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Letters to the Editor

Humoral and Cellular Immune Response to a Third Dose of SARS-CoV-2 Vaccine in Kidney Transplant Recipients Taking Belatacept

Mitchell, Jonathan MBBS1,2; Kim, Jake BA1; Alejo, Jennifer L. MD1; Chiang, Teresa P-Y. MD, MPH1; Karaba, Andrew H. MD, PhD3; Blankson, Joel N. MD, PhD3; Aytenfisu, Tihitina Y. BA3; Chang, Amy MD1; Abedon, Aura T. BS1; Avery, Robin K. MD3; Tobian, Aaron A. MD, PhD3; Massie, Allan B. PhD, MHS1,4; Levan, Macey L. JD, PhD1; Warren, Daniel S. PhD1; Garonzik-Wang, Jacqueline M. MD, PhD5; Segev, Dorry L. MD, PhD1,4; Werbel, William A. MD3

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doi: 10.1097/TP.0000000000004100
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Kidney transplant recipients (KTRs) have poor humoral immune responses to 2-dose severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, with noted improvement after receiving a third dose (D3).1,2 However, KTRs taking belatacept (KTR-bela) have a worse humoral response to 2-dose SARS-CoV-2 vaccination3 with minimal improvement after D3.4 However, the cellular response after D3 in KTR-bela has not been well defined and could provide some protection against coronavirus disease 2019 infection. The goal of this study was to characterize the impact of a third vaccine dose on the humoral and cellular immune responses in KTR-bela compared with KTRs not taking belatacept (KTR-controls).

Twenty-five KTR-bela and 26 KTR-controls without previously diagnosed SARS-CoV-2 infection, who received 3 doses of SARS-CoV-2 vaccine, were identified from a previously described observational cohort.1 Semiquantitative antispike serological testing was performed using the Roche Elecsys anti–SARS-CoV-2 S enzyme immunoassay, which tests for the receptor-binding domain, or the EUROIMMUN enzyme immunoassay, which tests for the S1 domain of the SARS-CoV-2 spike protein, at least 1 mo after dose 2 and repeated 2 to 4 wk after D3. Angiotensin-converting enzyme 2 (ACE2) inhibition (surrogate neutralization) of the vaccine strain and delta variant was measured using ACE2 MSD V-PLEX SARS-CoV-2 kits. This assay measures the ability of plasma to inhibit ACE2 binding to spike protein, and results are reported as percentage ACE2 inhibition. T-cell response was assessed using interferon-γ ELISpot assays as previously described.5 A result was considered positive with spot-forming units of >20 per million peripheral blood mononuclear cells and a stimulation index of >3. This study was approved by the Johns Hopkins Institutional Review Board, and participants provided informed consent electronically.

The KTR-bela group had substantially lower antispike seroconversion than KTR-controls after D3 (any positive: 36% versus 76.9%; high positive: 16% versus 61.5%; P = 0.003) despite similar demographics, clinical factors, and vaccines administered (Table 1). There were differences noted in percentage ACE2 inhibition versus the vaccine strain (median [interquartile range], 5.2 [2.8–6.5] versus 13.3 [8.6–23.9]; P < 0.01) as well as the delta variant (median [interquartile range], 5.0 [3.1–8.4] versus 11.9 [3.3–15.7]; P = 0.11). All tested KTR-bela had results below a level consistent with detectable neutralizing antibody2 and failed to meet criteria for a positive ELISpot (3 of 3).

TABLE 1. - Antibody response after 3 doses of SARS-CoV-2 vaccine in KTR-bela and KTR-control
Factor KTR-bela KTR-control P
N 25 26
Age, median (IQR) 61.9 (52.4–68.6) (n = 25) 59.7 (46.3–68.5) (n = 26) 0.78
Female 17 (68.0%) 14 (53.8%) 0.39
Non-White race 2 (8.0%) 0 (0.0%) 0.24
Time since transplant, median (IQR) 3.4 (2.1–8.8) (n = 25) 6.1 (2.1–12.6) (n = 26) 0.40
MMF 17 (68.0%) 21 (80.8%) 0.35
D2 vaccine type 0.58
 BNT162b2 13 (52.0%) 16 (61.5%)
 mRNA-1273 12 (48.0%) 10 (38.5%)
D3 vaccine type 0.26
 BNT162b2 9 (%) 8 (%)
 mRNA-1273 13 (%) 10 (%)
 Ad26.COV2.S 3 (%) 8 (%)
Pre-D3 antibody responsea 0.50
 Negative 20 (80.0%) 19 (73.1%)
 Low positive 4 (16.0%) 7 (26.9%)
 High positive 1 (4.0%) 0 (0.0%)
Post-D3 antibody responsea 0.003
 Negative 16 (64.0%) 6 (23.1%)
 Low positive 5 (20.0%) 4 (15.4%)
 High positive 4 (16.0%) 16 (61.5%)
% ACE2 inhibition, median (IQR)
 Vaccine strain 5.2 (2.8–6.5) (n = 5) 13.3 (8.6– 23.9) (n = 26) 0.008
 Delta variant 5.0 (3.1–8.4) (n = 5) 11.9 (3.3–15.7) (n = 26) 0.11
aNegative—anti-RBD <50 U/mL or anti-S1 <1.1 AU/mL; low positive—anti-RBD ≥50 U/mL but <250 U/mL or anti-S1 ≥1.1 AU/mL but <4 AU/mL; high positive—anti-RBD ≥250 U/mL or anti-S1 ≥4 AU/mL.
ACE2, angiotensin-converting enzyme 2; D2, dose 2; D3, dose 3; IQR, interquartile range; KTR-bela, kidney transplant recipients taking belatacept; KTR-control, kidney transplant recipients not taking belatacept; MMF, mycophenolate mofetil; RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Our findings of low seroconversion after D3 in KTR-bela are consistent with a recent report from Chavarot et al4 and extend their study by providing a similar control group receiving nonbelatacept immunosuppression. In addition, differences seen between the 2 groups in percentage ACE2 inhibition highlight the diminished potential for virus neutralization and the risks posed by novel SARS-CoV-2 variants. Most importantly, our study is the first to highlight the lack of cellular immune response to an additional vaccine dose in KTR-bela. Limitations include a lack of safety information, lack of vaccine-specific T-cell response testing, and small sample size.

These findings suggest minimal potential benefit to the cellular immune response and virus neutralization potential after D3 in KTR-bela. Investigation of alternative methods, such as preexposure monoclonal antibody prophylaxis, is necessary to improve protection against coronavirus disease 2019 in this particularly vulnerable group.


The authors thank the participants of the study, without whom this work would be impossible, as well as the Johns Hopkins Transplant Vaccine study team, including Brian J. Boyarsky, MD, PhD; Mayan Teles, BS; Julia Lopez, BA; Michael T. Ou, BS; Ross S. Greenberg, BA; Jake A. Ruddy, BS; Muhammad Asad Munir, MBBS; Michelle R. Krach, MS; and Iulia Barbur, BSE. They also thank Bezawit A. Woldemeskel, Caroline C. Garliss, and Ms Yolanda Eby for project support and guidance.


1. 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;174:1330–1332.
2. Karaba AH, Zhu X, Liang T, et al. A third dose of SARS-CoV-2 vaccine increases neutralizing antibodies against variants of concern in solid organ transplant recipients. Am J Transplant. [Epub ahead of print. December 24, 2021]. doi:10.1111/ajt.16933
3. 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;105:2119–2123.
4. Chavarot N, Morel A, Leruez-Ville M, et al. Weak antibody response to three doses of mRNA vaccine in kidney transplant recipients treated with belatacept. Am J Transplant. 2021;21:4043–4051.
5. Woldemeskel BA, Kwaa AK, Garliss CC, et al. Healthy donor T cell responses to common cold coronaviruses and SARS-CoV-2. J Clin Invest. 2020;130:6631–6638.
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