Mechanism Of Action
The hepatitis A virus belongs to the picornavirus family.
It is one of several hepatitis viruses that cause systemic disease with
pathology in the liver.
The incubation period for hepatitis A averages 28 days
(range: 15 to 50 days).1 The course of hepatitis A infection is
extremely variable, ranging from asymptomatic infection to icteric hepatitis
The presence of antibodies to HAV confers protection
against hepatitis A infection. However, the lowest titer needed to confer
protection has not been determined.
Pediatric Effectiveness Studies
Protective efficacy with HAVRIX has been demonstrated in
a double-blind, randomized controlled study in school children (age 1 to 16
years) in Thailand who were at high risk of HAV infection. A total of 40,119
children were randomized to be vaccinated with either HAVRIX 360 EL.U. or
ENGERIX-B 10 mcg at 0, 1, and 12 months. Of these, 19,037 children received 2 doses
of HAVRIX (0 and 1 months) and 19,120 children received 2 doses of control
vaccine, ENGERIX-B (0 and 1 months). A total of 38,157 children entered
surveillance at day 138 and were observed for an additional 8 months. Using the
protocol-defined endpoint ( ≥ 2 days absence from school, ALT level > 45
U/mL, and a positive result in the HAVAB-M test), 32 cases of clinical
hepatitis A occurred in the control group. In the HAVRIX group, 2 cases were
identified. These 2 cases were mild in terms of both biochemical and clinical
indices of hepatitis A disease. Thus the calculated efficacy rate for
prevention of clinical hepatitis A was 94% (95% Confidence Interval [CI]: 74,
In outbreak investigations occurring in the trial, 26
clinical cases of hepatitis A (of a total of 34 occurring in the trial)
occurred. No cases occurred in vaccinees who received HAVRIX.
Using additional virological and serological analyses
post hoc, the efficacy of HAVRIX was confirmed. Up to 3 additional cases of
mild clinical illness may have occurred in vaccinees. Using available testing,
these illnesses could neither be proven nor disproven to have been caused by
HAV. By including these as cases, the calculated efficacy rate for prevention
of clinical hepatitis A would be 84% (95% CI: 60, 94).
Immunogenicity In Children And Adolescents
Immune Response to HAVRIX 720 EL.U./0.5 mL at 11 to 25
Months of Age (Study HAV 210)
In this prospective, open-label, multicenter study, 1,084
children were administered study vaccine in one of 5 groups:
Children 11 to 13 months of age who received HAVRIX on a
0- and 6-month schedule;
Children 15 to 18 months of age who received HAVRIX on a
0- and 6-month schedule;
Children 15 to 18 months of age who received HAVRIX
coadministered with INFANRIX and Haemophilus b (Hib) conjugate vaccine (no
longer US-licensed) at month 0 and HAVRIX at month 6;
Children 15 to 18 months of age who received INFANRIX
coadministered with Hib conjugate vaccine at month 0 and HAVRIX at months 1 and
Children 23 to 25 months of age who received HAVRIX on a
0- and 6-month schedule.
Among subjects in all groups, 52% were male; 61% of
subjects were white, 9% were black, 3% were Asian, and 27% were other
racial/ethnic groups. The anti-hepatitis A antibody vaccine responses and GMTs,
calculated on responders for groups 1, 2, and 5 are presented in Table 2.
Vaccine response rates were similar among the 3 age groups that received
HAVRIX. One month after the second dose of HAVRIX, the GMT in each of the
younger age groups (11 to 13 and 15 to 18 months of age) was shown to be
similar to that achieved in the 23 to 25 months of age group.
Table 2: Anti-Hepatitis A Immune Response Following 2
Doses of HAVRIX 720 EL.U./0.5 mL Administered 6 Months Apart in Children Given
the First Dose of HAVRIX at 11 to 13 Months of Age, 15 to 18 Months of Age, or
23 to 25 Months of Age
|11-13 months (Group 1)
|15-18 months (Group 2)
|23-25 months (Group 5)
|Vaccine response = Seroconversion (anti-HAV ≥ 15
mlU/mL [lower limit of antibody measurement by assay]) in children initially
seronegative or at least the maintenance of the pre-vaccination anti-HAV
concentration in initially seropositive children.
CI = Confidence Interval; GMT = Geometric mean antibody titer.
a Calculated on vaccine responders one month post-dose 2. GMTs in
children 11 to 13 months of age and 15 to 18 months of age were non-inferior
(similar) to the GMT in children 23 to 25 months of age (i.e., the lower limit
of the two-sided 95% CI on the GMT ratio for Group 1/Group 5 and for Group
2/Group 5 were both ≥ 0.5).
In 3 additional clinical studies (HAV 232, HAV 220, and
HAV 231), children received either 2 doses of HAVRIX alone or the first dose of
HAVRIX concomitantly administered with other routinely recommended US-licensed
vaccines followed by a second dose of HAVRIX. After the second dose of HAVRIX,
there was no evidence for interference with the anti-HAV response in the
children who received concomitantly administered vaccines compared to those who
received HAVRIX alone. [See ADVERSE REACTIONS and Clinical Studies.]
Immune Response to HAVRIX 360 EL.U. Among Individuals
2 to 18 Years of Age
In 6 clinical studies, 762 subjects 2 to 18 years of age
received 2 doses of HAVRIX (360 EL.U.) given 1 month apart (GMT ranged from 197
to 660 mIU/mL). Ninety-nine percent of subjects seroconverted following 2
doses. When a third dose of HAVRIX 360 EL.U. was administered 6 months
following the initial dose, all subjects were seropositive (anti-HAV ≥ 20
mIU/mL) 1 month following the third dose, with GMTs rising to a range of 3,388
to 4,643 mIU/mL. In 1 study in which children were followed for an additional 6
months, all subjects remained seropositive.
Immune Response to HAVRIX 720 EL.U./0.5 mL Among
Individuals 2 to 19 Years of Age
In 4 clinical studies, 314 children and adolescents
ranging from 2 to 19 years of age were immunized with 2 doses of HAVRIX 720
EL.U./0.5 mL given 6 months apart. One month after the first dose,
seroconversion (anti-HAV ≥ 20 mIU/mL [lower limit of antibody measurement
by assay]) ranged from 96.8% to 100%, with GMTs of 194 mIU/mL to 305 mIU/mL. In
studies in which sera were obtained 2 weeks following the initial dose, seroconversion
ranged from 91.6% to 96.1%. One month following the booster dose at month 6, all
subjects were seropositive, with GMTs ranging from 2,495 mIU/mL to 3,644
In an additional study in which the booster dose was delayed
until 1 year following the initial dose, 95.2% of the subjects were
seropositive just prior to administration of the booster dose. One month later,
all subjects were seropositive, with a GMT of 2,657 mIU/mL.
Immunogenicity In Adults
More than 400 healthy adults 18 to 50 years of age in 3
clinical studies were given a single 1440 EL.U. dose of HAVRIX. All subjects
were seronegative for hepatitis A antibodies at baseline. Specific humoral
antibodies against HAV were elicited in more than 96% of subjects when measured
1 month after vaccination. By day 15, 80% to 98% of vaccinees had already seroconverted
(anti-HAV ≥ 20 mIU/mL [lower limit of antibody measurement by assay]).
GMTs of seroconverters ranged from 264 to 339 mIU/mL at day 15 and increased to
a range of 335 to 637 mIU/mL by 1 month following vaccination.
The GMTs obtained following a single dose of HAVRIX are
at least several times higher than that expected following receipt of immune
In a clinical study using 2.5 to 5 times the standard
dose of immune globulin (standard dose = 0.02 to 0.06 mL/kg), the GMT in
recipients was 146 mIU/mL at 5 days post-administration, 77 mIU/mL at month 1,
and 63 mIU/mL at month 2.
In 2 clinical trials in which a booster dose of 1440
EL.U. was given 6 months following the initial dose, 100% of vaccinees (n =
269) were seropositive 1 month after the booster dose, with GMTs ranging from
3,318 mIU/mL to 5,925 mIU/mL. The titers obtained from this additional dose
approximate those observed several years after natural infection.
In a subset of vaccinees (n = 89), a single dose of
HAVRIX 1440 EL.U. elicited specific anti-HAV neutralizing antibodies in more
than 94% of vaccinees when measured 1 month after vaccination. These
neutralizing antibodies persisted until month 6. One hundred percent of vaccinees
had neutralizing antibodies when measured 1 month after a booster dose given at
Immunogenicity of HAVRIX was studied in subjects with
chronic liver disease of various etiologies. 189 healthy adults and 220 adults
with either chronic hepatitis B (n = 46), chronic hepatitis C (n = 104), or
moderate chronic liver disease of other etiology (n = 70) were vaccinated with
HAVRIX 1440 EL.U. on a 0- and 6-month schedule. The last group consisted of alcoholic
cirrhosis (n = 17), autoimmune hepatitis (n = 10), chronic
hepatitis/cryptogenic cirrhosis (n = 9), hemochromatosis (n = 2), primary
biliary cirrhosis (n = 15), primary sclerosing cholangitis (n = 4), and
unspecified (n = 13). At each time point, geometric mean antibody titers (GMTs)
were lower for subjects with chronic liver disease than for healthy subjects.
At month 7, the GMTs ranged from 478 mIU/mL (chronic hepatitis C) to 1,245
mIU/mL (healthy). One month after the first dose, seroconversion rates in
adults with chronic liver disease were lower than in healthy adults. However, 1
month after the booster dose at month 6, seroconversion rates were similar in
all groups; rates ranged from 94.7% to 98.1%. The relevance of these data to
the duration of protection afforded by HAVRIX is unknown.
In subjects with chronic liver disease, local injection
site reactions with HAVRIX were similar among all 4 groups, and no serious
adverse events attributed to the vaccine were reported in subjects with chronic
Duration Of Immunity
The duration of immunity following a complete schedule of
immunization with HAVRIX has not been established.
Immune Response To Concomitantly Administered Vaccines
In 3 clinical studies HAVRIX was administered
concomitantly with other routinely recommended US-licensed vaccines: Study HAV
232: Diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed
(INFANRIX, DTaP) and Haemophilus b (Hib) conjugate vaccine (tetanus toxoid
conjugate) (manufactured by sanofi pasteur SA); Study HAV 220: Pneumococcal
7-valent conjugate vaccine (PCV-7) (manufactured by Pfizer), and Study HAV 231:
MMR and varicella vaccines. [See ADVERSE REACTIONS]
Concomitant Administration With DTaP and Hib Conjugate
Vaccine (Study HAV 232)
In this US multicenter study, 468 subjects, children 15
months of age were randomized to receive: Group 1) HAVRIX coadministered with
INFANRIX and Hib conjugate vaccine (n = 127); Group 2) INFANRIX and Hib
conjugate vaccine alone followed by a first dose of HAVRIX one month later (n =
132); or Group 3) HAVRIX alone (n = 135). All subjects received a second dose
of HAVRIX alone 6 to 9 months following the first dose. Among subjects in all
groups combined, 53% were male; 64% of subjects were white, 12% were black, 6%
were Hispanic, and 18% were other racial/ethnic groups.
There was no evidence for reduced antibody response to
diphtheria and tetanus toxoids (percentage of subjects with antibody levels ≥ 0.1
mIU/mL to each antigen), pertussis antigens (percentage of subjects with
seroresponse, antibody concentrations ≥ 5 EL.U./mL in seronegative subjects
or post-vaccination antibody concentration ≥ 2 times the pre-vaccination
antibody concentration in seropositive subjects, and GMTs), or Hib (percentage
of subjects with antibody levels ≥ 1 mcg/mL to polyribosyl-ribitol
phosphate, PRP) when HAVRIX was administered concomitantly with INFANRIX and
Hib conjugate vaccine (Group 1) relative to INFANRIX and Hib conjugate vaccine
administered together (Group 2).
Concomitant Administration With Pneumococcal 7-Valent
Conjugate Vaccine (Study HAV 220)
In this US multicenter study, 433 children 15 months of
age were randomized to receive: Group 1) HAVRIX coadministered with PCV-7
vaccine (n = 137); Group 2) HAVRIX administered alone (n = 147); or Group 3)
PCV-7 vaccine administered alone (n = 149) followed by a first dose of HAVRIX
one month later. All subjects received a second dose of HAVRIX 6 to 9 months
after the first dose. Among subjects in all groups combined, 53% were female;
61% of subjects were white, 16% were Hispanic, 15% were black, and 8% were
other racial/ethnic groups.
There was no evidence for reduced antibody response to
PCV-7 (GMC to each serotype) when HAVRIX was administered concomitantly with
PCV-7 vaccine (Group 1) relative to PCV- 7 administered alone (Group 3).
Concomitant Administration With MMR and Varicella
Vaccines (Study HAV 231)
In a US multicenter study, there was no evidence for
interference in the immune response to MMR and varicella vaccines (the
percentage of subjects with pre-specified seroconversion/seroresponse levels)
administered at 15 months of age concomitantly with HAVRIX relative to the
response when MMR and varicella vaccines are administered without HAVRIX. [See
1. Centers for Disease Control and Prevention. Prevention
of hepatitis A through active or passive immunization: Recommendations of the
Immunization Practices Advisory Committee (ACIP). MMWR 2006;55(RR-7):1-23.