Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients | Surgery | JAMA | JAMA Network
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Figure.  Antibody Levels of Study Participants After 2-Dose Series of SARS-CoV-2 mRNA Vaccine
Antibody Levels of Study Participants After 2-Dose Series of SARS-CoV-2 mRNA Vaccine

A, Roche Elecsys anti–SARS-CoV-2 S enzyme immunoassay (n = 470) tests for total antibody against the receptor-binding domain of the SARS-CoV-2 spike protein. The manufacturer cutoff for detectable antibody is 0.80 U/mL (shown as a horizontal orange line). The lowest value reported by the assay is <0.4 U/mL; the highest value is >250. B, EUROIMMUN enzyme immunoassay (n = 188) tests for IgG to the S1 domain of SARS-CoV-2 spike protein. The manufacturer cutoff for detectable antibody is 1.1 arbitrary units (shown as a horizontal red line). The lines beginning at dose 1 reflect the antibody trajectory of participants who had detectable antibody after dose 1. Orange dots represent the antibody levels of participants who had undetectable antibody after dose 1.

Table.  Demographic and Clinical Characteristics of Study Participants, Stratified by Immune Response to the 2 Doses of SARS-CoV-2 mRNA Vaccine
Demographic and Clinical Characteristics of Study Participants, Stratified by Immune Response to the 2 Doses of SARS-CoV-2 mRNA Vaccine
1.
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
2.
Jackson  LA, Anderson  EJ, Rouphael  NG,  et al; mRNA-1273 Study Group.  An mRNA vaccine against SARS-CoV-2.   N Engl J Med. 2020;383(20):1920-1931. doi:10.1056/NEJMoa2022483PubMedGoogle ScholarCrossref
3.
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. Published online March 15, 2021. doi:10.1001/jama.2021.4385PubMedGoogle Scholar
4.
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
5.
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. Published online January 21, 2021. doi:10.1128/JCM.02257-20PubMedGoogle Scholar
6.
Mueller  T.  Antibodies against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) in individuals with and without COVID-19 vaccination: a method comparison of two different commercially available serological assays from the same manufacturer.   Clin Chim Acta. 2021;518:9-16. doi:10.1016/j.cca.2021.03.007PubMedGoogle ScholarCrossref
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    3 Comments for this article
    EXPAND ALL
    Effect of Second Dose of COVID-19 mRNA Vaccine on Transplant Recipients
    Takuma Hayashi, MBBS, DMSci, GMRC, PhD | National Hospital Organization Kyoto Medical Center
    Although Boyarsky BJ et al. demonstrate an improvement in anti-spike antibody responses in transplant recipients after dose 2 compared with dose 1, their data suggest that a substantial proportion of transplant recipients likely remain at risk for COVID-19 after 2 doses of mRNA vaccine.

    Since transplant recipients must always take immunosuppressive drugs, we believe that transplant recipients do not have higher anti-SARS-CoV-2 antibody titers after COVID-19 mRNA vaccination compared to healthy individuals.

    The following contents have been published at the Japanese Society for Organ Transplantation.

    Generally, it has been reported that poor effect of the vaccine under
    taking immunosuppressive drugs. COVID-19 mRNA vaccination should be prioritized for transplant recipients.
    The prognosis for transplant recipients who develop COVID-19 is significantly poor. Therefore, COVID-19 mRNA vaccination is recommended for transplant recipients to prevent SARS-CoV-2 infection.
    COVID-19 mRNA vaccination is recommended for transplant recipients, even if the transplant recipient has previously developed COVID-19 or has antibodies to SARS-CoV-2.
    After COVID-19 mRNA vaccination, transplant recipients should wear masks, maintain social distance, and avoid stagnation.

    In general, the antiviral effect of vaccination depends on the immune activation of the vaccinated person. Therefore, it is essential to develop an anti-SARS-CoV-2 drug to prevent the serious illness of COVID-19 for transplant recipients who take daily immunosuppressive drugs.

    Dr. Hayashi T. Dr. Konishi I.
    National Hospital Organization Kyoto Medical Center
    CONFLICT OF INTEREST: None Reported
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    Effectiveness of COVID-19 vaccines at population level not yet estimated
    Sandro Tsang, PhD | People's Open Access Education Initiative
    For transplant recipients (not) receiving antimetabolites, (32%) 57% had no antibody response after 2 doses of mRNA vaccine. This finding implies that vaccinating immunocompromised individuals against COVID-19 with mRNA vaccine appears ineffective at individual levels. However, the virus can evolve within a host hidden for months and be transmitted to others (1). I hope that estimates of the effectiveness of different COVID-19 vaccines from a population health perspective will soon become available in the research pipeline. In any case, immunocompromised individuals should always be given priority to receive the vaccines to their own accord, since they are vulnerable individuals.

    Reference

    Abbasi J. Researchers Tie Severe Immunosuppression to Chronic COVID-19 and Virus Variants. JAMA. 2021;325(20):2033-2035. doi:10.1001/jama.2021.7212.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    A Pandemic of the Unvaccinated & Undervaccinated
    Stephen Strum, MD | Primary Practice of Hematology & Oncology
    The issue of vaccination involves some of the core concepts of true translational medicine (TM). For a vaccine to be effective, it must translate to a correlate of protection. With COVID-19 we have seen dramatically different rates of death, ICU admissions, hospitalizations, and severe COVID-19 infection between those unvaccinated, those partially vaccinated, and those with natural COVID-19 infection with or without subsequent vaccination(s). All of this appears to translate to a kinetic model that at its core reflects antigenic stimulation of the immune system, the nature (including intensity) of such stimulation, and the repeated exposure of antigenic stimulation (which usually can be equated with the number of vaccinations and dose administered).

    We currently only have one "handle" on such an assessment, and that related to a semi-quantitative IgG testing of humoral antibody levels (HALs). The Roche test identified as RBD-pan-Ig-quant (Elecsys Anti-SARS-CoV-2 S) is available per both LabCorp and Quest, with a turnaround time of 24 hours. Some virologists believe that we should have a goal of ≥ 300 U/ml as a surrogate correlate of protection.

    Given the above, why are studies not exploring breakthrough infections, their severity, and the issues of hospitalization, ICU admissions and deaths with such semi-quantitative testing? Why do we believe that two doses of Pfizer or of Moderna is the alpha and the omega (pun intended) of SARS-CoV-2 protection? For sure, we have a Pandemic of the Unvaccinated but we also have the serious issue of the under-vaccinated.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Research Letter
    May 5, 2021

    Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series 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(21):2204-2206. doi:10.1001/jama.2021.7489

    In contrast to immunocompetent participants in vaccine trials,1,2 a low proportion (17%) of solid organ transplant recipients mounted a positive antibody response to the first dose of SARS-CoV-2 messenger RNA (mRNA) vaccines, with those receiving anti–metabolite maintenance immunosuppression less likely to respond.3 In this study, we assessed antibody response after the second dose.

    Methods

    Transplant recipients without prior polymerase chain reaction–confirmed COVID-19 were recruited from across the US to participate in this prospective cohort through a digital campaign. Those who completed the 2-dose SARS-CoV-2 mRNA vaccine series between December 16, 2020, and March 13, 2021, were included and followed up through April 13, 2021. As described previously,3 semiquantitative antispike serologic testing was undertaken with the Roche Elecsys anti–SARS-CoV-2 S enzyme immunoassay, positive cutoff of at least 0.8 U/mL, which tests for the receptor-binding domain of the SARS-CoV-2 spike protein, or the EUROIMMUN enzyme immunoassay, positive cutoff of at least 1.1 arbitrary units, which tests for the S1 domain of SARS-CoV-2 spike protein, both key measures of humoral immune response.4,5 This study was approved by the Johns Hopkins institutional review board; participants provided informed consent electronically.

    The proportion of patients who developed a positive antibody response was assessed with an exact binomial confidence interval. The Fisher exact test was used to compare categorical variables, such as antimetabolite immunosuppression, and the Kruskal-Wallis test for continuous variables. All tests were 2-sided with α = .05. Analyses were performed using Stata 16.1/Windows.

    Results

    We studied 658 transplant recipients who received 2 doses of SARS-CoV-2 mRNA vaccine (Table); the first-dose results of 396 of these recipients were previously reported.3 At a median (IQR) of 21 (18-25) days after dose 1, antibody was detectable in 98 participants (15%) (95% CI, 12%-18%). At a median (IQR) of 29 (28-31) days after dose 2, antibody was detectable in 357 participants (54%) (95% CI, 50%-58%).

    Overall, of the 658 participants, 98 (15%) had measurable antibody response after dose 1 and dose 2; 301 (46%) had no antibody response after dose 1 or dose 2; and 259 (39%) had no antibody response after dose 1 but subsequent antibody response after dose 2 (Figure).

    Among all 658 participants, median (IQR) antibody levels after dose 2 were 2.14 U/mL (<0.4-245.8) (Roche) and 1.23 arbitrary units (0.13-6.38) (EUROIMMUN). Among the 357 with detectable antibody after dose 2, median (IQR) antibody levels were 142.1 U/mL (9.44->250) (Roche) and 6.48 arbitrary units (3.75-8.72) (EUROIMMUN) overall; 34.7 U/mL (5.38->250) (Roche) and 5.05 arbitrary units (2.33-7.02) (EUROIMMUN) in the 259 with no antibody response after dose 1; and >250 U/mL (>250->250) (Roche) and 9.23 arbitrary units (8.62-9.73) (EUROIMMUN) in the 98 with antibody response after dose 1.

    Among the 473 receiving antimetabolites, 38 participants (8%) had antibody response after dose 1 and dose 2; 268 (57%) had no antibody response after dose 1 or dose 2; and 167 (35%) had no antibody response after dose 1 but subsequent antibody after dose 2. Among the 185 participants not receiving antimetabolites, 60 (32%) had antibody response after dose 1 and dose 2; 33 (18%) had no antibody response after dose 1 or dose 2; and 92 (50%) had no antibody response after dose 1 but subsequent antibody after dose 2.

    Discussion

    In this study of the humoral response to 2 doses of mRNA SARS-CoV-2 vaccine among solid organ transplant recipients, the majority had detectable antibody responses after the second dose, although participants without a response after dose 1 had generally low antibody levels. Poor humoral response was persistently associated with use of antimetabolite immunosuppression.

    Although no threshold has been established for protective immunity, antibody levels were well below that which has been observed in immunocompetent vaccinees.6

    Limitations of this study include a sample that may lack external validity, lack of an immunocompetent control group, lack of assessment of postvaccination SARS-CoV-2, and lack of exploration of memory B-cell or T-cell responses.

    Although this study demonstrates an improvement in antispike antibody responses in transplant recipients after dose 2 compared with dose 1, these data suggest that a substantial proportion of transplant recipients likely remain at risk for COVID-19 after 2 doses of mRNA vaccine. Future studies should address interventions to improve vaccine responses in this population, including additional booster doses or immunosuppression modulation.

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

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

    Accepted for Publication: April 26, 2021.

    Published Online: May 5, 2021. doi:10.1001/jama.2021.7489

    Author Contributions: Drs Garonzik-Wang (principal investigator) and Segev 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: Boyarsky, Werbel, Avery, Massie, Segev, Garonzik-Wang.

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

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

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

    Statistical analysis: Boyarsky, Massie, Segev.

    Obtained funding: Segev, Garonzik-Wang.

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

    Supervision: Werbel, Massie, Segev, Garonzik-Wang.

    Conflict of Interest Disclosures: Dr Werbel reported receiving grants from the American Society of Transplantation Research Network Clinical Science Fellowship Grant. Dr Avery reported receiving grants 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 (Dr Boyarsky), K01DK101677 (Dr Massie), and K23DK115908 (Dr Garonzik-Wang) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); grant K24AI144954 (Dr Segev) from the National Institute of Allergy and Infectious Diseases (NIAID); and by grant gSAN-201C0WW from the Transplantation and Immunology Research Network of the American Society of Transplantation (Dr Werbel).

    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 here are the responsibility of the authors alone 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: In addition to the individuals recognized previously,3 we also acknowledge the following individuals for their assistance with this study, none of whom was compensated for his or her contributions. Yolanda Eby, MS (Department of Pathology, Johns Hopkins School of Medicine), for data collection; Teresa P-Y. Chiang, MD, MPH (Department of Surgery, Johns Hopkins School of Medicine) for data analysis; Sunjae Bae, MD, PhD (Department of Surgery, Johns Hopkins School of Medicine), for data analysis; Iulia Barbur, BSE (Department of Surgery, Johns Hopkins School of Medicine), for data collection; Muhammad Asad Munir, MBBS (Department of Surgery, Johns Hopkins School of Medicine), for data collection; Andrew H. Karaba, MD, PhD (Department of Medicine, Johns Hopkins School of Medicine), for data analysis; Andrea L. Cox, MD, PhD (Department of Medicine, Johns Hopkins School of Medicine), for data analysis; Justin R. Bailey, MD, PhD (Department of Medicine, Johns Hopkins School of Medicine), for data analysis; Anna P. Durbin, MD (Department of International Health, Johns Hopkins Bloomberg School of Public Health), for data analysis; and Kawsar R. Talaat, MD (Department of International Health, Johns Hopkins Bloomberg School of Public Health), for data analysis.

    References
    1.
    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
    2.
    Jackson  LA, Anderson  EJ, Rouphael  NG,  et al; mRNA-1273 Study Group.  An mRNA vaccine against SARS-CoV-2.   N Engl J Med. 2020;383(20):1920-1931. doi:10.1056/NEJMoa2022483PubMedGoogle ScholarCrossref
    3.
    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. Published online March 15, 2021. doi:10.1001/jama.2021.4385PubMedGoogle Scholar
    4.
    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
    5.
    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. Published online January 21, 2021. doi:10.1128/JCM.02257-20PubMedGoogle Scholar
    6.
    Mueller  T.  Antibodies against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) in individuals with and without COVID-19 vaccination: a method comparison of two different commercially available serological assays from the same manufacturer.   Clin Chim Acta. 2021;518:9-16. doi:10.1016/j.cca.2021.03.007PubMedGoogle ScholarCrossref
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