Protection from successive Omicron variants with SARS-CoV-2 vaccine and monoclonal antibodies in kidney transplant recipients

Abstract

Introduction: Kidney transplant recipients (KTRs) are at high risk of severe COVID-19, even when they are fully vaccinated. Additional booster vaccinations or passive immunization with prophylactic monoclonal antibodies are recommended to increase their protection against severe COVID-19.

Methods: Here, we describe the neutralization of SARS-CoV-2 Delta, Omicron BA.1, BA.2, BA.4, and BA.5 variants, firstly by 39 serum samples from vaccinated KTRs exhibiting anti-spike antibody concentrations ≥264 binding antibody units (BAU)/mL and, secondly, by tixagevimab/cilgavimab.

Results: No neutralization was observed for 18% of the KTRs, while serum from only 46% of patients could neutralize the five variants. Cross-neutralization of the Delta and Omicron variants occurred for 65-87% of sera samples. The anti-spike antibody concentration correlated with neutralization activity for all the variants. The neutralization titers against the Delta variant were higher in vaccinated KTRs who had previously presented with COVID-19, compared to those KTRs who had only been vaccinated. Breakthrough infections occurred in 39% of the KTRs after the study. Tixagevimab/cilgavimab poorly neutralizes Omicron variants, particularly BA.5, and does not neutralize BQ.1, which is currently the most prevalent strain.

Discussion: As a result, sera from seropositive vaccinated KTRs had poor neutralization of the successive Omicron variants. Several Omicron variants are able to escape tixagevimab/cilgavimab.

Keywords: COVID-19; SARS-CoV-2; cilgavimab; immunocompromized; kidney transplantation; neutralization; tixagevimab; vaccine.

Figure 1

Flow chart. Between August 23, 2021 and April, 262,022, 142 kidney transplant recipients (KTRs) received at least one dose of vaccine against SARS-CoV-2 before sampling for serology and had positive (> 33.8 binding antibody (Ab) units (BAU)/mL) anti-SARS-CoV-2 spike Ab in our laboratory. Of the 142 KTRs, 72 had anti-spike Ab concentrations <264 BAU/mL, and 70 had concentrations >264 BAU/mL. Neutralization assays results were available for 39 of these 70 KTRs and were included in the study. The Hybrid group is formed of 15 KTRs immunized against SARS-CoV-2 by vaccination and prior COVID-19, and the Vac group is formed of 24 KTRs immunized only by vaccination.

Figure 2

Neutralization of SARS-CoV-2 variants by sera from 39 kidney transplant recipients. (A) Profiles of SARS-CoV-2 variant neutralization and cross-neutralization by sera from 39 kidney transplant recipients. The cross-neutralizations are shown in a Venn diagram. Numbers in parentheses are the total numbers of sera that neutralized the variant. Seven sera had no neutralizing activity against the five SARS-CoV-2 variants, whereas 32 neutralized at least one variant. Eighteen neutralized all the variants. (B) Frequencies of cross-neutralization of Delta and different Omicron variants for the 32 sera that neutralized at least one variant. (C) Neutralization titers in the sera from 39 kidney transplant recipients according to the SARS-CoV-2 variant. The black bar represents the median value, and error bars represent the interquartile ranges of values. The black dashed line represents the cutoff for a detectable neutralization titer of 5. The neutralization titers against the five variants were compared using one-way ANOVA followed by Tukey’s multiple comparison test. *p < 0.05, **p < 0.002.

Figure 3

Anti-SARS-CoV-2 humoral immunity in 39 kidney transplant recipients according to anti-spike antibody concentrations. Concentrations of anti-SARS-CoV-2 IgG are expressed in Log10BAU/mL. The black bar represents the median value (A). Concentrations of anti-SARS-CoV-2 IgG were compared between sera with and without neutralizing activity for each virus using one-way ANOVA followed by Tukey’s multiple comparison test; *p < 0.05. Each point represents one serum sample. The point is green if the serum presented neutralizing activity and red if not. (B) Concentrations of anti-SARS-CoV-2 IgG were compared between sera neutralizing different numbers of variants.

Figure 4

Correlation analyses of anti-spike Ab with neutralization titers of the sera from 39 kidney transplant recipients against the different SARS-CoV-2 variants by simple linear regression. The correlation was performed by Pearson’s analysis. The concentrations of anti-spike Ab showed a strong correlation with the neutralization titer for each variant. The Pearson r was 0.72, 0.57, 0.67, 0.68, and 0.71 for the Delta, Omicron BA.1, Omicron BA.2, Omicron BA.4, and Omicron BA.5 variants, respectively; p < 0.0001.

Figure 5

Neutralization titers in the Hybrid group and the Vac group according to the SARS-CoV-2 variants. Neutralization titers were compared for each variant between the Hybrid group, formed of kidney transplant recipients immunized against SARS-CoV-2 by vaccination and prior COVID-19, and the Vac group, formed of patients immunized only by vaccination, using one-way ANOVA followed by Tukey’s multiple comparison test; *p < 0.05.

Figure 6

Weekly incidence of each major SARS-CoV-2 mutant and variant based on the genotyping performed at IHU Méditerranée Infection institute. SARS-CoV-2 genotyping was performed as previously described (Colson et al., 2022). Correspondence between genotype labels: Marseille-1: Pangolin lineage (Rambaut et al., 2020) B.1.416; Marseille-2: B.1.177; Marseille-4: B.1.160; and Marseille-5: B.1.367.

Figure 7

Breakthrough infections after seroneutralization study. Chronograms including events such as kidney transplantation, the last dose of vaccine before COVID-19, serology and COVID 19, are represented for 15 of the 38 patients, all of whom were kidney transplant recipients, at the last follow-up (December 28, 2022). The date of COVID-19 is given in form of Week (W) and Year (Y) numbers. The results of the seroneutralization of the Delta, Omicron BA.1, BA.2, BA.4 and BA.5 variants at the time of the serology are presented: the disk is blue if neutralization was observed, and red if not. If the virus responsible for COVID-19 was genotyped at our laboratory, the concerned variant in question is framed by a red square. In other cases, the supposed variant is circled by blue brackets, according to the weekly incidence of each major SARS-CoV-2 mutant and variant, based on the genotyping performed at our laboratory.

Figure 8

Neutralization curves for Omicron BA.2, BA.4, BA.5, and BQ.1 tested with monoclonal antibodies. (A) Omicron BA.2 tested with tixagevimab, cilgavimab, and a combination of both. (B) Omicron BA.4 tested with tixagevimab, cilgavimab, and a combination of both (C) Omicron BA.5 tested with tixagevimab, cilgavimab, and a combination of both. (D) Omicron BQ.1 tested with tixagevimab, cilgavimab, and a combination of both. (E) Comparison of each Omicron isolate tested with the tixagevimab/cilgavimab combination; BA.1 was considered as a control. Each experiment was performed four times. Bars represent the standard error.