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      SARS-CoV-2 vaccination in patients with liver disease: responding to the next big question

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          Abstract

          Since the onset of the COVID-19 pandemic, SARS-CoV-2 vaccine development has progressed at an unprecedented rate, with recent phase 3 trial data offering the tantalising prospect of achieving herd immunity.1, 2, 3 Until now, researchers have focused on the contribution of specific liver disease phenotypes, including transplantation and immunosuppression, to COVID-19 susceptibility and outcome. However, the hepatology community must now urgently turn its attention to characterising SARS-CoV-2 vaccine responses in these vulnerable patient groups. The Pfizer/BioNTech BNT162b2 mRNA, Moderna mRNA-1273, and the AstraZeneca/University of Oxford ChAdOx1-nCoV-19 chimpanzee adenovirus (ChAd) vector vaccines have each reported excellent safety profiles, marked efficacy in preventing symptomatic COVID-19 (62–95%), and have all gained rapid regulatory approval.1, 2, 3 Currently, it remains unclear why a significant minority of those vaccinated appear susceptible to SARS-CoV-2, although both host factors (eg, underlying chronic diseases or genetic susceptibility) and viral factors (eg, high viral load exposure, specific viral variants) are likely to have a contributory role. Despite the inclusion of nearly 100 000 participants in these trials, data for patients with liver disease are extremely limited (panel ). In the Pfizer vaccination study, 217 (0·6%) of 37 706 participants had liver disease, and only three (<0·1%) had moderate to severe liver disease. A similarly low proportion of patients with liver disease were included in the Moderna trial (196 [0·6%] of 30 351). The ChAdOx1-nCoV-19 vaccine trial explicitly omitted patients with pre-existing liver pathology. Notably, in each study the criteria used to classify liver disease and its severity remain unclear. In addition, all trials listed systemic immunosuppression as an exclusion criterion, thus preventing extrapolation of the data to immunosuppressed liver transplant recipients or patients with autoimmune liver disease. Furthermore, granular detail regarding liver safety profiles remains largely unpublished, although abnormal liver biochemistry was reported in only one of 12 021 participants receiving ChAdOx1-nCoV-19. ChAd vaccines for hepatitis C virus (HCV) have previously been safely given to a small number of patients with non-cirrhotic chronic HCV infection. 4 However, a detailed understanding of SARS-CoV-2 vaccine safety and the immunological response in patients with liver disease will almost exclusively come from post-licensing, real-world investigation. Panel Involvement of patients with liver disease in phase 3 SARS-CoV-2 vaccine trials and key outstanding questions Chronic liver disease and cirrhosis Trial inclusion and exclusion criteria • Pfizer/BioNTech: “liver disease” included but not defined • Moderna: “liver disease” included but not defined • Oxford/AstraZeneca: “liver disease” excluded (except Gilbert syndrome), “alcohol and drug dependency…injecting drug abuse in the 5 years preceding enrolment” excluded Key outstanding questions • Magnitude and duration of vaccine response • Disease severity in predicting vaccine response • Differential efficacies of single doses or additional booster doses • Risk of liver injury unknown Liver transplantation Trial inclusion and exclusion criteria • Pfizer/BioNTech: “Individuals who receive treatment with immunosuppressive therapy” excluded • Moderna: “Immunosuppressive or immunodeficient state” or “systemic immunosuppressants or immune-modifying drugs for >14 days” excluded • Oxford/AstraZeneca: “Any confirmed or suspected immunosuppressive or immunodeficient state” excluded Key outstanding questions • Magnitude and duration of vaccine response • Durability of response post-transplantation; optimal timing of prime and boost vaccination in relation to transplantation • Interactions with specific immunosuppression regimens • Differential efficacies of single doses or additional booster doses • Risk of liver injury unknown Immunosuppressed autoimmune liver disease (eg, autoimmune hepatitis) Trial inclusion and exclusion criteria • Pfizer/BioNTech: “Individuals with a history of autoimmune disease or an active autoimmune disease requiring therapeutic intervention” excluded • Moderna: “Immunosuppressive or immunodeficient state” or “systemic immunosuppressants or immune-modifying drugs for >14 days” excluded • Oxford/AstraZeneca: “Any autoimmune conditions” excluded Key outstanding questions • Magnitude and duration of vaccine response • The effects of specific immunosuppression regimens of vaccine response • Interactions with specific immunosuppression regimens • Differential efficacies of single doses or additional booster doses • Risk of liver injury unknown Patients with advanced liver disease have well recognised deficiencies in innate and humoral immunity, termed cirrhosis-associated immune dysfunction (CAID). Although attention has mostly focused on mechanisms leading to severe bacterial infections, CAID has also been shown to predispose to a variety of viral or fungal related diseases. 5 This same immune dysfunction might partly explain the severe complications of COVID-19 observed in patients with decompensated cirrhosis 6 and contribute to the impaired immunological responses seen with existing vaccinations. For example, rates of seroconversion after hepatitis B virus (HBV) immunisation, and the durability of humoral immunity after pneumococcal and influenza vaccination are all markedly reduced in patients with cirrhosis.7, 8, 9 It is therefore likely that patients with cirrhosis will have attenuated immune responses to SARS-CoV-2 vaccination. Nonetheless, given the high COVID-19-related mortality in patients with decompensated cirrhosis, it remains of utmost importance to prioritise vaccination in this subgroup. 6 Patient education regarding the benefit of SARS-CoV-2 vaccination programmes will also be essential, particularly given that routine immunisation uptake in patients with cirrhosis is often suboptimal. 10 The value of routine immunisation in liver transplant recipients is well established, with vaccine immunogenicity greatest in the pre-transplantation rather than the post-transplantation setting, even in the context of advanced liver disease. Current guidelines therefore recommend pre-transplant vaccination where possible, with any subsequent immunisation deferred until doses of immunosuppression have been reduced to maintenance levels. 11 The optimal timing of SARS-CoV-2 vaccine delivery within the transplantation pathway is undetermined, but currently due to the high global burden of COVID-19 should most likely be administered as soon clinically available. Blunting of the response in immunosuppressed liver transplant recipients is well recognised, with lower antibody titres reported following influenza, hepatitis A virus, HBV, and pneumococcal vaccinations. 12 At present, the product information for the mRNA vaccines recommends against their use in those with immunosuppressive conditions or when receiving immunosuppressive medications. This is presumably related to the lack of specific efficacy and safety data in these subpopulations. However, neither the ChAdOx1-nCoV-19 or the mRNA vaccine platforms contain live or attenuated virus and it therefore seems unlikely that immunisation represents a particular safety concern for these patients. Although historically there have been anxieties that vaccination in transplant recipients may lead to the development of alloimmunity and graft rejection, no clinical evidence has emerged to support this. 12 Although liver transplant recipients have comparable rates of COVID-19-related mortality to the matched general population, 13 they do have higher rates of admission to intensive care and may have been relatively more protected throughout the pandemic due to enhanced social distancing or shielding. Therefore, we still believe this group remains a vulnerable population and should be prioritised for vaccination, with the likely benefits far outweighing the potential risks. However, until it is established whether patients with liver disease and transplantation achieve optimal protection after immunisation, clinicians should remain vigilant for post-vaccination COVID-19 in these cohorts. More work is needed to define the precise laboratory correlates of vaccine protection following delivery of the mRNA and ChAdOx1-nCoV-19 platforms. Both vaccine types induce high concentrations of anti-spike IgG antibodies as measured ex-vivo14, 15 and also generate high levels of spike-specific CD4+ and CD8+ T cells,14, 15 which might improve durability of B-cell responses and help protect against future infection. In evaluating patient responsiveness it is therefore vital to assess for the magnitude and durability of both humoral and cellular responses. Finally, despite the frequency of post-vaccination SARS-CoV-2 infection in liver disease cohorts being unknown, it is likely to be rare in absolute terms. Therefore, large scale case reporting through platforms such as the COVID-Hep and SECURE-Cirrhosis registries may be the only mechanism through which to draw meaningful conclusions. Furthermore, disentangling the relative contributions of vaccine type, liver disease phenotype, and host factors to the immunisation response will require wide collaborative efforts to pool clinical and laboratory data. Currently, advice regarding vaccine delivery in disease subpopulations is inconsistent and subject to geographical variation. Detailed investigation of immune responses is therefore vital to ultimately allow the standardisation of vaccination guidelines. As we usher in the new era of SARS-CoV-2 immunisation, it is now of fundamental importance to examine the effect of new vaccines on patients with liver disease, for whom evidence is thin yet clinical consequences profound.

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          Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

          Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. Methods In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. Results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. Conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)
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            Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

            Abstract Background Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. Methods This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. Results The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. Conclusions The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)
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              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

              Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; p interaction =0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. Funding UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D’Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.
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                Author and article information

                Journal
                Lancet Gastroenterol Hepatol
                Lancet Gastroenterol Hepatol
                The Lancet. Gastroenterology & Hepatology
                Elsevier Ltd.
                2468-1253
                11 January 2021
                11 January 2021
                Affiliations
                [a ]Oxford Liver Unit, Translational Gastroenterology Unit, University of Oxford, Oxford, UK
                [b ]Cambridge Liver Unit, Cambridge University Hospitals NHS Trust, Addenbrookes Hospital, Cambridge, UK
                [c ]Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, USA
                [d ]Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Institut de Recerca Biomèdica August Pi-Sunyer (IDIBAPS), Barcelona, Spain
                [e ]Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
                [f ]National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, Birmingham, UK
                Article
                S2468-1253(21)00008-X
                10.1016/S2468-1253(21)00008-X
                7832019
                33444545
                2c701494-9952-447c-9ae2-658bb618d89b
                © 2021 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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