Neutralization of SARS-CoV-2 Variants of Concern in Kidney Transplant Recipients after Standard COVID-19 Vaccination

Abstract

Background and objectives: Antibody response after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is impaired in kidney transplant recipients. Emerging variants, such as B.1.617.2 (δ), are of particular concern because of their higher transmissibility and partial immune escape. Little is known about protection against these variants in immunocompromised patients.

Design, setting, participants, & measurements: In this prospective two-center study, antispike 1 IgG and surrogate neutralizing antibodies were measured in 173 kidney transplant recipients and 166 healthy controls with different vaccination schedules. In addition, different SARS-CoV-2 epitope antibodies from 135 vaccinated kidney transplant recipients were compared with antibodies in 25 matched healthy controls after second vaccination. In 36 kidney transplant recipients with seroconversion, neutralization against B.1.1.7 (α), B.1.351 (β), and B.1.617.2 (δ) was determined on VeroE6 cells and compared with neutralization in 25 healthy controls.

Results: Kidney transplant recipients had significantly lower seroconversion rates compared with healthy controls. After the second vaccination, antispike 1, antireceptor-binding domain, and surrogate neutralizing antibodies were detectable in 30%, 27%, and 24% of kidney transplant recipients, respectively. This compares with 100%, 96%, and 100% in healthy controls, respectively (P<0.001). Neutralization against B.1.1.7 was detectable in all kidney transplant recipients with seroconversion, with a median serum dilution that reduces infection of cells by 50% of 80 (interquartile range, 80-320). In contrast, only 23 of 36 (64%) and 24 of 36 (67%) kidney transplant recipients showed neutralization against B.1.351 and B.1.617.2, respectively, with median serum dilutions that reduce infection of cells by 50% of 20 (interquartile range, 0-40) and 20 (interquartile range, 0-40), respectively. Neutralization against different variants was significantly higher in healthy controls (P<0.001), with all patients showing neutralization against all tested variants.

Conclusions: Seroconverted kidney transplant recipients show impaired neutralization against emerging variants of concern after standard two-dose vaccination.

Clinical trial registry name and registration number: Observational study to assess the SARS-CoV-2 specific immune response in kidney transplant recipients (COVID-19 related immune response), DRKS00024668.

Keywords: COVID-19; SARS-CoV-2; kidney transplantation; vaccination; variants of concern.

Graphical abstract

Figure 1.

Study population to determine humoral immune responses to different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) two-dose vaccination regimens in kidney transplant recipients and healthy controls. In total, 339 participants were included in this study. Humoral response after vaccination was assessed in 173 kidney transplant recipients and 166 healthy controls. Analysis was done for 73 kidney transplant recipients and 115 healthy controls after first vaccination. Kidney transplant recipients and healthy controls received either an mRNA vaccine (n=57 and n=45, respectively) or an adenoviral vector–based vaccine (AZ; n=16 and n=70, respectively) as the first vaccine dose. Humoral response after the two-dose vaccination was assessed in 135 kidney transplant recipients and 134 healthy controls. Kidney transplant recipients received homologous mRNA/mRNA (n=109), homologous AZ/AZ (n=17), or heterologous AZ/mRNA two-dose vaccination (n=9). Healthy controls received homologous mRNA/mRNA (n=82), homologous AZ/AZ (n=17), or heterologous AZ/mRNA two-dose vaccination (n=35). For analysis of antibodies against various SARS-CoV-2 target epitopes and for analysis of neutralization against different variants of concern, kidney transplant recipients were compared with 25 healthy controls matched for type of vaccine, age, and sex.

Figure 2.

Antispike 1 (anti-S1) IgG antibodies and neutralizing antibodies in kidney transplant recipients and healthy controls with different SARS-CoV-2 two-dose vaccination regimens. (A) SARS-CoV-2 anti-S1 IgG antibodies were determined by a chemiluminescent immunoassay and are represented logarithmically as an anti-S1 IgG index in kidney transplant recipients and healthy controls with different vaccination regimens. The black dashed line represents the cutoff for detection. A semiquantitative index of greater than or equal to one was classified as positive. (B) The neutralizing capacity of antibodies (nAB) against SARS-CoV-2 was determined by a surrogate virus neutralization test in kidney transplant recipients and healthy controls with different two-dose vaccination regimens. A cutoff of ≥30% binding inhibition was applied according to the manufacturer’s instruction to define positivity. The black dashed line represents the cutoff for detection. (C) Pie charts show the distribution of positivity for anti-S1 IgG and neutralizing antibodies determined by the surrogate virus neutralization test for all kidney transplant recipients and healthy controls after first and second vaccinations. Some individuals had antibodies with neutralizing surrogate activity but no detectable anti-S1 IgG antibodies. This could be due to the presence of antibodies of different isotypes and also due to the independent validation of the two tests, resulting in different cutoffs for detection. (D) Courses of anti-S1 IgG antibodies and nAB measured by the surrogate virus neutralization test are shown for 36 kidney transplant recipients and 83 healthy controls with available sera after both first and second vaccinations. The black dashed lines represent the cutoff for detection for anti-S1 IgG and nAB, respectively. ***P<0.001.

Figure 3.

Neutralization of the variants of concern B.1.1.7 (α), B.1.351 (β), and B.1.617.2 (δ) in VeroE6 cells in all 36 seroconverted kidney transplant recipients and 25 healthy controls after two-dose vaccination against SARS-CoV-2. (A) The positivity of anti-S1 IgG index (chemiluminescent immunoassay), surrogate neutralizing antibodies (surrogate virus neutralization assay; nAB), and antireceptor-binding domain (anti-RBD) antibodies (multiplex bead-based assay) is shown in a color-coded Venn diagram for all 135 kidney transplant recipients after two-dose vaccination. Seroconversion was defined if at least two of the following antibodies were detectable: anti-S1 IgG, nAB, or anti-RBD IgG antibodies. Neutralization activity against variants of concern in VeroE6 cells was performed in 36 seroconverted kidney transplant recipients, represented in the Venn diagram by the green numbers. (B) Neutralizing activity against the variants of concern B.1.1.7 (α), B.1.351 (β), and B.1.617.2 (δ) was determined in a SARS-CoV-2 infection assay using VeroE6 target cells and serial two-fold dilutions of sera from all 36 kidney transplant recipients with seroconversion and 25 matched healthy controls after two-dose SARS-CoV-2 vaccination. The black dashed lines represent the cutoff for detection. (C) The correlation between anti-S1 IgG index (left panel), neutralizing SARS-CoV-2 antibodies measured by a surrogate virus neutralization test (center panel), and anti-RBD antibodies (right panel) with the neutralizing activity of the different variants of concern B.1.1.7 (α), B.1.351 (β), and B.1.617.2 (δ) in kidney transplant recipients was evaluated by Spearman correlation analysis. ID₅₀, serum dilution that reduces infection of cells by 50%. ***P<0.001. sVNT, surrogate neutralizing antibodies.