Antibody Responses Against Emerging SARS-CoV-2 Omicron Lineages After the Fourth Dose of mRNA Vaccine in Kidney Transplant Recipients.

Abstract

Data regarding antiviral immune responses in kidney transplant recipients (KTRs) to newer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron lineages after 4 monovalent messenger RNA (mRNA) vaccine doses are limited. To address that, we conducted a prospective single-center observational cohort study of KTRs who had previously received 3 SARS-CoV-2 monovalent mRNA vaccines (mRNA-1273 or BNT162b2) and collected samples before and 1 mo after the fourth monovalent vaccine dose. Samples from prepandemic KTRs and from immunocompetent individuals who had received 3 mRNA vaccines and had prior Omicron-lineage SARS-CoV-2 infection were used as negative and positive controls, respectively. Exclusion criteria, sample processing, and antibody assays have been described previously.1,2 The study was approved by the Mass General Brigham institutional review board (2021P000043/2017P000298). Twenty-five KTRs were enrolled in the study (Table 1). Prevaccination samples were obtained at a median of 17 d (interquartile range, 1–127) before the fourth vaccine, and postvaccination samples were collected at a median of 28 d (interquartile range, 21–37) postvaccination. No infections occurred between the prevaccination sample collection and the fourth vaccine. To evaluate antiviral antibody responses to SARS-CoV-2 variants, we measured IgG levels directed against the receptor-binding domain (RBD) of wild-type (WT) and Omicron lineages of SARS-CoV-2 before and after the fourth vaccine using ELISA. We found a significant increase in anti-RBD IgG levels against BA.2.12.1 (P = 0.025) and BA.4/BA.5 (P = 0.041) lineages, but not against WT (P = 0.175), B.1.1.529 (P = 0.178), and BA.2 (P = 0.109) lineages after the fourth vaccine (Figure 1A). For comparison, anti-RBD antibody levels were not detectable in prepandemic KTRs and were detectable at high levels in immunocompetent controls (Figure 1B). TABLE 1. - Baseline characteristics of KTRs Baseline characteristic n = 25 Age at enrollment (years), median (IQR) 63 (50–67) Female sex, n (%) 8 (32) First kidney transplant, n (%) 23 (92) Cause of ESKD, n (%) Glomerular disease 11 (44) Polycystic kidney disease 4 (16) Diabetic nephropathy 3 (12) Alport’s syndrome 1 (4) Lithium toxicity 1 (4) Unknown 5 (20) Pretransplant RRT, n (%) None 12 (48) Hemodialysis 13 (52) Donor source, n (%) Living related 7 (28) Living unrelated 8 (32) Deceased 10 (40) HLA ABDR mismatches, median (IQR) 4 (4–5) Class I PRA (%), median (range) 0 (0–69) Class II PRA (%), median (range) 0 (0–97) DSA at the time of vaccination, n (%) 3 (12) Induction immunosuppression, n (%) Antithymocyte globulin 20 (80) Basiliximab 2 (8) Data not available 3 (12) Maintenance immunosuppression, n (%) Tacrolimus 8 (32) Trough level in ng/mL, median (IQR) 5.6 (4.5–6.4) Everolimus 1 (4) Sirolimus 2 (8) Belatacept 17 (68) Mycophenolate 17 (68) Total daily dose in mg, median (IQR) 1000 (1000–1000) Prednisone 21 (84) Total daily dose in mg, median (IQR) 5.0 (5.0–5.0) History of allograft rejection, n (%) 6 (24) Months between most recent rejection and 1st vaccine dose, median (IQR) 6.4 (4.0–12.2) Serum creatinine (mg/dL), median (IQR) 1.4 (1.2–1.9) Estimated GFR (mL/min/1.73 m2), mean ± SD 55 ± 20 Urine protein to creatinine ratio (g/g), median (IQR) 0.2 (0.1–0.5) Previous SARS-CoV-2 infection, n (%) 7 (28%) mRNA vaccine received, n (%) BNT162b2 × 4 22 (88) mRNA-1273 × 4 1 (4) BNT162b2 × 3 followed by mRNA-1273 1 (4) mRNA-1273 × 3 followed by BNT162b2 1 (4) Years between transplantation and 1st vaccine dose, median (IQR) 4.2 (1.9–10.1) Days between 1st and 2nd vaccine dose, median (IQR) 21 (21–21) Months between 2nd and 3rd vaccine dose, median (IQR) 6.2 (6.0–6.5) Months between 3rd and 4th vaccine dose, median (IQR) 5.6 (5.3–6.0) ESKD, end-stage kidney disease; GFR, glomerular filtration rate; IQR, interquartile range; KTR, kidney transplant recipient; mRNA, messenger RNA; mTOR, mammalian target of rapamycin; PRA, panel-reactive antibodies; RRT, renal replacement therapy; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. FIGURE 1.: Assessment of anti-RBD antibody levels and neutralizing responses after the fourth dose of SARS-CoV-2 monovalent mRNA vaccine in KTRs. A, IgG levels against WT SARS-CoV-2 and Omicron-lineage RBD before and after the fourth vaccine dose in KTRs (n = 25) measured by ELISA. B, As control groups, IgG levels were quantified in triple vaccinated and Omicron-infected HCs (n = 7) and in PKCs (n = 15). C, Percentage neutralization of WT and Omicron-lineage SARS-CoV-2 before and after the fourth vaccine dose in KTRs (n = 25), compared with (D) HCs (n = 7), and PKCs (n = 15) measured by surrogate virus neutralization test. E, Proportion of KTRs (n = 25) with a positive neutralization response (≥30% neutralization threshold) before and after the fourth vaccine dose. F, Neutralizing responses against WT and Omicron lineages of SARS-CoV-2 after the fourth mRNA vaccine dose in KTRs stratified by breakthrough infection status (n = 7 for breakthrough infection [BT infxn] group; n = 18 for no BT infxn group). (A, C) Statistics by Wilcoxon matched-pairs signed rank test. F, Statistics by Mann Whitney U test. HC, healthy control; KTR, kidney transplant recipient; mRNA, messenger RNA; PKC, prepandemic kidney transplant control patient; RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; WT, wild type.Next, we assessed neutralizing antibody responses to WT and Omicron SARS-CoV-2 lineages using a surrogate virus neutralization test.3 After the fourth vaccine, we found a significant increase in the neutralization of WT SARS-CoV-2 (P = 0.049), BA.2 (P = 0.018), BA.2.12.1 (P < 0.001), and BA.4/BA.5 (P = 0.005), but no statistically significant increase in the neutralization of the B.1.1.529 lineage (P = 0.095, Figure 1C). No prepandemic KTRs had neutralizing responses against WT or any of the Omicron lineages tested, whereas all immunocompetent controls had neutralizing responses against WT and all the Omicron lineages tested (Figure 1D). Using the recommended 30% neutralization assay threshold,3 we found that the proportion of KTRs with neutralizing responses against Omicron lineages increased after the fourth dose. However, over 50% of KTRs did not have neutralizing responses against Omicron lineages after the fourth dose (Figure 1E). At a mean(±SD) follow-up of 6.7 ± 0.8 mo postvaccination, 7 KTRs (28%) had developed breakthrough SARS-CoV-2 infection, of whom one required admission, and none died. The percentage of neutralization against WT and all Omicron lineages was numerically lower in KTRs who developed breakthrough infections compared to those who did not, but this did not reach statistical significance (Figure 1F). No infections occurred in KTRs with ≥66% neutralization responses against any of the Omicron lineages. The limitations of our study include its single-center observational design, small sample size, and lack of T-cell response assessment. Our findings highlight the need for additional preventive strategies in KTRs, such as newer bivalent vaccines, which may improve antiviral responses against Omicron lineages in KTRs.4