Can monovalent hepatitis A and B vaccines be replaced by a combined hepatitis A/B vaccine during the primary immunization course?

A combined hepatitis A/B vaccine (Twinrix Adult) has been licensed in Germany since 1997. We investigated possible differences in immunogenicity and safety when changing over from vaccinations with monovalent vaccines made by different manufacturers to vaccinations with the combined hepatitis A/B vaccine in an open, randomized, multicenter trial. We therefore compared four different schemes changing over from concomitant vaccinations with monovalent vaccines against hepatitis A and B (Havrix 1440+Engerix-B or Vaqta+Gen H-B-Vax) to combined vaccination against hepatitis A+B with three injections of the combined hepatitis A/B vaccine (0, 1, and 6 month schedule). Local and general symptoms were mostly mild in all five groups. With complete three-dose course using the combined vaccine or an early changeover from monovalent vaccines to the combined vaccine, higher overall anti-HBs seroprotection rates and geometric mean concentrations (GMCs) against hepatitis B could be achieved as early as after 2 months as compared to those groups switching later to the combined vaccine. This study demonstrated for the first time that switching from monovalent hepatitis A and B vaccinations to the combined hepatitis A and B vaccination has no negative influence on the tolerability and improves the immunogenicity.     

Incremental system costs of introducing combined DTwP–hepatitis B–Hib vaccine into national immunization services in Ethiopia

Objective

With support from the GAVI Alliance a fully liquid combined DTwP–HepB–Hib (pentavalent) vaccine in a single dose vial was introduced into Ethiopia's routine immunization services in March 2007. This vaccine was substituted with DTwP in a 10-dose vial. We aimed to estimate the incremental system costs of pentavalent vaccine delivery.

Methods

Data on cold storage expansion and increased vaccine transport frequency were collected in four regions of Ethiopia over a 2-week period, as part of a Post-Introduction Evaluation of the new vaccine. Interviews were conducted with individuals at all levels of the health system. Information on the costs of training and communication to facilitate the introduction was collected from the Ministry of Health, UNICEF and WHO in Addis Ababa.

Results

The switch from a 10-dose DTwP to a single dose pentavalent vaccine increased refrigeration storage volume per fully vaccinated child by 106% at national and regional levels and by 71% at the three lower levels of vaccine distribution. Cold storage equipments were purchased at all levels and the frequency of vaccine collection more than doubled in many places. Incremental capital costs of cold storage equipment, training and communication amounted to US$ 4.8 million, or US$ 1.53 per child in the 2007 birth cohort. After annualizing capital costs and adding recurrent costs, system costs came to US$ 0.80 per child in the 2007 birth cohort. With a vaccination coverage rate of 78% this is equivalent to US$ 1.13 per fully vaccinated child. The most important system cost item is cold storage, amounting to US$ 0.62 per child in the birth cohort and US$ 0.03 per additional cm³ of cold storage.

Conclusion

In Ethiopia introduction of pentavalent vaccine necessitated considerable investments in additional cold storage equipment as well as an increase in vaccine transport frequency. A GAVI Alliance introduction grant of US$ 0.30 per child in the birth cohort would cover approximately 20% of the capital investments undertaken to facilitate introduction.     

Long-term (5-year) antibody persistence following two- and three-dose regimens of a combined hepatitis A and B vaccine in children aged 1–11 years

This study compared the long-term persistence of anti-hepatitis A (anti-HAV) and B (anti-HBs) antibodies, 5 years after vaccination of subjects aged 1–11 years with a combined hepatitis A and B vaccine either in a two-dose (0, 6 months, Adult formulation) or a three-dose (0, 1, 6 months, Paediatric formulation) schedule. At the end of the 5 years, all subjects (100%) in both groups continued to have anti-HAV antibodies ≥15 mIU/mL, while 94–97% of subjects in both groups had anti-HBs antibody concentrations ≥10 mIU/mL. Subjects with anti-HBs antibody concentration ≤10 mIU/mL were administered a challenge dose of hepatitis B vaccine. All subjects mounted a vigorous immune response to the challenge indicating the presence of immunological memory to HBV.     

Evaluation of a universal hepatitis B vaccination program and antenatal screening for hepatitis B surface antigen: Results from a real-world study 2015–2016

Background and AimsUniversal vaccination against hepatitis B virus (HBV) in infancy was implemented in Israel in 1992. This population-based study aimed to evaluate the coverage rate and cost-benefit of the HBV vaccination program among infants in Israel and the Hepatitis B surface antigen (HBsAg) status in their mothers.MethodsUsing the database of a health maintenance organization with 2 million members, we retrospectively identified, all the infants born in 2015–2016 and their mothers. Maternal data collected included age, ethnicity, country of birth and HBsAg status during pregnancy. HBV vaccination coverage among infants was calculated. A cost-benefit analysis of the HBV vaccination program was conducted based on the actual costs of HBV infection treatments in all HBsAg positive mothers.ResultsOur cohort included 72,792 mothers who gave birth to 77,572 live infants. A total of 71,107 (97.7%) mothers were screened for HBV during pregnancy, of them 124 (0.2%), who gave birth to 132 infants were HBsAg positive. HBV vaccination coverage rates were 94%, 93% and 89%, for the first, second and third dose, respectively. Birth dose coverage of 95% among infants born to HBsAg positive mothers was significantly higher compared to HBsAg negative or unscreened mothers (p < 0.001). The percentage of HBsAg positivity among mothers who were born in Israel, the Former Soviet Union or Ethiopia, were 0.1%, 0.8% and 5%, respectively (p < 0.001). Ethnic differences were not found between HBsAg positive and HBsAg negative mothers. Calculated benefit-to-cost ratios were 1.24:1 and 4.15:1, with and without antenatal HBsAg screening, respectively.ConclusionsThe Israeli vaccination program against HBV infection is epidemiologically and economically justified. High coverage rates among infants born to HBsAg positive mothers reflect very good adherence to the vaccination program and antenatal screening. Higher HBsAg positivity rates among immigrant mothers identify a high-risk population for HBV infection.     

Immunogenicity and safety of an investigational hepatitis B vaccine with a Toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared to a licensed hepatitis B vaccine in healthy adults 40–70 years of age

Background

The currently licensed hepatitis B vaccines have limitations including hyporesponsiveness in older adults, poor compliance, and the extended time for most persons to develop seroprotection (e.g. >6 months). A vaccine containing HBsAg combined with a Toll-like receptor 9 agonist adjuvant (HBsAg-1018) has been developed to overcome these limitations.

Methods

A Phase 3, multicenter, randomized, subject- and observer-blinded, active-controlled trial was conducted among healthy subjects 40–70 years of age comparing the immunogenicity and safety of two doses of HBsAg-1018 at 0 and 4 weeks to three doses of licensed hepatitis B vaccine, HBsAg-Eng, at 0, 4, and 24 weeks. The primary immunogenicity endpoint was noninferiority of the seroprotection rate (SPR; % with anti-HBs ≥10 mIU/mL) of HBsAg-1018 compared to the SPR of HBsAg-Eng at 8 weeks following the last dose of vaccine. Conditional upon meeting noninferiority, superiority of HBsAg-1018 over HBsAg-Eng was assessed. Safety was compared between the two vaccines.

Results

At the primary endpoint, the SPR for the HBsAg-1018 group (90.0%) was superior to the SPR for the HBsAg-Eng group (70.5%) with an SPR difference of 19.5% (95% CI, 14.7%, 24.7%). At week 28 when the SPR peaked in the HBsAg-Eng group (72.8%), the SPR in the HBsAg-1018 group (94.8%) was significantly higher than in the HBsAg-Eng group. The SPR in the HBsAg-1018 group was significantly higher than in the HBsAg-Eng group at each study visit from week 4 through week 52. The safety profiles for the two vaccines were similar.

Conclusion

When compared to the HBsAg-Eng three-dose regimen given at 0, 1, and 6 months, HBsAg-1018 demonstrated superior seroprotection with only two doses at 0 and 1 month. The safety profile of HBsAg-1018 was comparable to that of the licensed vaccine, HBsAg-Eng. HBsAg-1018 would provide a significant public health contribution toward the prevention of hepatitis B infection.     

Factors associated with effectiveness of the first dose of hepatitis B vaccine in China: 1992–2005

Background

In China, the prevalence of chronic hepatitis B infection was high because of perinatal and early childhood transmission. A three-dose hepatitis B vaccine schedule with a first dose as soon as possible after birth was introduced in 1992 and generalized in 2002 in the Expanded Programme of Immunization (EPI). In 2006, a serological survey evaluated the effectiveness of vaccination.

Methods

We conducted a restricted analysis of the national serological survey that sampled children and collected information on demographic characteristics, birth history, hepatitis B vaccination and hepatitis B surface antigen (HBsAg) status as determined by ELISA testing. We compared children who received the first dose in a timely way (i.e., within 24 h of birth) with others in terms of HBsAg status, stratified by birth cohort and place of birth.

Results

Three-dose hepatitis B vaccine coverage increased from 60.8% for children born in 1992–1997 to 93.2% for children born in 2002–2005. Meanwhile, timely birth dose coverage increased from 38.7% to 74.4%. Among 29,410 children born in 1992–2005 who had received three vaccine doses and no hepatitis B immune globulin, factors associated with being HBsAg-negative in multivariate analysis included receiving a timely birth dose (p = 0.04), birth after 1998 (p < 0.001), living in an urban setting (p = 0.008) and hospital birth (p = 0.001). The relative prevalence of HBsAg among children receiving the timely birth dose was lower for children born in county or larger hospitals (0.39), intermediate in township hospitals (0.73) and highest at home (0.87).

Conclusions

Hospital birth and receiving a timely birth dose are the main determinants of the field effectiveness of the first dose of hepatitis B vaccine. Efforts to increase the proportion of hospital deliveries are key to increasing timely birth dose coverage and its effectiveness.     

Implementing a birth dose of hepatitis B vaccine for home deliveries in Africa—Too soon?

Despite the recommendation of the World Health Organization (WHO) to provide the first hepatitis B vaccine dose at birth (within 24 h), there are epidemiological, economic and logistical reasons why this may not be the best approach for home births in Africa. The WHO policy presupposes that the epidemiology of hepatitis B infection in Africa is similar to the rest of the world and that the organizational, infrastructural and financial support is adequate. While babies born in health facilities may be relatively easy to immunize at birth, health systems and infrastructures in many resource-poor countries in Africa would be severely challenged, if required to reach home deliveries within 24 h of birth.     

Characteristics of immune memory 10–15 years after primary hepatitis B vaccination

Background and aimsThe definition of immune memory after hepatitis B vaccination is still under debate. Therefore, we analysed hepatitis B surface antigen (HBsAg)-specific memory in more detail by investigating the kinetics of humoral and cellular responses after hepatitis B booster vaccination.MethodsThe anti-HBs kinetics of 23 individuals with anti-HBs titres below 10 IU/l, who had been vaccinated 10–15 years ago, was monitored at day 0, 3, 7, 14 and 28 after booster vaccination. HBsAg-specific IFNγ- and IL5-secreting cells in enriched CD4⁺ fraction were measured at day 0, 7 and 28 post-booster by enzyme-linked immunospot assay (ELISpot).Results22 of 23 subjects showed similar anti-HBs kinetic curves, including 3 of 4 subjects who did not reach anti-HBs titres of 10 IU/l. The steep anti-HBs increase started between day 3 and 7 and peaked around day 14. A plateau or only minimal changes were visible between day 14 and 28. 17.4% of subjects showed pre-booster cellular responses, and this rate had increased to 47.8% and 56.5% after 7 and 28 days, respectively. The kinetic patterns of T cell responses differed considerably among subjects. A dominance of Th2 responses (IL5 secretion) over Th1 responses (IFNγ secretion) could be observed.ConclusionsThe presence of B cell memory could be shown by a typical anamnestic anti-HBs response curve after a booster dose in all but one individual. In contrast, T cell responses to booster vaccination, which occurred in approximately 50% of participants, were rather heterogeneous.     

Early exposure to the combined measles–mumps–rubella vaccine and thimerosal-containing vaccines and risk of autism spectrum disorder

ObjectiveThis case–control study investigated the relationship between the risk of Autism Spectrum Disorder (ASD) onset, and early exposure to the combined Measles–Mumps–Rubella (MMR) vaccine and thimerosal consumption measured from vaccinations in the highly genetically homogenous Japanese population.MethodsVaccination histories at 1, 3, 6, 12, 18, 24, and 36 months from birth were investigated in ASD cases (189 samples), and controls (224 samples) matching age and sex in each case. Crude odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to determine relationship between MMR vaccination and ASD. The differences in mean values of the thimerosal dosage between cases and controls were analyzed using an unpaired t-test. MMR vaccination and thimerosal dosage were also investigated using a conditional multiple-regression model.ResultsThere were no significant differences in MMR vaccination and thimerosal dosage between cases and controls at any age. Furthermore, the ORs (95% CIs) of MMR vaccination and thimerosal dosage associated with ASD in the conditional multiple regression model were, respectively, 0.875 (0.345–2.222) and 1.205 (0.862–1.683) at age 18 months, 0.724 (0.421–1.243) and 1.343 (0.997–1.808) at 24 months, and 1.040 (0.648–1.668) and 0.844 (0.632–1.128) at 36 months. Thus, there were no significant differences.ConclusionsNo convincing evidence was found in this study that MMR vaccination and increasing thimerosal dose were associated with an increased risk of ASD onset.     

Immunogenicity of an investigational hepatitis B vaccine with a toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared with a licensed hepatitis B vaccine in subpopulations of healthy adults 18–70 years of age

BackgroundImmunologic response to a complete vaccine regimen of currently licensed alum-adjuvanted hepatitis B vaccines is reduced in several subpopulations, including older adults, men, obese persons, and smokers. Two phase 3 trials in healthy adults demonstrated that 2 doses over 1 month of an investigational hepatitis B vaccine (HBsAg-1018) induced superior seroprotection rates (SPRs) to 3 doses over 6 months of the licensed vaccine Engerix-B^® (HBsAg-Eng).MethodsAn exploratory analysis of immunogenicity was conducted in subpopulations from pooled data for the 2 phase 3 trials.ResultsIn each subpopulation, the peak SPR in the HBsAg-1018 group was statistically significantly higher than the peak SPR in the HBsAg-Eng group. Peak HBsAg-1018 SPRs ranged from 91.6% to 99.7%, while peak HBsAg-Eng SPRs ranged from 67.7% to 92.9%.ConclusionIn these exploratory analyses, 2 doses of HBsAg-1018 induced statistically significantly higher rates of seroprotection than 3 doses of HBsAg-Eng across all subpopulations.     

Assessment of the timely administration of the hepatitis B and BCG birth dose and the primary infant vaccination schedule in 2015–2016 in the Mekong Delta,Viet Nam

IntroductionVietnam is implementing hepatitis B (HBV) birth dose (BD) vaccination since 2003 but coverage remains low, especially in the Mekong River Delta. This study aimed to determine the coverage of the HBV BD vaccination, to identify socio-demographic factors influencing HBV BD, and to assess reasons for non-immunization of neonates.MethodsA cross-sectional survey was conducted in 2015–2016. Mothers from 526 children aged 6–11 months living in 3 provinces in the Mekong River Delta - representing respectively urban, rural and remote area - were interviewed at home and infant vaccination documents were checked. The three-stage sampling method was adapted from WHO 30-cluster sampling. Predictors of HBV BD administration were identified with multiple regression analysis.ResultsThe overall HBV BD coverage (within 24 h) was 46.6% (compared to 44.5% for BCG) and was significantly higher in remote or rural than in urban area (OR 1.87 and 3.36, respectively), and in children whose father had a higher educational level (OR 2.76; 2.29 and 1.86, respectively, for master degree, bachelor and secondary school) as compared to a lower level. Main reasons for not having received HBV BD mentioned by parents were vaccines not offered by health care workers (53.0%), and illness of the infant (27.2%).ConclusionAlthough Vietnam started HBV BD vaccination more than 10 years ago, the coverage and timeliness need to improve to reach WHO targets (95% within 24 h after birth). Better training and information of health care workers, and better protocols ensuring timely HBV BD could address these vaccine administration thresholds.     

Immunity to hepatitis B persists in adolescents 15–16 years of age vaccinated in infancy with three doses of hepatitis B vaccine

ObjectiveVaccination of infants against hepatitis B virus (HBV) using hepatitis B vaccine is effective in preventing the infection during early childhood and there is a growing evidence of long-term protection. So far, no need for a booster dose has been identified in healthy subjects; however further follow-up continues to determine the exact duration of protection. We evaluated antibody persistence and immune response to a hepatitis B vaccine challenge dose in children aged 15–16 years, previously vaccinated with 3-doses of the same vaccine in infancy (third dose received before 18 months of age).MethodsA single hepatitis B vaccine challenge dose containing 10 μg hepatitis B surface (HBs) antigen was administered to adolescents aged 15–16 years. Blood samples were taken before and one month after the challenge dose to measure anti-HBs antibodies using a chemiluminescence immunoassay. Solicited local and general symptoms, as well as unsolicited and serious adverse events were recorded after the challenge dose.Results303 subjects were enrolled, of whom 302 and 293 subjects formed the total vaccinated and according-to-protocol cohorts, respectively. Pre-challenge, 65.4% (95% CI: 59.6–70.9) subjects were seroprotected (anti-HBs antibody concentration ≥10 mIU/mL). One month post-challenge, 97.9% (95% CI: 95.6–99.2) were seroprotected, while 90.8% (95% CI: 86.8–93.8) had anti-HBs antibody concentrations ≥100 mIU/mL. The post-challenge geometric mean concentration (GMC; 4134.9 [95% CI: 3114.2–5490.1]) was 150-fold higher than the pre-challenge GMC. Overall, 96.9% (95% CI: 94.2–98.6) subjects mounted an anamnestic response. The safety and reactogenicity profile of the hepatitis B vaccine challenge dose was consistent with previous experience.ConclusionsImmunity to hepatitis B persists in 15–16 year old adolescents following primary vaccination in infancy.Trial registrationhttp://www.clinicaltrials.gov NCT01847430.     

Evaluation of the immunogenic capability of the BCG strains BCGΔBCG1419c and BCGΔBCG1416c in a three-dimensional human lung tissue model

Tuberculosis (TB) still remains as an unmet global threat. The current vaccine is not fully effective and novel alternatives are needed. Here, two vaccine candidate strains derived from BCG carrying deletions in the BCG1416c or BCG1419c genes were analysed for their capacity to modulate the cytokine/chemokine profile and granuloma formation in a human lung tissue model (LTM). We show that the clustering of monocytes, reminiscent of early granuloma formation, in LTMs infected with BCG strains was similar for all of them. However, BCGΔBCG1419c, like M. tuberculosis, was capable of inducing the production of IL-6 in contrast to the other BCG strains. This work suggests that LTM could be a useful ex vivo assay to evaluate the potential immunogenicity of novel TB vaccine candidates.     

Lasting immune memory against hepatitis B following challenge 10–11 years after primary vaccination with either three doses of hexavalent DTPa-HBV-IPV/Hib or monovalent hepatitis B vaccine at 3, 5 and 11–12 months of age

BackgroundThe combined hexavalent diphtheria–tetanus–pertussis–hepatitis B-inactivated poliomyelitis – Haemophilus influenzae type b conjugate vaccine (Infanrix hexa™; DTPa-HBV-IPV/Hib: GlaxoSmithKline Vaccines) induces robust responses to the HBV component when administered at 3, 5 and 11–12 months of age. We assessed long term HBV antibody persistence 10–11 years after primary vaccination in infancy.MethodsAntibody persistence and immune memory were assessed post-primary vaccination at 3, 5, 11–12 months with DTPa-HBV-IPV/Hib, or monovalent HBV vaccine (Engerix™ B, GlaxoSmithKline Vaccines) co-administered with DTPa-IPV/Hib (Infanrix™-IPV/Hib, GlaxoSmithKline Vaccines) in 185 children aged 11–12 years. Blood samples were collected before and 1 month after a challenge dose of Engerix™ B (10 μg dose).Results10–11 years after primary vaccination the percentage of subjects with persisting anti-HBs antibody concentrations ≥10 mIU/ml was 48.4% in the DTPa-HBV-IPV/Hib group and 58.4% in the DTPa-IPV/Hib + HBV group. After the HBV challenge dose, the percentage with anti-HBs ≥100 mIU/ml increased from 14.7% to 93.6% in the DTPa-HBV-IPV/Hib group and 19.1% to 94.4% in the DTPa-IPV/Hib + HBV group. Anti-HBs GMCs increased by at least 187-fold in each group. An anamnestic response (≥4-fold increase in initially seropositive or anti-HBs concentration ≥10 mIU/ml in initially seronegative subjects) was observed in 96.8% and 96.6% of subjects in the DTPa-HBV-IPV/Hib and DTPa-IPV/Hib + HBV groups, respectively. No serious adverse events occurred that were considered related to challenge vaccination.ConclusionAdministration of HBV as part of a combination vaccine or as a monovalent vaccine induced long lasting immune memory against HBV in children primed at 3, 5 and 11 months of age. Antibody persistence and immune memory were similar, suggesting that protection afforded by DTPa-HBV-IPV/Hib and monovalent HBV vaccines, is likely to be of similar duration. The administration of HBV challenge dose 10–11 years after the 3, 5, 11–12 months primary schedule induced strong anamnestic responses and was well tolerated.This study is registered at www.clinicaltrials.gov NCT01138098.     

Assessing different measures of population-level vaccine protection using a case–control study

BackgroundCase–control studies have not been examined for their utility in assessing population-level vaccine protection in individually randomized trials.MethodsWe used the data of a randomized, placebo-controlled trial of a cholera vaccine to compare the results of case–control analyses with those of cohort analyses. Cases of cholera were selected from the trial population followed for three years following dosing. For each case, we selected 4 age-matched controls who had not developed cholera. For each case and control, GIS was used to calculate vaccine coverage of individuals in a surrounding “virtual” cluster. Specific selection strategies were used to evaluate the vaccine protective effects.Results66,900 out of 108,389 individuals received two doses of the assigned regimen. For direct protection among subjects in low vaccine coverage clusters, we observed 78% (95% CI: 47–91%) protection in a cohort analysis and 84% (95% CI: 60–94%) in case–control analysis after adjusting for confounding factors. Using our GIS-based approach, estimated indirect protection was 52% (95% CI: 10–74%) in cohort and 76% (95% CI: 47–89%) in case control analysis. Estimates of total and overall effectiveness were similar for cohort and case–control analyses.ConclusionThe findings show that case–control analyses of individually randomized vaccine trials may be used to evaluate direct as well as population-level vaccine protection.     

Non-clinical efficacy and safety of HyVac4:IC31 vaccine administered in a BCG prime–boost regimen

Despite the extensive success with the introduction of M. bovis Bacille Calmette-Guérin (BCG), tuberculosis (TB) remains a major global epidemic infecting between 8 and 9 million people annually with an estimated 1.7 million deaths each year. However, because of its demonstrated effectiveness against some of the most severe forms of childhood TB, it is now realized that BCG vaccination of newborns is unlikely to be replaced. Therefore, BCG or an improved BCG will continue to be used as a prime TB vaccine and there is a need to develop effective boost vaccines that would enhance and prolong the protective immunity induced by BCG prime immunization. We report on a heterologous booster approach using two highly immunogenic TB antigens comprising Ag85B and TB10.4 (HyVac4) delivered as a fusion molecule and formulated in the proprietary adjuvant IC31. This vaccine was found to be immunogenic and demonstrated greater protection in the more stringent guinea pig model of pulmonary tuberculosis than BCG alone when used in a prime/boost regimen. Significant difference in lung involvement was observed for all animals in the HyVac4 boosted group compared to BCG alone regardless of time to death or sacrifice. A vaccine toxicology study of the HyVac4:IC31 regimen was performed and it was judged safe to advance the vaccine into clinical trials. Therefore, all non-clinical data supports the suitability of HyVac4 as a safe, immunogenic, and effective vaccination in a prime–boost regimen with BCG.     

Molecular evolution of hepatitis B vaccine escape variants in China,during 2000–2016

Hepatitis B vaccine escape variants are the main threat to hepatitis B virus (HBV) infection in vaccination era worldwide. With 215 genotype B HBV and 313 genotype C HBV vaccine escape variants isolated from China during 2000–2016, we reported that genotype B HBV vaccine escape strains diverged in ∼1997 (95% HPD; 1987–2005), while genotype C HBV vaccine escape strains diverged in ∼1976 (95% HPD; 1955–2003). Additionally, the p-distance of genotype C HBV vaccine escape strains was 0.0291 ± 0.0169, which was significantly higher than that in the genotype B HBV (t = 131.02, p < 0.05). However, genotype B HBV vaccine escape strains evolved more rapidly than genotype C HBV (2.103 × 10⁻³ vs 1.083 × 10⁻³ substitutions/site/year). Bayesian skyline plot analysis showed that the populations of genotype C HBV vaccine escape strains fluctuated more than those in genotype B HBV. Four sites (A5T/S, L21S, T/A126S and T/N131I/A) and 13 sites (N3S, T5A, G10Q/R/E, L21S, T47K/A/V, L98V/P, I/S126N/V/T, Q129H/R/L, T131P/I/N/A, G145A/R, L175S/F, L213I/S, V224A/G) were found to be under positive selection in genotype B and C HBV vaccine escape strains, respectively. More importantly, N3S, L21S, T47K, L98V, I/S126T and L213I mutations were detected in 1 (2.5%), 1 (2.5%), 1 (2.5%), 3 (7.5%), 1 (2.5%), 1 (2.5%) genotype C HBV infected Chinese younger with neonatal HBV vaccination, respectively. Therefore, our results should be valuable in further understanding the molecular evolution of HBV and providing new ideas for the elimination of HBV infection.     

Immunogenicity and reactogenicity of a decennial booster dose of a combined reduced-antigen-content diphtheria–tetanus–acellular pertussis and inactivated poliovirus booster vaccine (dTpa–IPV) in healthy adults

BackgroundPertussis in adults and adolescents could be reduced by replacing traditional tetanus and diphtheria (Td) boosters with reduced-antigen-content diphtheria–tetanus–acellular pertussis (dTpa) vaccines. This study evaluated the administration of dTpa–IPV (dTpa–inactivated poliovirus) in adults ten years after they received a booster dose of either dTpa–IPV, dTpa+IPV or Td–IPV in trial NCT01277705.MethodsOpen multicentre, phase IV study (www.clinicaltrials.gov NCT01323959) in which healthy adults, who had received a previous dose of dTpa–IPV, dTpa+IPV or Td–IPV ten years earlier, received a single decennial booster dose of dTpa–IPV (Boostrix™-polio, GlaxoSmithKline Vaccines). Blood samples were collected before and one month after booster vaccination. Antibody concentrations against all vaccine antigens were measured and reactogenicity and safety were assessed.ResultsA total of 211 subjects (mean age 50.3 years) received vaccination of whom 201 were included in the according-to-protocol cohort for immunogenicity. Before the decennial dTpa–IPV booster, ≥71.0% subjects were seroprotected/seropositive against all vaccine antigens. One month after the booster dose, all subjects were seroprotected against tetanus and poliovirus types 2 and 3; ≥95.7% subjects were seroprotected against diphtheria and ≥98.3% against poliovirus type 1. Anti-pertussis booster responses for the various antigens were observed in ≥76.5% (pertussis toxoid; PT), ≥85.1% (filamentous haemagglutinin; FHA) and ≥63.2% (pertactin; PRN) of subjects. During the 4-day follow-up, the overall incidence of local AEs was 71.6%, 75.0% and 72.2% in dTpa–IPV, dTpa+IPV and Td–IPV groups, respectively. Pain was the most frequent solicited local adverse event (AE; ≥62.7% subjects) and fatigue the most frequent solicited general AE (≥18.5%). No serious AEs were reported during the study.ConclusionA booster dose of dTpa–IPV was immunogenic and well tolerated in adults who had received a booster dose of either dTpa–IPV, dTpa+IPV or Td–IPV, ten years previously and supports the repeated administration of dTpa–IPV.