key: cord-0790210-bk3qc6rf
authors: Sharma, Anand; Patnaik, Itish; Kumar, Ashok; Gupta, Rohit
title: COVID-19 vaccines in patients with chronic liver disease
date: 2021-06-19
journal: J Clin Exp Hepatol
DOI: 10.1016/j.jceh.2021.06.013
sha: b8a44f3731abb5723b30487658c0f4435ffccf73
doc_id: 790210
cord_uid: bk3qc6rf

The COVID 19 pandemic has caused mayhem globally since the beginning of 2020. Due to the immune dysfunction inherent to cirrhosis and the poor general condition, patients with chronic liver disease (CLD) are at higher risk of mortality and morbidity due to COVID-19. Recently a number of vaccines against SARS-Cov-2 have been granted approval for emergency use around the globe. Although the phase 2/3 trials of these vaccines show them to be safe and effective in the general population, data in patients with CLD is scarce. The number of patients with CLD enrolled into these trials is small; no liver related adverse effects have been reported yet. Various liver societies have come up with guidelines on vaccination in this population and recommend vaccination on a priority basis. Trials to assess the safety and efficacy of the COVID vaccines are under way and are likely to provide valuable insight into this matter.

The year 2020 was marked by a global pandemic that devastated developed and developing nations alike. Severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2) infection spread all over the world relentlessly, causing coronavirus disease 19 (COVID- 19) , which resulted in significant morbidity and mortality. Patients with pre-existing comorbidities and chronic illnesses were more vulnerable to disease and death caused by the virus. Patients with chronic liver disease (CLD) were noted to have higher mortality and decompensation following SARS-Cov-2 infection. However, the year also saw unprecedented scientific progress and human endeavor, which culminated in the discovery of a number of vaccines which are currently being administered to the global population in a phased manner. Our understanding of the risks and benefits of COVID-19 vaccine in patients with chronic liver disease is still evolving. This review aims at summarizing the currently available evidence regarding COVID-19 vaccines in this population.

Acute on chronic liver failure (ACLF), a condition that inherently carries a higher short term mortality 1 . Various mechanisms have been postulated for this increased mortality in CLD patients. Cirrhosis associated immune dysfunction (CAID), characterized by immune dysregulation leads to persistent systemic inflammation and increased susceptibility to infections 2 . Endotoxemia associated with cirrhosis leading to an exaggerated immune response and alteration in gut microbiota leading to immune dysregulation may contribute to the increased disease severity and mortality 2 . A related consequence of the alterations in immune system in cirrhosis is vaccine hypo responsiveness to non-COVID vaccines. Immunogenicity to hepatitis A virus (HAV) and hepatitis B virus (HBV) vaccines decreases with increasing severity of cirrhosis and can be addressed by administering higher vaccine doses 3 . The APCOLIS study from Asia reported outcomes of CLD patients with confirmed COVID infection. Of 228 patients, 20% cirrhotics presented as acute on chronic liver failure and mortality was noted in 43% of the decompensated cirrhotics. The complications increased with the severity of liver disease 4 .

The vaccines against SARS-Cov-2 can be categorized based upon the platform they are developed upon into mRNA vaccines, adenovirus vector vaccines and whole virion inactivated vaccines. mRNA based vaccines mRNA based vaccines involve delivery of synthetic mRNA into the cytoplasm of the host which uses the host ribosomes to translate into antigenic proteins which induce immunity against the virus 3 . Pfizer BioNTech vaccine (BNT162b2) and Moderna vaccine (mRNA-1273) belong to this class and contain mRNA that codes for the spike protein used by the virus to gain entry into the host.

These involve use of a replication incapable adenovirus as a vector to introduce the DNA coding for the spike protein into the host cells 3 . The AstraZeneca-University of Oxford vaccine (ChAdOx1 nCoV-19) and Johnson and Johnson vaccine belong to this category (JNJ-78436735)

The Bharat Biotech vaccine (BBV152) belongs to this category and contains β-propiolactone-inactivated whole virion 5 . The BNT 162b2 is an mRNA vaccine which is administered as two doses of 30g each via the intramuscular route 21 days apart 6 . The vaccine is available in multidose vials and needs to be stored at -60 o to -80 o C 3 , which may prove to be a logistic hurdle in developing countries. It was authorized for emergency use by the FDA based on the ongoing phase 1/2/3 randomized placebo-controlled trial published in December 2020. In the trial 43,448 volunteers were randomized to the vaccine arm and placebo arm in a 1:1 ratio. The vaccine demonstrated 95% efficacy in preventing COVID-19 when compared to placebo, which was maintained for subgroups defined by age, sex, body mass index, ethnicity and comorbidities. Among adverse events, local site reactions were the most frequent. Systemic symptoms like fever, joint pains, and chills occurred more commonly in the young patients and were more common after the second dose 7 . The above trial included 214 patients with mild liver disease and only 3 patients with moderate or severe liver disease. Patients with Hepatitis B and Hepatitis C infection were included, although the virological status and disease severity of these patients is not known. Patients on immunosuppressive medication were excluded. Hence, there is a paucity of available data on patients with liver disease.

The mRNA-1273 is also a mRNA vaccine that is administered as two doses of 100g each 28 days apart. It was licensed for use by the FDA based on a ongoing phase 3 randomized placebo-controlled trial published in December 2020, wherein 30,420 volunteers were randomized into the vaccine and placebo groups in 1:1 ratio. The vaccine demonstrated efficacy of 94.1% in preventing COVID-19.

Severe COVID-19 occurred only in the placebo group with one fatality. Vaccine related serious unsolicited adverse events occurred more commonly in the vaccine group but none resulted in fatality or study discontinuation. The unsolicited systemic and local reactions occurred more commonly after the second dose and in younger individuals 8 . The trial included a total of 196 patients with liver disease (distributed almost equally between vaccine and placebo group), though liver disease was not defined. Patients on systemic immunosuppressive medication were excluded from the trial. Efficacy and safety data was not available separately for the patients with liver disease 8 .

The ChAdOx1 nCoV-19 vaccine (AZD1222), developed by University of Oxford, contains replication deficient chimpanzee adenovirus as a vector carrying the gene encoding for the SARS-Cov-2 spike glycoprotein. The storage requirements are less stringent than for mRNA vaccines and can be stored between 2 and 8 o C 9 . It is manufactured by AstraZeneca and Serum Institute of India (SII). The AstraZeneca manufactured vaccine was licensed for emergency use in the United Kingdom (UK) in December 2020 3 . The Drug controller general of India (DCGI) gave its approval for use of the vaccine in India, manufactured by SII under the trade name COVISHIELD TM9 . The vaccine is administered in two intramuscular doses of 0.5ml each, 4-6 weeks apart. Antibody responses peaked on day 28 in patients who received a single dose and on day 56 in patients who received a booster dose 28 days after the first dose 10 The four trials mentioned above largely excluded liver disease patients. The trials conducted in UK and Brazil excluded patients with "severe" liver disease, although the criteria for severity were not clarified. Further they also excluded volunteers on immunosuppressive medications and those with alcohol dependency. The trial conducted in South Africa mentions liver function tests abnormalities, Australia antigen positivity, chronic liver disease and alcohol abuse as exclusion criteria. Liver function abnormalities were noted in only two patients (one each in vaccine and control groups) 11 .

According to the interim report of an Indian phase 2/3 randomised placebo controlled trial which recruited 1600 volunteers, seroconversion for anti-S IgG antibody was noted in 100% of participants who received COVISHIELD after 57 days of the second dose. Again, separate data is not available for liver disease patients 9 .

The BBV152 is a whole virion inactivated vaccine, manufactured by Bharat Biotech under the trade name COVAXIN TM . It was licensed for emergency use by the DCGI in January 2021. Two doses of the vaccine 28 days apart are recommended via the intramuscular route, each dose containing 6g of the whole virion inactivated coronavirus antigen 12 .

In a phase 2 trial of the vaccine, 380 patients were enrolled and randomised equally into two groups, both of which received the BBV152, but at different doses (3g and 6g). The primary outcomes were SARS-Cov-2 wild type neutralising antibody titres and seroconversion rates on day 56 and both were higher in the 6g group. This dose was chosen for phase 3 study. The trial excluded patients on immunosuppressive medications and those with chronic liver disease 13 .

Interim results of the phase 3 trial were announced in a press release by Indian council for medical research claiming a vaccine efficacy of 81% 14 . A study also showed the BBV152 vaccine to be effective against the UK variant of SARS-Cov-2 15 . It is not recommended at present to measure antibody titres after vaccination 3 .

As summarised above, data regarding COVID vaccines in CLD patients is sparse. Since patients with CLD have decreased immunogenicity to non-COVID vaccines, it is not yet clear whether the COVID vaccines will induce sufficient and durable immune response to the virus similar to individuals without CLD. The role of increasing severity of liver disease in determining the immune response to COVID vaccine also remains unclear at present. Though the trials conducted did not report significant hepatotoxicity, the number of liver disease patients enrolled were too less to conclude unequivocally regarding safety of the vaccines in this population. It is likely that more data in patients with CLD will emerge with post marketing surveillance. However, currently many trials are on-going, worldwide, in patients with liver disease as summarized in Table 2 Nevertheless, despite all the above mentioned recommendations, in view of the higher risk of COVID-19 related mortality in CLD patients, EASL and AASLD recommend prioritisation of COVID-19 vaccination in patients with advanced liver disease as well as those with immune mediated liver disease on immunosuppression 3,17 .

Patients with CLD on antivirals or immunosuppressive medications should not withhold their medications around the time of vaccination. But patients with recent fever are recommended not to get vaccinated till the infection is controlled 3 .

All the trials conducted on COVID vaccines excluded patients on immunosuppressive medications, thereby raising certain concerns in post-transplant setting. It remains to be seen whether vaccine efficacy and durability of immune response will be similar to the general population in the post-transplant patients on immunosuppression. Further, since the immunosuppression is highest immediately post-transplant, the timing of vaccination in relation to the transplant is unclear. Also, any worsening of liver function tests following vaccination may be difficult to interpret in post-transplant patients.

AASLD recommends COVID-19 vaccination in all patients who have undergone liver transplantation, preferably at least 3 month after liver transplant, once the immunosuppression has been reduced. Patients with ongoing acute rejection are recommended to get vaccinated after rejection has been tackled. It does not recommend lowering of immunosuppression to increase immunogenicity of the vaccine. Any rise in LFT should be thoroughly investigated to rule out rejection 3 .

Though it is better to receive the vaccine before liver transplant, deceased donor transplant should not be delayed due to vaccination. However, donors and recipients of live related liver transplant should preferable receive the second dose of the vaccine at least two weeks prior to transplant 3 .

According to the AASLD recommendations, patient with HCC should be considered for vaccination. It is not recommended to interrupt locoregional or systemic therapy for HCC for the purpose of vaccination 3 .

J o u r n a l P r e -p r o o f

The data regarding safety and efficacy of COVID-19 vaccines in CLD is sparse. However, there is sufficient data regarding the increased COVID-19 related mortality in this population. Presently clinical trials are ongoing to measure the immunogenicity and safety of the available COVID vaccines in patients with CLD 18 . Registries like the SECURE-cirrhosis and COVID-Hep are also constantly yielding such data on a large scale 19 . But, considering the devastation already caused by the pandemic, we cannot afford to wait till such data comes out.

The data on vaccines, though limited does not report significant liver related adverse event in the vaccinated population. There is also a lack of head to head trials as to which vaccine is superior in patients with liver disease. Such information is difficult to deduce from the existing literature, since vaccine trials largely excluded patients with significant hepatic impairment. Hence, in view of the high rate of complications and decompensation caused by COVID 19 in CLD, we feel that all patients with CLD should undergo vaccination. We do not have enough data to recommend any particular vaccine over the other. The international liver societies also recommend prioritised vaccination of patients with CLD. Studies in the future are likely to improve our understanding of the subject and vaccination may be tailored for CLD patients, but till then the fight must continue with whatever weapons we have. 

Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: An international registry study

COVID-19 and liver disease: mechanistic and clinical perspectives

AASLD Expert Panel Consensus Statement: Vaccines to Prevent COVID-19 Infection in Patients with Liver Disease

Pre-existing liver disease is associated with poor outcome in patients with SARS CoV2 infection; The APCOLIS Study (APASL COVID-19 Liver Injury Spectrum Study)

Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial

Vaccines and Related Biological Products Advisory Committee Meeting FDA Briefing Document. Pfizer-BioNTech COVID-19 Vaccine

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

ChAdOx1 nCoV-19 Corona Virus Vaccine)

Serum Institute Of India Pvt

Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial

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

Whole Virion Inactivated Corona Virus Vaccine)

Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, phase 2 trial, and 3-month follow-up of a double-blind, randomised phase 1 trial

Phase 3 Clinical Trial of COVAXIN, developed by ICMR & Bharat Biotech, shows 81% efficacy

Neutralization of UK-variant VUI-202012/01 with COVAXIN vaccinated human serum. bioRxiv

EASL position paper on the use of COVID-19 vaccines in patients with chronic liver diseases, hepatobiliary cancer and liver transplant recipients

A Prospective Study Comparing the Antibody Response of Subjects With Chronic Liver Disease to mRNA, Inactivated Virus and Adenovirus Vector COVID-19 Vaccines

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

Safety and Efficacy of a Non-replicating ChAdOx1 Vector Vaccine AZD1222 (COVISHIELD), for Prevention of COVID-19 in Patients With Liver Cirrhosis

A Norwegian Study of Vaccine Response to COVID-19 Vaccines in

A Study to Describe the Safety, Tolerability, Immunogenicity, and Efficacy of Vaccines Against COVID-19 in the Real World

Moderna vaccine (mRNA-1273) mRNA vaccine Efficacy: 94.1% compared to placebo Local AR:84.2%-88.6% Most common AR: Local pain Systemic AR:54.9-79.4% Most common: Fatigue, myalgia, arthralgia Serious AR-1%

•Immunogenicity indexseroconversion rates of neutralizing antibody •Safety index-incidence of adverse reactions •Immunogenicity index-seropositive rates of neutralizing antibody