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 | Nephrology | JAMA | JAMA Network
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Figure.  Anti–Receptor-Binding Domain (RBG) IgG Antibody Titers Measured 28 Days After the Third Dose of mRNA-1273 SARS-CoV-2 Vaccine in 159 Kidney Transplant Recipients
Anti–Receptor-Binding Domain (RBG) IgG Antibody Titers Measured 28 Days After the Third Dose of mRNA-1273 SARS-CoV-2 Vaccine in 159 Kidney Transplant Recipients

Horizontal dotted line indicates the cutoff for positivity (50 arbitrary units [AU]/mL). Blue lines indicate the antibody titers of kidney transplant recipients who seroconverted after the third dose (titers ≥50 AU/mL); orange lines, the evolution of antibody titers among nonresponders (titers <50 AU/mL). mRNA indicates messenger RNA.

Table.  Association Between Patient Characteristics, Immunosuppression, and Antibody Titers After the Third Dose of a SARS-CoV-2 mRNA Vaccine in 159 Kidney Transplant Recipients
Association Between Patient Characteristics, Immunosuppression, and Antibody Titers After the Third Dose of a SARS-CoV-2 mRNA Vaccine in 159 Kidney Transplant Recipients
1.
Boyarsky  BJ, Werbel  WA, Avery  RK,  et al.  Immunogenicity of a single dose of SARS-CoV-2 messenger RNA vaccine in solid organ transplant recipients.   JAMA. 2021;325(17):1784-1786. doi:10.1001/jama.2021.4385PubMedGoogle ScholarCrossref
2.
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.2021.7489PubMedGoogle ScholarCrossref
3.
Prendecki  M, Clarke  C, Brown  J,  et al.  Effect of previous SARS-CoV-2 infection on humoral and T-cell responses to single-dose BNT162b2 vaccine.   Lancet. 2021;397(10280):1178-1181. doi:10.1016/S0140-6736(21)00502-XPubMedGoogle ScholarCrossref
4.
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. Published online June 15, 2021. doi:10.7326/L21-0282PubMedGoogle Scholar
5.
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. Published online June 23, 2021. doi:10.1056/NEJMc2108861PubMedGoogle Scholar
6.
Caillard  S, Chavarot  N, Bertrand  D,  et al; French Society of Transplantation.  Occurrence of severe COVID-19 in vaccinated transplant patients.   Kidney Int. Published online May 23, 2021. doi:10.1016/j.kint.2021.05.011PubMedGoogle Scholar
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    1 Comment for this article
    EXPAND ALL
    Personalized Immunity Monitoring?
    Yang Xu, MD, PhD | Director, Laboratory of Special Diagnosis, Shanghai University of Medicine and Health Sciences
    Benotmane et al. report that 51% of the patients did not develop anti-SARS-CoV-2 antibodies after a third mRNA vaccine dose (1).

    Oekelen et al. showed that 15.8% of multiple myeloma patients did not develop SARS-CoV-2 spike IgG antibody after completing the recommended two-dose Pfizer-BioNTech or Moderna mRNA vaccination regimen in 320 patients using FDA EUA COVID-SeroKlir Kantaro SARS-CoV-2 IgG Ab Kit (2).

    Grupper et al. reported 85 of 136 kidney transplant recipients (62.5%) had negative SARS-CoV-2 spike IgG antibody after administration of two-dose of Pfizer-BioNTech SARS-CoV-2 vaccine (3).

    Rabinowich et al. found 42 of 80 liver transplant
    recipients (52.5%) did not develop neutralizing antibody after administration of two-doses of the Pfizer-BioNTech BNT162b2 SARS CoV-2 vaccine (4).

    Kim et al. reported differences in the titer of neutralizing antibody PRNT50 after vaccination with the Pfizer-BioNTech BNT162b2 vs the SinoVac inactivated vaccine in health-care workers (5): in people who received the Pfizer-BioNTech BNT162b2 vaccine after the second dose, the neutralizing antibody PRNT50 titer was 269; in contrast, the people who received the SinoVac inactivated vaccine after the second dose, the neutralizing antibody PRNT50 titer was 27.

    The US Food and Drug Administration (FDA) has made recommendations for SARS-CoV-2 immunity testing, which can detect SARS-CoV-2 neutralizing antibodies or correlates of immunity (6). Mount Sinai Laboratory (MSL) has received FDA EUA for use of the neutralization assay that has now been tested on over 30,000 patients (7, 8). The IgG neutralization test developed by MSL is also used for immunity assessment of Pfizer-BioNTech or Moderna vaccine (9).

    FDA authorized SARS-CoV-2 neutralization test might be a valuable immunity evaluation test after vaccination for people with underlying medical conditions or co-morbidities, such as cancer or immune deficiencies. The IgG neutralization test might be the most effective tool to quickly assess the effectiveness of vaccination in different populations from different countries.

    References

    1. Benotmane et al. JAMA. published online: July 23, 2021. doi:10.1001/jama.2021.12339.
    2. Oekelen et al. Cancer Cell. 39, 1028–1030 (2021).
    3. Grupper et al. Am. J. Transplant. 21, 2719-2726 (2021).
    4. Rabinowich et al. J. Hepatol. 75, 435-438 (2021).
    5. Lim et al. Lancet Microbe. https://doi.org/10.1016/S2666-5247(21)00177-4
    6. https://www.fda.gov/media/146746/download
    7. https://www.fda.gov/media/137029/download
    8. Wajnberg et al. Science. 370, 1227-1230 (2020).
    9. Krammer et al. N. Engl. J. Med. 384, 1372-1374 (2021).

    CONFLICT OF INTEREST: None Reported
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    Research Letter
    July 23, 2021

    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

    Author Affiliations
    • 1Department of Nephrology and Transplantation, Strasbourg University Hospital, Strasbourg, France
    • 2Department of Virology, Strasbourg University Hospital, Strasbourg, France
    JAMA. 2021;326(11):1063-1065. doi:10.1001/jama.2021.12339

    Studies have reported low seroconversion rates (58% after the second dose) in solid organ transplant recipients who received a messenger RNA (mRNA) SARS-CoV-2 vaccine.1,2 Based on this evidence, the French National Authority for Health issued a recommendation in April 2021 to administer a third vaccine dose in immunosuppressed patients who did not respond after 2 doses. We examined the antibody responses of kidney transplant recipients who did not respond to 2 doses and received a third dose (100 μg) of the mRNA-1273 (Moderna) vaccine.

    Methods

    All kidney transplant recipients followed up in the outpatient Kidney Transplantation Department of Strasbourg University Hospital between January 20, 2021, and June 3, 2021, with a negative history for COVID-19 and SARS-CoV-2 antispike IgG levels less than 50 arbitrary units (AU) per milliliter on the day of the first vaccine injection and 1 month after the second dose were included. All patients received a third vaccine dose between April 9, 2021, and May 12, 2021. The study protocol was approved by the local ethics committee and written informed consent was obtained.

    Anti–receptor-binding domain IgG response after the third vaccine dose was assessed using the ARCHITECT IgG II Quant test (Abbott). According to the manufacturer, titers greater than 50 AU/mL were considered positive (detection range, 6.8–80 000 AU/mL; positive agreement, 99.4%; negative agreement, 99.6%). The results of this assay have been shown to correlate with in vitro neutralization of SARS-CoV-2.3 Mean differences adjusted for the factors in the Table were calculated using general linear models. All calculations were performed using GraphPad Prism version 8.0 (GraphPad) and SPSS version 2020.0.0 (IBM). P < .05 (2-sided) was considered statistically significant.

    Results

    One month after the second dose, 159 kidney transplant recipients had IgG levels less than 50 AU/mL. The median age was 57.6 years (interquartile range [IQR], 49.6-66.1 years), 61.6% were men, and the median time from transplantation was 5.3 years (IQR, 1.9-11.1 years) (Table). Ninety-five patients (59.7%) had no antibody response after 2 doses (titers <6.8 AU/mL), and 64 patients (40.3%) showed a response below the positivity limit (titers, 6.8-49.9 AU/mL). The third dose was injected a median of 51 days (IQR, 48-59 days) after the second dose. The antibody response was measured a median of 28 days (IQR, 27-33 days) after the third vaccine injection, and 78 patients (49%) had antibody levels greater than 50 AU/mL (median antibody titers of responders, 586 AU/mL; IQR, 197.2-1920.1 AU/mL) (Figure). Patients who had a weak response after the second dose were more likely to develop an antibody response after the third dose compared with those without an antibody response (81.3% vs 27.4%, respectively; mean adjusted difference of antibody titers, 894.89 AU/mL [95% CI, 377.41-1410.37 AU/mL]; P = .001). Patients taking tacrolimus, mycophenolate, and steroids were less likely to develop anti–SARS-CoV-2 antibodies than those treated with other regimens (35% vs 63%, respectively; mean adjusted difference of antibody titers, −697.28 AU/mL [95% CI, −1193.00 to −201.56 AU/mL]; P = .006). Other variables associated with the titers of antibodies are shown in the Table. No severe adverse events were observed after the third dose.

    Discussion

    This study found that a third dose of mRNA-1273 vaccine induced a serologic response in 49% of kidney transplant recipients who did not respond after 2 doses. The findings in this large group of kidney transplant recipients are in accordance with other studies of solid organ transplant recipients.4,5 However, 51% of the patients did not develop anti–SARS-CoV-2 antibodies after the third dose, especially those receiving triple immunosuppression. The possibility that patients developed cellular immunity capable of conferring protection against severe disease was not assessed. However, the occurrence of severe COVID-19 in some vaccinated transplant recipients may suggest a lack of immunity.6

    Limitations of this study include that detailed B-cell and T-cell studies were not performed and that the antibody level that correlates with protection is unknown.

    In conclusion, the use of a third dose of vaccine may be considered in organ transplant recipients.

    Section Editors: Jody W. Zylke, MD, Deputy Editor; Kristin Walter, MD, Associate Editor.
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    Article Information

    Corresponding Author: Sophie Caillard, MD, PhD, Department of Nephrology and Transplantation, Strasbourg University Hospital, 1 Place de l’hôpital, 67091 Strasbourg, France (sophie.caillard@chru-strasbourg.fr).

    Accepted for Publication: July 9, 2021.

    Published Online: July 23, 2021. doi:10.1001/jama.2021.12339

    Author Contributions: Drs Benotmane and Caillard 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.

    Concept and design: Benotmane, Caillard.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Benotmane, Caillard.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Benotmane, Caillard.

    Administrative, technical, or material support: Gautier Vargas, Olagne, Cognard, Fafi-Kremer, Caillard.

    Supervision: Caillard.

    Conflict of Interest Disclosures: Dr Caillard reported receiving travel grants from Astellas, Novartis, and Sanofi and receiving lecture honoraria from Bristol Myers Squibb. Dr Benotmane reported receiving travel grants from Novartis, Sandoz, Fresenius Medical Care, and Chiesi. No other disclosures were reported.

    Additional Contributions: We thank all of the physicians (Jonas Martzloff, MD, Laura Braun Parvez, MD, Francoise Heibel, MD, Bruno Moulin, MD, PhD), the clinical research team (Danielle Roy, Annie Menguy, Hugo Servais), nurses (Sandra Ludwiller, Muriel Morvan, Karima Kedjam, Lucile Steinmetz, Christelle Appenzeller), and the secretaries (Amandine Bigot and Agathe Pillon) who work in the Department of Nephrology and Transplantation, Strasbourg University Hospital, Strasbourg, France, and who were involved in the vaccination program and patient follow-up. We are grateful to Marie Josée Wendling and Aurélie Velay (Department of Virology, Strasbourg University Hospital, Strasbourg, France) for their technical support and to Marc Hazzan (Department of Nephrology and Transplantation, Lille University Hospital, Lille, France) for statistical assistance. None of these individuals received compensation for their roles in the study.

    References
    1.
    Boyarsky  BJ, Werbel  WA, Avery  RK,  et al.  Immunogenicity of a single dose of SARS-CoV-2 messenger RNA vaccine in solid organ transplant recipients.   JAMA. 2021;325(17):1784-1786. doi:10.1001/jama.2021.4385PubMedGoogle ScholarCrossref
    2.
    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.2021.7489PubMedGoogle ScholarCrossref
    3.
    Prendecki  M, Clarke  C, Brown  J,  et al.  Effect of previous SARS-CoV-2 infection on humoral and T-cell responses to single-dose BNT162b2 vaccine.   Lancet. 2021;397(10280):1178-1181. doi:10.1016/S0140-6736(21)00502-XPubMedGoogle ScholarCrossref
    4.
    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. Published online June 15, 2021. doi:10.7326/L21-0282PubMedGoogle Scholar
    5.
    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. Published online June 23, 2021. doi:10.1056/NEJMc2108861PubMedGoogle Scholar
    6.
    Caillard  S, Chavarot  N, Bertrand  D,  et al; French Society of Transplantation.  Occurrence of severe COVID-19 in vaccinated transplant patients.   Kidney Int. Published online May 23, 2021. doi:10.1016/j.kint.2021.05.011PubMedGoogle Scholar
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