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Duration of Pertussis Immunity AfterDTaP Immunization: A Meta-analysisAshleigh McGirr, MPH, David N. Fisman, MD, MPH, FRCPC
abstractBACKGROUND AND OBJECTIVES: Pertussis incidence is increasing, possibly due to the introduction ofacellular vaccines, which may have decreased the durability of immune response. We soughtto evaluate and compare the duration of protective immunity conferred by a childhoodimmunization series with 3 or 5 doses of diphtheria-tetanus-acellular pertussis (DTaP).
METHODS: We searched Medline and Embase for articles published before October 10, 2013.Included studies contained a measure of long-term immunity to pertussis after 3 or 5 doses ofDTaP. Twelve articles were eligible for inclusion; 11 of these were included in the meta-analysis. We assessed study quality and used meta-regression models to evaluate therelationship between the odds of pertussis and time since last dose of DTaP and to estimatethe probability of vaccine failure through time.
RESULTS: We found no significant difference between the annual odds of pertussis for the3- versus 5-dose DTaP regimens. For every additional year after the last dose of DTaP, theodds of pertussis increased by 1.33 times (95% confidence interval: 1.23–1.43). Assuming85% vaccine efficacy, we estimated that 10% of children vaccinated with DTaP would beimmune to pertussis 8.5 years after the last dose. Limitations included the statistical modelextrapolated from data and the different study designs included, most of which wereobservational study designs.
CONCLUSIONS: Although acellular pertussis vaccines are considered safer, the adoption of thesevaccines may necessitate earlier booster vaccination and repeated boosting strategies toachieve necessary “herd effects” to control the spread of pertussis.
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
Ms McGirr conceptualized and designed the study, collected the data, performed the analyses, and drafted the initial manuscript; Dr Fisman conceptualized anddesigned the study, analyzed the data, and critically revised and reviewed the manuscript; and both authors approved the final manuscript as submitted.
www.pediatrics.org/cgi/doi/10.1542/peds.2014-1729
DOI: 10.1542/peds.2014-1729
Accepted for publication Nov 17, 2014
Address correspondence to Ashleigh McGirr, MPH, 155 College St, Room 744, Toronto, ON, M5S 3E3, Canada. E-mail: ashleigh.mcgirr@mail.utoronto.ca
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2015 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Ms McGirr’s graduate training is supported by a Doctoral Research Award from the Canadian Institutes for Health Research.
POTENTIAL CONFLICT OF INTEREST: Dr Fisman has received grant funding, honoraria, and unrestricted educational funding from GlaxoSmithKline (GSK), Merck, Novartis,and Sanofi Pasteur for work related to vaccination and from GSK and Sanofi Pasteur for work specifically related to pertussis vaccination strategies; he has alsoreceived honoraria from GSK for expert consultation unrelated to this manuscript. Ms McGirr has indicated she has no potential conflicts of interest to disclose.
PEDIATRICS Volume 135, number 2, February 2015 REVIEW ARTICLE by guest on May 24, 2018http://pediatrics.aappublications.org/Downloaded from
Pertussis, a highly contagious upperrespiratory infection caused byBordetella pertussis, is a poorlycontrolled vaccine-preventabledisease in Canada, despite relativelyhigh vaccine coverage rates.1,2 Diseaseincidence is highest in infants, withmortality rates greatest in infantsyounger than 3 months3; however, theburden of disease among adolescentsand adults has recently increasedconsiderably.3 Although this increasehas been attributed to a multitudeof factors, including aging ofundervaccinated cohorts4 and moresensitive laboratory testing methods,5
recent reports have suggested thatwaning immunity of vaccinatedindividuals may also contribute to theresurgence of pertussis.6–10
Vaccination against pertussis wasintroduced in Canada in 19431
and was associated with a markeddecline in the incidence of pertussis.3
However, small outbreaks of pertussiscontinued to persist with predictableseasonality.4 In 1997–1998, anacellular preparation of pertussisvaccine (diphtheria-tetanus-acellularpertussis [DTaP]) was introduced inCanada. This combination vaccine wasassociated with fewer side effects andhad a better safety profile than thepreviously used diphtheria-tetanus-whole cell pertussis (DTwP)vaccine.11,12 There are currently2 types of acellular preparations licensedfor use. The children’s preparation,DTaP, contains high concentrationsof antigens for diphtheria, tetanus,and acellular pertussis while theadolescent/adult formulation, Tdap,contains high concentrations ofantigens for tetanus, but lowerconcentrations of antigens fordiphtheria and acellular pertussis.1
Recommendations in Canada call forDTaP immunizations at 2, 4, and6 months and between 12 and23 months of age. A childhood boostervaccine (of either DTaP or Tdap)is recommended between ages 4and 6.1,13 Additional boosters foradolescents and adults arerecommended between ages 14 and 16
and once again as an adult.1,14
Although a similar 5-dose DTaP vaccineseries is used in Canada and the UnitedStates, globally there are a wide varietyof DTaP vaccination schedules thatare recommended. In many Europeancountries, a 3-dose DTaP vaccine seriesis offered, often in conjunction witha booster vaccine for school-agedchildren aged 4 to 9 years.15 The3-dose schedule typically recommendsvaccination at 2, 3, and 4 months; 2, 4,and 6 months; or 3, 5, and 11 monthsof age.15 However, despite widespreadimplementation of these differentimmunization programs and associatedlevels of uptake, pertussis persists.
A previous review by Wendelboeet al16 summarized several studiesrelating to the duration of protectiveimmunity conferred by naturalinfection with pertussis, with DTwP,and with DTaP. However, this studywas published in 2005, well before theexistence of much of the currentliterature. In addition, the review didnot include a meta-analysis of the keyresults. Thus, we believe there isa critical need for a systematicliterature review and meta-analysis toevaluate the weight of evidence aboutwaning pertussis immunity fromavailable studies, and to synthesize thisevidence.
Understanding waning immunity andits impact on the disease burden ofpertussis in different age groups iscritical to designing vaccinationprograms to control the spread ofpertussis in the community. Althoughethical issues surround the feasibilityof a randomized controlled trial to
evaluate vaccine-induced waningimmunity, decisions still need to bemade on optimal vaccine strategies,and systematic review and meta-analysis provide a mechanismwhereby such decisions can beinformed by the best available data.Our objectives were to (1) synthesizethe current literature surroundingwaning immunity to pertussis aftervaccination with 3 and 5 childhooddoses of DTaP and (2) estimate theduration of protective immunity topertussis after 3 and 5 doses of DTaPusing meta-analytic techniques.
METHODS
Search Criteria
A literature search was conducted byusing both Medline and Embasedatabases. In consultation witha research librarian at the Universityof Toronto, the search strategyconsisted of key words and medicalsubject headings. Similar terms andsynonyms were combined with an“OR” operator, and these distinctcomponents were linked togetherwith an “AND” operator. Search termsincluded “whooping cough,”“pertussis,” “diphtheria-tetanus-acellular pertussis vaccine,” “time-factors,” “follow-up studies,” “drugefficacy,” “outcome assessment,” and“treatment duration.” The searchstrategies were carried out withoutlimits on October 10, 2013. Theunique search strategies for eachdatabase can be found in Table 1.To ensure completeness, thereference lists of the included studies
TABLE 1 Search Strategies Used in the 2 Different Databases
Database Search Terms
Medline “exp Whooping Cough/ep, im, pc [Epidemiology, Immunology, Prevention & Control]” AND“exp Child/ OR exp Adolescent/” AND “exp Follow-Up Studies/ OR exp Time Factors/ ORexp Immunization Schedule/” AND “exp Diphtheria-Tetanus-Pertussis Vaccine/ad, im, st[Administration & dosage, Immunology, Standards] OR exp Diphtheria-Tetanus-acellularPertussis Vaccines/ad, im, st [Administration & Dosage, Immunology, Standards] OR expPertussis Vaccine/ad, im [Administration& Dosage]”
Embase “exp pertussis/dt, ep, pc [Drug Therapy, Epidemiology, Prevention]” AND “exp diphtheriapertussis tetanus vaccine/dt [Drug Therapy] OR exp pertussis vaccine/dt [Drug Therapy”AND “exp drug efficacy/ OR exp follow up/ OR exp risk assessment/ or exp outcomeassessment/ or exp treatment duration/” AND “child/ OR adolescent”
332 MCGIRR and FISMAN by guest on May 24, 2018http://pediatrics.aappublications.org/Downloaded from
were searched to identify any studiesthat had not been captured by theoriginal literature search.
Study Selection
Relevancy Screen
We reviewed the titles and abstractsof the retrieved articles to assess forrelevancy. All primary researcharticles, not including modelingstudies, that assessed a measure oflong-term immunity (.18 months offollow-up) were included. Studies inwhich pertussis immunity was not anoutcome, studies about diphtheria-tetanus toxoids-pertussis (DTP) orDTwP, studies about strategies toimprove vaccine uptake, and studiesabout adverse events aftervaccination were excluded at thisstage. Abstracts published inlanguages other than English weretranslated by using Google Translateto assess relevancy.17 Agreementbetween the 2 reviewers wasassessed by using the k statistic, andwhere discrepancies on the studyinclusion criteria existed, they wereresolved by discussion andconsensus.
Full-Text Review
The full texts of the studies screenedfor inclusion were read and includedin the review if they met thepredefined full-text inclusion criteria.Specifically, studies that used either3 or 5 childhood doses of DTaP andthat included a measure of time sincevaccination were included. To ensurecompleteness of the literaturesearch, the references of the includedstudies were scanned and relevantarticles were included in thesystematic review.
Quality Assessment
A modified version of the Downs andBlack critical appraisal tool forrandomized and nonrandomizedstudies was used to evaluate thequality of the included studies.18 Thisvalidated and widely used instrumentcontains 27 questions pertaining toreporting, external validity, internal
validity (bias and confounding), andpower.18,19 Each question was scoredas a 0 or 1, except for 1 question(reporting of confounders), whichwas scored from 0 to 2. For thepurpose of this study, the instrumentwas modified by removing thequestion about power because thedifferent study designs each havetheir own sample size requirement.One author (A.M.) analyzed thequality of the included studies. Studyquality categories were assigned onthe basis of the following modifiedDowns and Black scores: excellent(25–27), good (19–24), fair (14–18),and poor (#13).
Data Abstraction
Data from the relevant articles wereabstracted to calculate odds ratiosand SEs comparing the odds ofpertussis for each year since the lastdose of DTaP, where available. Oneyear after the last dose of DTaP was
chosen as the referent because themajority of articles presented theresults this way. When available,measures of association and SEs weretaken directly from the articles, andwhere tabular data existed, measuresof association and corresponding SEswere calculated manually. In 1 case,the referent data were obtained froma previously published article fromthe same research study.20 When theodds ratios were presented by usinga continuous predictor of time sincelast dose of DTaP, the logistic modelwas extrapolated to calculate oddsratios and SEs for each year. Riskratios for the serologic studies werecalculated by comparing the risk ofvaccine failure at the given timeperiod with the risk of vaccine failure1 year post–vaccine administration(assumed to be 18.8% for the 5-doseseries and 17.7% for the 3-doseseries, as per previous studies of thesame cohorts of subjects21,22). Risk
FIGURE 1Flowchart of studies included in the review and meta-analysis.
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TABLE2
Characteristicsof
Included
Studies
Study,year
(source)
Location
StudyDesign
Data
Source(s)
StudyPeriod
StudyPopulation
Vaccine
Schedule
Loss
ofImmunity
“CaseDefinition”
Control
Selection
Statistical
Technique
Covariates
Tartof
etal,
2013
(9)
Minnesota/
Oregon
Cohort
NationalNotifiable
Diseases
Surveillance
System
and
Immunization
Inform
ation
System
s
2000–2010
Childrenborn
between
1998
and2003
with
5recorded
dosesof
DTaP
with
lastbetween
ages
4and6
2,4,6,and
15–18
mo,
4–6y
Confirm
edcasesas
Councilof
State
andTerritorial
Epidem
iologists
Age-specific
populations
ofMinnesota
and
Oregon
Logbinomial
modelof
calculated
incidence
rates
Exam
ined
age
atreceiptof
fifth
dose
but
foundno
difference
Kleinet
al,
2012
(10)
Northern
California
Case-control
Kaiser
Perm
anente
Northern
California
databases
January2006–June
2011
Kaiser
Perm
anente
Northern
California
mem
bers
born
after
1999
withoutTdap
oranypertussisvaccine
betweenfifth
dose
and
PCRtest
date
2,4,6,and
15–18
mo,
4–6y
PCRpositivefor
pertussisandPCR
negativefor
parapertussis
PCRnegativefor
pertussisand
PCRnegativefor
parapertussis
Conditional
logistic
regression
(conditioned
oncalendar
time)
Age(4
to,7,
7t o
,10,
and10
to12),gender,
medical
clinic,race/
ethnicity
Misegades
etal,
2012
(47)
California
Case-control
Reportsto
local
health
departments
andmedical
records
2010–December
2010
Childrenaged
4to
10from
15California
counties(Alameda,Del
Norte,ElDorado,
Fresno,M
adera,Marin,
Merced,
Orange,
Riverside,SanDiego,
SanLuisObispo,Santa
Clara,SantaCruz,
Sonoma,and
Stanislaus)
2,4,6,and
15–18
mo,
4–6y
Probable
and
confirm
edcases
asdefinedby
Councilof
State
andTerritorial
Epidem
iologists,
suspectedcases
asdefinedby
the
California
Departmentof
PublicHealth
3controlspercase,
selected
through
reporting
clinicians
Logistic
regression
accountingfor
clustering
bycountyand
physician
Gender,age
atenrollm
ent,
andageat
fifth
dose
were
assessed
aspotential
confounders,
butnone
foundto
be
Witt
etal,
2012
(59)
Marin
County,
California
Retrospective
cohort
Kaiser
Perm
anente
electronic
medical
records
March 2010–October
2010
Childrenandadolescent
mem
bers
ofKaiser
Perm
anente
Medical
Center
inSanRafael,
California
2,4,6,and
15–18
mo,
4–6yof
age
PCRpositivefor
pertussis
Kaiser
Perm
anente
Medical
Center
populationas
awhole
Stratification
(vaccine
effectiveness
viascreening
method)
None
Zinkeet
al,
2010
(61)
Germ
any
Serologic
follow-up
studyof
RCT
ATPcohort
from
earlierRCT,
StudyB(Zinke
etal,200970 )
July 2006–December
2006
HealthyGerm
anchildren
between7and9yof
agewho
hadbeen
immunized
with
DTPa-
HBV-IPV-Hibvaccinein
previous
RCT
3,4,5,and
12–18
moof
age,4–6yof
age
Anti-PT
$5EL
U/mL
NASeropositivity
rates
None
Zepp
etal,
2007
(60)
Germ
any
Double-blind
crossover
Study
ATPcohort
from
earlierRCT(Knuf
etal,200669 )
Notspecified
Germ
anadolescentswho
wereenrolledand
compliedwith
the
protocol
ofaprevious
RCTwho
hadavailable
immunogenicity
data
3,4,5,and
12–18
moof
age,4–6yof
age
Anti-PT
$5EL
U/mL
Crossoverdesign
Seropositivity
rates
None
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TABLE2
Continued
Study,year
(source)
Location
StudyDesign
Data
Source(s)
StudyPeriod
StudyPopulation
Vaccine
Schedule
Loss
ofImmunity
“CaseDefinition”
Control
Selection
Statistical
Technique
Covariates
Gustafsson
etal,
2006
(41)
Sweden
(except
Gothenburg
andarea)
Surveillance
study
SwedishInstitute
forInfectious
DiseaseControl,
Statistics
Sweden,clinical
chartreview
October
1997–Septem
ber
2004
Swedishchildren
3,5,and12
mo
ofage
Culture
orPCR
confirm
edpertussis,
regardless
ofsymptom
s
NAIncidencerates
None
Lacombe
etal,
2004
(44)
Niakhar,
Senegal
Follow-upof
previous
RCT
Patientspreviously
enrolledin
RCT
(Simondonet
al,
199771)
Patientsenrolled
1990–1995
Newborn
infantsenrolled
inoriginal
RCT
2,4,and6mo
ofage
Coughlasting.20
dwith
bacteriologicor
serologic
confirm
ationor
linktodocumented
case
NALogistic
regression
Intensity
ofexposure,
birthrank,
height-for-
ageindexat
7mo
Olin
etal,
2003
(51)
Sweden
(except
Gothenburg
andarea)
Surveillance
study
SwedishInstitute
forInfectious
DiseaseControl,
Statistics
Sweden,clinical
chartreview
October
1997–Septem
ber
2000
Swedishchildrenborn
betweenJanuary1996
andSeptem
ber2000
3,5,and12
mo
ofage
Culture-or
PCR-
confirm
edpertussis,
regardless
ofsymptom
s
NAIncidencerates
None
Esposito
etal,
2002
(39)
Italy
Serum
antibody
study
Patientsenrolledin
clinicat
Universityof
Bologna
December1999
HealthyItalianchildren5
and6yoldwho
were
born
prem
atureand
given3dosesof
DTaP
asan
infant
3,5,and11
mo
ofage
PositiveELISA(EU/
mL)
foranti-PT,
cutoffvaluenot
specified
NASeropositivity
rates
None
Salmaso,
etal
2001
(55)
Piem
onte,
Veneto,
Friuli-
Venezia
Giulia,and
Puglia,Italy
Follow-upof
previous
RCT
Patientsremaining
under
surveillanceat
stage3of
RCT
(Greco
etal,
199620)
October
1995–October
1998
Newborn
infantsenrolled
inoriginal
RCT
2,4,and6mo
ofage
Laboratory-confirm
edpertussisinfection
andspasmodic
coughlasting
$14
dor
cough
lasting$21
d
NAVaccineefficacy
usingperson-
timeincidence
density
None
Esposito,
etal
2001
(38)
Italy
Serum
antibody
study
Patientsenrolledin
clinicsat
the
Universityof
Palerm
oandthe
Universityof
Bologna
December
1999–January
2000
HealthyItalianchildren5
and6yoldeither
given3dosesof
DTaP
asan
infant
orhad
clinicalpertussisas
aninfant
3,5,and11
mo
ofage
PositiveELISA(EU/
mL)
foranti-PT,
cutoffvaluenot
specified
NASeropositivity
rates
None
ATP,Accordingto
Protocol;D
TPa-HB
V-IPV-Hib,;EL,ELISAunits;ELISA,enzym
e-linkedimmunosorbent
assay;EU,ELISA
units;N
A,notapplicable;anti-PT,pertussisantitoxin;R
CT,randomized
controlledtrial.
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ratios and incident rate ratios wereassumed to approximate odds ratiosaccording to the rare diseaseassumption.23 These odds ratios andcorresponding SEs were enteredmanually into a spreadsheet foranalysis.
Statistical Analysis
All data analysis and statisticalmodeling were performed by using themetafor package in R StatisticalSoftware.24,25 Publication bias wasassessed by using funnel plots withasymmetry between the measures ofassociation and SEs quantified by usingEgger’s test.26 Random-effects modelsusing the DerSimonian-Laird estimatorwere used to pool the results betweenthe included studies onceheterogeneity, as assessed by usingHiggins’ I2 statistic, among theoutcomes was considered.27,28 A meta-regression model using theDerSimonian-Laird estimator was fit tothe data to evaluate the relationshipbetween the odds ratio of pertussis andtime since last DTaP vaccination.27 Toevaluate the importance of the numberof doses and the type of pertussis“diagnosis” (ie, clinical versusserologic), we included these variablesin the meta-regression model andevaluated the change in the estimate ofthe main effect. Using a range ofvaccine efficacy estimates from theUnited States and Canada we were ableto anchor the probability of vaccinefailure for the first year since DTaPseries completion.1,29,30 We assumedthat the probability of vaccine failurefollowed an exponential distribution,where the probability of immunity atsome time t was P(I)t =VE(exp[2 lt]),with VE being the efficacy ofvaccination during the initial periodafter series completion, and l
representing the rate of vaccine failure.Under this scheme, the mean durationof immunity among those who initiallyrespond to the vaccine is 1/l. With therare disease assumption, the predictedodds ratios from the meta-regressionwere assumed to approximate riskratios, allowing for the creation of
functions of probability of vaccinefailure through time.
RESULTS
Included Studies in Review
Of the 389 potentially relevantarticles identified through theliterature search, 339,10,31–61
underwent full-text review. Agreementbetween the independent reviewerswith respect to the title/abstract scanwas fair (k = 0.61). Six9,10,47,59–61 ofthese studies fit the 5-dose eligibilitycriterion to be included in this reviewand 6 studies38,39,41,44,51,55 met the3-dose criterion (Fig 1). None of thearticles published in languages otherthan English met inclusion criteria. Noadditional articles were identifiedthrough hand-searches of referencelists.
Of the included studies, 2 were case-control studies,10,47 2 were cohortstudies,9,59 3 were follow-up studiesfrom previously conductedrandomized controlled trials,44,55,61
2 were surveillance studies,41,51
2 were serum antibody studies,38,39 and1 was a double-blind crossover study60
(Table 2). Despite searching withoutlimits on publication dates, theincluded studies with 5 doses of DTaPwere all published between 2010 and2013 and the included studies with3 doses of DTaP were all publishedbetween 2001 and 2006. Themajority of the 5-dose includedstudies were conducted in the UnitedStates (California,10,47,59 Minnesota,9
and Oregon9), with the remaining5-dose studies conducted in citiesacross Germany.60,61 Almost all ofthe 3-dose studies were conductedin Europe (Italy38,39,55 andSweden41,51), although 1 study wasconducted in Senegal.44
The studies included in the analysisdiffered in terms of defining loss ofimmunity. The clinical studiescompared the incidence of pertussisfor every year since the vaccine wasadministered with the use of variouscase definitions of pertussis. Two of TA
BLE3
Quality
Assessmentof
theIncluded
Studies
Downs
andBlack
Criteria
Possible
Points
Study,year
(source)
Esposito
etal,
2001
(38)
Esposito
etal,
2002
(39)
Gustafsson
etal
(41)
Kleinet
al(10)
Lacombe
etal
(44)
Misegades
etal
(48)
Olin
etal
(51)
Salmasoet
al(55)
Tartof
etal
(9)
Witt
etal
(59)
Zepp
etal
(60)
Zinkeet
al(61)
Reporting
118
76
1010
95
76
44
7External
validity
31
13
22
13
11
31
1Internal
validity
Bias
76
54
54
43
45
55
3Confounding
63
33
45
33
34
34
2Total
2718
1616
2121
1714
1516
1514
13Quality
rating
Fair
Fair
Fair
Good
Good
Fair
Fair
Fair
Fair
Fair
Fair
Poor
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the studies used polymerase chainreaction (PCR) laboratory methodsonly,10,59 2 of the studies used cultureor PCR methods regardless ofsymptoms,41,51 1 used a cough lasting.20 days with bacteriologic orserologic confirmation or link toa documented case,44 and 1 usedlaboratory confirmed pertussisinfection and spasmodic cough lasting$14 days or cough lasting $21days.55 The remaining 2 studies usedthe Council of State and TerritorialEpidemiologists–confirmed casedefinition9 and the confirmed/probable case definition inconjunction with the suspected casedefinition from the CaliforniaDepartment of Public Health.47
The serologic studies compared thenumber of individuals who had levels ofimmunologic markers above a certainthreshold for every year since thevaccine was administered. Two of thestudies explicitly defined seropositivityas anti-PT ($5 EL U/mL),60,61 whereas2 defined seropositivity as positivity byusing an enzyme-linked
immunosorbent assay without a cleardescription of cutoff.38,39 These varyingclinical and serologic case definitions ofpertussis likely contributed to theobserved heterogeneity between thestudies (Table 2).
Quality Assessment
The included studies had a diverserange of quality. Two studies wereassessed as “good” quality,10,44
9 studies were assessed as “fair”quality,9,38,39,41,47,51,55,59,60 and1 study was assessed as “poor”quality61 (Table 3). Of the4 categories assessed with themodified Downs and Black ratingscale, reporting showed the biggestvariability in scores. Most commonly,studies scored poorly because ofundefined study aims, vague or nodescription of the study participantcharacteristics, and no mention ofparticipants lost to follow-up.
Included Studies in Meta-analysis
One study59 was excluded from themeta-analysis because of
contamination of the measure ofassociation. The study participantswere classified as being up-to-datefor age of immunization according tothe US Centers for Disease Controland Prevention Guidelines but weregrouped into age categories of 2 to7 years of age, 8 to 12 years of age,and 13 to 18 years of age. Because theCenters for Disease Control andPrevention recommends a boosterimmunization at 10 to 12 years ofage, some of the participants in the8- to 12-year age category and most ofthe participants in the 13- to 18-yearage category would have had theadolescent booster vaccine already.The authors highlighted this asa potential reason for the lowerattack rates of pertussis in the olderage groups. To ensure comparabilityof the estimates, the results from thisstudy were removed from the meta-analysis.
The study by Klein et al10 contained2 control groups (PCR-negativecontrols and matched controls) andused them to calculate 2 different
FIGURE 2Funnel plots and P values from Egger’s test evaluating the risk of publication bias for the odds ratios of pertussis for years 2 to 6 after the last dose ofDTaP. OR, odds ratio.
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odds ratios for pertussis. Because the2 control groups were compared withthe same case group, we used onlythe estimates for the PCR-negativecontrols because the authors believed
this measure contained the leastamount of bias. The study by Tartofet al9 contained 2 distinct studypopulations (Minnesota and Oregon)with separate measures of
association. Similarly, the study bySalmaso et al55 contained 2 studypopulations: 1 that was vaccinatedwith a DTaP vaccine made bySmithKline Beecham and the otherthat was vaccinated with a DTaPvaccine made by Chiron-Biocine. Assuch, we included both sets of resultsfrom each of these studies in theanalysis, for a total of 13 distinctestimates.
Meta-analysis Results
Publication Bias
There was no evidence of publicationbias for any of the years since the lastDTaP vaccine, with all funnel plotsshowing symmetry between themeasure of association and the SEaccording to Egger’s test (Fig 2).
Pooled Effects
Summary measures of associationalong with the observed Higgins’I2 measure of heterogeneity for everyyear since the last dose of DTaP areshown in Fig 3. The pooled oddsratios of pertussis were found toincrease with the time since the lastdose of DTaP, suggestingconsiderable waning immunity.Between-study heterogeneity wasalso found to increase for every yearsince the last dose of DTaP, with year2 showing moderate heterogeneityand years 3 to 6 showing substantialheterogeneity (Fig 4). This increasingheterogeneity in effect estimates asthe time since last DTaP vaccineincreases is likely due toa compounding effect of theheterogeneity in the study designs.
Meta-regression
The results from the final meta-regression model suggest that theodds of pertussis for every year sincethe last dose of DTaP was estimatedto increase by a multiple of 1.33 (95%confidence interval: 1.23–1.43)(Table 4, Fig 5). Because the oddsratio associated with the years sincelast DTaP variable did not changeappreciably when the number ofdoses variable was included, there is
FIGURE 3Forest plots showing the pooled odds ratios of pertussis for years 2 to 6 versus year 1 after the last doseof DTaP. Pooled odds ratios were calculated by using random-effects models with the DerSimonian-Lairdestimator. CB, Chiron-Biocine vaccine; I2, Higgins’ I2 measure of heterogeneity; MN, Minnesota; (OR),Oregon; OR, odds ratio; RE, random effects model; SB, SmithKline Beecham.
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evidence to suggest that the durationof protective immunity from DTaP isthe same for those given 3 or 5 dosesof the vaccine (Table 4). Similarly,when the definition of loss ofimmunity variable was included, theodds ratio again did not changeappreciably, suggesting that theduration of protective immunity fromDTaP is the same for the studiesmeasuring clinical markers of
pertussis and those measuringserologic markers (Table 4). However,the addition of these variableschanges the absolute risk of pertussis,with a higher risk of pertussis in thestudies examining the 5-dose vaccineseries and a lower risk of pertussis inthe studies that used serologicoutcomes (Table 4).
Using the above estimated odds ratioof 1.33, we created curves of the
predicted probability of vaccinefailure through time (Fig 6). From thisanalysis, the average duration ofvaccine protection from DTaP is∼3 years, assuming 85% vaccineefficacy. With this loss of protection, wepredict that only 10% of the childrenvaccinated with DTaP would beprotected by 8.5 years after the lastdose, but this could be higher orlower with alternate assumptionsregarding vaccine efficacy.
DISCUSSION
Understanding the duration ofprotective immunity conferred bya vaccine is critical to thedevelopment of immunizationguidelines and programs. To ourknowledge, this is the first systematicreview and meta-analysis of theduration of protective immunity topertussis after routine childhoodimmunization with DTaP. Ourfindings suggest that the odds ofpertussis increase by 1.33 times(95% confidence interval: 1.23–1.43)for every additional year since thelast dose of DTaP. With this loss ofprotection, we predict that only 10%of the children vaccinated with DTaPwould be protected by 8.5 years afterthe last dose, assuming an initialvaccine efficacy of 85%.1,30
Although we found that the odds ofpertussis for every year since the lastdose of DTaP did not depend on thenumber of doses, we did find thatthere was a greater absolute risk ofpertussis in the studies examining5 doses of DTaP and a lower absoluterisk of pertussis in the serologicstudies. Because the participants inthe 5-dose studies were older, onaverage, than the participants in the3-dose studies, this finding mayhighlight the increased risk ofpertussis in older age groups.Although infants ,1 year remain athighest risk of pertussis, recentsurveillance reports from the UnitedStates and Canada indicate that agegroups with the next highestincidence of pertussis include 7- to
FIGURE 4Relationship between heterogeneity between studies (as measured with Higgins’ I2) and time sincelast DTaP. Higgins’ I2 is a measure of the total variation between studies due to heterogeneity.28
TABLE 4 b Coefficients and Corresponding SEs for the 3 Different Meta-regression Models
Intercept Years Since Last DTaP 5 Doses Serologic Study
Model 1 0.321 (0.14) 0.289 (0.06)Model 2 20.053 (0.14) 0.26 (0.05) 0.719 (0.14)Model 3 20.003 (0.11) 0.2862 (0.04) 0.695 (0.11) 20.728 (0.16)
SEs are shown in parentheses. b coefficients represent the log of the odds ratio for every unit increase in the predictorvariable.
FIGURE 5Odds ratios of pertussis for each year since the last dose of DTaP. The circles, inversely weighted bystudy variability, represent the odds ratios calculated from each of the studies examining 5 doses ofDTaP, whereas the inverted triangles represent the odds ratios from the studies examining 3 doses ofDTaP included in the meta-analysis. The black line represents the fitted meta-regression curve ac-counting for the effects of time. In this meta-regression curve, dose type was assumed to be constant at5 doses and the diagnosis type was assumed to be constant at “clinical.” MN, Minnesota; OR, Oregon.
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10-year-olds (United States) and10- to 14-year-olds (Canada).62,63 Thelower absolute risk of pertussis in thestudies examining serologic outcomesmay be due to the sensitivity of thesetesting methodologies and theircorresponding anti-PT (pertussisantitoxin) cutoff levels.
It is important to highlight thelimitations of studies included in thisreview. Most studies were observationalin nature,9,10,38,39,41,47,51,59 allowingfor biases and confounding to distortmeasures of association. Although3 studies adjusted for potentialconfounders of interest (age, gender,race/ethnicity, age at fifth dose ofDTaP, medical clinic; Table 2),9,10,47
others did not, which may havecontributed to over- orunderestimates of the duration ofprotective immunity. Case-ascertainment bias could haveaffected individual study results:where nasopharyngeal swabs werenecessary for confirmation of the casedefinition of pertussis,9,10,41,44,47,51,59
physicians may have been more likelyto test sicker or more medicallycomplex patients due to the invasivenature of the procedure, which couldalter estimates of effect. One of thestudies specifically addressed thisconcern and implementedstandardized procedures forcollecting nasopharyngeal swabs forongoing coughs, regardless of otherclinical characteristics.55 Serologicfollow-up studies38,39,60,61 wouldnot be affected by this type of
case-ascertainment bias, but allserologic follow-up studies38,39,60,61
were funded by vaccine companiesproducing DTaP, potentially inducingbiases of another nature.
As with all systematic reviews, thisstudy had a number of limitations.Primarily, the follow-up periods forthe studies included in the meta-analysis ranged from 2 to 6 years,limiting estimates to this relativelybrief period. We extrapolated meta-regression results because longer-duration studies were not identified.Although we believe this assumptionwas necessary, it nonethelesspresents a limitation in theinterpretation of the results. Inaddition, we found considerablebetween-study heterogeneity,possibly an artifact of varying casedefinitions, study designs, and studypopulations. Third, the 3- and 5-doseseries each included differentdosing schedules (Table 2), whichmay have added to the observedheterogeneity.
However, this systematic review andmeta-analysis is the first of its kind tosynthesize the information andprovide a credible estimate on theduration of vaccine-inducedimmunity to pertussis. The reviewmethods were robust and captureda wide range of studies in multiplelanguages and countries ofpublication. Although translation withthe use of Google Translate isimperfect, it allowed us to determinecitation relevance for non-English
studies, thereby reducing thepotential for publication bias.26 Bysearching multiple databases and thereferences of included studies, we areconfident that the search captured allrelevant published studies, and wefound no evidence for publicationbias using Egger’s test and analysis ofthe funnel plots (Fig 2).
The results from this meta-analysishave important policy implications,mainly surrounding boostingstrategies for adolescents to ensurethat “herd effects” of pertussis aremaintained. Although an adolescentTdap booster is offered in Canada, itis recommended for teenagers aged14 to 16 years,1 which may be toolate and leave those aged 10 to14 years susceptible to pertussis.The adolescent Tdap booster isrecommended for youth between10 and 12 years of age in the UnitedStates and in many Europeancountries,15,64 which may representmore appropriate timing.
In addition, the results from thisanalysis have implications forrepeated pertussis vaccinations inadults. Previous research hashighlighted the importance of repeatTdap immunization for eachpregnancy.65 It has also beensuggested that a decennial boosterstrategy with Tdap may be aneffective and cost-effective way tocontrol the spread of pertussis amongadults.66–68 Although the risk ofpertussis infection may be lower inadults, assuming waning immunity toTdap is similar to waning immunityto DTaP, repeated booster vaccineswill be necessary to maintaina population with high levels ofvaccine coverage for pertussis.
Our findings also provideepidemiologists and mathematicalmodelers with credible data inputsfor modeling studies. The weight ofthe evidence suggests that theaverage duration of protectiveimmunity to pertussis after the fifthdose of DTaP is ∼3 to 4 years, a keyparameter in many studies evaluating
FIGURE 6Estimated probability of vaccine failure for different levels of vaccine efficacy.
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vaccination strategies and theireconomic impact. However, thisestimate of the probability of vaccinefailure is sensitive to the initialvaccine efficacy. The parameterizationof the function can be modified togenerate predictive values of durationof protection for different levels ofvaccine efficacy.
In summary, we performeda systematic literature review tounderstand the relationship betweenthe risk of pertussis and time sincepertussis vaccination. We foundevidence of waning immunity andestimated that the average durationof vaccine protection from DTaP is∼3 years, assuming 85% vaccineefficacy. With this loss of protection,we predict that only 10% of thechildren vaccinated with DTaP wouldbe protected by 8.5 years after thelast dose. With a preschool boosteroffered for children aged 4 to 6 years,our findings suggest that very fewchildren over age 10 would beprotected against pertussis, signalingthe need for an earlier adolescentTdap booster in Canada.
ACKNOWLEDGMENTS
We thank Carla Hagstrom for her helpin creating the literature searchstrategy.
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DOI: 10.1542/peds.2014-1729 originally published online January 5, 2015; 2015;135;331Pediatrics
Ashleigh McGirr and David N. FismanDuration of Pertussis Immunity After DTaP Immunization: A Meta-analysis
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Ashleigh McGirr and David N. FismanDuration of Pertussis Immunity After DTaP Immunization: A Meta-analysis
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