Humoral immune responses to inactivated COVID-19 vaccine up to 1 year in children with chronic hepatitis B infection

Abstract

Background: Inactivated SARS-CoV-2 vaccination has recently been approved for children aged 3-17 years in China. However, data on long-term humoral responses to inactivated vaccines in children with chronic hepatitis B (CHB) are still limited.

Methods: In this prospective observational study, CHB children after primary inactivated SARS-CoV-2 vaccines were recruited consecutively and followed up for 1 year. CHB adults from another cohort study (NCT05007665) were used as a control. The receptor-binding domain IgG antibody (anti-RBD-IgG), neutralizing antibody (NAb), neutralization against Omicron (BA2.12.1, BA.4 and BA.5), and memory B -cell (MBC) responses were evaluated.

Results: Overall, 115 CHB children and 351 CHB adults were included in this analysis. The antibody titers decreased over the first ~180 days and then plateaued up to 1 year in CHB children. However, lower and faster declines in antibody responses were observed in CHB adults. Interestingly, the seroprevalence of antibodies was still high after over 8 months in CHB children (anti-RBD-IgG [90%] and NAbs [83%]). However, neutralization against Omicron subvariants was significantly reduced in CHB children (-3.68-fold to -8.60-fold). Notably, neutralization against the BA.5 subvariant was obviously diminished in CHB children compared with adults. Moreover, CHB children had similar RBD-specific MBCs but higher RBD-specific atypical MBCs compared with adults.

Conclusion: Inactivated vaccination could elicit more robust and durable antibody responses to the wild-type SARS-CoV-2 strain in CHB children than in CHB adults but showed inferior responses to Omicron subvariants (especially to the BA.5 strain). Hence, new Omicron-related or all-in-one vaccines are needed immediately for CHB children.

Keywords: COVID-19; adolescent; antibody response; chronic hepatitis B; inactivated vaccine; memory B cells; omicron.

Figure 1

Comparisons of antibody responses after primary inactivated vaccination in CHB children and adults. (A) The kinetic changes in the titers of anti-RBD-IgG over time in CHB children (n=205) and adults (n=478). (B) The seropositivity rates and titers of anti-RBD-IgG at T1, T2, T3, T4 and T5 in CHB children and adults. (C) The kinetic changes in the titers of NAbs over time in CHB children and adults. (D) The seropositivity rates and titers of NAbs at T1, T2, T3, T4 and T5 in CHB children and adults. The plots were shown as median values with the 95% confidence interval. The dotted lines represent cut-off values. *P < 0.05; **P < 0.01; ***P < 0.001; ns, not statistically significant. anti-RBD-IgG, anti-receptor-binding-domain immunoglobulin G; NAbs, neutralizing antibodies. The Mann-Whitney U test was used for comparisons between groups. Modeling for the best fit curve (one phase decay) was performed to present the kinetic changes in antiboy responses over time.

Figure 2

Antibody responses after primary inactivated vaccination in different subgroups of CHB children. (A, B) Comparisons of the titers of anti-RBD-IgG (A) or NAbs (B) in CHB children grouped at 12 years of age. (C, D) Comparisons of the titers of anti-RBD-IgG (C) or NAbs (D) in CHB children grouped by sex. The plots were shown as median values with the 95% confidence interval. The dotted lines represent cut-off values. anti-RBD-IgG, anti-receptor-binding-domain immunoglobulin G; NAbs, neutralizing antibodies. The Mann-Whitney U test was used for comparisons between groups.

Figure 3

Neutralization against WT strain and Omicron subvariants after primary inactivated vaccination. (A) Comparisons of the neutralization against WT strain and Omicron subvariants in CHB children (n=15) and CHB adults (n=16). (B) Correlations between anti-RBD-IgG, NAbs and the neutralization. The plots were shown as geometric mean values with the 95% confidence interval. The dotted lines represent detection limit. The values of less than 10 for the pVNT50 indicate negative samples and were counted as 5. Red indicates a positive correlation between two variables, blue indicates a negative correlation, the number in each circle indicates the correlation coefficient, and the symbol “×” indicates not statistically significant. anti-RBD-IgG, anti-receptor-binding-domain immunoglobulin G; NAbs, neutralizing antibodies; WT, wild type; pVNT50, 50% pseudovirus neutralization titers.The Mann-Whitney U test was used for comparisons between groups. The Spearman method was used to analyze correlations between variables.

Figure 4

Comparisons of RBD-specific memory B-cell responses after primary inactivated vaccination in CHB children and adults. (A–D) The kinetic changes in the frequencies of RBD-specific MBCs (A) and the three subtypes of RBD-specific MBCs: RBD-specific rMBCs (B), RBD-specific actMBCs (C), and RBD-specific atyMBCs (D) over time in CHB children(n=198) and adults(n=320). The plots were shown as median values with the 95% confidence interval. *P < 0.05; **P < 0.01; ***P < 0.001; ns, not statistically significant. RBD, receptor-binding-domain; MBCs, memory B cells; rMBCs, resting MBCs; actMBCs, activate MBCs; atyMBCs, atypical MBCs. The Mann-Whitney U test was used for comparisons between groups. Modeling for the best fit curve (simple linear regression) was performed to present the kinetic changes in antibody responses over time.

Figure 5

Factors independently associated with antibody level after primary inactivated vaccination in CHB children. (A, B) Factors independently associated with the titers of anti-receptor-binding-domain immunoglobulin G (A) or neutralizing antibodies (B) after primary inactivated vaccination in CHB children. BMI, body mass index; ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; OR, odds ratio; CI, confidence interval. Multivariate binary logistic regression analysis was performed to investigate factors affecting antibody responses to inactivated vaccines in CHB children.