Published online September 1, 2006
PEDIATRICS Vol. 118 No. 3 September 2006, pp. e602-e609 (doi:10.1542/peds.2005-2755)
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nolan, T.
Right arrow Articles by Descamps, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nolan, T.
Right arrow Articles by Descamps, D.
Related Collections
Right arrow Infectious Disease & Immunity
Right arrowRelated AAP Red Book topics:
Pertussis (Whooping Cough)
Hepatitis A
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

ARTICLE

Immunogenicity and Safety of an Inactivated Hepatitis A Vaccine Administered Concomitantly With Diphtheria-Tetanus-Acellular Pertussis and Haemophilus influenzae Type B Vaccines to Children Less Than 2 Years of Age

Terry Nolan, MBBS, PhDa, Henry Bernstein, DOb, Mark M. Blatter, MDc, Kenneth Bromberg, MDd, Fernando Guerra, MD, MPHe, William Kennedy, MDf, Michael Pichichero, MDg, Shelly D. Senders, MDh, Andrew Trofa, MDi, Alix Collard, PhDj, Diane C. Sullivan, RNi and Dominique Descamps, MDj

a School of Population Health, University of Melbourne and Murdoch Children's Research Institute, Victoria, Australia
b Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
c Primary Physicians Research, Pittsburgh, Pennsylvania
d State University of New York, Health Science Center at Brooklyn, Vaccine Study Center, Brooklyn, New York
e Main Immunization Clinic, San Antonio, Texas
f University of California Los Angeles Center for Vaccine Research, Los Angeles Biomedical Research Institute at Harbor-University of California Los Angeles Medical Center, Torrance, California
g University of Rochester Medical Center, Rochester, New York
h Dr Shelly Senders & Associates, University Heights, Ohio
i GlaxoSmithKline, King of Prussia, Pennsylvania
j GlaxoSmithKline, Rixensart, Belgium


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. The availability of a hepatitis A virus vaccine for infant and early childhood immunization could reduce the transmission of hepatitis A virus in the United States. This study evaluated the immunogenicity and safety of a hepatitis A virus vaccine (Havrix, GlaxoSmithKline Biologicals, Rixensart, Belgium) administered concomitantly with diphtheria-tetanus-acellular pertussis and Haemophilus influenzae type b vaccines to children <2 years.

METHODS. In this open, comparative, multicenter study, 1084 healthy children aged 11 to 25 months were allocated (4:4:3:3:4 ratio) to 5 treatment groups based on age and previous vaccination history. Subjects 11 to 13 months of age received 2 doses of hepatitis A virus vaccine 6 months apart (N = 243). Subjects aged 15 to 18 months received 2 doses of hepatitis A virus vaccine 6 months apart (N = 241); or hepatitis A virus vaccine, diphtheria-tetanus-acellular pertussis, and H influenzae type b at month 0 and the second dose of hepatitis A virus vaccine 6 months later (N = 183); or diphtheria-tetanus-acellular pertussis and H influenzae type b at month 0 and hepatitis A virus vaccine at months 1 and 7 (N = 175). Subjects 23 to 25 months of age received hepatitis A virus vaccine at months 0 and 6 (N = 242). Immune responses were measured at baseline and 30 days after vaccine doses, and solicited and unsolicited adverse events were collected.

RESULTS. After 2 doses of hepatitis A virus vaccine, all of the subjects in all of the groups were seropositive. Coadministration of hepatitis A virus vaccine with diphtheria-tetanus-acellular pertussis and H influenzae type b vaccines did not impact the immunogenicity of the 3 vaccines, except for the antipertussis toxoid vaccine response, which was slightly decreased. Hepatitis A virus vaccine was well tolerated in children 11 to 25 months of age.

CONCLUSION. The administration of 2 doses of hepatitis A virus vaccine on a 0- and 6-month schedule starting at 11 to 13 months of age or at 15 to 18 months of age was as immunogenic and well tolerated as the administration of 2 doses in children 2 years of age. Immune responses to diphtheria-tetanus-acellular pertussis and H influenzae type b either given alone or coadministered with hepatitis A virus vaccine were similar except for antipertussis toxoid response.

Key Words: hepatitis A vaccine • immunogenicity • safety • children

Abbreviations: HAV—hepatitis A virus • DTaP—diphtheria-tetanus-acellular pertussis • Hib—Haemophilus influenzae type b • GMC—geometric mean concentration • ELU—enzyme-linked immunosorbent assay units • PT—pertussis toxoid • FHA—filamentous hemagglutinin • D—diphtheria toxoid • T—tetanus toxoid • PRP—polyribosylribitol phosphate • AE—adverse event • SAE—serious adverse event • CI—confidence interval

Hepatitis A is a highly infectious disease caused by the hepatitis A virus (HAV). Globally, an estimated 1.5 million clinical cases of hepatitis A occur each year.1 In the United States, however, rates of hepatitis A have gradually declined, particularly among children and in those states where routine childhood vaccination was recommended, suggesting an effect of childhood vaccination.2 Transmitted by the fecal-oral route and often clinically unrecognizable in children, outbreaks have occurred in day care centers and schools.3,4 In a study of adults without an identified source of hepatitis A infection, 57% of their households included a child <6 years, and the presence of a young child was associated with HAV transmission within the household.5 Prevention of hepatitis A in children may reduce its transmission to families and the community.

In January 2006, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices published a recommendation for HAV vaccination for all children in the United States at age 1 year (12–23 months).6 This recommendation has replaced previous geographic and risk-based recommendations.7 However, several other vaccines are often administered to this age group, including measles, mumps, and rubella vaccine; varicella vaccine; and booster doses of vaccines primed in the first year of life. To maximize vaccination opportunities at office visits, concomitant administration of these vaccines is needed and may help to reduce immunization program costs and increase compliance with published recommendations.

Havrix (GlaxoSmithKline Biologicals, Rixensart, Belgium) is a formalin-inactivated HAV vaccine that was licensed in the United States in 1995. Many studies have demonstrated it to be well tolerated and immunogenic in children ≥2 years of age.8,9 The present study was conducted to evaluate the immunogenicity and safety of Havrix when administered to children <2 years, either alone or coadministered with diphtheria-tetanus-acellular pertussis (DTaP) and Haemophilus influenzae type b (Hib) vaccines, which are recommended for children in this age group.

The 2 primary objectives of the study were sequential in that they were to demonstrate equivalence between the anti-HAV geometric mean concentrations (GMCs) after the second dose of HAV vaccine when the first dose was administered to children 15 to 18 and 23 to 25 months of age and then to demonstrate equivalence between the anti-HAV GMCs in children 11 to 13 and 23 to 25 months of age. Secondary objectives included the evaluation of the immune responses to all of the vaccine antigens after the first dose of HAV vaccine when given alone or coadministered with DTaP and Hib and the safety of all of the vaccines.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Participants
Healthy children 11 to 25 months of age were recruited from 14 sites in the United States and 1 site in Australia. Study entry criteria excluded any obvious health problems and included birth after a normal gestation period and completion of DTaP and Hib primary vaccinations according to the recommended schedule. Children were eligible for study entry regardless of their anti-HAV serologic status. However, they were excluded from study participation if there was previous vaccination for, history of, or known exposure to HAV.

Study Design
In this open, prospective, comparative, nonrandomized, multicenter study, subjects were allocated to 5 groups (4:4:3:3:4 ratio) based on their age and previous vaccination history (Fig 1). Subjects 11 to 13 months of age received 2 doses of HAV vaccine 6 months apart (group 1). Subjects 15 to 18 months of age were assigned to group 2, group 3, or group 4 depending on their previous status of DTaP and Hib vaccinations. Subjects who had received booster vaccinations of DTaP and Hib were assigned to group 2 and received 2 doses of HAV vaccine 6 months apart. Subjects who had not received DTaP and Hib booster vaccinations were assigned to group 3 or 4 to receive either HAV vaccine, DTaP, and Hib at month 0 and the second dose of HAV vaccine 6 months later (group 3) or DTaP and Hib at month 0 and HAV vaccine at months 1 and 7 (group 4). Subjects 23 to 25 months of age were assigned to group 5 and received HAV vaccine at months 0 and 6. All of the study vaccines were administered by intramuscular injection; HAV vaccine was administered in the left thigh, and other study vaccines administered at the same time were given in the right thigh. Other routinely recommended vaccinations were administered 30 days before or after protocol-specified vaccinations. Blood samples were collected prevaccination and 30 days after each dose of vaccine in all of the subjects with the exception of group 4 subjects, in whom no blood was drawn after the first dose of HAV vaccine.


Figure 1
View larger version (17K):
[in this window]
[in a new window]

  		FIGURE 1 Overview of study design.

 
Vaccines
Each 0.5-mL dose of HAV vaccine (Havrix, GlaxoSmithKline Biologicals) contained 720 enzyme-linked immunosorbent assay units (ELUs) of inactivated HAV antigen, 0.25 mg of aluminum, 0.5% (wt/vol) 2-phenoxyethanol, 0.3% (wt/vol) amino acid supplement, and 0.05 mg/mL of polysorbate 20. Each 0.5-mL dose of DTaP vaccine (Infanrix, GlaxoSmithKline Biologicals) contained 25 µg of pertussis toxoid (PT), 25 µg of filamentous hemagglutinin (FHA), 8 µg of pertactin, ≥30 IU (25 limit of flocculation unit [Lf]) of diphtheria toxoid (D), ≥40 IUs (10 Lf) of tetanus toxoid (T), 0.5 mg of aluminum as salts, 2.5 mg of 2-phenoxyethanol, and 150 mM of sodium chloride. Each 0.5-mL dose of conjugated Hib vaccine (OmniHIB, Pasteur-Mérieux, Sera et Vaccins, SA, Lyon, France) contained 10 µg of polyribosylribitol phosphate (PRP), 24 µg of T, 42.5 mg of sucrose, and 0.6 mg of Tris buffer.

Antibody Response
Seropositivity for anti-HAV was defined as antibody concentration ≥15 mIU/mL by enzyme-linked immunosorbent assay, the assay cutoff. HAV vaccine responders were defined as those subjects who converted from an initially seronegative to a seropositive status or if initially seropositive, maintained or demonstrated an increase above prevaccination concentrations.

For diphtheria and tetanus, seroprotection was defined as anti-D/anti-T concentrations ≥0.1 IU/mL. For the pertussis components (anti-PT, anti-FHA, and antipertactin), seropositivity was defined as antibody concentrations ≥5 ELU/mL against each antigen. Vaccine response to pertussis antigens was defined as the appearance of antibodies (concentration ≥5 ELU/mL) in initially seronegative subjects or postvaccination concentrations of ≥2 times the prevaccination concentrations in initially seropositive subjects. For PRP, 2 cutoffs (0.15 µg/mL and 1.0 µg/mL) were considered, and the percentages of subjects with concentrations above these cutoffs were computed.

Safety Evaluation
Parents/guardians recorded adverse events (AEs) on standardized diary cards on the day of vaccination and on the 3 subsequent days. Solicited local AEs included pain, swelling, and redness at the injection site(s), and solicited general (systemic) AEs included drowsiness, fever (rectal body temperature ≥38.0°C/100.4°F), irritability, and loss of appetite. Grade 3 (severe) solicited AEs were defined as pain at the injection site that resulted in the subject crying when the limb was moved and/or was spontaneously painful, redness and swelling at the injection site with the largest diameter of the affected area >20 mm, rectal temperature >39.5°C (>103.1°F), irritability or crying that could not be comforted and/or prevented normal activity, drowsiness that prevented normal activity, and loss of appetite where the subject did not eat at all.

All of the unsolicited AEs that occurred within 1 month after each dose of vaccine were recorded irrespective of severity or causal relationship to vaccination. All of the serious AEs (SAEs) were reported from the first dose of vaccine until 1 month after the last dose of vaccine.

Statistical Analysis
The Food and Drug Administration has established criteria for detecting a potential biological difference in antibody titers between 2 study groups, known as noninferiority testing.10 In the present study, sample size was calculated based on the 2 coprimary objectives being achieved sequentially. A sample size of ≥150 subjects in groups 1, 2, and 5 was planned for the primary end point analysis so that the power to reject each null hypothesis independently was 96%. Taking into account the contingency of the second test (which was only to be performed if equivalence was demonstrated during the first step), this sample size was to provide 92% power to show equivalence of the second primary objective. The power to conclude noninferiority of the vaccine response rate and/or GMCs of antibody responses to vaccines administered concomitantly with HAV vaccine was >99% for each individual test. Assuming reference rates >95% and SD in log10 scale of pertussis GMCs <0.37 leads to 88% power for showing noninferiority between groups 3 and 4 with respect to all of the components of DTaP for the effect of HAV vaccine on DTaP response, 95% power for the effect of HAV vaccine on the Hib response, and 95% power for the effect of DTaP and Hib on HAV vaccine response.

For immunogenicity, descriptive summaries of observed data were based on frequencies for binary end points (seropositivity, seroprotection, and vaccine response) with the associated 95% confidence interval (CI) derived using the exact method for percentages. For GMC computation, antibody concentration values were log transformed, and those below the assay cutoff were given an arbitrary value of half of the cutoff value.

For inference analyses based on antibody concentrations, the 95% CI for the GMC ratio (test over comparator) was calculated. For the equivalence tests based on the anti-HAV GMC in responders, the 2-sided 95% CIs for the GMC ratios were computed for each time point using a 1-way analysis of covariance model, including test group and country as fixed effects and prevaccination concentration as regressor. The anti-HAV GMC of the test group was considered equivalent to control if the computed 95% CI was included within the protocol-defined limits of [0.5; 2.0]. For pertussis antigens, the same approach was used. The GMC of the test group was considered to be noninferior to that of the control group if the lower limit of the computed interval was not less than the prespecified limit of 0.5.

When a binary end point was used for the inference, noninferiority was assessed through an asymptotic 95% CI on the difference (test minus control) in observed percentages. The response rate in the test group was considered to be noninferior to that of the control group if the lower limit of the computed 95% CI was greater than the prespecified limits (–5% for anti-HAV response and –10% for seropositivity/seroprotection rates for the other antigens).

For reactogenicity and overall safety analyses, the number and percentage (with exact 95% CI) of documented doses, as well as the number and percentage (with exact 95% CI) of subjects reporting ≥1 AE (local or general and solicited or unsolicited), ≥1 general AE (solicited or unsolicited), or ≥1 local AE (solicited or unsolicited) during the protocol-specified follow-up periods are presented. The 95% CIs of the percentages were calculated using the exact method for binomial variables.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Participants
A total of 1084 subjects were vaccinated, and ~70% of the study population was from the United States. There were 243 subjects in group 1, 241 in group 2, 183 in group 3, 175 in group 4, and 242 in group 5. Gender and race were distributed similarly across the groups: 52.4% of the subjects were boys, and the majority of subjects were white (61%). A total of 88 subjects withdrew from the study for the following reasons: protocol violation (n = 3), consent withdrawal (n = 20), migration from the study area (n = 16), lost to follow-up with an incomplete vaccination course (n = 33), lost to follow-up with a complete vaccination course (n = 8), AEs (n = 5), and other reasons (n = 3). Of those who withdrew for AEs, 1 subject in group 2 withdrew from the study because of an SAE; 151 days after receiving the first dose of HAV vaccine, the subject was hospitalized for papular urticaria, which was determined to be unrelated to vaccination. Four subjects withdrew because of a non-SAE: 1 subject in group 1 experienced mild drowsiness and moderate-to-severe irritability for days 0 to 3 after dose 1, which was suspected to be related to vaccination; 1 subject in group 2 experienced moderate (10 mm) redness on the day of the first vaccination, which was assessed to be causally related to vaccination; 1 subject in group 4 suffered a severe viral illness 33 days after dose 1, which was assessed as unlikely to be related to vaccination; and another subject in group 4 developed mild chickenpox 25 days after vaccination, which was assessed to be unrelated to vaccination.

Immunogenicity
The primary analysis for immunogenicity was performed on the according-to-protocol cohort, which included 881 subjects who received the study vaccines, had ≥1 postvaccination assay result from serum drawn according to the blood sampling schedule, and did not receive a vaccine that was not specified or forbidden. The anti-HAV seropositivity rates and GMCs are presented in Table 1. For the 2 coprimary objectives of the study, equivalence with respect to anti-HAV GMCs in responders after dose 2 of HAV vaccine between the 15- to 18-month-olds (group 2) and the 23- to 25-month-olds (group 5) was demonstrated (GMC ratio: 0.87; 95% CI: 0.73 to 1.05), as well as equivalence between the 11- to 13-month-olds (group 1) and the 23- to 25-month-olds (group 5; GMC ratio: 0.76; 95% CI: 0.63 to 0.91).


View this table:
[in this window]
[in a new window]

  		TABLE 1 Anti-HAV Seropositivity Rates and GMCs Calculated on All Subjects (ATP Cohort for Immunogenicity)

 
With regard to the secondary objectives, equivalence of anti-HAV GMCs in responders after the first dose of HAV vaccine was demonstrated between the 15- to 18-month-olds (group 2) and the 23- to 25-month-olds (group 5; GMC ratio: 0.81; 95% CI: 0.67 to 0.99), as well as between the 11- to 13-month-olds (group 1) and 23- to 25-month-olds (group 5; GMC ratio: 0.62; 95% CI: 0.51–0.75).

The immune response to the HAV antigen in 15- to 18-month-old subjects when they received HAV vaccine with and without coadministration of DTaP and Hib (group 3 versus group 2) was evaluated. The anti-HAV vaccine response post-dose 2 was 100% in group 2 and group 3, and the difference between groups was 0% (95% CI: –1.88 to 2.85). The lower limit of the 95% CI was higher than the predefined clinical limit for noninferiority (–5%); therefore, noninferiority was demonstrated.

After the second dose of HAV vaccine, 100% of 15- to 18-month-old and 23- to 25-month-old subjects (groups 2–5) demonstrated vaccine response to HAV vaccine regardless of age and prevaccination serological status. Of the 218 subjects in group 1 (11–13 months of age), 99.1% demonstrated vaccine response after the second dose (2 subjects who were initially seropositive before vaccination remained seropositive but did not achieve a vaccine response).

The immune response to the antigens contained in DTaP and Hib after concomitant administration of these vaccines with or without HAV vaccine (group 3 versus group 4) also was evaluated. All of the 15- to 18-month-old subjects who received HAV vaccine, DTaP, and Hib (group 3) and all of the 15- to 18-month-old subjects who received DTaP and Hib without HAV vaccine (group 4) were seroprotected for D and T at 1 month after vaccination. Noninferiority in these groups with respect to D and T was concluded.

The anti-PT, anti-FHA, and antipertactin immune responses after administration of DTaP and Hib in groups 3 and 4 are provided in Table 2 (vaccine response rates) and in Table 3 (GMC ratios). Noninferiority between 15- to 18-month-old subjects receiving DTaP and Hib with HAV vaccine and those receiving DTaP and Hib without HAV vaccine was demonstrated for all of the pertussis end points except for anti-PT vaccine response. For anti-PT vaccine response, 90.6% of subjects in group 3 (HAV vaccine, DTaP, and Hib) compared with 96.5% of subjects in group 4 (DTaP and Hib alone) met the criteria for vaccine response to PT 1 month after vaccination. The difference in the vaccine response was –5.94% (95% CI: –12.05 to 0.17). The lower limit of the 95% CI on the difference in vaccine response was lower than the predefined clinical limit for noninferiority (–10%); therefore, noninferiority could not be concluded between these 2 groups. However, noninferiority was demonstrated with respect to anti-PT GMCs, because the GMC ratio between groups 3 and 4 was 0.82 (95% CI: 0.65 to 1.03), with the lower limit higher than the predefined clinical limit for noninferiority (0.5).


View this table:
[in this window]
[in a new window]

  		TABLE 2 Difference in Anti-PT, Anti-FHA, and Antipertactin Vaccine Response Rates 1 Month After Vaccination With DTaP and Hib With and Without Coadministration With HAV Vaccine (ATP Cohort for Immunogenicity)

 

View this table:
[in this window]
[in a new window]

  		TABLE 3 Anti-PT, anti-FHA, and Antipertactin GMC Ratios 1 Month After Vaccination With DTaP and Hib With and Without Coadministration With HAV Vaccine (ATP Cohort for Immunogenicity)

 
For Hib immunogenicity, all of the subjects 15 to 18 months old who received HAV vaccine, DTaP, and Hib (group 3) and all of the subjects 15 to 18 months old who received DTaP and Hib alone (group 4) were seroprotected for PRP and had titers ≥1 µg/mL 1 month after vaccination. Noninferiority in groups 3 and 4 with respect to Hib response also was concluded.

Safety
The subject population evaluated for safety included all 1084 subjects who received ≥1 dose of study vaccine (total vaccinated cohort).

Solicited Local AEs
After the administration of HAV vaccine alone, redness was the most frequently occurring solicited local AE in groups 1 and 2, whereas pain at the injection site was the most frequently occurring AE in group 5 (Table 4). Overall, the rates of pain, redness, and swelling were similar in groups 1, 2, and 5. Solicited local AEs rated as grade 3 (severe) in intensity were uncommon in all 3 of the groups.


View this table:
[in this window]
[in a new window]

  		TABLE 4 Incidence of Solicited Local AEs Within the 4-Day Postvaccination Period Overall by Subject (Total Vaccinated Cohort)

 
Pain at the injection site also was the most frequently occurring solicited local AE after the administration of both DTaP and Hib in groups 3 and 4 (Table 4). Subjects in group 3 had somewhat higher overall rates of pain, redness, and swelling at the HAV vaccine, DTaP, and Hib injection sites compared with subjects in group 4. The rates of grade 3 injection-site AEs, however, were low and comparable in both groups.

Solicited General AEs
The most frequently occurring solicited general AE for all of the groups, regardless of age, was irritability (Table 5). Although the incidences of each solicited general AE in group 3, with the exception of fever, were somewhat higher compared with group 4, the rates of grade 3 solicited general AEs were low and comparable in both groups. Most of the solicited general AEs occurring in all 5 of the vaccine groups were considered to be related to vaccination.


View this table:
[in this window]
[in a new window]

  		TABLE 5 Incidence of Solicited General AEs Occurring Within the 4-Day Postvaccination Period Overall by Subject (Total Vaccinated Cohort)

 
Unsolicited AEs
Overall, the percentage of subjects experiencing ≥1 unsolicited AE was similar across all of the groups. The most frequently reported unsolicited AEs for all of the groups were upper respiratory tract infection (15.5%–23.7% of subjects) and otitis media (7.9%–17.8% of subjects). The most frequently occurring grade 3 unsolicited AEs were injection site reactions and vomiting (both 1.1% of subjects), and the unsolicited AE most frequently determined to be related to vaccination was injection site reaction.

SAEs
There were 42 SAEs reported for 38 subjects (6 subjects in group 1, 13 subjects in group 2, 8 subjects in group 3, 6 subjects in group 4, and 5 subjects in group 5). All but 2 subjects, 1 with ongoing diabetes mellitus and 1 who died as a result of an accident, recovered, and all but 3 subjects experienced events that the investigators considered to be unrelated to vaccination. One subject in group 2 experienced a febrile seizure considered by the investigator to have a suspected relationship to vaccination. Two other subjects experienced SAEs (1 had gastroenteritis and 1 had inflamed eczema), which were both considered by the investigator to have an unlikely relationship to vaccination.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
The results of the present study demonstrate that the administration of 2 doses of HAV vaccine starting either at 11 to 13 months of age or at 15 to 18 months of age is well tolerated and as immunogenic as the administration of HAV vaccine to children at ~2 years of age. Second, it was demonstrated that the immune responses to HAV vaccine, DTaP, and Hib were generally not impaired when administered together with the exception of the anti-PT vaccine response, for which the noninferiority limit was marginally exceeded. The clinical relevance of this finding is uncertain. Protection against pertussis after infant vaccination is well established, but the immune correlates of protection and the relative contribution of cell-mediated immunity compared with humoral immunity remain unknown.11,12 The persistence of clinical efficacy in the absence of sustained high levels of specific pertussis antibodies suggests that cell-mediated immunity plays an important role in protection against pertussis. Noninferiority was demonstrated for all of the other comparisons of pertussis responses, including anti-PT GMCs.

In the United States, thousands of cases of hepatitis A are reported each year despite the availability of HAV vaccines.13 The Advisory Committee on Immunization Practices now recommends routine HAV vaccination of all children at age 1 year (12–23 months).6 Two monovalent inactivated, whole-virus HAV vaccines (Havrix, GlaxoSmithKline Biologicals, and VAQTA, Merck & Co, Whitehouse Station, NJ) have been available in the United States since the mid-1990s for use in persons aged ≥2 years and are now indicated for use in children as young as 12 months of age.14,15 These vaccines are highly immunogenic, and generally 100% of persons seroconvert after a 2-dose series.16–18 In addition, in 2001, a combined hepatitis A and hepatitis B vaccine (Twinrix, GlaxoSmithKline Biologicals) was approved for adults in the United States. Protective efficacy with Havrix has been demonstrated in a double-blind, randomized, controlled study in >40000 children (aged 1–16 years) in Thailand.8 In this study, the vaccine efficacy for prevention of clinical hepatitis A was 94% (95% CI: 79% to 99%).

In 1999, Israel initiated a mass vaccination program among children <2 years in addition to continuing to immunize older high-risk groups.19 Two doses of HAV vaccine were administered to children at ages 18 and 24 months only, with no catch-up campaign. With a coverage rate of ~90% for the first dose and 85% for the second dose of HAV vaccine, reported hepatitis A disease was reduced by >96% after initiation of the program. In addition, a remarkable degree of herd protection was suggested, because a >95% reduction in overall reported hepatitis A disease was observed in all ages, even though the program was aimed at toddlers only (<3% of the population). Because children are the main transmitters of HAV in the community,5,7,20,21 a universal immunization program aimed at toddlers can be highly effective.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
The results of this study demonstrate that the administration of 2 doses of HAV vaccine on a 0- and 6-month schedule starting at 11 to 13 months of age or at 15 to 18 months of age is as well tolerated and immunogenic as administering 2 doses to children starting at ~2 years of age. Coadministration of HAV vaccine with DTaP and Hib vaccines does not seem to impact the immunogenicity of the 3 vaccines, with the exception of the anti-PT vaccine response. The clinical relevance, if any, of this latter finding requires additional study. Vaccination against hepatitis A in children as young as 12 months of age may substantially improve control of HAV transmission in the entire population.


   ACKNOWLEDGMENTS
 
This study was funded by a grant from GlaxoSmithKline Biologicals. Editorial assistance was underwritten by GlaxoSmithKline. Editorial support was provided by Scientific Therapeutics Information, Inc, Springfield, NJ.

We thank Marc Lievens and Brigitte Cheuvart of GlaxoSmithKline Biologicals, Rixensart, Belgium, for assistance in conducting the statistical analysis; Dr Anne Altmann and Jacinta O'Sullivan for assistance with study coordination in Melbourne; Drs Edward Curry, Victor Wong, and Maria Aguirre of Southern California Kaiser Permanente Medical Group and Susan Partridge (University of California Los Angeles Center for Vaccine Research), Los Angeles, for study coordination assistance; and the Children's Hospital Boston Primary Care Center and research nurses and other staff there and at all other study sites for their valuable contributions with recruitment, enrollment, and follow-up.


   FOOTNOTES
 
Accepted Feb 15, 2006.

Address correspondence to Terry Nolan, MBBS, PhD, School of Population Health, University of Melbourne, Victoria 3010, Australia. E-mail: t.nolan{at}unimelb.edu.au

Financial Disclosure: Dr Nolan has received research grants from GlaxoSmithKline to Murdoch Children's Research Institute. He has presented data at scientific conferences for GlaxoSmithKline and been reimbursed expenses for Data Safety and Monitoring Board membership for a GlaxoSmithKline phase III human papilloma virus study. Dr Bernstein has been a recipient of GlaxoSmithKline grant/research funding in the past. Dr Blatter is on the speakers bureau, clinical study grants, at GlaxoSmithKline, Sanofi Pasteur, and Wyeth. Dr Bromberg has spoken for GlaxoSmithKline and does vaccine studies for GlaxoSmithKline (herpes, now via National Institutes of Health/GlaxoSmithKline). Dr Guerra is on the speakers bureau for GlaxoSmithKline; his department is one of the study sites for vaccines. Dr Kennedy receives research funding and partial salary support from GlaxoSmithKline. Dr Pichichero received research grants in 2002–2004 from Abbott, Bristol-Myers/Squibb, GlaxoSmithKline, Johnson & Johnson, MedImmune, Sanofi Aventis, and Sanofi Pasteur; research grants in 2005 from Abbott, GlaxoSmithKline, MedImmune, Sanofi Aventis, and Sanofi Pasteur; honorarium in 2002–2004 for contiuing medical education speaking or ad hoc consulting from Abbott, Bristol-Myers/Squibb, GlaxoSmithKline, Sanofi Aventis, and Sanofi Pasteur; and honorarium in 2005 from Abbott, GlaxoSmithKline, Sanofi Aventis, and Sanofi Pasteur. Dr Trofa is an employee of GlaxoSmithKline (director, Vaccines for Viral Diseases, GlaxoSmithKline Biologicals). Drs Collard, Sullivan, and Descamps are employees of GlaxoSmithKline.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. World Health Organization. Hepatitis A vaccines. Wkly Epidemiol Rec. 2000;75 :38 –44[Medline]
  2. Wasley A, Samandari T, Bell BP. Incidence of hepatitis A in the United States in the era of vaccination. JAMA. 2005;294 :194 –201[Abstract/Free Full Text]
  3. Bonanni P, Colombai R, Franchi G, Lo Nostro A, Comodo N, Tiscione E. Experience of hepatitis A vaccination during an outbreak in a nursery school of Tuscany, Italy. Epidemiol Infect. 1998;121 :377 –380[CrossRef][Medline]
  4. Rajaratnam G, Patel M, Parry JV, Perry KR, Palmer SR. An outbreak of hepatitis A: school toilets as a source of transmission. J Public Health Med. 1992;14 :72 –77[Abstract/Free Full Text]
  5. Staes CJ, Schlenker TL, Risk I, et al. Sources of infection among persons with acute hepatitis A and no identified risk factors during a sustained community-wide outbreak. Pediatrics. 2000;106(4) . Available at: www.pediatrics.org/cgi/content/full/106/4/e54
  6. Centers for Disease Control and Prevention. Recommended childhood and adolescent immunization schedule: United States, 2006. Harmonized childhood and adolescent immunization schedule, 2006. MMWR Morb Mortal Wkly Rep. 2006;54 : Q1–Q4
  7. Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1999;48 :1 –37[Medline]
  8. Innis BL, Snitbhan R, Kunasol P, et al. Protection against hepatitis A by an inactivated vaccine. JAMA. 1994;271 :1328 –1334[Abstract/Free Full Text]
  9. Van Damme P, Thoelen S, Cramm M, De Groote K, Safary A, Meheus A. Inactivated hepatitis A vaccine: reactogenicity, immunogenicity, and long-term antibody persistence. J Med Virol. 1994;44 :446 –451[Web of Science][Medline]
  10. Yeh SH, Ward JI. Strategies for development of combination vaccines. Pediatr Infect Dis J. 2001;20(suppl 11) :S5 –S9[CrossRef]
  11. Ausiello CM, Lande R, Urbani, F, et al. Cell-mediated immunity and antibody responses to Bordetella pertussis antigens in children with a history of pertussis infection and in recipients of an acellular pertussis vaccine. J Infect Dis. 2000;181 :1989 –1995[CrossRef][Web of Science][Medline]
  12. Giuliano M, Mastrantonio P, Giammanco A, Piscitelli A, Salmaso S, Wassilak SG. Antibody responses and persistence in the two years after immunization with two acellular vaccines and one whole-cell vaccine against pertussis. J Pediatr. 1998;132 :983 –988[CrossRef][Web of Science][Medline]
  13. Centers for Disease Control and Prevention. Summary of notifiable diseases: United States, 2003. MMWR Morb Mortal Wkly Rep. 2005;52 :1 –85[Medline]
  14. Centers for Disease Control and Prevention. Notice to readers: FDA approval of VAQTA® (hepatitis A vaccine, inactivated) for children aged ≥1 year. MMWR Morb Mortal Wkly Rep. 2005;54 :1026
  15. Centers for Disease Control and Prevention. Notice to readers: FDA approval of Havrix® (hepatitis A vaccine, inactivated) for persons aged 1–18 years. MMWR Morb Mortal Wkly Rep. 2005;54 :1235 –1236
  16. Centers for Disease Control and Prevention. Hepatitis A. In: Atkinson W, Hamborsky J, Wolfe S, eds. Epidemiology and Prevention of Vaccine-Preventable Disease. 8th ed, 2nd printing (January 2005). Washington, DC: Public Health Foundation; 2005:177–189
  17. HAVRIX [Hepatitis A, Inactivated] prescribing information. Rixensart, Belgium: GlaxoSmithKline Biologicals; 2003
  18. VAQTA [Hepatitis A, Inactivated] prescribing information. Whitehouse Station, NJ: Merck & Co, Inc; 2003
  19. Dagan R, Leventhal A, Anis E, Slater P, Ashur Y, Shouval D. Incidence of hepatitis A in Israel following universal immunization of toddlers. JAMA. 2005;294 :202 –210[Abstract/Free Full Text]
  20. Meyerhoff AS, Jacobs RJ. Transmission of hepatitis A through household contact. J Viral Hepat. 2001;8 :454 –458[CrossRef][Web of Science][Medline]
  21. Smith PF, Grabau JC, Werzberger A, et al. The role of young children in a community-wide outbreak of hepatitis A. Epidemiol Infect. 1997;118 :243 –252[CrossRef][Medline]
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?



This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nolan, T.
Right arrow Articles by Descamps, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nolan, T.
Right arrow Articles by Descamps, D.
Related Collections
Right arrow Infectious Disease & Immunity
Right arrowRelated AAP Red Book topics:
Pertussis (Whooping Cough)
Hepatitis A
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?