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EASL position paper on the use of COVID-19 vaccines in patients with chronic liver diseases, hepatobiliary cancer and liver transplant recipients
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Published:February 06, 2021
Markus Cornberg1,2,3,*, Maria Buti4, Christiane S. Eberhardt5, Paolo Antonio Grossi6,7, Daniel Shouval8
According to a recent World Health Organization estimate, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, which originated in China in 2019, has spread globally, infecting nearly 100 million people worldwide by January 2021. Patients with chronic liver diseases (CLD), particularly cirrhosis, hepatobiliary malignancies, candidates for liver transplantation, and immunosuppressed individuals after liver transplantation appear to be at increased risk of infections in general, which in turn translates into increased mortality. This is also the case for SARS-CoV-2 infection, where patients with cirrhosis, in particular, are at high risk of a severe COVID-19 course. Therefore, vaccination against various pathogens including SARS-CoV-2, administered as early as possible in patients with CLD, is an important protective measure. However, due to impaired immune responses in these patients, the immediate and long-term protective response through immunisation may be incomplete. The current SARS-CoV-2 pandemic has led to the exceptionally fast development of several vaccine candidates. A small number of these SARS-CoV-2 vaccine candidates have already undergone phase III, placebo-controlled, clinical trials in healthy individuals with proof of short-term safety, immunogenicity and efficacy. However, although regulatory agencies in the US and Europe have already approved some of these vaccines for clinical use, information on immunogenicity, duration of protection and long-term safety in patients with CLD, cirrhosis, hepatobiliary cancer and liver transplant recipients has yet to be generated. This review summarises the data on vaccine safety, immunogenicity, and efficacy in this patient population in general and discusses the implications of this knowledge on the introduction of the new SARS-CoV-2 vaccines.
Evolving recommendations for the emerging COVID-19 vaccines for patients with chronic liver diseases including hepatobiliary cancer
Cumulative experience supports the perception that prevention of inflammation and infection in patients with CLD is essential for improving survival.1,46,47, 48 Indeed, such patients are at high risk of hepatic decompensation and increased mortality and, in the case of SARS-CoV-2 infection, of the extrahepatic sequalae of severe COVID-19.49,50
Of note, in the international registries SECURE-cirrhosis and COVID-Hep.net, hospitalised COVID-19 patients with cirrhosis had an overall case fatality rate of 38%, which was as high as 70% in Child-Pugh C patients, compared to 8% in non-cirrhotic patients, while mortality was similar in all age groups.50
Patients with hepatobiliary cancer need special consideration because, on the one hand, these patients usually have concomitant CLD or cirrhosis and, on the other hand, curative treatment options may be delayed in the case of COVID-19. Therefore, cancer patients should also be prioritised for vaccination against SARS-CoV-2, considering the phase of the malignant disease and therapy, age and comorbidity (see ESMO guidelines:10)
It is also notable that in this context, influenza and pneumococcal vaccines are recommended in patients with advanced liver disease despite concerns regarding somewhat reduced immunogenicity in this population (Table 1). Furthermore, influenza vaccination is considered safe and may prevent liver decompensation51and has been reported to reduce the risk of hospitalisation in patients with liver disease.20
In summary, there is currently no specific evidence to contradict the safety and generation of protective immunity by vaccines against COVID-19 in patients with CLD. Given the high risk of serious health consequences of SARS-CoV-2 infection in patients with cirrhosis and hepatobiliary cancer, the potential benefits of the vaccine, both to patients and to healthcare systems, are likely to outweigh the risks associated with vaccination. Thus, it is the opinion of the authors of the present communication that patients with CLD should be immunised against SARS-CoV-2 and patients with advanced cirrhosis, liver decompensation, and hepatobiliary cancer should be prioritised for COVID-19 vaccination. Finally, since the effectiveness of vaccination may be lower in these patients, immunisation against SARS-CoV-2 should be recommended to household members and healthcare professionals caring for these patients to reduce exposure to SARS-CoV-2. Meanwhile, current protective measures including use of masks, appropriate hand washing, and social distancing remain of great importance since it is not yet known whether vaccination confers sterilising immunity and prevents transmission from asymptomatic individuals.
Efficacy and safety of vaccines in patients with chronic liver diseases including patients with hepatobiliary cancer
Patients with chronic liver diseases (CLD) have per se an increased vulnerability to infections.1
However, the individual risk depends on the aetiology of CLD, comorbidity, co-medication and stage of liver disease.
Furthermore, as CLD and age progress, immune responses to and immune memory against certain vaccine-delivered antigens decline.2
Moreover, patients with alcohol-associated liver disease, CLD and cirrhosis (irrespective of aetiology) may have an impaired immune response to vaccination (Table 1), e.g. characterised by non or hypo-response to hepatitis B vaccination.3,4
Co-medication may also be a reason for an impaired or altered immune response to vaccination, e.g. in patients with autoimmune hepatitis taking immunosuppressive agents, leading to reduced seroconversion rates to hepatitis B vaccination and lower anti-HBs titres.5
An important factor affecting response to vaccination is the comorbidity of patients with CLD, i.e. metabolic diseases such as diabetes mellitus, steatohepatitis and obesity or chronic kidney disease (haemodialysis) as well as coeliac disease, which have been linked to declining vaccine response rates i.e. for standard hepatitis B vaccination.3,4
In this particular case, new vaccine formulations through inclusion of Pre-S1/Pre-S2 epitopes or more stimulating adjuvants are now available to improve or bypass hypo-responsiveness to conventional HBV vaccines.6, 7, 8
One of the most important factors for the success of vaccination is the stage of CLD at the time of immunisation. On the one hand, patients with cirrhosis are more susceptible to infections and their sequelae,1 and on the other hand the response to vaccination may be compromised, explained by cirrhosis-associated immune dysfunction (reviewed in9).
Despite the high number of study participants, only few patients with mild to moderate liver disease were included in the trials and patients with immunosuppressive conditions were excluded (reviewed in18). However, in real life, a substantial number of individuals have already been vaccinated worldwide, including patients with liver disease; thus, data on safety and effectiveness are expected to be available soon.
A frequently asked question which still awaits an answer is whether individuals should be vaccinated against SARS-CoV-2 after they have resolved the natural infection. The level of protection someone acquires from infection (so called "natural immunity") varies depending on the underlying disease and differs from person to person. To date, there is still no information about the duration of post-infection “natural” immunity, and, more importantly, despite the availability of new serologic assays, there is no established correlate of protection. This means that there are currently no standardised and validated data on SARS-CoV-2-specific immunity and the definition of serologic protection. Therefore, positive serology, even if detected 6 months or more after infection,45 does not yet confirm whether convalescent patients have acquired long-term protection. Hence, serological testing prior to COVID-19 vaccination is not recommended at present although it remains optional. Meanwhile, patients with a known history of SARS-CoV-2 infection are not suggested to be prioritised. Other issues to be determined in future studies include the duration of vaccine-induced protection, the requirement for booster vaccination(s) and the level of protection against emerging SARS-CoV-2 variants. Further research is also needed on the development of a diagnostic serological assay to differentiate between a past or vaccine-induced immunity and acute infection.

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