Vaccination Schedule and Age Influence Impaired Responsiveness to Hepatitis B Vaccination: A Randomized Trial in Central Asia

Abstract

Vaccination against hepatitis B virus (HBV) is the most cost-efficient measure to prevent infection. Still, vaccination coverage among adults in Central Asia, including Kyrgyzstan, remains suboptimal, and data about immune responses to HBV vaccination are lacking. HBV vaccination is given as three injections, whereby the second and third doses are given 1 and 6 months after the first (0-1-6 scheme). However, compliance with the third dose is low in Kyrgyzstan, presumably due to the long time interval between the second and third doses, suggesting that a shortened vaccination schedule could result in better adherence and increased seroconversion. Thus, we conducted a randomized trial of individuals aged 17-66 years comparing the 0-1-6 scheme against a shorter 0-1-3 scheme. Primary outcome measures were post-vaccination titers and the percentage of participants with protective post-vaccination titers (≥10 mIU/mL). Compliance with the completeness of blood draws and administered third vaccine dose was better with the 0-1-3 scheme than with the 0-1-6 scheme. In both study arms combined, younger age (<40 years) was associated with better vaccine protection. The 0-1-6 scheme resulted in higher post-vaccination titers (52 versus 15 mIU/mL, p = 0.002) and a higher seroprotection rate (85% versus 64%, p = 0.01) than the 0-1-3 scheme, whereby post-vaccination titers correlated negatively with age in the 0-1-3 scheme. Thus, the 0-1-6 scheme should continue to be the preferred HBV vaccination schedule, but interventions to improve compliance with the third vaccine dose are needed.

Keywords: Central Asia; Kyrgyzstan; aging; compliance; hepatitis B; immune response; study retention; vaccination; vaccine response.

Figure 1

Flow chart illustrating how the final study population was derived from the larger population that was screened in the original cross-sectional study on the prevalence of viral hepatitis in Kyrgyzstan [13].

Figure 2

Study design and age distribution. Participants received the 3-dose vaccination series against HBV at months 0, 1, and 3 or 6. Blood was drawn directly before each vaccination and once after the 3rd vaccination. Created with BioRender.com.

Figure 3

Anti-HBsAg antibody responses after each vaccine dose. (A) Box plots depict anti-HBsAg titers (minimum to maximum) with median and quartiles for each age group. (B) The same data are represented as line graphs with GMTs and SD. Mann–Whitney U test. * p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001.

Figure 4

Seroprotection rates and vaccine (non-)responders. (A) Proportion of individuals in each study age group according to seroprotection status (not seroprotected = anti-HBsAg level < 10 mIU/mL; seroprotected = anti-HBsAg level ≥ 10 mIU/mL). (B) Stratification of all participants combined.

Figure 5

Correlation analysis of age and anti-HBsAg titers after the 3rd vaccination. Associations between the age of study participants and antibody titers after the 3rd vaccination within either the (A) 0-1-3- or (B) 0-1-6-month vaccination schedule were assessed by Spearman correlation.

Figure 6

Correlation analysis of age and sex with anti-HBsAg titers after the 3rd vaccination. Associations between the age and sex of study participants with antibody titers after the 3rd vaccination within either the (A) 0-1-3- or (B) 0-1-6-month vaccination schedule were performed with the Spearman correlation test. Female (purple). Male (green).

Figure 7

Spearman correlation analysis of anti-HBsAg titers, fold-change, and interval days from M3/M6 to M4/M7. Graphs depict data from all participants combined. (A) Correlation between anti-HBsAg titers at M4/M7 and interval days. (B) Correlation between fold-change of anti-HBsAg titers from M3/M6 to M4/M7 and interval days. The fold-change was computed by the ratio of the anti-HBsAg titer measured at M4/M7 to the titer measured at M3/M6. ** p ≤ 0.01; **** p ≤ 0.0001.

Figure 8

Impact of the interval time from M3/M6 to M4/M7 on anti-HBsAg titers between the vaccination schedules. Participants with interval days of (A) <100 and (B) 100–255 from M3/M6 to M4/M7 were stratified according to their vaccination schedule (0-1-3 or 0-1-6). Significance of between-group differences was assessed by Mann–Whitney U test.