Pfizer/BioNTech’s mRNA COVID-19 Vaccine BNT162b2 Linked to Rare T Cell-Mediated Autoimmune Hepatitis, Study Suggests

Compiled by Rhee

On April 21, a study published in the Journal of Hepatology showed that the Pfizer/BioNTech COVID-19 mRNA vaccine (BNT162b2) may lead to a T-cell mediated autoimmune hepatitis.

Autoimmune Hepatitis: A Chronic Progressive Liver Inflammatory Disease Mediated by Autoimmune ResponsesAutoimmune hepatitis is a chronic progressive liver inflammatory disease mediated by autoimmune responses. Its clinical features include varying degrees of elevated serum transaminases, hypergammaglobulinemia, and positive autoantibodies. The histological hallmark is interface hepatitis characterized predominantly by lymphocytic and plasma cell infiltration. Severe cases can rapidly progress to cirrhosis and liver failure. Public data shows that the incidence rate of this type of hepatitis is 3 per 100,000 annually, occurring worldwide, with relatively higher incidence rates in European and American countries. The number of cases in China has shown a significant upward trend.

In this trial, a 52-year-old man experienced a biphasic acute hepatitis flare-up 2-3 weeks after receiving two doses of the Pfizer/BioNTech COVID-19 vaccine, with the condition recurring after each dose. The man reportedly had no significant medical history other than hypothyroidism.

Ten days after the first dose of the Pfizer-BioNTech COVID-19 vaccine (BNT162b2), the man developed jaundice, and liver function tests (LFT) indicated acute mixed hepatocellular/cholestatic hepatitis. The patient was hospitalized for treatment 25 days after vaccination.

Forty-one days after the first dose, the man received his second dose of the COVID-19 vaccine. Twenty days later, he developed symptoms of nausea and fatigue, and laboratory tests revealed a recurrence of acute mixed hepatitis.

Regarding the causes of hepatitis, researchers conducted serological and polymerase chain reaction tests on the patient, ruling out the possibility of infection by hepatitis A, B, C, or E viruses, cytomegalovirus, and Epstein-Barr virus. Autoimmune serology tests revealed mild hypergammaglobulinemia, antinuclear antibodies, borderline positive anti-mitochondrial M2 antibodies, and anti-smooth muscle antibodies, while LKM antibody tests were negative. Subsequent liver biopsy of the patient showed moderate lymphoplasmacytic infiltration, lobular necrosis, and apoptotic foci.

Study results showed that the patient's symptoms were consistent with autoimmune hepatitis and received treatment with budesonide at a dose of 9 mg/day. Budesonide is a glucocorticoid with potent local anti-inflammatory effects. Within weeks of treatment, the patient’s liver enzyme levels decreased.

However, 39 days after the initiation of treatment, the patient experienced a relapse, which the researchers attributed to the recurrence of hepatitis following a reduction in budesonide dosage. After resuming an eight-week course of the medication, the patient returned to normal, with no significant fluctuations observed in the SARS-CoV-2 S protein-specific antibodies. Additionally, the researchers noted infiltration of T cells, B lymphocytes, macrophages, granulocytes, and plasma cells in the patient’s liver tissue. The researchers stated that compared to liver tissue from healthy individuals, the immune cell count in this patient's liver increased by 5.3 times.

Notably, the T lymphocyte clusters (CD8) in the patient's liver tissue are the most abundant among their immune cells, which differs from typical autoimmune hepatitis. Meanwhile, the patient’s B cells and plasma cells are relatively low, whereas in typical autoimmune hepatitis, B cells and plasma cells are more abundant. Spatial analysis of different subsets of immune cells in the liver parenchyma revealed more extensive immune cell infiltration around the portal areas in the patient. Although the patient's B cells and plasma cells are mainly enriched around the portal areas, (CD8) T lymphocytes show a pan-lobular distribution. Notably, the patient exhibits a high accumulation of cytotoxic (CD8) T cells, while the levels of other granzyme B-expressing cells remain unchanged.

Next, the researchers used flow cytometry to further analyze the intrahepatic and peripheral populations of (CD8) T cells. The intrahepatic (CD8) T cell pool of patients showed enrichment of activation markers (CD38) and tissue residency markers (CD103, CD69, and CXC chemokine receptor 6 [CXCR6]). (CD8) T cells in peripheral blood also expressed CD38. The researchers noted that in patients who did not develop hepatitis after vaccination, the expression of CD38 (75.9%) was significantly higher than in the control group of healthy individuals (15.4%). Compared with peripheral blood, the SARS-CoV-2 S-specific (CD8) T lymphocytes in the intrahepatic (CD8) T cell population of patients were enriched by 3.4 times.

In addition, the abundance of S-specific (CD8) T lymphocytes in the patient's peripheral blood was 10.2 times that of Epstein-Barr virus-specific T cell control epitope-specific T lymphocytes. Moreover, the patient's CD38 levels decreased with budesonide treatment. However, when a relapse occurred during budesonide treatment, the expression of CD38 on SARS-CoV-2 S protein and other cytotoxic marker-specific (CD8) T cells increased again but returned to normal after systemic immunosuppressive treatment.

The study suggests that, mechanistically, the symptoms of this 52-year-old patient differ from typical spontaneous autoimmune hepatitis, which is usually associated with elevated peripheral immunoglobulins, plasma cell-predominant infiltration, and prominent interface hepatitis. In this clinical case, although there was a slight increase in peripheral immunoglobulins and intrahepatic enrichment of B cells and plasma cells, a more significant correlation was observed at the level of cytotoxic (CD8) T cells. Cytotoxic (CD8) T cells, including those activated by vaccine-induced SARS-CoV-2 S-specific responses, were highly enriched in the patient's liver to the extent that they became the most enriched immune cell population within the liver. Notably, the peripheral activation status of these SARS-CoV-2 S-specific (CD8) T cells correlated with the severity of hepatitis and the clinical course following the introduction of immunosuppressive therapy.

In conclusion, highly activated T cells accumulate and are evenly distributed in different areas of the liver in patients with liver inflammation after SARS-CoV-2 vaccination. Moreover, an enrichment of T cells reactive to SARS-CoV-2 can be observed among these liver-infiltrating T cells, suggesting that vaccination with Pfizer/BioNTech's COVID-19 mRNA vaccine (BNT162b2) may lead to immune-mediated hepatitis through triggered cellular immune mechanisms.

Notably, this is not the first case of autoimmune hepatitis triggered by a COVID-19 vaccine. In April last year, a 47-year-old healthy man developed symptoms of autoimmune hepatitis after receiving the Moderna vaccine. Three days after his first dose of the Moderna vaccine, the man experienced discomfort and jaundice. Further examination revealed that the histological pattern of injury was consistent with acute hepatitis, showing characteristics of autoimmune hepatitis or possible drug-induced liver injury.

Reference Source:

1. The Paper

2、SARS-CoV-2 vaccination can elicit a CD8 T-cell dominant hepatitis

3、Immune-mediated hepatitis with the Moderna vaccine, no longer a coincidence but confirmed