- •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.
Few studies have examined what happened to child survival when DTP and OPV were introduced in low-income countries. These vaccines were introduced in 1981 in an urban community in Guinea-Bissau from 3 months of age in connection with 3-monthly weighing sessions. Children were therefore allocated by birthday to receive vaccines early or late between 3 and 5 months of age. In this natural experiment vaccinated children had 5-fold higher mortality than not-yet-DTP-vaccinated children. DTP-only vaccinations were associated with higher mortality than DTP + OPV vaccinations. Hence, DTP may be associated with a negative effect on child survival.
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.
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.
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)).
DTP was associated with increased mortality; OPV may modify the effect of DTP.
- Diphtheria-tetanus-pertussis vaccine
- Measles vaccine
- Non-specific effects of vaccines
- Oral polio vaccine
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.
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.
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.
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).Table 1Median age of vaccination and coverage for BCG, DTP and OPV of study cohort.
|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.