Tropical Medicine and International Health doi:10.1111/j.1365-3156.2012.03093.

volume 17 no 12 pp 1492–1505 december 2012

Non-specific effects of diphtheria-tetanus-pertussis and measles

vaccinations? An analysis of surveillance data from Navrongo,
Ghana
Paul Welaga1, Jens Nielsen2, Martin Adjuik1, Cornelius Debpuur1, David A. Ross3, Henrik Ravn2,
Christine S. Benn2 and Peter Aaby4

1 Navrongo Health Research Centre, Navrongo, Ghana

2 Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark
3 London School of Hygiene and Tropical Medicine, London, UK
4 Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau

Abstract objectives Studies from low-income countries have suggested that routine vaccinations may have non-
specific effects on child mortality; measles vaccine (MV) is associated with lower mortality and
diphtheria-tetanus-pertussis (DTP) with relatively higher mortality. We used data from Navrongo,
Ghana, to examine the impact of vaccinations on child mortality.
methods Vaccination status was assessed at the initiation of a trial of vitamin A supplementation and
after 12 and 24 months of follow-up. Within the placebo group, we compared the mortality over the first
4 months and the full 2 years of follow-up for different vaccination status groups with different like-
lihoods of additional vaccinations during follow-up. The frequency of additional vaccinations was
assessed among children whose vaccination card was seen at 12 and 24 months of follow-up.
results Among children with a vaccination card, more than 75% received missing DTP or MV during
the first 12 months of follow-up, whereas only 25% received these vaccines among children with no
vaccination card at enrolment. Children without a card at enrolment had a significant threefold
higher mortality over the 2-year follow-up period than those fully vaccinated. The small group of
children with DTP3-4 but no MV at enrolment had lower mortality than children without a card and
had the same mortality as fully vaccinated children. In contrast, children with 1–2 DTP doses but no MV
had a higher mortality during the first 4 months than children without a card [MRR = 1.65 (0.95,
2.87)]; compared with the fully vaccinated children, they had significantly higher mortality after
4 months [MRR = 2.38 (1.07, 5.30)] and after 2 years [MRR = 2.41 (1.41, 4.15)]. Children with 0–2
DTP doses at enrolment had higher mortality after 4 months (MRR = 1.67 (0.82, 3.43) and after 2 years
[MRR = 1.85 (1.16, 2.95)] than children who had all three doses of DTP at enrolment.
conclusions As hypothesised, DTP vaccination was associated with higher child mortality than
measles vaccination. To optimise vaccination policies, routine vaccinations need to be evaluated in
randomised trials measuring the impact on survival.

keywords non-specific effects, vaccines, measles, diphtheria-tetanus-pertussis, mortality

2003b). Such NSE are presumably owing to modulation of

Introduction
Routine childhood vaccinations may have non-specific
effects (NSE) on morbidity and mortality in low-income
countries with a high burden of infectious diseases (Aaby
et al. 1995, 2003b; Kristensen et al. 2000). The best
known example is the studies of high-titre measles vaccine
(HTMV), which was associated with twofold higher
mortality for girls than the standard measles vaccine (MV).
HTMV was fully protective against measles infection, and
the effect was therefore a non-specific effect (Aaby et al.
the immune system. The experience with HTMV suggested
that NSE could have major effects on child survival. This
finding made us investigate whether other vaccines could
have NSE.
Using a landmark approach to survival analysis (Aaby
et al. 2007; Jensen et al. 2007), studies showed that the
common vaccinations used in infancy had differential
NSEs; BCG (Roth et al. 2006a,b) and MV were associated
with lower subsequent mortality (Aaby et al. 1995) and
diphtheria-tetanus-pertussis (DTP) with relatively higher

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Tropical Medicine and International Health
P. Welaga et al. Non-specific effects of diphtheria-tetanus-pertussis and measles vaccinations
subsequent mortality (Kristensen et al. 2000; Aaby et al.
2004a,b; Veirum et al. 2005). These results have been
controversial because they question basic assumptions of
the current vaccination programme and suggest that
changes in the programme might be needed (Fine & Smith
2007).
More data sets from other countries are therefore needed
to assess the magnitude of NSE and whether different
routine vaccinations have different NSE. Surprisingly, few
longitudinal studies in low-income countries have collected
routine information on vaccinations. The Ghana vitamin A
supplementation trial (Ghana VAST)’s Survival Study in
Kassena-Nankana District, Ghana, in 1989–1991 assessed
vaccination status at the initiation of the trial. Previously,
we have demonstrated that the impact of vitamin A
supplementation (VAS) may be modified by interaction
with vaccines (Benn et al. 2009). In the present analysis, we
have focused on the impact of vaccines on child mortality
among children who received placebo to study the impact
of vaccines in the absence of VAS.
Methods and subjects
Ghana VAST Survival Study
VAST was conducted between 1989 and 1991 (Ghana
VAST Study Team 1993; Binka et al. 1995; Ross et al.
1995; Benn et al. 2009). The details of this cluster
randomised trial of vitamin A supplementation (VAS) have
been described in the previous publications and the
Appendix. Dosing was every 4th month. Over the 2 years,
21 906 children were enrolled in the trial by receiving at
least one dose of either VAS or placebo, 13 462 being
enrolled in Round 1. VAS was associated with a 19%
(95%CI 2–32%) reduction in mortality.
Information on vaccinations
Vaccination information was collected systematically for
the children enrolled in Round 1. One year and 2 years
later, in Rounds 4 and 7, vaccination information was
collected again. Owing to an archiving error, dates of
measles vaccination from Round 7 were not saved in the
stored data files. The present analysis has been restricted to
children enrolled in Round 1 for whom there was follow-
up for the whole 2-year period; we only included children
who had received placebo since this group would not be
subject to vaccine ⁄ vitamin A interactions.
Data on vaccinations were collected de novo each time
without taking previous information into consideration
and only for children being alive at the visit. Thus, the
vaccination status of children who died between vaccina-
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volume 17 no 12 pp 1492–1505 december 2012
tion visits was not updated. Comparing information from
rounds 1 and 4 for the same children, there were minor
inconsistencies (Appendix).
Follow-up and verbal autopsies
All children in the study were visited every 4 months.
Deaths were identified through these visits and indepen-
dently by key informants based in the community. With the
intensive follow-up and the need to report, the status of all
children in the study it is unlikely that deaths were missed.
The verbal autopsy procedure for all deaths makes it
unlikely that surviving children were erroneously classified
as dead. The follow-up procedures were independent of the
vaccination status of the child.
When a child had died an attempt was made to complete
a verbal autopsy questionnaire with the mother ⁄ guardian
to ascertain the circumstances of the death and the
symptoms associated with the final illness. No information
on vaccines was collected. Questionnaires were read and
classified by two physicians (DAR, Fred Binka). If any of
the physicians classified a death as because of measles
infection, the death has been classified as measles in the
present analysis.
Background factors and nutritional status
Information on a number of socio-economic (SES) and
demographical background factors, feeding mode, vacci-
nation history, recent and past morbidity and anthropom-
etry were collected at the beginning of the study. Weight
and arm circumference (MUAC) was assessed in the same
rounds as vaccination information. We calculated weight-
for-age (WAZ) and MUAC z-scores using the WHO
standards (http://www.who.int/childgrowth/software/en).
We used a z-score cut-off of < )2 in analyses controlling
for malnutrition.
Analysis of vaccinations
Information from Rounds 1, 4 and 7 was used to calculate
the proportion of children who received vaccinations in the
years following enrolment. This proportion was estimated
among children whose health card had been seen at
enrolment and again 1 year or 2 years later, that is, among
surviving children. The incidence of vaccination was very
high in the first months after enrolment, because of a major
intensification of the vaccination programme before and
immediately after 1990, the year when the Expanded
Programme on Immunisation had targeted achieving 80%
coverage of vaccination globally (Kim-Farley 1992).
Therefore, a certain vaccination status in Round 1 or
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P. Welaga et al. Non-specific effects of diphtheria-tetanus-pertussis and measles vaccinations
Round 4 not only reflected which vaccines the child had
already received, but also which vaccines they were likely
to receive in the coming months. Hence, any vaccination
effects on mortality are likely to be a product of both
vaccination status at enrolment and the vaccines likely to
be received during follow-up. We have particularly focused
on the impact on survival in the first 4 months when the
information on immunisation status would be most valid.
However, we have also reported the mortality effect for the
full 2 years duration of the trial. For the present analyses,
children who had no health card at Round 1 have been
assumed to be ‘unvaccinated’.
We have emphasised two aspects of vaccination status:
first, children who had not yet received MV were likely to
receive MV during follow-up; second, children who had
not received all doses of DTP were likely to receive
additional doses of DTP during follow-up. We have
therefore distinguished between children who had received
0–2 doses (DTP0-2) or 3 or more doses of DTP (DTP3-4)
at enrolment. As indicated in Table 2, vaccination status at
enrolment was categorised into 6 groups.
Statistical analyses
Comparisons of background factors for children with and
without a health card were carried out using logistic
regression, linear regression or nonparametric tests. For the
assessment of the risk of dying within 4 months or 2 years,
the period at risk was defined as the time period between
the enrolment date and either the date the child died or was
censored or 4 months ⁄ 2 years later, whatever came first.
The survival data were analysed in Cox-proportional
hazards models with age as the underlying time and
reported as mortality rate ratios (MMRs) with 95%
confidence interval (CI). We also analysed the data using
time since visit as the timescale in a Cox model and
controlled for age as a categorised variable (6–11, 12–23
and 24–35 months). The results are essentially the same as
in the Cox model using age as the timescale (see Appendix).
Cox-proportional hazard assumptions were tested and
were not violated. Background factors associated with a
P < 0.10 were included in the final model using backward
selection. The study area was divided into four geograph-
ical Zones: North, South, East and West. As the WAZ
score was better for children who did not have a vaccina-
tion card – possibly due to less accurate age assessment (see
Appendix) – we also controlled for WAZ in all analyses.
Data were analysed in Stata 11.
To minimise the effect of survival bias, we used a
landmark approach with vaccinations status at enrolment
being a fixed time variable during follow-up (Jensen et al.
2007). Survival bias leads to differential misclassification
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volume 17 no 12 pp 1492–1505 december 2012
of vaccine status because children who survive have better
information than dead children because health cards for
dead children were often not available for vaccination
information to be updated. This makes vaccine informa-
tion for the dead children incomplete making vaccination
to be automatically associated with a strong beneficial
effect.
Results
Study population
A total of 6882 children were enrolled in the placebo group
in Round 1; 49% had a health card seen, 13% were said to
have a card but it was not seen, 37% did not have a card,
and 0.4% had no information recorded on their health
card status. The present analysis is restricted to children
whose card was seen (3397) or who had no card (2577).
Within the first 4 months 91 (1.5%) of these children died
and over the 2 years of the trial, 274 (4.6%) children died;
51 ⁄ 274 (19%) were because of measles and the two
physicians agreed on 47 of 51 diagnoses of measles.
Vaccination coverage
Fewer than 50% of the children had received BCG, DTP
and MV (Table 1). For those with a health card seen,
however, the coverage continued to increase until around
24 months of age. Most children had received their routine
vaccinations out-of-sequence; 76% had received BCG and
DTP simultaneously, and 86% (1771 ⁄ 2057) of those who
had received both MV and DTP had received MV and
DTP simultaneously or at least one DTP after MV.
Among children aged 3 years or older at enrolment,
subsequent vaccination intensity was limited. In the
following analysis, we have therefore focused on children
under 3 years of age in the placebo group (N = 3082;
Figure 1).
Vaccinations during follow-up
The vaccination intensity in the first 4 months after
enrolment was high for children with a health card
(Table 2). During the first 4 months, 50% (408 ⁄ 817)
received additional doses of DTP if they had a vaccination
card but had not received DTP3 at enrolment (Table 2,
Group 2, 3 and 5); 76% (621 ⁄ 817) received DTP within
12 months. Among children who had not had MV at
enrolment, 50% (276 ⁄ 549) received this vaccine during the
next 4 months (Table 2, Group 2, 3 and 4); 79%
(431 ⁄ 549) received MV within 12 months. In contrast,
children who had received DTP3-4 before enrolment
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P. Welaga et al. Non-specific effects of diphtheria-tetanus-pertussis and measles vaccinations

Table 1 Vaccination coverage at enrolment into the trial according to age in the placebo group

Coverage of vaccines

Children
Vaccine All children with card Coverage by age among children with a health card n (%)

5–11 months 12–17 months 18–23 months 24–35 months 36+ months
5974 3397 N = 358 N = 484 N = 409 N = 738 N = 1408
All n (%) n (%) n (%) n (%) n (%) n (%) n (%)

BCG 2639 (44) 2639 (78) 305 (85) 409 (85) 353 (86) 589 (80) 983 (70)
BCG with DTP* 2003 (76)* 258 (85) 341 (83) 291 (82) 466 (79) 647 (66)
Any DTP 2795 (47) 2795 (82) 308 (86) 436 (90) 368 (90) 636 (86) 1047 (74)
DTP3 ⁄ DTP4 1503 (25) 1503 (44) 87 (24) 183 (38) 191 (47) 378 (51) 664 (47)
Any OPV 2781 (47) 2781 (82) 312 (87) 424 (88) 369 (90) 629 (85) 1047 (74)
OPV3-5 1426 (24) 1426 (42) 80 (22) 165 (34) 180 (44) 366 (50) 635 (45)
MV 2208 (37) 2208 (65) 86 (24) 266 (55) 307 (75) 556 (75) 993 (71)
MV with DTP* 1352 (66)* 64 (76) 179 (70) 206 (69) 374 (71) 529 (60)
DTP after MV* 1096 (53)* 8 (10) 73 (28) 132 (44) 294 (55) 589 (66)

*Percentage only among children with a vaccine.

13 462 recruited in first round and vacci-

nation information collected

6580 received vitamin A 6882 received placebo

3330 were aged 6 – 35

months at enrolment

237 had health cards 1093 did not have 1989 had health 11 had no information
but were not seen health cards cards seen on health card

3082 children included

in analysis

207 deaths recorded at 2727 were alive 148 moved out of the
end of 2 years follow-up study area

Figure 1 Study population of children aged 6–35 months at enrolment into the placebo group.

(Table 2, Group 4 and 6) were unlikely to receive

additional doses of DTP during follow-up [6% (39 ⁄ 663)].
Among children not having a health card at enrolment,
only 25% received at least one dose of DTP or MV during
the first 12 month of follow-up (Table 2, Group 1).
Background factors
The children with and without a health card were different
in several respects (Table 3). Controlling for age, the
children with a vaccination card were more likely to still be

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P. Welaga et al. Non-specific effects of diphtheria-tetanus-pertussis and measles vaccinations

Table 2 Proportion of children receiving vaccination during follow-up, according to vaccination status at enrolment, among children
<36 months of age at enrolment into the placebo group

Age (months)
at entry n (%) % Received DTP (N) % Received MV (N)

6–11
Vaccination status at 12–23
enrolment 24–35 First 4 months First year 2 years First 4 months First year

1 No health card 265 (24.3) 18 (152 ⁄ 863) 25 (214 ⁄ 863) 24 (169 ⁄ 714) 14 (124 ⁄ 863) 25 (218 ⁄ 863)
409 (37.4)
419 (38.3)
2 Health card 48 (24.5) 59 (73 ⁄ 123) 78 (96 ⁄ 123) 81 (87 ⁄ 108) 45 (55 ⁄ 123) 77 (95 ⁄ 123)
(no DTP, no MV) 72 (36.7)
76 (38.8)
3 Health card + DTP1 ⁄ 2 182 (38.8) 57 (191 ⁄ 335) 81 (271 ⁄ 335) 83 (250 ⁄ 301) 47 (158 ⁄ 335) 78 (262 ⁄ 335)
(no MV) 201 (42.9)
86 (18.3)
4 Health card + DTP3 ⁄ 4 42 (38.5) 10 (9 ⁄ 91) 11 (10 ⁄ 91) 13 (10 ⁄ 80) 69 (63 ⁄ 91) 81 (74 ⁄ 91)
(no MV) 47 (43.1)
20 (18.4)
5 Health card + MV 41 (8.5) 40 (144 ⁄ 359)* 71 (254 ⁄ 359)* 74 (233 ⁄ 315)* NA NA
and DTP0-2 246 (50.7)
198 (40.8)
6 Health card + MV 45 (6.2) 5 (30 ⁄ 572)* 6 (33 ⁄ 572)* 5 (28 ⁄ 514)* NA NA
and DTP3-4 327 (44.8)
358 (49.0)

Group 1 consisted of those with no health card and was considered ‘unvaccinated’. Groups 2–6 all had health cards at Round 1.
Group 2 had not received DTP or MV (some of these children had, however, received BCG); Group 3 had received DTP1-2 but not
MV; Group 4 had received DTP3-4, but not MV; Group 5 had received DTP1-2 and MV; and Group 6 had received DTP3-4 and MV
(fully vaccinated).
*DTP vaccinations after MV.

Table 3 Background characteristics of children with and without a health card, among children <36 months of age at enrolment into
the placebo group

Odds ratio ⁄ mean difference

by background
Health card No health card characteristics (95% CI)

N = 1989 (65%) N = 1093 (35%) N = 3082

Sex (Males ⁄ N) 49.5% (984 ⁄ 1989) 50.9% (557 ⁄ 1093) 0.94 (0.81, 1.09)
Median age (months) 20.0 [IQR 13.6; 27.5] 19.6 [IQR 12.3; 28.0] P = 0.163*
Ever breastfed 100% (1989 ⁄ 1989) 99.9% (1092 ⁄ 1093) P = 0.164*
Still breastfeeding 81.0% (1612 ⁄ 1989) 75.4% (824 ⁄ 1093) 1.40 (1.16, 1.67)
Mean arm circumference MUAC z-scores )1.47 ()1.52; )1.41) )1.40 ()1.47; )1.33) )0.07 ()0.16, )0.02)
Mean weight-for-age z-score )1.94 ()2.00; )1.88) )1.67 ()1.76; )1.58) )0.27 ()0.37, )0.16)
BCG scar 80.9% (1609 ⁄ 1988) 15.0% (164 ⁄ 1093) 24.0 (19.6, 29.5)
Ever had measles before enrolment 2.0% (39 ⁄ 1989) 1.9% (21 ⁄ 1091) 1.02 (0.58, 1.83)
Previously admitted to hospital 4.6% (92 ⁄ 1989) 2.5% (27 ⁄ 1093) 1.91 (1.23, 3.08)
Radio in compound 31.3% (622 ⁄ 1985) 18.6% (202 ⁄ 1089) 2.0 (1.67, 2.41)

IQR, Inter Quartile Range.

*Kruskal–Wallis test.

breastfed. The children with a health card had lower children without a health card having been underesti-
weight-for-age z-scores (WAZ) than children with no card. mated. Also, children with a card were more likely to have
The difference in WAZ could be due to current age of the been hospitalised, presumably indicating that communities

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Tropical Medicine and International Health
P. Welaga et al. Non-specific effects of diphtheria-tetanus-pertussis and measles vaccinations
with high coverage had better contact with health services.
Fifteen per cent of the children without a health card had a
BCG scar. These children may have lost the card or never
been issued with one.
Mortality of different vaccination groups
In the first 4 months, the MRR for children with a
health card compared with children without a card and
adjusted for zone, WAZ and ownership of a radio was
0.97 (95%CI 0.61, 1.56); 1.10 (95%CI 0.56, 2.16) for
vaccinated girls and 0.86 (95%CI 0.44, 1.69) for vacci-
nated boys. Over the 2 years of follow-up, the children
with a card had significantly lower mortality than children
without a card [MRR = 0.61 (0.46, 0.82)].
Children who had received MV by enrolment had
slightly better WAZ than children who had received at
least one dose of DTP but not MV (DTP-vaccinated
children), the RR of WAZ < )2 being 0.93 (95%CI 0.88,
1.00) for MV children. Controlled for WAZ, over the first
4 months, the children who were MV-vaccinated at
enrolment had half the mortality of the children who were
initially only DTP-vaccinated [MRR = 0.51 (95%CI 0.27,
0.97)] (Table 4). The reduction in mortality could not be
explained by protection against measles deaths, as defined
by the verbal autopsies, since the MRR was 0.46 (95%CI
0.23, 0.89) when measles deaths were excluded from the
analysis (Table 4).
As vaccination status group at enrolment influenced the
likelihood of receiving additional vaccinations during
follow-up (Table 2), we also assessed the relative mortality
of these different vaccination status groups (Table 5). Fully
vaccinated children (Group 6) had lower mortality than
children without a card (Group 1), and this effect was
significant for the 2-year follow-up period [MRR = 0.37
(95%CI 0.23, 0.62)]. The small group of children with
Table 4 Mortality rate ratio during the first 4 months of follow-up for children with MV at enrolment vs. children with DTP without MV
at enrolment among children aged 6–35 months at enrolment into the placebo group
MR per 1000 years (Deaths ⁄ person-years) [children enrolled] {measles deaths}
Vaccination status
at enrolment Boys
MV at enrolment 33 (7 ⁄ 209) [593] {1}
(Table 2, Group 5 and 6)
DTP (No MV at enrolment) 127 (13 ⁄ 102) [289]
(Table 2, Group 3 and 4)
MRR MV ⁄ DTP 0.50 (0.19, 1.31)
(No MV at enrolment)*
MRR* (measles deaths excluded) 0.44 (0.16, 1.22)
MRR, Mortality Rate Ratio.
*Adjusted for age, zone, weight-for-age and ownership of radio.
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volume 17 no 12 pp 1492–1505 december 2012
DTP3-4 but no MV at enrolment (Group 4) had similar
mortality as fully vaccinated children (Group 6), and
roughly half the mortality rate compared with the children
without a card both after 4 months and 2 years, though
neither of these differences were statistically significant
(Table 5). Hence, missing vaccines was not per se a risk
factor for child mortality. The prevention of measles deaths
did not appear to explain the lower mortality among the
measles-vaccinated children and the children with DTP3-4
but no MV (Table 5).
In contrast, children with 1–2 doses of DTP but no MV
at enrolment (Table 5, Group 3) had a higher overall
mortality than children without a card (Group 1) during
the first 4 months of follow-up [MRR = 1.65 (95%CI
0.95, 2.87)], with mortality being significantly higher for
deaths that were not attributed to measles [MRR = 1.74
(95%CI 1.00, 3.05)]. The DTP1-2-vaccinated children
(Group 3) also had a twofold higher mortality rate than the
fully vaccinated children (Group 6) in the first 4 months
[MRR = 2.38 (95%CI 1.07, 5.30)] and over the 2 years
[MRR = 2.41 (95%CI 1.41, 4.15)].
Controlling for MV status (Table 6), we compared
children with missing doses of DTP (Table 5, Groups 2, 3
and 5) with children who had already received DTP3-4 at
enrolment (Table 5, Groups 4 and 6). Those missing doses
of DTP tended to have higher mortality during the first
4 months [MRR = 1.67 (95%CI 0.82, 3.43)] and had
significantly higher mortality over the full duration of the
study [(MRR = 1.85 (95%CI 1.16, 2.95)] than those with
DTP3-4 at enrolment (Table 6).
Discussion
The data from Navrongo provided several indications that
vaccines may have important NSE on child survival. The
children who had received MV at enrolment had twofold
Girls All
45 (10 ⁄ 220) [622] {1} 40 (17 ⁄ 429) [1215] {2}
139 (14 ⁄ 101) [289] 133 (27 ⁄ 203) [578]
0.52 (0.22, 1.23) 0.51 (0.29, 0.97)
0.48 (0.20, 1.16) 0.46 (0.23, 0.89)
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Table 5 Mortality rate (MR) per 1000 person-years (pyrs) and mortality rate ratio (MRR) for vaccinated compared with unvaccinated children, among children <36 months
by enrolment into the placebo group

Within 4-month follow-up Within 24-month follow-up:

MRR* (95% CI) MRR* (95% CI)

Median MR per Unadjusted (Vaccinated ⁄ Unadjusted (Vaccinated ⁄ No
Tropical Medicine and International Health

weight-for-age 1000 years MRR (95% CI) No heath card) MR per 1000 years MRR (95% CI) health card)
Group: Vaccination z-score at (deaths ⁄ pyrs) {MRR – without {MRR – without (deaths ⁄ pyrs) {MRR – without {MRR – without
status at enrolment N enrolment {measles deaths} measles deaths) measles deaths} {measles deaths} measles deaths) measles deaths}

1. No card 1093 )1.7 [)2.6; )0.8] 80 (31 ⁄ 389) {2} 1.0 (Reference) 1.0 (Reference) 51 (101 ⁄ 1998) {23} 1.0 (Reference) 1.0 (Reference)
2. Health card: 196 )1.9 [)2.9; )1.0] 58 (4 ⁄ 69) 0.72 (0.25, 2.05) 0.69 (0.24, 1.97) 30 (11 ⁄ 370) {2} 0.59 (0.32, 1.10) 0.55 (0.29, 1.02)
noDTP, noMV {0.77 (0.27, 2.19)} {0.75 (0.26, 2.13)} {0.63 {0.59 (0.29, 1.17)}
(0.31, 1.25)}
3. DTP1-2, no MV 469 )2.0 [)3.0; )1.2] 152 (25 ⁄ 164) 1.90 (1.12, 3.22) 1.65 (0.95, 2.87) 54 (46 ⁄ 854) {6} 1.07 (0.75, 1.51) 0.90 (0.63, 1.30)
{2.03 (1.19, 3.47)} {1.74 (1.00, 3.05)} {1.19 {1.03 (0.69, 1.52)}
(0.82, 1.75)}
4. DTP3-4, no MV 109 )1.8 [)3.0; )1.2] 52 (2 ⁄ 38) 0.66 (0.16, 2.74) 0.57 (0.13, 2.42) 24 (5 ⁄ 207) {1} 0.48 (0.20, 1.19) 0.44 (0.18, 1.08)
{0.70 (0.17, 2.94)} {0.61 (0.14, 2.61)} {0.50 {0.46 (0.17, 1.28)}
(0.18, 1.36)}
5. MV, DTP0-2 485 )1.9 [)2.8; )1.1] 47 (8 ⁄ 171){2} 0.58 (0.27, 1.27) 0.80 (0.36, 1.78) 26 (24 ⁄ 923) {3} 0.52 (0.33, 0.81) 0.62 (0.39, 0.97)
{0.47 (0.19, 1.23)} {0.66 (0.27, 1.61)} {0.58 {0.75 (0.46, 1.23)}
(0.36, 0.94)}
6. MV, DTP3-4 730 )1.8 [)2.6; )1.0] 35 (9 ⁄ 257) 0.44 (0.21, 0.92) 0.70 (0.32, 1.53) 14 (20 ⁄ 1408) 0.28 (0.18, 0.46) 0.37 (0.23, 0.62)
{0.47 (0.22, 0.98)} {0.76 (0.34, 1.69)} {0.36 {0.51 (0.30, 0.85)}
(0.22, 0.60)}
P. Welaga et al. Non-specific effects of diphtheria-tetanus-pertussis and measles vaccinations

Total 3082 )1.8 [)2.7; )1.0] 73 (79 ⁄ 1090){4} 36 (207 ⁄ 5760){35}

*Adjusted for age, zone, weight-for-age and ownership of radio (N = 3082).

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P. Welaga et al. Non-specific effects of diphtheria-tetanus-pertussis and measles vaccinations

Table 6 Mortality during follow-up according to number of doses of DTP received before enrolment, among children aged 6-35 months
who had a health card at enrolment into the placebo group

No MV at enrolment Had received MV at enrolment

(Table 2, Group 2, 3 and 4) (Table 2, Group 5 and 6) MR
Number of doses of MR per 1000 (Deaths ⁄ pyrs) per 1000 (Deaths ⁄ pyrs)
DTP at enrolment [children enrolled] {measles deaths} [children enrolled] {measles deaths}

4 months of follow-up
DTP0-2 124 (29 ⁄ 234) [665] {0} 47 (8 ⁄ 171) [485] {2}
DTP3-4 53 (2 ⁄ 38) [109] 35 (9 ⁄ 257) [730]
MRR (DTP0-2 ⁄ DTP3-4)* 2.29 (0.53, 9.78) 1.08 (0.38, 3.06)
[without measles deaths] [2.29 (0.53, 9.78)] [0.88 (0.30, 2.59)]
MRR (DTP0-2 ⁄ DTP3-4)* 1.67 (0.82, 3.43)
[without measles deaths] [1.60 (0.78, 3.28)]

24 months of follow-up
DTP0-2 47 (57 ⁄ 1224) [665] {8} 26 (24 ⁄ 923) [485] {3}
DTP3-4 24 (5 ⁄ 207) [109] {1} 14 (20 ⁄ 1408) [730]
MRR (DTP0-2 ⁄ DTP3-4)* 1.89 (0.75, 4.77) 1.70 (0.91, 3.17)
[without measles deaths] [1.93 (0.69, 5.41] [1.53 (0.81, 2.90]
MRR (DTP0-2 ⁄ DTP3-4)* 1.85 (1.16, 2.95)
[without measles deaths] [1.68 (1.03, 2.73)]

*Adjusted for age, zone, weight-for-age and ownership of radio and MV status at enrolment.

lower mortality than children who had received only
DTP and this difference was not explained by the
prevention of measles deaths. Furthermore, adjusted for
MV vaccination status at enrolment, those with incomplete
doses of DTP had higher mortality than the children
who had already received DTP3 before enrolment. These
trends are consistent with observations made in several
other studies from Africa (Aaby et al. 1995, 2006a,b,c;
Kristensen et al. 2000).
Strengths and weaknesses
This was an observational study of the effects of vaccina-
tion. Misclassification of vaccination status did occur. A
small proportion of vaccinated children were probably
wrongly classified as unvaccinated. Information on vacci-
nation dates may also have been missed or noted wrongly
for a few of the children. Assuming these misclassifications
to be random, such errors should tend to make the
estimated differences more conservative.
The Navrongo data set is special in several ways. First,
the study only included children older than 6 months and
there was very little follow-up time and only three deaths
before 9 months of age when BCG and DTP will usually
have their strongest NSE. Hence, the DTP vaccines
administered in the present study were likely to have been
given out-of-sequence, that is, DTP co-administered with
MV or DTP given after MV. The study is therefore less
relevant for assessing the impact of the primary series of
DTP vaccinations administered before 9 months of age.
Second, in Navrongo a large part of the population
remained unvaccinated at that time, and therefore, it
was possible to compare vaccinated with unvaccinated
children over a wide age range; the unvaccinated chil-
dren were not merely a small particularly frail subgroup,
which had been too weak to get vaccinated. Third, in
other studies, we have analysed the impact of a vaccine,
while it was presumed to be the latest vaccine received
(Aaby et al. 2004b,c, 2006a,b,c; Veirum et al. 2005).
This was not possible in this study because the time interval
for collection of vaccination data was too long. Hence,
vaccinations were evaluated as risk factors for mortality
taking into consideration the initial vaccination status and
whether additional vaccines may have been given during
follow-up.
It could be speculated that the increased mortality
associated with DTP merely represented poor social
conditions, disorganised parenting, differential ascertain-
ment of vaccinations or differential access to the EPI
programme. However, the DTP-vaccinated children would
have had better families or more compliant parents than
the unvaccinated children. Nonetheless, the DTP-
vaccinated children had higher mortality than the unvac-
cinated children. The late 1980s when these data were
collected was the introduction period for the EPI
programme, and many vaccines were given in campaigns

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Tropical Medicine and International Health
P. Welaga et al. Non-specific effects of diphtheria-tetanus-pertussis and measles vaccinations
and out-of-sequence. The process of who got vaccinated
when are likely to have been much more random depend-
ing on when there was a drive to organise vaccinations; for
example, the incidence of vaccinations was very high just
after the initiation of the trial.
Interpretation: differential mortality impact of DTP and
MV vaccinations
Compared with children who were MV-vaccinated at
enrolment, the DTP-vaccinated but MV-unvaccinated
children had twofold higher mortality. Using vaccination
status as a predictor of subsequent vaccinations we found
that the DTP0-2-vaccinated children had the highest
mortality, whereas those who had already received MV
and DTP3 had the lowest mortality, the difference being
2.5-fold.
Interestingly, the prevention of deaths attributed to
measles by verbal autopsy explained little of this reduction
in mortality. Similar observations have been made in
previous studies from Guinea-Bissau (Aaby et al. 1996b),
Senegal (Aaby et al. 1996a) and Bangladesh (Aaby et al.
2003a). MV-vaccinated children had worse WAZ z-score
than the unvaccinated children, and it seems unlikely that
the beneficial effect of MV is merely owing to a positive
selection bias. As supported by previous studies (Aaby
et al. 1995), MV may have a beneficial effect which is not
explained by the prevention of measles infection.
On the other hand, being only DTP-vaccinated at
enrolment was associated with higher mortality than the
rates of both unvaccinated and fully vaccinated children.
These children were likely to receive both MV and DTP
during follow-up and usually administered simultaneously.
Previous research has suggested that children who had had
simultaneous administration of MV and DTP had higher
subsequent mortality than children who had received MV
on its own as the most recent vaccine (Aaby & Benn
2009b). Also, in a small randomised study, girls rando-
mised to receive MV and DTP simultaneously had signif-
icantly poorer growth than children randomised to receive
MV only (Agergaard et al. 2011). In the present study, the
small group of DTP3-vaccinated children who were likely
to receive only MV during follow-up also had low
mortality. Control for baseline nutritional status did not
substantially reduce the mortality differences between the
various vaccination groups. The possibility that additional
DTP vaccinations during follow-up may have had a
negative effect was strengthened by the fact that children
with incomplete DTP doses tended to have higher mortality
than children with complete DTP doses at enrolment.
Given the uncertainty regarding who received additional
vaccinations during follow-up, the Navrongo data on the
1500
volume 17 no 12 pp 1492–1505 december 2012
NSE of vaccines should be interpreted with caution.
Furthermore, selection biases may have explained some
of the mortality differentials, but are unlikely to explain
all of them because the mortality effect of different
vaccines went in opposite directions. Specifically, the
Navrongo data set documented similar differential
effects of DTP and MV as have been reported in several
previous studies (Velema et al. 1991 Aaby et al. 1995,
2002, 2006c, 2012; Veirum et al. 2005).
Following studies suggesting a possible negative effect
of DTP on survival (Aaby et al. 1995; Kristensen et al.
2000), several WHO-sponsored studies from Africa
(Nyarko et al. 2001; Vaugelade et al. 2004; Elguero
et al. 2005) have argued that DTP had strong beneficial
effects, including a study from Navrongo based on data
collected in 1996–2000 (Nyarko et al. 2001). However,
these studies had survival bias, with the information on
vaccinations received being better for children who
survived (Aaby et al. 2007; Fine & Smith 2007; Jensen
et al. 2007) because health cards for dead children were
often not inspected for vaccination information after the
death of a child. The family often destroys the card after
the child’s death making vaccine status information for
the dead children incomplete. With survival bias, vacci-
nation will automatically be associated with a strong
beneficial effect.
These data were collected 20 years ago when most
children received vaccinations out-of-sequence and most
had DTP as the last vaccination, and it could be
speculated whether they had any relevance in the current
situation. However, it needs to be emphasised that there
are still many children getting vaccines out-of-sequence
in rural Africa, particularly in states with less well-
organised EPI (Aaby & Benn 2009b). Furthermore, the
problem of having DTP as the last vaccination may
become more common again. WHO’s SAGE (the Stra-
tegic Advisory Group of Experts on immunisation) has
recently recommended a booster dose of pertussis vaccine
given in the second year of life (WHO 2010), which
would again make DTP the last vaccination through
most of childhood.
Differences between sexes
In most studies of NSE of vaccines, we have emphasised
that they tend to differ for boys and girls (Aaby et al. 1995,
2002, 2004b, 2006a,c, 2007, 2012; Benn et al. 2009). The
data set in this study was too small to have been able to
detect anything but very large differences. There may be
other reasons that the sex-differential pattern was less clear
in the present study. Firstly, because of the infrequent
collection of vaccination status data, we could not evaluate
ª 2012 Blackwell Publishing Ltd
Tropical Medicine and International Health
P. Welaga et al. Non-specific effects of diphtheria-tetanus-pertussis and measles vaccinations
the NSE of the last known vaccine that the child received
with certainty. During follow-up, the children may have
received different vaccines with opposite sex-differential
effects, for example, MV after DTP or DTP after MV.
Secondly, the majority of children in Navrongo received a
live and inactivated vaccine simultaneously, that is, BCG
and DTP or DTP and MV together. We have previously
reported that a combined live and inactivated vaccine may
be better for girls than for boys (Aaby et al. 2004a, 2009a).
Conclusion
The present study adds to the growing evidence that the
impact of routine vaccinations cannot be explained merely
by prevention of targeted diseases or selection biases (Aaby
et al. 2007) and that DTP and MV may have different
effects for child survival (Velema et al. 1991; Kristensen
et al. 2000; Aaby et al. 2002, 2004a, 2006a,c, 2009a,
2012; Veirum et al. 2005; Benn et al. 2009). Randomised
controlled trials have documented that BCG and MV have
non-specific beneficial effects (Aaby et al. 2010, 2011;
Roth et al. 2010). There is a need for others to assess the
impact of routine vaccinations in further randomised trials
measuring mortality to improve the vaccination policy
currently implemented in high-mortality low-income
countries.
Acknowledgements
Funding was provided by grants from DANIDA and
European Union FP7 support for OPTIMUNISE. CB is
funded through an ERC Starting Grant.
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Appendix
Ghana VAST Survival Study
The GhanaVAST Survival Study was conducted between
1989 and 1991 (Ghana VAST Study Team 1993; Binka et al.
1995; Ross et al. 1995; Benn et al. 2009). A census was
carried out shortly before the trial started. The study area
was exclusively rural and extended families lived in com-
pounds. The area was divided in 185 clusters, which were
randomised to vitamin A supplementation (VAS) or placebo
within a double-blind trial. Children aged 6–90 months of
age were enrolled into an open cohort and were visited at
home every 4 months by trained fieldworkers, in a total of 7
rounds. They were dosed with vitamin A or placebo at each
round. Over the 2 years, 21 906 children were enrolled in
the trial by receiving at least one dose of either VAS or
placebo; 13 462 being enrolled in Round 1. Children who
moved out of the area were censored in the analysis at the
time of moving; children who moved from a cluster with one
treatment to a cluster with the opposite treatment were
censored at the time of receiving the new treatment. Children
who developed xerophthalmia were censored at the time of
diagnosis and received special intensive vitamin A treatment.
VAS was associated with a 19% (95%CI, 2–32%) reduction
in mortality (Ghana VAST Study Team 1993).
Age determination
At enrolment, the date of birth of the child was determined
from the health card if available. Otherwise, the date of
birth was assessed by means of detailed local events
calendars. If no exact date could be obtained, the date were
set to day 15 of the month of birth. The date of birth may
have been determined more precisely among children with
a health card. For example, in Round 1, there were more
children who had day 15 in a month as date of birth among
children without a health card (3772 ⁄ 5066, 74.5%) than
among those with a card (2764 ⁄ 6656, 41.5%) [Prevalence
ratio 1.79 (1.69, 1.91)], and the month of birth was
grouped close to the date of the enrolment month or
6 months earlier (P = 0.003), suggesting that the children
had been reported to be for instance 1 year or 1½ year,
rather than a year and some months. This may have made
the children in the group with no health card appear to
have been slightly younger than they truly were.
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P. Welaga et al. Non-specific effects of diphtheria-tetanus-pertussis and measles vaccinations

Information on vaccinations vaccination programme before and immediately after

1990, the year when the Expanded Programme on Immu-
Vaccination information was collected systematically for
nisation had targeted achieving 80% coverage of vaccina-
the children enrolled in Round 1. One year and 2 years
tion globally (Kim-Farley 1992). Therefore, a certain
later, in Rounds 4 and 7, vaccination information was
vaccination status in Round 1 or Round 4 not only
collected again. Owing to an archiving error, dates of
reflected which vaccines the child had already received, but
measles vaccination from Round 7 were not saved in the
also which vaccines they were likely to receive in the
stored data files.
coming months. Hence, any vaccination effects on
The collection of data on vaccinations was carried out
mortality are likely to be a product of both vaccination
de novo each time without taking previous information
status at enrolment and the vaccines likely to be received
into consideration and only for children being alive at the
during follow-up. We have particularly focused on the
visit. Thus, the vaccination status of children who died
impact on survival in the first 4 months when the infor-
between vaccination visits was not updated. Comparing
mation on immunisation status would be most valid.
information from rounds 1 and 4 for the same children (see
However, we have also reported the mortality effect for the
Appendix table), it is clear that some children made
full 2 years duration of the trial. Although some children
changes that should not have been possible, as all children
who did not have a vaccination card may have had one but
in Round 4 should have had the same status or have
lost it, it is likely that most had never had a card and had
received additional vaccinations since Round 1. However,
never received any vaccination. Furthermore, data from
8% (122 ⁄ 1602) who originally had a vaccination card
subsequent rounds showed that the uptake of vaccination
no longer had a card; 3% (30 ⁄ 931) of children who still
was low among children who initially had no health cards.
had a health card and who were originally reported as
For the present analyses, children who had no health card
having MV no longer had MV reported, and 3% (18 ⁄ 663)
at Round 1 have been assumed to be ‘unvaccinated’.
of children who still had a health card and who were
Information from Rounds 1, 4 and 7 was used to
originally fully DTP-vaccinated no longer had all three
calculate the proportion of children who received vacci-
DTP vaccinations noted. Such errors presumably came
nations in the years following enrolment. This proportion
from the field worker confusing the health cards of
was estimated as the proportion of children who had
different children, or the field worker noting that the child
received vaccination among children whose health card
had a card but forgetting to write the dates of some or all
had been seen at enrolment and again 1 year or 2 years
vaccinations.
later, that is among surviving children. Censored children
The main analysis of the impact of vaccinations has been
were excluded in calculating these proportions.
restricted to children enrolled in Round 1 for whom there
Among the vaccinated children, we have emphasised two
was follow-up for the whole 2-year period. We have
aspects of vaccination status: first, children who had not
elsewhere analysed the impact of VAS on survival and the
yet received MV were likely to receive MV during follow-
interactions with vaccinations (Benn et al. 2009). In the
up; second, children who had not received all doses of DTP
present analysis, we only included children who had
were likely to receive additional doses of DTP during
received placebo as this group would not be subject to
follow-up. We have therefore distinguished between
vaccine ⁄ vitamin A interactions.
children who had received 0-2 doses (DTP0-2) or three or
more doses of DTP (DTP3-4) at enrolment. Vaccination
status at enrolment was categorised into six groups. Group
Analysis of vaccinations
1 consisted of those with no health card and was
Vaccination information was only fully available with considered ‘unvaccinated’. Groups 2–6 all had health cards
intervals of 1 year. Hence, it was difficult to analyse the at Round 1. Group 2 had not received DTP or MV (some
mortality effect of the latest vaccines received until of these children had, however, received BCG); Group 3
receiving the next vaccination as we have performed in had received DTP1-2 but not MV; Group 4 had received
previous studies. Furthermore, the incidence of vaccination DTP3-4, but not MV; Group 5 had received DTP1-2 and
was very high, particularly in the first months after MV; and Group 6 had received DTP3-4 and MV (fully
enrolment, because of a major intensification of the vaccinated).

ª 2012 Blackwell Publishing Ltd 1503

1504
Appendix Table 1 Vaccination status at Rounds 1 and 4 for children who had a health card seen or had no card on both occasions. Navrongo, Ghana, 1989–1990
Tropical Medicine and International Health

Vaccination status at Round 4

4. Health
Vaccination status at 2. Health card, 3. Health card, card, DTP3-4, 5. Health card, 6. Health card,
enrolment (Round 1) 1. No card no DTP, no MV DTP1-2, no MV no MV MV, DTP 0-2 MV, DTP3-4 Total

1 No card 606 17 20 2 132 86 863

2 Health card, 29 21 7 0 40 55 152
no DTP, no MV
3 Health card, 31 7 56 10 58 204 366
DTP1-2, no MV
4 Health card, 3 2 0 10 0 79 94
DTP3-4, no MV
5 Health card, 35 2 7 2 142 206 394
MV, DTP0-2
6 Health card, 24 3 2 14 11 542 596
MV, DTP3-4
Total 728 52 92 38 383 1172 2465
P. Welaga et al. Non-specific effects of diphtheria-tetanus-pertussis and measles vaccinations

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volume 17 no 12 pp 1492–1505 december 2012
 Appendix Table 2 Mortality rate (MR) per 1000 person-years (pyrs) and mortality rate ratio (MRR) for vaccinated compared with unvaccinated children, among children
<36 months at enrolment into the placebo group

Within 4 months follow-up Within 24 months follow-up

MRR* (95% CI)

ª 2012 Blackwell Publishing Ltd

Median (Vaccinated ⁄ No MR per 1000
Group: weight- MR per Unadjusted MRR heath card) years Unadjusted MRR* (95% CI)
Vaccination for-age 1000 years (95% CI) {MRR – {MRR – (deaths ⁄ pyrs) MRR (95% CI) (Vaccinated ⁄ No
status at z-score at (deaths ⁄ pyrs) without measles without {measles {MRR – without health card) {MRR –
enrolment N enrolment {measles deaths} deaths) measles deaths} deaths} measles deaths) without measles deaths}
Tropical Medicine and International Health

1. No card 1093 )1.7 80 (31 ⁄ 389) {2} 1.0 (Reference) 1.0 (Reference) 51 (101 ⁄ 1.0 1.0 (Reference)
[)2.6; )0.8] 1998) {23} (Reference)
2. Health card: 196 )1.9 58 (4 ⁄ 69) 0.72 (0.25, 2.05) 0.65 (0.23, 1.84) 30 (11 ⁄ 0.59 0.53 (0.28, 0.99)
noDTP, noMV [)2.9; )1.0] {0.77 (0.27, 2.19)} {0.71 (0.25, 2.04)} 370) {2} (0.32, 1.10) 0.63 {0.57 (0.28, 1.13)}
(0.31, 1.25)}
3. DTP1-2, 469 )2.0 152 (25 ⁄ 164) 1.90 (1.12, 3.22) 1.79 (1.03, 3.11) 54 (46 ⁄ 1.07 0.93 (0.65, 1.33)
no MV [)3.0; )1.2] {2.03 (1.19, 3.47)} {1.87 (1.07, 3.26)} 854) {6} (0.75, 1.51) {1.05 (0.71, 1.56)}
{1.19 (0.82, 1.75)}
4. DTP3-4, 109 )1.8 52 (2 ⁄ 38) 0.66 (0.16, 2.74) 0.65 (0.15, 2.74) 24 (5 ⁄ 0.48 0.45 (0.18, 1.11)
no MV [)3.0; )1.2] {0.70 (0.17, 2.94)} {0.68 (0.16, 2.90)} 207) {1} (0.20, 1.19) {0.47 (0.17, 1.30)}
{0.50 (0.18, 1.36)}
5. MV, DTP0-2 485 )1.9 47 (8 ⁄ 171){2} 0.58 (0.27, 1.27) 0.74 (0.34, 1.65) 26 (24 ⁄ 0.52 0.58 (0.37, 0.91)
[)2.8; )1.1] {0.47 (0.19, 1.23)} {0.60 (0.24, 1.47)} 923) {3} (0.33, 0.81) {0.70 (0.42, 1.14)}
{0.58 (0.36, 0.94)}
6. MV, DTP3-4 730 )1.8 35 (9 ⁄ 257) 0.44 (0.21, 0.92) 0.61 (0.28, 1.35) 14 (20 ⁄ 0.28 0.35 (0.21, 0.57)
[)2.6; )1.0] {0.47 (0.22, 0.98)} {0.67 (0.31, 1.48)} 1408) (0.18, 0.46) {0.47 (0.28, 0.79)}
{0.36 (0.22, 0.60)}
Total 3082 )1.8 73 (79 ⁄ 1090){4} 36 (207 ⁄
[)2.7; )1.0] 5760){35}
P. Welaga et al. Non-specific effects of diphtheria-tetanus-pertussis and measles vaccinations

*Adjusted for age, zone, WAZ and ownership of radio (N = 3082).

Corresponding Author Paul Welaga, Navrongo Health Research Centre, PO Box 114, Navrongo, Ghana. E-mail: pwelaga@yahoo.com

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volume 17 no 12 pp 1492–1505 december 2012