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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

  • Markus Cornberg
    Correspondence
    Corresponding author. Address: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.
    Affiliations
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany

    Centre for Individualised Infection Medicine (CiiM), a joint venture of Helmholtz Centre for Infection Research and Hannover Medical School, Hannover, Germany

    German Center for Infection Research (DZIF), Partner-Site Hannover-Braunschweig, Hannover, Germany
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  • Maria Buti
    Affiliations
    Liver Unit. Hospital Universitario Valle Hebron and Ciber-ehd del Instituto Carlos III, Barcelona, Spain
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  • Christiane S. Eberhardt
    Affiliations
    Center for Vaccinology, University Hospitals of Geneva and Faculty of Medicine, University of Geneva, Switzerland and Emory Vaccine Center, Emory University, Atlanta, GA, USA
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  • Paolo Antonio Grossi
    Affiliations
    Infectious and Tropical Diseases Unit, Department of Medicine and Surgery University of Insubria and ASST-Sette Laghi, Varese, Italy

    Italian National Center for Transplantation, Rome, Italy
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  • Daniel Shouval
    Affiliations
    Liver Unit, Department of Medicine, Hadassah-Hebrew University Hospital, Jerusalem, Israel
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Published:February 06, 2021DOI:https://doi.org/10.1016/j.jhep.2021.01.032

      Summary

      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.

      Keywords

      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.
      • Angeli P.
      • Bernardi M.
      • Villanueva C.
      • Francoz C.
      • Mookerjee R.P.
      • Trebicka J.
      • et al.
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      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.
      • McMahon B.J.
      • Wainwright K.
      • Bulkow L.
      • Parkinson A.J.
      • Lindenbaum M.
      • Wainwright R.
      • et al.
      Response to hepatitis B vaccine in Alaska Natives with chronic alcoholism compared with non-alcoholic control subjects.
      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.
      • Shouval D.
      Hepatitis B vaccines.
      ,
      • Mendenhall C.
      • Roselle G.A.
      • Lybecker L.A.
      • Marshall L.E.
      • Grossman C.J.
      • Myre S.A.
      • et al.
      Hepatitis B vaccination - response of alcoholic with and without liver injury.
      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.
      • Wörns M.A.
      • Teufel A.
      • Kanzler S.
      • Shrestha A.
      • Victor A.
      • Otto G.
      • et al.
      Incidence of HAV and HBV infections and vaccination rates in patients with autoimmune liver diseases.
      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.
      • Shouval D.
      Hepatitis B vaccines.
      ,
      • Mendenhall C.
      • Roselle G.A.
      • Lybecker L.A.
      • Marshall L.E.
      • Grossman C.J.
      • Myre S.A.
      • et al.
      Hepatitis B vaccination - response of alcoholic with and without liver injury.
      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.
      • Shouval D.
      • Roggendorf H.
      • Roggendorf M.
      Enhanced immune response to hepatitis B vaccination through immunization with a Pre-S1/Pre-S2/S Vaccine.
      • Vesikari T.
      • Langley J.
      • Segall N.
      • Ward B.
      • Cooper C.
      • Poliquin G.
      • et al.
      Higher proportion of responders with hepatitis B antibody levels ≥100 miu/ml with the trivalent HepB vaccine, Sci-B-Vac, compared to Engerix-B: results from the phase 3 double-blind, randomized study comparing immunogenicity and safety (PROTECT).
      • Leroux-Roels G.
      Old and new adjuvants for hepatitis B vaccines.
      Table 1Efficacy of vaccines in patients with chronic liver diseases (examples).
      VaccineResponse in patients with chronic liver diseasesRef.
      Seasonal influenza vaccinePatients with cirrhosis (n = 20) had a lower response rate (75–85% vs. 100%) than healthy controls (n = 8) to the adjuvanted trivalent influenza vaccine. No safety concerns.
      • Gaeta G.B.
      • Stornaiuolo G.
      • Precone D.F.
      • Amendola A.
      • Zanetti A.R.
      Immunogenicity and safety of an adjuvanted influenza vaccine in patients with decompensated cirrhosis.
      Meta-analysis of 12 studies: effective antibody response may reduce the risk of all-cause hospitalisation in patients with chronic liver diseases (most patients had chronic viral hepatitis).
      • Härmälä S.
      • Parisinos C.A.
      • Shallcross L.
      • O’Brien A.
      • Hayward A.
      Effectiveness of influenza vaccines in adults with chronic liver disease: a systematic review and meta-analysis.
      Streptococcus pneumonia vaccinePatients with cirrhosis (n = 45) had a significant increase of IgA and IgG antibodies against the 23-valent pneumococcal vaccine at 1 month compared to baseline, however, larger decline in IgA and IgM at 6 months compared to controls.
      • McCashland T.M.
      • Preheim L.C.
      • Gentry-Nielsen M.J.
      Pneumococcal vaccine response in cirrhosis and liver transplantation.
      Hepatitis A vaccineSerum anti-HAV concentrations were significantly lower in patients with decompensated cirrhosis (n = 35) than in patients with cirrhosis (n = 49). Patients with Child-Pugh A had adequate responses (71% after the first and 98% after the booster dose). Child-Pugh class was the only factor predicting response to vaccination.
      • Arguedas M.R.
      • Johnson A.
      • Eloubeidi M.A.
      • Fallon M.B.
      Immunogenicity of hepatitis A vaccination in decompensated cirrhotic patients.
      Hepatitis B vaccinePatients with chronic liver diseases (n = 166, 34% cirrhosis) had lower response rates. Nine (26%) of 34 cirrhotic patients who received Engerix-B and 10 (45%) of 22 cirrhotic patients who received HeplisavB achieved immunity.
      • Amjad W.
      • Alukal J.
      • Zhang T.
      • Maheshwari A.
      • Thuluvath P.J.
      Two-dose hepatitis B vaccine (heplisav-B) results in better seroconversion than three-dose vaccine (engerix-B) in chronic liver disease.
      Systematic review of 11 studies: Lower rate of seroconversion in patients with chronic hepatitis C compared to healthy controls, both in cirrhotic and non-cirrhotic patients.
      • Liu J.
      • Wu H.
      • Chen H.
      Immune response to hepatitis B vaccine in patients with chronic hepatitis C infection: a systematic review and meta-analysis.
      Patients with cirrhosis on the waiting list for liver transplantation (n = 49) had low antibody responses (28%) compared to 97% for healthy controls (n = 113).
      • Villeneuve E.
      • Vincelette J.
      • Villeneuve J.P.
      Ineffectiveness of hepatitis B vaccination in cirrhotic patients waiting for liver transplantation.
      Patients with cirrhosis on the waiting list (n = 62) had low antibody responses (44% after 1st vaccine schedule, 62% after 2nd schedule)
      • Domínguez M.
      • Bárcena R.
      • García M.
      • López-Sanroman A.
      • Nuño J.
      Vaccination against hepatitis B virus in cirrhotic patients on liver transplant waiting list.
      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,
      • Angeli P.
      • Bernardi M.
      • Villanueva C.
      • Francoz C.
      • Mookerjee R.P.
      • Trebicka J.
      • et al.
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      and on the other hand the response to vaccination may be compromised, explained by cirrhosis-associated immune dysfunction (reviewed in
      • Albillos A.
      • Lario M.
      • Álvarez-Mon M.
      Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance.
      ).
      While data on safety and immunogenicity of hepatitis A, hepatitis B, seasonal influenza and streptococcus pneumonia vaccines in CLD are available (Table 1), there is insufficient data on vaccine response in patients with hepatobiliary cancer. Considering that patients with hepatocellular carcinoma often have cirrhosis, response to vaccines is expected to be impaired. In addition, it is known from other cancer types that the response to the vaccine may be lower depending on age, comorbidities, the underlying cancer and the chemotherapy administered (reviewed in
      ESMO
      COVID-19 vaccination in cancer patients: ESMO statements.
      ). Importantly, influenza vaccines also appear to be safe in the setting of chemotherapy, and the benefit of vaccination outweighs the potential risk.
      • Bitterman R.
      • Eliakim-Raz N.
      • Vinograd I.
      • Zalmanovici Trestioreanu A.
      • Leibovici L.
      • Paul M.
      Influenza vaccines in immunosuppressed adults with cancer.
      An emerging question is whether vaccines can be administered in patients receiving immune checkpoint inhibitors (ICI) because of concerns that vaccination could increase the incidence of immune-related adverse events.
      • Läubli H.
      • Balmelli C.
      • Kaufmann L.
      • Stanczak M.
      • Syedbasha M.
      • Vogt D.
      • et al.
      Influenza vaccination of cancer patients during PD-1 blockade induces serological protection but may raise the risk for immune-related adverse events.
      However, recent studies investigating the safety of seasonal influenza vaccination in patients receiving ICI showed no safety concerns with comparable rates of immune-related adverse events to those seen in clinical trials.
      • Chong C.R.
      • Park V.J.
      • Cohen B.
      • Postow M.A.
      • Wolchok J.D.
      • Kamboj M.
      Safety of inactivated influenza vaccine in cancer patients receiving immune checkpoint inhibitors.
      ,
      • Failing J.J.
      • Ho T.P.
      • Yadav S.
      • Majithia N.
      • Riaz !I Bin
      • Shin J.Y.
      • et al.
      Safety of influenza vaccine in patients with cancer receiving pembrolizumab.
      In addition, therapeutic RNA cancer vaccines are being tested in early clinical trials in patients with various cancers, including patients treated with ICI, and no safety concerns have been raised to date.
      • Sahin U.
      • Oehm P.
      • Derhovanessian E.
      • Jabulowsky R.A.
      • Vormehr M.
      • Gold M.
      • et al.
      An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma.
      • Burris H.A.
      • Patel M.R.
      • Cho D.C.
      • Clarke J.M.
      • Gutierrez M.
      • Zaks T.Z.
      • et al.
      A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors.
      • Bauman J.
      • Burris H.
      • Clarke J.
      • Patel M.
      • Cho D.
      • Gutierrez M.
      • et al.
      Safety, tolerability, and immunogenicity of mRNA-4157 in combination with pembrolizumab in subjects with unresectable solid tumors (KEYNOTE-603): an update.
      As a final note, there is no confirmed information yet on the tolerability, immunogenicity and safety of novel COVID-19 vaccines in patients with CLD, including patients with hepatobiliary cancer.
      • Marjot T.
      • Webb G.J.
      • Barritt A.S.
      • Ginà P.
      • Lohse A.W.
      • Moon A.M.
      • et al.
      SARS-CoV-2 vaccination in patients with liver disease: responding to the next big question.

      Efficacy and safety of vaccines in solid organ transplant recipients

      Solid organ transplant (SOT) recipients are at an increased risk of infection because of the immunosuppression required to prevent graft rejection. In addition, infections can be more severe in transplant recipients than in immunocompetent individuals.
      • Stucchi R.S.B.
      • Lopes M.H.
      • Kumar D.
      • Manuel O.
      Vaccine recommendations for solid-organ transplant recipients and donors.
      Therefore, vaccination is an important measure to prevent infections and their sequelae. However, the immunogenicity of vaccines in SOT recipients is lower than in immunocompetent individuals because of their underlying chronic disease and the administration of immunosuppressive therapy after transplantation, which may reduce the immune response of these patients to immunisations (Table 2). The quality and dosing of immunosuppression is certainly an important factor influencing the response to vaccination. Therefore, the timing of vaccination is important and it is recommended that vaccination should be completed prior to transplantation, ideally very early in the course of CLD
      • Danziger-Isakov L.
      • Kumar D.
      Vaccination of solid organ transplant candidates and recipients: guidelines from the American society of transplantation infectious diseases community of practice.
      ,
      • Fagiuoli S.
      • Colli A.
      • Bruno R.
      • Craxì A.
      • Gaeta G.B.
      • Grossi P.
      • et al.
      Management of infections pre- and post-liver transplantation: report of an AISF consensus conference.
      and latest at the time of listing.
      Table 2Efficacy and safety of vaccines in transplant recipients (examples).
      VaccineType of study/populationResponse in transplant recipientsRef.
      Seasonal influenza vaccineSystematic review of 36 studies

      SOT patients
      High variability of the response. Overall a 10% to 16% lower response rate in SOT recipients vs. controls. Calcineurin-inhibitors and azathioprine were associated with a slightly better response compared to sirolimus and MMF.
      • Eckerle I.
      • Rosenberger K.D.
      • Zwahlen M.
      • Junghanss T.
      Serologic vaccination response after solid organ transplantation: a systematic review.
      Meta-analysis with 8 studies (SOT patients):Transplant recipients receiving MMF had a significantly lower response rate.
      • Karbasi-Afshar R.
      • Izadi M.
      • Fazel M.
      • Khedmat H.
      Response of transplant recipients to influenza vaccination based on type of immunosuppression: a meta-analysis.
      Systematic review of 7 studies (SOT patients)Heterogenous responses. Despite alternative influenza vaccination strategies, seroconversion and seroprotection rates for influenza antigens were lower in SOT patients.
      • Chong P.P.
      • Handler L.
      • Weber D.J.
      A systematic review of safety and immunogenicity of influenza vaccination strategies in solid organ transplant recipients.
      Systematic review of 9 studiesA booster dose of the influenza vaccine did not effectively enhance immunogenicity in renal transplant recipients.
      • Liao Z.
      • Xu X.
      • Liang Y.
      • Xiong Y.
      • Chen R.
      • Ni J.
      Effect of a booster dose of influenza vaccine in patients with hemodialysis, peritoneal dialysis and renal transplant recipients: a systematic literature review and meta-analysis.
      Systematic review and meta-analysis15 studies reported influenza-like illness with comparable rates between vaccinated transplant patients and immunocompetent controls.

      55 studies reported on the serologic response to influenza vaccination. A weaker response to influenza vaccination was observed compared with immunocompetent controls, although some studies showed a comparable or increased response for some influenza subtypes.

      25 studies described adverse events at rates comparable to healthy or placebo-vaccinated controls.

      30 studies investigated rejection reactions or allograft function in transplant recipients vaccinated against influenza; however, no consistent evidence of an association with these outcomes or serious adverse events was found.
      • Beck C.R.
      • McKenzie B.C.
      • Hashim A.B.
      • Harris R.C.
      • Nguyen-Van-Tam J.S.
      Influenza vaccination for immunocompromised patients: systematic review and meta-analysis by etiology.
      Mumps, measles, and rubella vaccineSystematic review of 4 studies (SOT patients):Heterogenous responses. Overall, the observed positive response rates were above 70% in all but 1 study.
      • Eckerle I.
      • Rosenberger K.D.
      • Zwahlen M.
      • Junghanss T.
      Serologic vaccination response after solid organ transplantation: a systematic review.
      Adjuvanted subunit varicella zoster vaccineSystematic review of 6 studies (immunocompromised adults aged 18-49 years):Significant humoral and cellular immune responses even in patients with the highest level of immunosuppression (sustained for at least 24 weeks); no safety concern, no evidence of graft rejection compared to placebo groups.
      • É Racine
      • Gilca V.
      • Amini R.
      • Tunis M.
      • Ismail S.
      • Sauvageau C.
      A systematic literature review of the recombinant subunit herpes zoster vaccine use in immunocompromised 18–49 year old patients.
      Hepatitis A vaccineSystematic review of 17 studies (immunosuppressed patientsHeterogenous responses; lowest immune response in transplanted patients using multiple immunosuppressive drugs, especially after only 1 dose of vaccine.
      • Garcia Garrido H.M.
      • Veurink A.M.
      • Leeflang M.
      • Spijker R.
      • Goorhuis A.
      • Grobusch M.P.
      Hepatitis A vaccine immunogenicity in patients using immunosuppressive drugs: a systematic review and meta-analysis.
      Hepatitis B vaccineSystematic review of 7 studies (SOT patients):Low response rates in adult SOT recipients (6.7% to 36%) but higher response rate in the paediatric trials (63.6% to 100%)
      • Eckerle I.
      • Rosenberger K.D.
      • Zwahlen M.
      • Junghanss T.
      Serologic vaccination response after solid organ transplantation: a systematic review.
      Streptococcus pneumonia vaccineSystematic review of 9 studies (SOT patients):Overall response ranged from 32% to 100% with comparable responses in the control group, if included.
      • Eckerle I.
      • Rosenberger K.D.
      • Zwahlen M.
      • Junghanss T.
      Serologic vaccination response after solid organ transplantation: a systematic review.
      Tetanus vaccineSystematic review of 6 studies (SOT patients):High rate of responders in SOT recipients with conventional immunosuppression with no significant difference to healthy controls. Lower response in patients with anti-CD20 treatment.
      • Eckerle I.
      • Rosenberger K.D.
      • Zwahlen M.
      • Junghanss T.
      Serologic vaccination response after solid organ transplantation: a systematic review.
      Diphteria vaccineSystematic review of 4 studies (SOT patients):Comparable response rates in SOT recipients and controls.
      • Eckerle I.
      • Rosenberger K.D.
      • Zwahlen M.
      • Junghanss T.
      Serologic vaccination response after solid organ transplantation: a systematic review.
      SOT, solid organ transplantation; MMF, mycophenolate mofetil.
      There is some uncertainty regarding administration of live attenuated vaccines to transplant recipients and consequently, live attenuated vaccines are usually avoided after transplantation. Yet, a meta-analysis documented relatively preserved safety and efficacy for some live attenuated vaccines in paediatric and adult SOT recipients.
      • Croce E.
      • Hatz C.
      • Jonker E.F.
      • Visser L.G.
      • Jaeger V.K.
      • Bühler S.
      Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatory diseases, solid organ transplantation or after bone-marrow transplantation – a systematic review of randomized trials, observational studies and case re.
      Nevertheless, immunisation with live attenuated vaccines following transplantation is usually performed only after a careful risk-benefit assessment and not at the peak of immune suppression. This dilemma can be partially avoided through pre-transplant testing of antibody titres against measles, mumps and varicella and appropriate vaccination before transplantation.
      After transplantation, vaccination is usually not recommended in the first 3–6 months during the period of intense immunosuppression, as immune responses are expected to be decreased.
      • Danziger-Isakov L.
      • Kumar D.
      Vaccination of solid organ transplant candidates and recipients: guidelines from the American society of transplantation infectious diseases community of practice.
      Since transplant recipients may not have adequate protection against vaccine-preventable diseases in the early post-transplant period due to impaired immune responses or incomplete vaccination status, it is advised that household contacts of organ transplant recipients and candidates, as well as healthcare workers at transplant centres, if lacking specific immunity, are vaccinated against transmittable diseases, such as influenza, measles, mumps, pertussis, chickenpox and hepatitis B.
      • Danziger-Isakov L.
      • Kumar D.
      Vaccination of solid organ transplant candidates and recipients: guidelines from the American society of transplantation infectious diseases community of practice.
      ,
      • Fagiuoli S.
      • Colli A.
      • Bruno R.
      • Craxì A.
      • Gaeta G.B.
      • Grossi P.
      • et al.
      Management of infections pre- and post-liver transplantation: report of an AISF consensus conference.
      The same precaution applies to available COVID-19 vaccines.
      Immune memory to various vaccine-preventable disease wanes over time in transplant recipients and additional vaccine doses should be considered depending on the serological follow-up. Another aspect of vaccine safety is the hypothesis that immune response to vaccination could stimulate immunologic rejection reactions. However, to the best of our knowledge, there is currently no solid evidence that the recommended standard vaccines lead to allograft rejection in SOT recipients.
      • Mulley W.R.
      • Dendle C.
      • Ling J.E.H.
      • Knight S.R.
      Does vaccination in solid-organ transplant recipients result in adverse immunologic sequelae? A systematic review and meta-analysis.
      While data are available for most of the recommended vaccines in SOT (Table 2), there is so far no confirmed information on the tolerability, reactogenicity, immunogenicity and overall safety of COVID-19 vaccines in SOT patients given the design of the phase III trials.
      • Marjot T.
      • Webb G.J.
      • Barritt A.S.
      • Ginà P.
      • Lohse A.W.
      • Moon A.M.
      • et al.
      SARS-CoV-2 vaccination in patients with liver disease: responding to the next big question.

      COVID-19 vaccines

      According to a continuously updated report by the World Health Organization (WHO), more than 200 vaccine candidates have been evaluated in preclinical animal models and in human clinical trials worldwide (published on January 26, 2021, https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines).
      A wide variety of technologies/platforms have been used, such as mRNA, viral vectors, recombinant DNA, inactivated viruses, protein subunits and live attenuated viruses. Several comprehensive reviews are available that discuss the different vaccine candidates in more detail.
      • Mellet J.
      • Pepper M.S.
      A COVID-19 vaccine: big strides come with big challenges.
      • Connors M.
      • Graham B.S.
      • Lane H.C.
      • Fauci A.S.
      SARS-CoV-2 vaccines: much accomplished, much to learn.
      • Krammer F.
      SARS-CoV-2 vaccines in development.
      The high speed of COVID-19 vaccine development is unprecedented and exceptional, with several vaccines already approved by regulatory authorities within a year of the start of the pandemic. We will discuss 3 vaccines that have been approved by the EMA and FDA by February 2021 (Table 3).
      Table 3Summary of data for COVID-19 vaccines approved∗ to date (as of February 2021).
      VaccinePhase III dataSpecial featuresRef
      BNT162b2 (Tozinameran; Comirnaty)

      (BioNTech and Pfizer)

      RNA (embedded in lipid nanoparticles) encodes a variant of the SARS-CoV-2 spike protein
      N = 43,548 (randomised 1:1 vaccine vs. placebo)

      Efficacy 95% (9 vaccinated vs. 169 controls with COVID-19)

      10 cases of severe COVID-19; 9 in the placebo group

      Safety: Injection site reactions and systemic AEs (headache, fever, fatigue) most mild to moderate. SAE rates were below 4%.
      2 doses (30 μg) 21 days apart

      Storage at a temperature of -90 to -60°C for 6 months, storage at 2 to 8°C for up to 5 days and for up to 2 hours at room temperature (up to 30°C).
      • Polack F.P.
      • Thomas S.J.
      • Kitchin N.
      • Absalon J.
      • Gurtman A.
      • Lockhart S.
      • et al.
      Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine.
      mRNA-1273 (Moderna)

      RNA (embedded in lipid nanoparticles) encodes a variant of the SARS-CoV-2 spike protein
      N = 30,420 (randomised 1:1 vaccine vs. placebo)

      Efficacy 94.1% (11 vaccinated vs. 185 controls with COVID-19)

      30 cases of severe COVID-19 only in the placebo group

      Safety: Injection site reactions and systemic AEs (headache, fever, fatigue) most mild to moderate. SAE rates were low after the first dose and increased to around 16% after the second dose.
      2 doses (100 μg) 28 days apart

      Storage at a temperature of -25 to -15 °C for 7 months, storage at 2 to 8°C for up to 30 days and at 8–25°C for up to 12 hours, 6 hours after first dose was taken.
      • Baden L.R.
      • El Sahly H.M.
      • Essink B.
      • Kotloff K.
      • Frey S.
      • Novak R.
      • et al.
      Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
      ChAdOx1 nCoV-19 (AZD122)

      (AstraZenenca and University of Oxford) replication-deficient chimpanzee adenovirus vector, containing the full-length codon-optimised coding sequence of SARS-CoV-2 spike protein.
      Interim analysis (N = 11,636 from Brazil, South Africa, UK)

      Vaccine vs. MenACWY

      Efficacy 70.4% (30 [0.5%] of 5,807 vaccine recipients vs. 101 [1.7%] of 5,829 controls with COVID-19)

      Efficacy with 2 standard doses 62.1%

      Efficacy low dose/standard dose 90.0%

      Efficacy after 1 standard dose 64.1%

      Safety: 175 SAEs in 168 participants, 84 SAEs in the vaccine group and 91 in the control group.
      2 doses. A second dose could be given between 4 and 12 weeks after the first dose. Detailed storage information pending but expected to be less complex (stable at 2–8°C). The number of patients aged ≥70 years was low (3.8%).
      • Voysey M.
      • Clemens S.A.C.
      • Madhi S.A.
      • Weckx L.Y.
      • Folegatti P.M.
      • Aley P.K.
      • et al.
      Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.
      AE, adverse event; SAE, serious adverse event (grade 3); MenACWY, meningococcal group A, C, W, and Y conjugate vaccine. ∗by EMA or FDA (AZD122 so far only authorised in the UK, EMA/FDA approval was pending at submission of the manuscript).
      Two of these vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna), are based on mRNAs that encode variants of the SARS-CoV-2 spike glycoprotein and are encapsulated into lipid nanoparticles.
      • Polack F.P.
      • Thomas S.J.
      • Kitchin N.
      • Absalon J.
      • Gurtman A.
      • Lockhart S.
      • et al.
      Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine.
      ,
      • Baden L.R.
      • El Sahly H.M.
      • Essink B.
      • Kotloff K.
      • Frey S.
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      Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
      Both mRNA vaccines must be administered twice, 21–28 days apart according to the product information. The efficacy of both mRNA vaccines has been tested in large phase III trials with more than 70,000 participants, which showed that COVID-19 could be prevented in up to 95% of cases while the remaining cases were mostly not severe. Adverse events such as fatigue and fever – considered typical vaccination reactions – occurred more frequently in vaccinated than in placebo recipients. The incidence and severity of such adverse events appear to be somewhat higher compared to seasonal influenza vaccines (reviewed in
      • Connors M.
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      SARS-CoV-2 vaccines: much accomplished, much to learn.
      ). Importantly, the incidence of serious adverse events was similar in the vaccine and placebo recipients
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      The third approved vaccine (AZD1222), known as the Oxford–AstraZeneca vaccine, is a replication-deficient chimpanzee adenovirus vector, containing the full-length, codon-optimised gene encoding the SARS-CoV-2 spike protein. To date, only interim data from a phase II/III trial are available, showing efficacy of more than 70% without a serious safety signal. Of note, a subgroup of patients in the UK received a lower initial vaccine dose followed by booster vaccination with the standard dose and showed 90% efficacy, whereas the standard regimen resulted in vaccine efficacy of only 62%.
      • Voysey M.
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      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 in
      • Marjot T.
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      • Barritt A.S.
      • Ginà P.
      • Lohse A.W.
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      • et al.
      SARS-CoV-2 vaccination in patients with liver disease: responding to the next big question.
      ). 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,
      • L’Huillier A.G.
      • Meyer B.
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      Antibody persistence in the first six months following SARS-CoV-2 infection among hospital workers: a prospective longitudinal study.
      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.

      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.
      • Angeli P.
      • Bernardi M.
      • Villanueva C.
      • Francoz C.
      • Mookerjee R.P.
      • Trebicka J.
      • et al.
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      ,
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      • Jalan R.
      • Fernandez J.
      • Wiest R.
      • Schnabl B.
      • Moreau R.
      • Angeli P.
      • et al.
      Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013.
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • Caraceni P.
      • Laleman W.
      • Gambino C.
      • et al.
      PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.
      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.
      • Boettler T.
      • Marjot T.
      • Newsome P.N.
      • Mondelli M.U.
      • Maticic M.
      • Cordero E.
      • et al.
      Impact of COVID-19 on the care of patients with liver disease: EASL-ESCMID position paper after 6 months of the pandemic.
      ,
      • Marjot T.
      • Moon A.M.
      • Cook J.A.
      • Abd-Elsalam S.
      • Aloman C.
      • Armstrong M.J.
      • et al.
      Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: an international registry study.
      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.
      • Marjot T.
      • Moon A.M.
      • Cook J.A.
      • Abd-Elsalam S.
      • Aloman C.
      • Armstrong M.J.
      • et al.
      Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: an international registry study.
      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:
      ESMO
      COVID-19 vaccination in cancer patients: ESMO statements.
      ).
      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 decompensation
      • Leise M.D.
      • Talwalkar J.A.
      Immunizations in chronic liver disease: what should be done and what is the evidence.
      and has been reported to reduce the risk of hospitalisation in patients with liver disease.
      • Härmälä S.
      • Parisinos C.A.
      • Shallcross L.
      • O’Brien A.
      • Hayward A.
      Effectiveness of influenza vaccines in adults with chronic liver disease: a systematic review and meta-analysis.
      In the past, the development of new vaccines has repeatedly raised concerns regarding vaccine-induced adverse effects including unconfirmed reactivation of occult autoimmune phenomena.
      • Pellegrino P.
      • Clementi E.
      • Radice S.
      On vaccine’s adjuvants and autoimmunity: current evidence and future perspectives.
      • Gershwin L.J.
      Adverse reactions to vaccination: from anaphylaxis to autoimmunity.
      • Orbach H.
      • Agmon-Levin N.
      • Zandman-Goddard G.
      Vaccines and autoimmune diseases of the adult.
      This argument was often linked to the use of distinct adjuvants (i.e. aluminum hydroxide, Toll-like receptor agonists or lipid emulsions) in the formulation of subunit and inactivated vaccines.
      • Liang Z.
      • Zhu H.
      • Wang X.
      • Jing B.
      • Li Z.
      • Xia X.
      • et al.
      Adjuvants for coronavirus vaccines.
      However, no such causal link has been unequivocally established,
      • Elwood J.M.
      • Ameratunga R.
      Autoimmune diseases after hepatitis B immunization in adults: literature review and meta-analysis, with reference to ‘autoimmune/autoinflammatory syndrome induced by adjuvants’ (ASIA).
      ,
      • Genovese C.
      • La Fauci V.
      • Squeri A.
      • Trimarchi G.
      • Squeri R.
      HPV vaccine and autoimmune diseases: systematic review and meta-analysis of the literature.
      even for adjuvanted vaccines containing ASO3
      • Gabay C.
      • Bel M.
      • Combescure C.
      • Ribi C.
      • Meier S.
      • Posfay-Barbe K.
      • et al.
      Impact of synthetic and biologic disease-modifying antirheumatic drugs on antibody responses to the AS03-adjuvanted pandemic influenza vaccine: a prospective, open-label, parallel-cohort, single-center study.
      ,
      • Mahmud S.M.
      • Bozat-Emre S.
      • Mostaço-Guidolin L.C.
      • Marrie R.A.
      Registry cohort study to determine risk for multiple sclerosis after vaccination for pandemic influenza a(H1N1) with arepanrix, manitoba, Canada.
      or aluminum hydroxide or aluminum phosphate.
      • Confavreux C.
      • Suissa S.
      • Saddier P.
      • Bourdès V.
      • Vukusic S.
      Vaccinations and the risk of relapse in multiple sclerosis.
      Although long-term safety data on SARS-CoV-2 vaccination in patients with liver disease are not yet available, it is important to weigh the predicted benefit of vaccination against the potential risk of vaccination, especially given the already known serious consequences of SARS-CoV-2 infection in at-risk populations. It goes without saying that with the introduction of new vaccines, it will be crucial to carefully monitor the safety and immune response to vaccination in patients with liver disease. Ideally, national and international prospective registries (preferably without regulatory hurdles) should be initiated as soon as possible. Meanwhile in view of the satisfactory short-term safety records of the newly licensed vaccines, prevention of SARS-CoV-2 infection through vaccination should receive appropriate priority in patients at risk.
      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.

      Evolving recommendations for the emerging COVID-19 vaccines for liver transplant recipients

      As a general rule and based on the available experience on vaccination of organ transplant patients against other pathogens, it is advised that liver transplant candidates be vaccinated prior to transplantation whenever applicable. In addition, it is important to note that phase III trials of current vaccine candidates have excluded organ transplant recipients and patients receiving immunosuppressive drugs (reviewed in
      • Marjot T.
      • Webb G.J.
      • Barritt A.S.
      • Ginà P.
      • Lohse A.W.
      • Moon A.M.
      • et al.
      SARS-CoV-2 vaccination in patients with liver disease: responding to the next big question.
      ). Therefore, further clinical trials should include such patient populations. Consequently, the current recommendations for this particular risk group can at present only be based on theoretical considerations taking into account that immunogenicity and protective efficacy could potentially be lower in transplanted patients, depending on the intensity of immunosuppression.
      • Stucchi R.S.B.
      • Lopes M.H.
      • Kumar D.
      • Manuel O.
      Vaccine recommendations for solid-organ transplant recipients and donors.
      At the time of writing this article, it is too early to reach a judgement regarding the use of one type of vaccine or another. The COVID-19 vaccine platforms described here are mRNA vaccines and viral vector vaccines (Table 3). Certainly, there are open questions regarding the potential side effects, safety and long-term immunogenicity of these new vaccines in the transplant population. Viral vector vaccines can be replication competent (e.g., VSV-ZEBOV vector) or replication incompetent. The COVID-19 (chimpanzee) adenoviral vector vaccine (ChAdOx1-nCoV-19) is replication incompetent, which is reassuring when considering vaccination of the immunocompromised transplant recipient, in whom live attenuated vaccines are generally not advised.
      Similarly, there may be concerns that highly immunogenic vaccines could lead to immune-mediated rejection. However, a meta-analysis of 8 prospective controlled trials showed no increased risk of rejection with standard vaccination compared with non-vaccinated controls.
      • Mulley W.R.
      • Dendle C.
      • Ling J.E.H.
      • Knight S.R.
      Does vaccination in solid-organ transplant recipients result in adverse immunologic sequelae? A systematic review and meta-analysis.
      This finding was supported by data from registry analyses.
      • Mulley W.R.
      • Dendle C.
      • Ling J.E.H.
      • Knight S.R.
      Does vaccination in solid-organ transplant recipients result in adverse immunologic sequelae? A systematic review and meta-analysis.
      In this context it is also important to mention reports that the risk for allograft rejection may be increased in the case of systemic or graft infection which could be prevented, for example, by vaccination.
      • Fishman J.A.
      Infection in organ transplantation.
      Until more and robust safety data on COVID-19 vaccination in immunosuppressed patients are available, the benefits and potential risks of vaccination should be weighed individually. Based on current experience, it appears that in patients after liver transplantation, immunosuppression by itself is not an independent risk factor for an unfavourable course of COVID-19, but that age and comorbidities determine individual risk,
      • Webb G.J.
      • Moon A.M.
      • Barnes E.
      • Barritt A.S.
      • Marjot T.
      Determining risk factors for mortality in liver transplant patients with COVID-19.
      and these risk factors are particularly prevalent in these patients. In the early post-transplant period, when immunosuppression is at its peak, the immune response is likely to be attenuated. Thus, vaccination at a later time (3–6 months after transplantation), when immunosuppression can be reduced, should be considered. Hence, vaccination of patients at risk cannot always be accomplished in a timely manner and given the reduced effectiveness of vaccination in transplanted patients, vaccination of household members is important and should be prioritised to minimise exposure to SARS-CoV-2. In this context it is also important to prioritise vaccination among healthcare professionals caring for immunocompromised patients. To date, there is insufficient data to suggest that vaccination against SARS-CoV-2 confers sterilising immunity, and it is unclear whether vaccinated individuals may still transmit SARS-CoV-2. Still, so far, data from the Moderna vaccine trial suggest some level of protection by the vaccine against shedding of the virus in the absence of symptoms and thus a lower potential for transmission (reviewed in
      • Connors M.
      • Graham B.S.
      • Lane H.C.
      • Fauci A.S.
      SARS-CoV-2 vaccines: much accomplished, much to learn.
      ). Nonetheless, it is critical to continue general protective measures such as social distancing, hand washing, and wearing a mask until the current outbreak is under control.
      Once COVID-19 vaccines are introduced in immunocompromised patients, it will be important to monitor the humoral and cellular immune response to the different vaccines (following the first and second dose) as well as the infection rates in this population.

      Conclusion

      In conclusion, the rapid development of several vaccines against SARS-CoV-2 within the last year is indeed a remarkable achievement. The already licensed COVID-19 vaccines are immunogenic, and the short-term safety record appears excellent in healthy individuals aged ≥16. Thus, based on current knowledge, there is no evidence to contradict the safety and immunogenicity of currently approved vaccines in patients with CLD, hepatobiliary cancer or in immunocompromised patients after liver transplantation. Given the high risk of serious health consequences of SARS-CoV-2 infection in such patients, the potential benefits of the vaccine, both to higher-risk patients and to healthcare systems, are likely to outweigh the risks associated with vaccination. We therefore recommend SARS-CoV-2 vaccination in patients with CLD, hepatobiliary cancer and candidates for liver transplantation, with prioritisation in patients with risk factors for severe COVID-19. The optimal timing of vaccination in transplanted recipients is still unestablished but vaccination 3–6 months after transplantation is advisable.
      Summary of key interim recommendations∗
      • We recommend vaccination against SARS-CoV-2 for patients with chronic liver diseases and hepatobiliary cancer, as well as for liver transplant recipients.
      • Among these patients, vaccination should be prioritised in
        • patients with cirrhosis or liver decompensation
        • patients with hepatobiliary cancer
        • patients with chronic liver diseases and risk factors for severe COVID-19
        • liver transplant recipients with risk factors for severe COVID-19.
      • Vaccination against SARS-CoV-2 should be prioritised in household members of patients with cirrhosis, hepatobiliary cancer and liver transplant recipients, and in healthcare professionals caring for these patients.
      • Prospective registries should be established as soon as possible to monitor safety, immunogenicity and effectiveness of different SARS-CoV-2 vaccines in patients with chronic liver diseases and transplant recipients.
      These recommendations will be reviewed periodically as further information becomes available.

      Conflict of interest

      MC reports personal fees from Abbvie, personal fees from Gilead Sciences, personal fees from Merck Sharp & Dohme (MSD), personal fees from GlaxoSmithKline (GSK), personal fees from Janssen-Cilag, personal fees from Spring Bank Pharmaceuticals, personal fees from Novartis, from Swedish Orphan Biovitrum (SOBI), personal fees from Falk Foundation, grants and personal fees from Roche, outside the submitted work. PAG reports personal fees from Merck, Sharp & Dohme, personal fees from Biotest, personal fees from Angelini, personal fees from Nordic Pharma, personal fees from Vertex, personal fees from Gilead, personal fees from Astellas, outside the submitted work. MB, CSE and DS have nothing to disclose.

      Acknowledgements

      We thank Thomas Berg for reading the manuscript and helpful and constructive comments.

      Appendix A. Supplementary data

      The following is/are the supplementary data to this article:

      Author contributions statement

      All authors have contributed to the review.

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      • High acceptance rate of COVID-19 vaccination in liver transplant recipients
        Journal of HepatologyVol. 75Issue 2
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          We read with great interest the article by Cornberg et al., recently published in the Journal of Hepatology, reporting the European Association for the Study of the Liver (EASL) position on the use of coronavirus disease 2019 (COVID-19) vaccines in patients affected by chronic liver diseases, and in particular in liver transplant recipients.1 Indeed, despite evidence suggesting that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not associated with an increased risk of death in patients who received a liver transplant, these patients more frequently required ICU admission and invasive-ventilation compared to matched controls, and therefore do represent a subset of patients that can be considered especially frail, and at high-risk of severe complications of COVID-19.
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