Safety and Efficacy of SARS-CoV-2 Vaccines in Patients With Chronic Liver Diseases: A Systematic Review and Meta-Analysis

Abstract

Objectives:

This review aimed to assess the safety and efficacy of SARS-CoV-2 vaccines in patients with chronic liver disease (CLD).

Methods:

Cochrane Central Register of Controlled Trials, PubMed, Embase, and Web of Science were searched from 2020 to 2024. Data was extracted following Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. The random-effects model (when I² ≥ 50%) or fixed effect model (I² < 50%) was used.

Results:

29 studies were included in this review. Compared to healthy controls (HCs), patients with CLD had a higher incidence of mild adverse events (RR = 1.60, p < 0.001), while the incidence of severe adverse events was similar (RR = 1.08, p = 0.92). Seropositivity rates of three antibodies in patients were lower than in HCs [neutralizing antibody (RR = 0.86, p = 0.002), anti-spike antibody (RR = 0.97, p = 0.06) and anti-receptor binding domain antibody (RR = 0.95, p = 0.04)]. Compared to unvaccinated patients, vaccinated patients had lower rates of SARS-CoV-2 infection, hospitalization and death (p ≤ 0.05).

Conclusion:

SARS-CoV-2 vaccines showed good safety and efficacy in CLD patients, but antibody response appeared to be decreased. Therefore, SARS-CoV-2 vaccines and booster doses should be given priority in this vulnerable population.

Introduction

The rapid development and deployment of vaccinations against SARS-CoV-2, alongside a degree of naturally acquired immunity from past infection, has transformed the landscape of the COVID-19 pandemic. At a population level, vaccination has been shown to reduce SARS-CoV-2 infection and protect against hospitalisation and death from severe COVID-19. However, understanding the immunogenicity and effectiveness of vaccination programmes in vulnerable cohorts with chronic disease remains an important clinical priority [1]. Patients with liver diseases might have worse outcome from COVID-19 than the general population [2–4]. Fortunately, vaccination is effective in preventing SARS-CoV-2 infection, severe symptom and death [5–7]. And societies in Europe, United States and China have recommended SARS-CoV-2 vaccination of all patients with CLD [8–10]. However, previous large cohort clinical trials of SARS-CoV-2 vaccines only included a few patients with CLD [11–13], and did not show the separate results of these patients. To our knowledge, studies on the safety and efficacy of SARS-CoV-2 vaccines in patients with CLD were still limited, and varied in populations, vaccine types and results. So, there is a need to further explore the safety and efficacy of SARS-CoV-2 vaccines in patients with CLD.

This systematic review and meta-analysis was performed to better understand the safety and efficacy of SARS-CoV-2 vaccines in patients with CLD, and it may be helpful for clinical practice.

Methods

Protocol and Registration

This systematic review and meta-analysis was conducted following a pre-established protocol according to the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines [14]. The protocol was initially registered in PROSPERO (registration number CRD42022302993) on 12 January 2022 [15].

Eligibility Criteria

Studies were eligible for being included in this systematic review and meta-analysis if they met the following criteria: 1) study included at least 20 adults aged ≥18 years with chronic liver disease of any severity or etiology (liver transplantation recipients were excluded) with/without COVID-19; 2) intervention was full-course vaccination (one dose: Johnson & Johnson, Cansino; two doses: other type of SARS-CoV-2 vaccines) of any type of SARS-CoV-2 vaccine with specific interval time; 3) intervention was compared with placebo, other vaccines or no vaccination; 4) outcomes included incidence of mild adverse events (MAEs), or incidence of severe adverse events (SAEs), or seropositivity/seroconversion rates of antibodies against SARS-CoV-2, or SARS-CoV-2 infection, or COVID-19-related hospitalization, or COVID-19-related mortality; 5) study type was randomized or non-randomized controlled trial, or cohort study, or case-control study, or cross-sectional study.

We included studies published in any kind of language. Review articles, case reports, animal studies, editorials, clinical guidelines, comment, meeting abstract, studies on CLD patients but only including liver transplant recipients (response to the vaccination and clinical outcomes are likely to be strongly influenced by the immunosuppressive medication rather than the status of liver disease), studies without separate outcomes of patients with chronic liver diseases, and studies retracted from publication were excluded.

Study Identification

We searched the Cochrane Central Register of Controlled Trials, PubMed, Embase, and Web of Science (from 2020 to 1 June 2024) for relevant articles. The Medical Subject Headings (MeSH) terms and free-text terms used were as follows: liver diseases, hepatic diseases, chronic liver diseases, cirrhosis, hepatitis, NAFLD, alcoholic liver disease, COVID-19, COVID-19 vaccines, SARS-CoV-2, vaccine, vaccination, immunization. Combination of these MeSH terms and free-text terms were used in each database. Relevant reviews and the reference list of the included articles were also checked to search for additional studies. The detailed searching strategies are shown in Supplementary Table S1.

Study Selection

Titles and abstracts of all articles were screened by two independent reviewers to assess whether they met inclusion criteria. Studies deemed eligible were then included in the full-text review by two independent reviewers. Disagreements were resolved by discussion or consulting a third reviewer, and the reasons for exclusion were recorded.

Data Extraction and Quality Assessment

The data were extracted by two independent reviewers and saved in a standardized form. Data extracted include the follows: participants (the number of participants, demographic and clinical characteristics), interventions and comparators (vaccine type, dose, comparator type, number of participants in intervention and comparison group, follow-up time after full-course vaccination), outcomes (the outcomes mentioned above, the unit of outcome), study designs (study type, location, date), study quality and study bias, other information: authors, publication time, etc.

The Newcastle-Ottawa Scale [16] was used to assess the quality of cohort study, and based on the total scores, cohort studies were classified as having low (7–9 stars), moderate (5–6 stars), and high (1–4 stars) risk of bias, respectively. The checklist recommended by Agency for Healthcare Research and Quality (AHRQ) [17] was used to assess the quality of cross-sectional study, and for each item of the checklist, 1 point (answered “yes”) or 0 point (answered “no” or “unclear”) was assigned. Based on the total scores, cross-sectional studies were classified as having low [8–11], moderate [4–7], and high (0–3) risk of bias, respectively. The assessment was completed by two reviewers independently, and the discrepancy was resolved through discussion or consulting a third reviewer.

Data Synthesis and Statistical Analysis

The safety outcomes were the incidence of MAEs, and incidence of SAEs. The efficacy outcomes were seropositivity/seroconversion rates of antibodies against SARS-CoV-2, SARS-CoV-2 infection, COVID-19-related hospitalization, and COVID-19-related mortality. A meta-analysis will be conducted when more than one study per outcome is identified. The Higgins statistic (I²) was used to assess the heterogeneity of data from different studies. The random-effects model will be used when I² ≥ 50%, otherwise, the fixed effect model will be adopted. For dichotomous data (e.g., seropositivity rates), the levels were presented as rates (%) with 95% confidential interval (CI). Comparisons between rates were presented as risk ratio (RR) with 95% CI. All outcomes will be presented as forest plots, if appropriate. Subgroup analyses and meta-regression were not carried out due to the low number of studies. The funnel plots and Harbord’s test were used to evaluate the potential publication bias. A two-sided p-value less than 0.05 was considered significant. Review Manager 5.4.1 and Stata 12.0 were used for statistical analysis.

Results

Study Inclusion

6,893 records were identified through initial database searching, between which 2,269 records were removed records because of duplicates. Based on our inclusion and exclusion criteria, 4,536 records were excluded after title and abstract review, and further 29 records were excluded after full-text review. Ultimately, 29 studies were considered eligible and included in this literature review (Figure 1).

FIGURE 1

Of the 29 included studies [6, 18–45] (Table 1–3), 19 were prospective cohort studies, 8 was retrospective study, and 2 was cross-sectional study. In the 29 included studies, all patients were older than 18 years, and 17 studies included CLD patients with cirrhosis. 22 studies had a control group (18 studies used healthy people as controls and 4 study used unvaccinated CLD patients as controls). 11 studies included inactivated vaccines, 3 inactivated and viral vector vaccines, 2 viral vector vaccines, 4 mRNA and viral vector vaccines, 8 mRNA SARS-CoV-2 vaccines, and 1 mRNA, inactivated and viral vector vaccines. The follow-up time after full-course vaccination of the most included studies were more than 7 days. Overall, 25 studies evaluated the safety and/or antibody response of SARS-CoV-2 vaccines [18–21, 24–38, 40–45] (Tables 1, 2), 4 study evaluated the clinical outcome (SARS-CoV-2 infection, hospitalization and death) after full-course SARS-CoV-2 vaccination [6, 22, 23, 39] (Table 3). Besides, the risk of publication bias of all included studies was low or moderate (Supplementary Tables S2–S4).

Safety of SARS-CoV-2 Vaccination

Among the 15 studies reporting the safety of the SARS-CoV-2 vaccines, 12 had available results of MAEs, 15 had available results of SAEs, 5 had available results of MAEs of healthy controls, and 7 had available results of SAEs of healthy controls [18–21, 24–27, 29, 32, 35, 36, 42–44] (Table 1). In all 15 studies (2788 CLD patients), most adverse events were mild, and only six patients had SAEs (including local pain/swelling, fever, fatigue, headache, muscle pain, joint pain, diarrhea, and grade 3 ALT elevation) after SARS-CoV-2 vaccination. The results of meta-analysis showed that incidence of MAEs was 28.0% (95% CI 21.0%–36.0%) in CLD patients (Supplementary Table S5; Supplementary Figure S1A), and incidence of SAEs was 1.0% (95% CI 0%–27.0%) in CLD patients (Supplementary Table S5; Supplementary Figure S1B). Compared to healthy controls, CLD patients had higher incidence of MAEs (RR 1.60, 95% CI 1.27–2.02, p < 0.001) (Supplementary Figure S2A), while had similar incidence of SAEs (RR 1.08, 95% CI 0.23–5.11, p = 0.92) (Supplementary Figure S2B).

Antibody Response of SARS-CoV-2 Vaccination

In the 25 studies on the antibody response to SARS-CoV-2 vaccines, 5 determined the neutralizing antibody, 4 determined anti-spike antibody and neutralizing antibody, 2 determined anti-spike antibody and anti-receptor binding domain (RBD) antibody, 1 determined anti-RBD IgG, 7 determined anti-spike antibody, 5 determined neutralizing antibody and anti-RBD IgG, and 1 determined neutralizing antibody, anti-spike antibody and anti-RBD antibody [18–21, 24–38, 40–44] (Table 2). 18 studies had healthy controls. The results of meta-analysis showed seropositivity rates of neutralizing antibody, anti-spike antibody and anti-RBD antibody were 79.0% (95% CI 72.0%–87.0%), 94.0% (95% CI 91.0%–97.0%) and 96.0% (95% CI 93.0%–98.0%) in CLD patients, respectively (Supplementary Table S5). Compared to healthy controls, CLD patients had lower seropositivity rates of neutralizing antibody (RR 0.86, 95% CI 0.79–0.95, p = 0.002) (Figure 2A), anti-spike antibody (RR 0.97, 95% CI 0.95–1.00, p = 0.06) (Figure 2B) and anti-RBD antibody (RR 0.95, 95% CI 0.90–1.00, p = 0.04) (Figure 2C). Due to the fact that in evaluating the response of anti-spike antibody and anti-RBD antibody in patients with chronic liver disease after vaccination, some of the subjects in the literature were all patients with cirrhosis, we further conducted subgroup analysis, and the results remained unchanged (Supplementary Figures S3, S4).

FIGURE 2

Clinical Outcome After SARS-CoV-2 Vaccination

Four study assessed the association between SARS-CoV-2 vaccination and clinical outcome [6, 22, 23, 39] (Table 3). The results indicated that, compared to unvaccinated CLD patients, CLD patients after full-course vaccination of SARS-CoV-2 vaccines had lower rates of SARS-CoV-2 infection (RR 0.25, 95% CI 0.11–0.55, p < 0.001) (Figure 3A), COVID-19-related hospitalization (RR 0.28, 95% CI 0.12–0.66, p = 0.003) (Figure 3B) and death (RR 0.23, 95% CI 0.09–0.58, p = 0.002) (Figure 3C).

FIGURE 3

Publication Bias

The funnel plots showed no obvious asymmetry (Supplementary Figure S5), which indicated there might be no publication bias. Due to small number of eligible studies, only three outcomes (seropositivity rates of anti-spike antibody, neutralizing antibody, and COVID-19-related death) could be used to perform the Harbord’s test, and the result also indicated no publication bias (all p > 0.05) (Supplementary Table S6).

Discussion

This systematic review and meta-analysis focused on the safety and efficacy of SARS-CoV-2 vaccines in patients with CLD. By analyzing the 29 eligible studies, SARS-CoV-2 vaccines were revealed to be safe in CLD patients. Full-course vaccination of SARS-CoV-2 vaccines induced promising antibody response (seropositivity rates of three antibodies were all higher than 80%) in CLD patients, but the seropositivity rates were lower in CLD patients than in healthy controls, which might decrease the immune protection provided by vaccination. Furthermore, full-course vaccination of SARS-CoV-2 vaccines may reduce the SARS-CoV-2 infection, COVID-19-related hospitalization and death in CLD patients.

The safety of SARS-CoV-2 vaccines is a highly concerned issue, and some previous studies reported thrombosis [46] and myocarditis cases [47] after SARS-CoV-2 vaccination. In this review, most AEs of CLD patients were mild, and the SAEs of CLD patients were rare. And the incidences of AEs were similar between CLD patients and HCs. Moreover, no thrombosis or myocarditis was reported. So, the results indicated good safety of SARS-CoV-2 vaccines in CLD patients.

CLD patients have dysregulated innate and adaptive immunity, which might weaken the immune response to vaccine [9]. In this review, the results of meta-analysis revealed that the seropositivity rates of SARS-CoV-2 antibody tended to be lower in CLD patients than in healthy controls, which indicated CLD might also weaken patients’ immune response to COVID-19 vaccine. Whereas, full-course vaccination of SARS-CoV-2 vaccines could still induce considerable antibody response in CLD patients (seropositivity rates of three antibodies were all higher than 80%). Furthermore, SARS-CoV-2 vaccination brought significant clinical benefit to CLD patients (vaccinated patients had significant lower proportion of SARS-CoV-2 infection, COVID-19-related hospitalization and death than that in unvaccinated patients). Therefore, SARS-CoV-2 vaccines had good efficacy in CLD patients.

Strengths of this study are as follows: first, this study was conducted following a pre-established protocol and guidelines, and different databases were used for including eligible studies, which helped to improve the quality of this study; Second, so far, there is no random controlled trial with large samples on CLD patients. In this context, this study is the first systematic review and meta-analysis on the safety and efficacy of SARS-CoV-2 vaccines in CLD patients, so it may provide relatively high-quality evidence for clinical practice. This study still has several limitations. First, due to lack of related data, this study did not assess the long-term efficacy of SARS-CoV-2 vaccines in CLD patients. Second, the sample of included studies were relatively small, and there was no random controlled trial (RCT) with large samples on CLD patients. Third, in the literature included in the meta-analysis, the subjects mainly had mild chronic liver disease, and no subgroup analysis was conducted for liver diseases of different severity levels. Forth, the recent emergence and global spreading of omicron subvariants have shown striking antibody evasion [48] and posed a critical challenge to the efficacy of SARS-CoV-2 vaccines. But until now, no study explored the efficacy of SARS-CoV-2 vaccines in CLD patients against omicron subvariants. So, there is a need for the studies on the long-term efficacy of SARS-CoV-2 vaccines and the efficacy of SARS-CoV-2 vaccines against omicron subvariants in CLD patients, and large-sample RCT.

In conclusion, SARS-CoV-2 vaccines showed good safety and efficacy in CLD patients. However, antibody response appeared to be lower in CLD patients than in healthy controls. Therefore, SARS-CoV-2 vaccines and booster doses should be given priority in this vulnerable population.

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