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Weaker COVID-19 vaccine responses seen in people with advanced liver fibrosis

Liz Highleyman
05 July 2021
Professor Rifaat Safadi of Hadassah University Hospital, Jerusalem, speaking at an International Liver Congress 2021 press briefing

Among people with non-alcoholic fatty liver disease (NAFLD), those with more advanced liver fibrosis did not respond as well to the Pfizer-BioNTech COVID-19 vaccine, according to study results presented at the 2021 International Liver Congress. These and other findings from liver transplant recipients raise the question of whether a third booster dose could improve immune response.

Prior studies have shown that people with liver disease, including advanced cirrhosis and alcoholic liver disease, are more likely to develop severe COVID-19 and die from it. Another study found that fatty liver disease may help explain the greater likelihood of severe COVID-19 among people with obesity.

Given this increased risk, experts recommend that people with liver disease should be prioritised for COVID-19 vaccination. But questions remain about vaccine effectiveness in this population.



Cell of the liver.


A type of tumour affecting the lymph nodes.


Abnormal fat deposits in the liver.

Prof. Rifaat Safadi of Hadassah-Hebrew University Medical Centre in Jerusalem and colleagues evaluated the impact of chronic liver disease on the effectiveness of the Pfizer-BioNTech messenger RNA (mRNA) vaccine.

In one study, the researchers analysed a cohort of 719 HMO employees who received the vaccine and were tested for IgG antibodies against SARS-CoV-2 at least seven days after the second dose; 98.5% had a good response.

Two of the eleven non-responders had received kidney transplants. Transplant recipients take immunosuppressive drugs to prevent organ rejection, which could interfere with immune response. Five were taking immunosuppressive medications for rheumatoid arthritis, multiple sclerosis or lymphoma; other studies have shown that people with blood cancers to not respond as well to COVID-19 vaccines. Four had metabolic syndrome, characterised by abdominal obesity, high blood pressure and abnormal blood sugar, cholesterol and triglyceride levels.

In this cohort, 501 responders and 10 non-responders had lab test data available to calculate FIB-4 scores, a measure used to estimate liver fibrosis. 360 (70.5%) had a FIB-4 score below 1.3, 137 (26.8%) had a FIB-4 score between 1.3 and 2.67, and 14 (2.7%) had a FIB-4 score above 2.67). Among the responders, 68.0% of those with a FIB-4 score below 1.3 (ruling out advanced fibrosis) had an excellent response (an antibody titre of 200 AU/ml or higher) compared with 44.2% of those with a score above 2 (predictive of advanced fibrosis).

The researchers also evaluated 140 people with NAFLD who underwent liver biopsies. All but two (98.6%) responded to the vaccine, including 87 (62.1%) with an excellent response. Those who had an excellent response were younger, on average, than those with a weaker response (53.7 vs 61.5 years). Body mass index was similar in both groups.

People with more advanced fibrosis did not respond as well to vaccination, Safadi reported. Among those with mild fibrosis (stage F1), 39% had an excellent response while 28% had a weaker response. However, among those with advanced fibrosis (stage F3), just 14% had an excellent response and 17% had a weaker response. For those with cirrhosis (stage F4), the corresponding figures were 8% and 23%, respectively.

But liver steatosis, or fat accumulation, was actually associated with better vaccine response. Among those with grade 0 steatosis (<5% liver fat), 14% had an excellent response and 19% had a weaker response. For those with grade 1 (5-33% liver fat), the corresponding figures were 33% and 45%. Conversely, people with more liver fat were more likely to have an excellent response: 36% excellent vs 26% weak among those with grade 3 (33-66% liver fat) and 17% excellent vs 9% weak among those with grade 4 (>66% liver fat). Hepatocyte 'ballooning' and liver inflammation were similar in both groups.

"Older age, advanced fibrosis with decreased steatosis are risk factors for lower vaccine response for Pfizer’s BNT162b2 vaccine," the researchers concluded. "A third dose vaccine booster in those risk factor populations should be evaluated in future trials."

Speaking at a conference press briefing, Safadi also reported findings from a cohort of 90 liver transplant recipients who were tested for SARS-CoV-2 antibodies after receiving two doses of the vaccine. Of these, 52 (58.9%) produced an adequate immune response, with antibodies titres of at least 19 AU/ml, while 37 (41.1%) were non-responders. Five patients (5.6%) had breakthrough COVID-19, one after the first vaccine dose and four after the second dose. He noted that people who received transplants more recently had poorer responses, likely due to use of stronger immunosuppressive regimens.

Safadi noted that COVID-19 outcomes for liver transplant recipients improved after the vaccine rollout. Since June 2020, 41 transplant patients contracted COVID-19, including two who died; 36 of them were not vaccinated. There were no cases reported in April, May or June 2021. This may indicate that patients were protected by the vaccine despite some having low antibody levels, or it may reflect the fact that Israel has achieved population immunity thanks to high vaccine uptake. "Was that a result of their vaccination or the result of the population vaccination?," he asked. "That was the question."

EASL vice secretary Prof. Thomas Berg, who moderated the press briefing, brought up the point that antibody levels do not give a full picture of immunity, as memory B-cell and T-cell responses also play a role.

Safadi noted that the Israeli Ministry of Health is thinking now about third booster doses for people who have a lower antibody response or are at higher risk for non-response. Advanced fibrosis, as assessed by FIB-4 or biopsy, is a strong predictor of non-response.

"Now I'm just going to start to boost my transplant patients who failed to develop a serological response with a third vaccination," he said, adding that one person who had already received a third dose saw an elevation from zero to a "very nice titre."

Two recent studies published in Annals of Internal Medicine and the New England Journal of Medicine found that an extra booster dose improved antibody responses among organ transplant recipients, including about a dozen who received liver transplants. Further studies are underway to determine if the third dose strategy could also help people with immunosuppression due to other causes and people with liver disease, cancer and other co-morbidities associated with poor vaccine response.


Hakimian D et al (Safadi R presenting). Elderly with advanced liver fibrosis had lower response to Pfizer’s SARS-CoV-2 vaccine response. International Liver Congress, abstract OS-2854, 2021.