Long‐Term Immunity and Anamnestic Response Following Hepatitis B Vaccination: A Systematic Review and Meta‐Analysis

Fonzo M., Bertoncello C., Trevisan A.

AbstractLong-term immunity after HBV vaccination is still debated. When assessing immune persistence, several variables must be considered, the clear definition of which is crucial. Our aim was to assess protection 10–20 years after primary vaccination and to estimate the effect of age at first dose, sex and time elapsed between doses on long-term protection. We conducted a retrospective cohort study between January 2004 and December 2020. Antibody titres above 10 IU/L were considered protective. Geometric mean titres (GMT) were calculated. The effect of the above variables on long-term protection was assessed by logistic regression analysis. Included participants were 9459. Among those vaccinated during infancy, GMT gradually increased from 11 IU/L (first dose in 1st trimester of life) to 68 IU/L (4th trimester), while the proportion of individuals <10 IU/L remained stable between 1st and 2nd trimester (51%) and it decreased substantially in 3rd (28%) and even more so in the 4th (18%). A one-month delay in first and third dose administration was correlated with a −16% (AOR: 0.84; 95% CI: 0.78–0.91) and a −11% (AOR: 0.89; 95% CI: 0.85–0.94) risk of a titre <10 IU/L, respectively, ~20 years after immunisation. In contrast, similar changes do not comparably affect vaccination in adolescence. The start of vaccination at the third month of age is a compromise between the development of acceptable immunogenicity and the need to protect the infant as early as possible. However, the chance of slightly delaying the vaccine administration within the first year of life may be considered given the impact on long-term persistence of anti-HBs.

Sheena B.S., Hiebert L., Han H., Ippolito H., Abbasi-Kangevari M., Abbasi-Kangevari Z., Abbastabar H., Abdoli A., Abubaker Ali H., Adane M.M., Adegboye O.A., Adnani Q.E., Advani S.M., Afzal M.S., Afzal S., et. al.

SummaryBackground Combating viral hepatitis is part of the UN Sustainable Development Goals (SDGs), and WHO has put forth hepatitis B elimination targets in its Global Health Sector Strategy on Viral Hepatitis (WHO-GHSS) and Interim Guidance for Country Validation of Viral Hepatitis Elimination (WHO Interim Guidance). We estimated the global, regional, and national prevalence of hepatitis B virus (HBV), as well as mortality and disability-adjusted life-years (DALYs) due to HBV, as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. This included estimates for 194 WHO member states, for which we compared our estimates to WHO elimination targets. Methods The primary data sources were population-based serosurveys, claims and hospital discharges, cancer registries, vital registration systems, and published case series. We estimated chronic HBV infection and the burden of HBV-related diseases, defined as an aggregate of cirrhosis due to hepatitis B, liver cancer due to hepatitis B, and acute hepatitis B. We used DisMod-MR 2.1, a Bayesian mixed-effects meta-regression tool, to estimate the prevalence of chronic HBV infection, cirrhosis, and aetiological proportions of cirrhosis. We used mortality-to-incidence ratios modelled with spatiotemporal Gaussian process regression to estimate the incidence of liver cancer. We used the Cause of Death Ensemble modelling (CODEm) model, a tool that selects models and covariates on the basis of out-of-sample performance, to estimate mortality due to cirrhosis, liver cancer, and acute hepatitis B. Findings In 2019, the estimated global, all-age prevalence of chronic HBV infection was 4·1% (95% uncertainty interval [UI] 3·7 to 4·5), corresponding to 316 million (284 to 351) infected people. There was a 31·3% (29·0 to 33·9) decline in all-age prevalence between 1990 and 2019, with a more marked decline of 76·8% (76·2 to 77·5) in prevalence in children younger than 5 years. HBV-related diseases resulted in 555 000 global deaths (487 000 to 630 000) in 2019. The number of HBV-related deaths increased between 1990 and 2019 (by 5·9% [–5·6 to 19·2]) and between 2015 and 2019 (by 2·9% [–5·9 to 11·3]). By contrast, all-age and age-standardised death rates due to HBV-related diseases decreased during these periods. We compared estimates for 2019 in 194 WHO locations to WHO-GHSS 2020 targets, and found that four countries achieved a 10% reduction in deaths, 15 countries achieved a 30% reduction in new cases, and 147 countries achieved a 1% prevalence in children younger than 5 years. As of 2019, 68 of 194 countries had already achieved the 2030 target proposed in WHO Interim Guidance of an all-age HBV-related death rate of four per 100 000. Interpretation The prevalence of chronic HBV infection declined over time, particularly in children younger than 5 years, since the introduction of hepatitis B vaccination. HBV-related death rates also decreased, but HBV-related death counts increased as a result of population growth, ageing, and cohort effects. By 2019, many countries had met the interim seroprevalence target for children younger than 5 years, but few countries had met the WHO-GHSS interim targets for deaths and new cases. Progress according to all indicators must be accelerated to meet 2030 targets, and there are marked disparities in burden and progress across the world. HBV interventions, such as vaccination, testing, and treatment, must be strategically supported and scaled up to achieve elimination. Funding Bill & Melinda Gates Foundation.

Weng M.K., Doshani M., Khan M.A., Frey S., Ault K., Moore K.L., Hall E.W., Morgan R.L., Campos-Outcalt D., Wester C., Nelson N.P.

Hepatitis B (HepB) vaccines have demonstrated safety, immunogenicity, and efficacy during the past 4 decades (1,2).However, vaccination coverage among adults has been suboptimal, limiting further reduction in hepatitis B virus (HBV) infections in the United States.This Advisory Committee on Immunization Practices (ACIP) recommendation expands the indicated age range for universal HepB vaccination to now include adults aged 19-59 years.Removing the risk factor assessment previously recommended to determine vaccine eligibility in this adult age group (2) could increase vaccination coverage and decrease hepatitis B cases.

Pattyn J., Hendrickx G., Vorsters A., Van Damme P.

Abstract Hepatitis B is caused by the hepatitis B virus (HBV), which infects the liver and may lead to chronic liver disease, including cirrhosis and hepatocellular carcinoma. HBV represents a worldwide public health problem, causing major morbidity and mortality. Affordable, safe, and effective, hepatitis B vaccines are the best tools we have to control and prevent hepatitis B. In 2019, coverage of 3 doses of the hepatitis B vaccine reached 85% worldwide compared to around 30% in 2000. The effective implementation of hepatitis B vaccination programs has resulted in a substantial decrease in the HBV carrier rate and hepatitis B-related morbidity and mortality. This article summarizes the great triumphs of the hepatitis B vaccine, the first anticancer and virus-like-particle–based vaccine. In addition, existing unresolved issues and future perspectives on hepatitis B vaccination required for global prevention of HBV infection are discussed.

Mastrodomenico M., Muselli M., Provvidenti L., Scatigna M., Bianchi S., Fabiani L.

In Italy, vaccination against hepatitis B became compulsory for all the newborns and 12-years-old adolescents in 1991. The main purpose of this study was to evaluate the persistence of long-term protection against HBV in medical students of the University of L'Aquila and in postgraduates Medical Doctors (HCWs) working in San Salvatore Hospital. The second aim was to study the variables associated with a protective anti-HBs antibody level, such as age at vaccination, gender, time elapsed from the last dose of vaccination. Three hundred and forty-two subjects were enrolled from January 2017 to January 2019 and a blood sample was collected to evaluate the levels of serum HBsAg, anti-HBs and anti-HBc. Statistical analysis calculated a multivariable logistic regression model to examine predictors of a protective anti-HBs titer. The larger part (239, 70%) of the students had an anti-HBs titer >10 mIU/mL, those were statistically significant older (26.7 vs 24.5 years, p < .001), vaccinated at age 12 years (83.5% vs 59.9% among vaccinate at infancy, p < .001) and more frequently attending postgraduate medical school (80.8% vs 57.5% among healthcare profession school, p < .001). The multivariable logistic regression model showed that HBV vaccination at age of 12 was significantly and independently associated with protective titers (OR = 10.27, p = .019). The results agreed with literature on HBV vaccination, confirming the efficacy of vaccination after 20 years. In particular, our results suggest that adolescent administration is the main predictor of a protective title, regardless of gender, course and years since vaccinations.

Mahmood S., Shah K.U., Khan T.M.

A systematic review was performed to estimate the duration of protection of Hepatitis-B vaccine after primary vaccination during infancy. The number of seropositive participants with anti-HBs antibody titer ≥ 10 mIU/ml and seronegative participants who had anti-HBs antibody titer ≤ 10 mIU/ml after booster dose was the main outcome criteria to find out the protection time of Hepatitis-B vaccine. Twelve studies were selected for systematic review. Overall, results from the meta-analysis have revealed that the risk of Anti-HBs Titer ≤ 10 mIU/ml reduced by 50%. Upon performing the sub-group analysis it was revealed that the overall risk of having Anti-HBs Titre ≤ 10 mIU/ml was reduced up to 62% among the subjects age 21–30 years (0.38 [0.34, 0.44]; I2 = 0.0%, p = 0.938). Furthermore, it was observed that the risk of having titre level less than 10 mIU/ml for plasma derived vaccines were to be 56% [0.44, CI 0.33–0.57, I2 90.9%, p = <0.001]. Vaccination in early infancy does not ensure protection against Hepatitis-B infection. There is a strong correlation between the duration of protection and time elapsed after primary immunization during infancy.

Klinger G., Chodick G., Levy I.

Hepatitis B virus (HBV) vaccination has decreased the prevalence of chronic HBV infections and their sequelae. However, whether vaccination at birth provides lifelong protection is unclear.To assess long-term immunity following neonatal HBV immunization in a large population-based cohort.Using the database of a 2 million member sick fund in Israel, we identified all subjects born after introduction of universal HBV vaccination in Israel (January 1992 through December 2014), that were tested for hepatitis B surface antibody (anti-HBs Ab's). Years since vaccination were categorized into 5-year groups and linear trends in the seroprevalence of HBV immunity were calculated. Anamnestic response and presence of Hepatitis B surface antigen (HBs Ag) were assessed.Included were 20,634 tested individuals. Mean (±SD) age at testing was 14.8 (±5.4) years. Mean anti-HBs Ab levels declined with time to 16.39 mIU/ml in the 15-20 year group (P < 0.001). The proportion of negative results increased gradually (P < 0.001) to 66.7% after 15 years. Anamnestic response assessment showed that 604 of 644 seronegative subjects (93.8%, 95% CI: 91.6-95.5%) became seropositive after a booster dose. HBs Ag was identified in 91 of the 20,634 (4.4 per 1000 study participants).Following vaccination, anti-HB's Ab's progressively decline, with only a third of the population retaining protective levels after 15 years. In adolescence, anamnestic response shows that nearly all revaccinated adolescents exhibit immunity. A low rate of Hepatitis B infection was demonstrated despite vaccination of nearly all newborns.

Terrault N.A., Lok A.S., McMahon B.J., Chang K., Hwang J.P., Jonas M.M., Brown R.S., Bzowej N.H., Wong J.B.

Schillie S., Vellozzi C., Reingold A., Harris A., Haber P., Ward J.W., Nelson N.P.

Voysey M., Kelly D.F., Fanshawe T.R., Sadarangani M., O’Brien K.L., Perera R., Pollard A.J.

The design of infant immunization schedules requires an understanding of the factors that determine the immune response to each vaccine antigen.Deidentified individual participant data from GlaxoSmithKline clinical trials were obtained through Clinical Study Data Request. The data were requested on January 2, 2015, and final data were received on April 11, 2016.Immunogenicity trials of licensed or unlicensed vaccines administered to infants were included if antibody concentrations in infants were measured prior to the first dose of vaccine.The database was examined; studies that appeared to have appropriate data were reviewed.Antigen-specific antibody concentration measured 1 month after priming vaccine doses, before booster vaccination, and 1 month after booster vaccine doses.A total of 7630 infants from 32 studies in 17 countries were included. Mean (SD) age at baseline was 9.0 (2.3) weeks; 3906 (51.2%) were boys. Preexisting maternal antibody inhibited infant antibody responses to priming doses for 20 of 21 antigens. The largest effects were observed for inactivated polio vaccine, where 2-fold higher maternal antibody concentrations resulted in 20% to 28% lower postvaccination antibody concentration (geometric mean ratios [GMRs], type 1: 0.80; 95% CI, 0.78-0.83; type 2: 0.72; 95% CI, 0.69-0.74; type 3: 0.78; 95% CI, 0.75-0.82). For acellular pertussis antigens, 2-fold higher maternal antibody was associated with 11% lower postvaccination antibody for pertussis toxoid (GMR, 0.89; 95% CI, 0.87-0.90) and filamentous hemagglutinin (GMR, 0.89; 95% CI, 0.88-0.90) and 22% lower pertactin antibody (GMR, 0.78; 95% CI, 0.77-0.80). For tetanus and diphtheria, these estimates were 13% (GMR, 0.87; 95% CI, 0.86-0.88) and 24% (GMR, 0.76; 95% CI, 0.74-0.77), respectively. The influence of maternal antibody was still evident in reduced responses to booster doses of acellular pertussis, inactivated polio, and diphtheria vaccines at 12 to 24 months of age. Children who were older when first immunized had higher antibody responses to priming doses for 18 of 21 antigens, after adjusting for the effect of maternal antibody concentrations. The largest effect was seen for polyribosylribitol phosphate antibody, where responses were 71% higher per month (GMR, 1.71; 95% CI, 1.52-1.92).Maternal antibody concentrations and infant age at first vaccination both influence infant vaccine responses. These effects are seen for almost all vaccines contained in global immunization programs and influence immune response for some vaccines even at the age of 24 months. These data highlight the potential for maternal immunization strategies to influence established infant programs.

Henry B., Baclic O.

Leuridan E., Van Damme P.

After several decades of vaccination against hepatitis B virus in newborns, infants, adolescents, and adults, the question remains whether a booster dose is ever needed. Long-term protection is most commonly measured through 4 methods: the anamnestic response after administration of a booster dose, infection rate in vaccinated populations, in vitro B and T cell activity testing, and seroepidemiological studies. Long-term protection is present despite a decrease in anti-hepatitis B surface antibodies over time. The exact mechanism of long-term protection, however, is not yet fully understood. There is no need for boosters in immunologically potent persons as long as a full course was adequately administered that respected the recommended timelines, as evidenced by studies conducted up to 20 years after the original immunization course. However, a booster dose should be planned for immunocompromised patients, based on serological monitoring.

Gilca V., De Serres G., Boulianne N., De Wals P., Murphy D., Trudeau G., Massé R., Duval B.

Few data are available concerning the persistence of anti-HBs and the effect of booster doses given several years post-vaccination against hepatitis B during preadolescence. The objective of this open-labelled clinical trial was to evaluate the persistence of antibodies after vaccination with three paediatric doses of Engerix-B at the age of 8-10 years and the effect of a booster dose given 5 (Group Y5) or 10 (Group Y10) years later. Anti-HBs were measured before and one month post-primary vaccination, then 5 and 10 years later, before the booster dose, as well as one month and 1 year post-booster. The anamnestic response was defined as a >or=fourfold increase of anti-HBs post-booster (>or=10 IU/L) when compared to pre-booster. Ten years post-primary vaccination, 559 of the 652 initially randomized subjects (86%) were eligible for analysis. Group Y5, 5 years post-booster results: 99% of subjects had detectable levels of antibodies and 96% a titer >or=10 IU/L. The anti-HBs GMTs decreased from 114,489 IU/L one month post-booster to 3354 IU/L 5 years later. Group Y10 results: 10 years post-primary vaccination 96% of subjects had a detectable level of anti-HBs and 85% were above the threshold of 10 IU/L. The GMTs one month post-booster were 31,030 IU/L. The challenge with a booster demonstrated an anamnestic response in 99% of subjects in group Y5 and 100% of subjects in group Y10. All subjects were anti-HBc negative. The booster doses were well tolerated. The excellent anamnestic response observed after the booster dose demonstrates the persistence of immunity in virtually all young adults vaccinated at the age of 8-10 with three paediatric doses of Engerix-B.

Kao J., Wang J., Hung C., Yen Y., Hung S., Hu T., Lee C., Lu S.

To assess the differences of long-term efficacy between plasma-derived and recombinant hepatitis B virus (HBV) vaccines and the effectiveness of catch-up vaccination in adolescents with undetectable anti-HBs.Before 1992, infants born in Taiwan were immunized using plasma-derived HB vaccine, and thereafter, by using recombinant HB vaccine. From the only junior middle school of a rural township in central-southern Taiwan, 1788 (93.7%) students from five cross-sectional screenings, grouping into three birth cohorts (Group I: born during 1984-1986, II: 1986-1992 and III: 1992-1995), were enrolled for checking HBsAg, anti-HBs and anti-HBc. Students with undetectable HBsAg and anti-HBs underwent a booster dose (2.5ug) of recombinant HB vaccine (Engerix-B; GlaxoSmithKline, Rixensart, Belgium) and had anti-HBs re-checked 3 weeks later. Individuals who had remained undetectable for anti-HBs completed the other two doses of HB vaccines at 1 and 6 months later.The prevalence of HBsAg (11.4, 5.4 and 1.2%), anti-HBs (64.5, 44.1 and 36.0%) and anti-HBc (29.5, 12.5 and 4.4%) decreased from Group I to III (P

Siegrist C.-.

One of the major challenges in vaccinology is the development of products that are able to induce protective immunity in the early life period. There are clear differences between adult and neonatal immune responses in both mice and humans with respect to both humoral and cell-mediated immunity. As a rule, neonates respond poorly to T-independent polysaccharide antigens and make lower and less persistent antibody responses to T-dependent protein antigens. Nevertheless, B-cell priming in neonates may lead to the generation of memory B cells. Similarly, neonatal cell-mediated immune responses are of lower potency than those generated in adults, and a key factor underlying this phenomenon may be a less effective interaction between antigen and neonatal dendritic cells. In addition to immunological immaturity in the neonate, the presence of inhibitory concentrations of maternally derived antibody imposes a further barrier to effective early life vaccination. Novel vaccination strategies including early priming and subsequent boosting are most likely to counteract these effects and provide protection from exposure to infectious disease in early life.