Action And Clinical Pharmacology
Diphtheria is a serious communicable disease, primarily a
localized and generalized intoxication caused by diphtheria toxin, an
extracellular protein metabolite of toxigenic strains of Corynebacterium
diphtheriae. The disease occurs most frequently in unimmunized or partially
immunized individuals. The incidence of diphtheria in Canada has decreased from
9,000 cases reported in 1924 to extremely low levels. Only 1 or 2 cases have
been reported annually in recent years. The case fatality rate remains 5% to 10
%, with the highest death rates in the very young and elderly. If immunization
levels are allowed to fall and adults do not receive booster doses, disease
re-emergence may appear as demonstrated in the Commonwealth of Independent
States (former Soviet Union), where tens of thousands of cases with substantial
mortality have been reported. Protection against disease is due to the
development of neutralizing antibodies to the diphtheria toxin. Following
adequate immunization with diphtheria toxoid, it is thought that protection
persists for at least 10 years. Serum antitoxin levels of at least 0.01
antitoxin units per mL are generally regarded as protective.
This significantly reduces both the risk of developing
diphtheria and the severity of clinical illness. Immunization with diphtheria
toxoid does not, however, eliminate carriage of C. diphtheriae in the
pharynx, nose or on the skin.
Tetanus is an intoxication manifested primarily by
neuromuscular dysfunction caused by a potent exotoxin released by Clostridium
tetani. Immunization is highly effective, provides long-lasting protection
and is recommended for the whole population. Only 1 to 7 with an average of 5
cases of tetanus are now reported annually in Canada, while no deaths have been
recorded since 1995. The disease continues to occur almost exclusively among
persons who are unvaccinated, inadequately vaccinated or whose vaccination
histories are unknown or uncertain.
Spores of C. tetani are ubiquitous. Naturally
acquired immunity to tetanus toxin does not occur. Thus, universal primary
immunization and timed booster doses to maintain adequate tetanus antitoxin
levels are necessary to protect all age groups. Protection against disease is
due to the development of neutralizing antibodies to the tetanus toxin. Tetanus
toxoid is a highly effective antigen and a completed primary series generally
induces serum antitoxin levels of at least 0.01 antitoxin units per mL, a level
which has been reported to be protective. It is thought that protection
persists for at least 10 years.
Pertussis (whooping cough) is a disease of the
respiratory tract caused by Bordetella pertussis. Pertussis is highly
communicable (attack rates in unimmunized household contacts of up to 90% have
been reported) and can affect individuals of any age; however, severity is
greatest among young infants. Precise epidemiologic data do not exist, since
bacteriological confirmation of pertussis can be obtained in less than half of
the suspected cases. Most reported illness from B. pertussis occurred in
infants and young children in whom complications can be severe. Older children,
adolescents and adults, in whomic signs are often absent, may go
undiagnosed and may serve as reservoirs of disease. Pertussis epidemics are
cyclic and occur every 3 to 4 years. Pertussis has been controlled in Canada
through immunization. During the last 40 years, the incidence of pertussis has
decreased by > 90% although outbreaks continue to occur.
A recent study was conducted in Germany to assess the
efficacy of pertussis vaccine after partial and completed primary vaccination
series for preventing hospitalizations due to pertussis under field conditions.
Data was acquired by a nationwide, hospital based, active surveillance system.
After one dose of the vaccine, vaccine effectiveness was as high as 68%,
increasing to 91.8% after receipt of the second dose. Vaccine effectiveness of
3 and 4 doses of acellular vaccine were estimated to be 99.8% and 98.6%,
Antigenic components of B. pertussis believed to
contribute to protective immunity include: pertussis toxin (PT); filamentous
hemagglutinin (FHA); and pertactin. Although the role of these antigens in
providing protective immunity in humans is not well understood, clinical trials
which evaluated candidate acellular DTP vaccines manufactured by
GlaxoSmithKline supported the efficacy of 3 component INFANRIX® (DTaP).
Recently published data suggests a higher importance of the PT and pertactin
components in providing protection against pertussis.
INFANRIX® contains 3 pertussis antigens (PT, FHA and
pertactin), and has been shown to be effective in preventing World Health
Organization (WHO)-defined pertussis as well as clinically milder disease in
two published clinical trials when administered as a primary series.
A double-blind, randomized, placebo (DT)-controlled trial
conducted in Italy, sponsored by the U.S. National Institutes of Health (NIH),
assessed the absolute protective efficacy of INFANRIX® when administered at 2,
4 and 6 months of age. A total of 15,601 infants were immunized with 1 of 2
tri-component acellular DTP vaccines (containing inactivated PT, FHA and
pertactin), or with a whole-cell DTP vaccine manufactured by Sanofi Pasteur, or
with DT vaccine alone. The mean length of follow-up was 17 months, beginning 30
days after the third dose of vaccine. The population used in the primary
analysis of vaccine efficacy included 4,481 INFANRIX® vaccinees, 4,348
whole-cell DTP vaccinees and 1,470 DT vaccinees. After 3 doses, the protective
efficacy of INFANRIX® against WHO-defined typical pertussis (21 days or more of
paroxysmal cough with infection confirmed by culture and/or serologic testing)
was 84% (95% CI: 76% to 89%) while the efficacy of the whole-cell DTP vaccine
was 36% (95% CI: 14% to 52%). When the definition of pertussis was expanded to
include clinically milder disease with respect to type and duration of cough,
with infection confirmed by culture and/or serologic testing, the efficacy of
INFANRIX® was calculated to be 71% (95% CI: 60% to 78%) against > 7 days of
any cough and 73% (95% CI: 63% to 80%) against ≥ 14 days of any cough. A
longer follow-up of the Italian trial showed that after 3 doses, the absolute
efficacy of INFANRIX® against WHO-defined pertussis remained high at 84% among
children up to 4 years of age.
A prospective, blinded efficacy trial was also conducted
in Germany employing a household contact study design. In preparation for this
study, 3 doses of INFANRIX® were administered at 3, 4 and 5 months of age to
more than 22,000 children living in 6 areas of Germany in a large safety and
immunogenicity trial. Infants who did not participate in this trial could have
received whole-cell DTP vaccine (manufactured by Chiron Behring, Germany) or DT
vaccine. Calculation of vaccine efficacy was based on attack rates of pertussis
in household contactsified by vaccination status. Of the 173 unvaccinated
household contacts, 96 developed WHO-defined pertussis (21 days or more of
paroxysmal cough with infection confirmed by culture and/or serologic testing),
as compared to 7 of 112 contacts vaccinated with INFANRIX® and 1 of 75 contacts
vaccinated with whole-cell DTP vaccine. The protective efficacy of INFANRIX® was
calculated to be 89% (95% CI: 77% to 95%), with no indication of waning of
immunity up until the time of the booster. The protective efficacy of the
whole-cell DTP vaccine was calculated to be 98% (95% CI: 83% to 100%). When the
definition of pertussis was expanded to include clinically milder disease, with
infection confirmed by culture and/or serologic testing, the efficacy of
INFANRIX® against ≥ 7 days of any cough was 67% (95% CI: 52% to 78%) and
against ≥ 7 days of paroxysmal cough was 81% (95% CI: 68% to 89%). The
corresponding efficacy rates of INFANRIX® against ≥ 14 days of any cough
or paroxysmal cough were 73% (95% CI: 59% to 82%) and 84% (95% CI: 71% to 91%),
Several hepatitis viruses are known to cause a systemic
infection resulting in major pathologic changes in the liver (e.g., A, B, C, D,
E). Hepatitis B infection can have serious consequences including acute massive
hepatic necrosis, chronic active hepatitis and cirrhosis of the liver. It has
been estimated that more than 350 million people in the world are persistently
infected with hepatitis B virus.
Among infected infants, very few (5 -10%) recover
completely; the majority (up to 90%) become chronic carriers with the risk of
becoming a chronic carrier decreasing with age (children < 5 years 25% to
50%, adults 6% to 10%). Those patients who become chronic carriers can infect
others and are at increased risk of developing either cirrhosis or primary
Among other factors, infection with hepatitis B may be
the single most important factor for development of this carcinoma. Considering
the serious consequences of infection, immunization should be considered for
Mothers infected with hepatitis B virus can infect their
infants at, or shortly after, birth if they are carriers of the hepatitis B
surface antigen (HBsAg) or develop an active infection during the third
trimester of pregnancy. Infected infants usually become chronic carriers.
Therefore, screening of pregnant women for hepatitis B is recommended.
According to the Canadian Immunization Guide, hepatitis B prevention should
include programs for universal immunization of children, pre-exposure
vaccination of high-risk groups, universal HBsAg screening of all pregnant
women and post-exposure intervention for those exposed to disease, particularly
infants born to hepatitis B-infected mothers. There is no specific treatment
for acute hepatitis B infection. However, those who develop anti-HBs antibodies
after active infection are usually protected against subsequent infection.
Antibody titers ≥ 10 mIU/mL against HBsAg are recognized as conferring
protection against hepatitis B. Seroconversion is defined as antibody titers
≥ 1 mIU/mL.
Poliovirus is an enterovirus that belongs to the
picornavirus family. Three serotypes of poliovirus have been identified (types
1, 2 and 3). Poliovirus is highly contagious with the predominant mode of
transmission being person-to-person via the fecal-oral route. Infection may be
spread indirectly through contact with infectious saliva or feces or by contaminated
water or sewage.
Replication of poliovirus in the pharynx and intestine is
followed by a viremic phase where involvement of the central nervous system can
occur. While poliovirus infections are asymptomatic or cause nonspecific
symptoms (low-grade fever, malaise, anorexia and sore throat) in 90% to 95% of
individuals, 1% to 2% of infected persons will develop paralytic disease.
Following the introduction of inactivated poliovirus
vaccines (IPV) in Canada in 1955, the indigenous disease has been eliminated.
Since 1980, 12 paralytic cases have been reported in Canada, 11 of which were
determined to be vaccine-associated paralytic poliomyelitis (VAPP), with Oral
Polio Vaccine (OPV). The last reported case of VAPP occurred in 1995.
Forty seven studies involving over 19,000 infants and
children have been conducted in developed and developing countries with
GlaxoSmithKline's enhanced inactivated poliovirus vaccine, as trivalent IPV
vaccine or as a part of DTaP-IPV based combinations.
Haemophilus Influenzae Type b
Haemophilus influenzae type b (Hib) was the most
common cause of bacterial meningitis and a leading cause of other serious
invasive infections in young children prior to the introduction of other Hib
vaccines. About 55% to 65% of affected children had meningitis while the
remainder had epiglottitis, bacterimia, cellulitis, pneumonia or septic
arthritis. The case fatality rate of meningitis is about 5%. Severe neurologic
sequelae occur in 10% to 15% of survivors and deafness in 15% to 20% (severe in
3% to 7%).
Before the introduction of Hib conjugate vaccines in
Canada in 1988, there were approximately 2,000 cases of Hib disease annually.
Since then the overall incidence has fallen by more than 99%. The majority of
cases occur now in children too old to have received primary vaccination. In
1998, only 15 cases were reported in children < 5 years of age.
SCIENTIFIC AND PHARMACEUTICAL INFORMATION
Proper name: combined diphtheria and tetanus toxoids,
acellular pertussis, hepatitis B (recombinant), inactivated poliomyelitis, and
adsorbed conjugated Haemophilus influenzae type b vaccine
INFANRIX hexa® (combined diphtheria and tetanus toxoids,
acellular pertussis, hepatitis B (recombinant), inactivated poliomyelitis, and
adsorbed conjugated Haemophilus influenzae type b vaccine) contains
diphtheria toxoid, tetanus toxoid, three purified pertussis antigens [pertussis
toxoid (PT), filamentous haemagglutinin (FHA) and pertactin (69 kiloDalton
outer membrane protein)], hepatitis B virus surface antigen recombinant,
adsorbed onto aluminum salts, purified, inactivated poliovirus types 1, 2 and
3, Haemophilus influenzae type b polysaccharide conjugated to tetanus
Immune Response to INFANRIX hexa® Administered as a 3
Dose Primary Series
A total of 13,500 doses of INFANRIX hexa® (combined
diphtheria and tetanus toxoids, acellular pertussis, hepatitis B (recombinant),
inactivated poliomyelitis, and adsorbed conjugated Haemophilus influenzae
type b vaccine) have been administered to 4,590 infants from 6 weeks of age and
up as a primary series in clinical studies.
The immune responses to each of the antigens contained in
INFANRIX hexa® were evaluated in sera obtained 1 month after the third dose of
vaccine as compared to that following administration of commercially available
vaccines (INFANRIX® (diphtheria, tetanus, and acellular pertussis vaccine),
ENGERIX®-B (hepatitis B vaccine (recombinant)), Hib vaccine, and Oral Polio
Virus vaccine) simultaneously at separate sites, in a study conducted in the
U.S. The schedule of administration was 2, 4, and 6 months of age. One month
after the third dose of INFANRIX hexa®, immune response rates to each antigen
were comparable to rates seen following separately administered vaccines (see
Table 2 : Antibody Responses to Each Antigen Following
INFANRIX hexa® as Compared to INFANRIX®, ENGERIX®-B, Hib vaccine, and OPV (One
Month After Administration of Dose 3)
INFANRIX®, ENGERIX®-B, H1b vaccine, OPV
|Anti-Diphtheria % ≥ 0.1 IU/mL
|% ≥ 0.1 IU/mL
|% ≥ 10 mIU/mL
|% ≥ 8
|% ≥ 8
|% ≥ 8
|% ≥ 0.15 μg/mL
|% ≥ 1.0 μg/mL
|OPV manufactured by Wyeth
OmniHib manufactured by Sanofi Pasteur
% R = in initially seronegative subjects, appearance of antibodies (titre 35
EL.U./mL); in initially seropositive subjects, at least maintenance of
GMT = Geometric mean antibody titre
PT = Pertussis Toxoid
FHA = Filamentous Haemagglutinin
HBs = Hepatitis B surface (antigen)
V.R. = Vaccine Response (Vaccine response is defined as appearance of
antibodies in initially seronegative subjects or as at least maintenance of
pre-vaccination antibody titres in initially seropositive subjects.
Polio = Poliovirus
PRP = Polyribosyl-ribitol-phosphate
Clinical trials have investigated the tolerability and
immunogenicity of the vaccine in various schedules (i.e. 2, 3, 4 months; 3, 4,
5 months; 2, 4, 6 months; 3, 5, 11 months; 1.5, 2.5, 3.5 months). Results
obtained in all of the clinical studies for each of the components are
One month after the 3 dose primary vaccination course,
98.5 to 100% of infants vaccinated with INFANRIX hexa® had antibody titres of
≥ 0.1 IU/mL for both tetanus and diphtheria.
Following administration of a 4th dose of INFANRIX hexa® in
the second year of life, 100% of infants had antibody titres of ≥ 0.1
IU/mL for both tetanus and diphtheria.
One month after the 3 dose primary vaccination course,
the overall response rate for each of the 3 individual pertussis antigens (PT,
FHA, and pertactin) was between 97.2-99.3%, 95.2-100% and 95.9-99.3%,
Following administration of a 4th dose of INFANRIX hexa® in
the second year of life, a booster response was seen in at least 97.2%, 94.1%,
and 100% of vaccinated infants against the respective pertussis antigens. Since
a serological correlation for protection against pertussis disease does not
exist, the efficacy of the pertussis component presently relies on efficacy trials
Protective Efficacy Data
The efficacy of the DTaP component, against WHO-defined
typical pertussis ( ≥ 21 days of paroxysmal cough) was demonstrated in 2
The first was a perspective blinded household contact
study performed in Germany (3, 4, 5 months vaccination schedule). Based on data
collected from secondary contacts in households where there was an index case
with typical pertussis, the protective efficacy of the vaccine was 88.7%.
The second was a National Institutes of Health (NIH)
sponsored efficacy study performed in Italy (2, 4, 6 months vaccination
schedule). The vaccine efficacy was found to be 84%. In a follow-up of the same
cohort, efficacy was confirmed up to 60 months after completion of primary
vaccination without administration of a booster dose of pertussis.
Hepatitis B component
After the primary vaccination course with INFANRIX hexa®,
98.5 to 100% of infants developed protective antibody titres of ≥ 10
At one month after the booster dose, administered 18
months after primary vaccination, 97 to 100% of these subjects had protective
titres of ≥ 10 mIU/mL.
One month after the primary vaccination, the
seroprotection rates for each of the three serotypes (types 1, 2, and 3) were
99.2 to 100%, 94.5 to 99.0%, and 98.8 to 100%, respectively.
Following administration of the booster dose, at least
98.5%, 98.5%, and 100% of infants were seroprotected for the three serotypes,
One month after completion of the primary vaccination
course, the Geometric Mean Concentration (GMC) of antibodies ranged from 1.52
to 3.53 μg/mL, with between 93.5 and 100% of the subjects reaching
antibody titres ≥ 0.15 μg/mL.
One month after the booster dose given in the second year
of life, the GMC ranged from 19.1 to 94.0 μg/mL, with 99.5 to 100% of the
subjects reaching antibody titres ≥ 0.15 μg/mL.
These GMCs are numerically lower when compared to GMCs
resulting from separate administration of the Hib component, however they are
not different from those elicited by comparator vaccines DTaP-Hib and
Induction of immunological memory has been shown to be an
important and intrinsic part of the protective immune response following
administration of Hib conjugate vaccines. Children primed with INFANRIX hexa® had
an anamnestic response (defined as a rapid and substantial increase in antibody
level) on subsequent exposure to the antigen.
The effectiveness of the GlaxoSmithKline Hib component
(when combined with DTaP or DTaP-IPV) has been investigated through an
extensive post-marketing surveillance study conducted in Germany. Over a 4 ½
year follow-up period, the effectiveness of 3 primary doses of DTaP-Hib or
DTaP-IPV-Hib was 96.7%.
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