Divergent female–male mortality ratios associated with different routine vaccinations among female–male twin pairs

Peter Aaby1,2, Henrik Jensen1,2, Amabelia Rodrigues1, May-Lill Garly1,2, Christine Stabell Benn1,2, Ida Maria Lisse1 and Francois Simondon3

1 Bandim Health Project, Apartado 861, Bissau, Guinea-Bissau
2 Danish Epidemiology Science Centre, Artillerivej 5, 2300 Copenhagen S, Denmark
3 IRD, UR 24 Epidemiology and Prevention Research Unit, Dakar, Senegal

Correspondence: P Aaby, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark. E-mail: psb{at}mail.gtelecom.gw


    Abstract
 Top
 Abstract
 Subjects and Methods
 Results
 Discussion
 References
 
Background Observational studies have suggested that vaccinations have non-specific effects that differ by sex. In the absence of randomized trials, studies of female–male twin pairs would allow us to investigate whether an intervention had sex-specific effects on survival. We therefore examined mortality patterns among female–male twin pairs according to vaccination status.

Design We identified female–male twin pairs using the population registers from one urban district and three rural studies from Guinea-Bissau and Senegal and examined the female–male mortality ratio (MR) according to the last vaccine received among pairs in which a death occurred before 18 months of age. As background information, we examined sex- and age-specific mortality patterns in the pre-vaccination era.

Subjects In all, 626 female–male twin pairs identified between 1978 and 2000.

Results There was no sex difference in mortality for boys and girls in the pre-vaccination era. In the combined analysis of all studies, the female–male MR was 0.25 (95% CI: 0.05, 0.93) for pairs having received Bacille Calmette-Guerin (BCG) as the last vaccine, 7.33 (95% CI: 2.20, 38.3) for pairs having received diphtheria, tetanus, pertussis (DTP) as the last vaccine, and 0.40 (95% CI: 0.04, 2.44) for pairs having received measles vaccine as the last vaccine. The female–male MR varied significantly for BCG compared with DTP (exact test of homogeneity, P < 0.001) and for DTP compared with measles vaccine (exact test of homogeneity, P = 0.001).

Conclusion Non-specific effects of routine vaccinations are likely to be important and influence sex-specific mortality patterns in areas with high mortality. The effects of vaccines need to be considered in the planning of immunization programmes for low-income countries.


Keywords BCG, DTP, female–male twins, gender-specific mortality, measles vaccine, non-specific effects of vaccines

Accepted 8 July 2003

The introduction of routine vaccinations in low-income countries has been associated with major reductions in mortality.1–4 Several observational studies from low-income countries have suggested that the reduction cannot be explained merely by prevention of the targeted infections. Hence, routine immunizations may have non-specific effects on childhood survival that may be as important as the mortality reduction associated with the specific protection.1–8 Bacille Calmette-Guerin (BCG) vaccine, which is normally given at birth, and measles vaccine, given at 6–9 months of age (Figure), may reduce mortality by as much as 40–50%,1–4,7,8 i.e. much more than can be expected from preventing measles and tuberculosis-related deaths. In contrast, the diphtheria, tetanus, pertussis (DTP) and polio vaccines normally given between 1 and 5 months of age have not been associated with reduced mortality in areas with herd immunity against pertussis.1,2,7–10 Though both high-titre and standard-titre measles vaccines were strongly protective against measles infection, high-titre measles vaccine was associated with higher mortality, but only for girls.5,6,10 Both beneficial and negative effects of vaccines have been observed to be stronger for girls than for boys.3,5,6,8–11 The best arguments for non-specific effects have probably been that different vaccines have divergent effects,2,3,7,8 and that effects differ for boys and girls.3–6,8–11 Both of these facts would be difficult to explain as a result of selection bias.

Ideally, such observations should be examined in controlled intervention studies. However, controlled trials were not carried out before the vaccines were introduced, and ethically, it would not be possible to conduct randomized placebo-controlled trials with vaccines used routinely.

We have searched for other ways of examining the importance of non-specific effects of vaccines and the possible differential effects of vaccines for boys and girls. In female–male twin pairs, factors affecting sex-specific mortality would influence the female–male mortality ratio (MR), the susceptible sex having a higher risk of dying. Except for gender preferences, comparison within female–male twin pairs would control for confounding due to social conditions and cultural patterns. Using four community studies from Guinea-Bissau and Senegal, we therefore examined mortality in female–male twin pairs according to the last received vaccine.


    Subjects and Methods
 Top
 Abstract
 Subjects and Methods
 Results
 Discussion
 References
 
Introduction of vaccines in Guinea-Bissau and Senegal
The current vaccination schedule in Bissau is presented in Figure 1. In Bissau, BCG is recommended at birth but only became commonly used from the mid-1980s. DTP and oral polio vaccines were introduced for children aged >=3 months in June 1981. In 1987, the policy was changed to three doses of DTP and polio vaccines at 6, 10, and 14 weeks of age (Figure 1). Measles vaccine has been given from 9 months of age through most of the period. However, in the first years of the project when there were only annual vaccination campaigns, the measles vaccine was administered from 6 months of age. Furthermore, in connection with trials of high-titre measles vaccines5 and a two-dose measles vaccination schedule,12 measles vaccines were administered before 9 months old. In the rural areas, measles vaccine was used from 1981, DTP and oral polio vaccines from 1984, and BCG only from 1985–1986.



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Figure 1 The schedule for routine vaccinations in Guinea-Bissau: OPV = oral polio vaccine; DTP = diphtheria-tetanus-pertusis vaccine

 
In Senegal, a high-titre measles vaccination trial6 was started in 1987, and this study was followed by trials of acellular and whole-cell pertussis vaccines.13 Due to these trials, children were called systematically for vaccinations at the three local health centres. BCG was virtually always given together with the first dose of DTP; hence, very few children received BCG alone.

Pre-vaccination mortality
Previous studies from rural Senegal have found no sex-difference in mortality at 1–17 months of age in the pre-vaccination era.3,6 In Guinea-Bissau, we evaluated the female–male mortality pattern for children aged 1–17 months prior to the introduction of routine DTP and oral polio vaccine. We used our demographic surveillance data from Bandim 1, an urban area in Bissau city, as well as data from rural areas which have been followed since 1978 and 1979, respectively. Survival was followed from December 1978 to June 1981 in Bandim and from March 1979 to the time the first DTP and oral polio vaccines were introduced in 1984. The children were removed from the analysis from the date of vaccination if they received measles vaccine before 18 months of age in one of the campaigns (Table 1).


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Table 1 Female–male mortality ratios for unvaccinated children aged 1–17 months, Guinea-Bissau, 1978–1983

 
Urban twin study
The Bandim Health Project (BHP) has maintained a population register for the inhabitants of the districts of Bandim 1, Bandim 2, Belem, and Mindara in the capital of Guinea-Bissau since 1978, 1984, and 1995, respectively. All houses in the study area are visited monthly to identify pregnant women and newborn children. Assistants from the BHP visit all children at home every 3 months until age 3 years. The vaccination card is inspected if possible; for all children it is noted ‘card seen’, ‘no card-not vaccinated’, ‘card lost’, or ‘card not available’. In the present study, children were only registered as vaccinated if the project had provided the vaccination or the vaccination card had been seen.

Since the early phase of the BHP, birth and census forms recorded whether the person was born a twin.14,15 For the purpose of the present investigation, we collected all twin pairs registered since the start of the project.

Rural twin studies
We used three data sets from rural areas of Guinea-Bissau and Senegal to obtain more information on mortality among vaccinated female–male twin pairs.

Bissau 1
In the village study conducted in five regions of Guinea-Bissau since 1979, we followed communities with 6-monthly or annual visits as described previously.16

Bissau 2
Between 1990 and 1996, we conducted a study of 100 clusters of 100 women of fertile age in each cluster in the five major regions in Guinea-Bissau. As previously described,2 each cluster was visited very 6 months and pregnancies, births, and survival for children <5 years old were registered. At each visit vaccination status was assessed for around 60% of the children for whom someone was at home to find the vaccination card.

Senegal
In Niakhar, in rural Senegal, a population of around 29 000 has been followed since 1983, very few children being vaccinated during the first years of the study. The cohort of twins was born between February 1987 and February 1997 and followed to July 1997, i.e. the period of the vaccine trials. Since virtually all vaccines were provided by the project, vaccination status was inferred from the date of vaccination in Senegal.

Nutritional status
In Guinea-Bissau, until around 1990, we called children for weighing and vaccination sessions in connection with the 3-monthly examinations in the urban area and the 6-monthly visits to the villages in the rural areas. If the children attended, they were weighed and vaccinated if they had missed vaccinations. We compared the nutritional status of boys and girls in pairs who were both weighed on the same day, and who both received the first dose of DTP on the same day or later. Weight-for-age z-scores were calculated using the ANTHRO program.

Ascertainment of mortality
Ascertainment of deaths was done through routine visits to the homes of children <3 years old in the urban area, <5 years old in the rural areas of Guinea-Bissau, and to all families in rural Senegal. We reviewed verbal autopsy forms to assess whether deaths were due to infectious diseases or accidents. None of the deaths among vaccinated children were reported to be due to accidents. In the analysis of the impact of different vaccines, there were 47 deaths, reported to be due to diarrhoea (16), unspecified fever (16), respiratory infection (7), malaria (4), measles (2), malnutrition (1), and unknown causes (1).

Analysis of vaccination status
Pairs were only considered at risk from the day vaccination status had been registered. For example, if a pair was visited at 6 months of age and had received first BCG and then DTP, it would no longer be at risk of dying with BCG as the last vaccine since the twins had already received DTP before their vaccination status had been registered. Due to the longer interval between visits, there was less possibility of observing changes in vaccination status and subsequent death in the rural areas. Information on vaccination status depends on project assistants seeing the vaccination card in connection with the household visit. Mothers throw away the vaccination card when a child dies, and we therefore had no chance of inspecting the card later. Hence, for some children dying early, we had not seen the vaccination card before the child died. We limited the analysis to pairs for whom both had vaccinations documented in available records before death occurred.

Non-specific effects of vaccines may be due to stimulation of the immune system, and effects are therefore likely to be temporary; the children will receive other vaccines or other stimuli from infections. Hence, we examined the effect of a specific vaccine as long as it was the last vaccine received, which would usually not be a period of more than 3–9 months before a new vaccine was received. Once a pair was known to have received a new vaccine it entered the data set for this vaccine as such vaccines may change the sex ratio again.10 In Senegal, all pairs had received BCG and DTP simultaneously as the primary immunization, and simultaneous BCG and DTP vaccinations have therefore been considered a separate category (Table 2). Hence, BCG was analysed both as a separate vaccine and in combination with DTP. In the normal vaccination programme measles vaccine should be received after the third dose of DTP and OPV; many measles-vaccinated children were removed from the analysis because they received DTP simultaneously or after measles vaccination.10 A few twin pairs had received high-titre measles vaccines but most of these pairs were censored because they received other vaccines simultaneously.10 Hence, all pairs that contributed to the analysis of gender-specific mortality after measles vaccination had received standard measles vaccine.


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Table 2 Number of vaccinated female–male twins under observation and the number of girls and boys who died first in a pair according to the last vaccine(s) received. Children aged 1–17 months

 
We obviously did not have perfect information, especially in the Bissau studies, where we did not provide all the vaccines ourselves but obtained information at regular intervals. Thus, pairs may have received other vaccines after the vaccination we registered and before the child died. However, we were able partly to control for this by using information from the surviving twin and assuming that the dead twin would have received the same vaccines as the surviving one; it had no effect on the female–male MR (Table 2, footnote).

Only twins registered before 18 months old were included in the analysis. This was done because previous studies have found the non-specific effects of DTP, polio, and measles vaccines to be strongest between 1 and 18 months old.7 In Guinea-Bissau, most children receive booster doses of DTP and polio vaccines at 18 months old; the national immunization programme recommended booster doses in the 1980s, and the practice has continued even though it is no longer official policy (Figure 1).

Statistical analysis
The paired analysis included only opposite sex pairs where both twins had been vaccinated on the same day. In the paired analysis, female–male twin pairs were analysed as a matched case-control study with the first death as the case and the surviving twin being the control. After the death of the co-twin the second twin was removed from the analysis, as it could no longer be the first death in a pair. Exposure was taken to be female and non-exposure to be male. We examined whether the female/male MR depended on the last vaccine received.17 The analyses were done using exact conditional logistic regression and results are given as odds ratios with exact 95% CI and exact P-values for test of homogeneity.


    Results
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 Abstract
 Subjects and Methods
 Results
 Discussion
 References
 
In the pre-vaccination era, there was no difference in mortality for boys and girls between 1 and 17 months of age, girls having a few per cent lower mortality than boys (Table 1). Using data from both the urban and the rural village study, 42 pairs of female–male twins had been weighed before (N = 29) or on the same day (N = 13) as they received their first dose of DTP. The median age of these children was 2 months. There was no significant difference in weight-for-age z-score (w/a), the girls (mean: –1.84 [SD: 1.05]) being slightly better than the boys (mean: –2.15 [SD 1.16]).

Urban twin studies
There were 254 female–male pairs registered before 18 months old. Thirty-nine girls and 37 boys died in the first month of life. At 1–2 months of age, 11 boys and 7 girls died; they had either received no vaccine or BCG only. Between 3 and 17 months old, eight girls and five boys whose vaccination status was unknown died. Some pairs had not received vaccines because they belonged to the pre-vaccination era (1979–1981) or because they were travelling most of the time. Hence, we were able to include only 70 female–male pairs in the analysis of twins who had received BCG alone or together with DTP as the last vaccine, 86 pairs in the analysis of twins who had DTP vaccination documented as the last vaccine before receiving measles vaccine, and 84 pairs who had a record of measles vaccination before 18 months old. A total of 137 pairs contributed to one or more of the analyses of BCG, DTP, and measles vaccines.

Among the 70 pairs having received BCG as the last vaccine, three boys and no girl died first (Table 2). In 86 pairs with DTP registered as the last vaccination, usually together with oral polio, the girl died first in 13 pairs and the boy first in one pair, providing a female–male mortality odds ratio of 13.0 (95% CI: 1.95–553.5) (Table 2). The pattern was the same at age 3–8 months when six girls and one boy died first (odds ratio = 6.00, 95% CI: 0.7, 276.0) and at age 9–17 months when seven girls and no boy died first (odds ratio = undefined, P = 0.016). Among the 84 pairs with prospectively registered measles vaccination, the boy died first in five pairs and the girl in one pair, all deaths occurring between 6 and 17 months of age, the female–male MR being 0.20 (95% CI: 0.004, 1.79) (Table 2).

The female–male MR differed significantly for recipients of BCG (three boys and no girl) and DTP as the last vaccine (13 girls versus one boy) (test of homogeneity, P = 0.012) and for recipients of DTP and measles vaccine as the last vaccine (one girl versus five boys) (test of homogeneity, P = 0.004). Restricting the comparison to the age range 9–17 months when both DTP and measles vaccine recipients were represented, there was also a significant difference in the female–male MR for DTP and measles-vaccinated children (7/0 versus 1/5; test of homogeneity, P = 0.009).

Rural studies
The rural studies provided 372 female–male twin pairs having received vaccinations with 124 pairs in each of the three rural studies. For similar reasons of high mortality and long intervals between visits that prevented us from seeing all the changes in vaccination status, only a small proportion of twins which contributed pairs to the analyses of the effects of BCG, DTP, or measles vaccine. As will be seen in Table 2, the female–male MR was three female deaths versus nine male deaths (MR = 0.33, 95% CI: 0.06, 1.34) when BCG, with or without simultaneous DTP, was the last vaccine received. On the other hand, if DTP was the last vaccine, and measles vaccine had not been received yet, the female–male MR was nine female deaths versus two male deaths (MR = 4.50, 95% CI: 0.93, 42.8). The female- male MR for recipients of BCG versus DTP vaccine as last vaccine varied significantly (3/9 versus 9/2; tests of homogeneity, P = 0.019). Follow-up after measles vaccine was short in the rural studies because many children were vaccinated late or received later DTP vaccinations. Only one girl aged 14 months died first in the Senegalese study.

Combined analysis
The sex differential tendencies were the same in the urban and rural studies (Table 2). In the combined analysis of all four studies, the female–male MR was 0.25 (95% CI: 0.05, 0.93) for pairs having received BCG, with or without DTP, as the last vaccine, 7.33 (95% CI: 2.20, 38.3) for pairs having received DTP as the last vaccine, and 0.40 (95% CI: 0.04, 2.44) after measles as the last vaccine. The female–male MR varied significantly for BCG compared with DTP (3/12 versus 22/3; test of homogeneity, P < 0.001) and for DTP compared with measles vaccine (22/3 versus 2/5; test of homogeneity, P = 0.001). If we excluded children who had received simultaneous BCG and DTP, the female–male MR in the BCG group was 0.20 (95% CI: 0.004, 1.79), still significantly different from the female–male MR in the DTP group (1/5 versus 22/3; test of homogeneity, P = 0.004). Even if we included pairs not vaccinated on the same day or excluded pairs where the dead co-twin may have received a different vaccine before dying, there was no essential change in the female–male MR (Table 2)


    Discussion
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 Abstract
 Subjects and Methods
 Results
 Discussion
 References
 
To our knowledge the potential sex differential impact of risk factors for child mortality has not been examined in female–male twin pairs before. Only by combining several different demographic surveillance systems was it possible to obtain more than 600 pairs. Though this is a relatively large number of female–male pairs only a small proportion of these pairs contributed to the mortality analysis; many pairs were not included in the analysis for specific vaccines because one or both twins died or moved before being vaccinated, they were not home to have their vaccination card examined when the team visited the village, the twins had been vaccinated on different days, or they received several vaccines. Only 47 deaths contributed to the analysis, 15 deaths for the BCG analysis, 25 deaths for the DTP analysis, and 7 deaths for the analysis of measles vaccine (Table 2) and the results should therefore be considered with caution. Given the small number of events, the study provided surprisingly clear indications of interaction between type of vaccine and sex-specific mortality risk, the results being inhomogeneous for BCG compared with DTP as well as for DTP compared with measles vaccine. The female–male twin studies showed the same sex-divergent tendencies as in previous observational studies from Guinea-Bissau and Senegal;1–6,8 DTP vaccine has been associated with higher mortality1,2,7–10 which is more marked for girls,810 whereas BCG and measles vaccines have been associated with improved survival which was not explained by specific disease prevention,1,2,7 the effect again being more marked for girls.5,6,8,11

The sex differential effects observed in the present study are unlikely to have anything to do with the specific effects of vaccinations; the twins in a pair would presumably have similar exposure to TB, measles, or whooping cough. Though not identical, the similar genetic, social, and cultural background of female–male twins should make it unlikely that differential mortality can be explained as a result of confounding factors related to the conditions of boys and girls, unless mothers were treating boys and girls differently. However, preferential treatment of boys is unlikely to have had an important impact on mortality patterns, as there was no excess female mortality in the pre-vaccination era (Table 1). Retrospective data from Bissau,15 as well as prospective data from another rural area of Senegal in the 1980s,18 indicate that female twins in same-sex and opposite-sex pairs had lower mortality than male twins in the pre-vaccination area. A survey of twin data from Africa has also suggested that female twins have slightly lower mortality than male twins.19 In the present study, there was no difference in mortality for male and female twins in the neonatal period or in the post-neonatal period among children who had not yet received vaccination. There was no difference in nutritional status for boys and girls in female–male pairs before they received DTP vaccine. Furthermore, it would be difficult to explain why mothers would change from no sex preference to female preference after BCG, from female to male preference after DTP vaccination, and from male to female preference when the children had received measles vaccine. Finally, the female–male mortality difference between DTP- and measles-vaccinated children was similar when the two vaccine groups overlapped at age 9–17 months, and the increased female mortality among DTP-vaccinated children can therefore not be explained as an age-related phenomenon. Thus preferential treatment of sexes is very unlikely to explain the observations. Changes in female–male MR have been noted before. Increased female mortality was the essential feature of the high-titre measles vaccine studies, the girls vaccinated with high-titre measles vaccine having nearly two times higher mortality than female recipients of standard measles vaccine.5,10,20 Several studies have reported reduced female mortality after standard measles vaccine.1,3,6,8,11 In a study from rural Senegal comparing mortality in the pre-vaccination and post-vaccination eras, the female–male MR increased from 1.05 (95% CI: 0.76, 1.46) to 1.18 (95% CI: 0.56, 2.50) between 1 and 8 months of age, when BCG and DTP/polio had been given, whereas it declined from 1.04 (95% CI: 0.85, 1.28) to 0.65 (95% CI: 0.42, 1.02) among children aged 9–59 months who were likely to have received measles vaccine.3

The estimates of the female–male MR are likely to be extreme in the present study of twins. Twins are a natural form of crowding and are therefore more exposed to infections and have higher mortality;14 this would tend to amplify the differential effect of risk factors affecting mortality. Presumably for similar reasons, we observed very marked sex differential effects of the vaccines during the recent war in Guinea-Bissau when mortality was high.8

The present results add weight to the proposition that vaccines have major non-specific effects on childhood survival in high mortality areas.1,2 We need to understand the immune system of infants better to explain the opposite tendencies associated with different vaccines.2,5 DTP and oral polio vaccines are usually given together and the increased mortality associated with these vaccines in several studies1,2,7,8 could be due to either or the combination. However, we observed low mortality at the hospital in Bissau when oral polio was given alone because of shortage of DTP and high mortality when DTP was introduced as the first vaccine in rural areas of Guinea-Bissau.9,21 Hence, a possible negative effect is most likely due to DTP. The period of observation for specific vaccines was short because other vaccines would be given shortly after and the present study had too few deaths for specific vaccines to estimate the duration of non-specific effects. In other larger studies, we have found the beneficial effect of measles vaccine to be strongest within the first 6 months after vaccination.4 The effect of DTP has only been studied within a follow-up period of 6 months after vaccination and the effect did not change within that period.2,9

Aluminium hydroxide, the adjuvant of DTP, enhanced susceptibility to tuberculosis in animal studies.22 In studies comparing inactivated and live versions of respiratory syncytial virus (RSV) or influenza vaccines, inactivated vaccines have been associated with more severe morbidity upon challenge irrespective of whether the vaccine used alum or no adjuvant, though the effect seemed slightly stronger when alum was used.22–25 Inactivated and alum-based vaccines apparently boost a Th2 profile with a reduced INF-gamma to IL-4 ratio,2225 whereas live vaccines stimulate a Th1 profile26,27 with an increased INF-gamma to IL-4 ratio.23 Some recent studies have suggested that women react more to aluminium-containing vaccines.28 It might be worthwhile examining whether changes in adjuvant would make a difference to the increased female–male MR associated with DTP.8 Little research has been carried out on the immunological effects of changing the sequence of vaccinations,10 or of giving two vaccines with different profiles at the same time. We have suggested that the real cause of the problem of increased female mortality after high-titre measles vaccine may have been that high-titre measles vaccine was given early and many children therefore received DTP or injected polio vaccine (IPV) after measles vaccination.10 In the present study, many children in the rural areas came late for vaccination and therefore received the BCG vaccination and their first dose of DTP simultaneously. In Senegal, this combination of BCG and the first dose of DPT was common practice. Apparently, this combination was associated with lower mortality for girls. It should be important to explore immunological correlates of such unplanned combinations or sequences of vaccinations, which are quite common in many low-income countries.

None of the routine vaccines used in developing countries were introduced after randomized studies showing an impact of the vaccine on childhood survival.1,2 Instead, the impact has been assumed to be proportional to the mortality associated with the acute infection against which the vaccine is directed. This is no longer a tenable position.1,2 Routine vaccinations have contributed to major reductions in child mortality in low-income countries,1–4 but vaccines might have sex-specific non-targeted effects on survival that cannot be explained by information or selection bias, confounding, or preferential treatment of one sex. We have observed DTP to be associated with increased female mortality in several studies8–10 and no published study has refuted these gender-specific effects of vaccines. However, the WHO's Global Advisory Committee on Vaccine Safety (GACVS) has recently stated that they have sponsored four studies which have found no effect of gender for recipients of DTP.29 Since none of these studies has been published, it is difficult to assess how they might refute our observations. It should be a priority to determine whether the observations on gender-specific effects of vaccines are correct or biased. Should our observations turn out to be biased, it would strengthen the current use of DTP. On the other hand, if our observations are correct, it would be necessary to consider whether modifications of current policy could minimize the negative effect of DTP for girls; for example, providing a live vaccine shortly after the last dose of DTP might possibly reduce the negative non-specific effects without jeopardizing the specific protection against whooping cough. Otherwise, it might be necessary to develop a DTP vaccine based on a live carrier such as BCG.30 Taking the non-specific effects of vaccines into consideration in the planning of vaccination programmes might enhance the beneficial impact of immunizations on child survival in low-income countries.


KEY MESSAGES

  • In the pre-vaccination era, there was no difference in female–male mortality in early childhood in West Africa.
  • A number of studies have suggested that vaccines may affect the female–male mortality ratio (MR) in areas with high mortality.
  • We used female–male twin pairs from four cohort studies in Guinea-Bissau and Senegal to test the possible sex-differential effect of the last vaccine received.
  • Bacille Calmette-Guerin (BCG) as the last vaccine was associated with lower female than male mortality.
  • Diphtheria, tetanus, pertussis (DTP) as the last vaccine was associated with increased female mortality.
  • The female–male MR varied significantly for BCG compared with DTP and for DTP compared with measles vaccine.
  • The non-specific effects of vaccines need to be reviewed and possibly taken into consideration in the planning of immunization programmes in areas with high mortality.

 


    Acknowledgments
 
Research in Guinea-Bissau received funding from the Council for Development Research, the Danish Medical Research Council, Denmark, and the EU Commission (IC18CT95-0011). PA holds a research professorship grant from the Novo Nordisk Foundation.


    References
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 Abstract
 Subjects and Methods
 Results
 Discussion
 References
 
1 Aaby P, Samb B, Simondon F, Coll Seck AM, Knudsen K, Whittle H. Non-specific beneficial effect of measles immunization: analysis of mortality studies from developing countries. BMJ 1995;311:481–85.[Abstract/Free Full Text]

2 Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow-up study in Guinea-Bissau, West Africa. BMJ 2000;321:1435–38.[Abstract/Free Full Text]

3 Desgrées du Loû A, Pison G, Aaby P. The role of immunizations in the recent decline in childhood mortality and the changes in the female/male mortality ratio in rural Senegal. Am J Epidemiol 1995;142:643–52.[Abstract]

4 Aaby P, Bhuyia A, Nahar L, Knudsen K, Francisco A, Strong M. The survival benefit of measles immunization may not be explained entirely by the prevention of measles disease. Int J Epidemiol 2003;32:106–15.[CrossRef][ISI][Medline]

5 Knudsen KM, Aaby P, Whittle H et al. Child mortality following standard, medium and high titre measles immunization in West Africa. Int J Epidemiol 1996;25:665–73.[Abstract]

6 Aaby P, Samb B, Simondon F et al. Divergent mortality for male and female recipients of low-titre and high-titre measles vaccines in rural Senegal. Am J Epidemiol 1993;138:746–55.[Abstract]

7 Velema JP, Alihonou EM, Gandaho T, Hounye FH. Childhood mortality among users and non-users of primary health care in a rural West African community. Int J Epidemiol 1991;20:474–79.[Abstract]

8 Aaby P, Jensen H, Garly ML, Balé C, Martins C, Lisse I. Routine vaccinations and child survival in war situation with high mortality: Effect of gender. Vaccine 2002;21:15–20.[CrossRef][ISI][Medline]

9 Aaby P, Jensen H, Gomes J, Fernandes M, Lisse IM. The introduction of diphtheria-tetanus-pertussis vaccine and child mortality in rural Guinea-Bissau: An observational study. Int J Epidemiol 2004 (in press).

10 Aaby P, Jensen H, Samb B et al. Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus: a re-analysis of the West African studies. Lancet 2003;361:2183–88.[CrossRef][ISI][Medline]

11 Ashorn P, Maleta K, Espo M, Kulmala T. Male-biased mortality among 1–2 years old children in rural Malawi. Arch Dis Child 2002;87:386–87.[Abstract/Free Full Text]

12 Garly ML, Martins CL, Balé C et al. Early two-dose measles vaccination schedule in Guinea-Bissau: Good protection and coverage in infancy. Int J Epidemiol 1999;28:347–52.[Abstract]

13 Simondon F, Preziosi MP, Yam A et al. A randomized double-blind trial comparing a two-component acellular to a whole-cell pertussis vaccine in Senegal. Vaccine 1997;15:1606–12.[CrossRef][ISI][Medline]

14 Aaby P, Bukh J, Lisse IM et al. High case fatality rate in twins with measles. Lancet 1983;ii:690.

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16 Aaby P, Andersen M, Sodemann M, Jakobsen M, Gomes J, Fernandes M. Reduced childhood mortality after standard measles vaccination at 4–8 months compared with 9–11 months of age. BMJ 1993;307:1308–11.[ISI][Medline]

17 Jensen H. Analysis of Multivariate Survival Data from Longitudinal Epidemiological Studies. With Special Reference to the Impact of Routine Immunizations in Infancy. [PhD thesis]. Copenhagen: University of Copenhagen, 2002.

18 Aaby P, Pison G, Desgrées du Loû A, Andersen M. Lower mortality for female-female twins than for male-male and female-male twins in rural Senegal. Epidemiology 1995;6:419–22.[ISI][Medline]

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