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

334 MCGIRR and FISMAN by guest on May 24, 2018http://pediatrics.aappublications.org/Downloaded from

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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