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Evidence of Increase in Mortality After the Introduction of Diphtheria–Tetanus–Pertussis Vaccine to Children Aged 6–35 Months in Guinea-Bissau: A Time for Reflection?

Authors:
  • Bandim Health Project

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Background Whole-cell diphtheria–tetanus–pertussis (DTP) and oral polio vaccine (OPV) were introduced to children in Guinea-Bissau in 1981. We previously reported that DTP in the target age group from 3 to 5 months of age was associated with higher overall mortality. DTP and OPV were also given to older children and in this study we tested the effect on mortality in children aged 6–35 months.Methods In the 1980s, the suburb Bandim in the capital of Guinea-Bissau was followed with demographic surveillance and tri-monthly weighing sessions for children under 3 years of age. From June 1981, routine vaccinations were offered at the weighing sessions. We calculated mortality hazard ratio (HR) for DTP-vaccinated and DTP-unvaccinated children aged 6–35 months using Cox proportional hazard models. Including this study, the introduction of DTP vaccine and child mortality has been studied in three studies; we made a meta-estimate of these studies.ResultsAt the first weighing session after the introduction of vaccines, 6–35-month-old children who received DTP vaccination had better weight-for-age z-scores (WAZ) than children who did not receive DTP; one unit increase in WAZ was associated with an odds ratio of 1.32 (95% CI = 1.13–1.55) for receiving DTP vaccination. Though lower mortality compared with not being DTP-vaccinated was, therefore, expected, DTP vaccination was associated with a non-significant trend in the opposite direction, the HR being 2.22 (0.82–6.04) adjusted for WAZ. In a sensitivity analysis, including all children weighed at least once before the vaccination program started, DTP (±OPV) as the most recent vaccination compared with live vaccines or no vaccine was associated with a HR of 1.89 (1.00–3.55). In the three studies of the introduction of DTP in rural and urban Guinea-Bissau, DTP-vaccinated children had an HR of 2.14 (1.42–3.23) compared to DTP-unvaccinated children; this effect was separately significant for girls [HR = 2.60 (1.57–4.32)], but not for boys [HR = 1.71 (0.99–2.93)] (test for interaction p = 0.27).Conclusion Although having better nutritional status and being protected against three infections, 6–35 months old DTP-vaccinated children tended to have higher mortality than DTP-unvaccinated children. All studies of the introduction of DTP have found increased overall mortality.
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March 2018 | Volume 6 | Article 791
ORIGINAL RESEARCH
published: 19 March 2018
doi: 10.3389/fpubh.2018.00079
Frontiers in Public Health | www.frontiersin.org
Edited by:
Rumen Stefanov,
Plovdiv Medical University,
Bulgaria
Reviewed by:
Camille Locht,
INSERM, France
Marisa Theresa Gilles,
Western Australian Center for
Rural Health (WACRH), Australia
*Correspondence:
Peter Aaby
p.aaby@bandim.org
Specialty section:
This article was submitted to
Public Health Policy,
a section of the journal
Frontiers in Public Health
Received: 01August2017
Accepted: 02March2018
Published: 19March2018
Citation:
AabyP, MogensenSW, RodriguesA
and BennCS (2018) Evidence of
Increase in Mortality After the
Introduction of Diphtheria–Tetanus–
Pertussis Vaccine to Children Aged
6–35Months in Guinea-Bissau:
A Time for Reection?
Front. Public Health 6:79.
doi: 10.3389/fpubh.2018.00079
Evidence of Increase in Mortality
After the Introduction of Diphtheria–
Tetanus–Pertussis Vaccine to
Children Aged 6–35Months in
Guinea-Bissau: A Time for
Reection?
Peter Aaby1,2*, Søren Wengel Mogensen1, Amabelia Rodrigues1 and Christine S. Benn2,3
1 Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau, 2 Research Centre for Vitamins and Vaccines (CVIVA),
Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark, 3 OPEN, Institute of Clinical Research, University
of Southern Denmark, Odense University Hospital, Odense, Denmark
Background: Whole-cell diphtheria–tetanus–pertussis (DTP) and oral polio vaccine
(OPV) were introduced to children in Guinea-Bissau in 1981. We previously reported
that DTP in the target age group from 3 to 5months of age was associated with higher
overall mortality. DTP and OPV were also given to older children and in this study we
tested the effect on mortality in children aged 6–35months.
Methods: In the 1980s, the suburb Bandim in the capital of Guinea-Bissau was
followed with demographic surveillance and tri-monthly weighing sessions for chil-
dren under 3years of age. From June 1981, routine vaccinations were offered at the
weighing sessions. We calculated mortality hazard ratio (HR) for DTP-vaccinated and
DTP-unvaccinated children aged 6–35months using Cox proportional hazard models.
Including this study, the introduction of DTP vaccine and child mortality has been studied
in three studies; we made a meta-estimate of these studies.
Results: At the rst weighing session after the introduction of vaccines, 6–35-month-
old children who received DTP vaccination had better weight-for-age z-scores (WAZ)
than children who did not receive DTP; one unit increase in WAZ was associated with
an odds ratio of 1.32 (95% CI=1.13–1.55) for receiving DTP vaccination. Though
lower mortality compared with not being DTP-vaccinated was, therefore, expected,
DTP vaccination was associated with a non-signicant trend in the opposite direction,
the HR being 2.22 (0.82–6.04) adjusted for WAZ. In a sensitivity analysis, includ-
ing all children weighed at least once before the vaccination program started, DTP
(±OPV) as the most recent vaccination compared with live vaccines or no vaccine
was associated with a HR of 1.89 (1.00–3.55). In the three studies of the introduction
of DTP in rural and urban Guinea-Bissau, DTP-vaccinated children had an HR of
2.14 (1.42–3.23) compared to DTP-unvaccinated children; this effect was separately
signicant for girls [HR=2.60 (1.57–4.32)], but not for boys [HR=1.71 (0.99–2.93)]
(test for interaction p=0.27).
2
Aaby et al. Introduction of DTP to Children Aged 6–35Months
Frontiers in Public Health | www.frontiersin.org March 2018 | Volume 6 | Article 79
Conclusion: Although having better nutritional status and being protected against three
infections, 6–35months old DTP-vaccinated children tended to have higher mortality
than DTP-unvaccinated children. All studies of the introduction of DTP have found
increased overall mortality.
Keywords: bias in vaccine studies, diphtheria–tetanus–pertussis vaccine, heterologous effects, measles vaccine,
non-specic effects of vaccines, oral polio vaccine
KEY OBSERVATIONS
• DTP and oral polio vaccine (OPV) were rstintroduced to
children aged 6–35 months in June 1981 in an urban area
in Guinea-Bissau. Children who were DTP-vaccinated at
therstweighingsession aer the introduction of DTP had
signicantly better weight-for-age z-scores than those not
vaccinated.
• Although better survival was expected, the DTP-vaccinated
childrenhadtwofoldhighermortalitythanDTP-unvaccinated
children.
• In a meta-analysis of the three studies of the introduction
of DTP in urban and rural Guinea-Bissau, DTP-vaccinated
childrenhadtwofoldhighermortalitythanDTP-unvaccinated
children.
INTRODUCTION
Whole-cell diphtheria–tetanus–pertussis (DTP) vaccine is the
most commonly used vaccine in low-income countries with
poorhealth infrastructure,andthecoverageforthethirddose
of DTP-containing vaccines (DTP3) is the main performance
indicatorforvaccinationprograms(1).However,noprospective
study has shown thatreceiving DTP is associated with better
childsurvival(2,3).Onthecontrary,inthepast20yearsseveral
studies have suggested that DTP is associated with increased
childmortality,particularlyforgirls(24).
We recently examined what happened when DTP andoral
poliovaccine(OPV)wereintroducedtoinfantsaged3–5months
inGuinea-BissauinJune1981in connection with tri-monthly
weighing sessions in an urban community in Bandim (5). In
this age group,t hechild’s date ofbirth determined w hethera
childwasvaccinated earlyorlate.Children who werejustover
3monthsoldatthe time of thetri-monthlyweighing sessions
werevaccinatedatthatage;thosewhowerejustbelow3months
oldwouldonlybevaccinatedforthersttimeatalmost6months
ofage.Inthis“naturalexperiment,”DTP-vaccinatedchildrenhad
vefold higher mortality between 3 and 6 monthsof age than
childrennotyetvaccinatedwithDTP(5).
When we initiated vaccination with DTP and OPV in
Guinea-BissauinJune1981,wealsooeredacatch-upprogram
tochildrenaged 6–35 monthsattendingthe weighing sessions.
issituationprovidesanopportunitytocomparethesurvivalof
olderDTP-vaccinatedandDTP-unvaccinatedchildren.
In principle, children above 3 months of age attending the
weighing sessions were oered vaccination if vaccines and
equipment(syringes,sterilizationstove)wereavailable.However,
nurses and mothers were reluctant to vaccinate sick or weak
children.Otherreasonsfornotbeing vaccinated were that the
children were temporarily traveling, or that they stayed for
prolongedperiodsintheruralareaswhereaccesstohealthcare
waslimitedandchildmortalitywashigher.us,apartfromthe
specicdisease-protectiveeectof DTP,inherentbiaseswould
lead one to expect that DTP-vaccinated children had better
survivalthanDTP-unvaccinatedchildren.
MATERIALS AND METHODS
Background
BandimHealthProject(BHP)hasfollowedanurbancommunity
in the capital of Guinea-Bissau with a demographic surveil-
lancesystemsinceDecember1978. enationalimmunization
program in Guinea-Bissau started in 1986 with funding from
UNICEF. From January 1980, BHP conducted tri-monthly
weighingsessionsof all children inthe community to identify
malnourished children. From June 1981, vaccinations were
oeredinconnectionwiththeseweighingsessions.
Demographic Surveillance
Whentheprojectstartedin1978,childmortalitywasveryhigh.
Malnutritionwasassumedtobethemaincauseandastudywas,
therefore,initiated to determine why children were malnour-
ished(68).eareawasmappedandacensuswasconducted
(5). Four female health workers identied pregnant women,
encouragedwomen to attendtheantenatalclinic in thestudy
area,andfollowedchildrenwithanthropometricmeasurements
to assess growth patterns and detect malnourished children.
Eachhealthworkerfollowedapopulationof1,500–2,000indi-
viduals,thetotalnumberofindividualsinBandimbeingaround
6,300atthebeginningofthestudy.ehealthworkerkeptalist
ofchildrenunder3yearsofageineachoftheeightsub-districts
inBandim.Anexpatriatenursesupervisedthehealthworkers.
BHPhadnocomputerizedsurveillancesystemwhenthestudy
started,butBHPkeptanA5card(“BHPcard”)foreachchild,
whereweightsandvaccinationdateswerenoted.Withabirth
ratearound 5%, the annual birth cohort was around300–350
newborns.
eBandimpopulationwasverymobileformanyreasons.
First,itwasimportanttomaintaincontactwiththenatalvil-
lageforceremonialpurposesandtosecureaccesstorice,oen
byhelpingthefamilyduringthericeproductioncycle.Second,
manywomentriedtoobtaincashincomebygrowingfruitsor
vegetablesintheruralareasorbyproducingcashewwinetobe
soldinBissau.ird,motherswerenotsupposedtohavesexual
relationsduringbreastfeedingassemenisbelievedtodamage
breastmilk causing diarrhea in the child (9). Breastfeeding
FIGURE 1 | Flowchart of study population and children included in the
analyses. DOB, date of birth; [], died during follow-up. Children were only
included in the main analysis if they had taken part in a weighing session
after October 1, 1980.
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Frontiers in Public Health | www.frontiersin.org March 2018 | Volume 6 | Article 79
wasprolongedin Guinea-Bissau,between18and36months
in dierent ethnic groups. us, many women preferred to
stayinthe rural areaswiththeir family while breastfeeding.
eseculturalpatternsmeantthatsomemothersandchildren
wereaway forlongperiods. Typically,therewouldbefamily
membersinBandim,whowecouldaskaboutthewhereabouts
ofthechild.
Tri-Monthly Weighing Sessions
Wearrangedtri-monthlyweighingsessionsineachsub-district
(8).ehealthworkerinchargeadvisedmothersthedaybeforea
session.Ifachildwasnotpresent,itsvitalstatuswasascertained
byasking the family.efollowingmorning, the child’sweight
wasmeasuredonahangingSalterscaleandnotedonthechild’s
healthcardandtheBHPcard.
Vaccinations
erewasnocommunityvaccinationprograminGuinea-Bissau
whenBHPstartedvaccinations.Mothercouldhavetakentheir
childrentotheclinicoftheMotherandChildHealthProgramin
town.isclinicwasmainlyattendedbytheurbanelitesovery
fewchildren from Bandim hadreceived routinevaccinations
(5).InJune1981,BHPstartedtoprovidevaccinationsatthetri-
monthlyweighingsessions.Ahealthcenternurseaccompanied
thenutritionteamandvaccinatedeligiblechildren.
Eligiblechildrenwerebetween3monthsand3 yearsofthe
age.However, somechildreninthis age groupwerenotvacci-
nated.Both nurses andmothersthoughtthatsickorotherwise
weak children should not be vaccinated. e BHP card oen
indicatedthatthechildwas “sick,” “malnourished,”ororphan”
asanexplanationofwhyanage-eligiblechildhadnotbeenvac-
cinated.Other reasons fornotvaccinatingan age-eligible child
weretemporaryshortagesofvaccinesorsyringes.
ethreeDTPandOPVdosescouldbegivenfrom3months
ofagewithanintervalof1month,butsinceweonlyperformed
weighing sessions every 3 months, most children had longer
intervalsbetweenthethreedoses.Also,therewereseveralperi-
odswhereeitherOPVorDTPwasmissing[Ref.(5),Figure1].
eexpatriatenursesometimes organized additional vaccination
sessionsinwhichthechildrenwerenotweighed,butvaccinations
werenotedontheBHPcards.
Data Control
WeightsandvaccinationsfromtheBHPcardswereenteredinto
acomputerizedsystem in 1990–1991.Forthepresentanalysis,
informationondatesofvisit,weights,andvaccinationdateswas
checkedagainsttheoriginalcardsin2015.
The Study Cohort and Vaccination
Analyses
We included children born between June 1978 and December
1980andhenceaged6and35monthsinJune1981whenDTP
andOPVvaccinesbecameavailable(Figure1).Furthermore,it
wasaninclusioncriterionthatchildrenwereregisteredinthearea
beforethevaccinationsstarted.Weexcludedorphans,sincethey
werenotbreastfedand were likely to have dierent care; their
mortality was very high (10). Children who never attended a
weighingsessionaerbirthregistrationwerenotincludedinthe
analysis,sincetheirmothershadlikelylefortheruralareas.In
theanalyses,werestrictedthedatasettochildrentakingpartinat
leastoneweighingsessionaerOctober1980,8–9monthsbefore
vaccinationsstarted.iswasdonetoassurethatthechildrenhad
beenseenfairlyrecentlyandwere,therefore,likelytobearound
when the vaccinations started. Since the children were called
every3months,thetimeofdeathormigrationoutoftheareais
fairlyaccurate.
Vaccination Analyses
Weconductedthreecomplementaryanalysestoassesstheeect
ofDTPonchildsurvival.
Analysis 1
We compared DTP-vaccinated children and those who were
notDTP-vaccinatedwhen they came for their rstweighing
session aer the introduction of vaccinations in June 1981.
Since not all children were included, the analysis had less
power.Wefollowedchildrenfromtheirrstweighingsession
anduntiltheyreceivedtheirnextvaccinationortheymigrated,
died,orturned3yearsofage.us,childrenhadtobepresent
at a weighing session to be included in this analysisand we
couldadjustfortheweight-for-agez-score(WAZ)obtainedat
thatsession.
FIGURE 2 | Examinations are plotted on the axes of age and calendar time.
Each dot corresponds to a weighing examination of a child. The gray triangle
illustrates the age groups and periods, where follow-up time was included in
the survival analysis. The approximate tri-monthly regime of examinations is
visible in the distribution of dots on the horizontal axis.
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Analysis 2
In this analysis, children were considered DTP-vaccinated
from the date they received their rst DTP vaccination (with
or without OPV) in June 1981, or at one of the subsequent
weighing sessions (Figure2). Children were considered DTP-
unvaccinated from the date vaccination was rst oered in
theirsub-district, irrespective of whether they were present at
the weighing session, and until they were DTP-vaccinated at
asubsequentsession,migrated, died, or turned 3 years of age.
(e dierence between this analysis and Analysis 1 was that
children were consideredDTP-unvaccinated if they were age-
eligible, irrespective of whether they had attended a weighing
session or not, and vaccination status could change during
follow-up, so a child could contribute risk time rst as DTP-
unvaccinatedandthenasDTP-vaccinated.)
Analysis 3
Inthethirdanalysis,wecomparedmortalityofchildrenaccord-
ing to their most recent vaccination status; DTP-vaccinated
children were compared with children who had received no
vaccinationorlivevaccineonly (MV,OPV,orMV+ OPV) as
theirmostrecentvaccination.
Statistical Analyses
esurvivalofdierentvaccinationgroupswascomparedusing
aCox proportionalhazardmodelwith ageasunderlyingtime.
us,agewasinherentlycontrolledinthisanalysis.eWHO
WAZwasusedtoassessnutritionalstatus.Inanalysis1inwhich
wecomparedchildrenwhohadattendedweighingsessionsand
beenvaccinatedor notvaccinatedwe adjustedtheanalysis for
nutritional status (WAZ score). Since we provided almost all
vaccines,most vaccinationswereknown fromthedateof vac-
cination,butafewchildrenwerevaccinatedelsewhere.Toavoid
survivalbias,weusedalandmarkapproachinallanalyses(11);
hence,achild’svaccinationstatuswasonlyupdatedfromtheday
theinformationwascollected.
Studies of the Introduction of DTP
Includingthisstudy,thereareonlythreestudiesoftheintroduc-
tionofDTP, all fromGuinea-Bissau(5, 12). Wemadeameta-
estimateforthesestudies,sincetheyrepresentanunusualsetof
circumstancesinrelationtothediscussionofpotentialbiasesin
studiesofthenon-specic eects of vaccines (1317). First,in
allthreestudiesthenutritionalstatuswasworseforchildrennot
vaccinated.Second,weadministerednearlyallvaccines,somost
datesofvaccinationwereknownprecisely.ird,therewereno
campaigns with other vaccines or micronutrient supplements
atthetimeofthese studies. Fourth,they representallthe data
setsavailableon the introduction of DTP in Guinea-Bissau,so
reportingbiasisnotanissue(15).
RESULTS
Ofthe 890 childrenaged6–35 monthsregisteredinBandimin
June1981,wewerenotabletolocatetheBHPcardof107(12%)
childrenin2015; most will nothaveattendedan examination,
butsomecardsmayhavebeenlost.Afurther81hadaBHPcard,
but had not attended a weighing session since October 1980,
hadnoprecisevaccinationdates,orwereexcludedduetoother
considerations(seeFigure1).Hence,702childrenwereincluded
inthestudycohort;thenumberofdeathsand person-years in
thedierentvaccinegroupswas,therefore,limited (TableS1in
SupplementaryMaterial).
e temporal distribution of weighing sessions in this
cohort is shown in Figure 2. As documented in Table S2 in
SupplementaryMaterial,82and84%receivedDTP1andOPV1
beforetheyreached3yearsofage,themedianagesofvaccina-
tion being 633 and 614 days, respectively. It should be noted
thatonly38and49%ofthechildrenreceivedallthreedosesof
DTPandOPV,respectively,before3yearsofage.Duetoearlier
MVcampaigns(6,7),82%hadreceivedMVatamedianageof
348days.erewere42deathsbetween6and35monthsofage;
14hadfeverasthemainsymptom,13haddiarrheaordiarrhea
andvomiting,6diedfrommeasles,1hadrespiratoryinfection,
1wasmalnourished,1hadanemia,1didnoteat,and5hadno
information,mostlikelybecausethemother/familyhadmoved.
We compared background factorsfor DTP-vaccinated chil-
drenandchildrenwhoremainedDTP-unvaccinateduntilatleast
3yearsof age(Ta bl e 1 ).eDTP-vaccinatedchildrenwerefar
morelikelytohaveattendedweighingsessions,tohavereceived
measlesvaccine(MV)inthecampaigns,ortohavereceivedDTP
attheMotherandChildClinicbeforeJune1981(6,7).erewere
nodierencesindistributionofthesexes,twins,orethnicgroups.
Analysis 1
Atthe rst weighing sessionaer the vaccinationsstarted in June
1981,the WAZwasmuchhigherforthechildrenwho received
DTP(WAZ0.83)than forthosechildrenwhodidnotreceive
DTP (WAZ 1.17) (Ta b l e  1 ). An increase of one z-score was
associatedwithanoddsratio(OR)of1.32(95%CI=1.13–1.55)
TABLE 2 | Analysis 1: mortality rates (MR) per 100 person-years and hazard ratios (HR) of 6–35months old children who were either diphtheria–tetanus–pertussis
(DTP)-vaccinated or not DTP-vaccinated at their rst examination.
Mortality rate (deaths/person-years) HR (95% CI) HR (95% CI), adjusted for weight-
for-agez-scores (WAZ)
Vaccination status DTP (±OPV) No DTP
All children 9.68 (18/185.9) [394] 4.80 (5/104.1) [197] 2.01 (0.74–5.41) 2.22 (0.82–6.04)
Girls 11.15 (9/80.7) [191] 1.86 (1/53.7) [100] 6.67 (0.84–52.84) 7.03 (0.88–56.04)
Boys 8.58 (9/104.9) [202] 8.07 (4/49.6) [96] 1.04 (0.32–3.40) 1.28 (0.38–4.25)
Bandim, 1981–1983.
Children who have received DTP before June 2, 1981 were censored from the analysis.
TABLE 1 | Background factors for 6–35months old children who were
vaccinated or not vaccinated at their rst weighing session in June 1981.
Analysis 1 Diphtheria–tetanus–
pertussis (DTP)-
vaccinated at or
before rst session
DTP-unvaccinated
in rst
session
Mean weight-for-age z-score
(SD) at rst examination
0.83 (0.06) [394]¤1.17 (0.08) [197]¤
Analysis 2 DTP-vaccinated
during
follow-up
Not DTP-
vaccinated
during follow-up
N553 149
Male sex 51% (282) 53% (78)
Twin 3% (15) 2% (3)
Ethnic group
Pepel 51% (282) 48% (71)
Balanta 15% (84) 17% (25)
Other ethnic groups 34% (187) 36% (53)
Measles vaccinated before
June 1981
71% (391) 58% (86)
DTP before June 1981 6% (32)
Classied as malnourished 6% (33) 5% (8)
Mean number (SD) of weighing
sessions per year after start
of vaccinations
2.57 (0.06)#0.91 (0.09)#
#Comparison p<0.0001.
¤Comparison p=0.001.
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forbeingvaccinatedatthe rstweighingsession.Comparedwith
notbeingDTP-vaccinated,DTPvaccinationattherstweighing
session was associated with a non-signicantmortality hazard
ratio (aHR) of 2.22 (95% CI = 0.82–6.04) adjusted for WAZ
(Tabl e 2 ), the aHR being 7.03 (0.88–56.04) for girls, and 1.28
(0.38–4.25)forboys(testforinteractionp=0.17).
Analysis 2
Includingall childrenin the cohort, following them to 3years
ofage and allowingchildrentochangestatusduringfollow-up
whennewinformationwascollectedataweighingsession,hav-
ingreceivedDTP was associatedwitha non-signicant HR of
1.48(0.72–3.06)(Table3 ).eHRwas2.91(0.84–10.00)forgirls
and0.88(0.34–2.62)forboys.
Analysis 3
ChildrenwhoreceivedDTP(withorwithoutOPV)asthemost
recent vaccination had an HR of 1.77 (0.93–3.38) compared
with children who had received a live vaccine orno vaccine
atallandhad aHRof1.90(0.92–3.94) ifcomparedonlywith
children who had received live vaccine only (Table 4). In a
sensitivityanalysis,includingalsothe47childrenwhosemost
recent weighing session had been before October 1980, the
HRsforDTPwas1.89(1.00–3.55)(Tab l e 4 ),theHRbeing2.76
(1.07–7.07)forgirls,and1.34(0.56–3.22)forboys.
oughthegroupwassmall,itisworthnotingthatchildrenwho
receivedOPV-onlyhadlowmortality(TableS1inSupplementary
Material), the HR for DTP(±OPV)-vaccinated compared with
OPV-onlyvaccinatedchildrenwas3.76(0.89–15.83).
Studies of the Introduction of DTP
Inthe three studiesofintroductionof DTPinruralandurban
Guinea-Bissau, DTP vaccination was associated with a HR of
2.14 (1.42–3.23) compared with DTP-unvaccinated children
(Figure3).enegativeeectwasseparatelysignicantforgirls
[HR=2.60(1.57–4.32)],butnotforboys[HR=1.71(0.99–2.93)]
(Table S3 in Supplementary Material) (test for interaction
p=0.27).
DISCUSSION
Although lower mortality was expected for DTP-vaccinated
children compared with the frail unvaccinated children, DTP
vaccinationwasassociatedwithhighermortality,particularlyin
girls.
Strength and Weaknesses
ehome-visitsprecedingeachofthetri-monthlyweighingses-
sionsensuredthatwehadfollow-upinformationforallchildren
andrelativelyaccurateinformationonthetimeofmovementor
death.Intheinitialanalyses,weincludedonlychildrenwhohad
attendedthe 3-monthlyweighingsessionsatleast once within
thelast8–9months(5).ismeantthatchildrenmostlyliving
outsidetheareawerenotincluded;thesechildrenhadnoaccess
to community vaccinations and they lived elsewhere where
themortalityriskmaywellhavebeenmuchhigher.Wehadto
exclude some children because their cardcould not be found
(Figure1). eexcludedgroups (Figure 1) did nothavehigh
mortalitysotheincreasedmortalityofDTP-vaccinatedchildren
isnotduetoexclusionofunvaccinatedchildrenwithaparticu-
larlyhighmortality.Whenweincreasedthepowerofthestudy
byincludingchildrenonlyseenbeforeOctober1980(Figure1),
FIGURE 3 | Meta-analysis of the three studies of the introduction of diphtheria–tetanus–pertussis. The xed effects model gave an estimate of 2.14 (1.42–3.23) and
the random effects model gave 2.17 (1.39–3.38).
TABLE 4 | Analysis 3: mortality rates (MR) per 100 person-years and hazard ratios (HR) of 6–35months old children in relation to most recent vaccination.
Mortality rate (deaths/person-years) HR (95% CI)
Had weighing session after
October 1, 1980a
HR (95% CI)
All childrenb
Vaccination status Diphtheria–tetanus–
pertussis (DTP) (±OPV)
No DTP
All 6.2 (28/451.0) [535] 3.7 (14/382.0) [539] 1.77 (0.93–3.38) 1.89 (1.00–3.55)
Vaccination status DTP(±OPV) Only live vaccine
(MV, OPV, or MV+OPV)
All 6.2 (28/451.0) [535] 3.3 (10/303.84) [473] 1.90 (0.92–3.94) 1.99 (0.96–4.12)
Bandim, 1981–1983.
aSee Figure1; Adjustment for the most recent weight-for-age z-scores measurement did not change the estimate.
bInclude 47 children whose most recent weighing session prior to June 1981 had been before October 1980.
TABLE 3 | Analysis 2: mortality rates (MR) per 100 person-years and hazard
ratios (HR) of 6–35months old DTP-vaccinated and diphtheria–tetanus–pertussis
(DTP)-unvaccinated children.
Mortality rate (deaths/person-years) HR (95% CI)
DTP(±OPV) No DTP
All 5.4 (32/590.6) [553] 4.1 (10/242.5) [327] 1.48 (0.72–3.06)
Girls 6.9 (19/273.5) [270] 2.6 (3/116.4) [155] 2.91 (0.84–10.00)
Boys 4.1 (13/316.5) [282] 5.6 (7/125.1) [170] 0.88 (0.34–2.62)
Bandim, 1981–1983.
178 children were rst DTP-unvaccinated and then received DTP during follow-up.
Three children had no information on sex. If we adjusted for the most recent WAZ
measurement, the HR of 1.48 (0.72–3.06) became 1.52 (0.74–3.15).
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theHR estimateforDTP-vaccinatedversusDTP-unvaccinated
asmost recent vaccine changed from 1.77 (0.93–3.38) to 1.89
(1.00–3.55).
e inherent biases in this study are clearly in favor of the
DTP-vaccinated children (2): rst, the DTP vaccine protects
against three severe diseases. Second, the DTP-unvaccinated
childrenwereusuallychildrendeemedtoosickortooweaktobe
vaccinated,asevidencedbythenurse’snotesontheBHPcardand
bythefactthatthesechildrenhadworsenutritionalstatus.ird,
DTP-unvaccinatedchildrenattendedtheweighingsessions less
frequently(Ta bl e  1)andwere,therefore,morelikelytobestay-
ingforlongerperiodsintheruralareaswherethemortalityrisk
washigher (12). Noteworthy,we were able to obtain mortality
informationfromthesechildrenbecause theirfatherandother
relativesstayedinthestudyarea.
WHOexperts haveargued that the negative eect of DTP
is exaggerated, because studies have only been conducted
insituationswith herd immunityagainstpertussisand where
the benet of preventing pertussis would not be seen (13).
However, pertussis was endemic in the 1980s before the roll
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outofthevaccinationprograminGuinea-Bissau,butallthree
studiesoftheintroductionofDTPintourbanandruralareas
ofGuinea-BissaushowedexcessmortalityassociatedwithDTP
vaccination(5,12).
Comparison With Previous Studies
of DTP and OPV
Thisstudywassmall(TableS1inSupplementaryMaterial)and
manyresultswerenotstatisticallysignificant;somevariability
was,therefore,alsotobeexpected.Stilltheresultswerevery
similartothepreviousstudiesoftheintroductionofDTPand
OPV. All threestudieshaveaccurateassessmentofvaccina-
tion status andprospective follow-up; all three studies have
found that DTP is associated with an increase in all-cause
mortality (3). A previous meta-analysis suggested twofold
higher mortality for DTP-vaccinated children (3). However,
thisis probablyan underestimationofthe“true”effectsince
the unvaccinated groupis usually affected by various nega-
tivehealth selectionbiases,includingfrailtybias.Inthebest
studies,withnoselectionbiasorgoodcontrolforfrailtybias,
DTPhasbeenassociatedwithfourtofivetimeshighermortal-
ity(2,5).
As in this study, we have previouslyfound excess female
mortality after DTP vaccination (4). In our previous meta-
analysis, we compared DTP-vaccinated females with DTP-
unvaccinated, but BCG-vaccinated females, and DTP was
associatedwithanHRof2.54(1.68–3.86).Inthethreestudies
oftheintroductionofDTPveryfewoftheDTP-unvaccinated
hadreceivedBCG.Hence,DTPseemstohaveamarkednega-
tiveeffect for females irrespective ofwhether one compares
DTP-vaccinatedgirlswithtotallyunvaccinatedorwithBCG-
vaccinatedgirls.
erehavebeenfew studiesofOPVadministeredalone(5).
Itis,therefore,worth notingthatthe small numberofchildren
whoreceivedOPVonlyhadlowermortalitythanDTP-vaccinated
children in this study (Table S1 in Supplementary Material),
althoughthedierencewasnotstatisticallysignicant.Wehave
recentlybeenabletodocumentmarkedbenecialeectsofOPV
onall-cause mortalityinbothrandomized trials andinnatural
experimentswithOPVcampaigns(18,19).
Interpretation
Various WHO committees have previously reviewed the non-
specic eects of vaccines and have dismissed the possibility
thatDTPcouldhavenegativeeects,andhavesuggestedthatthe
negativeeectofDTPis likelytobe explainedbyuncontrolled
confounding or bias (1317). Recently, the Strategic Advisory
Groupof Exp erts onImmunization sponsored a review of the
potential non-specic eects of BCG, DTP, and MV (15, 16).
oughitwasnotedthatthemajorityofstudies(7/10)showeda
deleteriouseectofDTP,theevidencewasconsideredinconsist-
entbecausetwostudiesshowedabenecialeect.Furthermore,
thereviewinvoked“ahighriskofbias”foralltheobservational
studies(17).
However,itisimportanttoconsiderthedirectionofbias.All
documentedbiasesfavorthevaccinatedgroupbecausevaccination
isusuallydelayedinunhealthychildren,andDTP-unvaccinated
childrenshould,therefore,haveahigher mortality than vacci-
natedchildren(2,3).eWHOreviewmentionedfourpotential
biases,whichwouldfavortheunvaccinatedgroup(15).First,sick
childrenmightcomemoreoentoahealthcenterforconsulta-
tionand,therefore,be morelikelytoreceiveDTP, since WHO
has recommended vaccination of sick children; this bias was
clearlynotrelevantin Guinea-Bissau,whereneithernursesnor
mothersthoughtthatasickchildshouldbevaccinated.Second,
startingfollow-upfromasurveysometimeaertheactualDTP
vaccinationshadbeenadministered,aswouldoenhappenina
setting,wherevaccinationinformationiscollectedwithintervals,
could potentially mean that frail children in the unvaccinated
grouphad already died, and thattheDTP-vaccinatedchildren,
therefore, had an “unnaturally” high mortality (15). e one
study testing this found no evidence for such a bias (20) and
moreimportantly,several studies,includingallthreestudies of
theintroductionofDTPinGuinea-Bissau,startedobservationat
thedateofvaccinationforalmostallchildrenandfoundstrong
negativeeects.Hence,thisbiaswas notrelevantin thepresent
study. ird, censoring follow-up at subsequent MV would
remove some of the best children from the DTP-vaccinated
groupand,therefore,gives higher mortalityin the DTP group
(15).Again,thestudiesthathavetestedthispotentialbiashave
notfound evidence for suchabias(21)but,moreimportantly,
several studies—like the present one—did not censor for MV
and found equally strongnegative eects for DTP (2). Hence,
thisbiaswas notrelevantinthisstudy.Fourth,ithas been dis-
cussedwhetherabiasinreportingcouldhaveplayedarole(15).
eobservationof increased mortality aerDTPwasreported
morethan15yearsago(22),andhasnotbeencontradictedbya
properlyconductedprospectivestudy.Incontrast,severalother
groups have reported that DTP was associated with increased
overallmortality (2325) or higher femalethanmalemortality
(23,2628).Hence,reportingbiasisaveryunlikelyexplanation.
WehavenowreportedallthepossibledatasetsfromwhenDTP
wasintroducedinboth urbanandrural areasofGuinea-Bissau
(5,12); allshowedanegativeeectofDTP vaccination.Hence,
reportingbiasisnotrelevantinrelationtothestudiesoftheintro-
ductionofDTPfromGuinea-Bissau.erefore,thethreestudies
oftheintroduction ofDTPfromGuinea-Bissau(5,12)arenot
aectedbythetheoreticalbiasesusedtorecommendcautionin
theinterpretationofobservationalstudiessuggestingdeleterious
eectsfromDTP(1517).
e specic immunological mechanisms explaining why
DTPandOPVhaveNSEshavenotyetbeenidentied.However,
thereisanincreasingevidencethatlivevaccines(BCG,Vaccinia)
induce innate immune training producing stronger pro-
inammatoryresponseswhichmaylead to protection against
unrelated infections (29, 30). In contrast, studies of non-live
vaccine have suggestedt hatthey may induce tolerance which
couldenhance the susceptibility to unrelated infections (31). e
patternofworseeectsforfemalesthanformaleshaveturned
outtobesystematicforseveralnon-livevaccines,includingDTP
(4,26),inactivatedpoliovaccine(32),hepatitisBvaccine(33),
pentavalentvaccine(34),andRTS,Smalariavaccine(35).is
patternhasnotbeenstudiedfromanimmunologicalperspective
andanexplanationhasstilltobefound.
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Implications and Conclusion
OurdataclearlyshowedthatDTP vaccinationswere delayed
inunhealthychildren.Hence,healthierchildrenreceivedDTP
rst, and DTP-unvaccinated children should, therefore, have
hada higher mortality rate.Despitethis,DTPwasassociated
withincreased child mortality,particularlyforgirls.All three
studies of the introduction of DTP vaccine found negative
eectswhicharedierentfromwhatshouldhavebeenexpected
due to the disease-preventive eects of the vaccine and the
inherentbiasesfavoringvaccinatedchildren(5,12).eresults
arealso instarkcontrasttothestudiesoftheintroductionof
measlesvaccine, whichuniformlyshowvery strongmortality
reductions(6,7,15).Hence,thestudiesoftheintroductionof
DTPconstituteacleardangersignalthatDTPmaysubstantially
increaseall-causemortality.
Addingtothedangersignal,DTPisassociatedwithincreased
female mortality relative to male mortality in all available
studies. Girls did not havehigher mortality than boys in the
pre-vaccinationerainWestAfrica(2).Hence,thereisaneedfor
furtherresearchtoassesstheoverallmortalityeectofDTPand
howthe negativeeectsofDTP can be removedormodied.
Forexample,co-administrationofBCGandDTPmayreduce
the negative eect of DTP (21). Randomized trials have also
shownthatMV or BCG administeredshortlyaerDTP may
reducethenegativeeectofDTPandlowermortality(2).Such
alternativeimmunizationstrategiesshouldbefurthertestedin
randomizedtrials.
Given the threat from diphtheria, tetanus, and pertussis
and the less-eective acellular pertussis vaccine used in many
countries,itisunderstandablethattherehasbeenreluctancein
acceptingthatDTPcouldhavenegativeeectsforoverallhealth
inlow-incomecountries.However,thestudiesfromlow-income
countrieshavebeenconsistentin showingdeleterious eect of
DTP (3); furthermore, the rst studies are now showing that
non-live and live vaccines have dierential NSEs on hospital
admissions for infectious diseases in high-income countries
(36,37).Hence,itwouldseemtobehightimetosettlewhether
DTPhasnegativeeectsonoverallchildhealthandifithasnega-
tiveeectstoexplorewhetheralternativevaccinationschedules
couldremovetheproblem.
Inthecurrentglobalimmunizationsystem,thecoveragefor
thethirddoseofDTP(DTP3)isusedasthemainperformance
indicatorfornationalimmunizationprograms.iswill clearly
lead to an emphasis on increasing the coverage for DTP3 (1)
morethanthecoverageforothervaccines.Giventhatallstudies,
includingthepresentone,suggestthat DTP is associatedwith
increasedfemalemortality,thisisreallyanillogicalposition.We
needtouseprogramperformanceindicatorswhicharepositively
associatedwithbetterchildsurvival.
INDEPENDENCE
efunding agencieshadnorolein thestudydesign, datacol-
lection,data analysis, data interpretation,orthe writing of the
report.
TRANSPARENCY
erstauthorarmsthatthe manuscriptisanhonest, accu-
rate,and transparentaccountofthe studybeing reported; that
noimportantaspectsofthestudyhavebeenomitted;and that
any discrepancies from the study as planned (and, if relevant,
registered)havebeenexplained.
DATA SHARING
roughrequesttotheauthors.
ETHICS STATEMENT
estudyofnutritionalstatuswasplannedbetweentheSAREC
(Swedish Agency for Research Collaboration with Developing
Countries)and the Ministry ofHealthinGuinea-Bissau.ere
werenoethicalcommitteesforapprovalofhealthresearchatthe
timeofthestudy.e studywas explainedtothepopulationin
communitymeetingsorganizedbythe localcommitteeandthe
researcherspriortoinitiationofdatacollection.Consentwasnot
soughtfromindividualmothers,since theprojectimplemented
intended national policies for nutritional surveillance and
immunization.
AUTHOR CONTRIBUTIONS
CBandPAproposedthestudy.PAcollectedtheoriginaldata.
AR is responsible forthe demographic surveillance system.
SM and PA cleaned the data. SM conducted the statistical
analyses.ThefirstdraftwaswrittenbyPA;allauthorscontrib-
utedtothefinalversionofthepaper.PAwillactasguarantor
ofthestudy.
FUNDING
e present study and the cleaning of the original data were
supported by a common grant from DANIDA andt he Novo
Nordisk Foundation. e work on non-specic eects of
vaccines has been supported by the Danish Council for
DevelopmentResearch,MinistryofForeignAairs,Denmark
[grant number 104.Dan.8.f.], Novo Nordisk Foundation,
and European Union FP7 support for OPTIMUNISE (grant:
Health-F3-2011-261375). CSB held a starting grant from the
ERC(ERC-2009-StG-243149).CVIVAissupportedby a grant
from the Danish National Research Foundation (DNRF108).
PAheldaresearchprofessorshipgrantfromthe NovoNordisk
Foundation.
SUPPLEMENTARY MATERIAL
eSupplementaryMaterialforthisarticlecanbefoundonlineat
http://www.frontiersin.org/articles/10.3389/fpubh.2018.00079/
full#supplementary-material.
9
Aaby et al. Introduction of DTP to Children Aged 6–35Months
Frontiers in Public Health | www.frontiersin.org March 2018 | Volume 6 | Article 79
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10
Aaby et al. Introduction of DTP to Children Aged 6–35Months
Frontiers in Public Health | www.frontiersin.org March 2018 | Volume 6 | Article 79
inactivatedandlivevaccines,2005–2014.Clin Infect Dis(2017)65(5):729–37.
doi:10.1093/cid/cix44
Conict of Interest Statement:e authorsdeclare that the research wascon-
ductedintheabsenceofanycommercialornancialrelationshipsthat couldbe
construedasapotentialconictofinterest.
Copyright © 2018 Aaby, Mogensen, Rodrigues and Benn. is is an open-access
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... Beneficial off-target effects have also been described for other live vaccines, such as measles 5 and oral polio vaccines 6 . In contrast to live vaccines, nonlive vaccines, such as the diphtheria-tetanus-pertussis vaccines, have been suggested to be associated with increased childhood mortality 7 . ...
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Live attenuated vaccines often have beneficial non-specific effects, protecting against heterologous infectious and non-infectious diseases. We have developed a live attenuated pertussis vaccine, named BPZE1, currently in advanced clinical development. Here, we examined the prophylactic and therapeutic potential of its pertactin-deficient derivative BPZE1P in a mouse model of house dust mite (HDM)-induced allergic airway inflammation (AAI). BPZE1P was given nasally either before or after sensitization with HDM, followed by HDM challenge, or between two challenge episodes. Vaccination prior to sensitization reduced resistance in the airways, the numbers of infiltrating eosinophils and the concentrations of proinflammatory cytokines, such as IL-1α, IL-1β and IL-33, in the lungs but had no effect on Th2 cytokine levels. BPZE1P also protected when delivered after sensitization or between two challenge episodes. However, in this case the levels of Th2 cytokines in the lung were decreased without significant effects on IL-1α, IL-1β and IL-33 production. The vaccine restored lung function and decreased eosinophil influx in the lungs of HDM-treated mice. BPZE1P has a better take than BPZE1 in hosts vaccinated with acellular pertussis vaccines. Therefore, it has interesting potential as a preventive and therapeutic agent against AAI, even in acellular pertussis-vaccinated populations.
... Inadvertently, some vaccine promotion efforts may lead to higher death rates. Scientist Peter Aaby and colleagues have studied the mortality of children in Guinea-Bissau following various vaccines (Aaby et al., 2018;Kristensen, 2000). The measles vaccine reduces mortality significantly but the DTP triple vaccine (diphtheria, tetanus and pertussis) increases mortality, quite dramatically for young girls. ...
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Essay review of Robert F Kennedy Jr's book The Real Anthony Fauci, comparing its claims with academic critiques of biomedine.
... Sex influences the immune response to infections and vaccines [32][33][34], and sex-differential effects have been observed for offtarget effects of vaccination [35][36][37][38]. These include reduced allcause mortality following OPV in boys [39], greater benefit of measles-containing vaccines in girls [6,40,41], and possibly increased all-cause mortality in girls following diphtheriatetanus-pertussis vaccine [42][43][44][45][46] and the RTS,S vaccine [47][48][49][50][51]. Sex-based differences in immune responses are well described, and there is a sex-differential predisposition in auto-immune disorders [34,52,53]. The sex-differential immunological effect observed in our study is consistent with the finding that in Gambian infants there was a sex-differential effect in the immunomodulation induced by the co-administration of a non-live vaccine (diphtheria-tetanus-pertussis vaccination) and a live-attenuated vaccine (measles) [54]. ...
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Introduction Bacille Calmette-Guérin (BCG) and hepatitis B (HBV) vaccines are frequently given concomitantly at birth. Neonatal BCG vaccination induces off-target immunological effects. Whether HBV vaccine has immunomodulatory effects is unknown. As off-target effects might vary when vaccines are given simultaneously, this randomised controlled trial aimed to evaluate the influence of neonatal vaccination with BCG and/or HBV on heterologous immune responses. Methods A total of 185 neonates in Australia were randomised to receive either neonatal BCG-Denmark vaccine, HBV vaccine, both (BCG + HBV group), or none (No vaccine group). In-vitro responses to heterologous stimulants were assessed 7 days after vaccination. The influence of (i) randomisation group and (ii) sex on interferon-gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP-1), and tumour necrosis factor-alpha (TNF-α) responses was analysed using linear regression. Results Overall, BCG vaccination alone or with HBV co-administration reduced IFN-γ and MCP-1 responses to heterologous stimulants. HBV vaccination alone did not alter heterologous cytokine responses. In general, males produced more IFN-γ and TNF-α than females. We observed a sex-differential effect in relation to the influence of HBV co-administration on the effect of BCG on heterologous responses. Compared with males in the No vaccine group, males in the BCG + HBV group had lower IFN-γ and MCP-1 responses. In contrast, compared with females in the No vaccine group, females in the BCG group had higher IFN-γ response and lower MCP-1 responses. Conclusion Neonatal BCG vaccination resulted in lower cytokine responses to unrelated pathogens. HBV co-administration did not have a significant impact on responses overall but influenced the heterologous effects of neonatal BCG vaccination in a sex-differential manner.
... We need to give predictions on this issue because individual cases of vaccination against some infectious diseases have shown that vaccinated individuals may exhibit higher mortality over time and that vaccination with some vaccines may interfere with the efficacy of other vaccines. [7][8] Also, as the issue of the duration of vaccine protection has emerged, more people are concerned about how long the protection can be provided by the antibodies triggered by their immune response [4,9]. ...
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Infectious disease such as COVID-19 poses a considerable threat to public health when a pandemic strain emerges. Constructing a reliable mathematical model helps us quantitatively explain the kinetic characteristics of antibody-virus interactions, which could provide a reasonable prediction toward many sensitive concerns faced by the public, such as how to calculate protection time provided by the specific vaccine. A novel and robust model is developed to integrate antibody dynamics with virus dynamics in the host body. Our model is based on a comprehensive understanding of immunology principles rather than a simple data-fitting attempt by arbitrarily mathematical function selection. The physical-based mechanism would bring this model more reliable and broader prediction performance. This model gives quantitative insights between antibody dynamics and virus loading in the host body. Based on this model, we can estimate the antibody dynamic parameters with high fidelity. We could solve lots of critical problems, such as the calculation of vaccine protection time. We can also explain lots of mysterious phenomena such as antibody inferences, self-reinfection, chronic infection, etc. We suggest the best strategy in prolonging the vaccine protection time is not repeated inoculation but a directed induction of fast binding antibodies. Eventually, it will also inform the future construction of the mathematical model and help us fight against those infectious diseases.
... For example, BCG immunization, instead of having the immediate impact of alleviating mortality among children under 5, it has a long-term impact for adults by avoiding TB infections. Meanwhile, DPT's effect on under-five mortality is mixed (32,33). In fact, the immunization that offers the greatest impact on under-five mortality is the one for measles. ...
... These effects have been termed ''non-specific" [2]. General hypotheses of non-specific effects have been proposed from observations accumulated through epidemiological studies [1]; among these, that live vaccines enhance resistance towards unrelated infections [3][4][5][6][7][8][9][10][11][12], whereas non-live vaccines enhance susceptibility of females to unrelated infections [13][14][15][16][17][18][19][20][21][22][23], although many of these studies are considered at high risk of bias [24]. There is a lack of randomized trials of non-specific effects of non-live vaccines. ...
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Vaccines may affect recipients’ immune systems in ways that change morbidity or mortality rates to unrelated infections in vaccinated populations. It has been proposed that these non-specific effects differ by type of vaccine and by sex, with non-live vaccines enhancing susceptibility of females to unrelated infections, and live vaccines enhancing resistance in both sexes. Rabies vaccine–a non-live vaccine–has been associated with protection against unrelated central nervous system infections. Data from randomized controlled trials are needed to assess this effect against other illnesses. This phase IV, single-site, participant-blinded, randomized, placebo-controlled trial in a population of veterinary students on the rabies-free island of St. Kitts assessed the effect of a primary course of rabies vaccine on the incidence rate of weekly self-reported new episodes of common infectious disease (CID) syndromes, defined as a new episode of any one of the following syndromes in a particular week: upper respiratory illness (URI), influenza-like illness (ILI), diarrheal illness (DIA) or undifferentiated febrile illness (UFI). As a secondary objective, we tested for modification of the effect of rabies vaccine on study outcomes by sex. 546 participants were randomized (274 to rabies vaccine and 272 to placebo). No statistically significant differences between groups were observed for any study outcomes: CID incidence rate ratio (IRR) 0.95 (95% CI 0.77–1.18); URI IRR 1.15 (95% CI 0.86–1.54); ILI IRR 0.83 (95% CI 0.54–1.27); DIA IRR 0.93 (95% CI 0.70–1.24) and UFI IRR 1.09 (95% CI 0.48–2.44). In a secondary analysis, there was little evidence that sex modified the effect of vaccination on any of the evaluated outcomes, although the power to detect this was low. In conclusion, rabies vaccine did not provide protection against mild self-reported illness among a young and healthy group of adults attending veterinary school. Clinical trial registration. ClinicalTrials.gov: NCT03656198.
... It is now known that several live attenuated vaccines have this beneficial, nonspecific protective effect leading to decreased childhood mortality. Inactivated vaccines such as the diphtheria-tetanus-pertussis (DTP) vaccine have been suggested to induce an opposing program and can diminish the induction of trained immunity and possibly even lead to increased childhood mortality, especially among vaccinated girls (20,111). This is important for future vaccination strategies and also for the order in which vaccination programs are designed. ...
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Traditionally, the innate and adaptive immune systems are differentiated by their specificity and memory capacity. In recent years, however, this paradigm has shifted: Cells of the innate immune system appear to be able to gain memory characteristics after transient stimulation, resulting in an enhanced response upon secondary challenge. This phenomenon has been called trained immunity. Trained immunity is characterized by nonspecific increased responsiveness, mediated via extensive metabolic and epigenetic reprogramming. Trained immunity explains the heterologous effects of vaccines, which result in increased protection against secondary infections. However, in chronic inflammatory conditions, trained immunity can induce maladaptive effects and contribute to hyperinflammation and progression of cardiovascular disease, autoinflammatory syndromes, and neuroinflammation. In this review we summarize the current state of the field of trained immunity, its mechanisms, and its roles in both health and disease. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Background The live vaccines bacille Calmette-Guérin (BCG) and measles vaccine have beneficial non-specific effects (NSEs) reducing mortality more than can be explained by prevention of tuberculosis or measles infection. Live oral polio vaccine (OPV) will be stopped after polio eradication, we therefore reviewed the potential NSEs of OPV. Methods OPV has been provided in three contexts. First, co-administration of OPV and diphtheria-tetanus-pertussis (DTP) vaccine at 6, 10 and 14 weeks of age. Second, at birth (OPV0) with BCG. Third, in OPV campaigns (C-OPV) initiated to eradicate polio infection. We searched PubMed and EMBASE for studies of OPV with mortality as an outcome. We used meta-analysis to obtain combined relative risk (RR) of mortality associated with different uses of OPV. Results First, in natural experiments when DTP was missing, OPV-only compared with DTP + OPV was associated with 3-fold lower mortality in community studies (RR = 0.33 (0.14-0.75)) and a hospital study (RR = 0.29 (0.11-0.77)). Conversely, when OPV was missing, DTP-only was associated with 3-fold higher mortality than DTP + OPV (RR = 3.23 (1.27-8.21)). Second, in a randomised controlled trial, BCG + OPV0 vs. BCG + noOPV0 was associated with 32% (0-55%) lower infant mortality. Beneficial NSEs were stronger with early use of OPV0. Third, in five population-based studies from Guinea-Bissau and Bangladesh, the mortality rate was 24% (17-31%) lower after C-OPVs than before C-OPVs. Interpretation There have been few clinical polio cases reported in this century and no confounding factors or bias would explain all these patterns. The only consistent interpretation is that OPV has beneficial NSEs, reducing non-polio child mortality.
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Background: There are worrying indications that diphtheria-tetanus-pertussis (DTP) vaccine has negative non-specific effects for females. We previously found, in a trial of early-Bacillus Calmette-Guérin (BCG) to low weight (LW) neonates, that receiving early-DTP (before 2 months of age), was associated with increased female mortality compared with no-DTP/delayed-DTP. Within a subsequent LW trial, we aimed to retest this observation. Methods: Between 2010 and 2014, in Guinea-Bissau, 2,398 infants were randomised 1:1 to early-BCG (intervention) or delayed-BCG (standard practice for LW neonates) and visited at 2, 6 and 12 months of age to assess nutritional and vaccination status. DTP is recommended at 6 weeks of age. We examined the effect of having "early-DTP" versus "no-DTP" at the time of the 2-month visit on all-cause mortality between the 2- and 6-month visits in Cox models stratified by sex and adjusted for BCG-group and 2-month-weight-for-age (z-scores) providing adjusted mortality rate ratios (aMRRs). We analysed to which extent conditions varied between the present and the previous LW trials and how that might have affected the overall result of comparing the early-DTP and the no-DTP groups. Results: At the time of the 2-month visit, 75% (1,795/2,398) had received DTP. Those vaccinated had better anthropometric indices than no-DTP infants at birth and by 2 months of age. Between the 2- and 6-month visits, 29 deaths occurred. The early-DTP/no-DTP aMRR was 1.09 (95% CI: 0.44-2.69); 1.19 (0.45-3.15) for females and 0.77 (0.14-4.19) for males. Compared to the previous study, the present study cohort had 56% (30-72%) lower overall mortality, fewer no-DTP infants, higher BCG vaccination coverage and several more oral polio vaccine campaigns. Conclusion: We did not find that early-DTP was associated with increased female mortality as found in a previous study; differences in results may partly be due to a decline in overall mortality and changes in vaccination practices.
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Introduction Human non-live vaccines have been associated with detrimental non-specific effects (NSE), particularly in females. A large trial found 2-fold increased overall mortality in girls receiving a new malaria vaccine compared to the rabies vaccine used as a coontrol; a beneficial NSE of the rabies vaccine was proposed. Conversely, in dogs increased mortality was seen in females but not males following rabies vaccination of puppies born to immunized mothers. We investigated NSE of non-live rabies vaccine in piglets and the potential modifying effect of maternal priming with rabies vaccine. Methods In a Danish herd of commercial rabies virus-free pigs, 575 pregnant sows (2–3 weeks before scheduled farrowing) and 5747 of their offspring (median 6-day-old) were allocated (1:1) to non-live rabies vaccine (Versiguard rabies vet) or no rabies vaccine. Outcomes were overall mortality and antibiotic treatment until departure from the nursery (approximately age 12 weeks/30 kgs). Results Until weaning, overall offspring mortality was 2.2% (127 piglets died, rabies vaccine: n = 69; control: n = 58), the proportion ratio (PR) being 1.19 (95% confidence interval: 0.84–1.68). Until end of follow-up, mortality was 4.1% (233, rabies vaccine: n = 115; control = 118, PR: 0.97 (0.76–1.25)). Prior sow rabies vaccination did not affect piglet mortality. For mortality as well as risk of antibiotic treatment before weaning, there was indication of a beneficial effect of rabies vaccine in female piglets, but a negative effect in (castrated) male piglets from rabies-naïve sows. Prior sow vaccination significantly modified the vaccine effect estimate in female piglets toward a detrimental effect of rabies vaccine on treatment risk. These effects had waned by 12 weeks of age. Conclusion The study did not support the hypothesized beneficial NSE of rabies vaccine. Although under-powered for subgroup analyses, the study indicated effect modification by sex and maternal vaccination. Results could be different in a herd with higher mortality and infectious burden.
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Background A recent WHO review concluded that live BCG and measles vaccine (MV) may have beneficial non-specific effects (NSEs) reducing mortality from non-targeted diseases. NSEs of oral polio vaccine (OPV) were not examined. If OPV vaccination campaigns reduce the mortality rate, it would suggest beneficial NSEs. Setting Between 2002 and 2014, Guinea-Bissau had 15 general OPV campaigns and other campaigns with OPV plus vitamin A supplementation (VAS), VAS-only, MV, and H1N1 vaccine. In this period, we conducted seven randomized controlled trials (RCTs) with mortality as main outcome. Methods Within these RCTs, we assessed whether the mortality rate was lower after-campaign than before-campaign. We used Cox models with age as underlying time and further adjusted for low birth-weight, season and time trend in mortality. We calculated the adjusted mortality rate ratio (MRR) for after-campaign vs before-campaign. Results The mortality rate was lower after OPV-only campaigns than before, the MRR being 0.81 (95% CI = 0.68–0.95). With each additional dose of campaign-OPV the mortality rate declined further (MRR = 0.87 (95% CI: 0.79–0.96) per dose) (test for trend, p = 0.005). No other type of campaign had similar beneficial effects. Depending on initial age and with follow-up to 3 years of age, the number needed to treat with campaign-OPV-only to save one life was between 68 and 230 children. Conclusion Bissau had no case of polio infection so the results suggest that campaign-OPV has beneficial NSEs. Discontinuation of OPV-campaigns in low-income countries may affect general child mortality levels negatively.
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Background: WHO recommends BCG at birth and diphtheria-tetanus-pertussis (DTP)-containing vaccine at 6, 10 and 14weeks of age. However, BCG and DTP are often co-administered in low-income countries. The health implications have not been examined. Setting: We reanalysed data from Matlab, Bangladesh, to examine the influence of co-administration on mortality; 37,894 children born 1986-1999 were followed with registration of vaccinations and survival. Methods: Using Cox models, survival was analysed from 6weeks to 9months of age when measles vaccine is given; 712 children died in this age group. We calculated mortality rate ratios (MRR) for children starting the vaccination schedule with BCG-first, BCG+DTP1-first or DTP1-first. Results: Only 17% followed the WHO-schedule with BCG-first. Mortality was 16/1000 person-years for children who initiated the vaccination schedule with BCG+DTP1 but 32/1000 and 20/1000 for children who received BCG-first or DTP-first, respectively. Compared with BCG+DTP1-first and adjusting for background factors, the BCG-first-schedule was associated with 2-fold higher mortality (MRR=1.94 (1.42-2.63)). DTP1 administered after BCG-first was associated with higher mortality than receiving DTP1 with BCG (MRR=1.78 (1.03-3.03)). Conclusions: Co-administration of BCG and DTP may further reduce mortality. Since all observational studies support this trend, co-administration of BCG and DTP should be tested in randomised trials.
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Background: We examined the introduction of diphtheria-tetanus-pertussis (DTP) and oral polio vaccine (OPV) in an urban community in Guinea-Bissau in the early 1980s. Methods: The child population had been followed with 3-monthly nutritional weighing sessions since 1978. From June 1981 DTP and OPV were offered from 3months of age at these sessions. Due to the 3-monthly intervals between sessions, the children were allocated by birthday in a 'natural experiment' to receive vaccinations early or late between 3 and 5months of age. We included children who were <6months of age when vaccinations started and children born until the end of December 1983. We compared mortality between 3 and 5months of age of DTP-vaccinated and not-yet-DTP-vaccinated children in Cox proportional hazard models. Results: Among 3-5-month-old children, having received DTP (±OPV) was associated with a mortality hazard ratio (HR) of 5.00 (95% CI 1.53-16.3) compared with not-yet-DTP-vaccinated children. Differences in background factors did not explain the effect. The negative effect was particularly strong for children who had received DTP-only and no OPV (HR=10.0 (2.61-38.6)). All-cause infant mortality after 3months of age increased after the introduction of these vaccines (HR=2.12 (1.07-4.19)). Conclusion: DTP was associated with increased mortality; OPV may modify the effect of DTP.
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Objective To examine the effect of the first introduction of measles vaccine (MV) in Guinea-Bissau in 1979. Setting Urban community study of the anthropometric status of all children under 6 years of age. Participants The study cohort included 1451 children in December 1978; 82% took part in the anthropometric survey. The cohort was followed for 2 years. Intervention In December 1979, the children were re-examined anthropometrically. The participating children, aged 6 months to 6 years, were offered MV if they did not have a history of measles infection. There were no routine vaccinations in 1979–1980. Primary and secondary outcome measures Age-adjusted mortality rate ratios (MRRs) for measles vaccinated and not vaccinated children; changes in nutritional status. Results The nutritional status deteriorated significantly from 1978 to 1979. Nonetheless, children who received MV at the December 1979 examination had significantly lower mortality in the following year (1980) compared with the children who had been present in the December 1978 examination but were not measles vaccinated. Among children still living in the community in December 1979, measles-vaccinated children aged 6–71 months had a mortality rate of 18/1000 person-years during the following year compared with 51/1000 person-years for absent children who were not measles vaccinated (MRR=0.30 (0.12–0.73)). The effect of MV was not explained by prevention of measles infection as the unvaccinated children did not die of measles infection. Conclusions MV may have beneficial non-specific effects on child survival not related to the prevention of measles infection.
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Background: Recent studies have shown that some vaccines have beneficial effects that could not be explained solely by the prevention of their respective targeted disease(s). Methods: We used the MarketScan® United States (US) Commercial Claims Databases from 2005-2014 to assess the risk of hospital admission for non-targeted infectious diseases in children from 16 through 24 months according to the last vaccine type (live and/or inactivated). We included children continuously enrolled within a month of birth through 15 months who received at least three doses of Diphtheria-Tetanus-acellular Pertussis vaccine by end of 15 months of age. We used Cox regression to estimate hazard ratios (HRs), stratifying by birthdate to control for age, year and seasonality, and adjusting for sex, chronic diseases, prior hospitalizations, number of outpatient visits, region of residence, urban/rural area of domicile, prematurity, low birth weight, and mother's age. Results: 311,663 children were included. In adjusted analyses, risk of hospitalization for non-targeted infections from ages 16 through 24 months was reduced for those who received live vaccine alone compared with inactivated alone or concurrent live and inactivated vaccines (HR 0.50, 95% CI 0.43, 0.57 and HR 0.78, 95% CI 0.67, 0.91, respectively), and for those who received live and inactivated vaccines concurrently compared with inactivated only (HR 0.64, 95% CI 0.58, 0.70). Conclusions: We found lower risk of non-targeted infectious disease hospitalizations from 16 through 24 months among US children whose last vaccine received was live compared with inactivated vaccine, as well as concurrent receipt compared with inactivated vaccine.
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Background: Ten years ago, we formulated two hypotheses about whole-cell diphtheria-tetanus-pertussis (DTP) vaccination: first, when given after BCG, DTP increases mortality in girls and, second, following DTP there is an increase in the female/male mortality rate ratio (MRR). A recent review by WHO found no convincing evidence that DTP increases mortality in females. Methods: We used previous DTP reviews as well as the recent WHO review for assessing the hypotheses. As pre-specified we excluded studies with survival or frailty bias; if children had received BCG and DTP simultaneously; and if the children had received neonatal vitamin A. Results: In seven studies of BCG-vaccinated children, DTP vaccination was associated with a 2.54 (95% CI 1.68-3.86) increase in mortality in girls (with no increase in boys [ratio 0.96, 0.55-1.68]). In 10 studies of BCG-vaccinated children, the female-to-male mortality ratio was 2.45 (1.48-4.06) times higher after DTP than before DTP. In 15 studies of children who had received DTP after previous BCG vaccination, mortality was 1.53 (1.21-1.93) times higher in girls than boys. The findings were similar in studies conducted before and after formulation of the hypotheses. Conclusions: The two hypotheses were confirmed in the studies that fulfilled pre-specified criteria.
Article
Background: In addition to protection against the target diseases, vaccines may have non-specific effects (NSEs). Measles vaccine (MV) has beneficial NSEs, providing protection against non-measles deaths, most so for girls. By contrast, though protecting against diphtheria, tetanus and pertussis, DTP vaccine is associated with increased female mortality relative to male mortality. In 2008, Guinea-Bissau replaced DTP with the DTP-containing pentavalent vaccine (Penta; DTP-H. influenza type B-Hepatitis B) at 6, 10 and 14weeks and yellow fever vaccine (YF) was to be given with MV. We investigated possible sex-differential mortality rates following Penta and MV+YF vaccination. Methods: Bandim Health Project (BHP) registers vaccines given by the three government health centres in the study area and vital status through demographic surveillance. We assessed the association between sex and mortality by vaccination status in Cox proportional hazards models with age as underlying timescale. Follow-up was censored at a subsequent vaccination contact or after 6months of follow-up. Results: Between September 2008 and April 2011, we registered 23,448 vaccination contacts for children aged 42-365days; 17,313 were for Penta and 3028 for MV (2907 co-administered with YF). During follow-up 112 children died. The female/male mortality rate ratio was 1.73 (1.11-2.70) following Penta and 0.38 (0.12-1.19) after MV (p=0.02 for same effect). Adjusting for maternal education or weight-for-age at the time of vaccination did not change the estimates. Conclusion: Penta appears to have the same negative effects on mortality as those seen for DTP. Assessing post-vaccination mortality for boys and girls is necessary to improve the vaccination programme.
Article
Background: WHO recently reviewed the possible non-specific effects of diphtheria-tetanus-pertussis (DTP) vaccine. The results were considered inconsistent though most studies suggested deleterious effects. We examined whether inconsistencies in results reflected differences in effect of DTP or differences in the methodology used in different studies. Methods: If children remain unvaccinated because they are frail or if children (including dead ones) with no information on vaccination status are classified as 'unvaccinated', the mortality rate becomes unnaturally high among 'unvaccinated' controls. To measure this bias, we defined the "bias index" as the mortality rate ratio (MRR) between unvaccinated and vaccinated children. Results: Five studies had frail or poorly defined control groups and survival bias, the bias index being 2.0-8.0; in these studies DTP was associated with a MRR of 0.39 (0.18-0.83). Eight studies determined 'unvaccinated' by vaccination card and the bias index was 0.5-1.7; in these studies DTP was associated with a MRR of 2.00 (1.50-2.67). Conclusion: The observed inconsistencies in results were due to methodologic differences between studies. Bias does not seem to explain why DTP is associated with higher mortality.
Article
OBJECTIVES: In situations with vaccination coverage high enough to control pertussis, observational studies have reported divergent effects of diphtheria-tetanus-pertussis (DTP) vaccination on childhood survival. We examined whether this could be because of methodological differences. METHODS: Some studies of the impact of DTP updated information on vaccination retrospectively (retrospective updating approach) while others kept vaccination status fixed for the time between follow-up visits (landmark approach). First, we conducted simulations with these approaches to investigate the impact of different mortality levels, vaccination incidence rates, intervals between data collection visits, and the proportion of children whose vaccination card had not been seen after death. Second, we re-analysed data from Guinea-Bissau using the retrospective updating approach. RESULTS: In simulations, the retrospective updating approach produced rate ratio (vaccinated/unvaccinated) estimates biased towards zero because of a differential misclassification which created survival bias as risk-free observation time was allocated to the vaccinated group. The landmark approach produced rate ratio estimates biased towards one. Biases increased with interval between data collection visits and incidence of vaccination, but were unaffected by the underlying mortality level. Survival bias increased with the proportion of dead children whose vaccination status could not be updated. The re-analysis of data from Guinea-Bissau changed the estimated impact of DTP from an 84% higher mortality using the landmark approach to a 37% lower mortality using the retrospective updating approach. CONCLUSIONS: The apparent contradiction between DTP studies could be because of methodological differences. To assess child survival associated with routine vaccinations, studies minimizing the effect of biases are warranted.