Since the outbreak of coronavirus disease 2019 (COVID-19), more than 630 million people have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and more than 6.6 million deaths were reported as of 2 November 2022 (Johns Hopkins University, 2022). Vaccines are economical and effective in controlling and preventing the spread of COVID-19, as well as reducing its disease severity (Hodgson et al., 2021). To date, more than 370 vaccines against SARS-CoV-2 are in clinical and pre-clinical development, including inactivated, mRNA, adenovirus-based, and recombinant protein vaccines, and approximately 12.8 billion doses have been administered (WHO, 2022).

Accumulated evidence has demonstrated that vaccines against SARS-CoV-2 have good safety and efficacy (Polack et al., 2020; Voysey et al., 2021), and can induce a humoral response against SARS-CoV-2 (Fix et al., 2021; Xia et al., 2021). The seroconversion rates of specific anti-receptor binding domain (RBD) immunoglobulin G (IgG) to inactivated SARS-CoV-2 vaccines were 70.37–86.67% (Bueno et al., 2022), while those to RBD-subunit vaccines were 72–76% and 93–97% after two and three vaccine doses, respectively (Yang et al., 2021). However, most clinical trials were conducted in healthy subjects; only a few participants with pre-existing liver diseases were enrolled (Cornberg et al., 2021; Fix et al., 2021; Marjot et al., 2021a). Several studies have demonstrated that people with specific comorbidities, including chronic liver disease (CLD), cardiac disease, and obesity, or those using certain medications, may be at greater risk of developing severe COVID-19 (Docherty et al., 2020; Fix et al., 2021). The European Association for the Study of the Liver, American Association for the Study of Liver Diseases, and Chinese medical association suggest that patients with chronic hepatitis B (CHB) having a stable condition and no contraindications should be vaccinated against SARS-CoV-2 (Cornberg et al., 2021; Fix et al., 2021; Chinese Society of Hepatology, 2021); however, safety and efficacy data on this population are still limited. Recently, three studies focused on CHB, CLD, and non-alcoholic fatty liver disease (NAFLD) and came to the same conclusion that inactivated SARS-CoV-2 vaccines are safe in these populations (Wang J. et al., 2021; Xiang et al., 2021; Ai et al., 2022). A study found that, compared with a healthy population, inactivated SARS-CoV-2 vaccines induced a lower immunological response in patients with CLD, which included 87.8% of patients with CHB (Ai et al., 2022). In contrast, another study found that patients with CHB undergoing nucleos(t)ide analogs (NAs) therapy had significantly higher neutralizing antibody (NAb) titers than those who were not (Xiang et al., 2021).

NAs and Peg-interferon-alpha (Peg-IFNα) are the two main anti-hepatitis B virus (anti-HBV) treatment regimens. Compared to NAs treatment, Peg-IFNα-based treatment strategies could achieve a higher rate of sustained hepatitis B e antigen and hepatitis B surface antigen loss/seroconversion (Hu et al., 2018; Liu et al., 2018, 2020), though low tolerability and a higher risk of adverse events exist (Yeh et al., 2019). Nowadays, approximately 90% and 10% of patients with CHB in China receive NAs and interferon, respectively (Shan et al., 2019). However, whether different antiviral agents have different effects on the safety and immunogenicity of SARS-CoV-2 vaccines requires further evaluation. In this study, we compared the adverse reaction (ADR) rates and antibody levels against SARS-CoV-2 in patients with CHB undergoing NAs monotherapy or Peg-IFNα-based treatment, and healthy controls (HCs).

In the present study, we demonstrated that SARS-CoV-2 vaccines have acceptable safety in patients with CHB undergoing different antiviral therapies. The seropositivity rates of antibodies against SARS-CoV-2 vaccines were comparable between patients with CHB and HCs after two doses of the vaccine. However, both antibody seropositivity rates and titers declined noticeably over time in patients receiving NAs monotherapy than those receiving Peg-IFNα-based therapy.

An underlying disease is a risk factor for severe illness and death during SARS-CoV-2 infection. Several studies have shown that CLD is significantly associated with more severe COVID-19 and overall mortality (Kovalic et al., 2020; Kim et al., 2021). Preventive vaccination is one of the most effective ways to deal with the spread of the COVID-19. SARS-CoV-2 vaccines have been making unprecedented progress and have shown excellent safety profiles and efficacy in preventing symptomatic COVID-19 in healthy people (Marjot et al., 2021b). Although some studies have reported SARS-CoV-2 vaccination in patients with CHB, CLD, and NAFLD (Wang J. et al., 2021; Xiang et al., 2021; Ai et al., 2022), the safety and immunogenicity data on patients with CHB, especially those undergoing different anti-HBV drugs, is still insufficient.

The type and incidence of ADRs, predominantly occurring after the first dose, were similar between patients with CHB and HCs. All ADRs were self-limiting, tolerable, and quickly resolved. Our study did not observe any severe systematic ADR that required medical intervention. Further stratification analysis indicated that the incidence of ache at the injection site after the first dose was significantly higher in patients receiving Peg-IFNα-based therapy than in those receiving NAs monotherapy. This may be related to the short interval between Peg-IFNα injection and vaccination.

Recently, a clinical trial found higher levels of humoral immune responses in young and female recipients (Tanriover et al., 2021). Xiang et al. (2021) also reported that younger and female patients with CHB had higher anti-S-RBD IgG and NAb positive rates. A multinational, observer-blinded trial found similar vaccine efficacy across different subgroups defined by age (Polack et al., 2020). A higher proportion of male and older individuals in patients than in HCs were noted in our study, but no significant difference was found in IgG or NAb-positivity rates and titers between patients and HCs. Moreover, we also found no differences in antibody positivity rates and titers between patients of different ages and HCs (data not shown), suggesting that patients undergoing antiviral treatment can achieve the same level of vaccine protection as healthy people. This is consistent with the results reported by He et al. (2022) that seropositive rates of antibodies in CHB patients and HCs were similar at 1–3 months after vaccination. Xiang et al. (2021) observed that NA-treated patients with CHB can produce higher antibody levels than untreated patients. Ai et al. (2022) found no statistical difference in antibody seropositivity rate between patients undergoing antiviral therapy and those who did not. The inconsistent results may be due to the differences in sample size, liver function, and cirrhosis proportion of patients enrolled in the studies.

Specific antibody titers were correlated with protection against SARS-CoV-2 in animal models (Chandrashekar et al., 2020; Corbett et al., 2020). Clinical trials also revealed that vaccines with high levels of both binding and neutralizing antibodies were at low risk of severe illness and death (Anderson et al., 2020). Therefore, high levels of antibody titers against SARS-CoV-2 are associated with sufficient immune protective effects. Our data showed that seropositivity rates and titers of antibodies in patients with CHB declined more obviously 4–6 months after the second dose compared with HCs, indicating that the immune protection of the vaccine faded soon. A clinical trial demonstrated that administering a third vaccine dose 6–12 months after the second dose can boost immune response in healthy recipients (Wang K. et al., 2021). Our study firstly reported that an additional booster dose recalled robust and long-lasting antibodies against SARS-CoV-2 in NA-treated patients.

Interestingly, a negative correlation between the antibody titers and the days after vaccination only existed in patients receiving NAs monotherapy, but not in those receiving Peg-IFNα-based therapy. Compared with NAs, Peg-IFNα has an ability to stimulate humoral immunity and cellular immunity (Tang et al., 2018). In a clinical study, treatment with IFN-α2b limited the severity of COVID-19 (Zhou et al., 2020). In this study, we also detected higher levels of serum IFN-γ in patients receiving Peg-IFNα-based therapy. IFN-γ promotes macrophage activation and antigen presentation (Costela-Ruiz et al., 2020) and can enhance protective immunity when used as a vaccine adjuvant (Zhang et al., 2018). Furthermore, low levels of IFN-γ were associated with severe COVID-19 disease (Chen et al., 2020; Costela-Ruiz et al., 2020; Pedersen and Ho, 2020). Thus, we speculated that Peg-IFNα might help in maintaining high levels of antibodies against SARS-CoV-2 by promoting IFN-γ secretion.

Consistent with other findings (Banga et al., 2021), IgM antibodies against the RBD of the SARS-CoV-2 spike protein were not detected in most recipients in this study. This may be related to the fact that the vaccine mainly induces IgG antibody production (Banga et al., 2021). Another possible reason is the long interval between vaccination and blood withdrawal.

In conclusion, our study suggests that an additional booster dose with a shorter time interval is required for certain patients with CHB. However, our study has several limitations. First, this cross-sectional study had a small sample size and lacked dynamic observational data. Second, significant differences were found in the demographic characteristics and time of blood withdrawal between patients with CHB and HCs. Although PSM eliminated these differences, it led to a further reduction in cases. Third, neutralizing antibody detection cannot be equated to the virus neutralization test. Therefore, prospective longitudinal studies with larger sample sizes are needed to illustrate the characteristics of antibodies in patients with CHB and reveal the underlying immune mechanisms.

The original data presented in this study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Ethics Committee of The Fifth Medical Center of PLA General Hospital Ethics Committees. The patients/participants provided their written informed consent to participate in this study.

JF: study concept and design. W-XW, RJ, XZ, and S-NZ: acquisition of data. W-XW, RJ, and JF: analysis and interpretation of data. JF, W-XW, RJ, and J-WS: drafting of the manuscript. JF and F-SW: administrative, technical, or material support, study supervision. All authors contributed to the study conception and design, read and approved the final manuscript, including the authorship list, and critical revision of the manuscript for important intellectual content.