Past COVID-19 and immunosuppressive regimens affect the long-term response to anti-SARS-CoV-2 vaccination in liver transplant recipients

Abstract

Background & aims: The long-term immunogenicity of anti-SARS-CoV-2 vaccines in liver transplant (LT) recipients is unknown. We aimed to assess the long-term antibody response of the Pfizer-BioNTech® BNT162b2 vaccine in LT recipients compared to controls.

Methods: LT recipients underwent anti-SARS-CoV-2 anti-receptor-binding domain protein IgG (anti-RBD) and anti-nucleocapsid protein IgG antibody (anti-N) measurements at the first and 1, 4 and 6 months after the second vaccination dose.

Results: One hundred forty-three LT recipients and 58 controls were enrolled. At baseline, 131/143 (91.6%) LT recipients tested anti-N negative (COVID-19 naïve), and 12/143 (8.4%) tested positive (COVID-19 recovered) compared to negative controls. Among COVID-19 naïve, 22.1% were anti-RBD positives 1 month after the first vaccine dose, while 66.4%, 77%, and 78.8% were 1, 4 and 6 months following the second vaccine dose. In contrast, 100% of controls were positive at 4 months (p <0.001). The median anti-RBD titer 4 months after the second vaccine dose was significantly lower (32 U/ml) in COVID-19 naïve than in controls (852 U/ml, p <0.0001). A higher daily dose of mycophenolate mofetil (MMF) (p <0.001), higher frequency of ascites (p = 0.012), and lower serum leukocyte count (p = 0.016) were independent predictors of anti-RBD negativity at 6 months. All COVID-19 recovered patients tested positive for anti-RBD at each time point. The median antibody titer was similar in those taking MMF (9,400 U/ml, 11,925 U/ml, 13,305 U/ml, and 10,095 U/ml) or not taking MMF (13,950 U/ml, 9,575 U/ml, 3,500 U/ml, 2,835 U/ml, p = NS) 3 weeks after the first and 1, 4 and 6 months after the second vaccine dose, respectively.

Conclusions: In COVID-19-naïve LT recipients, the immunogenicity of anti-SARS-CoV-2 vaccination was significantly lower than that in controls. MMF was the main determinant of vaccination failure in SARS-CoV-2-naïve patients.

Lay summary: The immunogenicity of anti-SARS-CoV-2 vaccination in liver transplant recipients is currently unknown. Herein, we show that liver transplant recipients who have not previously had COVID-19 are less likely to mount effective antibody responses to vaccination than a control population. The main determinant of vaccination failure was the use of the immunosuppressive drug mycophenolate mofetil.

Keywords: liver transplantation; mRNA vaccine; mycophenolate mofetil.

Graphical abstract

Fig. 1

Timing schedule of the administration of the Pfizer-BioNTech® BNT162b2 vaccine doses and of the measurements of serum anti-SARS-CoV-2 antibodies in blood samples collected in liver-transplanted patients and controls.

Fig. 2

Anti-SARS-CoV-2 s-RBD antibody titers evaluated in COVID-19-naïve patients and controls. In COVID-19-naïve patients, the antibody titers were evaluated 3 weeks (19 days) after the first dose of the Pfizer-BioNTech® BNT162b2 vaccine and after 1 month (31±2 days), 4 months (125±5 days), and 6 months (165±4 days) following the second vaccine dose. Four months (134±15 days) after the second vaccine dose, antibody titers were evaluated in controls. Positive responders to vaccination were defined as those having reached an antibody titer ≥0.8 U/ml (light blue circles for patients and dark blue triangles for controls) while antibody titer <0.8 U/ml identified patient non-responders (white circles). Medians of antibody titers are reported for each time point, and the statistical analysis was performed by means of a non-parametric rank-sum (Mann-Whitney) test.

Fig. 3

Anti-SARS-CoV-2 s-RBD antibody titers evaluated in COVID-19-naïve patients who did or did not receive mycophenolate mofetil. Antibody titers were measured 3 weeks (19 days) after the first dose of Pfizer-BioNTech® BNT162b2 vaccine, and after 1 month (31±2 days), 4 months (125±5 days), and 6 months (165±4 days) following the second vaccine dose with regards to the inclusion (light blue circles) or the exclusion (white circles) of mycophenolate mofetil monotherapy or in combination with other immunosuppressive drugs. Positive responders to vaccination were defined as those having reached an antibody titer ≥0.8 U/ml. Medians of antibody titers are reported for each time point, and the statistical analysis was performed by means of a non-parametric rank-sum (Mann-Whitney) test.

Fig. 4

Anti-SARS-CoV-2 s-RBD antibody titers in COVID-19-recovered and in COVID-19-naïve patients. Anti-SARS-CoV-2 s-RBD antibody titers in COVID-19-recovered (light blue circles) and in COVID-19-naïve (white circles) patients evaluated before and after 3 weeks (19 days) of the first dose of Pfizer-BioNTech® BNT162b2 vaccine, as well as after 1 month (31±2 days), 4 months (125±5 days), and 6 months (165±4 days) following the second vaccine dose. Positive responders to vaccination were defined as those having reached an antibody titer ≥0.8 U/ml. Medians of antibody titers are reported for each time point.

Fig. 5

Anti-SARS-CoV-2 s-RBD antibody titers evaluated in COVID-19-recovered patients who did or did not receive mycophenolate mofetil. Anti-SARS-CoV-2 s-RBD antibody titers evaluated in COVID-19-recovered (n = 12) patients before and after 3 weeks (19 days) of the first dose of Pfizer-BioNTech® BNT162b2 vaccine, as well as after 1 month (31±2 days), 4 months (125±5 days), and 6 months (165±4 days) following the second vaccine dose. Patients were divided with regard to adopting immunosuppressive treatment, including (light blue circles) or excluding (white circles) mycophenolate mofetil. Positive responders to vaccination were defined as those having reached an antibody titer ≥0.8 U/ml. Medians of antibody titers are reported for each time point, and the statistical analysis was performed by means of a non-parametric rank-sum (Mann-Whitney) test.