3 years into the COVID-19 pandemic, it has had a significant impact on human health and economic development. Based on WHO statistics, as of April 22, there are approximately 497 million confirmed patients and 6.179 million deaths in the world because of COVID-19.
Novel Coronavirus (SARS-CoV-2) shares a partly similar structure with the SARS virus 18 years ago, while it is more infectious and accommodates better to temperature changes. Besides, seasonal changes have little sway over the virus. As a consequence, people lay their hope of eradicating the pandemic on vaccines.
During the research and development of the vaccines, enterprises like Pfizer, Moderna, Johnson & Johnson, AstraZeneca, and Sinovac have contributed much to the combat of the disease and also acquired a great revenue from the new COVID-19 vaccines. Among those vaccines, the mRNA vaccine has risen sharply and set off a global boom in development for its short R&D cycle and high protection rate. COVID-19 mRNA vaccine (BNT162b2, brand name: Comirnaty), jointly developed by Pfizer/BioNTech, is one of the earliest widely used mRNA COVID-19 vaccines globally, which has gained 36.781 billion US dollars in profit last year.
However, on April 21, a case released in the Journal of Hepatology, an international authoritative journal in the field of liver diseases, struck BNT162b2. According to the research, BNT162b2 may cause a T cell-mediated autoimmune hepatitis.
Autoimmune hepatitis is a chronic progressive liver inflammatory disease mediated by the autoimmune reaction. Its clinical features are elevated serum transaminase of various levels, hypergammaglobulinemia, and positive autoantibody. Its histological features are interfacial hepatitis mainly infiltrated by lymphocytes and plasma cells. Severe cases can rapidly progress to liver cirrhosis and liver failure.
This clinical research from Germany has disclosed a bimodal attack of acute hepatitis after vaccinating two doses of the Pfizer mRNA vaccine (the attacks occur after two vaccinations). This male patient is 52 years old with no other medical history except hypothyroidism.
The patient began to show symptoms of progressive nausea, fatigue, anorexia, and pruritus nearly 10 days after the vaccination of the first dose of BNT162b2. He experienced jaundice next and paid a visit to a primary health physician on the 25th day after vaccination. Liver function examination (LFT) revealed acute mixed hepatocyte/cholestatic hepatitis (ALT: 2130 U/l, AP: 142 U/l, γ-GT: 217 U/l, bilirubin 7.7 mg/dl).
Serological and/or PCR tests excluded the possibility of viral hepatitis A, B, C, and E, as well as cytomegalovirus and Epstein-Barr virus infections. The patient recovered quickly without special treatment and was discharged 3 days later. The level of liver enzymes of the patient gradually decreased to the normal condition over the next 2 weeks.
Subsequently, the patient was inoculated with the second dose of BNT162b2 41 days after the first one. After 20 days, the patient relapsed with acute mixed hepatitis. The patient's liver function improved after oral taking budesonide daily. However, his disease relapsed after 39 days, and finally eased under the treatment of systemic steroids combined with ursodeoxycholic acid.
Autoimmune serological examination showed that the patient had mild hyperglobulinemia, antinuclear antibody (ANA), antimitochondrial M2 antibody (AMA-M2), and anti-smooth muscle antibody was critically positive, while the anti-LKM test was still negative.
Analysis of liver tissue showed that immune infiltration was dominated by activated cytotoxic CD8 T cells with panlobular distribution. Enrichment of CD4 T cells, B cells, plasma cells, and bone marrow cells were also observed compared with the control. Compared with peripheral blood, intrahepatic infiltration showed enrichment of CD8 T cells with SARS-CoV-2 specificity.
It is worth noting that the T lymphocyte cluster in the liver tissue of patients is the richest among their immune cells, which differs from typical autoimmune hepatitis, and the researchers found that there is a wider infiltration of immune cells around the portal vein of patients.
The researchers finally concluded that the vaccination with the BNT162b2 vaccine may cause immune-mediated hepatitis through the cellular immune mechanism. These results imply that: T cells are the key pathogenic immune cell type of this vaccine-associated immune hepatitis, and this "mysterious hepatitis" is a new subtype of autoimmune hepatitis.
While this is the case, some professionals in the vaccine industry believe that: in the BNT162b2 vaccine, liposome encapsulation technology is introduced, and liposome is easy to get enriched in the human liver, which remains a safety concern of mRNA vaccine in the industry before, but no related problems have been identified in clinical researches. The recently popular Omicron variant can infect the liver. In this case, if the virus infects the liver, and the vaccine antigen carried by liposome is also enriched in the liver, the situation may become very complicated. Some others stand opposite instead. It is of little possibility that the liposome of the mRNA vaccine will be enriched in the liver to trigger an unexpected T cell hyperimmune response since the amount of vaccine is very small and it is difficult to reach the liver.
There is no conclusion on the causes of the above case, and further research is required.
In fact, before the release of the article, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) published the discussion results of the above case on April 8 local time and concluded that: the existing evidence does not prove the causal relationship between COVID-19 mRNA vaccine and autoimmune hepatitis, and there is no need to update the vaccine product information currently. EMA showed that it would keep closely supervising any new situation reports and take corresponding measures when necessary.
Children's "mysterious hepatitis" has also emerged in the world other than the above case. Since January this year, there have been many cases of acute hepatitis in children of unknown origin in the United States, Europe, and Japan. As of April 26, more than 190 cases of unexplained hepatitis in children have been reported worldwide. Besides, 17 cases suffer from hepatic failure and 1 case dies. Among them, about 74 cases are positive for F41 adenovirus, 20 cases are found to catch SARS-CoV-2, and another 19 people are infected with both. Till now, experts are still researching whether this disease is caused by such adenovirus.
Now WHO tentatively defines this "mysterious hepatitis" as "acute severe childhood hepatitis of unknown origin", with judging criteria as follows. The patient develops the disease after January 2022. He or she is at the age of 16 years old younger and suffers from acute hepatitis (not caused by hepatitis A, B, C, D, and E viruses). The level of aspartate aminotransferase or alanine aminotransferase exceeds 500U/L.
Currently, most of the affected children are 5 years old or younger. Observation shows that the duration from infection to onset of pediatric patients is usually no more than half a year, and the possible symptoms include influenza-like symptoms, gastrointestinal problems, fever and jaundice, alkaptonuria, etc. About 17 children in the world have received or need to receive liver transplantation due to liver failure. Adenovirus is a seasonally transmitted disease, and most adenovirus diseases are self-limiting. But for those with low immune function, a fatal infection may occur. This happens occasionally in healthy children and adults.
At present, adenovirus infection combined with COVID-19 is likely to be considered the cause of this hepatitis by the international analysis. According to researchers, the control measures during COVID-19 decrease children's exposure to external pathogens. After reopening, children may get easier to catch the virus as well as more serious symptoms when exposed to the adenovirus on account of the decline of existing immunity, which means that they are not stimulated by pathogen immunity for a long time. Besides, adenovirus infection is accompanied by SARS-CoV-2 or previous infections. Adenovirus infection combined with current SARS-CoV-2 or other pathogen infections is also one of its causes. Experts also believe that a new adenovirus variant may have appeared.
At present, the world is still enveloped in the cloud of "mysterious hepatitis". Compared with the disease itself, the unknown cause of the disease is more frightening. According to the current evidence, the mRNA vaccine is safe, and the expansion of vaccination should not be affected. According to WHO, the priority at present is to determine the etiology, guide further clinical and public health actions and clarify risk factors.
1. Boettler T, Csernalabics B, Salié H, Luxenburger H, Wischer L, Alizei ES, Zoldan K, Krimmel L, Bronsert P, Schwabenland M, Prinz M, Mogler C, Neumann-Haefelin C, Thimme R, Hofmann M, Bengsch B. SARS-CoV-2 vaccination can elicit a CD8 T-cell dominant hepatitis. J Hepatol. 2022 Apr 21:S0168-8278(22)00234-3. doi: 10.1016/j.jhep.2022.03.040. Epub ahead of print. PMID: 35461912.
2. Can COVID-19 mRNA vaccine cause autoimmune hepatitis? Professionals' answers, China Business Network.
3. Acute hepatitis of unknown aetiology–the United Kingdom of Great Britain and Northern Ireland.WHO.4. Investigation into cases of hepatitis of unknown aetiology among young children, Scotland, 1 January 2022 to 12 April 2022.Eurosurveillance.Volume 27, Issue 15, 14/Apr/2022.
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