Recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematological diseases are at risk of severe disease and death from COVID-19. To determine the safety and immunogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines, samples from 50 infection-naive allo-HSCT recipients (median, 92 months from transplantation, range, 7-340 months) and 39 healthy controls were analyzed for serum immunoglobulin G (IgG) against the receptor binding domain (RBD) within spike 1 (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; anti–RBD-S1 IgG) and for SARS-CoV-2–specific T-cell immunity, reflected by induction of T-cell–derived interferon-γ in whole blood stimulated ex vivo with 15-mer SI-spanning peptides with 11 amino acid overlap S1-spanning peptides. The rate of seroconversion was not significantly lower in allo-transplanted patients than in controls with 24% (12/50) and 6% (3/50) of patients remaining seronegative after the first and second vaccination, respectively. However, 58% of transplanted patients lacked T-cell responses against S1 peptides after 1 vaccination compared with 19% of controls (odds ratio [OR] 0.17; P = .009, Fisher’s exact test) with a similar trend after the second vaccination where 28% of patients were devoid of detectable specific T-cell immunity, compared with 6% of controls (OR 0.18; P = .02, Fisher’s exact test). Importantly, lack of T-cell reactivity to S1 peptides after vaccination heralded substandard levels (<100 BAU/mL) of anti–RBD-S1 IgG 5 to 6 months after the second vaccine dose (OR 8.2; P = .007, Fisher’s exact test). We conclude that although allo-HSCT recipients achieve serum anti–RBD-S1 IgG against SARS-CoV-2 after 2 vaccinations, a deficiency of SARS-CoV-2–specific T-cell immunity may subsequently translate into insufficient humoral responses.

Cirrhosis entails elevated risk of COVID-19-associated mortality. This study determined T cell-mediated and antibody reactivity against the spike 1 (S1) protein of SARS-CoV-2 among 48 patients with cirrhosis and 39 healthy controls after mRNA COVID-19 vaccination. SARS-CoV-2-specific T-cell reactivity was measured by induced level of T cell-derived interferon-γ (IFN-γ) in blood cells stimulated ex vivo with multimeric peptides spanning the N-terminal portion of S1. S1-induced IFN-γ was quantified before and after the 1^st and 2^nd vaccination (BNT162b2, Pfizer-BioNTech or mRNA-1273, Moderna) alongside serum IgG against the receptor-binding domain (RBD) within S1 (anti-RBD-S1 IgG). T-cell reactivity against S1 was reduced in patients with cirrhosis after the 1^st (p <0.001 vs. controls) and 2^nd (p <0.001) vaccination. Sixty-eight percent of patients lacked detectable S1-specific T-cell reactivity after the 1^st vaccination vs. 19% in controls (odds ratio 0.11, 95% CI 0.03-0.48, p = 0.003) and 36% remained devoid of reactivity after the 2^nd vaccination vs. 6% in controls (odds ratio 0.12, 95% CI 0.03-0.59, p = 0.009). T-cell reactivity in cirrhosis remained significantly impaired after correction for potential confounders in multivariable analysis. Advanced cirrhosis (Child-Pugh class B) was associated with absent or lower T-cell responses (p <0.05 vs. Child-Pugh class A). The deficiency of T-cell reactivity was paralleled by lower levels of anti-RBD-S1 IgG after the 1^st (p <0.001 vs. controls) and 2^nd (p <0.05) vaccination. Patients with cirrhosis show deficient T-cell reactivity against SARS-CoV-2 antigens along with diminished levels of anti-RBD-S1 IgG after dual COVID-19 vaccination, highlighting the need for vigilance and additional preventative measures. EudraCT 2021-000349-42 T cells are a pivotal component in the defence against viruses. We show that patients with cirrhosis have impaired SARS-CoV-2-specific T-cell responses and lower antibody levels after mRNA vaccination against COVID-19 compared with healthy controls. Patients with more advanced liver disease exhibited particularly inferior vaccine responses. These results call for additional preventative measures in these patients.

Metabolic pressure shifts signaling pathways of nuclear receptors, including the bile acid receptor FXR, which are sensitive to nutritional inputs. We performed an FXR ChIP-seq–centered multiomic analysis of liver biopsy samples from individuals with or without obesity, who were treated with either placebo or the FXR agonist obeticholic acid, to define metabolic adaptions of FXR signaling pathways. FXR occupied substantially more DNA binding sites in individuals with obesity, and FXR activation by OCA robustly changed the transcriptional output. Integration of ChIP-seq and RNA-seq data showed that mitochondrial function and substrate oxidation were the top metabolic pathways selectively modulated by FXR activation in individuals with obesity. FXR activation restored compromised substrate oxidation by enhancing β-oxidation and oxidative phosphorylation along with antagonizing ROS production. In line with this, the amount of reduced glutathione in patients with obesity normalized after OCA treatment. In summary, FXR signaling profoundly differs in patients with obesity, consisting of changes in DNA binding profiles and transcriptional programs, which enhance energy substrate utilization in this patient cohort.

This review addresses the vital role of vaccinations in managing patients with chronic liver disease (CLD), especially in the context of the post-COVID-19 landscape. The pandemic has highlighted the unique vulnerabilities of CLD patients, including those awaiting liver transplantation and post-transplant individuals, who face heightened risks of infection due to compromised immune responses. Recent advancements in vaccine technology, such as mRNA platforms, novel adjuvants, and advanced delivery systems, have significantly accelerated vaccine development, enhancing both speed and efficacy. Moreover, the emergence of personalized vaccines, tailored to everyone’s unique immunological profile, presents new opportunities, particularly for those with chronic conditions. This review synthesizes the current state of evidence regarding vaccine recommendations for CLD patients, focusing on their response to vaccinations and proposing effective strategies to protect this vulnerable group from vaccine-preventable diseases. It also explores the challenges in implementing these strategies and considers the impact of emerging vaccine delivery systems on improving outcomes for CLD patients. The paper aims to provide nuanced guidance on vaccination in the rapidly evolving healthcare landscape, addressing both technological innovations and comprehensive patient care strategies.

Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis, which is mostly characterized by psychomotor slowing. However, psychotic symptoms such as visual and olfactory hallucinations may sometimes also be present. In contrast, auditory hallucinations are uncommon in chronic liver disease. In this case report, we present a patient with liver cirrhosis due to excessive alcohol consumption who presented to the emergency department with disorientation and signs of infection. Initial assessment led to the diagnosis acute on chronic liver failure exacerbated by infection leading to encephalopathy. The patient was admitted and successfully treated with antibiotics, Lactulose and Rifaximin. Gastroscopy showed varices without bleeding stigmata and Propranolol 20 mg was initiated as primary prophylaxis. Upon follow-up, the patient was clinically stable but had developed visual and auditory hallucinations which raised the suspicion that HE was not the cause. CT scan of the brain was unremarkable and the hallucinations were considered to be caused by Propranolol and disappeared shortly after switching to Carvedilol.