ABSTRACT
The immunogenicity of COVID-19 vaccines in patients with liver cirrhosis remains largely unknown. The purpose of this meta-analysis was to investigate the immunogenicity of COVID-19 vaccines in patients with cirrhosis and compare the humoral and cellular immune responses following complete COVID-19 vaccination between cirrhosis patients and healthy controls. A systematic literature search was conducted in PubMed, EMBASE, and Web of Science from 1 January 2020 to 22 August 2023. Sixteen studies with 2127 cirrhosis patients were included. The pooled seroconversion rate in patients with cirrhosis following complete COVID-19 vaccination was 92.4% (95% CI, 86.2%–96%, I2 = 90%) with significant between-study heterogeneity. Moreover, COVID-19 vaccination elicited a higher humoral immune response in patients of compensated cirrhosis as compared with decompensated cirrhosis (RR = 1.069, 95% CI, 1.011–1.131, I2 = 17%, p = .019). Additionally, 10 studies were included for comparison analysis of seroconversion rate between cirrhosis patients and healthy controls. The results showed that the seroconversion rate in patients with cirrhosis was slightly lower compared with healthy controls (RR = 0.972, 95% CI, 0.955–0.989, I2 = 66%, p = .001). Meanwhile, the pooled RR of cellular immune response rate for cirrhosis patients vs. healthy controls was 0.678 (95% CI, 0.563–0.817, I2 = 0, p < .0001). Our meta-analysis demonstrated that COVID-19 vaccination elicited diminished humoral and cellular immune responses in patients of cirrhosis. Patients with cirrhosis particularly decompensated cirrhosis who have completed full-doses of COVID-19 vaccination should receive continuous attention and preemptive measures.
KEYWORDS:
Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the culprit of the coronavirus disease 2019 (COVID-19), has been responsible for almost 770 million cases and more than 6.9 million deaths worldwide by 30th August 2023.Citation1 Patients with comorbidities including chronic liver diseases, particularly cirrhosis, are at a high risk of severe COVID-19 and COVID-19-associated mortality.Citation2–4 Vaccination is the most effective measure to protect the population from severe COVID-19. Therefore, the European Association for the Study of Liver Disease (EASL) and the American Association for the Study of Liver Disease (AASLD) guidelines recommended that patients with liver cirrhosis be prioritized for COVID-19 vaccination.Citation5,Citation6
Cirrhosis is characterized by immune dysregulation with several abnormalities in components of the innate and adaptive immune system, which is associated with poor immune response to vaccines against hepatitis B, influenza, and pneumococcus.Citation7–9 Therefore, it is important to evaluate the immune response against COVID-19 vaccines in patients with liver cirrhosis. Despite the safety and effectiveness of COVID-19 vaccines in phase III, placebo-controlled clinical trials have been reported in the general population,Citation10–12 limited data are available on the immunogenicity of COVID-19 vaccines in patients with cirrhosis. A few observational studies have reported a suboptimal antibody response following COVID-19 vaccination in patients with cirrhosis compared to healthy controls.Citation13–15 However, another study suggested that the seroconversion rate was similar between cirrhotic patients and a reference group of health-care workers.Citation16 In view of the inconsistent results in the above-mentioned studies, the immunogenicity of COVID-19 vaccine in patients with cirrhosis remains controversial. A meta-analysis with large clinical samples is warranted to draw a reliable conclusion.
In this study, we performed a systematic review and quantitative meta-analysis to compare the humoral and cellular immune response following COVID-19 vaccination in patients with cirrhosis and healthy controls.
Methods
Search strategy
We searched PubMed, EMBASE, and Web of Science for available studies published in English from 1 January 2020 to 22 August 2023. To identify all the articles regarding the immunogenicity of COVID-19 vaccines in patients with cirrhosis, we used the following keywords alone or in combination for literature search: “SARS-CoV-2,” “COVID-19,” “2019-nCoV,” “severe acute respiratory syndrome coronavirus 2,” “liver disease,” “liver cirrhosis,” “hepatic cirrhosis,” “vaccine,” “vaccination,” and “immunization.” References of the included studies were also manually searched to select additional studies. This systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.Citation17
Inclusion and exclusion criteria
Studies were included if they met the following criteria: (1) Study population: adult patients with liver cirrhosis following full dose of COVID-19 vaccination without prior COVID-19 infection; (2) Outcomes: We calculated the pooled seroconversion rate of anti-SARS-CoV-2 spike antibody or anti-receptor-binding domain (RBD) antibody or neutralizing antibody (Nab) against SARS-CoV-2 in patients of liver cirrhosis following vaccination. The seroconversion rate was reported in the following sequence: anti-spike antibody, anti-RBD antibody, or neutralization antibody. The pooled relative risk (RR) for seroconversion rate in patients with compensated cirrhosis (CC) as compared to patients with decompensated cirrhosis (DC) was estimated. We also compared the seroconversion rate and detectable T-cell immune response rate between patients with liver cirrhosis and healthy controls.
Exclusion criteria included: (1) case reports, reviews, meta-analyses, guidelines, editorials, and comments; (2) reports with less than 20 patients; (3) publications with insufficient data and studies in non-English languages; (4) If participants with and without prior COVID-19 infection were enrolled in a study, subjects with prior COVID-19 infection were excluded. The flow diagram of the study selection has been drafted in accordance with the PRISMA principle.Citation17
Data extraction and quality assessment
Two authors screened independently to determine which studies should be included, and any discrepancy was resolved by a third author. The extracted data included the first author, publication date, country, gender and mean age of participants, type of vaccine, time interval between the second dose of vaccination and antibody testing, type of antibody, method of antibody testing, and outcomes of interest. The data are shown to be median and interquartile range were transformed into mean and standard deviation (SD) according to the formula below (https://smcgrath.shinyapps.io/estmeansd/). The quality of the included observational studies was assessed using the Newcastle-Ottawa scale (NOS) which consists of three categories (quality of the selection, comparability, and the outcome of study). Scores range from 0 to 9, and the risk of bias in the studies was considered as low risk (7–9 points), moderate risk (4–6 points), and high risk (0–3 points), respectively.
Statistical analysis
Statistical analyses were performed using R statistical software version 4.2.2.Citation18 The “metaprop” command in R was performed to estimate the pooled seroconversion rate with 95% confidence interval (CI) in patients, with liver cirrhosis following full-dose of COVID-19 vaccination. The “metabin” function was used to estimate the risk ratio (RR) with 95% confidence interval of humoral and cellular immune response rates between patients and healthy controls as well as between CC and DC. The I2 statistic was used to evaluate the heterogeneity of the pooled estimate. Heterogeneity was considered as low (<25%), moderate (25%–75%) and high (>75%). If there was no evidence of between-studies heterogeneity (I2 ≤ 50%), a fixed-effects model was used to combine the data. Otherwise, a random-effects model was selected. To explore the potential source of heterogeneity, subgroup analysis and meta-regression based on type of vaccine, type of antibody, method of antibody testing, the gender, mean age of participants and time interval between the second dose of vaccination and antibody testing were performed. Sensitivity analysis was performed using a leave-one-out method to confirm the robustness of outcomes. Publication bias was determined by funnel plot and Egger's test if the number of included studies >10. A trim-and-fill method was used to adjust for publication bias. p value less than .05 was regarded as statistically significant.
Results
Study characteristics
A total of 4074 articles were identified according to the search terms. Firstly, duplicated articles (n = 968) were excluded. After reviewing the titles and abstracts, 3007 articles were ruled out and 99 articles underwent full-text screening. Eighty-three articles were excluded due to the following reasons: reviews, editorials, comments, studies with wrong patient population or overlapping cohort or no outcome of interest. Finally, 16 articles with 2127 cirrhosis patients and 843 healthy controls were included in our meta-analysis. shows the full PRISMA flow diagram of study selection. The characteristics of included studies are shown in . Most of the studies were from Europe and Asia, with only one study from Americas. The quality of the studies was evaluated and shown in . Eight studies showed a low risk of bias and other eight studies showed a moderate risk of bias. The time interval between the last dose and antibody testing ranged from 14 to 112 days.
Figure 1. PRISMA flowchart of included and excluded studies.
Table 1. Characteristics of the included studies.
Table 2. Quality assessment of the included studies by Newcastle-Ottawa scale (NOS).
Humoral immune response after full dose of COVID-19 vaccination in cirrhosis patients
Sixteen eligible studies reported humoral immune response in 2127 cirrhosis patients following a full dose of COVID-19 vaccination. Among the 16 studies, 4 studiesCitation19–22 reported both Nab and anti-spike antibody, 2 studies only reported NabCitation15,Citation23 and 10 studies only reported anti-spike or anti-RBD antibody.Citation13,Citation14,Citation16,Citation24–30 The pooled seroconversion rate (14 studies of anti-spike and/or anti-RBD and 2 studies of Nab) was 92.4% (95% CI, 86.2%–96%) () with considerable heterogeneity (I2 = 90%, p < .01). Sensitivity analysis showed that the pooled estimate was robust (Supplemental Figure S1). The funnel plot (Supplemental Figure S2) and the result of Egger's test (p < .0001) indicated the existence of publication bias. Trim-and-fill method was used to adjust for publication bias, and the pooled seroconversion rate was 80.1% (95% CI, 60.5%–91.3%) after adjusting.
Figure 2. Forest plot of the seroconversion rate following complete COVID-19 vaccination in patients of cirrhosis. CI, confidence interval.
Subgroup analysis and meta-regression
Subgroup analysis was performed to identify potential sources of heterogeneity based on type of antibody, type of vaccine and method of antibody testing. The pooled seroconversion rate of anti-spike antibody in cirrhosis patients was significantly higher than that of neutralizing antibody (94% (95% CI, 88.4%–97%) vs 74.8% (95% CI, 64.3%–83%), p < .01) (Supplemental Figure S3). The pooled seroconversion rate after complete vaccination with mRNA vaccine, adeno-associated virus (AAV), and inactivated vaccine was 94.7% (95% CI, 88.7%–97.6%), 93.7% (95% CI, 70.2%–98.9%) and 81.9% (95% CI, 62%–92.6%), respectively (Supplemental Figure S4). The pooled seroconversion rate detected with ECLIA, CLIA, and ELISA was 95.1% (95% CI, 71.9%–99.3%), 89.1% (95% CI, 78.8%–94.8%), and 96.5% (95% CI, 91.2%–98.6%), respectively (Supplemental Figure S5).
Meta-regression shows a trend toward significance between seroconversion rate and antibody type (p = .06). However, no association of pooled seroconversion rate with type of vaccine (p = .11), method of antibody testing (p = .3), time interval between the last dose and antibody testing (p = .76), mean age (p = .62), and male ratio (p = .77) were found.
Comparison of humoral immune response between compensated cirrhosis and decompensated cirrhosis
Nine studies compared the humoral immune response between compensated cirrhosis (n = 955) and decompensated cirrhosis (n = 486) after complete vaccination. The seroconversion rate in patients with compensated cirrhosis was higher as compared to patients with decompensated cirrhosis (RR = 1.069, 95% CI = 1.011–1.131, I2 = 17%, p = .019) (). The sensitivity analysis confirmed the robustness of the result (Supplemental Figure S6).
Figure 3. Forest plot of the comparison of seroconversion rate between compensated cirrhosis and decompensated cirrhosis.
Comparison of humoral immune response between cirrhosis patients and healthy controls
There were 10 studies (1077 patients and 843 controls) that compared seroconversion rate following complete COVID-19 vaccination between cirrhosis patients and healthy controls. Compared with healthy controls, the cirrhosis patients exhibited a slightly lower seroconversion rate with moderate heterogeneity (RR = 0.972, 95% CI = 0.955–0.989, I2 = 66%, p = .001) (). The RR value did not change markedly by sensitivity analysis, confirming the stability of the result (Supplemental Figure S7). Subgroup by type of vaccine demonstrated significant between-group differences with a higher rate of heterogeneity in the group of inactivated vaccines (Supplemental Figure S8).
Figure 4. (a) Forest plot of the comparison of humoral immune response between cirrhosis patients and healthy controls; (b) Forest plot of the comparison of cellular immune response between cirrhosis patients and healthy controls.
Comparison of cellular immune response between cirrhosis patients and healthy controls
Only two studies reported detectable T-cell immune response rate in 68 patients and 50 controls. The T-cell immune response rate following complete COVID-19 vaccination in cirrhosis patients was significantly lower as compared with healthy controls (RR = 0.678, 95% CI = 0.563–0.817, I2 = 0, p < .0001) (). We compare the method used to analyze cellular immunity and type of vaccine employed between the two studies. Both two studies quantified interferon-gama (IFN-γ) production which was released by T cells upon in vitro stimulation with peptides derived from the SARS-COV-2 spike antigen to analyze cellular immunity. Although both studies used ELISA as the detection method, the ELISA test kit used in the two studies was from different companies, resulting in difference in cutoff values which were regarded as positive cellular immunity. In addition, patients and healthy controls in both two studies mainly received full doses of mRNA vaccination. Although the method applied and type of vaccine employed in the two studies were similar, the results of the cellular immunity should be interpreted with caution considering only two studies were included in the meta-analysis.
Discussion
To our knowledge, this is the first meta-analysis to report immunogenicity of COVID-19 vaccines in patients with liver cirrhosis. Our results show that the pooled seroconversion rate following complete COVID-19 vaccination was 92.4% in patients with cirrhosis with considerable heterogeneity. The humoral immune response in patients with decompensated cirrhosis was significantly lower as compared with compensated cirrhosis. In addition, both the humoral and cellular immune response in patients with cirrhosis were impaired when compared to healthy controls.
Up to now, only two meta-analysesCitation31,Citation32 have reported the seroconversion rate after COVID-19 vaccination in patients with chronic liver disease, in which subgroup analysis based on cirrhosis status has been performed. The pooled rate of humoral immune response in the cirrhosis patients was found 94% (95% CI, 82%–100%) in one study (328 patients)Citation32 and 85% (95% CI, 75%–91%) in another study (406 patients).Citation31 Our study observed that the pooled seroconversion rate was 92.4% (95% CI, 86.2%–96%) in 2127 patients of cirrhosis with considerable heterogeneity. This inconsistency may be explained by different sample sizes and types of detected antibodies. As all of the included articles in our meta-analysis, except for two reported seroconversion rates of anti-spike or anti-RBD antibody, we calculated the pooled seroconversion rate mainly based on data of anti-spike or anti-RBD antibody with only two data of Nab. Neutralizing antibody has been considered as proxy indicator of protection from symptomatic COVID-19 infection.Citation33 Studies have demonstrated that measurement of anti-spike or anti-RBD IgG results in a slightly higher seroconversion rate than that of Nab.Citation19–22 Consistent with these studies, subgroup analysis in our study confirmed that the pooled seroconversion rate of anti-spike or anti-RBD antibody in cirrhosis patients was 94% (95% CI, 88.4%–97%), which was significantly higher than that of neutralizing antibody (74.8%; 95% CI, 64.3%–83%).
Patients with cirrhosis display cirrhosis-associated immune dysfunction (CAID) that predisposes patients to bacterial and viral infections as well as poor response to various vaccinations.Citation34 Several studies have showed that patients with cirrhosis, particularly decompensated cirrhosis, have diminished antibody levels after COVID-19 vaccination compared with healthy controls.Citation13–15,Citation27 Recently, Simão et al. have reported that cirrhosis is associated with a lower serological response to COVID-19 vaccines in patients with chronic liver disease.Citation35 In line with these studies, our results suggested that the cirrhosis patients exhibited a slightly lower seroconversion rate after COVID-19 vaccination compared to healthy controls. Additionally, patients with decompensated cirrhosis manifested inferior vaccine response compared to patients with compensated cirrhosis.
T-cell responses have been associated with protection from severe COVID-19 infection despite a lack of seroconversion.Citation36,Citation37 Expectedly, similar to the result found in humoral immune response, we observed that T-cell immune response was significantly impaired compared to the healthy controls. However, only two studies were combined, although no heterogeneity was found and the result should be interpreted with caution. More studies regarding cellular immune response in cirrhosis patients are needed to provide a reliable conclusion.
Given that cirrhosis patients exhibit a diminished humoral and cellular immune response following COVID-19 vaccination compared to healthy controls, measures aim to enhance the immunization rate, e.g. further booster doses or heterologous vaccination which has been observed in other conditions characterized by impaired immunity should be considered in patients with cirrhosis.Citation38,Citation39 Currently, there were limited studies reporting the immune responses to the additional booster doses in patients with cirrhosis. A recent study demonstrated that the booster dose of COVID-19 vaccination significantly increased the SARS-COV-2 specific wild-type antibody levels.Citation40 Another study observed higher immunogenicity of both humoral and cellular responses to the heterologous COVID-19 vaccine regimen compared to homogeneous regimens in patients with cirrhosis.Citation41 Therefore, we speculate that further booster doses of COVID-19 vaccination with heterologous regimens could possibly enhance the immune response of patients with cirrhosis.
Even though humoral and cellular immune responses to COVID-19 vaccination seem to be inferior in patients with cirrhosis, evidence provided by real-world study has demonstrated the effectiveness of COVID-19 vaccines in patients with cirrhosis as shown in reduced rates of SARS-COV-2 infection, severe COVID-19 and COVID-19 related mortalities.Citation42,Citation43 Administration of a third dose of COVID-19 vaccine is associated with a reduced risk of breakthrough infection, severe/critical COVID-19, and COVID-19-related death compared to two doses of vaccine.Citation44,Citation45 With the continuing emergence of novel viral variants, the effectiveness of COVID-19 vaccination could be possibly faded, as evidenced by the finding that serological titers to Omicron subvariants and neutralization activity against Omicron subvariants in patients with cirrhosis following 2 or 3 doses of COVID-19 vaccination were significantly lower compared to wild-type SARS-COV-2.Citation40,Citation46 In addition, another study demonstrated that COVID-19 vaccination was less effective against symptomatic COVID-19 during the Omicron period compared to the Alpha and Delta periods.Citation47 However, they also found that vaccine effectiveness against severe/critical COVID-19 was highest during Omicron and lowest during the Delta period.Citation47 The above evidences provide reassurance to patients with cirrhosis and clinicians treating them.
Inevitably, the present study has several limitations. First, a significant magnitude of heterogeneity exists in our study. To explore the potential origin, we performed subgroup analysis and meta-regression based on antibody type, type of vaccine, method of antibody testing, time interval between the last dose and antibody testing, mean age, and male ratio. However, no significant association of pooled seroconversion rate with these above factors except antibody type was found. Studies have suggested that comorbidities (diabetes, obesity, chronic kidney disease, etc.)Citation48–50 and the etiology of cirrhosis (particularly autoimmune hepatitis taking suppression drugs)Citation51 are associated with the inferior humoral immune response of COVID-19 vaccine. However, the individual study included in this present meta-analysis comprised a heterogeneous population of various comorbidities and disease etiology. Subgroup analysis and meta-regression regarding specific comorbidity and disease etiology could not be performed due to lack of data. Second, all of the included studies are observational which could result in potential bias and cannot be adjusted by meta-analysis. Third, the test kits used to detect antibody and the cutoff value to define a positive seroconversion vary among different studies. Finally, only 2 studies are available to retrieve data regarding the rate of cellular immune response following COVID-19 vaccination, which might not be sufficient.
In conclusion, our study demonstrated that COVID-19 vaccination elicited a diminished humoral and cellular immune response in patients with cirrhosis. Booster vaccination may be considered in patients with cirrhosis who have completed full doses of COVID-19 vaccination. As the continuous emergence of novel SARS-COV-2 variants, self-protective behaviors should be followed by cirrhosis patients even if they have received COVID-19 vaccination. An updated meta-analysis, which includes more well-designed clinical trials with large sample size, is needed in the future.
Author contributions
Lichen Ouyang designed the search strategy, screened studies for eligibility, conducted the data analysis, and wrote the first draft of the manuscript. Yeli Gong conceived the study, screened studies for eligibility, and critically revised the manuscript. Gang Lei addressed discrepancies in screening and data extraction and critically revised the manuscript. All coauthors were involved in the final editing of the manuscript. The corresponding authors attest that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
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References
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