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ORIGINAL STUDIES
Epidemiology of Pertussis and Haemophilus influenzae type b
Disease in Canada With Exclusive Use of a Diphtheria-Tetanus-
Acellular Pertussis-Inactivated Poliovirus-Haemophilus influenzae
type b Pediatric Combination Vaccine and an Adolescent-Adult
Tetanus-Diphtheria-Acellular Pertussis Vaccine
Implications for Disease Prevention in the United States
David P. Greenberg, MD,*† Martha Doemland, PhD;* Julie A. Bettinger, PhD, MPH,‡
David W. Scheifele, MD,‡ and Scott A. Halperin, MD,§ for the IMPACT Investigators; Valerie Waters, MD,¶
and Kami Kandola, MD, MPH储
Background: During the decade 1998-2007, a combination DTaP
5
-IPV/
Hib vaccine was used exclusively in Canada to immunize infants and
young children against diphtheria, tetanus, pertussis, polio, and invasive
Haemophilus influenzae type b (Hib) disease.
Methods: Medline was used to search for publications during 1996 –2008
related to the epidemiology and vaccine prevention of pertussis and
invasive Hib disease in Canada. Related abstracts and presentations were
reviewed, when available, and epidemiologic data since 1985 were ob-
tained from the Public Health Agency of Canada public Web site.
Results: Reports of pertussis have declined substantially in preschool and
school-aged children during the past decade, and cyclical peaks in disease
incidence have been blunted or eliminated. In provinces and territories
where Tdap
5
vaccine has been administered to 14- to 16-year-olds, marked
reductions of pertussis have been documented in adolescents as well as
younger age groups, possibly due to herd immunity. Incidence rates of
invasive Hib disease among Canadian children ⬍5 years declined mark-
edly after introduction of Hib conjugate vaccines, and the disease has
remained under control with exclusive use of DTaP
5
-IPV/Hib vaccine.
Most cases of invasive Hib disease occur among unimmunized or only
partially vaccinated children. The reduction of Hib case reports has been
documented throughout Canada, including among Aboriginal children who
are at high risk for this disease.
Conclusions: The Canadian experience with DTaP
5
-IPV/Hib and Tdap
5
vaccines is relevant to the United States because immunization schedules,
vaccination coverage rates, and epidemiologic patterns of pertussis and Hib
diseases are similar in the 2 countries, and because both vaccines are
licensed for use in the United States.
Key Words: DTaP-IPV/Hib vaccine, diphtheria-tetanus-acellular
pertussis vaccines, Haemophilus influenzae type b polysaccharide
vaccine, inactivated poliovirus vaccine, epidemiology
(Pediatr Infect Dis J 2009;28: 521–528)
Apediatric combination vaccine, DTaP
5
-IPV/Hib (Pentacel,
Sanofi Pasteur Limited, Toronto, Canada), was licensed in
Canada in May 1997 and was introduced in all provinces and
territories between July 1997 and April 1998.
1,2
DTaP
5
-IPV/Hib
vaccine is comprised of a liquid formulation of diphtheria and
tetanus toxoids, 5 acellular pertussis components (aluminum phos-
phate adjuvant), and inactivated poliovirus serotypes 1, 2, and 3
(DTaP
5
-IPV) used to reconstitute lyophilized Haemophilus influ-
enzae type b (Hib) vaccine. The Hib component is comprised of
purified capsular polysaccharide (polyribosylribitol phosphate;
PRP) conjugated to tetanus toxoid (PRP-T).
1
The 5 acellular
pertussis antigens contained in DTaP
5
-IPV/Hib vaccine are per-
tussis toxoid (PT), filamentous hemagglutinin (FHA), pertactin
(PRN), and 2 fimbrial proteins (types 2 and 3; FIM). During the
3-year period (1994 –1997) before the introduction of DTaP
5
-IPV/
Hib, most Canadian provinces and territories used a whole-cell
pertussis combination vaccine, DTwP-IPV/Hib.
DTaP
5
-IPV/Hib vaccine is administered to children in Can-
ada at 2, 4, 6, and 18 months of age, and DTaP
5
-IPV is given as
a booster dose at 4 to 6 years.
3
DTaP
5
-IPV/Hib has been the
exclusive vaccine used to immunize Canadian children 2 through
18 months of age against diphtheria, tetanus, pertussis, polio, and
Hib disease during the years 1998 through 2007.
In May 1999, a tetanus and reduced diphtheria toxoids and
acellular pertussis vaccine, Tdap
5
(Adacel, Sanofi Pasteur Lim-
ited), containing the same 5 acellular pertussis components as
DTaP
5
-IPV/Hib vaccine, was licensed in Canada for persons aged
11 through 54 years. In May 2000, the National Advisory Com-
mittee on Immunization (NACI) stated that Tdap could be given to
replace 1 dose of tetanus and diphtheria toxoids (Td) vaccine in
Accepted for publication December 22, 2008.
From the *Scientific and Medical Affairs, Sanofi Pasteur Inc, Swiftwater, PA;
†Department of Pediatrics, University of Pittsburgh School of Medicine,
Pittsburgh, PA; ‡Vaccine Evaluation Center, BC Children’s Hospital and
the University of British Columbia, Vancouver, British Columbia, Canada;
§Clinical Trials Research Center, IWK Health Center and Dalhousie Uni-
versity, Halifax, Nova Scotia, Canada; ¶Division of Infectious Diseases,
Hospital for Sick Children, Toronto, Ontario, Canada; and 㛳Stanton Terri-
torial Health Authority, Yellowknife, Northwest Territories, Canada.
Supported by the Public Health Agency of Canada for pertussis and Hib
surveillance.
Presented in part at the Fifth Pediatric Infectious Disease Conference, October
9-11, 2005, Napa, CA.
Some of the surveillance activity reported herein was conducted as part of the
Canadian Immunization Monitoring Program Active (IMPACT), a national
surveillance initiative managed by the Canadian Paediatric Society (CPS)
and conducted by the IMPACT network of paediatric investigators on
behalf of the Public Health Agency of Canada (PHAC)’s Center for
Immunization and Respiratory Infections.
Address for correspondence: David P. Greenberg, MD, Sanofi Pasteur Inc,
One Discovery Drive, Swiftwater, PA 18370. E-mail: david.greenberg@
sanofipasteur.com.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions
of this article on the journal’s Web site (www.pidj.com).
Copyright © 2009 by Lippincott Williams & Wilkins
ISSN: 0891-3668/09/2806-0521
DOI: 10.1097/INF.0b013e318199d2fc
The Pediatric Infectious Disease Journal • Volume 28, Number 6, June 2009 www.pidj.com |521
adolescents and adults, but Tdap was not recommended for uni-
versal use.
4
In September 2003, after a consensus conference on
pertussis in Canada, NACI issued a revised statement to recom-
mend universal administration of 1 dose of Tdap for all adoles-
cents and adults.
5
The first province to adopt Tdap
5
vaccine for
administration to adolescents aged 14 to 16 years was Newfound-
land and Labrador in 1999,
6
followed by Northwest Territories in
2000
7
; British Columbia, Ontario, and Quebec in 2004; and the
remainder of Canadian provinces and territories in 2005.
This report describes the epidemiology of 2 important
infectious diseases, pertussis and invasive Hib disease, before and
during the use of DTaP
5
-IPV/Hib and Tdap
5
vaccines in Canada.
Additionally, the Canadian experiences with these vaccines will be
discussed as they relate to the control of pertussis and Hib in the
United States.
The immunization programs implemented to prevent per-
tussis and Hib infections in Canada have evolved with time. For
pertussis, important milestones include the introduction of the first
whole-cell vaccine in 1943, adsorbed whole-cell vaccines in the
early 1980s, acellular vaccine for children in 1997, and acellular
vaccine for adolescents and adults in 1999. For invasive Hib
disease, important milestones include the introduction of uncon-
jugated Hib vaccine for 2-year-olds in 1986, Hib conjugate vaccine
for toddlers in 1988 and for infants in 1992, and incorporation of
this component into whole-cell and acellular pertussis combination
vaccines in 1992 (DTwP-Hib), 1994 (DTwP-IPV/Hib), and 1997
(DTaP
5
-IPV/Hib).
Historical Perspective of the Epidemiology of
Pertussis in Canada
Pertussis (“whooping cough”) has been a reportable disease
in Canada since 1924. A case of pertussis is reported by Canadian
health authorities when Bordetella pertussis is grown from an
appropriate clinical specimen or identified by a polymerase chain
reaction (PCR) assay. Alternatively, a case is reported when the
patient is epidemiologically linked to a laboratory-confirmed case
and the patient has one or more of the following symptoms for
which there is no other known cause: paroxysmal cough of any
duration, cough ending in vomiting or associated with apnea, or
cough with inspiratory whoop.
8
Before the introduction of whole-cell vaccine in Canada,
pertussis was a major cause of death among young children
(primarily, infants ⬍1 year) and a source of serious complications,
including pneumonia, seizures, and encephalopathy.
3
Historically,
cyclic peaks of pertussis incidence occurred approximately every 3
to 5 years, with major outbreaks occurring in the mid-1930s to
early 1940s. These epidemiologic patterns are similar to those
observed in the United States and worldwide.
After the introduction of whole-cell pertussis vaccine in
1943, a sharp decline of cases was reported in Canada followed by
a slower but steady decline between the mid-1950s and early
1970s. The reported incidence decreased from 160 to 180 cases per
100,000 in the 1930s to ⬍20 cases per 100,000 during the 1970s
and through the mid 1980s (Fig. 1, Supplemental Digital Content
1, http://links.lww.com/A969 ).
3,9
Before the introduction of
whole-cell vaccine, pertussis occurred most commonly among
children aged 1 to 5 years, with fewer than 20% of cases reported
among infants.
10
Availability of whole-cell pertussis vaccine pre-
cipitated an overall decline of reported cases among preschool and
young school-aged children and prevented widespread outbreaks
in the general population. A consequence of whole-cell vaccine
use was a shift of the disease burden to infants ⬍1 year of age and
a modest increase of disease among adolescents and young
adults.
9,10
During the late 1980s and early-to-mid 1990s, a resurgence
of pertussis was reported among all age groups in Canada, result-
ing from a number of factors, including relatively low efficacy of
the whole-cell vaccine used during that time, waning vaccine- and
natural infection-induced immunity among adolescents and adults,
and increased physician awareness, diagnosis, and reporting of the
disease.
9,10
The increase in case reports during the 1990s was not
associated with any decline of immunization rates among Cana-
dian children.
11
Children who were given whole-cell vaccine
during 1980 to 1997 constitute a cohort that to the present day
report persistently elevated rates of pertussis.
Historic Perspective of the Epidemiology of
Invasive Hib Disease in Canada
Hib meningitis has been reportable nationally in Canada
since 1979 and all other invasive Hib diseases have been report-
able since 1986. The current definition of a laboratory-confirmed
case of invasive Hib disease includes any patient with isolation of
Hib from a normally sterile body site or from the epiglottis in a
patient with epiglottitis, or demonstration of Hib antigen in cere-
brospinal fluid.
8
Before introduction of effective Hib vaccines in the late
1980s and early 1990s, 1 in 200 –250 Canadian children younger
than 5 years developed invasive Hib infection; 3% to 5% of these
children died.
12
The majority of cases occurred in children 6 to 24
months of age and meningitis comprised 55% to 65% of all
reported Hib cases.
3,12
During the prevaccine era, Hib was the
most common cause of bacterial meningitis in young children,
resulting in severe neurologic sequelae in 10% to 15% of survivors
and deafness in 15% to 20%. It was also a major cause of
potentially life-threatening epiglottitis, septicemia, cellulitis, pneu-
monia, septic arthritis, and pericarditis.
The first Hib vaccine, unconjugated PRP, was licensed in
Canada in 1986, but its ability to protect children was limited
because it was not consistently immunogenic in those under 24
months of age.
12
PRP was replaced in 1988 by PRP-diphtheria
toxoid conjugate (PRP-D) vaccine administered at 18 months of
age, which later was proven to have an efficacy of only 74% to
88%.
12
More effective Hib conjugate vaccines were introduced in
1991 for use in toddlers and in 1992 for infants starting at 2 months
of age. Hib conjugate vaccines contributed to a steep decline of
cases during the late 1980s and early 1990s. PRP-tetanus toxoid
conjugate (PRP-T) vaccine has been the Hib vaccine used in all
Canadian provinces and territories since 1995, as a component of
either whole-cell or acellular pertussis combination vaccines.
Epidemiology of Pertussis in the Last 2 Decades
in Canada
Although the incidence of pertussis in Canada had de-
creased ⬎90% compared with the peaks in the 1930s to 1940s,
rates increased significantly in the late 1980s and early 1990s.
13
An epidemiologic investigation of an outbreak of pertussis in Nova
Scotia in 1994 revealed that the effectiveness of the whole-cell
vaccine used in the region was only 57% against laboratory-
confirmed pertussis among children ⱖ4 years who had received 5
doses of vaccine compared with partially immunized or nonim-
munized children.
13
Similar effectiveness was found among chil-
dren attending child care centers (56%) and schools (51%) in
Quebec.
14
Potential explanations for the less-than-optimal perfor-
mance of the Canadian whole-cell vaccine include a relatively
poor antibody response to PT or interference between the pertussis
and poliovirus components in the combined vaccine. Concerns
related to the vaccine’s effectiveness and safety led to the decision
to replace the whole-cell (DTwP-IPV/Hib) vaccine with an acel-
lular (DTaP
5
-IPV/Hib) vaccine in 1997. The DTaP
5
components
Greenberg et al The Pediatric Infectious Disease Journal • Volume 28, Number 6, June 2009
© 2009 Lippincott Williams & Wilkins522 | www.pidj.com
of the acellular vaccine had been tested in an efficacy trial in
Sweden in 1992 to 1995 and had demonstrated a superior safety
profile compared with the DTwP control, with an efficacy of 85%
against World Health Organization-defined pertussis (ie, ⱖ21
consecutive days of paroxysmal cough with laboratory confirma-
tion of B. pertussis).
15
Clinical trials of DTaP
5
-IPV/Hib vaccine in
Canada further confirmed the safety and immunogenicity of this
combination product.
16
Both passive and active surveillance systems have docu-
mented a significant decline of reported pertussis cases and inci-
dence rates among Canadian children since the introduction of
DTaP
5
-IPV/Hib vaccine. In the national Notifiable Disease Re-
porting System (NDRS), confirmed cases are reported by provin-
cial health authorities to the Public Health Agency of Canada
(PHAC). As shown in Figure 2, typical cyclical peaks of pertussis
incidence were observed in 1990, 1994 –1995, and 1998. Based on
the usual 3 to 5 year cycles, another peak was expected between
2001 and 2003, but none occurred. In fact, there has been no new
peak since national introduction of DTaP
5
-IPV/Hib vaccine was
completed in 1998.
From October 2005 to March 2006, a laboratory-confirmed
outbreak of pertussis occurred primarily in preschool-aged chil-
dren isolated to the Toronto region and not observed elsewhere in
Canada. There was an almost 6-fold increase in the absolute
number of positive respiratory specimens and more than 2-fold
increase in the percentage of respiratory specimens positive by
PCR for B. pertussis compared with the previous year. Although
the isolation of B. pertussis was confirmed by culture in only a
small minority of cases (⬍3%), the PCR results were validated
with multiple laboratories using different methodologies and
showed that the outbreak was not due to contamination in the
laboratory, as has been previously described in pseudo-outbreaks
of pertussis.
17,18
This was not, however, a classic pertussis outbreak. Most of
the cases were preschool children previously immunized with an
effective acellular pertussis (DTaP
5
-IPV/Hib) vaccine. In addition,
despite evidence that B. pertussis was widely circulating in the
Toronto community, only 1 unimmunized infant case was hospi-
talized for an illness requiring intubation and mechanical ventila-
tion, secondary to RSV and B. pertussis coinfection. In addition,
although the proportion of cases that met a clinical case definition
for pertussis (42%) was significantly higher in cases than
controls, it was considerably lower than the percentage of cases
meeting a clinical definition in other reported pertussis out-
breaks (⬎80%).
19,20
In contrast to other studies reporting a
secondary attack rate of 20% to 29% in children 0 through 4
years,
21,22
the secondary attack rate in this outbreak was only
8%. Moreover, an alternate respiratory organism was identified in
one-third of cases, suggesting that at least in this subset of cases,
symptoms may have been due to a cause other than B. pertussis.
This was likely a milder pertussis outbreak that may have been
moderated by high vaccination rates and may have been inflated to
some degree by transient nasopharyngeal carriage of B. pertussis.
After the last national peak of pertussis disease in Canada in
1998, reported cases decreased substantially among children aged
1 through 9 years (Fig. 2).
23
Between 1998 and 2004 (the last year
for which PHAC data are available), the rate of pertussis among
children aged 1 through 4 years declined from 118.6 cases per
100,000 to 21.7 cases per 100,000, representing an 81.7% reduc-
tion. Comparable reductions were observed among children aged 5
through 9 years, with an 86.9% decline between 1988 and 2006
(149.1 cases per 100,000 to 19.4 cases per 100,000). The highest
incidence, morbidity, and mortality associated with pertussis in
Canada occurred among infants ⬍12 months of age. The incidence
rates in this age group have remained steady since 2001 (range,
71.3–91.6 cases per 100,000) and the majority occur among those
who are ⬍6 months of age, too young to have completed the infant
vaccination series.
9,10
Of 19 pertussis-related deaths between 1989
and 2000 in Canada, 16 were infants; all but 1 of the infants was
younger than 3 months of age, and only 1 had received any
vaccination.
9
The overall effectiveness of DTaP
5
-IPV/Hib vaccine in
reducing the occurrence of pertussis has been further documented
by investigators participating in the Immunization Monitoring
Program, Active (IMPACT), through active disease surveillance of
inpatients at 12 tertiary care hospitals in Canada. The IMPACT
network encompasses 90% of tertiary care pediatric beds in Can-
ada and includes data on hospitalized children from birth through
16 years of age. Patients from all Canadian provinces and territo-
ries may be transferred to IMPACT centers for care depending on
the severity of disease and referral patterns. A nurse monitor
assigned to each hospital conducts disease surveillance by review-
ing microbiology records and daily admissions and discharges.
24
Bettinger et al
2
recently reviewed the IMPACT pertussis
database for the period of January 1991 through December 2004.
During this time, there were 2096 pertussis admissions in IM-
PACT centers: 1174 during the whole-cell era (children who
received DTwP-combination vaccines during 1991–1996) and 842
during the acellular era (children who received DTaP
5
-IPV/Hib
vaccine during 1999 –2004); 80 who might have received either
whole-cell or acellular vaccine during the transition period,
1997 to 1998, were excluded from analysis. Among children
aged 1 through 4 years, the incidence of pertussis leading to
hospitalization decreased approximately 85% from the whole-
cell period to the acellular period (4.6 – 0.7 cases per 100,000
population). In addition, after the switch to DTaP
5
-IPV/Hib
vaccine, the typical 3- to 5-year peak did not recur in children
older than 1 year.
2
Compared with the whole-cell vaccine era, the preponder-
ance of hospitalized cases during the acellular era shifted to
younger age groups, primarily infants too young to have been
immunized (⬍2 months of age; 39.0% in the acellular era vs.
26.1% in the whole-cell era; P⬍0.0001) or too young to have
received a second dose (2–3 months of age; 42.9% vs. 34.2%; P⬍
0.0001).
2
At the same time, there was a decline in the proportion
of hospitalized cases that occurred among children old enough to
have received 2 to 3 doses of vaccine (4 –11 months of age; 15.1%
acellular era vs. 27.3% whole-cell era) and among 6- to 23-month-
FIGURE 2. Age-specific rates of pertussis, Canada, 1988–
2004.
23
DTaP
5
-IPV/Hib vaccine was adopted for infants
and children throughout Canada during 1997–1998.
The Pediatric Infectious Disease Journal • Volume 28, Number 6, June 2009 DTaP
5
-IPV/Hib Vaccine
© 2009 Lippincott Williams & Wilkins www.pidj.com |523
old children appropriately vaccinated for age (vaccine failures;
2.3% vs. 11.4%; P⬍0.0001). Of 17 fatalities, only 1 received any
vaccine (a 9-week-old who received 1 dose of whole-cell vaccine)
and all but 1 (a 6-month-old) were ⱕ10 weeks of age. Figure 3
shows the IMPACT data through 2006, demonstrating a continued
decline of hospitalized cases of pertussis during the DTaP
5
-IPV/
Hib era.
IMPACT data during 1995 through 2001 also demonstrated
significant reductions during the acellular era in the rates of
hospitalizations for febrile seizures (79%) and for hypotonic-
hyporesponsive episodes (60%-67%), temporally associated with
pertussis vaccination compared with the whole-cell era.
25
A remarkable change in the epidemiology of pertussis has
occurred among a unique and apparently susceptible cohort of
children in Canada. Between the early 1990s and the present, the
peak age of pertussis disease has increased in step with the aging
of the population of children who were vaccinated with whole-cell
vaccine before the introduction of DTaP
5
-IPV/Hib vaccine in 1997
to 1998. Skowronski et al
10
were the first to observe this effect by
analyzing data from outbreaks occurring in British Columbia in
1990, 1993, 1996, and 2000. During successive outbreaks, the
proportion of cases decreased among infants ⬍1 year and children
1 through 4 years, while the proportion increased among adoles-
cents and adults. Compared with an outbreak in 1996, a greater
proportion of cases were reported among 10- to 19-year-olds
during a subsequent outbreak in 2000 (12% in 1996 vs. 34% in
2000). The median age of pertussis cases shifted from 5 years in
1993 to 6 years in 1996 to 11 years in 2000.
10
Data from the British
Columbia Centre for Disease Control now extend through 2006 (Fig.
4, Supplemental Digital Content 1, http://links.lww.com/A969); the
peak age of pertussis cases shifted from preschool and young
school aged children in 1993 and 1996 to adolescents and adults in
2000, 2003, and 2006.
The same phenomenon of a marching age cohort also has
been described by Halperin,
26
who analyzed data for the entire
country. Each year, from 1989 through 2004, the age of peak
incidence increased by 1 year, demonstrating that children given
whole-cell vaccine in the 1980s to mid-1990s remained at sub-
stantially higher risk of contracting pertussis compared with chil-
dren given acellular pertussis vaccine (DTaP
5
-IPV/Hib). Exclud-
ing infants ⬍1 year, the peak incidence of pertussis occurred
among 1- to 4-year-olds in 1989 and 1992, 5- to 9-year-olds in
1996, and 10- to 14-year-olds in 2000 and 2004.
Adolescent and Adult Tdap
5
Vaccine
Tdap
5
was licensed in Canada in 1999, but NACI did not
recommend universal use of the vaccine for adolescents and adults
until 2003.
5
The universal program goals were to protect adoles-
cents and adults and to “decrease the morbidity and mortality of
pertussis across the entire lifespan”. In addition, NACI hoped that
the program would help protect infants by reducing their exposure
to the organism.
Newfoundland and Labrador (1999) and Northwest Terri-
tories (2000) adopted Tdap
5
vaccine before the universal recom-
mendations were issued. Newfoundland and Labrador instituted
universal administration of Tdap
5
vaccine to all ninth grade chil-
dren (14 –16 year olds) beginning in September 1999.
6
A school-
based immunization program achieved an overall coverage rate of
95% by 2005. Pertussis outbreaks occurred in this region in 1994,
primarily among 1- to 9-year-olds, and in 1999, primarily among
5- to 9-year-olds. Since the introduction of Tdap
5
vaccine, the only
subsequent outbreak occurred in 2003. Most of the cases in 2003
were reported among 10- to 14-year-olds, but there were no cases
among children who had received Tdap
5
. In 2004, only 5 cases
were reported across all age groups.
6
It may be that the addition of
Tdap
5
vaccine for adolescents contributed to the reduced overall
case reports, but a substantial number of cases reported during the
2003 outbreak occurred among adults, suggesting that the NACI
recommendations to immunize all adults with Tdap should be
implemented.
In October 2000, Northwest Territories was the second
region to adopt Tdap
5
vaccine, with universal implementation for
all 14- to 16-year-olds in early 2001.
7
Large pertussis outbreaks
occurred in 1993 and 1999 and a small outbreak was seen in 1996,
but no outbreaks were observed after introduction of Tdap
5
in
2001. The overall incidence of pertussis across all age groups
decreased from 7.5 cases per 10,000 population during 1993–1996
(whole-cell era) to 7.2 cases per 10,000 in 1997 through 2000
(early DTaP
5
-IPV/Hib era) to only 1.1 cases per 10,000 in 2001
through 2004 (DTaP
5
-IPV/Hib and Tdap
5
era). In contrast to 132
total cases reported in 1993 and 88 cases in 1999, only 1 case was
reported in both 2003 and 2004 (0.2 cases per 10,000; Fig. 5,
Supplemental Digital Content 1, http://links.lww.com/A969).
7
Subsequently, 5 cases were reported in 2005, 2 cases in 2006, and
no cases in 2007. None of the 7 cases in 2005 to 2006 were
adolescents or adults who had been immunized with Tdap
5
. The
local government has approved public funding and has encouraged
a single booster dose of Tdap
5
vaccine for all adults residing in
Northwest Territories.
In 2004, British Columbia adopted Tdap
5
with administra-
tion of the vaccine to all 14- to 16-year-olds. In the short time since
its introduction, the pertussis incidence among 15- to 19-year-olds
decreased from 45 cases per 100,000 in 2003 to 7 cases per
100,000 in 2006, representing an 84% decline from the peak.
27
Among 10- to 14-year-olds, incidence rates decreased from 149
cases per 100,000 in 2003 to 24 cases per 100,000 in 2006 (84%
reduction), suggesting that Tdap
5
vaccination might be having an
effect on pertussis disease among the adolescent population. The
decline among 10-to 14-year-olds also may reflect some residual
protection from their toddler and preschool booster doses of
acellular vaccine (relative to the earlier cohort who received only
whole-cell vaccine) or possibly herd immunity from Tdap
5
vaccine
use among older adolescents.
FIGURE 3. Annual number of hospitalized cases of pertus-
sis, IMPACT Centers, 1991–2006 (J. Bettinger, personal
communication, 2007).
2,54
DTaP
5
-IPV/Hib vaccine was
adopted for infants and children throughout Canada dur-
ing 1997–1998 and Tdap
5
vaccine was adopted for adoles-
cents in most regions during 2004–2005.
Greenberg et al The Pediatric Infectious Disease Journal • Volume 28, Number 6, June 2009
© 2009 Lippincott Williams & Wilkins524 | www.pidj.com
Epidemiology of Invasive Hib Disease in the Last 2
Decades in Canada
By the time DTaP
5
-IPV/Hib combination vaccine was li-
censed in 1997, the reported incidence of invasive Hib disease
among children ⬍5 years had already decreased by ⬎95%, com-
pared with the pre-Hib vaccine era, as a result of widespread use
of Hib conjugate vaccines.
3
Since 1998, when DTaP
5
-IPV/Hib
vaccine was adopted by all provinces and territories, the incidence
of Hib disease in this vulnerable age group has remained very low,
⬍1 case per 100,000 children each year (range, 0.44 – 0.91 cases
per 100,000 per year; Fig. 6).
23
Comprehensive reports of invasive Hib disease have been
published from investigators of the IMPACT surveillance network.
The estimated number of children with invasive Hib disease in
IMPACT hospitals decreased from 485 cases in 1985 to an average
of fewer than 10 cases per year since 1997, a decrease of ⱖ98%
(Fig. 7).
12,28
A steady decline of cases was reported from 1988 to
1992, when PRP-D vaccine was given to toddlers, and a steep
decline occurred from 1992 to 1993 when Hib conjugate vaccines
were introduced for infants.
12
During 1991–1994, 36 cases were
considered vaccine failures; 3 among recipients of unconjugated
PRP vaccine, 27 after PRP-D vaccine, 3 after PRP-T vaccine, and
3 after other Hib vaccines.
12
Scheifele et al
28
summarized their data for 29 Hib cases
reported in the IMPACT network during 2001–2003. Fifteen
(52%) of the children were ⬍12 months of age, 9 (31%) were 1
through 5 years, and 5 (17%) were ⱖ6 years; 20 (69%) were male.
Fifteen (52%) were diagnosed with meningitis, 6 (21%) with
pneumonia and bacteremia, 4 (14%) with epiglottitis, and 4 (4%)
with other invasive diseases. The overall case fatality rate was 7%.
Among the 29 cases, only 2 were considered vaccine failures
(defined as occurring at least 4 weeks after completing the primary
series) in previously healthy children; 7 failures occurred in
children who were immunocompromised or had chronic underly-
ing medical conditions. In contrast, 20 of the cases had no or
incomplete vaccination, including 11 who were too young to have
completed the primary series, 7 due to parental refusal (including
1 who was also too young to complete the series), 2 due to delayed
completion of the primary series, and 1 had an uncertain but
incomplete vaccination history. Of 5 children who had received 4
age-appropriate doses of DTaP
5
-IPV/Hib vaccine, 4 had predis-
posing conditions and 1 was previously healthy.
28
A similar pattern was observed when the IMPACT investi-
gators compiled their data for 24 Hib cases reported during 2004
through 2007.
29,30
Fifteen (63%) of the 24 children were incom-
pletely immunized: 11 were too young to complete the primary
series of DTaP
5
-IPV/Hib vaccine (⬍12 months of age) and 4 were
unimmunized by parental choice (2–5 years).
30
Three cases were
considered vaccine failures after 3 doses, including 2 children who
were ⱖ24 months of age and had not yet received a toddler booster
dose. Five cases were considered vaccine failures after 4 doses,
including 3 noncompromised children (2, 6, and 6 years of age)
and 2 who were immunocompromised (6 and 9 years of age). One
additional case occurred in a 17-year-old previously given 1 dose
of PRP-D vaccine at 2 years of age. The estimated incidence rate
for children aged 0 to 16 years during 2004 –2007 was 0.1 per
100,000 for all Hib cases and 0.05 per 100,000 for Hib vaccine
failures. Case totals in 2004 –2007 were similar to those in 1998 –
2003, suggesting no loss of effectiveness due to recently intro-
duced and concurrently administered pneumococcal conjugate and
meningococcal conjugate vaccines.
30
Hib Disease in High-Risk Populations
Certain socio-ethnic populations are at substantially higher
risk for Hib disease and its potentially life-threatening complica-
tions. These populations include native inhabitants in both Canada
(including Inuit, First Nations, and Me´tis; collectively referred to
as Aboriginals) and the United States (including Eskimo, Inuit, and
Aleut; collectively referred to as Alaska Native).
31,32
The PHAC
and the Arctic Investigations Program of the CDC maintain joint
surveillance in the polar region of both countries. Since 1999, the
PHAC and Arctic Investigations Program have participated in a
larger network of public health agencies, hospitals, and reference
laboratories in 8 countries that are located, at least in part, in the
arctic region, known as the International Circumpolar Surveillance
(ICS) program.
33
The Aboriginal population under surveillance in
the polar region of Canada (Yukon, Northwest Territories, Nu-
navut, northern regions of Labrador, and Quebec) is approximately
78,400 persons, and the Native population under surveillance in
Alaska is approximately 124,500 persons (Table 1).
32
During comparable 5-year periods of surveillance (the most
recent years in each country for which complete ICS data are
available), DTaP
5
-IPV/Hib vaccine was used in Canada (2000 –
FIGURE 6. Incidence of invasive Hib disease in children
aged ⬍5 years, Canada, 1989–2002.
23
PRP-D vaccine was
adopted for toddlers in 1988 and several Hib conjugate
vaccines were introduced for infants in 1992. DTaP
5
-IPV/
Hib vaccine was adopted for infants and children through-
out Canada during 1997–1998.
FIGURE 7. Invasive Hib disease among children in the IM-
PACT surveillance network, 1985–2006.
12,28,29,55–57
PRP-D
vaccine was adopted for toddlers in 1988 and several Hib
conjugate vaccines were introduced for infants in 1992.
DTaP
5
-IPV/Hib vaccine was adopted for infants and chil-
dren throughout Canada during 1997–1998.
The Pediatric Infectious Disease Journal • Volume 28, Number 6, June 2009 DTaP
5
-IPV/Hib Vaccine
© 2009 Lippincott Williams & Wilkins www.pidj.com |525
2004) and PRP-OMP vaccine (PRP conjugated to the outer mem-
brane protein of Neisseria meningitidis group B; Merck & Co, Inc,
Whitehouse Station, NJ) was used in Alaska (2002–2006). Only 4
cases of Hib disease were reported to the ICS program among
Canadian children younger than 5 years during 2000 –2004; of
these, 3 were among Aboriginal children. In Alaska, 7 cases were
reported during 2002–2006; 6 were among Alaska Native chil-
dren.
34,35
The rates of invasive Hib disease were similar among the
Canadian Aboriginal population (0.8 cases per 100,000 per year)
and Alaska Native population (1.0 cases per 100,000 per year).
H. influenzae Nontype b Disease
The occurrence of invasive Hib disease has been so rare in
recent years that nontype b strains have become the focus of
several reports from Canada. In Manitoba, among 52 H. influenzae
strains isolated from patients with invasive disease during 2000 –
2004, only 3 (6%) were serotype b, whereas 26 (50%) were
serotype a, 3 (6%) were other serotypes, and 20 (38%) were
nontypeable.
36
In a follow-up report, Tsang et al summarized their
data from Manitoba for the period of 2000 through 2006.
37
The
database was expanded to 122 isolates of H. influenzae; 36 (30%)
were serotype a, 5 (4%) were Hib, 12 (10%) were other serotypes,
and 69 (57%) were nontypeable. The majority of serotype a cases
(72%) occurred in infants ⬍24 months of age. Of the 5 Hib cases,
4 occurred in infants ⬍12 months of age (vaccine histories and age
of onset not available) and 1 occurred in a 52-year-old adult.
In a recent review of IMPACT data for 1996 through 2001,
166 H. influenzae strains were characterized from children diag-
nosed with invasive disease.
38
Eighty-nine (54%) were caused by
nontype b serotypes, 58 (35%) were Hib, and 19 (11%) were not
serotyped. Among the 89 nontype b cases, 47 (53%) were non-
typeable, 25 (28%) were caused by serotype a, 11 (12%) serotype
f, 4 (4%) serotype d, and 2 (2%) serotype e. The majority of the
serotype a cases (20 关80%兴) occurred in infants ⬍1 year of age, 24
(96%) occurred in 4 western Canadian provinces, and 19 (76%)
occurred among Aboriginal children.
38
Of the 58 Hib cases, 21
(36%) were classified as vaccine failures (14 received PRP-T
vaccine 关in whole-cell or acellular pertussis combination vaccines;
number of each not reported兴and 7 received PRP-D or PRP
vaccine), 21 (36%) received no Hib vaccine, and 16 (28%) were
incompletely vaccinated for age.
38
A similar shift of serotypes has occurred in the arctic region.
During 2000 –2005, 138 cases of H. influenzae were reported to the
ICS program from Alaska and northern Canada.
39
Among 88
typeable strains, 42 (48%) were serotype a, 27 (31%) Hib, 12
(14%) serotype f, and 7 (8%) other serotypes. In recent years,
among all typeable H. influenzae, serotype a is the most prevalent
serotype in the North American Arctic.
33,39
DISCUSSION
During the past decade, DTaP
5
-IPV/Hib vaccine was the
exclusive vaccine administered to Canadian infants and toddlers to
protect them against diphtheria, tetanus, pertussis, polio, and Hib
infections. Pertussis and invasive Hib disease have been well-
controlled, as reflected by reduced rates of these diseases in
national, provincial, and IMPACT data.
2,27,28,40
The national de-
cline in incidence rates of pertussis among preschool and school
aged children after 1998 demonstrates the effectiveness of the
acellular pertussis components of the DTaP
5
-IPV/Hib combination
vaccine. The decline of pertussis among adolescents in provinces
and territories that have adopted universal Tdap
5
immunization
programs for 14- to 16-year-olds indicates that Tdap
5
vaccine is
effective in this population.
DTaP
5
-IPV/Hib and Tdap
5
vaccines licensed in Canada in
1997 and 1999, and Daptacel (Sanofi Pasteur Limited), licensed in
the United States in 2002 as a stand-alone DTaP
5
vaccine, all
contain the same 5 acellular pertussis components which are as
follows: PT, FHA, PRN, and FIM types 2 and 3. Based on
immunogenicity analyses,
41–43
the expected efficacies of Tdap
5
(licensed in the United States in 2005) and DTaP
5
-IPV/Hib vac-
cines (licensed in the United States in 2008) against pertussis
should be comparable to the rates observed with DTaP
5
vaccine in
a prospective, randomized, controlled comparative efficacy trial
conducted in Sweden in 1992–1995.
15
The estimated efficacy of
DTaP
5
vaccine in the Sweden trial was 85% against WHO-defined
pertussis (laboratory confirmation and ⱖ21 consecutive days of
paroxysmal cough) and 78% against pertussis of any severity
including mild disease (laboratory confirmation and ⱖ1 day of
cough).
National, IMPACT, and regional surveillance data confirm
very low rates of invasive Hib disease in Canada, with an average
of only 3 breakthrough cases (after receipt of 3 or 4 DTaP
5
-IPV/
Hib vaccine doses) occurring each year among approximately 1.7
million Canadian children younger than 5 years.
28
Even among
Aboriginal children, cases of Hib disease are rare; only 3 occurred
among these high-risk children in a 5-year period.
34,35
Most Hib
cases in Canada are reported among children with no or incom-
plete vaccination or in children who have an underlying medical
condition, including various causes of immunodeficiency.
28
The epidemiology of pertussis and invasive Hib disease are
similar in the United States and Canada. As in Canada, whole-cell
vaccines were introduced in the United States in the 1940s, leading
to a ⬎99% decline in the incidence of reported pertussis cases
from a peak of approximately 150 cases per 100,000 population in
the prevaccine era.
44
A nadir was reached when only 1010 cases
were reported in 1976.
45
However, since the early 1980s, reported
pertussis cases have steadily increased, reaching 25,827 cases in
2004, the highest number since 1959.
45
Reported cases have
increased among all age groups, but most dramatically among
adolescents and adults. In recent years, two-thirds of the total cases
reported in Canada and the United States have been among
adolescents and adults.
23,46,47
In the United States, the increase in
pertussis case reports has been ascribed to waning immunity after
childhood vaccination; to increased awareness among physicians,
other healthcare professionals, and the public; to improved avail-
ability of diagnostic tools; and to lower protection afforded by
previously used whole-cell vaccine.
44,48
Despite increased num-
bers of reported pertussis cases, underreporting remains a major
TABLE 1. International Circumpolar Surveillance,
Canada, and United States
31,33-35,39
Canada Alaska
Regions Yukon, Northwest Territories,
Nunavut, Northern
Labrador, and Quebec
Alaska
Total population 132,956 655,435
Native population
(% of total
population)
⬃78,400 (59%) ⬃124,500 (19%)
Surveillance 5 yr (2000 –2004) 5 yr (2002–2006)
Vaccine DTaP
5
-IPV/Hib vaccine PRP-OMP vaccine
Hib cases ⬍5 yrs
old
4 (3 native) 7 (6 native)
Ages (no. doses
received before
illness)
1.6 mo (0)
3.7 mo (unknown)
3.9 mo (partial*
1.4 yr (partial*
4.6 mo (2) 1.1 yr (2)
5.7 mo (0) 2.4 yr (3)
9.3 mo (2) 2.6 yr (3)
3.6 yr (3)
*Received at least 1 dose but not fully immunized.
Greenberg et al The Pediatric Infectious Disease Journal • Volume 28, Number 6, June 2009
© 2009 Lippincott Williams & Wilkins526 | www.pidj.com
issue for all age groups, but perhaps more so for adolescents and
adults because of the often atypical appearance of their illness.
Based on recent epidemiologic studies, between 800,000 and 3.3
million cases of pertussis are estimated to occur among adoles-
cents and adults in the United States annually.
49
As with pertussis, the epidemiology of invasive Hib disease
in the United States is similar to that of Canada. Although
reporting was not complete in the early 1980s, approximately 1
case of Hib disease is estimated to have occurred per 200 to 250
children less than 5 years in both the United States and Canada
before availability of Hib vaccines.
3,50
Hib vaccine introduction in
the United States followed a timeline similar to that of Canada:
unconjugated PRP vaccines were introduced for 18-month-olds in
1985 and Hib conjugate vaccines for toddlers in 1988 and infants
in 1990 to 1991.
50
As in Canada, the use of these vaccines in the
United States led to a marked decline of the reported incidence of
Hib disease in the late 1980s and early 1990s. In Canada, except
for a brief period following the introduction of several types of Hib
conjugate vaccines for infants in 1992, PRP-T vaccine has been the
exclusive Hib vaccine used in Canada, first in the whole-cell
combination vaccines and then in the acellular pertussis combina-
tion DTaP
5
-IPV/Hib vaccine used since 1997. In contrast, in the
United States, 3 Hib conjugate vaccines were used for many years
after their introduction in the early 1990s: PRP-T, PRP-OMP, and
HbOC (PRP conjugated to a mutant form of diphtheria toxoid;
Wyeth, Pharmaceuticals Inc, Philadelphia, PA; distribution in the
United States stopped in 2004).
Historically, the antibody response to the Hib component in
combination vaccines has been a concern.
51
In trials conducted in
the 1990s, vaccines that combined Hib with DTaP vaccines, other
than the Canadian 5-component acellular pertussis vaccine, in-
duced antibody responses to the Hib component that were signif-
icantly lower than responses achieved when DTaP and Hib vac-
cines were administered separately.
52
In contrast, studies of
DTaP
5
-Hib combination vaccines using the Canadian 5-compo-
nent acellular pertussis vaccine have demonstrated no immuno-
logic interference, and these results have been confirmed by
the effectiveness of DTaP
5
-IPV/Hib vaccine against invasive
Hib disease in Canadian children, including high-risk Aborigi-
nals.
16,28,34,35,42,53
In US clinical trials, DTaP
5
-IPV/Hib vaccine generated
antibody responses to the diphtheria, tetanus, pertussis, polio, and
Hib components comparable to those achieved by separately
administered US-licensed DTaP
5
, IPV (IPOL; Sanofi Pasteur Lim-
ited), and Hib (ActHIB; Sanofi Pasteur SA, Lyon, France) vac-
cines.
42
Given the similar epidemiologic patterns of disease in
Canada and the United States, the similar immunization schedules
and vaccine coverage rates in the 2 countries, and the similar
antibody responses to the pertussis and Hib components in DTaP
5
-
IPV/Hib vaccine compared with separately administered DTaP
5
and Hib vaccines, DTaP
5
-IPV/Hib is expected to provide the same
level of protection in the United States as experienced with this
combination vaccine in Canada, and as currently experienced in
the United States with separate vaccines.
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