Long-Term Immuno-Response and Risk of Breakthrough Infection After SARS-CoV-2 Vaccination in Kidney Transplantation

Abstract

Background: Kidney transplant (KTx) recipients exhibit impaired responses to SARS-CoV-2 vaccination. Correlates of vaccine-induced immunity and risk factors for breakthrough infection are not fully defined. This study evaluated the humoral response trajectories and determinants of breakthrough infection in KTx recipients. Methods: KTx recipients received two doses of the BNT162b2 mRNA vaccine three weeks apart and a booster after six months. Patients were categorized based on pre-vaccination status: previous COVID-19 disease (DIS), asymptomatic SARS-CoV-2 infection (INF), or infection-naïve (NEG). Serum anti-spike antibody titers were assessed at baseline, before the second dose, and at 1, 3, 6, 9, and 12 months. Linear mixed models and survival analyses were performed. Results: Of 326 enrolled patients, 189 with complete time-point data were included in the longitudinal analysis. Antibodies were detectable in 89% of DIS/INF at baseline and 91% before the second dose, but were negligible in NEG. In NEG, the seropositivity increased after vaccination and booster, reaching 78% at 12 months. Age (-5% per year, p < 0.001) and BMI (+10% per unit, p = 0.004) influenced titers; antimetabolites and steroids had strong negative effects (-70%, p = 0.005; -84%, p = 0.001). Breakthrough infections occurred in 104 (31.9%); 40% were asymptomatic, and 2 patients died. An mTOR inhibitor was associated with a reduced infection risk (OR 0.27 [CI: 0.09-0.70], p = 0.009). Higher antibody titers correlated with delayed infection (p = 0.063). Conclusions: In KTx patients, humoral response to SARS-CoV-2 vaccination is limited in infection-naïve patients but improved by booster dosing; the hybrid immunity is more effective. Immunosuppressive regimens influence the immune response, and mTOR inhibitors may protect against breakthrough infection.

Keywords: BNT162b2; COVID; SARS-CoV-2; hybrid immunity; immune response; infection risk; kidney transplant; mRNA vaccine.

Figure 1

The behavior of titer and prevalence of protective level of anti-spike Ab across patient status and time-points during the study. (Top): Line-plot titer distribution (points represent the mean values of titer in the specific group/time-point, error-bars represent 95%-CI; dashed line is the threshold for protective anti-S Ab level). (Middle): Box-plots Ab titer distribution (bold lines represent the median value; dashed line is the threshold for protective Ab level). (Bottom): Prevalence of positive anti-S Ab titer (95%-CI by Clopper–Pearson). Time-points: Administration of vaccine: V1 = before 1st dose; V2 = before 2nd dose. M1, M3, M6, M9, and M12 = 1, 3, 6, 9, and 12 months after 2nd dose; M9 and M12 = 3 and 6 months after booster. Box-plot: Anti-S Ab titers are on the log₁₀ scale.

Figure 1

The behavior of titer and prevalence of protective level of anti-spike Ab across patient status and time-points during the study. (Top): Line-plot titer distribution (points represent the mean values of titer in the specific group/time-point, error-bars represent 95%-CI; dashed line is the threshold for protective anti-S Ab level). (Middle): Box-plots Ab titer distribution (bold lines represent the median value; dashed line is the threshold for protective Ab level). (Bottom): Prevalence of positive anti-S Ab titer (95%-CI by Clopper–Pearson). Time-points: Administration of vaccine: V1 = before 1st dose; V2 = before 2nd dose. M1, M3, M6, M9, and M12 = 1, 3, 6, 9, and 12 months after 2nd dose; M9 and M12 = 3 and 6 months after booster. Box-plot: Anti-S Ab titers are on the log₁₀ scale.

Figure 2

Behavior of titer and prevalence of protective level of anti-spike Ab in kidney transplant patients never infected by SARS-CoV-2 (NEG group) during vaccination and after booster and/or COVID-19 infection. (Top): Line-plot titer distribution (error bars represent 95%-CI; dashed line is the threshold for protective anti-S Ab level). (Bottom): Prevalence of positive anti-S Ab titer of neutralizing SARS-CoV-2 Ab (with 95%-CI estimated by Clopper–Pearson). Time-points: Administration of vaccination cycle (V1, V2), 1, 3, and 6 months post-vaccine (booster administration) (M1, M3, M6), and 9 and 12 months post-vaccine (M9, M12).

Figure 3

Forest plot analysis of the risk of SARS-CoV-2 infection in kidney transplant patients after anti-SARS-CoV-2 mRNA vaccination, according to individual characteristics (adjusted for factors listed in Table 3) at different time-points along the follow-up: completion of vaccine cycle (V2, red color), 3- and 6-month post-vaccine follow-up (M3, M6, green and blue colors, respectively).

Figure 4

The Kaplan–Meier analysis of the risk of COVID-19 infection in KTx patients after the anti-SARS-CoV-2 mRNA vaccination, according to the presence of a positive level of neutralizing Ab, started at the 3-month and 6-month post-vaccine time (M3, M6). Participants were classified as “protected” (blue curve) or “unprotected” (red curve) based on the presence of a positive neutralizing antibody titer at 3 months and 6 months after the two vaccine doses. The Kaplan–Meier curves have been aligned, starting the plotting from 6 months and 3 months after the full vaccination for the two analyses, respectively. No infection events were recorded before these time-points. The booster administration occurred in the timeframe between 3 and 6 months after the vaccination. Dashed lines represent the median time to infection of the groups.