The two authors share co-first authorship.
Editor: Ji Hoon Kim, Korea University Guro Hospital, Korea
Studies of hepatic steatosis (HS) effect on COVID-19 vaccine immunogenicity are lacking. We aimed to compare immunogenicity of BNT162b2 and CoronaVac among moderate/severe HS and control subjects.
Two hundred ninety-five subjects who received BNT162b2 or CoronaVac vaccines from five vaccination centers were categorized into moderate/severe HS (controlled attenuation parameter ≥268 dB/m on transient elastography) (n=74) or control (n=221) groups. Primary outcomes were seroconversion rates of neutralising antibody by live virus Microneutralization (vMN) assay (titer ≥10) at day21 (BNT162b2) or day28 (CoronaVac) and day56 (both). Secondary outcome was highest-tier titer response (top 25% of vMN titer; cutoff: 160 [BNT162b2] and 20 [CoronaVac]) at day 56.
For BNT162b2 (n=228, 77.3%), there was no statistical differences in seroconversion rates (day21: 71.7% vs. 76.6%; day56: 100% vs. 100%) or vMN geometric mean titer (GMT) (day21: 13.2 vs. 13.3; day56: 91.9 vs. 101.4) among moderate/severe HS and control groups respectively. However, lower proportion of moderate/severe HS patients had highest-tier response (day56: 5.0% vs. 15.5%;
While there was no difference in seroconversion rate between moderate/severe HS and control groups after two doses of vaccine, a lower proportion of moderate/severe HS patients achieved highest-tier response for either BNT162b2 or CoronaVac.
• There is no difference in the seroconversion rate of neutralising antibody between patients with and without moderateto-severe hepatic steatosis after two doses of vaccines (for either BNT162b2 or CoronaVac).
• A lower proportion of patients with moderate-to-severe hepatic steatosis achieve a highest-tier humoral response after two doses of vaccines (for either BNT162b2 or CoronaVac).
• There are no serious adverse reactions in COVID-19 vaccine recipients with moderate-to-severe hepatic steatosis.
The ongoing coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged into a global health burden. As of March 2022, COVID-19 has affected more than 400 million people and caused nearly 6 million deaths worldwide. Apart from measures such as social distancing, quarantine and isolation, vaccination is crucial in preventing infection, severe disease and death [
Chronic liver disease is associated with a higher infection risk and disease severity of COVID-19, especially those with liver cirrhosis [
Neutralising antibody level is a surrogate marker of vaccine effectiveness [
In Hong Kong, both mRNA and inactivated vaccines are available. Therefore, we aimed to conduct a longer-term prospective cohort study to compare immunogenicity of BNT162b2 and CoronaVac (after both first and second doses) and adverse events in patients with moderate-to-severe HS and control subjects.
This is a prospective cohort study recruiting adult COVID-19 vaccine recipients (BNT162b2 and CoronaVac) from five local vaccination centers. Exclusion criteria included age <18 years, transplant patients, patients taking immunosuppressives/chemotherapy, inflammatory bowel disease, other medical diseases (cancer, hematological, rheumatological and autoimmune diseases), those with prior COVID-19 infection (identified from history taking or presence of antibodies to SARS-CoV-2 nucleocapsid protein which are not inducible by BNT162b2 and therefore is an indicator of past infection).
Severity of HS was defined by controlled attenuation parameter (CAP) ≥248 dB/m measured by transient elastography using Fibroscan® (Echosens, Paris, France): mild (CAP 248-267 dB/m), moderate (CAP 268-279 dB/m) and severe (CAP ≥280 dB/m) [
Recruited subjects received either BNT162b2 or CoronaVac according to their preference. They received two doses of intramuscular BNT162b2 (0.3 mL) and CoronaVac (0.5 mL) 3 weeks and 4 weeks apart, respectively. Their blood samples were collected at four time-points: (i) before vaccination (baseline), (ii) 21 days (for BNT162b2) or 28 days (for CoronaVac) after first dose, (iii) 56 days after first dose (for both BNT162b2 and CoronaVac), and (iv) 180 days after first dose for BNT162b2 only (CoronaVac data was unavailable at this time point). Live virus Microneutralization (vMN) assay was performed in 96-well plate as described previously (
Subjects were requested to record any systemic and local events daily for 7 days after both first and second dose of vaccine. The severity of adverse events were graded as 1, 2, 3, and 4, according to toxicity grading scale by U.S. Department of Health and Human Services [
The study was approved by the Institutional Review Board of the University of Hong Kong (HKU) and Hong Kong West Cluster (HKWC) of Hospital Authority.
Primary outcomes of interest are seroconversion rates at three time points after first dose for BNT162b2 (day21, day56, and day180) and two time points for CoronaVac (day28 and day56).
Secondary outcomes of interest are (i) highest-tier titer response; (ii) overall and individual adverse events after both first and second doses. We defined the top 25% of vMN titer (i.e., above 75 percentile) as highest-tier titer response based on D56 data, while the remainders as having suboptimal humoral immune response. The 25% was an arbitrary cut-off as there is still no international consensus. A cut-off of 160 and 20 antibody tier was adopted for BNT162b2 and CoronaVac, respectively. Top 25% was selected as cut-off as vaccine effectiveness waned by time [
Subjects with moderate or severe HS were grouped as “HS” and those with mild or no HS were regarded as control group. Covariates included age >70, sex, overweight/obesity, smoking, alcohol use, hypertension, DM, liver fibrosis (liver stiffness measurement >6.5 kPa) [
Sensitivity analysis was carried out by comparing moderate/severe HS subjects fulfilling criteria of MAFLD and control groups (subjects without HS or those with mild HS). The definition of MAFLD [
All statistical analyses were conducted in R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria) statistical software. Data is displayed as median (interquartile range [IQR]) for continuous variables, and as number of patients (percentage) for categorical variables. The Mann-Whitney U test was used for two continuous variables, and the chi-square test or Fisher exact test was used for categorical variables to assess the statistical significance between groups. Geometric mean titer (GMT) with 95% confidence interval (CI) was used to express the average vMN titer. A multivariable logistic regression model was used to estimate adjusted odds ratio (aOR) of highest-tier titer response with HS as well as all aforementioned covariates. For the purpose of statistical analysis, an MN titer of <10 was considered as 5. A two-sided P-value ≤0.05 was considered as statistically significant.
A total of 295 subjects (moderate/severe HS: 74 [25.1%; 73 fulfilled the criteria of MAFLD] and control group: 221 [74.9%]) were enrolled. The demographics of subjects are shown in
The median age was similar between two groups, for either BNT162b2 (HS: 51.1 years vs. control: 50.9 years;
HS-associated comorbidities including hypertension, diabetes, alcohol intake were also included in
All subjects had vMN titer lower that of the detection limit.
Among HS group, seroconversion rate of BNT162b2 was higher than CoronaVac after both first dose (71.7% vs. 7.1%,
Among control group, seroconversion rate of BNT162b2 was higher than CoronaVac after both first dose (76.6% vs. 15.1%,
On univariate analysis, the OR of highest-tier titer response to BNT162b2 with HS was 0.29 (95% CI, 0.07–0.86). On multivariable analysis, HS was the only independent factor associated with this outcome (aOR, 0.24; 95% CI, 0.05–0.87) (
On univariate analysis, OR of highest-tier titer response to CoronaVac with HS was 0.24 (95% CI, 0.05–0.88). Multivariable analysis did not reveal an association between HS and highest-tier antibody titer response.
One hundred ninety (83.3%) BNT162b2 recipients and 36 (53.7%) CoronaVac recipients reported adverse events within 7 days of first dose of vaccine (
Among BNT162b2 recipients, HS group showed higher rate of systemic reaction than control group (35 [58.3%] vs. 65 [38.7%],
Among CoronaVac recipients, HS group showed lower rate of any adverse event (4 [28.6%] vs. 32 [60.4%],
One hundred ninety-four (85.1%) BNT162b2 recipients and 30 (44.8%) CoronaVac recipients reported adverse events within 7 days of second dose of vaccine (
Among BNT162b2 recipients, there was no significant difference in frequency of adverse events between HS and control groups (any adverse event: 51 [85%] vs. 143 [85.1%],
Among CoronaVac recipients, HS group showed lower rate of any adverse event (3 [21.4%] vs. 27 [50.9%],
This prospective cohort study demonstrates that BNT162b2 is more immunogenic than CoronaVac in terms of neutralising antibody response. While there was no difference in the seroconversion rate between moderate/severe HS and control groups for either BNT162b2 or CoronaVac, a lower proportion of the former group achieved a highest-tier humoral response after two doses of vaccines. Similar findings were observed when MAFLD patients with moderate/severe HS were compared with controls.
It has been suggested that patients with chronic liver disease display immune dysfunction in which predisposes them to infections, organ inflammatory damage and poor response to vaccinations [
Diagnosis of NAFLD was made by either liver biopsy or clinical findings without proportion specified, and immunogenicity according to the severity of HS was not measured. Moreover, immunogenicity after single dose of vaccine, and longer-term data were not evaluated. In correlation with the recent study, our study further evaluated the effectiveness of CoronaVac as well as BNT162b2 in vaccine immunogenicity with HS. Our study is unique in a few different ways. First, we assessed the vaccine immunogenicity after both the first and second doses of vaccination. Second, we used live virus for analysis which is the gold standard for analysing vaccine humoral response [
To our knowledge, our study is the first to compare the immunogenicity of both inactivated virus and mRNA vaccines among patients with and without moderate/severe HS. We found no difference in the seroconversion rate or vMN GMT after either first or second dose between the HS and control groups, regardless of the vaccine platform. Although the level of antibody or neutralizing activity required to confer protection against future infection is currently not well defined, a higher level of antibodies is likely associated with a higher level of protection against future infections [
Regarding safety, COVID-19 vaccines were well tolerated with mild and self-limiting adverse events. There were difference in safety profile after 1st dose and 2nd dose vaccine for different vaccine platforms. After 1st dose vaccine, HS group showed higher rate of systemic adverse events than control group among BNT162b2 recipients. The underlying mechanism was not well understood but it could be related to circulating concentrations of inflammatory cytokines. After 2nd dose vaccine, adverse events were generally similar between HS and control groups, except for the difference in local reactions of CoronaVac recipients between HS and control groups. It could be explained by higher subcutaneous tissue thickness in patients with HS that serve as a protective barrier to localized pain [
Several limitations of our study should be noted. First, the sample size was relatively small considering the potential interaction between different vaccine platforms and HS severity. In particular, there were only 14 subjects with moderate/severe HS in CoronaVac recipients. Further study with a larger sample size will allow for better evaluation. Second, although HS was defined by CAP measured by transient elastography, magnetic resonance elastography (MRE) with high diagnostic accuracy of 0.9 was still remained as the most sensitive non-invasive modality in diagnosing HS [
While there was no difference in the seroconversion rate between subjects with or without moderate/severe HS after two doses of either BNT162b2 or CoronaVac, a lower proportion of moderate/severe HS patients achieved a highest-tier humoral response for both types of vaccines. Whether HS is an independent risk factor for poorer vaccine immunogenicity warrants further investigation.
Drs. Ka-Shing Cheung and Lok-Ka Lam were involved with study concept and design; acquisition of data; analysis and interpretation of data; drafting of manuscript; Drs. Rex Wan Hin Hui, Xianhua Mao, Ruqi R Zhang and Kwok-Hung Chan were involved with analysis and interpretation of data; and critical revision of the manuscript for important intellectual content. Profs. Wai-Kay Seto and Man-Fung Yuen were involved with the study concept and design; analysis and interpretation of data; drafting of manuscript; critical revision of the manuscript for important intellectual content; and study supervision. The corresponding author had full access to all data, and was fully responsible for the data integrity and statistical analysis. All authors revised the manuscript and approved the final version of this article.
The authors have no conflicts to disclose.
Supplementary material is available at Clinical and Molecular Hepatology website (
Neutralizing antibody responses of patients receiving BNT162b2 (n=228)
Adverse events after 1st and 2nd dose of BNT162b2 and CoronaVac
alanine aminotransferase
adjusted odds ratio
controlled attenuation parameter
confidence interval
coronavirus disease 2019
diabetes mellitus
geometric mean titer
hepatic steatosis
interquartile range
metabolic-associated fatty liver disease
magnetic resonance elastography
non-alcoholic fatty liver disease
non-alcoholic steatohepatitis
severe acute respiratory syndrome coronavirus 2
virus Microneutralization
Baseline characteristics of patients
BNT162b2 |
CoronaVac |
|||||
---|---|---|---|---|---|---|
Moderate/severe HS |
Control (n =168) | Moderate/severe HS |
Control (n=53) | |||
Age ≥70 years | 2 (3.3) | 3 (1.8) | 0.482 | 1 (7.1) | 2 (3.8) | 0.588 |
Male sex | 33 (55.0) | 50 (29.8) | <0.001 | 7 (50.0) | 13 (24.5) | 0.064 |
BMI (kg/m2) | 27.2 (24.5–29.1) | 22.3 (20.2–24.0) | <0.001 | 26.2 (24.8–26.8) | 23.1 (21.0–24.6) | <0.001 |
Overweight/obesity, BMI ≥23 kg/m2 | 54 (90.0) | 65 (38.7) | <0.001 | 12 (85.7) | 29 (54.7) | 0.034 |
Smoker | 8 (13.3) | 14 (8.3) | 0.260 | 4 (28.6) | 6 (11.3) | 0.107 |
Alcohol | 1 (1.7) | 7 (4.2) | 0.366 | 0 (0.0) | 3 (5.7) | 0.362 |
Hypertension | 12 (20.0) | 21 (12.5) | 0.156 | 5 (35.7) | 6 (11.3) | 0.028 |
Diabetes mellitus | 11 (18.3) | 6 (3.6) | <0.001 | 2 (14.3) | 2 (3.7) | 0.140 |
Liver stiffness (kPa) | 4.8 (4.1–5.9) | 4.3 (2.5–5.0) | <0.001 | 4.5 (3.7–6.1) | 4.3 (3.6–5.0) | 0.267 |
Fibrosis, liver stiffness measurement >6.5 kPa | 8 (13.3) | 11 (6.5) | 0.103 | 3 (21.4) | 1 (1.9) | 0.006 |
CAP score (dB/m) | 294 (276–314) | 217 (196–236) | <0.001 | 281 (274–305) | 218 (202–240) | <0.001 |
Values are presented as median (interquartile range) and number (%).
HS, hepatic steatosis; BMI, body mass index; CAP, controlled attenuation parameter.
59 (98.3%) of 60 moderate/severe HS subjects had metabolic-associated fatty liver disease (MAFLD).
All moderate/severe HS subjects had MAFLD.
Comparison between neutralizing antibody response of patients receiving BNT162b2 and CoronaVac
BNT162b2 | CoronaVac | ||||
---|---|---|---|---|---|
Whole cohort | 228 | 67 | |||
Seroconversion rate |
|||||
D21 (BNT162b2)/D28 (CoronaVac) | 171/227 (75.3) | 9/67 (13.4) | <0.001 | ||
D56 | 228/228 (100.0) | 53/67 (79.1) | <0.001 | ||
D180 | 156/157 (99.4) | NA | NA | ||
vMN GMT | |||||
D21 (BNT162b2)/D28 (CoronaVac) | 13.3 (11.9–14.7) | 5.7 (5.2–6.2) | <0.001 | ||
D56 | 98.4 (88.2–110.0) | 13.4 (11.2–15.8) | <0.001 | ||
D180 | 40.5 (35.9–45.6) | NA | NA | ||
Moderate/severe HS | 60 |
14 |
|||
Seroconversion rate |
|||||
D21 (BNT162b2)/D28 (CoronaVac) | 43/60 (71.7) | 1/14 (7.1) | <0.001 | ||
D56 | 60/60 (100.0) | 9/14 (64.3) | <0.001 | ||
D180 | 40/40 (100.0) | NA | NA | ||
vMN GMT | |||||
D21 (BNT162b2)/D28 (CoronaVac) | 13.2 (10.7–16.2) | 5.3 (4.8–5.8) | <0.001 | ||
D56 | 91.9 (75.9–111.1) | 9.1 (6.8–12.1) | <0.001 | ||
D180 | 39.3 (31.8–48.9) | NA | NA | ||
Control | 168 | 53 | |||
Seroconversion rate |
|||||
D21 (BNT162b2)/D28 (CoronaVac) | 128/167 (76.6) | 8/53 (15.1) | <0.001 | ||
D56 | 168/168 (100.0) | 44/53 (83.0) | <0.001 | ||
D180 | 116/117 (99.1) | NA | NA | ||
vMN GMT | |||||
D21 (BNT162b2)/D28 (CoronaVac) | 13.3 (11.8–15.0) | 5.8 (5.3–6.6) | <0.001 | ||
D56 | 101.4 (88.2–115.6) | 14.8 (12.2–18.0) | <0.001 | ||
D180 | 41.0 (35.2–47.5) | NA | NA |
vMN GMT is presented as mean (95% confidence interval).
D21, day21; D28, day28; D56, day56; D180, day180; vMN GMT, virus microneutralization geo-metric mean titer; NA, not available; HS, hepatic steatosis.
Seroconversion rate is considered as positive if vMN titer >10.
59 (98.3%) of 60 moderate/severe HS subjects had metabolic-associated fatty liver disease (MAFLD).
All moderate/severe HS subjects had MAFLD.
Neutralizing antibody responses of patients receiving BNT162b2 (n=228)
Moderate/severe HS (n=60) | Control (n=168) | ||
---|---|---|---|
Seroconversion rate |
|||
D21 | 43/60 (71.7) | 128/167 (76.6) |
0.442 |
D56 | 60/60 (100.0) | 168/168 (100.0) | 1.000 |
D180 | 40/40 (100.0) |
116/117 (99.1) |
1.000 |
Highest-tier response rate |
|||
D56 Highest-tier response rate | 3/60 (5.0) | 26/168 (15.5) | 0.037 |
D180 Highest-tier response rate | 0/40 (0.0) | 3/117 (2.6) | 0.570 |
vMN GMT | |||
D21 | 13.2 (10.7–16.2) | 13.3 (11.8–15.0) | 0.841 |
D56 | 91.9 (75.9–111.1) | 101.4 (88.2–115.6) | 0.675 |
D180 | 39.3 (31.8–48.9) | 41.0 (35.2–47.5) | 1.000 |
Fifty-nine (98.3%) of 60 moderate/severe HS subjects had MAFLD.
vMN GMT is presented as mean (95% confidence interval).
HS, hepatic steatosis; D21, day21; D56, day56; D180, day180; vMN GMT, virus microneutralization geometric mean titer.
Seroconversion rate is considered as positive if vMN titer >10.
Subjects with missing data are excluded.
Highest-tier response is defined as vMN titer >160.
Factors associated with highest-tier neutralizing antibody response at day 56 among BNT162b2 recipients on multivariable analysis
Adjusted OR | 95% CI | ||
---|---|---|---|
Age, ≥70 years | <0.001 | – | 0.995 |
Male sex | 1.62 | 0.62–4.05 | 0.312 |
Moderate/severe HS |
0.24 | 0.05–0.87 | 0.047 |
Hypertension | 0.23 | 0.01–1.29 | 0.173 |
Diabetes mellitus | 1.13 | 0.06–8.36 | 0.915 |
Overweight/obesity, BMI ≥23 kg/m2 | 0.94 | 0.37–2.28 | 0.891 |
Alcohol use | <0.001 | – | 0.994 |
Smoking | 0.32 | 0.02–1.86 | 0.300 |
Fibrosis | 1.09 | 0.16–4.69 | 0.913 |
Past gastrointestinal surgery | 3.25 | 0.64–13.92 | 0.121 |
Renal impairment | <0.001 | – | 0.993 |
OR, odds ratio; CI, confidence interval; HS, hepatic steatosis; BMI, body mass index.
59 (98.3%) of 60 moderate/severe HS subjects had metabolic-associated fatty liver disease.
Neutralizing antibody responses of patients receiving CoronaVac (n=67)
Moderate/severe HS (n=14) | Control (n=53) | ||
---|---|---|---|
Seroconversion rate |
|||
D28 | 1/14 (7.1) | 8/53 (15.1) | 0.438 |
D56 | 9/14 (64.3) | 44/53 (83.0) | 0.125 |
Highest-tier response rate |
|||
D56 Highest-tier response rate | 3/14 (21.4) | 28/53 (52.8) | 0.036 |
vMN GMT |
|||
D28 | 5.3 (4.8–5.8) | 5.8 (5.3–6.6) | 0.420 |
D56 | 9.1 (6.8–12.1) | 14.8 (12.2–18.0) | 0.021 |
All moderate/severe HS subjects had MAFLD.
vMN GMT is presented as mean (95% confidence interval).
HS, hepatic steatosis; D28, day28; D56, day56; D180, day180; vMN GMT, virus microneutralization geometric mean titer.
Seroconversion rate is considered as positive if vMN titer >10.
Highest-tier response is defined as vMN titer >20.
Live virus Microneutralization (vMN) assay
Definition of metabolic-associated fatty liver disease (MAFLD)