The Introduction of Diphtheria-Tetanus-Pertussis and Oral Polio Vaccine Among Young Infants in an Urban African Community: A Natural Experiment
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Article InfoHighlights
- •When DTP and OPV were introduced in Guinea-Bissau in 1981, allocation by birthday resulted in a natural experiment of being vaccinated early or late.
- •Between 3 and 5 months of age, children who received DTP and OPV early had 5-fold higher mortality than still unvaccinated children.
- •In the only two studies of the introduction of DTP and OPV, co-administration of OPV with DTP may have reduced the negative effects of DTP.
Abstract
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
between sessions, the children were allocated by birthday in a ‘natural
experiment’ to receive vaccinations early or late between 3 and 5 months
of age. We included children who were <6 months
of 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 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 3 months 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.
Keywords:
Diphtheria-tetanus-pertussis vaccine, DTP, Measles vaccine, Non-specific effects of vaccines, Oral polio vaccine1. 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 measles vaccine (MV), surprisingly few studies examined the
introduction of vaccines and their impact on child survival (Aaby et al., 1983, Aaby et al., 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 community “trials” and before-after studies in several countries (Aaby et al., 1984, Aaby et al., 1993, Aaby et al., 2003a, Holt et al., 1990, Kapoor and Reddaiah, 1991). Hence, a vaccine may have non-specific 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 recommended further
research (Higgins et al., 2014, Strategic Advisory Group of Experts on Immunization, 2014).
Though protective against the target diseases, DTP may increase susceptibility to unrelated infections (Aaby et al., 2003b, Aaby et al., 2004a, Aaby et al., 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 reported beneficial effects (Higgins et al., 2014)
and that most studies underestimated the benefit 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-specific effects of vaccines Working Group, 2014).
On
the other hand, the “unvaccinated” children 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 first
introduced, but not always given together, in 1981–1983 in 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-fledged national program was
implemented with UNICEF support in 1986 (Aaby et al., 1984, Aaby et al., 2004a).
2.2. Demographic Surveillance
In
1978–1979, under-five mortality was nearly 500/1000. Since malnutrition
was assumed to be the main cause, a study was initiated to determine
why children were malnourished (Aaby et al., 1983).
However, severe malnutrition was not evident, and to understand the
high mortality 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 anthropometric
measurements to assess growth patterns and detect malnourished children.
Each health worker followed a population of 1500–2000 individuals. The
health workers were supervised by an expatriate 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
surveillance 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 maintain 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 advised mothers the day before a community
weighing. The following morning, the weight was measured and noted on
the child's growth card and the BHP card. When the World Food Program
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 vaccination
sessions (Table 1).
| 1980 | 1981 | 1982 | 1983 | 1981–1983 | |
|---|---|---|---|---|---|
| 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 the cohort 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 days of age.
Median age: ‘year’ means 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: ‘year’ means the year when the child turned exactly 1 year (or 6 months) old and coverage was assessed. Only children surviving to 1 year (or 6 months) of age were assessed for coverage. Children turning 1 year in 1984 were thus not presented in the table.
Median age: ‘year’ means 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: ‘year’ means the year when the child turned exactly 1 year (or 6 months) old and coverage was assessed. Only children surviving to 1 year (or 6 months) of age were assessed for coverage. Children turning 1 year in 1984 were thus not presented in the table.
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 administered intramuscularly
and OPV as an oral drop. When both vaccines were administered at the
same session OPV was usually given first 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 first. 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 administer 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).
Fig. 1
Each vaccination of the specified type is plotted according age of the recipient and date of vaccination.
The
expatriate nurse sometimes organized additional vaccination sessions in
which the children were not weighed. During these sessions,
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’, ‘malnourished’ or ‘orphan’ as an
explanation of why an age-eligible child had not been vaccinated.
2.5. Data Control
When
a computerized system became available in 1990–1991, weights and
vaccinations from the BHP cards were entered. For the present analysis,
all information on dates of visit, weights and vaccination dates was
checked against the original cards. A few cards were not available or
could no longer be found (Fig. 2).
Fig. 2
Flowchart of study population and children included in the analyses.Notes: DOB = date of birth; [] indicates the number of deaths before 6 months of age in the group.
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 children 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 community 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 3–5-month-old Children
Though
not individually randomized, the present study is a natural experiment
with limited bias in group allocation: With 3-monthly intervals between
weighing sessions, children were allocated by their birthday to receive
their first vaccinations early or late between 3 and 5 months of age (Fig. 3). We therefore compared 3–5-month-old children who had received DTP (±OPV)
vaccinations early with children who had not yet received these
vaccinations. Since there were no healthy “unvaccinated” children after
6 months of age unless they had travelled, we censored follow-up of all
children at 6 months of age (Fig. 3).
Fig. 3
Natural experiment study design.Note: Children were weighed every third month. After 3 months of age they received DTP and OPV on weighing days if they were healthy. Children who attended but were not vaccinated at a weighing session after 3 months of age were censored in the survival analysis comparing DTP-vaccinated and unvaccinated children.
Sick
children were not vaccinated, in the main analysis we therefore
censored ‘unvaccinated’ children 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 examined 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-unvaccinated also came from children 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 compared the
background factors for the children who were DTP vaccinated, attended a
weighing session between 3 and 5 months but were not vaccinated and
those who did not attend a weighing session (Table 2).
| DTP-vaccinated at 3–5 months | Attended weighing session at 3–5 months, not vaccinated | Did not attend weighing session at 3–5 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 | ||||
| 46.8% | 54.8% | 45.0% | |
| 11.8% | 13.4% | 16.3% | |
| 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] |
| As DTP vaccinated | 73.3 | 1.8 | 2.0 | |
| As unvaccinated | 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) | |
We also examined the
mortality of children who due to logistic reasons had received DTP-only.
Absences and travelling patterns are unlikely to differ between
children who at their first vaccination had received DTP1 + OPV versus
DTP1-only; these two groups were equally likely to receive subsequent
vaccinations both 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 compared using a Cox
proportional hazard model with age as underlying time.
Children
were classified 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 children had received BCG at the maternity ward without proper
documentation 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
information was collected. Due to the additional vaccination sessions
organized by the expatriate nurse some “unvaccinated” children received a
vaccine before the weighing session where they changed status to
“vaccinated”; it is noted in the footnote to Table 3
how many had received such vaccinations. As a sensitivity analysis we
also did an analysis including the additional vaccination sessions as
landmarks. For the remainder of this paper, we will refer to these
landmarks as vaccination-days-without-weighing.
| Age group 3–5 months | Mortality rate (deaths/person-years) | HR (95% CI) for DTP vs unvaccinated | ||
|---|---|---|---|---|
| All | ||||
| Unvaccinated (N = 651) | 4.5 (5/111.4) | DTP (±OPV) (N = 462) | 17.4 (11/63.1) | 5.00 (1.53–16.3) |
| DTP only (N = 101) | 35.2 (5/14.2) | 10.0 (2.61–38.6) | ||
| DTP + OPV (N = 361) | 12.3 (6/48.9) | 3.52 (0.96–12.9) | ||
| Girls | ||||
| Unvaccinated (N = 313) | 1.9 (1/51.9) | DTP (±OPV) (N = 222) | 13.3 (4/30.1) | 9.98 (0.81–123.0) |
| DTP only (N = 44) | 16.2 (1/6.2) | 12.0 (0.56–257.2) | ||
| DTP + OPV (N = 178) | 12.5 (3/23.9) | 9.50 (0.73–124.0) | ||
| Boys | ||||
| Unvaccinated (N = 338) | 6.7 (4/59.5) | DTP (±OPV) (N = 240) | 21.2 (7/33.0) | 3.93 (1.01–15.3) |
| DTP only (N = 57) | 49.8 (4/8.0) | 8.93 (2.01–39.7) | ||
| DTP + OPV (N = 183) | 12.0 (3/24.9) | 2.21 (0.44–11.0) | ||
Notes: There were no
deaths due accidents in this age group. BCG is disregarded in the
analysis. Hence, the unvaccinated children have not received DTP, OPV or
MV but may have received BCG. Of the 651 unvaccinated children, 219
received DTP and/or OPV before their first weighing examination. These
children counted as ‘unvaccinated’ until their first weighing
examination. Of the 462 children who received DTP (±OPV),
177 received an additional DTP or OPV before 6 months of 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.
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 of deaths and
control for season and calendar time did not change estimates (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 children
were included in the study cohort. The median ages for DTP1 and OPV1
were 121 and 118 days, respectively (Table 1). The vaccination coverage at 6 months of age was 55% for DTP1; 3% got DTP3 (Table 1).
Coverage for MV was only 6%. Of the DTP1, OPV1 and MV vaccinations
noted on the BHP card 90–95% 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 (0.93–1.24) for receiving a
vaccination at that weighing session.
3.1. Natural Experiment with 3–5-month-old Children
There
were no marked differences in background factors for the three groups
of children who were DTP vaccinated at 3–5 months of age, those who
attended a weighing session but were not vaccinated, and those who did
not attend a weighing session at 3–5 months of age (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 3–5 months of age were
significantly 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 < 0.001) (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-unvaccinated’ was associated with a HR of 5.00 (1.53–16.3) (Table 3);
the HR was 9.98 (0.81–123) for girls and 3.93 (1.01–15.3) for boys. If
we also included vaccinations given on
vaccinations-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
(2.61–38.6) (Table 3).
The difference between DTP-only children and DTP-plus-OPV does not
reflect differences in follow-up and other vaccinations since the time
to 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 results 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 (1.20–12.8) 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 mortality from 3
to 12 months of age after the introduction of these vaccines. The
mortality rate for all 3–11 months old children increased 2-fold
(HR = 2.12 (1.07–4.19)) from 1980, before vaccinations, to 1982–1983,
after the introduction of DTP and OPV (Table 4).
| Mortality rate | 1980 | 1981 | 1982 | 1983 | HR (95% CI) for 1982–1983 versus 1980 |
|---|---|---|---|---|---|
| Children aged 3–11 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 (1.07–4.19) |
Notes: Event recorded as accidents were not removed from this analysis.
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
vaccination, mortality was 5 times higher for DTP-vaccinated children.
Co-administration of OPV with DTP may have reduced the negative effects
of DTP.
4.2. Strength and Weaknesses
The
present analysis assessed DTP and child survival in a “natural
experiment” in which the children were allocated by the timing of their
birth and community weighing sessions and the group allocation was
therefore not influenced by the usual selection biases to the same
extent as most other studies of DTP (Aaby et al., 2016).
To assure that the censoring 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 unvaccinated children had slightly worse nutritional
status before 3 months of age than the children who were subsequently
DTP vaccinated (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 estimates from the natural experiment
may therefore still be conservative.
The estimated
effects of DTP and OPV are unlikely to have been influenced by other
vaccinations since very few had received other vaccines; if the children
who may have received BCG were censored in the analysis the result was
essentially the same (Supplementary Table 2).
The
3-monthly community examinations assured that we had follow-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 field
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 general 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 examinations. 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 infection.
The
present study was not a planned trial. The study would have been a
cleaner natural experiment if vaccinations had only been administered at
the weighing sessions. However, the expatriate nurse did organize
additional vaccinations and some ‘unvaccinated’ children had therefore
already received a vaccination before coming for a weighing session.
These ‘misclassifications’ do 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 mortality (Aaby et al., 2004a).
All studies that documented vaccination status and followed children
prospectively indicate that DTP has negative effects; a meta-analysis of
the eight studies found 2-fold higher mortality for DTP-vaccinated
compared with DTP-unvaccinated, mostly BCG-vaccinated controls (Aaby et al., 2016) (Appendix A).
The
negative effect of DTP was much worse in this natural experiment than
has been reported in previous studies of DTP. This is presumably due to
the “unvaccinated” control 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 document marked beneficial NSEs of OPV. In an RCT,
OPV at birth (OPV0) reduced infant mortality by 32% (0–57%) before the
children received campaign-OPV (Lund et al., 2015).
In Bissau campaign-OPV reduced the mortality rate by 19% (5–32%)
(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 combination of DTP and OPV (Aaby et al., 2004b). Thus, OPV may have modified the negative effect of DTP.
This pattern was also seen when DTP was first introduced in the rural areas of Guinea-Bissau in 1984 (Aaby et al., 2004a).
OPV was not used the first year and the HR for DTP versus unvaccinated
was 5.00 (0.63–39.7). 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 (2.61–38.6) for DTP-only
but 3.52 (0.96–12.9) for children who received DTP and OPV
simultaneously (Table 3).
Based on these two studies of the introduction of DTP, the HR compared
with DTP-unvaccinated children was significantly different for children
who had received DTP-only (HR = 8.14 (2.63–15.2)) and for children who
received both DTP and OPV (HR = 2.21 (1.16–4.19)) (test of interaction,
p = 0.049). Hence, simultaneous administration of DTP and OPV may have
alleviated the negative non-specific effect of DTP.
5. Conclusions
DTP
was associated with 5-fold higher mortality than being unvaccinated. No
prospective study has shown beneficial survival effects of DTP.
Unfortunately, DTP is the most widely used vaccine, and the proportion
who receives DTP3 is used globally as an indicator of the performance 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 available 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 simultaneously 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 committee 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 unchallenged, the present study may
remain the closest we will ever come to a RCT of the NSEs of DTP.
Funding
The
present study 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-specific effects of vaccines has been supported 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 Research
Foundation ( DNRF108 ). PA held a research professorship grant from the
Novo Nordisk Foundation.
Conflict of Interest
Nothing to declare
Contributions
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 first draft
was written by PA; all authors contributed to the final version of the
paper. PA and SWM will act as guarantors of the study.
Independence
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 subsequent prospective studies have supported a negative effect (Aaby et al., 2016). Furthermore, DTP may have a negative effect when given simultaneously with or after MV (Aaby et al., 2003b, Aaby et al., 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 administered after MV because HTMV had been given early at
4–5 months of age (Aaby et al., 2003b).
DTP
has not been shown to have beneficial 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 updated follow-up time for DTP-vaccinated children
who survived but children who died without their vaccination status
being documented were classified as “unvaccinated”. Such procedures give
a misleading high mortality rate in the unvaccinated group, and the
comparison of DTP-vaccinated survivors and “unvaccinated” children will
therefore give a beneficial estimate for DTP (Aaby et al., 2016).
If the mortality rate of unvaccinated children is unnaturally
increased, the HR of unvaccinated 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 (0.15–1.15) in the
3–5 months age group (Supplementary Table 2). In studies with survival
bias and unnaturally high mortality in the unvaccinated group, the bias
index has been 3–8 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 studies showed a
deleterious effect of DTP but they concluded that the results were
inconsistent because two studies showed a beneficial effect. The
beneficial 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 (2.93–3.95) and 7.52 (5.15–10.97), respectively (Aaby et al., 2016).
SAGE's
working group on non-specific 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 reduced 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, Aaby et al., 2004b, Aaby et al., 2012). OPV has probably reduced the overall negative 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 >5–6% of infant deaths in the only existing African study of the impact of pertussis on child mortality (Mahieu et al., 1978), it is not surprising that DTP is also associated with a strong negative effect prior to vaccine-induced herd immunity (Aaby et al., 2012).
Appendix B. Supplementary Data
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