Cirrhosis is associated with lower serological responses to COVID-19 vaccines in patients with chronic liver disease

Abstract

Background & aims: The response of patients with chronic liver disease (CLD) to COVID-19 vaccines remains unclear. Our aim was to assess the humoral immune response and efficacy of two-dose COVID-19 vaccines among patients with CLD of different aetiologies and disease stages.

Methods: A total of 357 patients were recruited in clinical centres from six European countries, and 132 healthy volunteers served as controls. Serum IgG (nM), IgM (nM), and neutralising antibodies (%) against the Wuhan-Hu-1, B.1.617, and B.1.1.529 SARS-CoV-2 spike proteins were determined before vaccination (T0) and 14 days (T2) and 6 months (T3) after the second-dose vaccination. Patients fulfilling inclusion criteria at T2 (n = 212) were stratified into 'low' or 'high' responders according to IgG levels. Infection rates and severity were collected throughout the study.

Results: Wuhan-Hu-1 IgG, IgM, and neutralisation levels significantly increased from T0 to T2 in patients vaccinated with BNT162b2 (70.3%), mRNA-1273 (18.9%), or ChAdOx1 (10.8%). In multivariate analysis, age, cirrhosis, and type of vaccine (ChAdOx1 > BNT162b2 > mRNA-1273) predicted 'low' humoral response, whereas viral hepatitis and antiviral therapy predicted 'high' humoral response. Compared with Wuhan-Hu-1, B.1.617 and, further, B.1.1.529 IgG levels were significantly lower at both T2 and T3. Compared with healthy individuals, patients with CLD presented with lower B.1.1.529 IgGs at T2 with no additional key differences. No major clinical or immune IgG parameters associated with SARS-CoV-2 infection rates or vaccine efficacy.

Conclusions: Patients with CLD and cirrhosis exhibit lower immune responses to COVID-19 vaccination, irrespective of disease aetiology. The type of vaccine leads to different antibody responses that appear not to associate with distinct efficacy, although this needs validation in larger cohorts with a more balanced representation of all vaccines.

Impact and implications: In patients with CLD vaccinated with two-dose vaccines, age, cirrhosis, and type of vaccine (Vaxzevria > Pfizer BioNTech > Moderna) predict a 'lower' humoral response, whereas viral hepatitis aetiology and prior antiviral therapy predict a 'higher' humoral response. This differential response appears not to associate with SARS-CoV-2 infection incidence or vaccine efficacy. However, compared with Wuhan-Hu-1, humoral immunity was lower for the Delta and Omicron variants, and all decreased after 6 months. As such, patients with CLD, particularly those older and with cirrhosis, should be prioritised for receiving booster doses and/or recently approved adapted vaccines.

Keywords: COVID-19 vaccine; Chronic liver disease; Cirrhosis; Humoral immunity; SARS-CoV-2.

Graphical abstract

Fig. 1

Wuhan-Hu-1 antibody titres after SARS-CoV-2 vaccination in patients with CLD. (A) Violin plots representing IgG, IgM, and neutralisation levels before (T0) and 2 weeks after (T2) the second vaccine dose (n = 212). (B) Correlation between IgM and neutralisation levels with IgG levels at T2. (C) IgG, IgM, and neutralisation levels before (T0) and 2 weeks after the first (T1) and second (T2) vaccine doses (n = 44). Black horizontal lines indicate the median, and grey dotted lines indicate the IQR. Pairwise comparisons were calculated using the Wilcoxon test for comparisons between two groups or the Friedman test followed by Dunn's post hoc test for multiple comparisons. Association between two variables was assessed by Spearman’s correlation coefficient with Gaussian approximation. ∗p <0.05; ∗∗p <0.01; ∗∗∗p <0.001; ∗∗∗∗p <0.0001. CLD, chronic liver disease; NAb, neutralising antibodies.

Fig. 2

Wuhan-Hu-1 IgG levels 2 weeks after the second SARS-CoV-2 vaccine dose (T2) in patients with CLD according to demographic and clinical characteristics, and type of vaccine. Violin plots representing IgG levels. Black horizontal lines indicate the median, and grey dotted lines indicate the IQR. For comparisons between two groups, parametric or non-parametric data was analysed using Student’s t test or the Mann–Whitney test, respectively. For multiple comparisons, parametric or non-parametric data were compared using ANOVA or the Kruskal–Wallis test, respectively, followed by Bonferroni’s or Dunn’s post hoc test. ∗p <0.05; ∗∗p <0.01; ∗∗∗p <0.001; ∗∗∗∗p <0.0001. CLD, chronic liver disease; MRFLD, metabolic-related fatty liver disease.

Fig. 3

Wuhan-Hu-1 IgG, IgM, and neutralisation levels, and B.1.617 (Delta) and B.1.1.529 (Omicron) IgG titres in vaccinated patients with CLD and healthy volunteers at T2 and T3. (A) Violin plots representing IgG levels at T2. Patients with IgG antibody titres above or below 418.95 nM (median; red horizontal line) were defined as a high or low responders, respectively(B) Violin plots representing IgM and neutralisation levels in high and low responders. (C) Violin plots representing Wuhan-Hu-1, B.1.617, and B.1.1.529 IgG titres in patients with CLD at T2 and T3 (left), and B.1.617 and B.1.1.529 IgG levels in high and low responders (right). (D) Wuhan-Hu-1, B.1.617, and B.1.1.529 IgG titres in healthy controls and patients with CLD at T2 and T3. Black horizontal lines indicate the median, and grey dotted lines indicate the IQR. Pairwise comparisons between different variants or different time points were calculated using the Wilcoxon test for comparisons between two groups or Friedman test followed by Dunn's post hoc test for multiple comparisons. For comparisons between two independent groups, parametric or non-parametric data were analysed using Student’s t test or the Mann–Whitney test, respectively. ∗∗∗p <0.001; ∗∗∗∗p <0.0001. CLD, chronic liver disease; NAb, neutralising antibodies.

Fig. 4

T3 Wuhan-Hu-1 IgG levels 6 months after the start of vaccination (T3) in patients with CLD according to demographic and clinical characteristics, and type of vaccine. Violin plots representing IgG levels. Black horizontal lines indicate the median, and grey dotted lines indicate the IQR. For comparisons between two groups, parametric or non-parametric data were analysed using Student’s t test or the Mann–Whitney test, respectively. For multiple comparisons, parametric or non-parametric data were compared using ANOVA or the Kruskal–Wallis test, respectively, followed by Bonferroni’s or Dunn's post hoc test. ∗p <0.05; ∗∗p <0.01; ∗∗∗p <0.001. CLD, chronic liver disease; MRFLD, metabolic related fatty liver disease.