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 Usón, 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.