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

André Lopes Simão; Carolina Santos Palma; Laura Izquierdo-Sanchez; Antonella Putignano; Angela Carvalho-Gomes; Andreas Posch; Paola Zanaga; Irina Girleanu; Mariana Moura Henrique; Carlos Araújo; Delphine Degre; Thierry Gustot; Iván Sahuco; Elia Spagnolo; Sofia Carvalhana; Miguel Moura; Diogo Ae Fernandes; Jesus M Banales; Manuel Romero-Gomez; Anca Trifan; Francesco Paolo Russo; Rudolf Stauber; Marina Berenguer; Christophe Moreno; João Gonçalves; Helena Cortez-Pinto; Rui E Castro

doi:10.1016/j.jhepr.2023.100697

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

JHEP Rep. 2023 May;5(5):100697. doi: 10.1016/j.jhepr.2023.100697. Epub 2023 Feb 20.

Authors

André Lopes Simão¹, Carolina Santos Palma¹, Laura Izquierdo-Sanchez^{1

2}, Antonella Putignano³, Angela Carvalho-Gomes^{4

5}, Andreas Posch⁶, Paola Zanaga^{7

8}, Irina Girleanu⁹, Mariana Moura Henrique¹, Carlos Araújo¹, Delphine Degre¹⁰, Thierry Gustot¹⁰, Iván Sahuco⁴, Elia Spagnolo^{7

8}, Sofia Carvalhana¹¹, Miguel Moura¹¹, Diogo Ae Fernandes¹, Jesus M Banales^{2

5

12

13}, Manuel Romero-Gomez¹⁴, Anca Trifan⁹, Francesco Paolo Russo^{7

8}, Rudolf Stauber⁶, Marina Berenguer^{4

5}, Christophe Moreno³, João Gonçalves¹, Helena Cortez-Pinto^{11

15}, Rui E Castro¹

Affiliations

¹ Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
² Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
³ Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, C.U.B. Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
⁴ Hepatology & Liver Transplantation Unit, La Fe University Hospital, University of Valencia, CIBER-EHD and IIS La Fe, Valencia, Spain.
⁵ National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, "Instituto de Salud Carlos III" (ISCIII), Madrid, Spain.
⁶ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
⁷ Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale-Università di Padova, Padua, Italy.
⁸ Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy.
⁹ 'Grigore T. Popa' University of Medicine and Pharmacy, 'St. Spiridon' Emergency Hospital, Institute of Gastroenterology and Hepatology, Iasi, Romania.
¹⁰ Institute for Medical Immunology, Erasme Campus, Brussels, Belgium.
¹¹ Departamento de Gastrenterologia, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.
¹² Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.
¹³ Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
¹⁴ Digestive Diseases Department, Virgen del Rocío University Hospital, Institute of Biomedicine of Seville (IBIS: HUVRocío/CSIC/US), University of Seville, Seville, Spain.
¹⁵ Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

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.