To test the real life impact and cost effectiveness of child health interventions it is necessary to have individual-based data on health intervention uptake as well as on health status. The present project takes advantage of the Health and Demographic Surveillance Systems (HDSS) sites in the INDEPTH Network in Africa. The HDSS sites can provide the platform for
This programme is being implemented at three sites in Guinea-Bissau, Burkina Faso, and Ghana. Using the HDSSs as a platform OPTIMUNISE will test the four hypotheses formulated in a recent paper in Tropical Medicine and International Health (TMIH) about the negative non-specific and sex-differential effects of diphtheria-tetanus-pertussis (DTP) vaccine and the beneficial non-specific effects of measles vaccine (MV).
Already implemented health interventions can usually only be evaluated in observational studies, because it would be unethical to conduct a randomised trial of the “real life effects” of a recommended WHO policy. Hence, OPTIMUNISE has modified the current data collection systems to include information on all routine and campaign interventions in childhood to conduct such observational studies. However, it may be ethically justified to test modifications of the current programmes in RCTs and obtain unbiased estimates of the effect of certain aspects of a health programme.
Such trials may also cast light on interactions between different interventions and test the observations made in the observational studies. OPTIMUNISE is testing in rural Burkina Faso and Guinea-Bissau a recent finding from a randomised trial in urban Guinea-Bissau: providing early MV at 4.5 and 9 months of age compared with the recommended MV at 9 months of age reduced overall mortality between 4.5 and 36 months of age by 50% if the children had not received vitamin A at birth.
Fortunately, mortality has declined in Africa in the last decade and it may become increasingly difficult to measure the overall impact on mortality of existing and new interventions. OPTIMUNISE is therefore aiming to identify the best relevant comparable outcome parameters which correlate with child mortality/survival and which can be used to assess the overall health impact of interventions in future assessments.
The many vertical health interventions led by WHO, UNICEF or other organisations like American Red Cross are undertaken with little attempt to asses their local impact on health and on the local health system. Child health programmes in low-income countries are justified in terms of their assumed impact on child survival and how they may contribute to reaching the Millennium Development Goals 4.
However, the assessment of this impact is usually based on measurements of performance indicators for a particular programme, e.g. vaccination coverage, and assumptions about efficacy of the intervention and about the burden of the particular health problem. These assumptions are mostly based on small-scale studies of the immediate target condition; e.g., a vaccine is evaluated for its clinical protection against the targeted disease. Correspondingly, assessments of cost effectiveness tend to be narrowly confined to disease-specific costs and savings.
Observational studies and randomised trials in several African countries have shown that this procedure is not reliable. First, vaccines and micronutrients have beneficial or negative non-specific effects; i.e. effects which are not explained by prevention of the targeted infections or deficiencies. Recent studies of BCG have shown that such non-specific effects may be due to epigenetic reprogramming of the innate immune system. Second, these effects are frequently sex-differential. Third, interventions interact producing stronger beneficial or negative effects; for example, vitamin A given together with DTP may increase mortality for girls. Fourth, vaccines and micronutrients are often given out of the recommended schedule and this can have marked effects on mortality.
To develop the capacity of existing HDSS in Africa to monitor the real life effects of child health intervention programs to promote evidence-based policy.
To measure the health impact and cost-effectiveness of the existing major child health programmes with vaccines (BCG, DTP, and measles vaccine) and vitamin A controlling for determinants of compliance.
To evaluate in a two-center RCT a specific modification of the current child health programme: To provide an additional measles vaccine at age 4 months, in addition to the recommended measles vaccine at age 9 months.
OPTIMUNISE has modified the current data collection systems to include information on all routine and campaign interventions in childhood. A guide to data collection has been uploaded on the INDEPTH website.
The protocol for the RCT on early measles vaccine has been approved and the recruitment of trial participants stated in the second half of 2012 in Guinea-Bissau and in the beginning of 2013 in Burkina Faso.
Since RCTs among low-birth-weight children have shown that BCG reduces neonatal mortality with more than 30%, it is planned to use the “natural experiment” of villages being visited monthly by vaccination teams in Burkina Faso and Guinea-Bissau to examine the impact of the age of BCG vaccination on neonatal mortality.
Data collection on the prospective observational study at the three sites is ongoing and the first papers have been submitted and presented at conferences. Studies from Ghana have shown a strong correlation between the decline in the age of BCG vaccination and the decline in neonatal mortality. Studies from Guinea-Bissau have shown that additional GAVI support for the vaccination programme lead to a higher DTP3 coverage but a lower MV coverage; this is unfortunate since MV is associated with better survival but DTP is not. We have also found within a RCT that hospitalisations correlated well with mortality outcomes and early MV had a particularly beneficial effect in reducing non-measles related respiratory infections. Consistent with the TMIH hypotheses we are finding negative effects of DTP particularly for girls and negative effects when inactivated vaccines are given after MV.
Though not directly funded by this grant, OPTIMUNISE scientists are also trying to examine whether the observations on non-specific effects are relevant in high-income settings; studies of hospitalisation in Denmark have shown that MV (MMR) reduces admissions for lower respiratory infections with 21% and if DTP is given after MMR the risk of admission is strongly increased.
It is hypothesized that OPTIMUNISE will show major beneficial effects of measles vaccine and BCG which will strongly modify the cost-effectiveness of the current programme and will point to several problems in the way the programme is currently being implemented.
If the non-specific effects are going to be confirmed by this research, and if this would be taken into global health policy consideration, this would imply large savings and major reductions in mortality in high-mortality areas, for instance by vaccinating earlier with measles vaccine.
The Scientific Advisory Group of Experts (SAGE) of the WHO immunization programme is currently conducting a review of the non-specific effects of BCG, DTP and measles vaccine. A working group on the non-specific effects of vaccines has been established in early 2013; one OPTIMUNISE scientist (CS Benn) is a member of the working group.