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The Introduction of Diphtheria-Tetanus-Pertussis and Oral Polio Vaccine Among Young Infants in an Urban African Community: A Natural Experiment

  • Bandim Health Project

Abstract and Figures

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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Research Paper
The Introduction of Diphtheria-Tetanus-Pertussis and Oral Polio Vaccine
Among Young Infants in an Urban African Community: A
Natural Experiment
Søren Wengel Mogensen
, Andreas Andersen
, Amabelia Rodrigues
, Christine S Benn
, Peter Aaby
Bandim Health Project, Indepth Network, Apartado 861, Bissau, Guinea-Bissau
Research Centre for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institute, Artillerivej 5, 2300 Copenhagen S, Denmark
OPEN, Institute of Clinical Research, University of Southern Denmark/Odense University Hospital, 5000 Odense C, Denmark
abstractarticle info
Article history:
Received 4 June 2016
Received in revised form 21 January 2017
Accepted 29 January 2017
Available online 1 February 2017
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 3 months of age at these sessions. Due to the 3-monthly intervals be-
tween sessions, the children were allocated by birthday in a natural experimentto receive vaccinations early or
late between3 and 5 months of age. We included children who were b6 monthsof age when vaccinations started
and children born until the end of December 1983. We compared mortality between 3 and 5 months of age of
DTP-vaccinated and not-yet-DTP-vaccinated children in Cox proportional hazard models.
Results: Among 35-month-old children, having received DTP (±OPV) was associated with a mortality hazard
ratio (HR ) of 5.00 (95% CI 1.5316.3) comparedwith not-yet-DTP-vaccinatedchildren. 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 (2.6138.6)). All-cause infant mortality after 3 months of age increased after the
introduction of these vaccines (HR = 2.12 (1.074.19)).
Conclusion: DTP was associated with increased mortality; OPV may modify the effect of DTP.
© 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
Diphtheria-tetanus-pertussis vaccine
Measles vaccine
Non-specic effects of vaccines
Oral polio vaccine
1. Introduction
Individually randomized studies to measure impact on child survival
of different vaccines were not conducted when the Expanded Program
on Immunization (EPI) was introduced in low-income countries in the
1970s. The disease-protective effects were well documented, so the
main issue was at which age to introduce the vaccine most effectively
(The Expanded Programme on Immunization, 1982). Except for mea-
sles vaccine (MV), surprisingly few studies examined the introduction
of vaccines and their impact on child survival (Aaby et al., 1983,
2003a; Holt et al., 1990; The Kasongo Project Team, 1981). One trial of
measles-vaccinated and measles-unvaccinated communities in Congo
showed a larger than expected reduction in child mortality (Aaby et
al., 1981); this observation was subsequently corroborated by commu-
nity trialsand before-after studies in several countries (Aaby et al.
1984, 1993, 2003a; Holt et al., 1990; Kapoor and Reddaiah, 1991).
Hence, a vaccine may have non-specic effects (NSEs) on susceptibility
to other infections (Aaby et al., 1995). WHO's Strategic Advisory Group
of Experts on Immunization (SAGE) recently reviewed the potential
NSEs of BCG, diphtheria-tetanus-pertussis (DTP) and MV and recom-
mended further research (Higgins et al., 2014; Strategic Advisory
Group of experts on Immunization, 2014).
Though protective against the target diseases, DTP may increase sus-
ceptibility to unrelated infections (Aaby et al., 2003b, 2004a, 2012)
(Appendix A). The SAGE review noticed that the majority of studies
found a detrimental effect of DTP (Higgins et al., 2014). However,
SAGE considered the evidence inconsistent because two studies report-
ed benecial effects (Higgins et al., 2014) and that most studies
underestimated the benet of DTP because studies were conducted in
situations with herd immunity. Furthermore, all studies gave DTP and
OPV together, making it impossible to separate effects of DTP and OPV
(SAGE non-specic effects of vaccines Working Group, 2014).
On the other hand, the unvaccinatedchildren in these studies have
usually been frail children too sick or malnourish to get vaccinated, and
the studies may therefore have underestimated the negative effect of
DTP. We therefore examined what happened when DTP and OPV
were rst introduced, but not always given together, in 19811983 in
EBioMedicine 17 (2017) 192198
Corresponding author at: Bandim Health Project, Statens Serum Institute, Artillerivej
5, 2300 Copenhagen S, Denmark.
E-mail address: (P. Aaby).
Joint rst-authorship.
2352-3964/© 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (
Contents lists available at ScienceDirect
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the capital of Guinea-Bissau. In this situation the children were allocated
by birthday to receive vaccines early or late and the unvaccinated
were therefore not frail children.
2. Methods
2.1. Background
Bandim Health Project (BHP) has followed an urban community
with a demographic surveillance system since December 1978, and
took part in the introduction of vaccines well before a full-edged na-
tional program was implemented with UNICEF support in 1986 (Aaby
et al., 1984, 2004a).
2.2. Demographic Surveillance
In 19781979, under-ve mortality was nearly 500/1000. Since mal-
nutrition was assumed to be the main cause, a study was initiated to de-
termine why children were malnourished (Aaby et al., 1983). However,
severe malnutrition was not evident, and to understand the high mor-
tality we started a health and demographic surveillance system
(HDSS). The area was mapped and a census conducted. Four health
workers were employed to identify pregnant women, encourage
women to attend ante-natal clinics, and to follow children with anthro-
pometric measurements to assess growth patterns and detect malnour-
ished children. Each health worker followed a population of 15002000
individuals. The health workers were supervised by anexpatriate nurse.
For each sub-district in Bandim, the responsible health worker kept
a list of children under three years of age. BHP had no computerized sur-
veillance system until 1990 but kept an A5 card (BHP card) for each
child, where weights and vaccination dates were noted. The child's
growth card was kept by the mother.
The Bandim population was very mobile. It was important to main-
tain contact with the natal village for ceremonial purposes and to secure
rice. Furthermore, mothers were not supposed to have sexual relations
during breastfeeding (Jakobsen et al., 2004). Breastfeeding was
prolonged in Guinea-Bissau. Thus, many women stayed in the rural
areas with their natal family while breastfeeding. These cultural
traditions introduced variability in the participation in weighing and
vaccination sessions.
2.3. Anthropometry
We arranged quarterly weighing sessions in each sub-district. The
responsible health worker advisedmothers the day before a community
weighing. The following morning, the weight was measured and noted
on the child's growth card and the BHPcard. When the World Food Pro-
gram provided supplementary feeding this was given to families with
malnourished children.
2.4. Vaccinations
There was no community vaccination program in 1981 except that
we had organized a few measles vaccination campaigns (Aaby et al.,
1984). Mothers could take their children to the Mother and Child Health
Program in town. However, this clinic was mainly attended by the
urban elite. Few children were vaccinated before BHP organized vacci-
nation sessions (Table 1).
In June 1981, BHP started to provide vaccinations at the quarterly
weighing sessions. A health center nurse accompanied the weighing
team and vaccinated eligible children. DTP and OPV were provided
from 3 months and MV from 9 months of age. OPV-at-birth was not
given then.The three DTP and OPV doses could be given with an interval
of one month but since we only arranged weighing every three months,
most children had longer intervals between doses. DTP was adminis-
tered intramuscularly and OPV as an oral drop. When both vaccines
were administered at the same session OPV was usually given rst
and then DTP; the children would usually start crying after DTP due to
the pain of the injection and it would therefore have complicated the
administration of OPV to give DTP rst. There were several periods
where either OPV or DTP was missing (Fig. 1). BCG was rarely provided
at the weighing sessions since most nurses were not trained to admin-
ister intra-dermal vaccination. A total of 269 children may have been
BCG vaccinated as they had a vaccination date on their card (N =
192) or were noted to have received BCG but no date given (N = 77).
The expatriate nurse sometimes organized additional vaccination
sessions in which the children were not weighed. During these sessions,
Table 1
Median age of vaccination and coverage for BCG, DTP and OPV of study cohort.
1980 1981 1982 1983 19811983
Median age in days (N vaccines)
BCG 9 (4) 48.5 (50) 34 (46) 25 (68) 33 (164)
DTP1 97 (12) 127 (147) 121 (164) 117 (278) 121 (589)
OPV1 98 (12) 118 (185) 121.5 (170) 117 (225) 118 (580)
MV 181 (5) 141 (53) 157 (2) 110 (1) 141.5 (56)
Coverage at 6 months of age
BCG 1.7% (5/289) 3.5% (12/342) 23.7% (72/304) 17.4% (57/327) 14.5% (141/973)
DTP1 4.2% (12/289) 31.3% (107/342) 61.2% (186/304) 73.1% (239/327) 54.7% (532/973)
DTP3 2.4% (7/289) 0.9% (3/342) 4.3% (13/304) 4.0% (13/327) 3.0% (29/973)
OPV1 4.2% (12/289) 43.0% (147/342) 62.5% (190/304) 69.7% (228/327) 58.1% (565/973)
OPV3 2.4% (7/289) 2.0% (7/342) 4.3% (13/304) 4.0% (13/327) 3.4% (33/973)
MV 2.8% (8/289) 15.2% (52/342) 0.7% (2/304) 0% (0/327) 5.5% (54/973)
Coverage at one year of age
BCG 2.6% (3/116) 2.4% (7/294) 15.4% (51/332) 17.4% (46/264) 11.7% (104/890)
DTP1 2.6% (3/116) 32.7% (96/294) 71.1% (236/332) 83.0% (219/264) 61.9% (551/890)
DTP3 2.6% (3/116) 4.4% (13/294) 18.4% (61/332) 43.2% (114/264) 21.1% (188/890)
OPV1 2.6% (3/116) 37.4% (110/294) 77.4% (257/332) 84.8% (224/264) 66.4% (591/890)
OPV3 2.6% (3/116) 12.2% (36/294) 32.5% (108/332) 44.3% (117/264) 29.3% (261/890)
MV 15.5% (18/116) 68.0% (200/294) 34.0% (113/332) 51.1% (135/264) 50.3% (448/890)
Notes: The inclusion criteria for thecohort in Table 1 are the same as for our study cohort: weight examination after 15 days of age and contribute time between 91 and 183 daysof age.
Median age: yearmeans the year the vaccination was given, and median age is the median age at time of vaccination with a given vaccine among children vaccinated before turning
6 months. E.g. the 4 BCG vaccines in the 1980 column were given in 1980 to children with a median age of 9 days.
Coverage: yearmeansthe year when thechild turned exactly1 year (or 6 months)old and coveragewas assessed. Onlychildren survivingto 1 year (or 6 months)of age were assessedfor
coverage. Children turning 1 year in 1984 were thus not presented in the table.
193S.W. Mogensen et al. / EBioMedicine 17 (2017) 192198
vaccinations were noted on the BHP cards. Both nurses and mothers
thought that sick children should not be vaccinated; the BHP card
often indicated that the child was sick,malnourishedor orphanas
an explanation of why an age-eligible child had not been vaccinated.
2.5. Data Control
When a computerized system became available in 19901991,
weights and vaccinations from the BHP cards were entered. For the
present analysis, all information on dates of visit, weights and vaccina-
tion dates was checked against the original cards. A few cards were
not available or could no longer be found (Fig. 2).
2.6. The Study Cohort
We included children born from December 3, 1980 as they would
become eligible for vaccination before 6 months of age (Fig. 2). Few chil-
dren were vaccinated with BCG (Table 1). Children who travelled and
never attended any session were not included in the unvaccinated
group. Children weighed within a fortnight of their birth to obtain a
birth weight were only included if they took part in a subsequent com-
munity weighing session. Furthermore, we excluded orphans since they
were not breastfed and were likely to have different care. The cohort is
depicted in Supplementary Fig. 1.
2.7. Natural Experiment for 35-month-old Children
Though not individually randomized, the present study is a natural
experiment with limited bias ingroup allocation:With 3-monthlyinter-
vals between weighing sessions, children were allocated by their birth-
day to receive their rst vaccinations early or late between 3 and
5monthsofage(Fig. 3). We therefore compared 35-month-old chil-
dren who had received DTP (±OPV) vaccinations early with children
who had not yet received these vaccinations. Since there were no
healthy unvaccinatedchildren after 6 months of age unless they had
travelled, we censored follow-up of all children at 6 months of age
(Fig. 3).
Sick children were not vaccinated, in the main analysis we therefore
censored unvaccinatedchildren who attended a weighing session but
did not receive a vaccination (Fig. 3). Since the censoring of sick children
could have introduced a bias, we also conducted an intention-to-treat
analysis in which the censored children were transferred to the DTP
group. Hence, in this analysis we compared the mortality of the
intended-DTP-vaccinated group and the not yet DTP-vaccinated group.
Children were included from 91 days of age if they had been exam-
ined in a weighing session before 91 days; if they were only seen in a
weighing session after 3 months of age they were only included from
the day seen. DTP was not administered elsewhere and the follow-up
time of children was therefore counted as DTP-unvaccinated time in
the survival analysis until BHP provided the vaccine. Time as DTP-un-
vaccinated also came fromchildren who did not turn up at the weighing
sessions between 3 and 5 months of age but had been seen before
3 months of age and therefore were part of the community cohort
(Fig. 3). Hence, the DTP-vaccinated and DTP-unvaccinated children
were all children from the same cohort of children born in Bandim
and their allocation depended on the timing of their birth date, the
timing of the weighing sessions and their travelling pattern. We
Fig. 1. Each vaccination of the specied type is plotted according age of the recipient and date of vaccination.
Fig. 2. Flowchart of studypopulation and children included in the analyses. Notes: DOB =
date of birth; [] indicates the number of deaths before 6 months of age in the group.
194 S.W. Mogensen et al. / EBioMedicine 17 (2017) 192198
compared the background factors for the children who were DTP vacci-
nated, attended a weighing session between 3 and 5 months but were
not vaccinated and those who did not attend a weighing session
(Table 2).
We also examined the mortality of children who due to logistic rea-
sons had received DTP-only. Absences and travelling patterns are un-
likely to differ between children who at their rst vaccination had
received DTP1 + OPV versus DTP1-only; thesetwo groups were equally
likely to receive subsequent vaccinationsboth with respect to timing of
subsequent vaccinations and coverage (data available on request).
2.8. Statistical Methods
First possible enrolment date was June 2, 1981, when DTP and OPV
vaccinations were introduced. Different vaccination groups were com-
pared using a Cox proportional hazard model with age as underlying
Children were classied according to their most recent vaccination
(Supplementary Table 1). We ignored BCG vaccinations in the main
analysis because we gave few BCG vaccinations (Table 1) and some chil-
dren had received BCG at the maternity ward without proper documen-
tation as some children had a BCG scar but no vaccination card. To avoid
survival bias, we used a landmark approach (Jensen et al., 2007); hence,
a child's vaccination status was only updated from the day the informa-
tion was collected. Due to the additional vaccination sessions organized
by the expatriate nurse some unvaccinatedchildren received a vac-
cine before the weighing session where they changed status to vacci-
nated; it is noted in the footnote to Table 3 how many had received
such vaccinations. As a sensitivity analysis we also did an analysis in-
cluding the additional vaccination sessions as landmarks. For the re-
mainder of this paper, we will refer to these landmarks as vaccination-
The WHO z-score for weight-for-age was used to assess nutritional
status. Control for sub-district, ethnic group and twinning did not
change the results (data not shown). There was no obvious clustering
Fig. 3. Natural experiment studydesign. Note: Children were weighed everythird month. After3 months of age theyreceived DTP and OPVon weighing daysif they were healthy.Children
who attendedbut were not vaccinated at a weighing session after 3 months of age were censored in the survival analysis comparing DTP-vaccinated and unvaccinated children.
Table 2
Background factors children in the main analysis of vaccination and mortality between 3 and 5 months of age.
DTP-vaccinated at
35 months
Attended weighing session at
35 months, not vaccina ted
Did not attend weighing
session at 35 months
Number 662 186 209
Male sex 52.1% 53.2% 54.1%
Twin 2.7% 2.2% 2.9%
Birth weight (SD) 3.23 (0.025) 3.28 (0.061) 3.22 (0.051)
Ethnic group
Pepel 46.8% 54.8% 45.0%
Balanta 11.8% 13.4% 16.3%
Other ethnic groups 41.4% 31.7% 38.8%
Mean weight-for-age z-score (SD) at examination before 3 months of age 0.30 (0.037) 0.34 (0.084) 0.43 (0.066)
Follow-up time (person-years) between 3 and 5 months;
[Median number of days of follow]
All time 135.5 [92] 36.8 [86] 47.4 [92]
73.3 1.8 2.0
62.2 35.1 45.4
Mean number (SD) of weighing sessions per year between 6 and 11 months
of age
2.7 (0.03) 2.2 (0.07) 1.6 (0.08)
195S.W. Mogensen et al. / EBioMedicine 17 (2017) 192198
of deaths and control for season and calendar time did not change esti-
mates (data not shown).
There were 18 deaths between 3 and 5 months of age: 3 had cough
and respiratory infections as the main symptom, 3 had fever (presumed
malaria), 2 were due to diarrhea, 5 had diarrhea and vomiting, 1 was a
sudden death, and 4 had no information on cause.
2.9. Ethics
The study of nutritional status was planned by SAREC (Swedish
Agency for Research Collaboration with Developing Countries) and the
Ministry of Health in Guinea-Bissau.
3. Results
Of 1356 children registered in Bandim and followed to 3 months of
age (Fig. 2), 286 were never weighed, had no card or their card was
lost. An additional 13 children had inconsistent information, vaccinations
marked with a cross but without dates or were orphans. Hence, 1057 chil-
dren were included in the study cohort. The median ages for DTP1 and
OPV1 were 121 and 118 days, respectively (Table 1). The vaccination cov-
erage at 6 months of age was 55% for DTP1; 3% got DTP3 (Table 1). Cover-
age for MV was only 6%. Of the DTP1, OPV1 and MV vaccinations noted on
the BHP card 9095% had been administered by the BHP.
For children examined after 91 days, a one-unit increase in w/a z-
score was associated with an odds ratio of 1.07 (0.931.24) for receiving
a vaccination at that weighing session.
3.1. Natural Experiment with 35-month-old Children
There were no marked differences in background factors for the three
groups of children who were DTP vaccinated at 35monthsofage,those
who attended a weighing session but were not vaccinated, and those who
did not attend a weighing session at 35monthsofage(Table 2). Birth
weight was similar in the three groups. Weight-for-age z-score before
3 months of age did not differ for the three groups (Table 2). Those who
did not attend a weighing session at 35 months of age were signicantly
less likely to attend later weighing sessions during infancy, the mean
number of visits being lower for those not attending than for those
being DTP-vaccinated (p b0.001) (Table 2); hence, they are likely to
have travelled more than those who were DTP-vaccinated.
In the main experiment depicted in Fig. 3, DTP vaccination (±OPV)
compared with DTP-unvaccinatedwas associated with a HR of 5.00
(1.5316.3) (Table 3); the HR was 9.98 (0.81123) for girls and 3.93
(1.0115.3) for boys. If we also included vaccinations given on vaccina-
tions-days-without-weighing in the landmark analysis, DTP (± OPV)
compared with unvaccinated was associated with a HR of 3.90 (1.20
12.3). When DTP had been given alone without OPV the HR was 10.0
(2.6138.6) (Table 3). The difference between DTP-only children and
DTP-plus-OPV does not reect differences in follow-up and other vacci-
nations since the timeto DTP2 and prevalence of DTP2 was the same for
DTP-only and DTP-plus-OPV vaccinated children (data not shown). If
we excluded the 269 children who may have been BCG vaccinated re-
sults were similar (Supplementary Table 2).
If the analysis was conducted as an intention-to-treat analysis in
which the children weighed but not vaccinated were not censored but
transferred to the DTP group, the intended-DTP-vaccinated group had
a HR of 3.92 (1.2012.8) compared with the not-yet vaccinated group
(Supplementary Table 3).
3.2. Secondary Analyses
Since the introduction of DTP and OPV apparently was associated
with increased mortality, we examined what happened to infant mor-
tality from 3 to 12 months of age after the introduction of these vac-
cines. The mortality rate for all 311 months old children increased 2-
fold (HR = 2.12 (1.074.19)) from 1980, before vaccinations, to
19821983, after the introduction of DTP and OPV (Table 4).
4. Discussion
4.1. Main Observations
DTP vaccinations were associated with increased infant mortality even
though there was no vaccine-induced herd immunity. When unvaccinated
controls were normal children who had not yet been eligible for vaccina-
tion, mortality was 5 times higher for DTP-vaccinated children. Co-adminis-
tration of OPV with DTP may have reduced the negative effects of DTP.
4.2. Strength and Weaknesses
The present analysisassessed DTP and child survival in a natural ex-
perimentin which the children were allocated by the timing of their
birth and community weighing sessions and the group allocation was
therefore not inuenced by the usual selectionbiases to the same extent
as most other studies of DTP (Aaby et al., 2016). To assure that the cen-
soring from the main analysis of children who were not vaccinated had
not produced the unexpected strong result we made an intention-to-
treat analysis but this did not change the result. If anything the un-
vaccinated children had slightly worse nutritional status before
3 months of age than the children who were subsequently DTP vac-
cinated(p=0.09)(Table 2); the unvaccinated children travelled
more than the DTP vaccinated children. These biases would tend to
favor rather than increase mortality in the DTP group and the
Table 3
Mortality rate and hazard rate (HR) for children from 3 months of age until rst examination without vaccination or 6 months of age. Natural experiment.
Age group
35 months Mortality rate (deaths/person-years) HR (95% CI) for DTP vs unvaccinated
(N = 651)
4.5 (5/111.4) DTP OPV) (N = 462) 17.4 (11/63.1) 5.00 (1.5316.3)
DTP only (N = 101) 35.2 (5/14.2) 10.0 (2.6138.6)
DTP + OPV (N = 361) 12.3 (6/48.9) 3.52 (0.9612.9)
(N = 313)
1.9 (1/51.9) DTP OPV) (N = 222) 13.3 (4/30.1) 9.98 (0.81123.0)
DTP only (N = 44) 16.2 (1/6.2) 12.0 (0.56257.2)
DTP + OPV (N = 178) 12.5 (3/23.9) 9.50 (0.73124.0)
(N = 338)
6.7 (4/59.5) DTP OPV) (N = 240) 21.2 (7/33.0) 3.93 (1.0115.3)
DTP only (N = 57) 49.8 (4/8.0) 8.93 (2.0139.7)
DTP + OPV (N = 183) 12.0 (3/24.9) 2.21 (0.4411.0)
Notes:There were no deaths due accidents in thisage group. BCG is disregarded in the analysis.Hence, the unvaccinated children have not received DTP, OPVor MV but may have received
BCG. Of the 651 unvaccinated children, 219 received DTP and/orOPV before their rst weighing examination. These children counted as unvaccinateduntil their rst weighing exami-
nation. Of the 462 children who received DTP (±OPV), 177 receivedan additional DTP or OPV before 6 monthsof age. The OPV-only is not presented in the table because there were no
deaths and very little follow-up time in this age group.
196 S.W. Mogensen et al. / EBioMedicine 17 (2017) 192198
estimates from the natural experiment may therefore still be
The estimated effects of DTP andOPV are unlikely tohave been inu-
enced by other vaccinations since very few had received other vaccines;
if the children who may have received BCG were censored in the analy-
sis the result was essentially the same (Supplementary Table 2).
The 3-monthly community examinations assured that we had fol-
low-up information for all children and relatively accurate information
on the time of death. Some children were excluded because a BHP
card could not be found and we did not know whether they had been
vaccinated or were travelling. Most likely, BHP cards may never have
been made because the child was not coming for examination, or the
card may have disappeared at community examinations, at the later
handling of BHP cards by eld workers or data entry clerks, or due to
mice. However, the few missing cards are unlikely to have affected the
main analysis as the mortality rate in this group was similar to the gen-
eral mortality rate (Fig. 2).
To assure comparability of vaccinated and unvaccinated groups, also
with respect to travelling, we included only children who had been
weighed in Bandim in connection with the 3-monthly community ex-
aminations. This meant that children who mostly stayed outside the
area were not included in the analysis; these children had no access to
community vaccinations and they lived elsewhere where the mortality
risk might have been quite different, e.g. due to a higher risk of malaria
The present study was not a planned trial. The study would have
been a cleaner natural experiment if vaccinations had only been admin-
istered at the weighing sessions. However, the expatriate nurse did or-
ganize additional vaccinations and some unvaccinatedchildren had
therefore already received a vaccination before coming for a weighing
session. These misclassicationsdo not explain the increased mortality
in the DTP group. The estimate for DTP-vaccinated (±OPV) compared
with DTP-unvaccinated children was 4-fold higher mortality when we
included these additional landmarks in the analysis.
4.3. Comparison with Previous Studies of DTP and OPV
There is only one other study of the introduction of DTP. In rural
Guinea-Bissau, DTP (±OPV) was associated with 2-fold higher mortal-
ity (Aaby et al., 2004a). All studies that documented vaccination status
and followed children prospectively indicate that DTP has negative ef-
fects; a meta-analysis of the eight studies found 2-fold higher mortality
for DTP-vaccinated compared with DTP-unvaccinated, mostlyBCG-vac-
cinated controls (Aaby et al., 2016)(Appendix A).
The negative effect of DTP was much worse in this natural experi-
ment than has been reported in previous studies of DTP. This is presum-
ably due to the unvaccinatedcontrol children in previous studies
having been a frail subgroup too frail to get vaccinated. Previous studies
have not been able to compare DTP-vaccinated children with normal
controls. Hence, most previous studies have probably underestimated
the negative effect of DTP.
The potentially differential effects of DTP and OPV have only been
examined in few studies. However, we have recently been able to doc-
ument marked benecial NSEs of OPV. In an RCT, OPV at birth (OPV0)
reduced infant mortality by 32% (057%) before the children received
campaign-OPV (Lund et al., 2015). In Bissau campaign-OPV reduced
the mortality rate by 19% (532%) (submitted). When DTP was missing
for several months in Bissau, we showed that the all-cause case-fatality
at the pediatric ward was 3-fold lower if the children had OPV-only as
their most recent vaccination rather than the recommended combina-
tion of DTP and OPV (Aaby et al., 2004b). Thus, OPV may have modied
the negative effect of DTP.
This pattern was also seen when DTP was rst introduced in the
rural areas of Guinea-Bissau in 1984 (Aaby et al., 2004a). OPV was not
used the rst year and the HR for DTP versus unvaccinated was 5.00
(0.6339.7). In the period from 1985 to 1987, when DTP and OPV
were nearly always administered together, the MRR was 1.90 (0.91
3.97). In the present study, the hazard ratio was 10.0 (2.6138.6) for
DTP-only but 3.52 (0.9612.9) for children who received DTP and OPV
simultaneously (Table 3). Based on these two studies of the introduc-
tion of DTP, the HR compared with DTP-unvaccinated children was sig-
nicantly different for children who had received DTP-only (HR = 8.14
(2.6315.2)) and for children who received both DTP and OPV (HR =
2.21 (1.164.19)) (test of interaction, p = 0.049). Hence, simultaneous
administration of DTP and OPV may have alleviated the negative non-
specic effect of DTP.
5. Conclusions
DTP was associated with 5-fold higher mortality than being unvacci-
nated. No prospective study has shown benecial survival effects of
DTP. Unfortunately, DTP is the most widely used vaccine, and the pro-
portion who receives DTP3 is used globally as anindicator of the perfor-
mance of national vaccination programs.
It should be of concern that the effect of routine vaccinations on all-
cause mortality was not tested in randomized trials. All currently avail-
able evidence suggests that DTP vaccine may kill more children from
other causes than it saves from diphtheria, tetanus or pertussis. Though
a vaccine protects children against the target disease it may simulta-
neously increase susceptibility to unrelated infections.
The recently published SAGE review called for randomized trials of
DTP (Higgins et al., 2014). However, at the same time the IVIR-AC com-
mittee to which SAGE delegated the follow-up studies of the NSEs of
vaccines has indicated that it will not be possible to examine the effect
of DTP in an unbiased way. If that decision by IVIR-AC remains unchal-
lenged, the present study may remain the closest we will ever come
to a RCT of the NSEs of DTP.
The presentstudy and cleaning of the original data was supported by
a common grant from DANIDA and the Novo Nordisk Foundation (FU-
11-551). The work on non-specic effects of vaccines has been support-
ed by the Danish Council for Development Research, Ministry of Foreign
Affairs, 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 Re-
search Foundation (DNRF108). PA held a research professorship grant
from the Novo Nordisk Foundation.
Table 4
Mortality rates (deaths/100 person-years) between 3 and 11 months of age by study year.
Mortality rate 1980 1981 1982 1983
HR (95% CI) for 19821983 versus
Children aged
311 months
4.7 (10/211.8)
(N = 547)
7.2 (18/250.8)
(N = 678)
8.0 (19/237.1)
(N = 632)
12.1 (30/247.5)
(N = 638)
2.12 (1.074.19)
Notes: Event recorded as accidents were not removed from this analysis.
197S.W. Mogensen et al. / EBioMedicine 17 (2017) 192198
Conict of Interest
Nothing to declare
CSB and PA proposed the study. PA collected the original data. AR is
responsible for the demographic surveillance system. SWM and PA
cleaned the data. SWM and AA conducted the statistical analyses. The
rst draft was writtenby PA; all authors contributed to the nal version
of the paper. PA and SWM will act as guarantors of the study.
The funding agencies had no role in the study design, data collection,
data analysis, data interpretation, or the writing of the report.
Data Sharing
Through request to the authors
Appendix A. The DTP Controversy
The issue of DTP vaccination and child mortality in high mortality
areas was raised 15 years ago when a study from rural Guinea-Bissau
showed 1.84-fold higher mortality for children who had received
DTP1 vaccination (Aaby et al., 2016; Kristensen et al., 2000). All subse-
quent prospective studies have supported a negative effect (Aaby et
al., 2016). Furthermore, DTP may have a negative effect when given si-
multaneously with or after MV (Aaby at el., 2003b, 2012). For example,
the negative effect of high-titer measles vaccination (HTMV) in girls,
which led to the global withdrawal of HTMV, was due to DTP being ad-
ministered after MV because HTMV had been given early at 45months
of age (Aaby et al., 2003b).
DTP has not been shown to have benecial effects in RCTs or natural
experiments. The current policy for DTP has only been examined by
reanalyses of existing data sets collected for other purposes. All such
studies have had methodological problems related to different forms
of frailty and survival bias (Aaby et al., 2012). These studies have up-
dated follow-up time for DTP-vaccinated children who survived but
children who died without their vaccination status being documented
were classied as unvaccinated. Such procedures give a misleading
high mortality rate in the unvaccinated group, and the comparison of
DTP-vaccinated survivors and unvaccinatedchildren will therefore
give a benecial estimate for DTP (Aaby et al., 2016). If the mortality
rate of unvaccinated children is unnaturally increased, the HR of unvac-
cinated children versus children who have received at least one vaccine
may indicate how much bias there might be in the study, and we have
called this HR the bias-index. All studies with prospective follow-up
have had a bias index below 2.0 (Aaby et al., 2016); in the present
study the bias index was 0.41 (0.151.15) in the 35 months age
group (Supplementary Table 2). In studies with survival bias and unnat-
urally high mortality in the unvaccinated group, the bias index has been
38 times higher (Aaby et al., 2016).
SAGE recently reviewed the potential NSEs of BCG, MV and DTP
(Higgins et al., 2014; Strategic Advisory Group of experts on
Immunization, 2014). The reviewers indicated that the majority of stud-
ies showed a deleterious effect of DTP but they concluded that the re-
sults were inconsistent because two studies showed a benecial effect.
The benecial effect in these studies was not surprising because the
mortality rate in the unvaccinated group was unnaturally high, and
the bias index was 3.40 (2.933.95) and 7.52 (5.1510.97), respectively
(Aaby et al., 2016).
SAGE's working group on non-specic effects of vaccines further
emphasized that the overall effect remains unclear because DTP has
been given in combination with other vaccines and under
circumstances where the burden of the target diseases has been re-
duced to a very low level. However, several previous studies have
shown that the negative effect of DTP-plus-OPV was not due to OPV
(Aaby et al., 2004a,b, 2012). OPV has probably reduced the overall neg-
ative effect of DTP. Previous studies have indicated that DTP (±OPV)
was associated with a 2-fold higher mortality than DTP-unvaccinated
children (Aaby et al., 2016). Since pertussis did not account for N56%
of infant deaths in the only existing African study of the impact of per-
tussis on child mortality (Mahieu et al., 1978), it is not surprising that
DTP is also associated with a strong negative effect prior to vaccine-in-
ducedherdimmunity(Aaby et al., 2012).
Appendix B. Supplementary Data
Supplementary data to this article can be found online at http://dx.
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... Approximately 50 of the 500 children vaccinated developed paralysis. [76] A 2017 study [77] showed that WHO's popular DTP vaccine is killing more African children than the diseases it prevents. DTP-vaccinated girls suffered ten times the death rate of children who had not yet received the vaccine. ...
... DTP-vaccinated girls suffered ten times the death rate of children who had not yet received the vaccine. [77] The haste in the deployment of the Covid-19 vaccine based on Emergency Use Approval occasioned by the fast spread and virulence of covid-19 did not give much time for African countries to carry out independent assessment of the suitability of the approved vaccines. [78] This is coupled with the paucity of standard indigenous and independent facilities to carry out the quality and content assessment of the recommended vaccines and their suitability for the indigenous populace that's mostly hungry for food. ...
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Vaccines played tremendous role in the treatment and subsequent eradication of once deadly infectious diseases. They are currently at the fore of the regimen for maintenance and optimization of health in our disease infested world. Vaccines work with the body's natural defences to develop immunity to disease. As long as the natural antibodies to existing disease conditions exist in any physiological system, it will be able to intercept and prevent the virulence of such infecting agents. The current practice of relying mainly on vaccines to contain the infection of coronaviruses during the flu season is maintained with less than convincing proof of reasonableness. This is because the nature of coronaviruses seems to suggest that they are not as vaccine preventable as diseases like polio and rickettsiae. They tend to have rapid conformational changes, which make them not capable of being contained by a specific form of vaccine for a long time, and a lot of funds are spent producing vaccines for different variants in flu seasons. Baring the cost of vaccine production, it is quite unlikely that the world can hold onto the coronavirus and prevent it from further variations while competent vaccines are produced for existing forms. It also seems unrealistic to embark on the production and inoculation of everyone with new vaccines for all strains of a universal virus. When viable vaccines can be produced for all forms of the coronavirus, then their transmission from person to person can be stopped. If this herd immunity is achieved, the virus will over time not exist in isolation and will gradually be eliminated. This is the hope for the Covid-19 vaccines and vaccine candidates, but it continues to look like a mirage. The
... While low coverage of interventions leads to low impact [12][13][14], the impact of interventions can be low even when coverage is high if the quality of the interventions is poor or there are adverse events associated with the interventions. Poorer child survival has been documented with health facility and skilled delivery compared to home deliveries [15], iron intake [16], diphtheria, pertussis, and tetanus (DPT) vaccine [17,18], and malaria vaccine [19,20]. To achieve rapid mortality decline and possibly achieve the Sustainable Development Goals (SDG) 3 target 2, information on interventions with the potential to rapidly reduce mortality is required. ...
... Regarding the eating habits of Ghanaians, results from the literature are inconsistent. While Buxton [29] recorded that 63 % of Junior High Students in Ghana reported skipping breakfast on school-going days, Intiful and Lartey [30] recorded 86 % of students aged [6][7][8][9][10][11][12][13][14][15][16][17][18][19] years old in the Eastern Region of Ghana taking breakfast on the day they were interviewed. 45 % of adolescents reported eating two home-cooked meals a day, and 34 % preferred a soft drink during the day [29]. ...
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Background Despite a 53 % decline in under-five mortality (U5M) worldwide during the period of the Millennium Development Goals (MDGs), U5M remains a challenge. Under-five mortality decline in Ghana is slow and not parallel with the level of coverage of child health interventions. The interventions promoted to improve child survival include early initiation of breastfeeding, clean postnatal care, and skilled delivery. This study sought to assess the effectiveness of these interventions on U5M in Ghana. Methods A quasi-experimental study was conducted using secondary data of the 2008 and 2014 Ghana Demographic and Health Surveys. Coarsened Exact Matching and logistic regression were done. The interventions assessed were iron intake, early initiation of breastfeeding, clean postnatal care, hygienic disposal of stool, antenatal care visits, skilled delivery, intermittent preventive treatment of malaria in pregnancy, and tetanus toxoid vaccine. Results There were 2,045 children under-five years and 40 (1.9 %) deaths in 2008. In 2014, the total number of children under-five years was 4,053, while deaths were 53(1.2 %). In 2014, children less than one month old formed 1.6 % of all children under-five years, but 47.8 % of those who died. Mothers who attended four or more antenatal care visits were 78.2 % in 2008 and 87.0 % in 2014. Coverage levels of improved sanitation and water connection in the home were among the lowest, with 11.6 % for improved sanitation and 7.3 % for water connection in the home in 2014. Fifty-eight (58), 1.4 %, of children received all the eight (8) interventions in 2014, and none of those who received all these interventions died. After controlling for potential confounders, clean postnatal care was associated with a 66% reduction in the average odds of death (aOR = 0.34, 95 %CI:0.14–0.82), while early initiation of breastfeeding was associated with a 62 % reduction in the average odds of death (aOR = 0.38, 95 % CI: 0.21–0.69). Conclusions Two (clean postnatal care and early initiation of breastfeeding) out of eight interventions were associated with a reduction in the average odds of death. Thus, a further decline in under-five mortality in Ghana will require an increase in the coverage levels of these two high-impact interventions.
... In addition, it is now well recognized that sex influences the immune response to infections and vaccines, 43,49,50 and sex-differential effects have been observed for off-target effects of vaccination. 12,51-53 These include reduced all-cause mortality after the oral poliovirus vaccine in boys, 54 greater benefit of measles-containing vaccines in girls, [55][56][57] and increased all-cause mortality in girls after diphtheria-tetanus-pertussis vaccine [58][59][60][61][62][63] and the RTS,S malaria vaccine. [64][65][66][67][68] The potential mechanism underlying these differences remains uncertain; sex chromosomes and sex hormones could both play a role. ...
Increasing evidence suggests that early-life bacillus Calmette-Guérin (BCG) vaccine could prevent atopic eczema through its beneficial off-target effects. In this meta-analysis, 3 randomized control trials with similar methods were included and enabled robust estimations with low heterogeneity, involving a total of 5655 children randomized to early-life BCG Denmark (n = 2832) or no BCG (n = 2823). Meta-analyses suggest a beneficial effect of BCG to prevent eczema (risk ratio [RR], 0.89; 95% confidence interval [CI], 0.82-0.98). In subgroup analyses, BCG was more beneficial in boys (RR, 0.84; 95% CI, 0.74-0.95) and in children born to 2 atopic parents (RR, 0.81; 95% CI, 0.68-0.97). The NNT to prevent one case of eczema among children of 1 or 2 atopic parent was 20 (95% CI, 12-50). Bacillus Calmette-Guérin Denmark leads to an 11% reduction in the risk of eczema in early life. A greater effect was observed with increasing predisposition. Given its well-established safety profile, neonatal BCG vaccination should be considered for children of atopic parents.
... Conversely The results were similar in the studies directly comparing DTP-only and DTP + OPV (Table 2). Between 3 and 8 months Mogensen et al [21] overlaps with reference [17] as it covers the same cohort but only in the age group 3-5 months, where the study was a natural experiment with limited selection bias. c Reported, directly or inversed, in the original publication. ...
Full-text available
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.
... 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]. ...
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.
... 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. ...
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. NCT03656198.
Full-text available
Background Oral Polio Vaccine (OPV) may improve resistance to non-polio-infections. We tested if OPV reduced the risk of illness and mortality prior to COVID-19-vaccines being available. Methods During the early COVID-19 pandemic, houses in urban Guinea-Bissau were randomised 1:1 to intervention or control. Residents aged 50 + years were invited to participate. Participants received bivalent OPV (single dose) or nothing. Rates of mortality, admissions, and consultation for infections (primary composite outcome) during 6 months of follow-up were compared in Cox proportional hazards models adjusted for age and residential area. Secondary outcomes included mortality, admissions, consultations, and symptoms of infection. Results We followed 3726 participants (OPV: 1580; Control: 2146) and registered 66 deaths, 97 admissions and 298 consultations for infections. OPV did not reduce the risk of the composite outcome overall, hazard ratio (HR) = 0.97 (95%CI: 0.79-1.18). OPV reduced the risk in males (HR = 0.71 (0.51-0.98) but not in females (HR = 1.18 (0.91-1.52), p for same effect = 0.02). OPV also reduced the risk in BCG scar-positive (HR = 0.70 (0.49-0.99) but not in scar-negative participants (HR = 1.13 (0.89-1.45), p = 0.03). OPV had no overall significant effect on mortality (HR = 0.96 (0.59-1.55)), admissions (HR = 0.76 (0.49-1.17)) or recorded consultations (HR = 0.99 (0.79-1.25)), but the OPV group reported more episodes with symptoms of infection (6050 episodes; HR = 1.10 (1.03-1.17)). Conclusion In line with previous studies, OPV had beneficial non-specific effects in males. Trial Registration
Background Polio eradication campaigns are intended to complement routine immunization. Studies addressing factors associated with campaign coverage are warranted to identify children missed by campaigns. Methods Bandim Health Project runs demographic surveillance with registration of routine immunization and campaign participation data in urban Guinea-Bissau. We assessed coverage and factors associated with receiving campaign polio vaccines in children aged 0–35 months in two polio eradication campaigns conducted in 2017 and 2018 using univariate and multivariate regression models. Results Campaign coverage reached 84% in 2017 and 88% in 2018. We found lower coverage among children of young and not formally educated mothers in univariate analyses; Children <9 months and Fula children had lower campaign coverage in both univariate and multivariate analyses. Conclusions To increase campaign coverage in urban Guinea-Bissau attention may be directed at informing young mothers, mothers of young children, mothers without formal education, and the Fula ethnic group about campaigns.
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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Background West African studies have suggested that national immunisation campaigns with oral polio vaccine (C-OPV) may non-specifically reduce all-cause child mortality rate by 15–25%. We investigated whether C-OPVs had similar non-specific effects in rural Bangladesh from 2004 to 2019. Methods Chakaria, is a health and demographic surveillance system (HDSS) in Southern Bangladesh. From 2004–2011 the HDSS covered a random sample of households; from 2012 to 2019 it covered a random sample of villages. Using Cox proportional hazards models, we calculated hazard ratios (HR) comparing mortality for children under 3 years of age after C-OPV versus before C-OPV to assess the effect of receiving a C-OPV. We allowed for different baseline hazard function in the two periods (2004–2011, 2012–2019), with separate models for each period. Findings There were 768 deaths (2.1%) amongst 36,176 children. The HR after C-OPV was 0.69 (95% confidence interval: 0.52–0.90). National campaigns providing vitamin A or measles vaccine did not have similar effects. Each additional dose of C-OPV was associated with a reduction in the mortality rate by 6% (−2 to 13%). The number needed to treat with C-OPV to save one life between 0 and 35 months of age was 88 (81–96). Interpretation This is the fourth study to show that C-OPV has beneficial non-specific effects on child survival. All studies have shown a beneficial effect of C-OPV on child health. Stopping OPV as planned after polio eradication without any mitigation plan could have detrimental effects for overall child health in low-income countries. Funding The Chakaria HDSS was funded by international sponsors. No sponsor had any influence on the preparation of the article.
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Background. Routine vaccines may have nonspecific effects on mortality. An observational study found that OPV given at birth (OPV0) was associated with increased male infant mortality. We investigated the effect of OPV0 on infant mortality in a randomized trial in Guinea-Bissau. Methods. A total of 7012 healthy normal-birth-weight neonates were randomized to BCG only (intervention group) or OPV0 with BCG (usual practice). All children were to receive OPV with pentavalent vaccine (diphtheria, tetanus, pertussis, Haemophilus influenzae type b, and hepatitis B) at 6, 10, and 14 weeks of age. Seven national OPV campaigns were also conducted during the trial period. Children were followed to age 12 months. We used Cox regression to calculate hazard ratios (HRs) for mortality. Results. The trial contradicted the original hypothesis about OPV0 increasing male infant mortality. Within 12 months, 73 children in the BCG + OPV group and 87 children in the BCG-only group died, all from infectious diseases. Comparing BCG + OPV0 vs BCG only, the HR was 0.83 (95% confidence interval [CI], .61–1.13): 0.72 (95% CI, .47–1.10) in boys and 0.97 (95% CI, .61–1.54) in girls. For children enrolled within the first 2 days of life, the HR for BCG + OPV0 vs BCG only was 0.58 (95% CI, .38–.90). From enrollment until the time of OPV campaigns, the HR was 0.68 (95% CI, .45–1.00), the beneficial effect being separately significant for males (0.55 [95% CI, .32–.95]). Conclusions. This is the only randomized trial of the effect of OPV0 on mortality. OPV0 may be associated with nonspecific protection against infectious disease mortality, particularly when given early in life. There are reasons to monitor mortality when OPV is being phased out. Clinical Trials Registration. NCT00710983.
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Measles vaccines (MV) have sex-differential effects on mortality not explained by protection against measles infection. The authors examined whether whole-cell diphtheria-tetanus-pertussis (DTP) vaccine has sex-differential and non-specific effects. DATA SOURCES AND ELIGIBILITY: Following previous reviews and a new search, the effect of DTP on mortality up to the next vaccination was assessed in all studies where DTP was given after BCG or DTP was given after MV and there was prospective follow-up after ascertainment of vaccination status. High-mortality countries in Africa and Asia. The initial observation of negative effect of DTP generated six hypotheses, which were examined in all available studies and two randomised trials reducing the time of exposure to DTP. Consistency between studies. In the first study, DTP had negative effects on survival in contrast to the beneficial effects of BCG and MV. This pattern was repeated in the six other studies available. Second, the two 'natural experiments' found significantly higher mortality for DTP-vaccinated compared with DTP-unvaccinated children. Third, the female-male mortality ratio was increased after DTP in all nine studies; in contrast, the ratio was decreased after BCG and MV in all studies. Fourth, the increased female mortality associated with high-titre measles vaccine was found only among children who had received DTP after high-titre measles vaccine. Fifth, in six randomised trials of early MV, female but not male mortality was increased if DTP was likely to be given after MV. Sixth, the mortality rate declined markedly for girls but not for boys when DTP-vaccinated children received MV. The authors reduced exposure to DTP as most recent vaccination by administering a live vaccine (MV and BCG) shortly after DTP. Both trials reduced child mortality. These observations are incompatible with DTP merely protecting against the targeted diseases. With herd immunity to whooping cough, DTP is associated with higher mortality for girls. Randomised studies of DTP are warranted to measure the true impact on survival.
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To examine whether the reduction in mortality after standard titre measles immunisation in developing countries can be explained simply by the prevention of acute measles and its long term consequences. An analysis of all studies comparing mortality of unimmunised children and children immunised with standard titre measles vaccine in developing countries. 10 cohort and two case-control studies from Bangladesh, Benin, Burundi, Guinea-Bissau, Haiti, Senegal, and Zaire. Protective efficacy of standard titre measles immunisation against all cause mortality. Extent to which difference in mortality between immunised and unimmunised children could be explained by prevention of measles disease. Protective efficacy against death after measles immunisation ranged from 30% to 86%. Efficacy was highest in the studies with short follow up and when children were immunised in infancy (range 44-100%). Vaccine efficacy against death was much greater than the proportion of deaths attributed to acute measles disease. In four studies from Guinea-Bissau, Senegal, and Burundi vaccine efficacy against death remained almost unchanged when cases of measles were excluded from the analysis. Diphtheria-tetanus-pertussis and polio vaccinations were not associated with reduction in mortality. These observations suggest that standard titre measles vaccine may confer a beneficial effect which is unrelated to the specific protection against measles disease.
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Objective: To examine the association between routine childhood vaccinations and survival among infants in Guinea-Bissau. Design: Follow up study. Participants: 15 351 women and their children born during 1990 and 1996. Setting: Rural Guinea-Bissau. Main outcome measures: Infant mortality over six months (between age 0-6 months and 7-13 months for BCG; diphtheria, tetanus, and pertussis; and polio vaccines and between 7-13 months and 14-20 months for measles vaccine). Results: Mortality was lower in the group vaccinated with any vaccine compared with those not vaccinated, the mortality ratio being 0.74 (95% confidence interval 0.53 to 1.03). After cluster, age, and other vaccines were adjusted for, BCG was associated with significantly lower mortality ratio (0.55 (0.36 to 0.85)). However, recipients of one dose of diphtheria, tetanus, and pertussis or polio vaccines had higher mortality than children who had received none of these vaccines (1.84 (1.10 to 3.10) for diphtheria, tetanus, and pertussis). Recipients of measles vaccine had a mortality ratio of 0.48 (0.27 to 0.87). When deaths from measles were excluded from the analysis the mortality ratio was 0.51 (0.28 to 0.95). Estimates were unchanged by controls for background factors. Conclusions: These trends are unlikely to be explained exclusively by selection biases since different vaccines were associated with opposite tendencies. Measles and BCG vaccines may have beneficial effects in addition to protection against measles and tuberculosis.
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.
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.
In a zone with a high measles case-fatality rate the risk of dying between the ages of 7 and 35 months for a vaccinated population was compared with that for an unvaccinated control-group. Life-table analysis for both groups showed that measles vaccination reduced the risk of dying at the age of maximum exposure to measles. The gain in survival probability, however, tended to diminish afterwards, to approach that of the unvaccinated group.
Objective: To examine the association between routine childhood vaccinations and survival among infants in Guinea-Bissau.Design: Follow up study.Participants: 15 351 women and their children born during 1990 and 1996.Setting: Rural Guinea-Bissau.Main outcome measures: Infant mortality over six months (between age 0-6 months and 7-13 months for BCG, diphtheria, tetanus, and pertussis, and polio vaccines and between 7-13 months and 14-20 months for measles vaccine).Results: Mortality was lower in the group vaccinated with any vaccine compared with those not vaccinated, the mortality ratio being 0.74 (95% confidence interval 0.53 to 1.03). After cluster, age, and other vaccines were adjusted for, BCG was associated with significantly lower mortality (0.55 (0.36 to 0.85)). However, recipients of one dose of diphtheria, tetanus, and pertussis or polio vaccines had higher mortality than children who had received none of these vaccines (1.84 (1.10 to 3.10) for diphtheria, tetanus, and pertussis). Recipients of measles vaccine had a mortality ratio of 0.48 (0.27 to 0.87). When deaths from measles were excluded from the analysis the mortality ratio was 0.51 (0.28 to 0.95). Estimates were unchanged by controls for background factors.Conclusions: These trends are unlikely to be explained exclusively by selection biases since different vaccines were associated with opposite tendencies. Measles and BCG vaccines may have beneficial effects in addition to protection against measles and tuberculosis.
The female/male mortality ratio among unimmunized children and children vaccinated with standard or high-titer measles vaccines was examined for all children born in the period 1985-1991 in a rural area of Senegal. The female/male mortality ratio from 9 months to 5 years of age for unvaccinated children was 0.94 (95% confidence interval (CI) 0.75-1.19), significantly different from the ratio of 0.64 (95% CI 0.48-0.85) for recipients of the Schwarz standard measles vaccine (p = 0.040). In the 4-year period, where high-titer measles vaccines were used in the study area, the female/male mortality ratio was 1.33 (95% CI 1.00-1.78) for recipients of high-titer Edmonston-Zagreb or Schwarz vaccines compared with 0.67 (95% CI 0.42-1.07) for recipients of the Schwarz standard vaccine (p = 0.013). Hence, the Schwarz standard and high-titer measles vaccines have divergent sex-specific effects on mortality throughout childhood. Further studies of the underlying mechanisms are needed.
In the course of 2 years' surveillance of whooping cough by fornightly home visits among a population of 24 000 in a rural area of Kenya, 918 cases were observed with a peak of 218 in December 1974-January 1975. The attack rate was highest (15.8%) during the first year of life; for the age group 0-6 years it was 12.8%. Ninety percent of cases occurred in children 6 years of age and younger. The median age was 3.5 years, the age range 1 month to 13 years. Girls were significantly more affected than boys. The overall case fatality rate was 1.3% but among infants it was 2.5 times higher. In order to contribute to the improvement of immunization coverage in countries where health resources are limited, a schedule of child immunization requiring a minimum number of contacts with the children was introduced in the study area with the aim of evaluating its effectiveness in protecting children introduced in the study area with the aim of evaluating its effectiveness in protecting children from clinical pertussis. In this trial, the effect of two and three diphtheria-pertussis-tetanus vaccine (DPT) doses was compared. Pertussis agglutinating antibody determinations showed an equally satisfactory response after two and three DPT vaccine doses.