Safety and immunogenicity of a pediatric formulation of inactivated hepatitis A vaccine in Argentinean children. The role of young children in a community-wide outbreak of hepatitis A. Comparison of immunogenicity and persistence between inactivated hepatitis A vaccine Healive® and Havrix® among children: A 5-year follow-up study Long-term Serologic Follow-up of Children Vaccinated with a Pediatric Formulation of Virosomal Hepatitis A Vaccine Administered With Routine Childhood Vaccines at 12–15 Months of Age Persistence of seropositivity among persons vaccinated for hepatitis A during infancy by maternal antibody status: 15‐year follow‐up Persistence of hepatitis A vaccine induced seropositivity in infants and young children by maternal antibody status: 10‐year follow‐up [The study on the 0, 12 month vaccination schedule' of Healive inactivated hepatitis A vaccine in children]. Protection against hepatitis A by an inactivated vaccine. Immunogenicity and protectivity of a new liposomal hepatitis A vaccine. Model based estimates of long-term persistence of inactivated hepatitis A vaccine-induced antibodies in adults. Long-term Antibody Persistence in Children After Vaccination With the Pediatric Formulation of an Aluminum-free Virosomal Hepatitis A Vaccine Impact of Hepatitis A vaccination with a two-dose schedule in Panama: Results of epidemiological surveillance and time trend analysis. A controlled trial of a formalin-inactivated hepatitis A vaccine in healthy children. Duration of protection against hepatitis A for the current two-dose vaccine compared to a three-dose vaccine schedule in children. Inactivated hepatitis A vaccine-induced antibodies: follow-up and estimates of long-term persistence.
BACKGROUND Children are a reservoir of hepatitis A virus and must be considered as primary targets of any immunization strategy . The safety and immunogenicity were evaluated for a new formulation of an inactivated hepatitis A vaccine , Avaxim 80 units , containing one-half the antigen dose of the adult formulation . METHODS The safety of two doses of this vaccine given 6 months apart was evaluated in an open study in 537 Argentinean children 12 months to 15 years old . Immunogenicity was evaluated at Weeks 0 , 2 , 24 and 27 in a subgroup of 120 subjects . RESULTS Two weeks after the first vaccine dose , > 99 % of initially seronegative children had seroconverted ( titers > or = 20 mIU/ml ) , with a geometric mean titer of 98.5 mIU/ml . Before booster at 24 weeks all subjects had seroconverted . A strong anamnestic response was observed after the second dose at which time the geometric mean titer had increased > 35-fold , and antibody titers were consistent with long term protection . Immediate adverse reactions were observed in 3 of 537 ( 0.6 % ) subjects after the first dose . Local reactions were mild and transient and did not increase with subsequent doses . Among the systemic events reported during the 7-day follow-up period , 37 cases of fever after the first dose and 22 cases after the second dose were reported . Only 3 cases of fever were clearly related to vaccination ( < or = 38.2 degrees C ) after the first injection , all of which subsided in less than 1 day . CONCLUSIONS This study demonstrated the safety and immunogenicity of a pediatric formulation of hepatitis A vaccine in children ages 12 months to 15 years in healthy children ages 12 to 47 months An Hasidic Jewish community has experienced recurrent hepatitis A outbreaks since 1980 . To assess risk factors for illness during a 1985 - 6 outbreak , the authors review ed case records and r and omly selected 93 households for an interview and serologic survey . In the outbreak , 117 cases of hepatitis A were identified , with the highest attack rate ( 4.2 % ) among 3 - 5 year olds . Among the survey households , the presence of 3 - 5 year olds was the only risk factor that increased a household 's risk of hepatitis A ( indeterminant relative risk , P = 0.02 ) . Furthermore , case households from the outbreak were more likely to have 3 - 5 years olds than were control households from the survey ( odds ratio = 16.4 , P < 0.001 ) . Children 3 - 5 years old were more likely to have hepatitis A and may have been the most frequent transmitters of hepatitis A in this community . Hepatitis A vaccination of 3 - 5 year olds can protect this age group and might prevent future outbreaks in the community ABSTRACT Background : Inactivated vaccines for hepatitis A virus ( HAV ) infection are widely used in China . Mass vaccination programs drive the need for data on long-term persistence of vaccine-induced protection . Methods : A prospect i ve , r and omized , open-label clinical trial was conducted to compare geometric mean concentrations ( GMCs ) and seroconversion rates ( SRs ) of anti-HAV antibody elicited by the inactivated vaccines Healive and Havrix for 5 y post immunization , in which 400 healthy children were r and omly assigned in a 3:1 ratio to receive 2 doses of Healive or Havrix at 0 and 6 month . Anti-HAV antibody concentration was detected by microparticle enzyme immunoassay ( MEIA ) during the study . Furthermore , an attempt was made to predict persistence of protective immunogenicity by using a suitable statistical model . Results : The GMCs were significantly higher after vaccination with Healive than after Havrix as comparator vaccine at 1 , 6 , 7 , 18 , 30 , 42 , 54 and 66 month ( P < 0.01 ) with the peak point at 7 month ( 3427.2 mIU/ml for Healive and 1441.9 mIU/ml for Comparator ) . Similarly significant differences of SRs were found between the 2 groups at 1 and 6 month ( P < 0.01 ) . Afterwards , the SRs of both groups reached 100 % at 7 month and did not decline until 66 month(99.1 % for Healive and 97.5 % for Comparator ) . A linear mixed model with a change point at 18 month(Model 3 ) was found to be suitable to predict persistence of protective immunogenicity induced by vaccines . It was estimated that the duration of protection for Healive was at least 20 y with a lower limit of GMC 95 % confidence interval ( CI ) no less than 20 mIU/mL. Conclusions : Compared with Havrix , the new preservative-free inactivated hepatitis A vaccine ( Healive ) in 2 doses showed better persistence of antibody concentrations for 5 y after full-course immunization among children and the persistence of protective immunogenicity was estimated for at least 20 Background : The aim of this open-label , active-controlled , parallel group , phase 2 follow-up study was to assess the long-term immunogenicity of Epaxal Junior , the pediatric dose of an aluminum-free virosomal inactivated hepatitis A virus ( HAV ) vaccine , in children receiving routine childhood vaccines ( RCV ) . Methods : Healthy children ( 12–15 months old , ≥8 kg weight ) were r and omized ( 1:1:1 ) to group A : Epaxal Junior + RCV ( day 1 ) ; group B : Epaxal Junior ( day 1 ) + RCV ( day 29 ) and group C : Havrix 720 + RCV ( day 1 ) . All 3 groups received 2 doses of HAV vaccines 6 months apart . Children who completed the primary study were followed up from 18 months to 7.5 years post booster . Results : Of 291/327 r and omized children who had completed the primary study , 157 were followed for the 7.5-year analysis ( group A : 50 ; group B : 54 ; and group C : 53 ) . Of these , 152 children  had protective levels of anti-HAV antibodies [ ≥10 mIU/mL ; 98 % ( group A ) ; 96.3 % ( group B ) ; 96.2 % ( group C ) ] . Anti-HAV geometric mean concentrations were similar in groups A and B at all the time points ( 1.5- , 2.5- , 3.5- , 5.25- and 7.5-year time point ) but slightly lower in group C. Predictions of the median duration of persistence of seroprotective antibody levels , using the linear mixed model were similar in all groups : ( group A : 19.1 years , group B : 18.7 years , group C : 17.3 years ) . Conclusions : Immunization with Epaxal Junior administered with RCVs at 12 months elicited protective response beyond 7.5 years in almost all children . Assessing the kinetic of anti-HAV antibody titers decline over time , the moment to reach antibody concentrations below the accepted protective level may occur earlier than previously estimated The effect of passively transferred maternal antibody to hepatitis A virus ( anti‐HAV ) on the duration of seropositivity after hepatitis A vaccination during infancy and early childhood is unclear . We obtained levels of anti‐HAV at intervals through age 15‐16 years among three groups of Alaskan Native children who initiated a two‐dose inactivated hepatitis A vaccination series at ages 6 months ( group 1 ) , 12 months ( group 2 ) , and 15 months ( group 3 ) , each group r and omized according to maternal anti‐HAV status . Seropositivity ( anti‐HAV ≥20 mIU/mL ) 30 years after the second vaccine dose among the three groups was predicted using a r and om effects model . One hundred eighty‐three children participated in the study ; follow‐up did not differ significantly by vaccine group or maternal anti‐HAV status . Although the frequency of seropositivity among all participants through age 10 years was high ( 100 % among groups 2 and 3 and > 90 % among group 1 ) , there was a decrease thereafter through age 15‐16 years among group 1 children , who initiated vaccination at age 6 months ( 50%‐75 % ) , and among maternal anti‐HAV‐positive children in groups 2 and 3 ( 67%‐87 % ) , who initiated vaccination at ages 12 months and 15 months , respectively . Nonetheless , the model indicated that anti‐HAV seropositivity should persist for ≥30 years after vaccination in 64 % of all participants ; among those seropositive at age 15‐16 years , 84 % were predicted to remain so for ≥30 years . Conclusion : Most children vaccinated during early childhood available for sampling maintained seropositivity through age 15‐16 years ; however , seropositivity was less frequent among those starting vaccination at age 6 months and among maternal antibody‐positive participants who started vaccination at age 12 months or 15 months ; overall , our findings support current vaccine recommendations and continued follow‐up of this cohort . ( Hepatology 2016;63:703–711 Persistence of seropositivity conferred by hepatitis A vaccine administered to children < 2 years of age is unknown and passively transferred maternal antibodies to hepatitis A virus ( maternal anti‐HAV ) may lower the infant 's immune response to the vaccine . One hundred ninety‐seven infants and young children were r and omized into three groups to receive a two‐dose hepatitis A vaccine : group 1 at 6 and 12 months , group 2 at 12 and 18 months , and group 3 at 15 and 21 months of age . Within each group , infants were r and omized by maternal anti‐HAV status  . Anti‐HAV levels were measured at 1 and 6 months and at 3 , 5 , 7 , and 10 years after the second dose of hepatitis A vaccination . Children in all groups had evidence of seroprotection ( > 10 mIU/mL ) at 1 month after the second dose . At 10 years , all children retained seroprotective anti‐HAV levels except for only 7 % and 11 % of children in group 1 born to anti‐HAV – negative and anti‐HAV – positive mothers , respectively , and 4 % of group 3 children born to anti‐HAV – negative mothers . At 10 years , children born to anti‐HAV – negative mothers in group 3 had the highest geometric mean concentration ( GMC ) ( 97 mIU/mL ; 95 % confidence interval , 71‐133 mIU/mL ) and children born to anti‐HAV – positive mothers in group 1 had the lowest GMC ( 29 mIU/mL ; 95 % confidence interval , 20‐40 mIU/mL ) . Anti‐HAV levels through 10 years of age correlated with initial peak anti‐HAV levels ( tested at 1 month after the second dose ) . Conclusion : The seropositivity induced by hepatitis A vaccine given to children < 2 years of age persists for at least 10 years regardless of presence of maternal anti‐HAV . ( HEPATOLOGY 2012 OBJECTIVE To evaluate the safety , immunogenicity and fit dosage of Healive inactivated hepatitis A vaccine ( HAV ) in children . METHODS A total of 85 susceptible aged 4 - 10 years with HAV seronegative children , had been enrolled from two adjacent villages in a county . The volunteers were r and omized allocated into two groups and to receive a priming dose of 250 U/0.5 ml/dose or 500 U/1.0 ml/dose of Healive vaccine , produced by Sinovac Biotech Co , Ltd. A booster of the same dose was given at 12th month . Local and systemic side effects were examined and seroconversion rate as well as geometric mean titers of anti-HAV antibody were tested at 3-week , 12-month after the primary dose and at 1 month after the booster dose . RESULTS The vaccine was well tolerated in both groups . At 21 days after the primary dose , the seroconversion rates were 94.4 % , 100.0 % and geometric mean titers ( GMT ) were 195 mIU/ml and 370 mIU/ml in 250 U and 500 U groups respectively . At 12 months after the primary dose , the seroconversion rate of anti-HAV was 100.0 % , and GMT raised to 361 mIU/ml , 456 mIU/ml ( P > 0.05 ) respectively . One month after the booster dose , GMT raised to 14 893 mIU/ml , 21 696 mIU/ml . CONCLUSION GMT of the 0 , 12 month schedule was higher than other schedule after the booster vaccination . The Healive inactivated vaccine can be used for emergency vaccination . The Healive inactivated vaccine produced by Sinovac Company Ltd was safe and highly immunogenic . Two hundred and fifty U/dose was considered appropriate for children OBJECTIVE To evaluate the safety and efficacy of a new inactivated hepatitis A vaccine . DESIGN Double-blind r and omized controlled trial stratified by community . SETTING Community-based in Thail and . STUDY PARTICIPANTS A total of 40,119 children , aged 1 to 16 years , attending 148 primary schools : 38,157 ( 95 % ) entered surveillance a mean of 138 days after receiving vaccine dose 1 ; 33,586 ( 84 % ) completed the controlled trial of 532 days ; and 31,075 ( 81 % ) received crossover vaccine and remained under surveillance until day 844 . INTERVENTION Participants received hepatitis A vaccine or control hepatitis B vaccine starting January 7 , 1991 ( doses in months 0 , 1 , and 12 ) , and crossed over to the alternate vaccine 18 months later . MAIN OUTCOME MEASURE Cases of hepatitis A ( symptoms , alanine aminotransferase levels of 45 U/L or higher , and IgM to hepatitis A virus ) were identified by evaluating school absences of 2 or more days . RESULTS There were no serious adverse reactions despite administration of more than 109,000 doses of hepatitis A vaccine . Among initially seronegative recipients of two doses of hepatitis A vaccine , the proportion with 20 mIU/mL or more of antibody to hepatitis A virus before and 5 months after a 1-year booster was 94 % and 99 % , respectively . Of 6976 episodes of illness during the controlled trial , there were 40 cases of hepatitis A ; 38 were in the control group . Of the 40 cases , six , all in controls , occurred after the 1-year booster dose . Following two doses of hepatitis A vaccine ( days 138 through 386 ) , protective efficacy was 94 % ( 95 % confidence interval , 79 % to 99 % ) ; cumulative efficacy including the postbooster period ( days 138 to 532 ) was 95 % ( 95 % confidence interval , 82 % to 99 % ) . The two hepatitis A vaccine recipients who had symptomatic infections ( 257 and 267 days after dose 1 ) appeared to have been partially protected since their illnesses were brief and associated with only slight increases in alanine aminotransferase . CONCLUSIONS Inactivated hepatitis A vaccine is safe ; when administered in two doses , it protects against hepatitis A for at least 1 year In this study we investigated a new liposomal hepatitis A vaccine ( Epaxal ) developed by the Swiss Serum and Vaccine Institute clinical ly and immunologically using a one dose priming schedule and a booster injection after 1 year . This vaccine contains formalin inactivated hepatitis A virus particles attached to phospholipid vesicles together with influenza virus haemagglutinin . Two doses of the vaccine were administered at months 0 and 12 in 117 volunteers . Blood sample s were drawn at days-7 , 14 and 28 and after 6 , 12 and 13 months , local and systemic reactions were monitored by means of question naires . Immunogenicity was evaluated as usual by the determination of anti-HAV from the collected sera using the ELISA technique . In order to evaluate the protective efficacy of the vaccine induced antibodies a sample of 25 sera mainly from vaccinees showing low ELISA titres was additionally analysed by means of a virus NT . The vaccine was excellently tolerable and highly immunogenic . Seroconversion evaluated by ELISA was 97 and 99 % , respectively , 14 and 28 days after the first dose and 100 % after the second dose . NT titres were well correlated with ELISA titres and showed similar seroconversion rates even in the early phase of immunization . The results of this study show that with two doses of the liposomal hepatitis A vaccine administered at months 0 and 12 early protection within 14 days and long lasting immunity can be achieved BACKGROUND In this paper , we review the results of existing statistical models of the long-term persistence of  hepatitis A vaccine-induced antibodies in light of recently available immunogenicity data from 2 clinical trials ( up to 17 years of follow-up ) . METHODS Healthy adult volunteers monitored annually for 17 years after the administration of the first vaccine dose in 2 double-blind , r and omized clinical trials were included in this analysis . Vaccination in these studies was administered according to a 2-dose vaccination schedule : 0 , 12 months in study A and 0 , 6 months in study B ( NCT00289757/NCT00291876 ) . Antibodies were measured using an in-house ELISA during the first 11 years of follow-up ; a commercially available ELISA was then used up to Year 17 of follow-up . Long-term antibody persistence from studies A and B was estimated using statistical models for longitudinal data . Data from studies A and B were modeled separately . RESULTS A total of 173 participants in study A and 108 participants in study B were included in the analysis . A linear mixed model with 2 changepoints allowed all available results to be accounted for . Predictions based on this model indicated that 98 % ( 95%CI : 94 - 100 % ) of participants in study A and 97 % ( 95%CI : 94 - 100 % ) of participants in study B will remain seropositive 25 years after receiving the first vaccine dose . Other models using part of the data provided consistent results : ≥95 % of the participants was projected to remain seropositive for ≥25 years . CONCLUSION This analysis , using previously used and newly selected model structures , was consistent with former estimates of seropositivity rates ≥95 % for at least 25 years Background : The pediatric dose of the virosomal hepatitis A vaccine Epaxal ® , Epaxal ® Junior , is safe and immunogenic in children from 1 to 17 years of age . The present study investigated the long-term immunogenicity of Epaxal ® Junior . The st and ard doses of Epaxal ® and aluminum-adsorbed hepatitis A vaccine ( Havrix ® Junior ) were used as comparators . Methods : A total of 271 children who had completed a 0/6-month immunization schedule ( priming and booster dose ) participated in this follow-up study . Anti-hepatitis A virus ( HAV ) antibody levels were measured using a microparticle enzyme immunoassay ( HAVAB 2.0 Quantitative ; Abbott Diagnostics , Wiesbaden , Germany ) starting at 18 months following the second dose , and then yearly until 66 months ( ie , 5.5 years ) after the second dose . Results : All subjects tested at Month 66 still had protective anti-HAV antibodies ( ≥10 mIU/mL ) . Antibody titers were generally lower in subjects 1–7 years old than in subjects 8–17 years old and higher in females 11–17 years old than in males 11–17 years old . In addition , an age-dependent decay was observed , that is , antibody decreased more rapidly in younger than in older children . Conclusions : Vaccination of children with two doses of Epaxal ® Junior confers a real-time protection of at least 5.5 years . This protection is estimated to last approximately 25 years . Younger children showed lower antibody titers and a faster antibody decline than older children . Additional follow-up studies are needed beyond 5.5 years to further assess the long-term immunogenicity of Epaxal ® Junior PURPOSE In April 2007 , Panama introduced Hepatitis A universal vaccination using a two-dose schedule ( Havrix( ® )junior ; GSK Vaccines , Belgium ) . We assessed the impact of this hepatitis A vaccine three years after it was recommended for universal mass vaccination in Panama . MATERIAL S AND METHODS Hepatitis A vaccination impact was assessed using two different approaches . The first approach used retrospective data ( incidence and number of cases for all age groups ) , collected from the passive surveillance of the Epidemiologic Surveillance System of the Ministry of Health of hepatitis A and unspecified hepatitis before ( 2000 - 2006 ) and after ( 2008 - 2010 ) introduction of hepatitis A vaccine .  The second approach was a prospect i ve hospital-based active surveillance for hepatitis cases conducted in subjects ( 0 - 14 years ) during 2009 - 2011 at three sentinel hospitals in Panama . RESULTS Overall , the annual incidence of hepatitis A and unspecified hepatitis in 2008 , 2009 and 2010 were 13.1 , 7.9 and 3.7 per 100,000 subjects , lower than the baseline incidence of 51.1 per 100,000 subjects . In comparison to the mean baseline period ( 2000 - 2006 ) , there was an 82 % mean reduction in the overall hepatitis-related outcomes ( hepatitis A and unspecified hepatitis ) after vaccine introduction ( 2008 - 2010 ) in all age groups . In the hospital-based surveillance ( 2009 - 2011 ) , of the 42 probable viral hepatitis A cases , nine cases were confirmed as acute hepatitis A ( 8 in 2009 , 1 in 2010 ) . Of these confirmed cases , two belonged to the targeted vaccine group ( 1 - 4 years ) but were not vaccinated . CONCLUSIONS Our study suggests that the introduction of two-dose hepatitis A vaccines in Panama has contributed to the reduction in the incidence of overall hepatitis-related outcomes for all age groups , suggesting herd protection . Additional monitoring is required to document a sustained long-term effect BACKGROUND Although inactivated hepatitis A vaccine is known to be well tolerated and immunogenic in healthy children and adults , its efficacy has yet to be established . METHODS To evaluate the efficacy of the hepatitis A vaccine in protecting against clinical ly apparent disease , we conducted a double-blind , placebo-controlled trial in an Hasidic Jewish community in upstate New York that has had recurrent outbreaks of hepatitis A. At the beginning of a summer outbreak , 1037 healthy seronegative children 2 to 16 years of age were r and omly assigned to receive one intramuscular injection of a highly purified , formalin-inactivated hepatitis A vaccine or placebo . A case was defined by the presence of typical signs and symptoms , a diagnostic increase in IgM antibody to hepatitis A , and a serum concentration of alanine aminotransferase at least twice the upper limit of normal . Cases occurring greater than or equal to 50 days after the injection were included in the evaluation of efficacy . The children were followed for a mean of 103 days . RESULTS A total of 519 children received vaccine , and 518 received placebo .  The vaccine was well tolerated , with no serious adverse reactions . From day 50 after the injection , 25 cases of clinical ly apparent hepatitis A occurred in the placebo group and none in the vaccine group ( P less than 0.001 ) , confirming that the vaccine had 100 percent protective efficacy . Before day 21 , seven cases occurred in the vaccine group and three cases in the placebo group . After that time , there were no cases among vaccine recipients and 34 cases among placebo recipients . CONCLUSIONS The inactivated purified hepatitis A vaccine that we tested is well tolerated , and a single dose is highly protective against clinical ly apparent hepatitis BACKGROUND Hepatitis A is mostly a self-limiting disease but causes substantial economic burden . Consequently , United States Advisory Committee for Immunization Practice s recommends inactivated hepatitis A vaccination for all children beginning at age 1 year and for high risk adults . The hepatitis A vaccine is highly effective but the duration of protection is unknown . METHODS We examined the proportion of children with protective hepatitis A antibody levels ( anti-HAV ≥20 mIU/mL ) as well as the geometric mean concentration ( GMC ) of anti-HAV in a cross sectional convenience sample of individuals aged 12 - 24 years , who had been vaccinated with a two-dose schedule in childhood , with the initial dose at least 5 years ago . We compared a subset of data from persons vaccinated with two-doses ( 720 EL.U. ) at age 3 - 6 years with a demographically similar prospect i ve cohort that received a three-dose ( 360 EL.U. ) schedule and have been followed for 17 years . RESULTS No significant differences were observed when comparing GMC between the two cohorts at 10 ( P=0.467 ) , 12 ( P=0.496 ) , and 14 ( P=0.175 ) years post-immunization . For the three-dose cohort , protective antibody levels remain for 17 years and have leveled-off over the past 7 years . CONCLUSION The two- and three-dose schedules provide similar protection > 14 years after vaccination , indicating a booster dose is not needed at this time . Plateauing anti-HAV GMC levels suggest protective antibody levels may persist long-term To estimate the long-term persistence of anti-HAV antibodies , 120 ( schedule 0 - 6 ) and 194 ( schedule 0 - 12 ) adults were vaccinated and followed-up annually for 6 years . Shortly after the last dose , anti-HAV levels fell sharply ( annual decline rate delta > 65 % ) . Thereafter , delta diminished to 10 - 15 % . GMTs 5.5 years after the last dose were 522 mIU/ml ( 0 - 6 group ) and 749 mIU/ml ( 0 - 12 group ) ; all subjects except one maintained detectable antibodies . The average delta over the whole follow-up period was 15 - 20 % , result ing in an estimated persistence of anti-HAV levels > or = 20 mIU/ml for 20 - 25 years . These estimates were similar for both applied calculation methods ( GMT or individual based ) and both vaccination schedules . Because the individual antibody levels tended to stabilise between the last two measurements , the hypothesis of a slow , log-linear decrease and its matching calculation methods might be subject to reconsideration . With the current methodology , however , detectable antibodies are estimated to persist for 20 - 25 years
The WHO recommends integration of universal mass vaccination ( UMV ) against hepatitis A virus ( HAV ) in national immunization schedules for children aged ≥1 year , if justified on the basis of acute HAV incidence , declining endemicity from high to intermediate and cost-effectiveness .
This recommendation has been implemented in several countries .