Pediatrics 2015 Tiwari Peds.2014 2291

First Pertussis Vaccine Dose andPrevention of Infant MortalityTejpratap S.P. Tiwari, MDa, Andrew L. Baughman, PhD, MPHb, Thomas A. Clark, MD, MPHa

abstractBACKGROUND: American infants are at highest risk of severe pertussis and death. We investigatedthe role of $1 pertussis vaccinations in preventing pertussis-related deaths and risk markersfor death among infants aged ,42 days.

METHODS: We analyzed characteristics of fatal and nonfatal infant pertussis cases reportednationally during 19912008. Infants were categorized into 2 age groups on the basis ofeligibility to receive a rst pertussis vaccine dose at age 6 weeks; dose 1 was considered validif given $14 days before illness onset. Multivariable logistic regression was used to estimatethe effect of $1 pertussis vaccine doses on outcome and risk markers.

RESULTS: Pertussis-related deaths occurred among 258 of 45 404 cases. Fatal and nonfatalcases were conrmed by culture (54% vs 49%) and polymerase chain reaction (31% vs27%). All deaths occurred before age 34 weeks at illness onset; 64% occurred before age 6weeks. Among infants aged $42 days, receiving $1 doses of vaccine protected againstdeath (adjusted odds ratio [aOR]: 0.28; 95% condence interval [CI]: 0.110.74),hospitalization (aOR: 0.69; 95% CI: 0.630.77), and pneumonia (aOR: 0.80; 95% CI:0.680.95). Risk was elevated for Hispanic ethnicity (aOR: 2.28; 95% CI: 1.363.83) andAmerican Indian/Alaska Native race (aOR: 5.15; 95% CI: 2.3711.2) and lower forrecommended antibiotic treatment (aOR: 0.28; 95% CI: 0.160.47). Among infantsaged ,42 days, risk was elevated for Hispanic ethnicity and lower with recommendedantibiotic use.

CONCLUSIONS: The rst pertussis vaccine dose and antibiotic treatment protect against death,hospitalization, and pneumonia.

WHATS KNOWN ON THIS SUBJECT: Few studieshave established the protective efcacy of 1 to 3primary doses of diphtheria-tetanus-whole-cellpertussis (DTwP)/diphtheria-tetanus-acellularpertussis (DTaP) vaccines against pertussis,hospitalization, or pertussis complications ininfants. However, vaccine effectiveness againstinfant pertussis death has not been previouslyreported.

WHAT THIS STUDY ADDS: This is the rst study toreport the protective role of $1 DTwP/DTaPdoses among vaccine-eligible infants aged $6weeks against death, hospitalization, andcomplications from pertussis. It describes riskmarkers for death among vaccine-ineligibleinfants aged ,6 weeks.

aMeningitis and Bacterial Vaccine Preventable Diseases Branch, Division of Bacterial Diseases, National Centerfor Immunization and Respiratory Diseases, and bDivision of Global HIV/AIDS, Center for Global Health, Centers forDisease Control and Prevention, Atlanta, Georgia

Dr Tiwari conceptualized, designed, analyzed, and drafted the initial manuscript and revised themanuscript; Dr Baughman conceptualized, designed, planned, and performed statistical analysesand reviewed the manuscript; Dr Clark conceptualized, designed, and reviewed the initialmanuscript and revised the manuscript; and all authors approved the nal manuscript assubmitted.

The ndings and conclusions in this study are those of the authors and do not necessarilyrepresent the views of the Centers for Disease Control and Prevention.

www.pediatrics.org/cgi/doi/10.1542/peds.2014-2291

DOI: 10.1542/peds.2014-2291

Accepted for publication Mar 19, 2015

Address correspondence to Tejpratap S.P. Tiwari, MD, Centers for Disease Control and Prevention,NCIRD/DBD/MVPD Branch, Mail Stop C-25, 1600 Clifton Rd, NE, Atlanta, GA 30333. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright 2015 by the American Academy of Pediatrics

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Pertussis causes signicant morbidityand deaths, particularly amongunvaccinated infants.15 The trend inpertussis infant morbidity hasincreased steadily since 1977,68 andthe fatality rate increased at anaverage 9% annually during the1990s, with Hispanics beingoverrepresented compared with thegeneral population.2 Most deathsoccurred in infants who were eitherage-ineligible to commence theroutine childhood immunizationseries at 2 months of age withcombined diphtheria and tetanustoxoids and either whole-cellpertussis (wP) or acellular pertussis(aP) vaccines (diphtheria-tetanus-whole-cell pertussis [DTwP]/diphtheria-tetanus-acellular pertussis[DTaP]) or had received ,3 DTwP/DTaP doses by age 6 months.2

Before 1997, wP vaccines were usedexclusively for the primary childhoodseries but are now unavailable in theUnited States. In 1997, the AdvisoryCommittee on ImmunizationPractices (ACIP) recommended thataP vaccines be used in the primarychildhood series,9 and aP vaccineshave now completely replaced wPvaccines. Licensed aP vaccines maycontain 2 to 5 pertussis antigens.9,10

A licensed monovalent DTaP productwas used from 1998 to 2000.Acellular vaccines with $3 antigeniccomponents showed higher efcacythan 1- or 2-component vaccines andmatched the protection afforded bywP vaccines.11

The ACIP recommends that childrenreceive 5 doses of DTaP vaccine atages 2, 4, 6, 15 to 18 months and at 4to 6 years of age.12 National coveragerates with 3 doses of DTwP/DTaPvaccines by 6 months of age weresustained at .90% over the past 2decades.13 In many countries, DTwP/DTaP vaccination routinely starts at 6weeks of age. Studies haveestablished the protective efcacy ofDTwP/DTaP vaccines againstpertussis,14,15 hospitalization,1,16 orpertussis complications in infants15

when 1 to 3 doses are administeredby 6 months of age.1417 However, theprotective role of each vaccine doseagainst death has not been reported.We evaluated the role of $1 DTwP/DTaP vaccinations in preventingdeaths, hospitalizations, andcomplications from pertussis amonginfants aged $6 weeks and describerisk markers for fatal pertussisamong infants aged ,6 weeks whowere age-ineligible for vaccination.

METHODS

An infant was dened as a child aged,365 days. We reviewed allconrmed or probable cases ofnonfatal and fatal infant pertussiswith disease onset from 1991through 2008 reported to theNational Notiable DiseasesSurveillance System (NNDSS) and theCenters for Disease Control andPrevention. The NNDSS is a passivereporting surveillance system that isdependent on electronically reportedcases from all states every week18.Since 1990, the Council for State andTerritorial Epidemiologists deneda clinically compatible case as anillness with cough lasting for $2weeks plus 1 classic pertussissymptom (ie, paroxysms, whoop, orposttussive vomiting) and withoutany other cause. Clinically compatiblecases were reported as probablecases. A clinically compatible casewas classied as conrmed ifBordetella pertussis was isolated byculture from a nasopharyngeal swabor if epidemiologically linked toa culture-conrmed case. In 1995, thecase denition for a conrmed casewas expanded to include cases withacute cough of any duration fromwhich B pertussis was isolated. In1997, the polymerase chain reaction(PCR) test was also accepted aslaboratory diagnostic test forconrmation in a clinicallycompatible case. However, a coughillness of ,2 weeks duration andwith a positive PCR test was classiedas a probable case.19 For this study,

all probable and conrmed fatal andnonfatal infant pertussis cases wereincluded as reported. We did notascertain case denitions byconrming minimum duration ofcough or presence of a pertussissymptom. Fatal cases were veriedwith state and local healthdepartments by using pertussis caseand death investigation worksheets,death certicates, available hospitalmedical records.

Statistical Analysis

Characteristics of fatal cases werecompared with those of nonfatalcases by using bivariate analysis.Characteristics included year ofdisease onset, date of birth, age,gender, race, ethnicity (reportablefrom 1995), state of residence,vaccination history (pertussis vaccinedoses received), vaccine type (wP oraP), symptoms and signs (paroxysmalcough, whoop, posttussive vomiting,and apnea), complications(hospitalizations, pneumonia,encephalopathy, and seizures),antibiotic treatment (a macrolide orco-trimoxozole), and method oflaboratory conrmation (eg, cultureor PCR). States of residence weregrouped into regions (South, West,Northeast, and Midwest) as dened inthe US census.20 A case wasconsidered as treated witha recommended antibiotic ifa macrolide (erythromycin,clarithromycin, or azithromycin) orco-trimoxozole was given during thecourse of illness.21 We evaluated theassociation between eachcharacteristic and fatal pertussis byPearsons x2 test and also estimatedodds ratios (ORs) and 95%condence intervals (CIs). The casefatality rate (CFR) was calculated asfollows: (number of infant pertussisdeaths/total number of infantpertussis cases) 3 100.

The rst pertussis vaccine dose isroutinely administered from 56 days(8 weeks) of age.12 However, thecurrent ACIP recommendation allowsfor the rst dose to be administered

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as early as 6 weeks of age,particularly during outbreaks.12,22

The timing of the rst dose wasconsidered to be valid if it wasreceived $42 days after birth. Thetiming of the second and thirdpertussis vaccine doses wereconsidered valid if they met theminimum age criteria foradministering each respective dose(10 weeks for dose 2, 14 weeks fordose 3) and a minimum interval of 4weeks between the 3 doses.22

Because protection due to vaccinationis unlikely to start from the day ofvaccination, for our primary analysiswe considered a dose as beingeffective if it was administered $14days before the illness-onset date.14

The data were analyzed separately forinfants aged ,42 days who wereineligible to receive any dose ofvaccine and for infants aged $42days who were eligible to receive atleast 1 dose of vaccine before the dateof onset of disease. In addition, datawere separately analyzed for infantswho were between 56 and 90 days ofage and eligible to routinely receivetheir rst dose of vaccine under theroutine childhood immunizationschedule. We also investigated theeffect of vaccine type (wP or aP) onfatal outcome.

We performed multivariable analysisto select independent variables forinclusion in a logistic regressionmodel using a backward-eliminationprocedure. Candidate independentvariables included age at onset ofillness, gender, race, ethnicity, regionof residence, recommendedantibiotics during course of illness,and number of valid doses ofpertussis vaccinations before illnessonset. Age at onset (days) was treatedas a continuous variable for modelparsimony and was included withethnicity in every model irrespectiveof its statistical signicance. Separateanalyses were performed for vaccine-ineligible infants aged ,42 days,vaccine-eligible infants aged $42days, and infants aged 56 to 90 days.

Last, we estimated the burden of fatalpertussis cases that could potentiallybe averted by timely vaccination withthe rst dose administered routinelyat 56 to 90 days, and as early as 42days of age.

Because not all reported cases werelaboratory-conrmed and may haveincluded false-positive reports, weret multivariable models for casesthat were laboratory-conrmedeither by culture or PCR. Last, weperformed multivariable analysisusing 4 pertussis complications(hospitalization, pneumonia,encephalopathy, and seizures) asindependent outcomes in a similarmanner as for fatal outcome. Allanalyses were performed by usingSAS software, version 9.3.23 (SASInstitute, Cary, NC).

RESULTS

From 1991 through 2008, pertussis-related deaths had occurred in 258(0.57%) of 45 404 reported infantcases. In the bivariate analysis, anincreased odds of a fatal outcome wasshown in cases with Hispanicethnicity, American Indian/AlaskaNative race, southern region ofresidence, apnea, and pertussis-associated complications; a lowerodds of fatal outcome was associatedwith cases with paroxysmal cough,whoop, or treatment witha recommended antibiotic (Table 1).The CFR among Hispanic infants wassignicantly higher than in non-Hispanic infants (1.26% vs 0.75%)(Table 1), even after the analysis wasrestricted to the period 19952008when race/ethnicity was reportable.All fatal cases and 90% of nonfatalcases occurred among infants beforeage 34 weeks at illness onset (Fig 1).The CFR declined with increasing age,from 2.36% at age 1 week to 0.28% atage 12 weeks (Fig 1B), and wassimilar among boys and girls (0.53%vs 0.62%; P = .21).

Among infants aged ,42 days of age(Table 2), the odds of a fatal outcomedecreased with increasing weeks of

age (P , .01) and was higher forinfants with Hispanic than for thosewith non-Hispanic ethnicity (OR:1.46; 95% CI: 1.072.01; P = .02) andhigher among cases from the South(OR: 2.31; 95% CI: 1.314.07) andWest (OR: 1.78: 95% CI: 1.013.15)regions compared with those fromthe Northeast (referent). Amonginfants aged $42 days (Table 2), theodds of a fatal outcome decreasedwith each increasing week of age (P,.01) and was higher for infants withHispanic compared with those withnon-Hispanic ethnicity (OR: 1.64;95% CI: 1.072.50) and for AmericanIndian/Alaska Native race (OR: 3.7;95% CI: 1.777.75); however,geographic region of residence wasnot associated with fatal pertussis.

Among infants aged $42 days,vaccination data were known for 91(99%) cases and 15 291 (45%) ofnonfatal cases; vaccination status wasunknown for 1 fatal case and 18 807nonfatal cases. When compared withno vaccine dose, the receipt of $1pertussis vaccine doses was stronglyprotective against fatal pertussis (OR:0.17; 95% CI: 0.080.36) (Table 2).The protective effect persisted in oursensitivity analyses, which assumedthat all cases with unknownvaccination status were eithervaccinated (OR: 0.04; 95% CI:0.020.09) or unvaccinated (OR: 0.50;95% CI: 0.241.03) (P = .06)(Table 2).

Multivariable Analysis

Among age-eligible infants (age $42days), the receipt of $1 pertussisvaccine doses was associated witha 72% decrease in the estimatedrelative risk of fatal pertussis(adjusted OR [aOR]: 0.28; 95% CI:0.110.74) after adjusting for age atonset, Hispanic ethnicity, race, andtreatment with a recommendedantibiotic (Table 3). The associationstrengthened (aOR: 0.20; 95% CI:0.060.68) when only culture- orPCR-conrmed cases were includedin the model. No fatal case but 2638nonfatal cases had unknown

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TABLE 1 Characteristics of All Fatal and Nonfatal Pertussis Cases in Infants: United States, 19912008

Characteristic Fatal Cases, n (%) Nonfatal Cases, n (%) CFRa Pb OR (95% CI)

Total 258 (100) 45 146 (100) 0.57Gender

Male 121 (46.9) 22 780 (50.8) 0.53 .21 1.00 (Referent)Female 137 (53.1) 22 039 (49.2) 0.62 1.17 (0.921.50)Unknown, n, % missing 0, 0 327, 0.7

RaceWhite 195 (82.3) 20 707 (78.2) 0.93 ,.01 1.00 (Referent)Black 25 (10.5) 4344 (16.4) 0.57 0.61 (0.400.93)American Indian/Alaska Native 13 (5.5) 689 (2.6) 1.85 2.00 (1.143.53)Asian/Pacic Islander 4 (1.7) 738 (2.8) 0.54 0.58 (0.211.55)Other or unknown, n, % missing 21, 8.1 18 668, 41.4

EthnicityHispanic 111 (45.1) 8701 (32.8) 1.26 ,.01 1.69 (1.312.17)Non-Hispanic 135 (54.9) 17 860 (67.2) 0.75 1.00 (Referent)Unknown, n, % missing 12, 4.7 18 585, 41.2

RegionNortheast 25 (9.7) 7083 (15.7) 0.35 ,.01 1.00 (Referent)Midwest 52 (20.2) 11 599 (25.7) 0.45 1.27 (0.792.05)South 92 (35.7) 12 154 (26.9) 0.75 2.14 (1.383.34)West 89 (34.5) 14 310 (31.7) 0.62 1.76 (1.132.75)

DiagnosisCulture 136 (53.8) 14 403 (49.2) 0.94 .03 1.00 (Referent)PCR 79 (31.2) 8017 (27.4) 0.98 1.04 (0.791.38)Epidemiologic link 9 (3.6) 1229 (4.2) 0.73 0.78 (0.391.53)DFA 28 (11.1) 5507 (18.8) 0.51 0.54 (0.360.81)Serology 1 (0.4) 114 (0.4) 0.87 0.93 (0.136.70)Unknown, n, % missing 5, 1.9 15 876, 35.2

SymptomsAny coughYes 255 (99.6) 35 936 (99.8) 0.70 .64 0.64 (0.094.60)No 1 (0.4) 90 (0.2) 1.10 1.00 (Referent)Unknown, n, % missing 2, 0.1 9120, 20.2

Cough duration,c n, median (IQR), d 77, 14 (10 23) 21 190, 24 (1734) Paroxysmal cough

Yes 182 (82) 31 469 (90.9) 0.58 ,.01 0.46 (0.320.64)No 40 (18) 3155 (9.1) 1.25 1.00 (Referent)Unknown, n, % missing 36, 14.0 10 522, 23.3

ApneaYes 176 (76.2) 18 739 (55.6) 0.93 ,.01 2.55 (1.883.46)No 55 (23.8) 14 944 (44.4) 0.37 1.00 (Referent)Unknown, n, % missing 27, 10.5 11 463, 25.4

WhoopYes 82 (41.2) 18 578 (56.1) 0.44 ,.01 0.55 (0.410.73)No 117 (58.8) 14 546 (43.9) 0.80 1.00 (Referent)Unknown, n, % missing 59, 22.9 12 022, 26.6

Posttussive vomitingYes 133 (61.3) 22 893 (66.7) 0.58 .09 0.79 (0.601.04)No 84 (38.7) 11 431 (33.3) 0.73 1.00 (Referent)Unknown, n, % missing 41, 15.9 10 822, 24.0

ComplicationsHospitalized

Yes 249 (98.4) 21 820 (63.4) 1.13 ,.01 36.0 (13.496.6)No 4 (1.6) 12 604 (36.6) 0.03 1.00 (Referent)Unknown, n, % missing 5, 1.9 10 722, 23.7

PneumoniaPositive 201 (90.5) 4008 (19.6) 4.78 ,.01 39.3 (25.061.6)Negative 21 (9.5) 16 442 (80.4) 0.13 1.00 (Referent)Unknown, n, % missing 36, 14.0 24 696, 54.7

EncephalopathyYes 20 (9.9) 82 (0.2) 19.61 ,.01 45.5 (27.375.7)No 182 (90.1) 33 925 (99.8) 0.53 1.00 (Referent)Unknown, n, % missing 56, 21.7% 11 139, 24.7


vaccination status but had knownvalues for the other variablesincluded in the nal model; ina sensitivity analysis and assumingthat all of these cases with unknownvaccination had received 1 previouspertussis vaccination, the aOR was0.10 (95% CI: 0.040.26), andassuming that all of these cases withunknown vaccination wereunvaccinated, the aOR was 0.47 (95%CI: 0.181.23).

In a multivariable analysis thatincluded only infants aged 56 to 90days (the age when the rst dose ofpertussis vaccine is usuallyadministered during the 2-monthpediatric visit), data on 28 fatal casesand 2901 nonfatal cases wereincluded in a model that adjusted forage at onset, Hispanic ethnicity, race,receipt of a recommended antibiotic,and pertussis vaccination ($1 vs0 doses). In this analysis, we founda similar effect of vaccination (aOR:0.28; 95% CI: 0.032.24) as that forall infants $42 days of age (Table 3).Among infants aged 56 to 90 dayswith pertussis conrmed by culture-

or PCR (24 fatal cases and 2006nonfatal cases), and including thesame covariates, the effect of a singledose of vaccine was similar (aOR:0.34; 95% CI: 0.042.81).

The protective effect of $1 doses ofpertussis vaccine among all infants$42 days of age was clearly shownagainst hospitalization (aOR: 0.69;95% CI: 0.630.77) and pneumonia(aOR: 0.80; 95% CI: 0.680.95)(Table 4) but not against seizures andencephalopathy.

Information on vaccine type (wP oraP) or brand was poorly reported,and we were unable to directlycompare any effect of receiving wPversus aP vaccines during the studyperiod. We used 2 time periods(19911996 and 19972008) assurrogates for vaccine type. Before1997, wP vaccines were usedexclusively. The ACIP recommendedthe aP vaccine for use in the primaryseries among infants in the UnitedStates in late 1996. Most infants bornafter 2000 likely received the DTaPvaccine as the rst 3 doses of theseries. The protective effect of

a pertussis vaccine dose was greater(Table 3) among cases reportedduring the DTaP period (19972008;aOR: 0.17; 95% CI: 0.040.73)compared with the DTwP period(19911996; aOR: 0.67; 95% CI:0.112.82).

Preventing Pertussis Deaths by On-Time DTwP/DTaP Vaccination

In the analysis that included onlyinfants eligible for their rst dose(aged 5690 days) and assuming thatthe rst dose provided 72%protection (aOR: 0.28, above) and allinfants received their rst dose ofpertussis vaccine at exactly age 8weeks, then 41 (72%) of the 57deaths that occurred after age 8weeks could have been averted for anoverall reduction of 16% (41 of 258)of all infant pertussis deaths.

We also t the nal multivariablemodel for infants aged $42 dayswhere the number of doses ofpertussis vaccinations was 0, 1, or$2doses and found protective effects forthe rst dose (aOR: 0.27; 95% CI:0.100.76) and for $2 doses (aOR:

TABLE 1 Continued

Characteristic Fatal Cases, n (%) Nonfatal Cases, n (%) CFRa Pb OR (95% CI)

SeizuresYes 33 (16.0) 491 (1.5) 6.30 ,.01 12.8 (8.718.7)No 173 (84.0) 32 899 (98.5) 0.52 1.00 (Referent)Unknown, n, % missing 52, 20.2 11 756, 26.0

Recommended antibiotics during course of illnessYes 156 (73.2) 28 941 (85.9) 0.54 ,.01 0. 45 (0.330.61)No or none 57 (27.8) 4734 (14.1) 1.19 1.00 (Referent)Unknown, n, % missing 45, 17.4 11 471, 25.4

Gestational aged Not collected,32 weeks 20 (10.3)3235 weeks 40 (20.5)$36 weeks 135 (69.2)Unknown, n, % missing 63, 24.4

Maternal aged Not collected,20 years 48 (28.7)2024 years 51 (30.5)$25 years 68 (40.7)Unknown, n, % missing 91, 35.3

Age at disease onset,d n, median (IQR), wk 258, 4 (27) 45 146, 10 (619)Age at death,d n, median (IQR), d 258, 51 (3175)

IQR, interquartile range; , not applicable.a (Number of deaths/number of cases) 3 100.b Pearsons x2 test.c Of those coughing at nal interview.d Of those with available information.


0.38; 95% CI: 0.043.33) whencompared with no dose. On the basisof these results, assuming that therst dose provided 73% protectionagainst death and if all infantsreceived their rst dose of pertussisvaccine at exactly age 6 weeks (42days), then 68 (74%) of the 92 deathsthat occurred after age 42 days wouldhave been averted for an overallreduction of 26% (68 of 258) of allinfant pertussis deaths.

DISCUSSION

Among vaccine-eligible infants, ourstudy shows a protective effect of $1doses of pertussis vaccine inpreventing pertussis-associateddeaths, hospitalizations, andpneumonia. The protective effect

persisted even after controlling forother potential risk markers, age atillness onset, Hispanic ethnicity, race,and use of a recommended antibiotic.Because only 2 fatal cases received$2 doses, we were unable to explorea vaccine dose-response. Although theprotective effect of 1 dose of vaccinewas also separately shown during theperiod when DTaP vaccines wereexclusively administered, this effectwas not statistically signicant duringthe DTP period. In outbreaksituations, clinicians may attempt tocommence vaccination at 6 weeksrather than at the 2-month well-childofce visit when the vaccine isroutinely given. Other routinelyrecommended vaccines at 2 monthscan also be given at this visit.

Although B pertussis possessesa range of antigenic factors, there isno established serologic correlate ofprotection with a quantiableprotective antibody response againstany antigen. Because the rst vaccinedose does not result in measurableantipertussis antibody levels, othermechanisms may be operative. Thebiological plausibility of 1 dose toevoke a cellular immune responsewas shown in murine2426 andnonhuman primate2729 studies. A Thelper (Th) 1/Th17 cellular immuneresponse and elimination of Bpertussis organisms follows naturalinfection or vaccination with wPvaccines in murine2426 andbaboon28 models. However, a Th2/Th1, although predominantly Th2-mediated, humoral response ispromoted by aP vaccination eventhough other cell-mediated cytokinepathways may also exist.3032

Additional studies are required toelucidate the mechanism of vaccine-induced cellular immune response to1 pertussis vaccine dose because thispathway is not fully understood.

Vaccine-ineligible infants (aged ,42days) can develop severe disease andfatal complications. In this study, 24%of nonfatal infant cases and 64% ofinfant deaths occurred among infantsaged ,42 days. Because our ndingssuggest infant vaccination couldpotentially avert 16% to 26% of allinfant deaths, additional strategiesare required to enhance immunity innewborns or to reduce exposure to Bpertussis among vaccine-ineligibleinfants. In 2012, the ACIPrecommended the use of a dose oftetanus toxoid, reduced diphtheriatoxoid, and acellular pertussis,adsorbed (Tdap) during eachpregnancy to provide passivetransplacental maternal antibodiesand to likely protect the newborn(s)during the period before the rstDTaP dose.33 The role of maternalimmunization in preventing infantpertussis was shown in baboons.34

The safety and effectiveness ofmaternal immunization when the

FIGURE 1A, Distribution of pertussis cases by age at disease onset and CFR: United States, 19912008. B,Distribution of fatal cases and CFR by age at disease onset in infants: United States, 19912008.


vaccine is administered at least 1week before delivery in preventingdisease and deaths in infants ,3months of age have been reported inEngland.35,36 In addition to reducingexposure among newborns to sick

household members, the ACIPrecommends a strategy ofcocooning,37 which requires thatpersons who are likely to be incontact with the newborn be up-to-date with vaccination with an age-

appropriate pertussis vaccine (DTaP,Tdap). A recent study in Tdap-vaccinated baboons challenged with Bpertussis exposure showed protectionfrom disease but not colonization,38

and these animals transmitted

TABLE 2 Selected Characteristics of Fatal and Nonfatal Pertussis in Infants, by Age at Onset of Pertussis: United States, 19912008

Characteristic ,42 Days Old $42 Days Old

FatalCases,n (%)

NonfatalCases,n (%)

CFR P a OR (95% CI) FatalCases,n (%)

NonfatalCases,n (%)

CFR P a OR (95% CI)

Total 166 (100) 11 048 (100) 1.48 92 (100) 34 098 (100) 0.27Age at onset of illness

06 days 4 (2.4) 440 (4.0) 0.90 ,.01 1.00 (Referent) NA NA NA NA713 days 22 (13.2) 909 (8.2) 2.36 2.66 (0.917.77) NA NA NA NA1420 days 42 (25.3) 2026 (18.3) 2.03 2.28 (0.816.39) NA NA NA NA2127 days 43 (25.9) 2553 (23.1) 1.66 1.85 (0.665.19) NA NA NA NA2834 days 31 (18.7) 2629 (23.8) 1.17 1.30 (0.463.69) NA NA NA NA3541 days 24 (14.5) 2491 (22.6) 0.95 1.06 (0.373.07) NA NA NA NA4248 days NA NA NA NA 26 (28.3) 2490 (7.3) 1.03 ,.01 1.00 (Referent)4955 days NA NA NA NA 9 (9.8) 2428 (7.1) 0.37 0.36 (0.170.76)5662 days NA NA NA NA 15 (16.3) 2506 (7.4) 0.60 0.57 (0.301.08)6369 days NA NA NA NA 9 (9.8) 2381 (7.0) 0.38 0.36 (0.170.77)7076 days NA NA NA NA 8 (8.7) 2115 (6.2) 0.38 0.36 (0.160.80)7783 days NA NA NA NA 5 (5.4) 1761 (5.2) 0.28 0.27 (0.100.71)84364 days NA NA NA NA 20 (21.7) 20 417 (59.9) 0.10 0.09 (0.050.17)

GenderMale 73 (44.0) 5450 (49.7) 1.32 .14 1.00 (Referent) 48 (52.2) 17 330 (51.2) 0.28 .85 1.00 (Referent)Female 93 (56.0) 5517 (50.3) 1.66 1.26 (0.921.71) 44 (47.8) 16 522 (48.8) 0.27 0.96 (0.641.45)Unknown, n, % missing 0, 0 81, 0.7 0, 0 246, 0.7

RaceWhite 129 (86.0) 5171 (79.2) 2.43 .12 1.00 (Referent) 66 (75.9) 15 536 (77.9) 0.42 ,.01 1.00 (Referent)Black 14 (9.3) 966 (14.8) 1.43 0.58 (0.331.01) 11 (12.6) 3378 (16.9) 0.32 0.77 (0.401.45)AI/AN 5 (3.3) 180 (2.8) 2.70 1.11 (0.452.75) 8 (9.2) 509 (2.6) 1.55 3.70 (1.777.75)A/PI 2 (1.3) 215 (3.3) 0.92 0.37 (0.091.52) 2 (2.3) 523 (2.6) 0.38 0.90 (0.223.68)Other/unknown, n, % missing 16, 9.6 4516, 40.9 5, 5.4 14 152, 41.5

EthnicityHispanic 74 (46.5) 2582 (37.3) 2.79 .02 1.46 (1.072.01) 37 (42.5) 6119 (31.2) 0.60 .02 1.64 (1.072.50)Non-Hispanic 85 (53.5) 4341 (62.7) 1.92 1.00 (Referent) 50 (57.5) 13 519 (68.8) 0.37 1.00 (Referent)Unknown, n, % missing 7, 4.2 4125, 37.3 5, 5.4 14 460, 42.4

RegionNortheast 15 (9.0) 1687 (15.3) 0.88 ,.01 1.00 (Referent) 10 (10.9) 5396 (15.8) 0.18 .53 1.00 (Referent)Midwest 29 (17.5) 2580 (23.4) 1.11 1.26 (0.682.36) 23 (25.0) 9019 (26.4) 0.25 1.38 (0.652.89)South 64 (38.6) 3115 (28.2) 2.01 2.31 (1.314.07) 28 (30.4) 9039 (26.5) 0.31 1.67 (0.813.44)West 58 (34.9) 3666 (33.2) 1.56 1.78 (1.013.15) 31 (33.7) 10 644 (31.2) 0.29 1.57 (0.773.21)

Recommended antibiotics duringcourse of illnessYes 104 (74.8) 7517 (88.3) 1.36 ,.01 0.39 (0.270.58) 52 (70.3) 21 424 (85.2) 0.24 ,.01 0.41 (0.250.68)No or none 35 (25.2) 997 (11.7) 3.39 1.00 (Referent) 22 (29.7) 3737 (14.8) 0.59 1.00 (Referent)Unknown, n, % missing 27, 16.3 2534, 22.9 18, 19.6 8937, 26.2

Number of valid doses of pertussisvaccinations before illness onsetb

0 NA NA NA NA 83 (91.2) 9838 (64.3) 0.84 ,.01 1.00 (Referent)$1 NA NA NA NA 8 (8.8)c 5453 (35.7)d 0.15 0.17 (0.080.36)e

Unknown, n, % missing NA NA NA NA 1, 1.1 18 807, 55.2

AI/AN, American Indian/Alaska Native; A/PI, Asian/Pacic Islander; NA, not applicable.a Pearsons x2 test.b Doses of pertussis vaccine were counted as valid if they were administered $14 days before illness onset.c Seven fatal cases reported 1 dose, 0 fatal cases reported 2 doses, and 1 fatal case reported 3 doses.d A total of 3674 nonfatal cases reported 1 dose, 917 nonfatal cases reported 2 doses, and 862 nonfatal cases reported 3 doses.e One fatal case and 18 807 nonfatal cases had unknown vaccination status; assuming that all of these cases were truly vaccinated, the OR (95% CI) was 0.04 (0.020.09), and assumingthat all of these cases were truly not vaccinated, the OR (95% CI) was 0.50 (0.241.03) (P = .06).


infection to naive contacts. However,although aP-vaccinated persons maybe colonized, transmission usuallyoccurs from symptomatic persons. Thecocooning strategy is alsoprogrammatically challenging toimplement39 and requires furtherevaluation. Last, a potential strategy toactively enhance immunity in

newborns is to introduce a dose ofDTaP,40 an aP vaccine,41,42 or anothernovel vaccine43,44 at or shortly afterbirth. However, a stand-alone aPvaccine is not commercially availableand few immunogenicity studies havebeen conducted to evaluate theprotective effect of a birth dose ofDTaP or aP vaccines4042 or the

potential interference of the birth doseon antibody response to subsequentvaccine doses in the primary series.

NNDSS data may not have uniformlycaptured all fatal2 or nonfatal casesdue to underreporting. Our resultsare unlikely to have been biased,because it is unlikely that there waspreferential underreporting ofvaccinated cases compared withunvaccinated cases. It is also unlikelythat incompletely vaccinated caseswere less likely to be tested,diagnosed, and reported becauseproviders are aware that 3 doses areneeded for protection. Incompletevaccine-related data prevented anevaluation of different aP (25antigens) or wP vaccine types.Gestational age was not a dataelement in the NNDSS and preventedevaluation of prematurity risk.4548

CONCLUSIONS

Health professionals should ensureon-time rst-dose pertussis

TABLE 3 Multivariable Analysis of Factors Associated With Fatal Pertussis in All Infants and in Culture- or PCR-Positive infants, by Age at Onset ofPertussis: United States, 19912008

Characteristic OR (95% CI) for All Infants OR (95% CI) for Culture- or PCR-Positive Infants

,42 Days Old(n = 133 f, 5360 nf)a

$42 Days Old(n = 66 f, 9001 nf)b

,42 Days Old(n = 110 f, 3593 nf)a

$42 Days Old(n = 53 f, 5950 nf)b

Age at onset of illness (days) 0.976 (0.9600.992) 0.990 (0.9840.997) 0.973 (0.9550.991) 0.991 (0.9840.999)Ethnicity

Hispanic 1.49 (1.062.11) 2.28 (1.363.83) 1.45 (0.992.13) 2.16 (1.203.91)Non-Hispanic 1.00 (Referent) 1.00 (Referent) 1.00 (Referent) 1.00 (Referent)

Race Not included Not includedWhite 1.00 (Referent) 1.00 (Referent)Black 0.92 (0.402.09) 0.96 (0.392.37)AI/AN 5.15 (2.3711.2) 6.67 (2.8415.6)A/PI 1.39 (0.335.90) 1.82 (0.427.84)

Recommended antibiotics during course of illnessYes 0.43 (0.290.64) 0.28 (0.160.47) 0.42 (0.270.65) 0.27 (0.150.49)No or none 1.00 (Referent) 1.00 (Referent) 1.00 (Referent) 1.00 (Referent)

Number of valid doses of pertussis vaccinationsbefore illness onsetc

0 NA 1.00 (Referent) NA 1.00 (Referent)$1 NA 0.28 (0.110.74)d NA 0.20 (0.060.68)

AI/AN, Native American/Alaska Native; A/PI, Asian/Pacic Islander; f, fatal cases; NA, not applicable; nf, nonfatal cases.a The model included age at onset of illness, ethnicity, and recommended antibiotics during course of illness.b The model included age at onset of illness, race, ethnicity, recommended antibiotics during course of illness, and number of valid doses of pertussis vaccinations before illness onset.c Doses of pertussis vaccine were counted as valid if they were administered $14 days before illness onset.d The aOR (95% CI) of applying this model to all infants aged 56 to 90 days, where the race categories AI/AN and A/PI were pooled to avoid model-tting problems due to small numbers offatal cases (28 fatal cases, 2901 nonfatal cases), was 0.28 (0.032.24) and for culture- or PCR-conrmed cases (24 fatal and 2006 nonfatal cases) was 0.34 (0.042.81). The aOR (95% CI) ofapplying this model to the wP vaccine era (19911996), where age was categorized into 2 groups on the basis of median age (,99 days,$99 days) to avoid model-tting problems due toa small number of fatal cases (15 fatal cases, 835 nonfatal cases), was 0.67 (0.112.82); and the aOR (95% CI) of applying the original model with age as a continuous variable to the DTaPvaccine era (19972008; 51 fatal cases, 8166 nonfatal cases) was 0.17 (0.040.73).

TABLE 4 Multivariable Analysis of Effect of $1 Pertussis Vaccine Doses on Death andComplications Among infants $42 Days Old: United States, 19912008

Outcomea Number With Outcome inthe Model

Effect of Pertussis VaccineDoses ($1 vs 0), OR (95% CI)

Yes No

Deathb 66 9001 0.28 (0.110.74)Hospitalizationc 4748 3999 0.69 (0.630.77)Pneumoniad 947 4069 0.80 (0.680.95)Encephalopathye 27 8599 1.40 (0.563.46)Seizurese 107 8524 0.82 (0.521.29)a Each outcome was modeled separately and did not include any other outcome as an independent variable.b The model included age at onset of illness, race, ethnicity, recommended antibiotics during course of illness, andnumber of valid doses of pertussis vaccinations before illness onset.c The model included age at onset of illness, race, ethnicity, recommended antibiotics during course of illness, gender,region, and number of valid doses of pertussis vaccinations before illness onset.d The model included age at onset of illness, race, ethnicity, recommended antibiotics during course of illness, region, andnumber of valid doses of pertussis vaccinations before illness onset.e The model included age at onset of illness, race, ethnicity, and number of valid doses of pertussis vaccinations beforeillness onset.


vaccination as early as 6 weeks ofage during pertussis outbreaks andprovide early recommendedantibiotic treatment. Therecommendations apply globallyand particularly in countries whereDTP/DTaP vaccinations routinelybegin at 6 weeks of age. Infants whoare age-ineligible for vaccinationwill benet from strengtheningstrategies that provide immunity to

newborns and prevent exposure toB pertussis.

ACKNOWLEDGMENTS

We thank Ms Pamela Srivastava, MsKristin Brown, and Mr Kashif Iqbalat the Centers for Disease Controland Prevention for their previouswork in maintaining the pertussissurveillance database over the past

decade; personnel from local andstate health departmentsconducting pertussis surveillance;and health care providers forreporting cases to make theseanalyses possible. We also thank MsAmanda Faulkner, Dr Kris Bisgard,Amanda Cohn, and Dr NancyMessonnier for contributions,reviewing the manuscript drafts,and providing insightful comments.

FINANCIAL DISCLOSURE: The authors have indicated they have no nancial relationships relevant to this article to disclose.

FUNDING: The study was supported by the Centers for Disease Control and Prevention (CDC) and was determined to be exempt from CDC institutional review board

review.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conicts of interest to disclose.

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DOI: 10.1542/peds.2014-2291; originally published online May 4, 2015;Pediatrics

Tejpratap S.P. Tiwari, Andrew L. Baughman and Thomas A. ClarkFirst Pertussis Vaccine Dose and Prevention of Infant Mortality

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