IJE Advance Access originally published online on July 23, 2007
International Journal of Epidemiology 2007 36(5):1022-1029; doi:10.1093/ije/dym142
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Non-specific effects of diphtheria–tetanus–pertussis vaccination on child mortality in Cebu, The Philippines
1Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
2Population and Family Health Sciences Department, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
3Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
4Harvard Medical School, Boston MA, 02115, USA.
*Corresponding author. Johns Hopkins Bloomberg School of Public Health 615 N. Wolfe Street, E8527, Baltimore, MD 21205, USA. E-mail: gchan{at}jhsph.edu
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Abstract |
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Background To determine the non-specific effects of diphtheria, tetanus and pertussis (DTP) vaccination and sex on mortality before 30 months of age among those who received Bacille Calmette Guerin (BCG) vaccine in a high mortality area.
Methods This analysis used a longitudinal study of child survival monitoring the use of primary care services, morbidity and mortality in Metro Cebu, The Philippines. Participants included 14 537 children under 30 months of age who received a BCG vaccination from July 1988 to January 1991. The main outcome measure was all-cause mortality.
Results Mortality before 30 months of age was 57% lower among BCG-vaccinated children who received DTP vaccination than BCG-vaccinated children who did not receive DTP vaccination {hazard ratio (HR) for vaccinated vs unvaccinated 0.43 [95% confidence interval (CI) 0.21–0.88]}. Females had lower mortality rates [HR = 0.19 (0.04–0.86), P = 0.03] than males among DTP-unvaccinated children. The protective effect of DTP vaccination was more pronounced in males [HR 0.32 (0.14–0.73)] than in females [HR 0.86 (0.18–4.23)]. DTP vaccination increased (interaction term P = 0.08) the female-to-male mortality ratio to 0.76 (0.52–1.12).
Conclusions Among BCG-vaccinated children under 30 months of age, DTP vaccination is associated with improved survival. The increased female–male mortality ratio is associated with reduced mortality among males following DTP vaccination rather than increased mortality among female children.
Keywords Non-specific vaccine effects, sex differences, DTP vaccine, child survival
Accepted 13 June 2007
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Introduction |
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Specific vaccines, such as the standard titer measles and the Bacille Calmette Guerin (BCG) vaccine, have been thought to provide non-specific effects by protecting against diseases other than the ones addressed directly by the vaccine.1,2 Recent studies have begun to assess possible non-specific effects of diphtheria, tetanus and pertussis (DTP) vaccination. In Guinea-Bissau, Kristensen et al.3 reported deleterious effects on child survival that they attributed to non-specific harmful effects of DTP. In addition, recent studies have claimed that this possible harmful effect was more pronounced among females.4–8 Other studies have found beneficial non-specific effects or no harmful effects associated with DTP.9–12
Such variable results have been attributed to incomplete data on vaccination status, especially that of deceased children, or methodologic issues, leading to varying levels of survival bias.13 Studies that associated DTP vaccination with increased mortality typically classified DTP vaccination status as a time-fixed variable held constant between study visits (‘landmark approach’). Studies that showed no adverse effects or beneficial effects of DTP vaccination tended to classify DTP exposure as a time-varying variable changing on the date of vaccination, based on retrospectively updated information obtained at subsequent visits (‘retrospective approach’).14 In these previous studies with periodic surveillance visits, the vaccination status for children who died between visits was often incomplete; falsely classifying these children as unvaccinated could create bias leading to spurious findings of benefit from vaccination.
We used data from an observational study with complete vaccination information in Cebu, The Philippines to examine the association between DTP vaccination and survival. Because a high proportion of children had received BCG vaccine and to avoid selection bias, we included only BCG-vaccinated children to determine if DTP-vaccinated children had a difference in mortality compared with DTP-unvaccinated children. The primary aim of the study was to investigate non-specific effects of DTP vaccination on mortality, including differential effects by sex. Statistical models were fit with both retrospective and landmark approaches to compare potential differences in results.
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Methods |
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Study design
An open cohort study was conducted to assess the use of primary care services, morbidity and mortality among children less than 30 months of age in Metro Cebu, The Philippines between July 1988 and January 1991. At that time approximately 1.25 million people lived in Metro Cebu, which was divided into 253 barangays (administrative units). The infant mortality rate in 1990 in Metro Cebu was 52 deaths per 1000 live births. A stratified random sample of 7 urban and 26 rural barangays was selected, providing an equal proportion of mothers from rural and urban areas. A baseline survey on children less than 30 months of age, identified by a household census, was conducted to collect socioeconomic, health and environmental data. This survey served as the first round of the longitudinal study. Periodic monitoring surveys were repeated every 6 months to record information on vaccinations, use of other health services and morbidity. New births and in-migrants to the study area were added during subsequent rounds. Ongoing active mortality surveillance was carried out using local informants who were traditional midwives or health workers living in the sample area. When a death was identified, a post mortem verbal autopsy was conducted to determine a specific cause of death. Additional information about the study design and baseline characteristics about the population are discussed elsewhere.15,16 Records missing household or maternal data were excluded.
Vaccination status
According to the recommended vaccination schedule in The Philippines, children should receive a BCG vaccine at less than 11 weeks of age, diphtheria, tetanus and pertussis and poliomyelitis vaccines at 6, 10 and 14 weeks, and measles vaccine at 9 months of age.16 Only the first dose of DTP vaccination was considered, with or without the poliomyelitis vaccine. Vaccination status was determined from vaccination cards in the home or from clinic records; month and year of vaccinations were recorded. Vaccination dates were assumed to occur at the 15th of each month to best approximate the age of vaccination (Because the 15th of the month was assumed, some children who were born and vaccinated before the 15th were recorded as being vaccinated before birth. The 376 children who were recorded as vaccinated with BCG before being born and the 11 children who were recorded as vaccinated with DTP before being born were recoded to be vaccinated for the respective vaccine at day one of age. One child was recorded as receiving BCG and DTP after death and was recoded as vaccinated one day before death). Vaccine information for children who died was collected postmortem. Children were excluded if vaccination status was not updated after death in the retrospective approach to avoid misclassifying vaccinated children as unvaccinated. A sensitivity analysis was done to assess any potential differences in results by excluding these deaths versus including these deaths as unvaccinated. Children who died without vaccine information post mortem were included in the landmark approach, since vaccination status was fixed from the prior visit and therefore not dependent on post mortem data.
Distinctions were made between the following situations: ‘received vaccine with known date’ (considered vaccinated on that date), ‘received vaccine but date unknown’ (considered vaccinated on the date of visit), ‘received unknown vaccine’ (censored at date of receipt of unknown vaccine, i.e. all subsequent information ignored), ‘do not know if received vaccine’ (considered unvaccinated), and ‘did not receive vaccine’ (considered unvaccinated).
Mortality outcome
Deaths identified in the initial round of the study were excluded. In subsequent rounds, death information was obtained via post mortem interviews until the study end date (January 1991). The main outcome measure was all-cause mortality. Non-specific effects of DTP were also assessed on cause-specific mortality, specifically acute lower respiratory infections and diarrhoea, as determined by validated verbal autopsy.17
Statistical methods
Differences in the prevalence ratio for background factors among females and males were analysed with a generalized linear model with binomial variability and a logit link function to correct for over-dispersed logistic models. Examination of the relationship between background characteristics and rate ratios for mortality and vaccination were analysed through Poisson regression (STATA v.9; StataCorp, College Station, TX, USA).
The effect of DTP vaccine on survival was analysed through Cox proportional hazards regression models with time-varying covariates to account for changes in vaccination status over time. The origin was BCG vaccination. The timescale was weeks from BCG vaccination. The retrospective approach began accumulating person-time for each child on the date of the child's BCG vaccination; vaccination status was updated on the exact date of DTP vaccination, including for deaths. The landmark approach began accumulating person-time for each child on the date of the child's first survey; DTP vaccination status was fixed during the interval between follow-up visits. Vaccination status was then updated on the date of visit.
A time-varying discrete variable was constructed for the initial receipt of DTP vaccine. Additional analyses were done with time-varying continuous variables to assess the effect of length of time since DTP vaccination on mortality. DTP vaccination was categorized as: no DTP, and a duration of DTP vaccination according to 1–12, 13–25 and 
26 weeks. Tabulated results are presented in terms of hazard ratios, with values less than one indicating a protective effect of the tested variable.
To create a time-varying model, potentially important variables associated with vaccination and/or mortality in a Poisson regression model (P < 0.10) were entered into a forward stepwise selection procedure (with threshold at P < 0.05).
In the Cox models, differences in survival due to age were adjusted for by stratifying the baseline hazard function on age of BCG vaccination (in five-week intervals until 26 weeks of age, then from 26 to 52 weeks, and greater than or equal to 52 weeks) unless otherwise noted. Generalized estimation equations and robust variance estimation were also used to account for within-household correlations.18 Neither season nor period influenced mortality, and were not adjusted for in the models.
Censoring occurred at the earliest of: 30 months of age, out-migration, lost to follow-up, receipt of first unknown vaccine, receipt of the measles vaccine and administrative end of study (January 1991). Those alive at their last visit but not seen again were designated as being lost to follow-up. Children who were lost to follow-up or out-migrated were censored at 3 months (1/2 of follow-up interval) following the date of the last visit.
All analyses were performed using STATA (v.9; StataCorp, College Station, TX, USA).
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Results |
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Study population and vaccination coverage
A total of 18 964 children less than 30 months of age were enrolled in the original study. Details on the selection of the study population are presented in Figure 1. Of the 18 587 children with complete baseline data, 4030 children (21.68%) did not receive BCG and were excluded. The analysis is based on information for 14 334 children and represents 879 377 child-weeks of observation. Over the 2.5 years of follow-up, there were 137 recorded deaths. In the landmark approach, the analysis was based on 10 231 children and the number of child-weeks decreased to 559 869 weeks.
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Baseline characteristics of the study population by sex are shown in Table 1. The sample was equally distributed among females and males. A greater proportion of females had a birth weight of less than or equal to 2500 grams than males (29.15% vs 25.71%, P < 0.001). All children included in the study were vaccinated with BCG, with 58% of children receiving the vaccine by 11 weeks of age. Most children (97%) received at least one dose of DTP. There were no differences between sexes in the number of children receiving the second and third dose of DTP vaccine.
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Higher maternal education, TV/radio ownership and normal birth weight (>2500 grams) were associated with lower mortality (Table 2). Children from families with higher maternal education and prenatal care from a nurse/midwife were more likely to receive DTP vaccination than their counterparts. Other characteristics such as female sex, normal birth weight and TV ownership were associated with a lower incidence of DTP vaccination (Table 2). Vaccination cards were present at home in 82.9% of the sample and vaccination records were found in clinics for 94.1% of those without vaccination cards at home.
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Survival Analysis
Effect of DTP on mortality
Among BCG-vaccinated children, there was an estimated 57% reduction [HR 0.43 (95%CI 0.21–0.88)] in the risk of death for DTP-vaccinated children compared with those unvaccinated after adjusting for age and other risk factors. In the landmark approach using the same covariates, DTP vaccination was associated with a hazard ratio (HR) of 0.87 (0.33–2.29)
Effect of DTP on mortality by sex
In separate analyses by sex, the effect of DTP on males was associated with a 68% [HR 0.32 (0.14–0.73)] estimated reduction in the risk of death. Among females, DTP was associated with a reduction in mortality by 14% [HR 0.86 (0.18–4.23)] (Figure 2). In the landmark approach, the effect of DTP on mortality was similar for males and females [HR 0.85 (0.25–2.87) and HR 0.96 (0.26–5.15), respectively].
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Effect of DTP on mortality with sex as an effect modifier
In the combined analysis with interaction terms, the difference in the reduction of mortality by DTP was substantially smaller among females than among males suggesting a possible interaction between sex and DTP (P = 0.08). The female–male mortality ratio for DTP-unvaccinated children was 0.19 (0.04–0.86) and increased for DTP-vaccinated children to 0.76 (0.52–1.12). In the landmark approach, there was little evidence of an interaction (P = 0.71) between sex and DTP vaccination status. The female–male mortality ratio for DTP-unvaccinated children was 0.55 (0.10–3.03) and increased to 0.77 (0.49–1.21) for DTP-vaccinated children (Table 3). In the cause-specific mortality analyses, similar results were seen with deaths due to acute lower respiratory disease and deaths due to a combination of acute respiratory disease and diarrhoea.
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Duration of DTP vaccination
Among children with the same amount of time at risk since BCG vaccination, for every week increase in duration of DTP vaccination the hazard of death decreased by 2% [HR 0.98 (0.96–0.99)]. As DTP duration increased from no DTP to 1–12, 13–25
26 weeks, the risk of death decreased [HR 0.68 (0.29–1.57), HR 0.57 (0.26–1.27), HR 0.28 (0.13–0.62), respectively] after adjusting for age of BCG vaccination. The female–male mortality ratio increased when comparing the effect of sex on mortality in each strata of DTP duration [no DTP HR 0.16 (0.04–0.72); 0–12 weeks HR 0.76 (0.35–1.66); 13–25 weeks HR 0.87 (0.44–1.74); 26 weeks HR 0.90 (0.55–1.47)]. By 26 weeks after receipt of DTP there was no difference in hazard ratios between sexes compared with the no DTP category where females had a much lower risk of death compared with males. Results are similar to those in the combined analysis with interaction terms. Again, a sex-specific differential effect of vaccination over time was seen (Figure 3).
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Discussion |
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In Cebu where mortality from diphtheria, tetanus and pertussis is low, the DTP vaccine was associated with a non-specific reduction in overall mortality during the first 30 months of age in BCG-vaccinated children. DTP vaccination had beneficial effects for males with the retrospective approach. Although these effects were not as pronounced for females, there were no harmful effects. The female–male mortality ratio increased following DTP vaccination as a result of the dramatic reduction in mortality among males following DTP vaccination rather than from increased mortality among females. A continuous time-varying analysis of DTP exposure found similar results. A sex-specific differential effect of the vaccine persisted over time, even though males and females received subsequent DTP doses at similar ages and rates.
In all observational studies, there exist unmeasured confounding variables that cannot be controlled, such as the cultural and psychological aspects of caretakers. We restricted our analysis to only those children who were BCG vaccinated to minimize the selection bias against those who were not DTP vaccinated. Data were collected on potential confounders, which may indicate preferential vaccination to particular types of children such as males or females or those at high or low risk of death. In Cebu, most clinics immunized children despite mild infections.19 There were slightly more low birth weight females than males in the sample and this was controlled for in the analysis. Vaccination rates varied between baseline characteristics, such as sex, birth weight and socioeconomic status. The magnitude of the differences in vaccination associated with these characteristics was small. While our models adjusted for these possible confounders, it is difficult to separate the independent effects of vaccinations from the other factors linked to them.
To avoid misclassification of vaccination status, several steps were taken to ensure complete records. If vaccination cards were not found at home, documentation retrieval was done to verify and/or obtain records of children at agencies such as hospitals, public clinics and private clinics. The study included records of the date on which vaccine status was recorded. The absence of records was distinguished from the absence of vaccination. A potential source of misclassification may have existed for children whose mother/caretaker ‘did not know’ if they had received a vaccine. These children were classified as unvaccinated, with the assumption that receipt of a vaccine would be memorable. Misclassification of vaccinated children as unvaccinated would bias any association between vaccination and mortality towards the null. Errors in recording vaccinations may also nullify any vaccine effect. However, in a random sample of the study population, 98% of vaccination visits were observed to be correctly recorded on the child's vaccine form.19 To maximize the registration of deaths, children were censored at first migration from the area. To avoid the effects of additional vaccines, children were also censored at receipt of first unknown vaccine or measles vaccine.
Deaths that were identified in the initial round of the study were excluded to decrease selection bias. Deaths after the initial round were included since active mortality surveillance, verified by the six-monthly household visits, ensured the identification of all children who died.
Divergent results have been attributed to the different methodologies used to analyse datasets containing missing vaccine information for children who have died. In studies where vaccine status is retrospectively updated during subsequent visits, there exists a potential for survivor bias.20 In order to record vaccinations that occur between visits, a child must survive to the next visit. For a child who dies between visits, no documentation of any new vaccinations exists unless vaccination status is updated post mortem. The landmark approach eliminates survivor bias by updating vaccination status at fixed intervals. However, the approach may introduce other biases from the loss of information.
In our study, the landmark approach drove the association between vaccination and mortality towards the null, as expected. Updating the vaccination status only on the date of household visits non-differentially misclassified some observation time for vaccinated children as unvaccinated. Crude categorization of vaccination status by time intervals may not be able to distinguish any effects of DTP vaccine on mortality. Sample size was reduced in the landmark approach yielding less precise estimates. However, if a true protective association between DTP on mortality exists, it is unlikely that such changes in methodology would drastically reverse the inference from protective to harmful. In our analysis using the landmark approach, the protective association between DTP and mortality remained.
The retrospective approach provided a more precise analysis allowing for correct classification of vaccination status for children who died between visits, rather than delaying updates until the next visit. Since vaccination status in this study was updated post mortem, there was no survivor bias. In the sensitivity analysis examining the potential effect of survivor bias, classification of two deaths with unknown vaccination status as unvaccinated yielded little difference in results.
The combined beneficial effects of DTP and BCG against childhood mortality in our study is consistent with studies in Papua New Guinea, Burkina Faso, India and Bangladesh.9–12 In contrast, Kristensen et al.3 reported that BCG and DTP together had beneficial effects, but that the combined effects were less protective than BCG alone. Furthermore, our study did not show any adverse effects associated with DTP vaccination for girls, contrary to the results in Guinea Bissau.4,6
There are several reasons why our results may differ from the results found in Guinea Bissau. We examined the effect of DTP in BCG-vaccinated children. In most of the previous studies, the BCG status of children was not clear. For example, in a twin study using female–male pairs, Aaby et al.6 examined mortality based on the last vaccine received BCG or DTP. In Aaby's study6 as well as the study by Verium et al.8, conclusions suggesting increased female mortality were based on female–male ratios. It is not clear from the literature whether the increased female-to-male ratios following vaccination in some of these studies were due to increased mortality among females or decreased mortality among males.13 The study population in Cebu was different than those in Guinea-Bissau in several key respects. In Guinea-Bissau, the sex-effect studies were done in a hospital-based setting,8 during the war,4 and using twin pairs (including twins from Senegal).6 The conditions of these twin pairs, hospital or war-torn settings, may not be generalizable to the larger community-based populations in Cebu. Furthermore, deaths in different regions of the world may result from different diseases or from the interaction of several diseases such as malnutrition, malaria, diarrhoea or pneumonia. Most deaths in Cebu were due to diarrhoea or pneumonia,21 whereas in Guinea-Bissau malaria or pneumonia was a common cause of mortality in children under five.22 In our analyses of cause-specific mortality, DTP vaccine reduced deaths due to acute lower respiratory disease or acute lower respiratory disease and diarrhoea. Non-specific beneficial effects of DTP may be more pronounced in certain infectious diseases. The various interactions among different diseases coupled with the complex relationships of immune stimulation by combinations of vaccines are not fully understood.
To date, there are no known biological mechanisms for the non-specific effects of vaccinations and the divergent patterns for DTP between sexes. Biologically, the adjuvant of DTP, aluminium hydroxide, is known to be a strong promoter of Th2 response, which may be hypothesized to elicit a stronger immune response among males. Further clinical research is needed in this area.
Since our results did not find any harmful effects of the DTP vaccine specific to BCG-vaccinated girls, there is no reason to alter the vaccination schedule or change the current vaccination strategies at this time. The apparent non-specific mortality benefit in boys is impressive and provides further justification for ensuring complete immunization of all infants.
KEY MESSAGES
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Acknowledgements |
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Thanks to Connie Gultiano of the University of San Carlos, Cebu for assistance with data collection, David Peters for information on the Cebu dataset and James Tonascia, Mark Van Natta, John McGready, and Young Chae for their assistance with data analysis. The original data were collected with funding from the US Agency for International Development to the Johns Hopkins School of Public Health. Project was exempt from federal regulations as defined by 45 CFR 46.101.(b)(4).
Conflict of interest: None declared.
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  P. Aaby, C. S. Benn, J. Nielsen, and H. Ravn Sex-differential non-specific effects of BCG and DTP in Cebu, The Philippines Int. J. Epidemiol., February 1, 2009; 38(1): 320 - 323. [Full Text] [PDF]
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