.

Critical revision of the manuscript for important intellectual content: Reindl-Schwaighofer, Heinzel, Mayrdorfer, Jabbour, Hofbauer, Merrelaar, Eder, Regele, Doberer, Spechtl, Aschauer, Koblischke, Paschen, Eskandary, Hu, Öhler, Bhandal, Kleibenböck, Jagoditsch, Reiskopf, Heger, Bond, Böhmig, Strassl, Weseslindtner, Indra, Aberle, Oberbauer.

Statistical analysis: Reindl-Schwaighofer, Heinzel, Oberbauer.

Obtained funding: Reindl-Schwaighofer, Heinzel, Indra.

Administrative, technical, or material support: Reindl-Schwaighofer, Heinzel, Mayrdorfer, Jabbour, Hofbauer, Merrelaar, Eder, Regele, Doberer, Spechtl, Aschauer, Koblischke, Paschen, Hu, Öhler, Bhandal, Jagoditsch, Reiskopf, Heger, Bond, Strassl, Weseslindtner, Indra, Aberle, Binder, Oberbauer.

Supervision: Reindl-Schwaighofer, Heinzel, Oberbauer.

Other−laboratory work: Indra.

Conflict of Interest Disclosures: Dr Heinzel reported grants from the Medical University of Vienna (Transplantation Research Platform's Start-Up Grant 2020) during the conduct of the study. Dr Böhmig reported grants from Vitaeris, Behring, and MorphoSys, and consulting fees from Hansa, outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by the Medical University of Vienna, the Austrian Agency for Health and Food Safety, and the Medical-Scientific Fund of the Mayor of the Federal Capital of Vienna (Dr Aberle, No. Covid003), the Christine Vranitzky-Stiftung research grant 2020 (Dr Reindl-Schwaighofer), and the Medical University of Vienna Transplantation Research Platform's Start-Up Grant 2020 (Mr Heinzel).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: The authors are grateful for support from the Austrian Agency for Health and Food Safety and the work of the clinical and administrative personnel of the Division of Nephrology and Dialysis at the Medical University of Vienna, without whom this study would not have been possible.

Data Sharing Statement: See Supplement 3.

References
1.
Weinhandl  ED , Wetmore  JB , Peng  Y , Liu  J , Gilbertson  DT , Johansen  KL .  Initial effects of COVID-19 on patients with ESKD.   J Am Soc Nephrol. 2021;32(6):1444-1453. doi:10.1681/ASN.2021010009 PubMedGoogle ScholarCrossref
2.
Nair  V , Jandovitz  N , Hirsch  JS ,  et al.  An early experience on the effect of solid organ transplant status on hospitalized COVID-19 patients.   Am J Transplant. 2021;21(7):2522-2531. doi:10.1111/ajt.16460PubMedGoogle ScholarCrossref
3.
Cowan  M , Chon  WJ , Desai  A ,  et al.  Impact of immunosuppression on recall immune responses to influenza vaccination in stable renal transplant recipients.   Transplantation. 2014;97(8):846-853. doi:10.1097/01.TP.0000438024.10375.2d PubMedGoogle ScholarCrossref
4.
Sadoff  J , Gray  G , Vandebosch  A ,  et al; ENSEMBLE Study Group.  Safety and efficacy of single-dose Ad26.CoV2.S vaccine against COVID-19.   N Engl J Med. 2021;384(23):2187-2201. doi:10.1056/NEJMoa2101544 PubMedGoogle ScholarCrossref
5.
Grupper  A , Rabinowich  L , Schwartz  D ,  et al.  Reduced humoral response to mRNA SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients without prior exposure to the virus.   Am J Transplant. 2021;21(8):2719-2726. doi:10.1111/ajt.16615PubMedGoogle ScholarCrossref
6.
Boyarsky  BJ , Werbel  WA , Avery  RK ,  et al.  Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients.   JAMA. 2021;325(21):2204-2206. doi:10.1001/jama.2021.7489 PubMedGoogle ScholarCrossref
7.
Chavarot  N , Ouedrani  A , Marion  O ,  et al.  Poor anti-SARS-CoV-2 humoral and T-cell responses after 2 injections of mRNA vaccine in kidney transplant recipients treated with belatacept.   Transplantation. 2021;105(9):e94-e95. doi:10.1097/TP.0000000000003784 PubMedGoogle ScholarCrossref
8.
Ou  MT , Boyarsky  BJ , Chiang  TPY ,  et al.  Immunogenicity and reactogenicity after SARS-CoV-2 mRNA vaccination in kidney transplant recipients taking belatacept.   Transplantation. 2021;105(9):2119-2123. doi:10.1097/TP.0000000000003824 PubMedGoogle ScholarCrossref
9.
Cucchiari  D , Egri  N , Bodro  M ,  et al.  Cellular and humoral response after MRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients.   Am J Transplant. 2021;21(8):2727-2739. doi:10.1111/ajt.16701 PubMedGoogle ScholarCrossref
10.
Sattler  A , Schrezenmeier  E , Weber  UA ,  et al.  Impaired humoral and cellular immunity after SARS-CoV-2 BNT162b2 (tozinameran) prime-boost vaccination in kidney transplant recipients.   J Clin Invest. 2021;131(14):150175. doi:10.1172/JCI150175 PubMedGoogle Scholar
11.
Spencer  AJ , McKay  PF , Belij-Rammerstorfer  S ,  et al.  Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice.   Nat Commun. 2021;12(1):2893. doi:10.1038/s41467-021-23173-1 PubMedGoogle ScholarCrossref
12.
He  Q , Mao  Q , An  C ,  et al.  Heterologous prime-boost: breaking the protective immune response bottleneck of COVID-19 vaccine candidates.   Emerg Microbes Infect. 2021;10(1):629-637. doi:10.1080/22221751.2021.1902245 PubMedGoogle ScholarCrossref
13.
Shaw  RH , Stuart  A , Greenland  M , Liu  X , Nguyen Van-Tam  JS , Snape  MD ; Com-COV Study Group.  Heterologous prime-boost COVID-19 vaccination: initial reactogenicity data.   Lancet. 2021;397(10289):2043-2046. doi:10.1016/S0140-6736(21)01115-6 PubMedGoogle ScholarCrossref
14.
Hillus  D , Schwarz  T , Tober-Lau  P ,  et al; EICOV/COVIM Study Group.  Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1 nCoV-19 and BNT162b2: a prospective cohort study.   Lancet Respir Med. 2021;S2213-2600(21)00357-X. doi:10.1016/S2213-2600(21)00357-XPubMedGoogle Scholar
15.
Tenbusch  M , Schumacher  S , Vogel  E ,  et al; DZIF-VACCELERATE-CoVaKo study team.  Heterologous prime-boost vaccination with ChAdOx1 nCoV-19 and BNT162b2.   Lancet Infect Dis. 2021;21(9):1212-1213. doi:10.1016/S1473-3099(21)00420-5 PubMedGoogle ScholarCrossref
16.
Benotmane  I , Gautier  G , Perrin  P ,  et al.  Antibody response after a third dose of the mRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients with minimal serologic response to 2 doses.   JAMA. 2021. doi:10.1001/jama.2021.12339 PubMedGoogle Scholar
17.
Werbel  WA , Boyarsky  BJ , Ou  MT ,  et al.  Safety and immunogenicity of a third dose of SARS-CoV-2 vaccine in solid organ transplant recipients: a case series.   Ann Intern Med. 2021;174(9):1330-1332. doi:10.7326/L21-0282 PubMedGoogle ScholarCrossref
18.
Kamar  N , Abravanel  F , Marion  O , Couat  C , Izopet  J , Del Bello  A .  Three doses of an mRNA COVID-19 Vaccine in solid-organ transplant recipients.   N Engl J Med. 2021;385(7):661-662. doi:10.1056/NEJMc2108861 PubMedGoogle ScholarCrossref
19.
Hall  VG , Ferreira  VH , Ku  T ,  et al.  Randomized trial of a third dose of mRNA-1273 vaccine in transplant recipients.   N Engl J Med. 2021;385(13):1244-1246. doi:10.1056/NEJMc2111462 PubMedGoogle ScholarCrossref
20.
Dimeglio  C , Herin  F , Martin-Blondel  G , Miedougé  M , Izopet  J .  Antibody titers and protection against a SARS-CoV-2 infection.   J Infect. 2021;S0163-4453(21)00483-7. doi:10.1016/j.jinf.2021.09.013PubMedGoogle Scholar
21.
Feng  S , Phillips  DJ , White  T ,  et al; Oxford COVID Vaccine Trial Group.  Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection.   Nat Med. 2021. doi:10.1038/s41591-021-01540-1 PubMedGoogle Scholar
22.
Doberer  K , Schiemann  M , Strassl  R ,  et al.  Torque teno virus for risk stratification of graft rejection and infection in kidney transplant recipients: a prospective observational trial.   Am J Transplant. 2020;20(8):2081-2090. doi:10.1111/ajt.15810 PubMedGoogle ScholarCrossref
23.
Greinacher  A , Thiele  T , Warkentin  TE , Weisser  K , Kyrle  PA , Eichinger  S .  Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination.   N Engl J Med. 2021;384(22):2092-2101. doi:10.1056/NEJMoa2104840 PubMedGoogle ScholarCrossref
24.
Stumpf  J , Siepmann  T , Lindner  T ,  et al.  Humoral and cellular immunity to SARS-CoV-2 vaccination in renal transplant versus dialysis patients: A prospective, multicenter observational study using mRNA-1273 or BNT162b2 mRNA vaccine.   Lancet Reg Health Eur. 2021;9:100178. doi:10.1016/j.lanepe.2021.100178PubMedGoogle Scholar
25.
Hosseini-Moghaddam  SM , Alhomayeed  B , Soliman  N , Weir  MA , House  AA .  Primary Epstein-Barr virus infection, seroconversion, and post-transplant lymphoproliferative disorder in seronegative renal allograft recipients: a prospective cohort study.   Transpl Infect Dis. 2016;18(3):423-430. doi:10.1111/tid.12533 PubMedGoogle ScholarCrossref
26.
Boudreault  AA , Xie  H , Rakita  RM ,  et al.  Risk factors for late-onset cytomegalovirus disease in donor seropositive/recipient seronegative kidney transplant recipients who receive antiviral prophylaxis.   Transpl Infect Dis. 2011;13(3):244-249. doi:10.1111/j.1399-3062.2011.00624.x PubMedGoogle ScholarCrossref
27.
De Vlaminck  I , Khush  KK , Strehl  C ,  et al.  Temporal response of the human virome to immunosuppression and antiviral therapy.   Cell. 2013;155(5):1178-1187. doi:10.1016/j.cell.2013.10.034 PubMedGoogle ScholarCrossref
28.
Schmidt  T , Klemis  V , Schub  D ,  et al.  Immunogenicity and reactogenicity of heterologous ChAdOx1 nCoV-19/mRNA vaccination.   Nat Med. 2021;27(9):1530-1535. doi:10.1038/s41591-021-01464-w PubMedGoogle ScholarCrossref
29.
Aslam  S , Adler  E , Mekeel  K , Little  SJ .  Clinical effectiveness of COVID-19 vaccination in solid organ transplant recipients.   Transpl Infect Dis. 2021;23(5):e13705. doi:10.1111/tid.13705 PubMedGoogle Scholar
30.
Poland  GA , Jacobson  RM .  Clinical practice: prevention of hepatitis B with the hepatitis B vaccine.   N Engl J Med. 2004;351(27):2832-2838. doi:10.1056/NEJMcp041507 PubMedGoogle ScholarCrossref
31.
Weinreich  DM , Sivapalasingam  S , Norton  T ,  et al; Trial Investigators.  REGN-COV2, a neutralizing antibody cocktail, in outpatients with COVID-19.   N Engl J Med. 2021;384(3):238-251. doi:10.1056/NEJMoa2035002 PubMedGoogle ScholarCrossref
AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

Close
Want full access to the AMA Ed Hub?
Become an AMA member now
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
Want full access to the AMA Ed Hub?
Become an AMA member now
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Close
Close

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close
Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue