Our understanding of the hepatic consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its resultant coronavirus disease 2019 (COVID-19) has evolved rapidly since the onset of the pandemic. In this Review, we discuss the hepatotropism of SARS-CoV-2, including the differential expression of viral receptors on liver cell types, and we describe the liver histology features present in patients with COVID-19. We also provide an overview of the pattern and relevance of abnormal liver biochemistry during COVID-19 and present the possible underlying direct and indirect mechanisms for liver injury. Furthermore, large international cohorts have been able to characterize the disease course of COVID-19 in patients with pre-existing chronic liver disease. Patients with cirrhosis have particularly high rates of hepatic decompensation and death following SARS-CoV-2 infection and we outline hypotheses to explain these findings, including the possible role of cirrhosis-associated immune dysfunction. This finding contrasts with outcome data in pharmacologically immunosuppressed patients after liver transplantation who seem to have comparatively better outcomes from COVID-19 than those with advanced liver disease. Finally, we discuss the approach to SARS-CoV-2 vaccination in patients with cirrhosis and after liver transplantation and predict how changes in social behaviours and clinical care pathways during the pandemic might lead to increased liver disease incidence and severity.

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The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants.

Involvement of patients with liver disease in phase 3 SARS-CoV-2 vaccine trials and key outstanding questions Chronic liver disease and cirrhosisTrial inclusion and exclusion criteria • Pfizer/BioNTech: "liver disease" included but not defined • Moderna: "liver disease" included but not defined • Oxford/AstraZeneca: "liver disease" excluded (except Gilbert syndrome), "alcohol and drug dependency…injecting drug abuse in the 5 years preceding enrolment" excluded Key outstanding questions • Magnitude and duration of vaccine response • Disease severity in predicting vaccine response • Differential efficacies of single doses or additional booster doses • Risk of liver injury unknown Liver transplantation Trial inclusion and exclusion criteria • Pfizer/BioNTech: "Individuals who receive treatment with immunosuppressive therapy" excluded • Moderna: "Immunosuppressive or immunodeficient state" or "systemic immunosuppressants or immune-modifying drugs for >14 days" excluded • Oxford/AstraZeneca: "Any confirmed or suspected immunosuppressive or immunodeficient state" excluded Key outstanding questions • Magnitude and duration of vaccine response • Durability of response post-transplantation; optimal timing of prime and boost vaccination in relation to transplantation • Interactions with specific immunosuppression regimens • Differential efficacies of single doses or additional booster doses • Risk of liver injury unknown Immunosuppressed autoimmune liver disease (eg, autoimmune hepatitis) Trial inclusion and exclusion criteria • Pfizer/BioNTech: "Individuals with a history of autoimmune disease or an active autoimmune disease requiring therapeutic intervention" excluded • Moderna: "Immunosuppressive or immunodeficient state" or "systemic immunosuppressants or immune-modifying drugs for >14 days" excluded • Oxford/AstraZeneca: "Any autoimmune conditions" excluded Key outstanding questions • Magnitude and duration of vaccine response

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Many safe and effective severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccinations dramatically reduce risks of coronavirus disease 2019 (COVID‐19) complications and deaths. We aimed to describe cases of SARS‐CoV‐2 infection among patients with chronic liver disease (CLD) and liver transplant (LT) recipients with at least one prior COVID‐19 vaccine dose. The SECURE‐Liver and COVID‐Hep international reporting registries were used to identify laboratory‐confirmed COVID‐19 in CLD and LT patients who received a COVID‐19 vaccination. Of the 342 cases of lab‐confirmed SARS‐CoV‐2 infections in the era after vaccine licensing, 40 patients (21 with CLD and 19 with LT) had at least one prior COVID‐19 vaccination, including 12 who were fully vaccinated (≥2 weeks after second dose). Of the 21 patients with CLD (90% with cirrhosis), 7 (33%) were hospitalized, 1 (5%) was admitted to the intensive care unit (ICU), and 0 died. In the LT cohort (n = 19), there were 6 hospitalizations (32%), including 3 (16%) resulting in mechanical ventilation and 2 (11%) resulting in death. All three cases of severe COVID‐19 occurred in patients who had a single vaccine dose within the last 1‐2 weeks. In contemporary patients with CLD, rates of symptomatic infection, hospitalization, ICU admission, invasive ventilation, and death were numerically higher in unvaccinated individuals. Conclusion: This case series demonstrates the potential for COVID‐19 infections among patients with CLD and LT recipients who had received the COVID‐19 vaccination. Vaccination against SARS‐CoV‐2 appears to result in favorable outcomes as attested by the absence of mechanical ventilation, ICU, or death among fully vaccinated patients.

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