October 25, 2023 People with cirrhosis and who receive a liver transplant are more susceptible to COVID-19 breakthrough infection Study finds people with chronic liver disease and post-liver transplantation are at higher risk of getting infected with SARS-CoV-2 after COVID-19 primary series vaccination and identifies predictive factors associated with breakthrough infection.

BARCELONA—Inadequate supply and lower acceptance rate of COVID-19 vaccines among the adult population remains a matter of concern, particularly in high-risk groups such as patients with chronic liver disease and liver transplant recipients. In people receiving a liver transplant, reduced antibody response to COVID-19 vaccination is known to be associated with the use of immunosupressants and older age. The variable response to COVID-19 vaccines in people with cirrhosis has largely prevented the identification of factors associated with risk and severity of breakthrough infection in this group. The COBALT study – COVID-19 vaccination and biomarkers in cirrhosis and post-liver transplantation – coordinated and sponsored by the European Foundation for the Study of Chronic Liver Failure (EF CLIF) with the support of the Foundation for Liver Research, the European Liver and Intestine Transplant Association (ELITA), the European Liver Patients' Association (ELPA), and the European Association for the Study of the Liver (EASL) aimed to determine the degree of protection conferred by COVID-19 vaccines in people with chronic liver disease and post-liver transplantation. The study published in Hepatology Communications provides evidence of the heterogenous response of COVID-19 vaccine primary series and identifies factors predicting poor vaccine response and risk of breakthrough infection in people with cirrhosis, patients with autoimmune liver disease without cirrhosis, and who have undergone liver transplantation compared to healthy individuals with no previous COVID-19 infection episode and no infection with human immunodeficiency virus.

The COBALT study analyzed clinical data and biological samples in 642 participants from 25 centers across UK, Italy and Spain.

“We started to design the study very shortly after the first vaccines were introduced in December 2020. It was clear that many liver patients were shielding, and it was unclear if they would receive the same protection from vaccination as healthy individuals”, said co-first author Gautam Mehta, Co-Principal Investigator of the COBALT study at University College London, UK.

People with previous complications of cirrhosis who received a liver transplant for more than 6 months showed a weaker antibody response to COVID-19 vaccination compared to people with cirrhosis, autoimmune liver disease or healthy individuals. In the post-liver transplant group, coronary artery disease, immunosuppressant treatment, upregulation of B cell activating factor – a cytokine that regulates B cell survival, maturation and differentiation –, and lower levels of lymphotoxin-alpha – a proinflammatory cytokine – were associated with reduced COVID-19 vaccine response. In people with cirrhosis, older age, decompensation of cirrhosis and severity of systemic inflammation were associated with poor antibody response to COVID-19 vaccines. Patients with autoimmune liver disease without cirrhosis were able to mount a more robust antibody response when given two-dose mRNA vaccines compared to one- or two-dose adenovirus vector vaccine administration. However, mRNA vaccines failed to elicit higher antibody responses in the cirrhosis or liver transplant groups.

"Importantly, this study identified systemic inflammation as a key factor impacting vaccine response in cirrhosis. Although COVID-19 rates are not as high as they were, the fundamental observations in this study have implications for other vaccines in cirrhosis. It may be that treating inflammation, by targeting the gut or using albumin for example, may enhance vaccine response for other infections in cirrhosis", added Mehta.

"One of the limitations of these results was that although we have accounted for many demographic and biological variables in multivariable analyses of vaccine response and infection risk, but we were unable to account for other major factors influencing breakthrough infection such as local prevalence of infection, viral load exposure and shielding behavior. This limitation and the relatively small number of infections means that these data should be interpreted cautiously", said co-first author Eva Uson, Statistician at EF CLIF, Spain.

Symptomatic breakthrough infection was not significantly different among disease groups or compared to healthy subjects. Factors associated with risk of breakthrough infection included lower serum albumin concentration in the cirrhosis group, older age and lower high-density lipoprotein in the autoimmune liver disease group, and CD40 ligand – an early activation marker of T cells – in the post-liver transplantation group. In contrast, fully vaccinated healthy individuals who received adenovirus vector vaccines were more likely to experience breakthrough infection.

“This study is a true collaborative effort involving many liver disease focussed investigators and organizations that came together at the height of the pandemic to address a fundamentally important question. In addition to providing critical data in terms of COVID vaccine responses, the study highlighted the unmet need of cirrhosis patients for attention to non-COVID vaccinations. Finally, the data generated in the COBALT study will provide critical insights into mechanisms underlying immune dysfunction in cirrhosis patients", explained co-senior author Rajiv Jalan, Co-Principal Investigator of the COBALT study at University College London, UK, and at EF CLIF, Spain.

"We still don’t know the medium-term durability of vaccine response to COVID-19, and this is something we are currently looking at. These data will inform booster health policy as we move into the winter season", concluded Mehta.

This study was sponsored by the European Foundation for the Study of Chronic Failure (EF CLIF), Spain, and the Foundation for Liver Research, UK.

Other authors on the study are Antonio Riva, Maria Pilar Ballester, Montserrat Pujadas, Ângela Carvalho-Gomes, Ivan Sahuco, Ariadna Bono, Federico D'Amico, Raffaela Viganò, Elena Diago, Beatriz Tormo Lanseros, Elvira Inglese, Dani Martinez Vazquez, Rajni Sharma, Hio Lam Phoebe Tsou, Nicola Harris, Annelotte Broekhoven, Marjolein Kikkert, Shessy P. Torres Morales, Sebenzile K. Myeni, Mar Riveiro-Barciela, Adriana Palom, Nicola Zeni, Alessandra Brocca, Annarosa Cussigh, Sara Cmet, Desamparados Escudero-García, Matteo Stocco, Leonardo Antonio Natola, Donatella Ieluzzi, Veronica Paon, Angelo Sangiovanni, Elisa Farina, Clara di Benedetto, Yolanda Sánchez-Torrijos, Ana Lucena-Varela, Eva Román, Elisabet Sánchez, Rubén Sánchez-Aldehuelo, Julia López-Cardona, Itzel Canas-Perez, Christine Eastgate, Dhaarica Jeyanesan, Alejandro Esquivel Morocho, Simone Di Cola, Lucia Lapenna, Giacomo Zaccherini, Deborah Bongiovanni, Paola Zanaga, Katia Sayaf, Sabir Hossain, Javier Crespo, Mercedes Robles-Díaz, Antonio Madejón, Helena Degroote, Javier Fernández, Marko Korenjak, Xavier Verhelst, Javier García-Samaniego, Raúl J. Andrade, Paula Iruzubieta, Gavin Wright, Paolo Caraceni, Manuela Merli, Vishal C Patel, Amir Gander, Agustín Albillos, Germán Soriano, Maria Francesca Donato, David Sacerdoti, Pierluigi Toniutto, Maria Buti, Christophe Duvoux, Paolo Antonio Grossi, Thomas Berg, Wojciech G. Polak, Massimo Puoti46, Anna Bosch-Comas6, Luca Belli, Patrizia Burra, Francesco Paolo Russo31,32, Minneke Coenraad16, José Luis Calleja, Giovanni Perricone, Marina Berenguer, Joan Claria, Richard Moreau, Vicente Arroyo, Paolo Angeli, Cristina Sánchez, Javier Ampuero, Salvatore Piano, and Shilpa Chokshi.

Publication information

Mehta G, Riva A, Ballester MP, Uson E, Pujadas M, Carvalho-Gomes Â, Sahuco I, Bono A, D’Amico F, Viganò R, Diago E, Lanseros BT, Inglese E, Vazquez DM, Sharma R, Tsou HLP, Harris N, Broekhoven A, Kikkert M, Morales SPT, Myeni SK, Riveiro-Barciela M, Palom A, Zeni N, Brocca A, Cussigh A, Cmet S, Escudero-García D, Stocco M, Natola LA, Ieluzzi D, Paon V, Sangiovanni A, Farina E, di Benedetto C, Sánchez-Torrijos Y, Lucena-Varela A, Román E, Sánchez E, Sánchez-Aldehuelo R, López-Cardona J, Canas-Perez I, Eastgate C, Jeyanesan D, Morocho AE, Di Cola S, Lapenna L, Zaccherini G, Bongiovanni D, Zanaga P, Sayaf K, Hossain S, Crespo J, Robles-Díaz M, Madejón A, Degroote H, Fernández J, Korenjak M, Verhelst X, García-Samaniego J, Andrade RJ, Iruzubieta P, Wright G, Caraceni P, Merli M, Patel VC, Gander A, Albillos A, Soriano G, Donato MF, Sacerdoti D, Toniutto P, Buti M, Duvoux C, Grossi PA, Berg T, Polak WG, Puoti M, Bosch-Comas A, Belli L, Burra P, Russo FP, Coenraad M, Calleja JL, Perricone G, Berenguer M, Clària J, Moreau R, Arroyo V, Angeli P, Sánchez C, Ampuero J, Piano S, Chokshi S, Jalan R. Serological response and breakthrough infection after COVID-19 vaccination in cirrhosis and liver transplantation. Hepatol Commun 2023, 7(11):e0273. DOI: 10.1097/HC9.0000000000000273

About COBALT

The aim of the COBALT study is to determine the protective effect of COVID-19 vaccination in liver disease. Patients with cirrhosis have been shown to have markedly worse outcomes from COVID-19. Moreover, there is very little data on the effectiveness of SARS-CoV-2 vaccines in cirrhosis or liver transplant patients since they were not included in initial clinical trials. We will compare responses after dose 2 and dose 3 of the vaccine with healthy controls, to look at the level of antibody response. We will also investigate the durability of response and degree of protection against breakthrough SARS-CoV-2 infection.

About EF CLIF

The European Foundation for the Study of Chronic Liver Failure (EF CLIF) is a private non-profit organization connecting biomedical researchers and healthcare professionals with each other, with patients and patient associations, and with society. The fundamental purpose of EF CLIF, reflected in its founding Statements of 2015, is to advance knowledge and promote research and education in liver disease to improve the prognosis of patients living with chronic liver failure.

The Foundation has made pioneering efforts in conducting a series of large, international prospective studies that have been instrumental in reclassifying the trajectory of patients with chronic liver failure and led to the clinical, prognostic and pathophysiological definition of the syndrome referred to as “acute-on-chronic liver failure” characterized by acute decompensation of cirrhosis, severe systemic inflammation, organ failures, and high short-term mortality. We are inspiring best clinical practices for the management of patients with chronic liver failure and promoting a more sustainable and equitable healthcare system.

Within the EF CLIF, the European Association for the Study of the Liver (EASL) Chair supports research activities through the EASL-CLIF Consortium, a network of 120 tertiary care and university hospitals in 28 European countries. The Grifols Chair promotes translational studies in centers across Europe and North America within the framework of the European Network for Translational Research (ENTR) with 21 centers in 7 countries. Over the last five years, EF CLIF has successfully expanded its geographical scope providing the context to support transcontinental collaborative research projects. The Global Projects chapter, which includes 96 centers in 22 countries, provides the framework to promote research in cirrhosis across the world with the aim to help to build consensus and ensure health equity worldwide.