Effect of early two-dose measles vaccination on childhood mortality and modification by maternal measles antibody in Guinea-Bissau, West Africa: A single-centre open-label randomised controlled trial.

Background: Early 2-dose measles vaccine (MV) at 4 and 9 months of age vs. the WHO strategy of MV at 9 months of age reduced all-cause child mortality in a previous trial. We aimed to test two hypotheses: 1) a 2-dose strategy reduces child mortality between 4 and 60 months of age by 30%; 2) receiving early MV at 4 months in the presence versus absence of maternal measles antibodies (MatAb) reduces child mortality by 35%. Methods: Single-centre open-label community-based randomised controlled trial in Guinea-Bissau, with 2:1 block-randomisation by sex to a 2-dose (4 + 9 months) vs. 1-dose (9 months) MV strategy. Healthy children were eligible 4 weeks after the 3rd diphtheria-tetanus-pertussis-containing vaccine. Before randomisation a blood sample was collected to determine MatAb level. The primary outcome was all-cause mortality. Hazard ratios (HR) were derived from Cox regression in the per protocol population. We tested for interactions with national campaigns with oral polio vaccine (C-OPV). Trial registration: NCT01486355. Findings: Between August 2011-April 17th 2015, 6,636 children were enroled, 6,598[n2-dose=4,397; n1-dose=2,201] were included in the analysis of the primary outcome, The HR(2-dose/1-dose) between 4 and 60 months was 1.38 (95%CI: 0.92-2.06) [deaths: n2-dose=90; n1-dose=33]. Before the 9-month MV and the HR(1-dose/no dose) was 0.94 (0.45-1.96) [deaths: n2-dose=21; n1-dose=11]. The HR(2-dose/1-dose) was 0.81 (0.29-2.22) for children, who received no C-OPV [deaths/children: n2-dose=10/2,801; n1-dose=6/1,365], and 4.73 (1.44-15.6) for children, who received C-OPV before and after enrolment (p for interaction=0.027) [deaths/children: n2-dose=27/1,602; n1-dose=3/837]. In the 2-dose group receiving early MV at 4 months, mortality was 50% (20-68%) lower for those vaccinated in the presence of MatAb vs. the absence of MatAb [deaths/children: nMatAb=51/3,132; nnoMatAb=31/1,028]. Interpretation: The main result contrasts with previous findings but may, though based on a small number of events, be explained by frequent OPV campaigns that reduced the mortality rate, but apparently interacted negatively with early MV. The beneficial non-specific effects of MV in the presence of MatAb should be investigated further. Funding: ERC, Danish National Research Foundation, the Danish Council for Development Research, Ministry of Foreign Affairs, Novo Nordisk Foundation, European Union and the Lundbeck Foundation.

The Effect of a Second Dose of Measles Vaccine at 18 Months of Age on Nonaccidental Deaths and Hospital Admissions in Guinea-Bissau: Interim Analysis of a Randomized Controlled Trial.

BACKGROUND: The world is set on the eradication of measles. Continuation of the measles vaccine (MV) after eradication could still reduce morbidity because the MV has so-called beneficial nonspecific effects. We evaluated the effect of a "booster" dose of the MV on overall severe morbidity. METHODS: We conducted a randomized controlled trial among children aged 17.5 to 48 months in Guinea-Bissau, where the MV is recommended only at 9 months of age. At the time of this interim analysis, 3164 children had been allocated 1:1 to a second dose of measles vaccine (MV2) at 18 months of age or to no vaccine. Severe morbidity (a composite outcome of nonaccidental deaths and hospital admissions) rate ratios (SMRRs) were calculated by Cox regression analysis censored for national oral polio vaccine (OPV) campaigns. RESULTS: There were no measles cases during the trial period. There were 43 nonaccidental deaths or hospital admissions during follow-up. Severe morbidity was 2.6 per 100 person-years in the MV2 group and 3.6 per 100 person-years among controls; hence, the estimated effect of MV2 on severe morbidity was 28% (SMRR, 0.72; 95% confidence interval [CI], .38-1.38). At 12 months of follow-up, the number needed to treat to prevent 1 severe morbidity event was 137 children. After OPV campaigns, the estimated effect of MV2 was reduced to 9% (SMRR, 0.91; 95% CI, .46-1.81). CONCLUSIONS: MV2 may reduce nonmeasles severe morbidity by 28% (-38% to 62%), although this did not achieve statistical significance in this study. If significant in higher powered studies, this has major implications for child health, even after measles eradication. CLINICAL TRIALS REGISTRATION: NCT02943681.

Measles virus antibody responses in children randomly assigned to receive standard-titer edmonston-zagreb measles vaccine at 4.5 and 9 months of age, 9 months of age, or 9 and 18 months of age.

The World Health Organization recommends administration of measles vaccine (MV) at age 9 months in low-income countries. We tested the measles virus antibody response at 4.5, 9, 18, and 24 months of age for children randomly assigned to receive standard-titer Edmonston-Zagreb MV at 4.5 and 9 months, at 9 months, or at 9 and 18 months of age. At 4.5 months of age, 75% had nonprotective measles virus antibody levels. Following receipt of MV at 4.5 months of age, 77% (316/408) had protective antibody levels at 9 months of age; after a second dose at 9 months of age, 97% (326/337) had protective levels at 24 months of age. In addition, the response at both 9 and 24 months of age was inversely correlated with the antibody level at receipt of the first dose of MV, and the second dose of MV, received at 9 months of age, provided a significant boost in antibody level to children who had low antibody levels. In the group of 318 children who received MV at 9 months of age, with or without a second dose at 18 months of age, 99% (314) had protective levels at 24 months of age. The geometric mean titer at 24 months of age was significantly lower in the group that received MV at 4.5 and 9 months of age than in the group that received MV at 9 months of age (P = .0001). In conclusion, an early 2-dose MV schedule was associated with protective measles virus antibody levels at 24 months of age in nearly all children. Clinical Trials Registration. NCT00168558.

The effect of early measles vaccination on thymic size. A randomized study from Guinea-Bissau.

UNLABELLED: In low-income countries early measles vaccine (MV) is associated with reduced child mortality which cannot be explained by prevention of measles. A large thymus gland in infancy is also associated with reduced mortality. We hypothesized that early MV is associated with increased thymic size. Within a randomized trial providing MV at age 4.5 and 9 months or MV only at age 9 months, thymic size was assessed by ultrasound at age 4.5 months, before randomization to early MV or no early MV, and 4 weeks later. Among 656 children, there was no effect of early MV on thymic size, the geometric mean size ratio being 0.99 (95% CI: 0.96-1.02). In a post hoc analysis early MV was associated with a negative effect in healthy children but a positive effect in ill children. In conclusion, early MV at age 4.5 months had no overall effect on thymus size 4 weeks later. TRIAL REGISTRATION: http://clinicaltrials.gov, NCT01486355.

Measles antibody levels after vaccination with Edmonston-Zagreb and Schwarz measles vaccine at 9 months or at 9 and 18 months of age: a serological study within a randomised trial of different measles vaccines.

UNLABELLED: Standard-titre Schwarz (SW) and Edmonston-Zagreb (EZ) measles vaccines (MV) are both used in the routine immunisation programme. Within a trial of different strains of MV, we examined antibody responses in both one-dose and two-dose schedules when the first dose was administered at 9 months. SETTING AND METHODS: The trial was conducted in an urban area in Guinea-Bissau where we have had a health and demographic surveillance system and studied strategies to prevent measles infection since 1978. In the present study, children were randomised to SW or EZ as the first MV and furthermore randomised to a second dose of the same MV or no vaccine at 18 months of age. We obtained blood samples from 996 children at baseline; post-vaccination blood samples were collected at 18 and 24 months of age to assess measles antibody levels after one or two doses of MV. RESULTS: At age 18 months all had responded to the first dose and only 1% (8/699) of the children had non-protective antibody levels irrespective of vaccine type. SW was associated with significantly higher levels of measles antibodies (geometric mean titre (GMT)=2114 mIU/mL (95%CI 1153-2412)) than EZ (GMT=807 mIU/mL (722-908)) (p=0.001). Antibody concentration was significantly higher in girls than in boys after EZ but not after SW. Antibody levels were higher in the rainy than the dry season. There was no clear indication that a booster dose at 18 months increased the antibody level at 24 months of age. CONCLUSIONS: Maternal antibody levels have declined significantly in recent years and 99% had protective levels of measles antibody following primary MV at 9 months of age. It is unlikely that measles prevention and child health will be improved by increasing the age of MV as currently recommended.

The effect of high-dose vitamin A supplementation at birth on measles incidence during the first 12 months of life in boys and girls: an unplanned study within a randomised trial.

Vitamin A treatment reduces mortality during acute measles infection, and vitamin A supplementation (VAS) to children above 6 months of age may reduce the incidence of measles infection. The effect of VAS at birth on measles incidence is unknown. In a randomised placebo-controlled trial in Guinea-Bissau, normal-birth-weight newborns were randomised to 50 000 IU (15 mg) VAS or placebo. During the trial, a measles epidemic occurred. We linked data from the trial with data from the measles infection surveillance and studied the effect of VAS on the measles incidence before 12 months of age in both sexes. A total of 165 measles cases were identified among the 4183 children followed from 28 d of age. Up to 6 months of age, the incidence rate ratio of measles for VAS compared with placebo was 0·54 (95 % CI 0·25, 1·15) among boys and 1·57 (95 % CI 0·80, 3·08) among girls (test of interaction, P = 0·04). The corresponding figures at 12 months were 0·67 (95 % CI 0·43, 1·05) and 1·17 (95 % CI 0·76, 1·79) (test of interaction, P = 0·08). VAS compared with placebo tended to be associated with less measles hospitalisation or death during the first 6 months of life in boys (P = 0·06), but not in girls. VAS at birth may affect the susceptibility to measles infection during the first 6 months of life in a sex-differential manner.

Girls may have lower levels of maternal measles antibodies and higher risk of subclinical measles infection before the age of measles vaccination.

BACKGROUND: Previous studies have suggested that girls may have lower maternal measles antibody levels than boys. Girls might therefore be more likely to contract measles infection before the normal age of measles vaccination at 9 months of age. METHODS: In connection with a clinical trial of different measles vaccination strategies, we collected pre-measles vaccination blood samples at 4.5 months of age from two subgroups of children. Samples from these children were used to assess possible differences in maternal antibody levels for boys and girls. At 9 months of age another subgroup of children was sampled before the normal measles vaccination; these samples were used to assess the frequency of subclinical measles infection among boys and girls. RESULTS: We determined measles-specific antibody levels for 812 children at 4.5 months of age and for 896 children at 9 months of age. At 4.5 months of age girls were less likely to have protective maternal antibody levels, the male-female ratio for protective antibody level being 1.23 (1.00-1.51). Among children sampled at 9 months of age, girls were more likely to have protective levels, the female-male ratio for having protective antibody levels being 1.65 (0.98-2.78) (p=0.054) and the geometric mean titre was significantly higher for girls (p=0.007). Children who lived in houses with known measles cases were more likely to have protective levels at 9 months of age even though they had not reported measles infection. Since we had excluded children with known measles infection, girls may have been more likely to have had subclinical measles infection. Combining clinical and possible subclinical measles infection, girls tended to be more likely than boys to contract measles infection before 9 months of age, the RR being 1.36 (0.97-1.90). CONCLUSIONS: Girls lost maternal measles antibodies more rapidly than boys and well before 9 months of age. They may be more likely to contract subclinical measles infection before the current age of measles vaccination.

Increased female-male mortality ratio associated with inactivated polio and diphtheria-tetanus-pertussis vaccines: Observations from vaccination trials in Guinea-Bissau.

BACKGROUND: The 2-fold increase in female mortality after high-titer measles vaccine may have occurred because many children received diphtheria-tetanus-pertussis (DTP) vaccine or inactivated polio vaccine (IPV) after high-titer measles vaccine. OBJECTIVE: We examined whether DTP vaccine and IPV were associated with increased female mortality when they were the most recent vaccine administered to children who had not received measles vaccine. SETTING AND DESIGN: IPV was used as a control vaccine in 4 randomized trials of early measles vaccination (MV) with enrollment at 4-6 months of age conducted in Guinea-Bissau. Many children had not received all 3 DTP vaccinations before enrollment, and therefore received DTP after IPV or MV. We examined whether DTP vaccination status at enrollment affected the female-male mortality ratio. POPULATION: 9544 children enrolled in 4 trials. MAIN OUTCOME MEASURE: The female-male mortality ratio in different vaccine groups. RESULTS: Females had a higher mortality rate than males among children randomized to receive IPV (mortality rate ratio [MR] 1.52, 95% CI 1.02-2.28), but females had a similar mortality rate to males among children randomized to receive MV (MR 1.01, 0.69-1.46) and among children in the IPV group after they had received MV at 9 months of age or later (MR 0.88, 0.68-1.14). Children who had not received a third dose of DTP before enrollment (and were likely to receive DTP after MV or IPV) tended to have a higher mortality than children who had received all 3 doses of DTP (MR 1.30, 0.97-1.73). This effect was seen only among girls (MR 1.61, 1.08-2.40) and not among boys (MR 1.02, 0.67-1.54). Girls had a lower mortality when MV was the most recent vaccine received rather than DTP or IPV (MR 0.49, 0.28-0.87). CONCLUSIONS: Randomization to IPV was associated with higher female than male mortality. However, the increased female mortality might result from additional doses of DTP received after enrollment and before measles vaccination.

Prophylactic antibiotics to prevent pneumonia and other complications after measles: community based randomised double blind placebo controlled trial in Guinea-Bissau.

OBJECTIVE: To investigate whether prophylactic antibiotics can prevent complications of measles. DESIGN: Community based, randomised, double blind, placebo controlled trial. SETTING: Bandim Health Project study area in Bissau, Guinea-Bissau, west Africa. PARTICIPANTS: 84 patients with measles during a measles epidemic in Bissau in 1998 (fewer than originally planned owing to interruption by war). INTERVENTIONS: Sulfamethoxazole-trimethoprim (co-trimoxazole) or placebo for seven days. MAIN OUTCOME MEASURES: Pneumonia and admission to hospital. Also weight change during the first month of infection, diarrhoea, severe fever, oral thrush, stomatitis, conjunctivitis, and otitis media. RESULTS: The median age of the patients with measles was 5.4 (range 0.49-24.8) years. One of 46 participants who received co-trimoxazole developed pneumonia, in contrast to six of 38 participants who received placebo (odds ratio 0.08 (95% confidence interval 0 to 0.56), adjusted for age group). The number needed to treat was 7 (4 to 48). All three participants admitted to hospital had received placebo (P=0.09). The weight gain during the first month after inclusion was 15 (2-29) g/day in the placebo group and 32 (23-42) g/day in the co-trimoxazole group (P=0.04, adjusted for age group, weight for age at inclusion, measles vaccination status, and duration of disease). Significantly less conjunctivitis occurred among recipients of co-trimoxazole than placebo, as well as a non-significant tendency to less diarrhoea, severe fever, oral thrush, and stomatitis. Complications of otitis media were the same in the two groups. CONCLUSIONS: The group that received prophylactic antibiotics had less pneumonia and conjunctivitis and had significantly higher weight gains in the month after inclusion. The results indicate that prophylactic antibiotics may have an important role in the management of measles infection in low income countries. TRIAL REGISTRATION: Clinical trials NCT00168532.

Vitamin A supplementation during war-emergency in Guinea-Bissau 1998-1999.

BACKGROUND: Vitamin A supplementation is recommended by WHO in emergency situations. OBJECTIVE: To evaluate the impact of Vitamin A supplementation on childhood mortality in an emergency situation. DESIGN: Since this was not a randomised study, we evaluated the impact in different ways; we used the variation in the delay of provision of Vitamin A in a step-wedged design, compared wartime with pre-wartime mortality and examined whether Vitamin A as a free commodity reduced cultural and social-economic inequalities in childhood mortality. SUBJECTS: 5926 children 6 months to 5 years of age, resident in four suburbs in the capital of Guinea-Bissau between October 1, 1998 and March 31, 1999. INTERVENTIONS: From October 1, 1998 until the end of the war in 1999 all children present in the study area were offered Vitamin A at regular three-monthly visits to their homes. RESULTS: Using the variation in the provision of Vitamin A, we found a slight non-significant reduction in mortality for children between 6 months and 5 years of age (mortality ratio (MR) 0.49; 95% CI 0.09-2.70). Comparing with a three-year period before the war, children offered Vitamin A at home during the war had a 12% reduction in mortality (MR 0.88; 0.41-1.87), whereas the overall impact of the war was an 89% increase in mortality (MR 1.89; 1.32-2.71). Vitamin A supplementation was associated with a reduction in cultural and socio-economic inequalities. CONCLUSIONS: Vitamin A supplementation may have a beneficial impact on childhood mortality in an emergency situation.

Hepatitis B vaccination associated with higher female than male mortality in Guinea-bissau: an observational study.

OBJECTIVE: Studies from high mortality areas have suggested that diphtheria-tetanus-pertussis may be associated with an increase in the mortality of girls relative to boys. We therefore examined whether hepatitis B vaccine (HBV) was associated with sex-specific differences in mortality. DESIGN: As part of a randomized trial of measles vaccine, a subcohort of 876 children was offered HBV at 7(1/2), 9 and 10(1/2) months of age. We examined whether this cohort differed in mortality rate and female-male mortality ratio compared with previous and subsequent birth cohort enrolled in the same trial. SETTING: Four districts in Bissau, the capital of Guinea-Bissau. SUBJECTS: Six annual birth cohorts of 8906 children registered in the study area and followed from 1(1/2) to 12 months of age between March 1995 and February 2001. Of these children, 6399 took part in a 2-dose measles vaccination trial; of those born between March 1996 and February 1997, 876 received HBV. MAIN OUTCOME MEASURES: (1) The mortality rate ratio (MR) between 7(1/2) and 12 months and 1(1/2) and 7(1/2) months old children; (2) the female-male MR among trial children having received HBV plus measles vaccine or only measles vaccine. RESULTS: In cohorts not receiving HBV, the MR for children 7(1/2)-12 and 1(1/2)-7(1/2) months of age was 0.97 "95% confidence interval (95% CI), 0.79-1.24", whereas the MR was 1.62 (95% CI 1.09-2.41) in the cohort receiving HBV at 7(1/2) months (test of homogeneity, P = 0.030). Among children enrolled in the measles vaccination trial, HBV-vaccinated children 7(1/2)-12 months of age had higher mortality than both prior and subsequent cohorts who had not received HBV (MR = 1.81; 95% CI 1.19-2.75), the difference being particularly strong for girls (MR=2.27; 95% CI 1.31-3.94). In the cohort who had received both HBV and measles vaccine, the female-male MR between 9 and 24 months of age was 2.20 (95% CI 1.07-4.54) compared with 0.96 (95% CI 0.70-1.32) in trial participants who had received measles vaccine only (test for homogeneity, P = 0.040). With longer follow-up, these tendencies remained the same. CONCLUSIONS: These comparisons suggested changes in the mortality pattern after the introduction of HBV, particularly for girls. Hence in areas with high mortality, HBV may affect girls' and boys' susceptibility to infections differently.

Breastfeeding status as a predictor of mortality among refugee children in an emergency situation in Guinea-Bissau.

OBJECTIVE: To identify the population risk factors in emergency situations, we studied breastfeeding status as a predictor for child mortality during a war in Guinea-Bissau. METHODS: Data on breastfeeding status are routinely collected by the surveillance system of the Bandim Health Project in Bissau. We used data collected during a 3-month period prior to the war in Guinea-Bissau in June 1998 to assess the impact of breastfeeding status on mortality in an emergency. We compared the war cohort with two cohorts of children who had had their breastfeeding status assessed in a similar way by the surveillance system in the 3 months prior to June 1996 and June 1997. As very few are weaned prior to 9 months of age and the median age of weaning is 22 months, we assessed the risk of dying over a 3-month period for breastfed and weaned children aged 9-20 months. RESULTS: Controlling for age, weaned children experienced a sixfold higher mortality [mortality rate (MR) = 5.73 (95% CI 2.40-13.71)] during the first 3 months of the war compared with children still breastfeeding. In the two control cohorts from 1996 and 1997, weaned children did not have higher mortality than the breastfed children over a similar 3-month period. Mortality in weaned children was five times higher [MR = 4.96 (1.44-16.63)] during the first 3 months of the conflict than in a similar group of weaned children from early June 1996 and June 1997, whereas there was no significant difference in mortality between breastfed children during the conflict and the preceding years [MR = 1.46 (0.84-2.55)]. Control for other background factors, including living with mother, gender, ethnic group, mother's schooling and district, did not change these differences. CONCLUSION: The protective effect of breastfeeding against infections may be particularly important in emergencies. Continuing or recommencing breastfeeding should be emphasized in emergency situations.

Hypothesis: Vitamin A supplementation and childhood mortality: amplification of the non-specific effects of vaccines?

Most areas of health research will have accepted data and a dominating interpretation. If the interpretation is not correct, contradictions will accumulate, and it will eventually become clear that the current interpretation is untenable. In this situation, the best hypothesis is the one that accounts for all of the known data as well as the apparent contradictions. The area of vitamin A supplementation and childhood mortality in developing countries is afflicted with many contradictions and there is a need for a new hypothesis. We propose that the effect of vitamin A supplementation may depend on the amplification of non-specific effects of vaccines on childhood mortality.

Survival of previously measles-vaccinated and measles-unvaccinated children in an emergency situation: an unplanned study.

BACKGROUND: Previous studies have suggested that standard measles vaccine may reduce mortality by more than the number of deaths thought to be caused by measles infection in areas with high mortality. However, these observations have not been based on randomized trials. METHODS: During the recent war in Guinea-Bissau, most children fled from the city of Bissau and immunization services in the country broke down for several months. We were performing a trial in which children were randomized at 6 months of age to receive either measles vaccine or inactivated polio vaccine. Because of the war many children did not receive the dose of measles vaccine planned for 9 months of age. We were able to monitor mortality during the war and after. RESULTS: Included in the study were 433 children 6 to 11 months of age. Fifteen children died (3.6%) during the first 3 months of the war before vaccination programs were resumed, 4 of 214 measles-vaccinated children and 11 of 219 children who had received inactivated polio vaccine. The effect of measles vaccine was marked for girls [mortality rate ratio (MR), 0.00; 95% confidence limits, 0.0 to 0.37], whereas there was no difference for boys (MR = 1.02; 95% confidence limits, 0.25 to 3.88). In a combined analysis controlling for factors that differed between the two groups, the MR for measles-vaccinated children was 0.30 (95% confidence limits, 0.08 to 0.87). Prolonging the period of observation to the end of 1998 or including the prewar period did not modify the significant beneficial effect of measles vaccine for girls. Twenty-two of the children in the cohort were reported to have had measles, 8 cases occurring during the 3 months of the war. Exclusion of measles cases in the analysis did not change the results; children who had received measles vaccine had a MR of 0.28 (95% confidence limits, 0.06 to 0.89) during the first 3 months of the war. CONCLUSIONS: Consistent with previous observational studies, measles vaccination was associated with a reduction in mortality that cannot be explained by the prevention of measles infection. This nonspecific beneficial effect was particularly strong for girls. Further studies are needed to examine the extent of nonspecific effects in settings with high mortality.

BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa. A non-specific beneficial effect of BCG?

Previous studies have suggested that the bacille Calmette-Guérin (BCG) vaccine may have a non-specific beneficial effect on childhood survival in areas with high mortality. We examined whether BCG-vaccinated children with a BCG scar or a positive tuberculin reaction had better survival than children without such reactions. As part of an ongoing two-dose measles vaccine trial for which children were recruited at 6 months of age, we examined 1813 children for BCG scar at 6 months of age and 813 BCG-vaccinated children were skin-tested for delayed hypersensitivity to tuberculin, tetanus and diphtheria. We found that BCG-vaccinated children with a BCG scar had significantly lower mortality compared with BCG scar-negative children, the mortality ratio in the first 12 months of follow-up being 0.41 (0.25-0.67). BCG-vaccinated children with a positive tuberculin test had a mortality ratio of 0.45 (0.24-0.85) compared with tuberculin negative children. These results were unchanged by control for potential confounders or using different cut-off points for a tuberculin-positive response. Exclusion of dead children who had HIV antibodies did not modify the estimate (mortality rate (MR)=0.46 (0.23-0.94)). After censoring for tuberculosis (TB) exposure at home, the mortality ratios for having a scar and being tuberculin-positive were 0.46 (0.27-0.79) or 0.42 (0.21-0.84), respectively. Children positive to tetanus or diphtheria in the skin test had the same mortality as children not responding to these vaccine-related antigens. Thus, BCG scar and a positive tuberculin reaction were associated with better survival in early childhood in an area with high mortality. Since nothing similar was found for responders to diphtheria-tetanus-pertussis (DTP) vaccine, and the effect could not be explained by protection against tuberculosis, the effect of BCG vaccination could be due to non-specific immune-stimulation protecting against other infections.

Routine vaccinations and child survival in a war situation with high mortality: effect of gender.

Non-specific effects of vaccination may be different for boys and girls. Due to the sequential administration of vaccines, it is difficult to separate the effect of different vaccines. We tested sex-specific effects of diphtheria, tetanus, pertussis (DTP) and polio vaccines and measles vaccines during the recent war (1998) in Guinea-Bissau when there was no functioning immunisation programme in the country. The study included 1491 children aged 1-17 months in four urban districts in Bissau. Vaccination status had been assessed in the study area in the 3 months before the war. The effect of DTP and polio vaccines was assessed for children who had not received measles vaccine. The effect of measles vaccine was evaluated for children aged 6-17 months. Compared with measles-unvaccinated children, measles-vaccinated children had lower mortality (mortality ratio (MR)=0.44 (95% CI 0.20-1.00)), the difference being marked for girls (0.25 (0.09-0.71)) but not for boys (0.84 (0.26-2.75)) (test of homogeneity, P=0.095). If measles cases were censored in the analysis, the mortality ratio for vaccinated and unvaccinated children was 0.38 (0.16-0.89). DTP and polio-vaccinated children did not have lower mortality than unvaccinated children. The female-male mortality ratio for DTP and polio-vaccinated children was 3.08 (1.11-8.56) and 0.63 (0.28-1.40) for measles-vaccinated children, a significant inversion of the ratios (test of homogeneity, P=0.013). The divergent female-male mortality ratios are unlikely to be explained by a selection bias going in different directions for different vaccines. The reduction associated with measles vaccination was unrelated to prevention against measles infection. Non-specific effects of vaccination should be assessed separately for boys and girls. Taking these effects into consideration may have implications for child mortality patterns in developing countries.