Prevention of pertussis: recommendations derived from the second Global Pertussis Initiative roundtable meeting.

Abstract

The Global Pertussis Initiative (GPI) was established in 2001 to assess the global extent of the ongoing problem of pertussis and to evaluate and prioritize pertussis control strategies. Exchange of data, knowledge, and experience, facilitated by discussion and debate, resulted in the formulation, in 2002, of the following recommendation: all countries should consider expanding existing vaccination strategies to include adding pertussis booster doses to pre-school children (4-6 years old), to adolescents, and to those specific adults that have the highest risk of transmitting Bordetella pertussis infection to vulnerable infants. The GPI met again in 2005, where it reinforced its previous recommendation for universal adolescent immunization. Additionally, the GPI recommended implementation of the cocoon strategy (immunization of family members and close contacts of the newborn) in countries where it is economically feasible, and encouraged efforts toward global standardization of pertussis disease clinical definitions and diagnostics. Universal adult vaccination is a logical goal for the ultimate elimination of pertussis disease, but feasibility issues remain obstacles to implementation.

Full text

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Vaccine 25 (2007) 2634–2642
Prevention of pertussis: Recommendations derived from the
second Global Pertussis Initiative roundtable meeting
Kevin D. Forsytha,∗, Carl-Heinz Wirsing von Konigb,
Tina Tanc, Jaime Carod, Stanley Plotkine,f
aDepartment of Pediatrics, Flinders Medical Centre and Flinders University, Adelaide, South Australia
bInstitut fur Hygiene und Laboratoriumsmedizin, Krefeld, Germany
cFeinburg School of Medicine, Northwest University and the Children’s Memorial Hospital, Chicago, Illinois, United States
dCaro Research Institute, Concord, Massachusetts, United States
eUniversity of Pennsylvania, Philadelphia, United States
fSanofi-Pasteur, Pennsylvania, United States
Received 29 June 2006; received in revised form 16 November 2006; accepted 10 December 2006
Available online 22 December 2006
Abstract
The Global Pertussis Initiative (GPI) was established in 2001 to assess the global extent of the ongoing problem of pertussis and to evaluate
and prioritize pertussis control strategies. Exchange of data, knowledge, and experience, facilitated by discussion and debate, resulted in the
formulation, in 2002, of the following recommendation: all countries should consider expanding existing vaccination strategies to include
adding pertussis booster doses to pre-school children (4–6 years old), to adolescents, and to those specific adults that have the highest risk of
transmitting Bordetella pertussis infection to vulnerable infants. The GPI met again in 2005, where it reinforced its previous recommendation
for universal adolescent immunization. Additionally, the GPI recommended implementation of the cocoon strategy (immunization of family
membersandclosecontactsofthenewborn)incountrieswhereitiseconomicallyfeasible,andencouragedeffortstowardglobalstandardization
of pertussis disease clinical definitions and diagnostics. Universal adult vaccination is a logical goal for the ultimate elimination of pertussis
disease, but feasibility issues remain obstacles to implementation.
© 2006 Elsevier Ltd. All rights reserved.
Keywords: Pertussis; Epidemiology; Immunization strategies; Transmission; Reporting; Infection; Infants; Adults; Adolescents; Health economics
1. Introduction
The Global Pertussis Initiative (GPI) was established in
2001 with three main objectives: to raise the profile of per-
tussis as an important and preventable disease that warrants
greater global public health attention; to improve under-
standing of the increasing incidence of reported pertussis;
and to develop effective immunization strategies for pertus-
sis control. The GPI is composed of 37 experts in the field
of pertussis from 17 countries worldwide and its work is
supported by an unrestricted educational grant from sanofi
∗Corresponding author. Tel.: +618 8204 4459; fax: +618 8204 3945.
E-mail address: Kevin.Forsyth@flinders.edu.au (K.D. Forsyth).
pasteur. After in-depth evaluation of the available data, pri-
oritization of various immunization strategies, creation of
a health economic model to study the cost effectiveness
of the proposed strategies, and identification of potential
barriers to implementation of the recommendations and pos-
sible solutions to these barriers, the GPI concluded that
current vaccination strategies needed to be reinforced and
expanded.Vaccinationshouldincludetheadditionofbooster
doses for adolescents in developed countries. Additionally,
the group recommended that immediate universal adolescent
vaccination and immunization of healthcare and childcare
workers should be instituted. Australia introduced an adoles-
centboosterin2003,andtheadditionofanadolescentbooster
wassuggestedforArgentinaandJapan[1].Someothercoun-
0264-410X/$ – see front matter © 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.vaccine.2006.12.017

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K.D. Forsyth et al. / Vaccine 25 (2007) 2634–2642
2635
tries, including, Austria, Canada, France, Germany, and the
United States, have incorporated an adolescent booster dose
into their current immunization schedules, as advocated by
the GPI [2].
The GPI held its second roundtable meeting in December
2005 to re-evaluate previous recommendations and to dis-
cuss the progress made in pertussis control since their first
meeting in 2002. Twenty-three members of the GPI, led by
theChairman,ProfessorStanleyPlotkinoftheUnitedStates,
met for 2 days to present the latest developments on the epi-
demiology and diagnosis of pertussis and to examine various
vaccination strategies with the aim of proposing updated rec-
ommendations.Thispapersummarizesthekeypointsderived
from the meeting and presents the group’s recommendations
for adolescent and selective adult immunization.
2. Epidemiology of pertussis
Although progress has been made since the first GPI
meeting in 2002 toward gaining a better understanding of
the transmission and control of pertussis, in 2006 the dis-
ease remains an important public health concern. The World
Health Organization (WHO) estimates that at least 27 mil-
lionchildrendidnotreceiveDTP3in2004,andestimatesthat
294,000 deaths from pertussis in children under age 5 (2002
data) could have been preventable by vaccines [3]. It contin-
ues to be endemic worldwide, with an estimated 50 million
cases occurring annually, 90% of which are in developing
countries [4,5]. Infants remain the most vulnerable group.
From 1997 to 2000 in the United States, 20% of all pertussis
cases required hospitalization; 90% of those patients were
infants <1 year old [6]. Incidence rates vary widely, but the
general resurgence of reported pertussis, especially among
the adolescent and adult populations, indicates that current
immunization schedules, among other factors, inadequately
protect against the disease.
In the pre-vaccine era, pertussis was universally present
with cyclic peaks every 2–5 years. Reported cases averaged
157 per 100,000 in the United States and occurred almost
exclusively in unvaccinated children [7,8]. The early use of
whole-cell vaccines and the implementation of an immu-
nization schedule in the United States were highly effective,
reducing the incidence of reported pertussis to <1 case per
100,000 during the 1970s. Since 1984, there has been a
modest increase, although some would say a resurgence,
in reported pertussis, to 9 per 100,000, with cyclic peaks
still occurring at 2–5-year intervals [7,9]. It is believed that
endemic adolescent and adult disease is likely to be respon-
sibleforthecyclicpatternstillseeninunvaccinatedchildren.
2.1. Evolution of Bordetella pertussis
To determine whether B. pertussis is polymorphic or
evolving, members of the GPI roundtable agreed that the
followingmustbeaccomplished:temporalanalysisandcom-
parison of clinical isolates in different parts of the world;
analysis and comparison of clinical isolates collected before
and after introduction of vaccination in the region of inter-
est; and analysis of the epidemiology of the disease in the
regionofinterest.Thefewstudiesthatwereconductedbefore
the mid-1980s on the evolution of B. pertussis generally
concluded that some strains were subject to rapid muta-
tionsandotherswererelativelystable[10,11].Lateranalyses
using typing techniques such as multi-locus enzyme elec-
trophoresis(MLEE)toanalyzeproteinshaveindicatedthatB.
pertussis exhibits very restricted genetic diversity compared
with other bacterial species [12,13].
Results obtained with the use of more recent typ-
ing techniques that allow analysis of portions of the
bacterial genome, such as restriction fragment length poly-
morphism (RFLP), multi-locus sequence typing (MLST),
multiple antigen sequence typing (MAST), and multiple-
locus-variable-numbertandemrepeatanalysis(MLVA),have
concurred that B. pertussis shows very restricted genetic
diversity, but some differences are seen between vaccine
strains and circulating isolates [14]. Small and seasonal dif-
ferencesareseenwhentypingtechniquesareusedtoanalyze
the whole genome [15]. In a study where pulsed-field gel
electrophoresis was used to type B. pertussis strains isolated
from children with severe versus mild illness, no significant
differences in PFGE patterns were found between groups
[16]. This indicates that variability in severity of pertussis
could not be attributed to specific hypervirulent clones of B.
pertussis.
Recentstudieshaveindicatedthatincountrieswithahigh
rateofvaccination,polymorphismofB.pertussisisverylim-
itedandgeneticdiversityseemstodecreaseslowlyovertime,
withdifferencesingenesequencesofPTandPRN,twocom-
ponents included in several acellular component pertussis
(aP) vaccines [15]. Data on duration of immunity in France
after wP or aP vaccines show that the level of protection has
not changed in the past 10 years although circulating isolates
were shown to have changed [17,18]. Data on isolates col-
lected in Japan, a country using aP vaccines for more than 20
years, indicate that the antigenic divergence found between
B. pertussis vaccine strains and circulating strains have not
affected the efficacy of pertussis vaccination in Japan [19].
2.2. New data on pertussis in Europe
TheEUVAC-NETprojectcompriseda5-yearsurveillance
period during which data were collected on the epidemiol-
ogyandburdenofreportedpertussisin16Europeancountries
and to assess the burden of disease in adolescents and adults
[20,21]. The study pooled national surveillance data from
1998 to 2002, and showed a wide variation in reported inci-
dence, from 0.1 per 100,000 population for Portugal (a total
of 47 reported cases) to 123.9 per 100,000 for Switzerland
(a total of 845 reported cases). Countries north of Germany
were shown to have a higher incidence of reported pertussis
than countries in southern Europe. The incidence tended to

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increase from 1998 to 2002 in adults and possibly in infants.
Seasonality data suggest a synchronization of cases in chil-
drenfrom0to4yearsold.Becausetherewasnouniformcase
definition among the 16 participating countries, or stringent
surveillance processes, there was likely significant under-
reportingofcasesandofdeathsinmanyofthecountriesunder
study. The EUVAC-NET data did not include information on
vaccination coverage for all the countries, but sub-analyses
of the available data for Denmark (a total of 997 cases from
1998to2002),Italy(17,702cases),TheNetherlands(26,232
cases), and Norway (12,748 cases) indicated that one dose of
aPprotectedagainsthospitalization,mostnotablyinchildren
less than 1 year of age [20].
Comparison of the data between the EUVAC-NET coun-
tries may not be appropriate due to the high variability of
the surveillance systems and diagnostic and reporting meth-
ods, but EUVAC-NET was the first pertussis surveillance
study that might allow for an examination of incidence data
between European countries. In contrast, there is a serious
lack of information regarding the incidence of pertussis in
thedevelopingworld,includingLatinAmerica,Africa,Asia,
and India. Better diagnostic tools and better reporting will
likely prove that current numbers grossly underestimate the
true incidence. For epidemiologically and clinically valuable
data to be collected, there is a need to enhance and harmo-
nize surveillance systems among countries worldwide, using
standardclinicalandmicrobiologicaldefinitionsofpertussis.
Availabilityofsingle-sampleserologyusinganti-PTIgGand
anti-PT IgA may provide a better approximation of true rates
of infection in adolescent and adult populations.
Clearly, there are different surveillance systems, different
diagnosticprotocols,evendifferentclinicaldefinitionsofper-
tussisdiseaseworldwide.TheGPIrecognizestheseproblems
and seeks to find some process to enhance standardization
globally. Policy issues around infectious disease and immu-
nizationarehandleddifferentlyindifferentjurisdictions.The
GPI would consider convening a pertussis standardization
summit to begin a process of harmonization of pertussis pro-
tocols internationally. Only then can true comparisons be
undertaken and better understanding of pertussis disease be
gleaned.
3. Differential diagnosis
Correct diagnosis of pertussis can be a challenge because
of the overlap of symptoms with other respiratory infections
caused by viruses and other bacteria. Differential diagnosis
of prolonged cough, even with paroxysms, may include Bor-
detella parapertussis, Bordetella bronchiseptica, Chlamydia
pneumoniae, Mycoplasma pneumoniae, adenoviruses, respi-
ratory syncytial virus (RSV), human parainfluenza viruses,
influenza viruses A and B, rhinovirus, and human metapneu-
movirus [22].
Although culture is now less frequently used than in years
past for laboratory confirmation of causative pathogens, bac-
terial isolates are still needed for genotypic and phenotypic
analysis.Real-timePCRisbeingincreasinglyused;itsadvan-
tages include offering a result within a few hours, and no
requirement for samples to be handled post-amplification,
which will reduce the risk of contamination. The Euro-
pean Research Programme for Improved Pertussis Strain
Characterization and Surveillance (EUpertstrain) published
a consensus paper in 2005 that addressed the methodology
andtheapplicationofreal-timePCRfordetectingBordetella
DNA [23]. It concluded that real-time PCR is more sensitive
than culture for the detection of B. pertussis and B. para-
pertussis, especially after the first 3–4 weeks of coughing
and after antibiotic therapy has been started. There are still
problems with quality control and standardization; a good
working model for global use is still 2–4 years away from
being available.
There is good evidence that PT IgG geometric mean
titre correlates with severity of symptoms [24], and that an
IgG–PT cut-off of 100U/ml for serodiagnosis is reliable in
all age groups. Furthermore, an IgG–PT of <10U/ml is asso-
ciated with increased risk of re-infection [25]. Serology is
therefore a reliable test for clinicians to diagnose B. pertussis
infection,butitshouldbefurtherimprovedandstandardized,
primarily in relation to anti-PT IgG. A reference serum pre-
pared by the FDA is currently generally accepted, but a new
one being tested is expected to become the WHO reference
serum. The serological cut-off for confirmation of diagnosis
will probably be similar worldwide.
4. Prevention of pertussis: vaccination strategies
Since it was established in 2001, GPI members have
reviewed the international literature and exchanged data,
knowledge, experience, and opinion through teleconfer-
ences, a password-protected interactive Web site, and the
two roundtable meetings. With the goal of identifying and
addressing potential barriers to pertussis control, they evalu-
atedanumberofimmunizationstrategies,includinguniversal
immunization of adolescents; universal immunization of
adults; selective immunization of new mothers, and family
and close contacts of newborns (cocoon strategy); selective
immunization of healthcare workers; selective immuniza-
tion of childcare workers; implementation of a fourth or
fifth booster dose for all pre-school children (4–6 years
of age); and improvement of current infant and toddler
immunization strategies. An outcome of the first major
GPI symposium was a clear recognition that adolescent
vaccination was an important additional step to help con-
trol pertussis disease in the adolescent populations. This
second GPI symposium has expanded on this earlier rec-
ommendation, in that the ongoing problems of severe
pertussis disease in the neonatal and infant populations
have been better clarified and understood, with a particu-
lar focus on possible intervention strategies to address this
problem.

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4.1. Adolescent vaccination
The GPI previously noted that the incidence of pertus-
sis in adolescents appears to be increasing, as shown in
studies from regions as diverse as Canada, Poland, and the
United States [26–29]. Pertussis is a particularly serious ill-
nessamongunvaccinatedorincompletelyvaccinatedinfants,
and adolescents have been shown to be an important source
of infection for young infants. A recent Centers for Disease
Control and Prevention (CDC) study of 774 infant cases of
reported pertussis from four states showed that among 264
infants for whom a source could be identified, 56% were
adults ≥20 years of age and 20% of the sources were 10–19
years of age [30]. Adding boosters to existing childhood
schedules(pre-schooloradolescent)andboostersforspecific
adult subgroups at highest risk of transmitting B. pertussis
infection to infants were expanded immunization strategies
recommended previously by the GPI.
Pertussis continues to be a worldwide problem even
though immunogenic and effective vaccines are available
and can be safety administered beyond childhood [31–33].
A study in Prince Edward Island in Canada explored the
immunogenicity of Tdap after different vaccination intervals
(2–9 years) in cohorts who had previously been vaccinated
withDTwP,DTaP,and/orTd(dependingontheirage)[34,35].
The results showed that Tdap was well tolerated by adoles-
cents who were immunized after intervals of 2 to ≥10 years
after receiving a previous DTwP/DTaP/Td-containing vac-
cine and that it can be safely administered at intervals as
short as 18 months after prior tetanus, diphtheria, or per-
tussis vaccination. A more recent study to assess the safety
and immunogenicity of a sixth dose of Tdap vaccine in ado-
lescents showed that, regardless of the prior DTaP/DTwP
vaccination history, a sixth sequential dose of Tdap appears
safe and immunogenic [36].
The Advisory Committee on Immunization Practices
(ACIP) of the CDC has recently recommended routine Tdap
vaccination for adolescents, based on the following: “evi-
dence regarding the burden of pertussis among adolescents;
negative effects of pertussis outbreaks involving adolescents
on the community and the public health system; studies
suggesting use of Tdap among adolescents will likely be
safe, effective, and economical; and the established infras-
tructure for adolescent vaccination” [37]. Other countries,
including Canada, Austria, Australia, France, and Germany,
haveintroduceduniversalimmunizationofadolescents;early
evidence suggests that they are effective, but surveillance
will be required to confirm this [38]. The duration of pro-
tection (and need for an adult booster after the adolescent
one) is not known. Some studies indicate that antibody lev-
els may decrease after 3 years, but they remain significantly
higher than pre-booster immunization levels [39]. As more
data from vaccinated cohorts become available, it will be
clearerwhetheradecennialadultboosterwillbeneeded.The
GPI recommendation of universal adolescent immunization
programs is still valid based on the continued high rates of
adolescentpertussisinregionsthatdonothaveboosterdoses
after school entry.
4.2. Adult vaccination
There are two potential approaches to vaccinating adults:
universal adult vaccination to build up herd immunity and
eradicate B. pertussis infection; and selective vaccination
of those adults who are at highest risk of transmitting B.
pertussisinfectiontovulnerableinfantstominimizetheinci-
denceandimpactofdiseaseintheseinfants.Currently,inthe
United States and elsewhere, disease prevention in adults is
not widely practiced: for example, although annual flu vacci-
nation is recommended for healthcare workers, CDC survey
data for 2004 indicated a vaccination coverage level of only
42% [40]. Experts and supporting models support the notion
that universal vaccination would markedly reduce the inci-
dence of pertussis disease among all ages [32,41,42]. In the
past, pertussis did not have a sufficiently high profile to drive
a change in preventive medicine practices. However, some
recent events have led to an increased public awareness of
adolescent and adult pertussis and also the need for a more
universal approach to adult immunization. Specifically, the
dramatic increase in reported pertussis in adolescents and
adults has resulted in extensive media coverage and dissem-
ination of the information that new vaccines are available
[43,44]. In the opinion of the GPI, the concern about avian
influenza and the publicity surrounding new human papil-
lomavirus (HPV) vaccines that can prevent cervical cancer
have led to an increased general awareness about vaccines
foradolescentsandadults,andincreasinglyourpublichealth
policy bodies are advocating ‘whole-of-life’ immunization
strategies.
The Adult Pertussis Trial (APERT), sponsored by the
National Institutes of Health (NIH), has demonstrated the
efficacy of acellular pertussis vaccines in preventing pertus-
sis disease in adolescents and adults [45,46]. Subjects who
received either a dose of a tricomponent acellular vaccine
(n=1391) or a hepatitis A vaccine (controls, n=1390) were
monitoredfor2.5years.Ninecasesofpertussisinthecontrol
groupandonecaseinthegroupthatreceivedtheacellularper-
tussis vaccine met the primary case definition (culture, PCR,
andserologicalcasecriteria),yieldinganoverallvaccineeffi-
cacy of 92% (95% confidence interval, 32–99%). Among
cases that were confirmed by culture or PCR assay, five were
in the control group and none were in the vaccine group. The
duration of protection and prevention of secondary disease
were not assessed in this study.
The safety of vaccination in adolescents and adults is well
documented,butmoredataareneededonthesafetyofrepeat
doses of Tdap. Pertussis prevention advocacy will be key
to overcoming implementation issues, but payment will be
an issue in many countries (particularly developing coun-
tries). For an adult vaccination program to be successful,
key components must include education and public aware-
ness. Advocacy among healthcare providers is important

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K.D. Forsyth et al. / Vaccine 25 (2007) 2634–2642
in driving vaccine coverage and needs to be emphasized
in most countries. Because there is a moral imperative for
healthcare workers to protect themselves and those in their
care,hospitalsmightconsidermandatoryvaccinationoftheir
employees. With education, childcare workers and parents
andfamiliesofneonatesmayaccepttherationaleforvaccina-
tion more quickly than the general population. Furthermore,
adults with chronic underlying lung disease, such as chronic
obstructive pulmonary disease (COPD), may also benefit
from pertussis immunization. Findings from one study in
patients with COPD indicated that as much as 31% of acute
exacerbations might be caused by Bordetella infections [47].
The new ACIP recommendations to replace Td with Tdap
among adults in the United States are highly significant.
This indicates a policy shift to adult pertussis disease pre-
vention, and although it may not have an immediate effect,
the leadership in immunization provided by the ACIP will
likely lead to increased adult immunization uptake over time
[48]. Twelve European countries currently recommend Td
vaccination every 10 years.
4.3. Cocoon strategy
Several recent studies indicate that adults – mothers, in
particular – are an important source of B. pertussis infec-
tion to unvaccinated or incompletely vaccinated infants. A
national active monthly surveillance program of child health
specialists conducted in 2001 in Australia revealed that 140
infants (median age at diagnosis, 8 weeks) were hospitalized
with pertussis and 4 infants (<6 weeks old) died [49]. Of 97
(69%) infants who had not been vaccinated for pertussis, 63
(65%)wereundertheageofthefirstscheduleddoseofDTPa
vaccine (<8 weeks old). A coughing contact was identified
for half the cases, and 68% of those were adults, usually one
of the infant’s parents. Other studies have confirmed these
results and indicate that parents act as primary vectors in
30–57% of infant cases [9,30,50,51].
Vaccinationofhouseholdmembers(includingparentsand
siblings) of newborns, known as the cocoon strategy, should
be considered as a first step toward (or a component of)
universal adult vaccination. A study designed to evaluate
the impact of five adolescent/adult immunization strategies
showed that although the cocoon strategy leads to only a
9–17% reduction in typical adult cases, there is a strong indi-
rect effect on infants and young children: a decrease by 70%,
65%, and 69% was noted in cases among the 0–3-month-
old, 4–23-month-old, and 2–4-year-old groups, respectively
[52].Ifuniversaladultvaccinationisnotyetafeasibleoption,
the cocoon strategy should be recommended, even though it
can only reduce (but not eliminate) the risk of infants acquir-
ingseverepertussisdisease.Althoughtargetedimmunization
strategies have not been successful for the control of other
infectious diseases, it is considered that the cocoon strategy
is worthy of implementation for pertussis [53,54]. Even pro-
tecting just some infants would be considered a success. The
cocoon strategy is recommended in Australia, France, Ger-
many, and Austria, although there are no requirements in
these countries to enforce this policy, and vaccine coverage
is currently low [38,55].
4.4. Maternal vaccination
Neonatesareuniquelyatriskformanydifferentinfections
that cause substantial morbidity and mortality worldwide.
The immune system of neonates is immature and relatively
ineffective, and a US study by Healy et al. has shown that
babies born during recent years have low levels of pertussis-
specific antibody [56]. They found that although placental
transfer of pertussis antibodies is efficient, low maternal lev-
els and their rapid decay in infant sera leave infants with
little protection against life-threatening pertussis in early
infancy. Although Healy’s data provide some support for the
rationale of maternal immunization with acellular pertussis
vaccines, there is clearly a role for cellular immunity in per-
tussisprevention,andgiventherelativecellularparesisofthe
infantandtheresistancetoinjectingthepregnanthumanwith
any biological agent, it is unlikely maternal immunization
alone will significantly reduce the incidence of B. pertussis
infection in infants; it needs to be part of a broader vac-
cination strategy, including adolescents and at least those
adultswhoposethebiggestthreatofinfectiontounprotected
infants.
During the 1930s and 1940s, the possibility of protecting
newbornsagainstpertussisbyimmunizingtheirmothersdur-
ing pregnancy was investigated, but no further work in that
area was published until recently. Some animal and human
studieshaveprovidedlimitedbutpromisingdataonmaternal
pertussisimmunizationasabasisforfutureimmuneresponse
[57–59].TheACIPrecentlystatedthatpregnancyisnotacon-
traindication to Tdap or Td vaccination, and guidance on the
use of Tdap during pregnancy is currently under considera-
tion [48]. Immunization during pregnancy has the potential
to protect both mother and infant during a vulnerable period
in their lives. Transplacental transfer of antibodies is safer
and less expensive than administration of immunoglobulin
preparations to the infant. There is proven antibody transfer
fromvaccinatedwomentotheirunborninfants,butmoredata
areneededonwhetherthelevelsoftransferredantibodiesare
sufficient to protect the neonate from B. pertussis infection.
There is also uncertainty about whether maternal immuniza-
tion could affect the immunogenicity and efficacy of primary
and/or booster vaccination in infants/children [60–62].
4.5. Neonatal vaccination
In the United States from 1938 to 1940, there were
more than 10,000 recorded pertussis deaths, 70% of which
occurred in infants (most were younger than 4 months) [63].
In recent years, there has been a resurgence of reported per-
tussis in infant populations, as demonstrated by studies in
Canada, France, Germany, and the Netherlands [9,64–66].
In Australia over the past 20 years, hospitalization rates for

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2639
infants <5 months have remained unchanged despite exten-
sive immunization coverage [49].
Several studies conducted during the past decade have
confirmed earlier findings of acceptable safety, efficacy, and
immunogenicity of pertussis vaccination (DTwP), in full-
term and pre-mature infants [67,68]. A study by Englund
et al. showed that there was no suppression of subsequent
vaccine immunogenicity in infants born to mothers with
high antibody levels after primary immunization with Tdap
(although after whole-cell pertussis vaccine, higher levels
of pre-existing antibody were associated with substantial
(28–56%) reductions in the subsequent antibody response
to pertussis toxin) [69]. Neonatal and maternal vaccinations
are similar ways to achieve the same goal, but maternal vac-
cination has fewer implementation issues, although will not
givecellularimmunoprotectionfortheinfant.Theissuessur-
rounding neonatal vaccination are complex. It is practice in
some countries to give hepatitis B vaccine at birth. However,
the uptake is relatively low, partly because the immunization
delivery infrastructure has not traditionally included mid-
wives. It is unclear if newborn pertussis immunization will
induce sufficient and timely immunity. Clearly further trials
are needed, and the GPI strongly endorses such trials to be
undertaken.
5. Utilization of Tdap in 4–6 year olds
Booster doses of DTaP vaccines given at 4–6 years of
age are commonly followed by large injection site reactions,
with an increase in redness, swelling, and pain compared to
previous reactions [70]. Several studies have shown that the
adolescent/adult formulation diphtheria, tetanus, and acel-
lular pertussis combination vaccine with lower pertussis and
diphtheriaantigencontent(Tdap)wassignificantlylessreac-
togenic and slightly less immunogenic than the pediatric
formulation combination vaccine (DTaP) when given as a
booster to 4–6-year-old children [71–73].
As booster responses to all antigens appear adequate with
Tdap, it might be preferable to use Tdap or Tdap-IPV (inac-
tivated poliomyelitis viruses vaccine) from mid-childhood
onwards. Where both Tdap and DTaP are licensed, coun-
tries need to determine which vaccine to use. Australia and
Switzerland currently use DTaP for primary immunization
and the pre-school booster. Germany has recently introduced
Tdap as a fifth dose, given at 5–6 years of age, while contin-
uing to recommend Tdap-IPV at 9–17 years (previously the
fifth dose, but now the sixth dose).
Further studies would be useful to confirm that Tdap
(±IPV) vaccines are not inferior in immunogenicity and are
less reactogenic compared to full-content DTaP (±IPV) vac-
cines. Because Tdap vaccines may be significantly better
tolerated, more studies are warranted on their routine use
for children 4–6 years of age. These studies should be done
with vaccines from both major manufacturers (sanofi pasteur
and Glaxo SmithKline).
6. Economic assessment
An understanding of the impact of vaccination on disease
transmission (i.e., capturing herd immunity) is a key to being
able to assess the economic value of adult strategies. A mod-
eling study conducted by Drs. A. Van Rie and J. Caro was
designed to provide transmission probabilities data to better
assess the impact of the following adolescent and adult vac-
cination strategies in the United States: routine adolescent
vaccination; the cocoon strategy; and routine adult vaccina-
tion every 10 years (unpublished data presented at the GPI
Roundtable Meeting, December 9, 2005, Paris, France). Pre-
liminary results of that study, using an updated computer
simulation incorporating the most current US epidemiologi-
cal information, indicate the following:
• If vaccinations were introduced using any of the three
strategies above, the overall incidence of infection would
decrease.
• Routine adolescent vaccination would have an important
effect on the incidence of pertussis in the 0–19 year olds,
reducing infection to 40% of its current level.
• The cocoon strategy plus routine adolescent vaccination
would effect a further 50% reduction in infant pertussis,
but would have no substantial additional impact on the
incidence of pertussis infection in the general population.
Morbidityandsocietalcosts(especiallyabsenteeismfrom
school or work) associated with reported pertussis in adoles-
centsandadultshavebeenshowntobeincreasing[74].When
the infected adults are healthcare workers, serious adverse
health (transmission to patients, colleagues, and family) as
well as economic consequences can result [75]. Although
there are limited new data examining both direct and indirect
costsassociatedwithimmunization,investigatorshavebegun
to use models to examine adolescent and adult vaccination
strategies, and utility estimates have also been developed.
Computer simulations predict that the cocoon strategy will
becosteffective(ifassumptionsonincidence,costspercase,
and extent of herd immunity are accurate, and implemen-
tation of the vaccination schedule is feasible), although the
relative ranking of the various adolescent/adult vaccination
strategiesremainsunclear[42,76].Anumberoflimitationsto
these models persist: cost data are scanty, especially for mild
cases; the extent of herd immunity is unknown; no data exist
from outside Europe, North America, and Australia; and the
long-term effectiveness of the vaccines is uncertain.
7. Conclusions and recommendations
Since 2001, there has been notable progress in the under-
standing of B. pertussis disease, but it continues to affect
millions of people worldwide and is a major cause of infant
mortality, especially in developing countries. Previously, the
GPI recommended that an acellular pertussis vaccine be
incorporated into the current dT vaccine schedule for adoles-

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K.D. Forsyth et al. / Vaccine 25 (2007) 2634–2642
cents,eitherasdTaPorasastandaloneaPbooster,andseveral
countries have incorporated that recommendation into their
immunization schedule [77]. The GPI also recommended
increased and improved surveillance, improved detection,
and greater awareness of pertussis as a major public health
problem in order to arrive at a measure of the true incidence
of the disease and the effectiveness of any immunization
strategy. At their second meeting, the GPI acknowledged
thecontinuingneedforimprovedsurveillanceanddiagnosis,
and reinforced their previous recommendations for expand-
ing pertussis vaccination to adolescents. They emphasized
theimportanceofeachcountryensuringthatcurrentpertussis
immunizationschedulesareimplementedandenforced.This
second meeting addressed quite specifically the problems of
neonatal and infant pertussis disease, and after reviewing
and discussing available data the GPI has further endorsed
implementation of the cocoon strategy in countries where it
is economically possible, as well as selective vaccination of
healthcare workers and childcare workers. Universal adult
vaccination may be justified by the available epidemiologi-
cal data, but its feasibility is currently in question. As new
data continue to support the immunogenicity and safety of
Tdap vaccines in adolescents and adults, an efficient way to
immunize these populations would be to substitute Tdap or
Tdap–IPVvaccinesfortheTdvaccineboosterscurrentlyrec-
ommended in many countries. Standardization of diagnostic
tests, reagents and clinical criteria are urgently required; the
GPI is willing to support or generate such a process.
OngoingresearchanddiscussionamongtheGPImembers
will focus on issues that must be resolved with the aim of
preventing infant morbidity and mortality from pertussis and
tailoring strategies to fit the needs of each country. The GPI
members concurred that there is a vital need for adequate
pertussis surveillance and reporting systems in all countries,
and that feasibility issues are assuming a major role in the
design and implementation of vaccination strategies.
References
[1] Forsyth K, Nagai M, Lepetic A, Trindade E. Pertussis immunization
in the global pertussis initiative international region: recommended
strategies and implementation considerations. Pediatr Infect Dis J
2005;24:S93–7.
[2] Forsyth KD, Campins-Marti M, Caro J, Cherry JD, Greenberg D,
Guiso N, et al. New pertussis vaccination strategies beyond infancy:
recommendations by the global pertussis initiative. Clin Infect Dis
2004;39:1802–9.
[3] Global Immunization Data 2004. World Health Organization.
Available at:http://www.who.int/immunization monitoring/data/
GlobalImmunizationData.pdf#search=%222004%20global%
20immunization%20pertussis%22 [accessed 14 September, 2006].
[4] Halperin SA. Pertussis immunization for adolescents: what are we
waiting for? Can J Infect Dis Med Microbiol 2001;12:74–6.
[5] Crowcroft NS, Pebody RG. Recent developments in pertussis. Lancet
2006;367:1926–36.
[6] O’Brien JA, Caro JJ. Hospitalization for pertussis: profiles and case
costs by age. BMC Infect Dis 2005;5:57.
[7] Cherry JD. The epidemiology of pertussis and pertussis immunization
intheUnitedKingdomandtheUnitedStates:acomparativestudy.Curr
Probl Pediatr 1984;14:1–78.
[8] Centers for Disease Control and Prevention. Pertussis—United States,
1997–2000. Morb Mortal Wkly Rep 2002;51:73–6.
[9] Centers for Disease Control and Prevention. Pertussis—United States,
2001–2003. Morb Mortal Wkly Rep 2005;54:1283–6.
[10] Stanbridge TN, Preston NW. Variation of serotype in strains of Borde-
tella pertussis. J Hyg (Lond) 1974;73:305–10.
[11] GoldmanS,HanskiE,FishF.SpontaneousphasevariationinBordetella
pertussis is a multistep non-random process. EMBO J 1984;3:1353–6.
[12] Musser JM, Hewlett EL, Peppler MS, Selander RK. Genetic diver-
sity and relationships in populations of Bordetella spp. J Bacteriol
1986;166:230–7.
[13] van der Zee A, Mooi F, Van Embden J, Musser J. Molecular evo-
lution and host adaptation of Bordetella spp.: phylogenetic analysis
usingmultilocusenzymeelectrophoresisandtypingwiththreeinsertion
sequences. J Bacteriol 1997;179:6609–17.
[14] Schouls LM, van der Heide HG, Vauterin L, Vauterin P, Mooi FR.
Multiple-locus variable-number tandem repeat analysis of Dutch Bor-
detella pertussis strains reveals rapid genetic changes with clonal
expansion during the late 1990s. J Bacteriol 2004;186:5496–505.
[15] Weber C, Boursaux-Eude C, Coralie G, Caro V, Guiso N. Polymor-
phism of Bordetella pertussis isolates circulating for the last 10 years
in France, where a single effective whole-cell vaccine has been used
for more than 30 years. J Clin Microbiol 2001;39:4396–403.
[16] Heininger U, Frei R, Cherry JD, Stehr K. Comparison of pulsed field
gelelectrophoresispatternsofBordetellapertussisisolatesfromunvac-
cinated children with severe or mild pertussis. Pediatr Infect Dis J
2004;23:211–7.
[17] GrimprelE,BegueP,AnjakI,NjamkepoE,FrancoisP,GuisoN.Long-
term human serum antibody responses after immunization with whole-
cellpertussisvaccineinFrance.ClinDiagnLabImmunol1996;3:93–7.
[18] Guiso N, Begue P, Cohen R. Comparison of pertussis antibody levels
in children up to 5 years of age primed at 2, 3, 4 months and booster
in a second year of life with either DTPa or DTPw based combination
vaccines in France. In: 40th ICAAC. 2000 [abstract 62].
[19] Kodama A, Kamachi K, Horiuchi Y, Konda T, Arakawa Y. Antigenic
divergence suggested by correlation between antigenic variation and
pulsed-field gel electrophoresis profiles of Bordetella pertussis isolates
in Japan. J Clin Microbiol 2004;42:5453–7.
[20] GlismannS,RonneT,TozziA.TheEUVAC-NETproject:creationand
operationofasurveillancecommunitynetworkforvaccinepreventable
infectious diseases. Euro Surveill 2001;6:94–8.
[21] Celentano LP, Massari M, Paramatti D, Salmaso S, Tozzi AE. Resur-
gence of pertussis in Europe. Pediatr Infect Dis J 2005;24:761–5.
[22] Versteegh FG, Weverling GJ, Peeters MF, Wilbrink B, Veenstra-van
Schie MT, van Leeuwen-Gerritsen JM, et al. Community-acquired
pathogens associated with prolonged coughing in children: a prospec-
tive cohort study. Clin Microbiol Infect 2005;11:801–7.
[23] Riffelmann M, Wirsing von Konig CH, Caro V, Guiso N. Nucleic
acid amplification tests for diagnosis of Bordetella infections. J Clin
Microbiol 2005;43:4925–9.
[24] Horby P, Macintyre CR, McIntyre PB, Gilbert GL, Staff M, Hanlon M,
et al. A boarding school outbreak of pertussis in adolescents: value of
laboratory diagnostic methods. Epidemiol Infect 2005;133:229–36.
[25] Versteegh FG, Mertens PL, de Melker HE, Roord JJ, Schellekens JF,
TeunisPF.Age-specificlong-termcourseofIgGantibodiestopertussis
toxin after symptomatic infection with Bordetella pertussis. Epidemiol
Infect 2005;133:737–48.
[26] Ntezayabo B, De Serres G, Duval B. Pertussis resurgence in Canada
largely caused by a cohort effect. Pediatr Infect Dis J 2003;22:22–7.
[27] Greenberg DP. Pertussis in adolescents: increasing incidence brings
attention to the need for booster immunization of adolescents. Pediatr
Infect Dis J 2005;24:721–8.
[28] Gzyl A, Augustynowicz E, Rabczenko D, Gniadek G, Slusarczyk J.
Pertussis in Poland. Int J Epidemiol 2004;33:358–65.

Page 8

K.D. Forsyth et al. / Vaccine 25 (2007) 2634–2642
2641
[29] Klement E, Uliel L, Engel I, Hasin T, Yavzori M, Orr N, et al. An
outbreak of pertussis among young Israeli soldiers. Epidemiol Infect
2003;131:1049–54.
[30] Bisgard KM, Pascual FB, Ehresmann KR, Miller CA, Cianfrini C, Jen-
ningsCE,etal.Infantpertussis:whowasthesource?PediatrInfectDis
J 2004;23:985–9.
[31] Southern J, Andrews N, Burrage M, Miller E. Immunogenicity
and reactogenicity of combined acellular pertussis/tetanus/low dose
diphtheria vaccines given as a booster to UK teenagers. Vaccine
2005;23:3829–35.
[32] Pichichero ME, Rennels MB, Edwards KM, Blatter MM, Mar-
shall GS, Bologa M, et al. Combined tetanus, diphtheria, and
5-componentpertussisvaccineforuseinadolescentsandadults.JAMA
2005;293:3003–11.
[33] Vergara R, Tregnaghi M, Ussher J, Navarro S, Ruttimann R, Potin M,
et al. Reduced-antigen-content-diphtheria–tetanus–acellular-pertussis
and inactivated polio vaccine as a booster for adolescents 10 to 14
years of age. Eur J Pediatr 2005;164:377–82.
[34] HalperinSA.Canadianexperiencewithimplementationofanacellular
pertussisvaccinebooster-doseprograminadolescents:implicationsfor
the United States. Pediatr Infect Dis J 2005;24:S141–6.
[35] Halperin SA, Sweet L, Baxendale D, Neatby A, Rykers P, Smith B,
et al. How soon after a prior tetanus–diphtheria vaccination can one
give adult formulation tetanus–diphtheria–acellular pertussis vaccine?
Pediatr Infect Dis J 2006;25:195–200.
[36] Pichichero ME, Casey JR, Francis AB, Marsocci SM, Murphy M,
Hoeger W, et al. Acellular pertussis vaccine boosters combined
with diphtheria and tetanus toxoid boosters for adolescents: safety
and immunogenicity assessment when preceded by different 5-dose
DTaP/DTwP schedules. Clin Pediatr (Phil) 2006;45:613–20.
[37] Broder KR, Cortese MM, Iskander JK, Kretsinger K, Slade BA,
Brown KH, et al. Preventing tetanus, diphtheria, and pertussis among
adolescents: use of tetanus toxoid, reduced diphtheria toxoid and
acellularpertussisvaccinesrecommendationsoftheAdvisoryCommit-
tee on Immunization Practices (ACIP). MMWR Recomm Rep 2006;
55:1–34.
[38] Heininger U, Cherry JD. Pertussis immunisation in adolescents and
adults—Bordetella pertussis epidemiology should guide vaccination
recommendations. Expert Opin Biol Ther 2006;6:685–97.
[39] Edelman KJ, He Q, Makinen JP, Haanpera MS, Nguyen Tran Minh
N, Schuerman L, et al. Pertussis-specific cell-mediated and humoral
immunity in adolescents 3 years after booster immunization with acel-
lular pertussis vaccine. Clin Infect Dis 2004;39:179–85.
[40] Smith NM, Bresee JS, Shay DK, Uyeki TM, Cox NJ, Strikas RA.
Prevention and control of influenza: recommendations of the Advisory
Committee on Immunization Practices (ACIP). MMWR Recomm Rep
2006;55:1–42.
[41] Lee GM, Lebaron C, Murphy TV, Lett S, Schauer S, Lieu TA. Per-
tussis in adolescents and adults: should we vaccinate? Pediatrics
2005;115:1675–84.
[42] Purdy KW, Hay JW, Botteman MF, Ward JI. Evaluation of strate-
gies for use of acellular pertussis vaccine in adolescents and adults:
a cost–benefit analysis. Clin Infect Dis 2004;39:20–8.
[43] Brody JE. Protected from pertussis? Most likely, you’re not. New York
Times; 2006, February 7.
[44] Altman LK. New booster vaccine urged to fight whooping cough. New
York Times; 2005, July 1.
[45] Ward JI, Cherry JD, Chang SJ, Partridge S, Lee H, Treanor J, et al.
Efficacyofanacellularpertussisvaccineamongadolescentsandadults.
N Engl J Med 2005;353:1555–63.
[46] Le T, Cherry JD, Chang SJ, Knoll MD, Lee ML, Barenkamp S, et al.
Immune responses and antibody decay after immunization of adoles-
cents and adults with an acellular pertussis vaccine: the APERT Study.
J Infect Dis 2004;190:535–44.
[47] Bonhoeffer J, Bar G, Riffelmann M, Soler M, Heininger U. The role
of Bordetella infections in patients with acute exacerbation of chronic
bronchitis. Infection 2005;33:13–7.
[48] Centers for Disease Control and Prevention. ACIP votes to recom-
mend use of combined tetanus, diphtheria and pertussis (Tdap) vaccine
for adults. Available at: http://www.cdc.gov/nip/vaccine/tdap/tdap
adult recs.pdf [accessed February 27, 2006].
[49] Elliott E, McIntyre P, Ridley G, Morris A, Massie J, McEniery J, et
al. National study of infants hospitalized with pertussis in the acellular
vaccine era. Pediatr Infect Dis J 2004;23:246–52.
[50] Mertsola J, Ruuskanen O, Eerola E, Viljanen MK. Intrafamilial spread
of pertussis. J Pediatr 1983;103:359–63.
[51] Floret D. Pediatric deaths due to community-acquired bacterial infec-
tion. Survey of French pediatric intensive care units. Arch Pediatr
2001;8(Suppl. 4):705s–11s.
[52] Van Rie A, Hethcote HW. Adolescent and adult pertussis vaccina-
tion: computer simulations of five new strategies. Vaccine 2004;22:
3154–65.
[53] Centers for Disease Control and Prevention. Hepatitis B vaccina-
tion among high-risk adolescents and adults—San Diego, California,
1998–2001. MMWR Morb Mortal Wkly Rep 2002;51:618–21.
[54] Centers for Disease Control and Prevention. Hepatitis B vaccination
coverage among adults—United States, 2004. MMWR Morb Mortal
Wkly Rep 2006;55:509–11.
[55] Austrailian immunisation handbook, 8th ed. National Health and Med-
ical Research Council; 2003.
[56] Healy CM, Munoz FM, Rench MA, Halasa NB, Edwards KM, Baker
CJ. Prevalence of pertussis antibodies in maternal delivery, cord, and
infant serum. J Infect Dis 2004;190:335–40.
[57] Fischer GW, Ottolini MG, Mond JJ. Prospects for vaccines during
pregnancy and in the newborn period. Clin Perinatol 1997;24:231–49.
[58] Van Rie A, Wendelboe AM, Englund JA. Role of maternal pertussis
antibodies in infants. Pediatr Infect Dis J 2005;24:S62–5.
[59] Elahi S, Buchanan RM, Babiuk LA, Gerdts V. Maternal immunity pro-
vides protection against pertussis in newborn piglets. Infect Immun
2006;74:2619–27.
[60] Hanlon M, Nambiar R, Kakakios A, McIntyre P, Land M, Devine P.
Pertussis antibody levels in infants immunized with an acellular per-
tussiscomponentvaccine,measuredusingwhole-cellpertussisELISA.
Immunol Cell Biol 2000;78:254–8.
[61] Lagos R, Munoz A, Dumas R, Pichon S, Zambrano B, Levine M, et al.
Immunological priming of one dose of inactivated hepatitis A vaccine
given during the first year of life in presence of maternal antibodies.
Vaccine 2003;21:3730–3.
[62] Rowe J, Poolman JT, Macaubas C, Sly PD, Loh R, Holt PG. Enhance-
ment of vaccine-specific cellular immunity in infants by passively
acquired maternal antibody. Vaccine 2004;22:3986–92.
[63] Cherry JD. Pertussis in the preantibiotic and prevaccine era, with
emphasis on adult pertussis. Clin Infect Dis 1999;28(Suppl. 2):
S107–11.
[64] Halperin SA, King J, Law B, Mills E, Willems P. Safety and immuno-
genicity of Haemophilus influenzae-tetanus toxoid conjugate vaccine
given separately or in combination with a three-component acellular
pertussis vaccine combined with diphtheria and tetanus toxoids and
inactivated poliovirus vaccine for the first four doses. Clin Infect Dis
1999;28:995–1001.
[65] Herzig P, Hartmann C, Fischer D, Weil J, von Kries R, Giani G, et
al. Pertussis complications in Germany—3 years of hospital-based
surveillance during the introduction of acellular vaccines. Infection
1998;26:227–31.
[66] de Melker HE, Conyn-van Spaendonck MA, Rumke HC, van Wijn-
gaardenJK,MooiFR,SchellekensJF.PertussisinTheNetherlands:an
outbreak despite high levels of immunization with whole-cell vaccine.
Emerg Infect Dis 1997;3:175–8.
[67] Khalak R, Pichichero ME, D’Angio CT. Three-year follow-up of
vaccine response in extremely preterm infants. Pediatrics 1998;101:
597–603.
[68] Kirmani KI, Lofthus G, Pichichero ME, Voloshen T, D’Angio CT.
Seven-year follow-up of vaccine response in extremely premature
infants. Pediatrics 2002;109:498–504.

Page 9

2642
K.D. Forsyth et al. / Vaccine 25 (2007) 2634–2642
[69] Englund JA, Anderson EL, Reed GF, Decker MD, Edwards KM,
Pichichero ME, et al. The effect of maternal antibody on the serologic
response and the incidence of adverse reactions after primary immu-
nizationwithacellularandwhole-cellpertussisvaccinescombinedwith
diphtheria and tetanus toxoids. Pediatrics 1995;96:580–4.
[70] Pichichero ME, Edwards KM, Anderson EL, Rennels MB, Englund
JA,YergDE,etal.Safetyandimmunogenicityofsixacellularpertussis
vaccines and one whole-cell pertussis vaccine given as a fifth dose in
four- to six-year-old children. Pediatrics 2000;105:e11.
[71] Diez-Domingo J, Delgado JD, Ballester A, Baldo JM, Planelles MV,
Garces M, et al. Immunogenicity and reactogenicity of a combined
adsorbed tetanus toxoid, low dose diphtheria toxoid, five component
acellular pertussis and inactivated polio vaccine in six-year-old chil-
dren. Pediatr Infect Dis J 2005;24:219–24.
[72] ScheifeleDW,HalperinSA,OchnioJJ,FergusonAC,SkowronskiDM.
A modified vaccine reduces the rate of large injection site reactions to
the preschool booster dose of diphtheria–tetanus–acellular pertussis
vaccine: results of a randomized, controlled trial. Pediatr Infect Dis J
2005;24:1059–66.
[73] Nilsson L, Faldella G, Jacquet JM, Storsaeter J, Silfverdal SA, Ekholm
L. A fourth dose of DTPa–IPV vaccine given to 4–6 year old children
in Italy and Sweden following primary vaccination at 3, 5 and 11–12
months of age. Scand J Infect Dis 2005;37:221–9.
[74] Lee GM, Lett S, Schauer S, LeBaron C, Murphy TV, Rusinak D, et
al. Societal costs and morbidity of pertussis in adolescents and adults.
Clin Infect Dis 2004;39:1572–80.
[75] Ward A, Caro J, Bassinet L, Housset B, O’Brien JA, Guiso N. Health
and economic consequences of an outbreak of pertussis among health-
care workers in a hospital in France. Infect Control Hosp Epidemiol
2005;26:288–92.
[76] Scuffham PA, McIntyre PB. Pertussis vaccination strategies for
neonates—an exploratory cost-effectiveness analysis. Vaccine 2004;
22:2953–64.
[77] Tan T, Halperin S, Cherry JD, Edwards K, Englund JA, Glezen P,
et al. Pertussis immunization in the global pertussis initiative North
American region: recommended strategies and implementation con-
siderations. Pediatr Infect Dis J 2005;24:S83–6.