A New Insight into Updating the Hepatitis B Vaccination Strategy from an Experimental Study in Mice

Background: A new phenomenon has appeared that more and more child-bearing age women are positive for anti-HBs as a result of the effective hepatitis B vaccination. Whether maternal anti-HBs acquired transplacentally plays a negative role in newborn infants' immune response to hepatitis B vaccine (HepB Vac), it remains controversial and has not been paid enough attention. We first design the study to access if maternal anti-HBs inhibit the immune response of HepB Vac in mice Methods: From 2016 to 2018, 361 BALB/c mice were bred. All the mice were divided into two groups (group A and group B) according to the different doses of HepB Vac (2μg, 5μg) injected to mice. Each group was sub-divided into four subgroups according to the different doses of hepatitis B immunoglobulin (HBIG) (50 IU, 25 IU, 0 IU) injected combined with the first dose of HepB Vac and different intervals between HepB Vac doses (0- 4-8 week, 0-1-2 week). Antibody against hepatitis B surface antigen (anti-HBs) was tested four weeks after the third dose of HepB Vac. Findings: Among 361 mice, 10 were anti-HBs＜10 mIU/mL, 31 were anti-HBs＜ 100 mIU/mL and 199 were anti-HBs >1000 mIU/mL. Multivariate logistic regression analysis showed that among groups of HBIG=0 IU(1), HBIG=25IU(2) and HBIG=50 IU(3), anti-HBs＜100 mIU/mL accounted for 1*1%, 23*1%, 20*7% respectively, p= 0*002, (1) vs (3), RR= 0*032, 95% CI [0*004, 0*255], p= 0*001, (2) vs (3), RR= 1*359, 95% CI [0*588, 3*144], p= 0*473; HepB Vac 5 μg vs 2 μg, the rate of anti-HBs＜100 mIU/mL was 4*5% vs 25*6%, RR=0*093, 95% CI [0*035, 0*250], p=0*000; intramuscular injection vs hypodermic injection, the rate of anti-HBs＜100 mIU/mL was 6.1% vs 23*7%, RR=0*139, 95% CI [0*056, 0*346], p= 0*000. Among groups of HBIG= 0 IU, HBIG= 25 IU and HBIG= 50 IU, the mean titer of anti-HBs (log10mIU/m) in subgroup of HepB Vac 5 μg was 5*09±0*36, 4*29±1*07, 3*97±1*02 respectively, p= 0*000; the mean titer of anti-HBs (log10mIU/m) in subgroup of HepB Vac 2 μg was 4*89±0*59, 3*32±1*21, 2*56±0*85 respectively, p= 0*000. Group of 0-4-8 week vs 0-1-2 week, the mean titer of anti-HBs (log10mIU/m) in subgroup of HepB Vac 5 μg was 4*54±0*83 vs 5*09±0*36, p= 0*003; the mean titer of anti-HBs (log10mIU/m) in subgroup of HepB Vac 2 μg was3*97±0*85 vs 4*89±0*59, p= 0*000. Another multivariate logistic regression analysis showed that HBIG= 0 IU, HepB Vac 5μg and intramuscular injection are the independent promotion factors for anti-HBs >1000 mIU/mL. Interpretation: HBIG has a negative impact on both the rate of effective immune response and the response level of anti-HBs. Schemes of higher dose of HepB Vac, longer intervals between doses of HepB Vac and intramuscular injection can be considered as factors contributed to obtaining an optimal immune effect. Funding Statement: This study was funded by National Nature Science Foundation (youth scientific fund). grant number 81502900 Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: The study was approved by the Ethics Committee of Qingdao Municipal Hospital affiliated with Qingdao University.