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 ​(Table1).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).