Syed Manzoor Ahmed Hanifi 2018

Hanifi, Syed Manzoor Ahmed. 2018. Non-specific effects of vaccines and sex-differential child mortality in rural Bangladesh.

In the current health paradigm, equality in child health outcomes is considered a key to development. Higher mortality among females than males has been reported in the Asian region compared to the rest of the word. The excess female deaths have usually being explained as the result of sex-differential treatment of children in health care. 

During the last two decades, Bangladesh has achieved exceptional improvements in the survival of under-5 children, especially for females. Reducing poverty and increasing health resources have been considered the key explanations for this decrease in mortality. 

It has recently been proposed that vaccines, beside their important specific effects, may also have “non-specific effects”, affecting overall mortality more than previously assumed. These effects differ by sex; the live vaccines like BCG and measles vaccine (MV) have been associated with overall mortality reduction for non-related diseases, particularly for females. In contrast, the non-live diphtheria-tetanus-pertussis-containing vaccines (including pentavalent vaccine (Penta)) have been associated with increased overall female mortality. 

The observations of non-specific effects stem primarily from areas with no known sex-differential treatment of children. In this thesis, we investigated whether childhood vaccinations were associated with sex-differential mortality in Bangladesh, and could explain some of the observed trends in female-male-mortality ratios over time and age groups in a rural area of Bangladesh. 

The thesis consists of three papers testing eight hypotheses. The studies were based on data from the HDSS sites in Chakaria and Matlab, Bangladesh. We used ecological study designs as well as individual-based cohort studies and also conducted a meta-analysis. 

First, we examined sex-differential health care-seeking behaviour of children with respect to age-appropriate vaccinations and confirmed that favouring of boys over girls in medical care-seeking behaviour, even for free immunization, is prevalent in Chakaria. 

Second, in individual-based cohort studies we showed that in the age group from 6 weeks to 9 months of age, for children who were only BCG vaccinated (BCG-only), the adjusted female-male mortality ratio was 0.47 (0.09-2.48). However, among children who had Penta as the most recent vaccination, the adjusted female-male mortality ratio was 9.91 (1.16-84.44). Hence, the adjusted female-male mortality ratio differed significantly for BCG-only and for Penta as the most recently administered vaccination (test of interaction, p=0.02). 

Simultaneous administration of BCG and DTP-containing vaccine may be associated with slightly lower mortality compared with BCG first followed by DTP-containing vaccine.

In the 9-36 months age group having MV as the predominant vaccination, MV compared to Penta was more beneficial for girls than boys, the reduction in all-cause mortality being 61% (95% CI: 4-84%) among girls whereas mortality tended to increase by 13% (95% CI:-141-47%) among boys (p=0.05, test of interaction). Among measles-vaccinated children, girls had significantly lower mortality than boys, the adjusted female-male mortality ratio being 0.42 (0.21-0.87) (p=0.05, test of interaction).

MV was associated with a reduced hospital admission due to lower respiratory infections, children who had MV-only as their most recent vaccine had an adjusted hospitalization ratio of 0.68 (0.54-0.84) compared to children, who had Penta as their most recent vaccine. The effect was similar in boys and girls. 

Children who received MV-only as their most recent vaccine also had a lower risk of being severely malnourished (adjusted odds ratio: 0.77 (0.64-0.92)) compared to children, who had Penta as their most recent vaccine. The benefits may have been slightly more pronounced for girls (adjusted odds ratio: 0.68 (0.54-0.86)) than for boys (adjusted odds ratio: 0.91 (0.69-1.20)) (p=0.11, test for interaction). 

Third, in ecological studies we examined the female-male mortality ratio according to the age groups dominated by different vaccines and found that the ratio was low among children aged 0-6 weeks (when BCG is the predominant vaccination), was high among children aged 6 weeks to 9 months (Penta predominant vaccination), and was low among children aged 9-36 months of age (MV predominant vaccination). 

Furthermore, we showed that before and after the introduction of EPI, the female-male mortality ratio was significantly inversed for 1-4-year-old children for whom MV is the predominating vaccine. Before introduction of EPI the mortality was about 2/3 higher for females than for males, whereas after introduction of EPI, the female mortality was 5% lower compared with male mortality (test of interaction, p<0.001).

In conclusion, our findings support that vaccines may have non-specific sex-differential effects on mortality, also in an area with strong sex-differences in health seeking behaviour. The individual-based studies showed the expected inversions in female-male mortality by vaccination status. As predicted, when a live vaccine was the most recent vaccine, female mortality was lower compared with when a non-live vaccine was the most recent vaccine, and compared with the mortality of boys. The findings were corroborated by ecological studies showing that female-male mortality differ accordingly across age groups, and before and after the introduction of the EPI. Based on these data, MV may be one of the major explanations for the large decline in female mortality from 1-4 years of age in Bangladesh. 

The findings underline the importance of considering NSEs of vaccines when scheduling vaccination programs, and before the introduction of new vaccines like inactivated polio vaccine or the withdrawal of live vaccines like MV and OPV.