Immunogenicity of a Single Dose of SARS-CoV-2 Messenger RNA Vaccine in Solid Organ Transplant Recipients | Vaccination | JAMA | JAMA Network
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Table.  Demographic and Clinical Characteristics of Study Participants, Stratified by Immune Response to the First Dose of SARS-CoV-2 Messenger RNA Vaccine, and Associations With Developing an Antibody Response (N = 436)
Demographic and Clinical Characteristics of Study Participants, Stratified by Immune Response to the First Dose of SARS-CoV-2 Messenger RNA Vaccine, and Associations With Developing an Antibody Response (N = 436)
1.
Boyarsky  BJ, Ou  MT, Werbel  WA,  et al.  Early development and durability of SARS-CoV-2 antibodies among solid organ transplant recipients: a pilot study.   Transplantation. Published online January 19, 2021. doi:10.1097/tp.0000000000003637PubMedGoogle Scholar
2.
Klein  SL, Pekosz  A, Park  HS,  et al.  Sex, age, and hospitalization drive antibody responses in a COVID-19 convalescent plasma donor population.   J Clin Invest. 2020;130(11):6141-6150. doi:10.1172/JCI142004PubMedGoogle ScholarCrossref
3.
Patel  EU, Bloch  EM, Clarke  W,  et al.  Comparative performance of five commercially available serologic assays to detect antibodies to SARS-CoV-2 and identify individuals with high neutralizing titers.   J Clin Microbiol. 2021;59(2):e02257-20. doi:10.1128/JCM.02257-20PubMedGoogle Scholar
4.
Higgins  V, Fabros  A, Kulasingam  V.  Quantitative measurement of anti-SARS-CoV-2 antibodies: analytical and clinical evaluation.   J Clin Microbiol. Published online March 19, 2021. doi:10.1128/JCM.03149-20PubMedGoogle Scholar
5.
Jackson  LA, Anderson  EJ, Rouphael  NG,  et al; mRNA-1273 Study Group.  An mRNA vaccine against SARS-CoV-2—preliminary report.   N Engl J Med. 2020;383(20):1920-1931. doi:10.1056/NEJMoa2022483PubMedGoogle ScholarCrossref
6.
Walsh  EE, Frenck  RW  Jr, Falsey  AR,  et al.  Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates.   N Engl J Med. 2020;383(25):2439-2450. doi:10.1056/NEJMoa2027906PubMedGoogle ScholarCrossref
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    2 Comments for this article
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    T-cell response?
    Nancy Marlin, Ph.D. | San Diego State University
    In the absence of detectable antibodies, is it likely that CD4+ and CD8+ cells would respond to the mRNA vaccine and provide some protection to SOT recipients?
    CONFLICT OF INTEREST: None Reported
    Response from the International Society of Heart and Lung Transplantation
    Saima Aslam, MD, MS | University of California San Diego
    The ISHLT COVID-19 Task Force applauds Dr Boyarsky et al for their initiative in studying immune responses to SARS-CoV-2 vaccination in solid organ transplant (SOT) recipients (1). As clinical trials assessing SARS-CoV-2 vaccines excluded patients with SOT, this study is a necessary step to fill that knowledge gap. The authors assessed the immune response to the first dose of both the Pfizer-BioNTech and Moderna mRNA vaccines in 436 SOT recipients. Immune responses, based on the presence of anti-spike protein antibodies using semiquantitative assays with a sensitivity between 84-87%, developed in only 17% of participants at a median of 20 days from vaccine administration. Lack of antibody response in this study was associated with the use of anti-metabolite immunosuppression, older age, and receipt of the Pfizer-BioNTech vaccine.

    The low vaccine response rate is concerning though not entirely unexpected as SOT recipients have lower rates of immune response to other vaccines as well (2). We strongly caution against concluding that this preliminary data implies reduced clinical efficacy because the study did not report on immune response following the full 2-dose regimen, did not test Th1 cellular response, and did not explicitly assess immunization for protection against severe COVID-19 as a clinical end-point.

    Immunosuppressed patients are known to have prolonged viral shedding of actively replicating virus which may promote the development of viral variants (3). Additionally, recent literature suggests worse outcomes in SOT recipients with COVID-19 (4). The effect of immunization on duration of viral shedding and clinical outcomes remains unknown for this population. Until more complete data are available including the impact of the second planned doses for both mRNA vaccines, we urge continued priority for SARS-CoV-2 vaccination in SOT recipients and support for vaccination of household members in order to reduce risk for vulnerable patients. We urge transplant providers to continue a stable immunosuppression regimen at the time of vaccination due to the risk of organ rejection until more comprehensive data are available. Lastly, given the low immune response to the first dose, we recommend that after vaccination, SOT recipients be encouraged to continue masking and social distancing during the pandemic, as advised by transplant societies including the International Society of Heart and Lung Transplantation (5).

    Saima Aslam
    Lara Danziger-Isakov
    ISHLT COVID-19 Task Force


    1. Boyarsky BJ WW, Avery RK; et al. Immunogenicity of a Single Dose of SARS-CoV-2 Messenger RNA Vaccine in Solid Organ Transplant Recipients. JAMA. 2021.
    2. Eckerle I, Rosenberger KD, Zwahlen M, Junghanss T. Serologic vaccination response after solid organ transplantation: a systematic review. PLoS One. 2013;8(2):e56974.
    3. Aydillo T, Gonzalez-Reiche AS, Aslam S, et al. Shedding of Viable SARS-CoV-2 after Immunosuppressive Therapy for Cancer. N Engl J Med. 2020;383(26):2586-2588.
    4. 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. 2020.
    5. SARS-CoV-2 Vaccination in Heart and Lung Transplantation: Recommendations from the ISHLT COVID-19 Task Force. https://ishlt.org/ishlt/media/Documents/COVID19_Vaccine-Recommendations_3-15-2021.pdf. Accessed 3/17/2021.
    CONFLICT OF INTEREST: Grant funding from the Cystic Fibrosis Foundation, honoraria from Gilead
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    Research Letter
    March 15, 2021

    Immunogenicity of a Single Dose of SARS-CoV-2 Messenger RNA Vaccine in Solid Organ Transplant Recipients

    Author Affiliations
    • 1Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
    • 2Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    • 3Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland
    JAMA. 2021;325(17):1784-1786. doi:10.1001/jama.2021.4385

    Immunocompromised individuals have been excluded from studies of SARS-CoV-2 messenger RNA (mRNA) vaccines. In such patients, the immune response to vaccination may be blunted. To better understand the immunogenicity of mRNA vaccines in immunocompromised individuals, we quantified the humoral response to the first dose in solid organ transplant recipients.

    Methods

    Transplant recipients across the US were recruited though social media to participate in this prospective cohort, and those who underwent SARS-CoV-2 vaccination between December 16, 2020, and February 5, 2021, were included. The study was approved by the Johns Hopkins University institutional review board and participants provided informed consent electronically. Participants underwent either at-home blood sampling with the TAPII blood collection device (Seventh Sense Biosystems) or standard venipuncture.

    The TAPII samples were tested using an enzyme immunoassay (EUROIMMUN) that tests for antibodies to the S1 domain of the SARS-CoV-2 spike protein.1 The venipuncture samples were tested using the anti–SARS-CoV-2 S enzyme immunoassay (Roche Elecsys) that tests for antibodies against the receptor-binding domain of the SARS-CoV-2 spike protein. Both tests are semiquantitative, correspond to mRNA vaccine antigens, and are consistently correlated with neutralizing immunity.2-4 The sensitivity and specificity of the enzyme immunoassays are excellent for detection of the antispike humoral response to SARS-CoV-2 infection (sensitivity of 87.1% and specificity of 98.9% for EUROIMMUN3 and sensitivity of 84.0% and specificity of 100% for Roche Elecsys4) and are analogous to the antispike antibody assays used during immunogenicity assessments in mRNA vaccine clinical trials.

    We assessed the proportion of patients who developed a positive antibody response with exact binomial 95% CIs. We evaluated the associations among demographic and clinical characteristics, vaccine type, and positive antibody response using modified Poisson regression with a robust variance estimator. A sensitivity analysis of vaccine type limited to those tested 14 to 21 days after vaccination was performed. All tests were 2-sided with α = .05. Analyses were performed using Stata version 16.1 (StataCorp).

    Results

    There were 436 transplant recipients included in the study (Table). None had a prior polymerase chain reaction–confirmed diagnosis of COVID-19. The median age was 55.9 years (interquartile range [IQR], 41.3-67.4 years), 61% were women, and 89% were White transplant recipients; 52% received the BNT162b2 vaccine (Pfizer-BioNTech) and 48% received the mRNA-1273 vaccine (Moderna). The median time since transplant was 6.2 years (IQR, 2.7-12.7 years). The maintenance immunosuppression regimen included tacrolimus (83%), corticosteroids (54%), mycophenolate (66%), azathioprine (9%), sirolimus (4%), and everolimus (2%). At a median of 20 days (IQR, 17-24 days) after the first dose of vaccine, antibody (anti-S1 or anti–receptor-binding domain) was detectable in 76 of 436 participants (17%; 95% CI, 14%-21%).

    Transplant recipients receiving anti–metabolite maintenance immunosuppression therapy were less likely to develop an antibody response than those not receiving such immunosuppression therapy (37% vs 63%, respectively; adjusted incidence rate ratio [IRR], 0.22 [95% CI, 0.15-0.34]; P < .001) (Table). Older transplant recipients were less likely to develop an antibody response (adjusted IRR, 0.83 [95% CI, 0.73-0.93] per 10 years; P = .002). Those who received mRNA-1273 were more likely to develop an antibody response than those receiving BNT162b2 (69% vs 31%, respectively; adjusted IRR, 2.15 [95% CI, 1.29-3.57]; P = .003). This association was similar in a sensitivity analysis limited to those tested 14 to 21 days after vaccination (n = 245; adjusted IRR, 2.29 [95% CI, 1.32-3.94]; P = .003).

    Discussion

    In this study of immunogenicity of the first dose of the mRNA SARS-CoV-2 vaccine among solid organ transplant recipients, the majority of participants did not mount appreciable antispike antibody responses. However, younger participants, those not receiving anti–metabolite maintenance immunosuppression, and those who received the mRNA-1273 vaccine were more likely to develop antibody responses. These results contrast with the robust early immunogenicity observed in mRNA vaccine trials, including 100% antispike seroconversion by day 15 following vaccination with mRNA-12735 and by day 21 following vaccination with BNT162b2.6

    Limitations include a convenience sample that may lack generalizability, lack of serial measurements after vaccination, and lack of a concurrent control group without immunosuppression. In addition, these data represent the humoral response to the first dose of a 2-dose series.

    These findings of poor antispike antibody responses in organ transplant recipients after the first dose of mRNA vaccines suggest that such patients may remain at higher early risk for COVID-19 despite vaccination. Deeper immunophenotyping of transplant recipients after vaccination, including characterization of memory B-cell and T-cell responses, will be important in determining vaccination strategies as well as immunologic responses after the second dose.

    Section Editor: Jody W. Zylke, MD, Deputy Editor.
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    Article Information

    Accepted for Publication: March 8, 2021.

    Published Online: March 15, 2021. doi:10.1001/jama.2021.4385

    Corresponding Author: Dorry L. Segev, MD, PhD, Department of Surgery, Johns Hopkins University Medical Institutions, 2000 E Monument St, Baltimore, MD 21205 (dorry@jhmi.edu).

    Author Contributions: Drs Segev and Garonzik-Wang 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: All authors.

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

    Drafting of the manuscript: Boyarsky, Werbel, Avery, Massie, Segev, Garonzik-Wang.

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

    Statistical analysis: Boyarsky, Massie, Segev.

    Administrative, technical, or material support: Boyarsky, Tobian, Segev, Garonzik-Wang.

    Supervision: Massie, Segev, Garonzik-Wang.

    Conflict of Interest Disclosures: Dr Avery reported receiving grant support from Aicuris, Astellas, Chimerix, Merck, Oxford Immunotec, Qiagen, and Takeda/Shire. Dr Segev reported serving as a consultant to and receiving honoraria for speaking from Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallincrodt, and Thermo Fisher Scientific. No other disclosures were reported.

    Funding/Support: This work was supported by the Ben-Dov family; grants F32DK124941 (awarded to Dr Boyarsky), K01DK101677 (to Dr Massie), and K23DK115908 (to Dr Garonzik-Wang) from the National Institute of Diabetes and Digestive and Kidney Diseases; grant gSAN-201C0WW (to Dr Werbel) from the Transplantation and Immunology Research Network of the American Society of Transplantation; and grant K24AI144954 (to Dr Segev) from the National Institute of Allergy and Infectious Diseases.

    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.

    Disclaimer: The analyses described are the responsibility of the authors and do not necessarily reflect the views or policies of the US Department of Health and Human Services. The mention of trade names, commercial products, or organizations does not imply endorsement by the US government.

    Additional Contributions: We acknowledge the following individuals for their assistance with this study, none of whom was compensated for his or her contributions: Oliver B. Laeyendecker, PhD, Yukari C. Manabe, MD, Christine M. Durand, MD, Caoilfhionn M. Connolly, MD, and Julie J. Paik, MD, MHS (all 5 for analysis and affiliated with the Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland); William A. Clarke, PhD, and Patrizio P. Caturegli, MD, MPH (both for analysis and affiliated with the Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland); Aaron M. Milstone, MD, MHS (data collection and analysis), and Ani Voskertchian, MPH (data collection) (both affiliated with the Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland); and Sunjae Bae, MD, PhD (analysis), Michael T. Ou, BS (data collection and writing/editing assistance), and Richard Wang, BA, Aura T. Teles, BS, Ross S. Greenberg, BA, Jake A. Ruddy, BS, Leyla R. Herbst, BA, Michelle R. Krach, MS, Michael D. Irving, BA, Kayleigh M. Herrick-Reynolds, MD, Mackenzie A. Eagleson, MD, Andrew M. Hallett, MD, and Victoria A. Bendersky, MD (11 for data collection) (all 13 affiliated with the Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland).

    References
    1.
    Boyarsky  BJ, Ou  MT, Werbel  WA,  et al.  Early development and durability of SARS-CoV-2 antibodies among solid organ transplant recipients: a pilot study.   Transplantation. Published online January 19, 2021. doi:10.1097/tp.0000000000003637PubMedGoogle Scholar
    2.
    Klein  SL, Pekosz  A, Park  HS,  et al.  Sex, age, and hospitalization drive antibody responses in a COVID-19 convalescent plasma donor population.   J Clin Invest. 2020;130(11):6141-6150. doi:10.1172/JCI142004PubMedGoogle ScholarCrossref
    3.
    Patel  EU, Bloch  EM, Clarke  W,  et al.  Comparative performance of five commercially available serologic assays to detect antibodies to SARS-CoV-2 and identify individuals with high neutralizing titers.   J Clin Microbiol. 2021;59(2):e02257-20. doi:10.1128/JCM.02257-20PubMedGoogle Scholar
    4.
    Higgins  V, Fabros  A, Kulasingam  V.  Quantitative measurement of anti-SARS-CoV-2 antibodies: analytical and clinical evaluation.   J Clin Microbiol. Published online March 19, 2021. doi:10.1128/JCM.03149-20PubMedGoogle Scholar
    5.
    Jackson  LA, Anderson  EJ, Rouphael  NG,  et al; mRNA-1273 Study Group.  An mRNA vaccine against SARS-CoV-2—preliminary report.   N Engl J Med. 2020;383(20):1920-1931. doi:10.1056/NEJMoa2022483PubMedGoogle ScholarCrossref
    6.
    Walsh  EE, Frenck  RW  Jr, Falsey  AR,  et al.  Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates.   N Engl J Med. 2020;383(25):2439-2450. doi:10.1056/NEJMoa2027906PubMedGoogle ScholarCrossref
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