OPTIMUNISE

Title: Optimising the impact and cost-effectiveness of child health intervention programmes of vaccines and micronutrients in low-income countries

Acronym: OPTIMUNISE
Contract/Grant agreement number: FP7-HEALTH-F3-2011-261375

EC contribution: 2.999.970 €
Duration: 66 months
Starting date: 01/03/2011

Third report: 01-03-2014 to 31-08-2015

1. Publishable summary

Project context:

Child health programmes in low-income countries are justified by their assumed disease-specific effects on child survival, and how they may contribute to reaching the Millennium Development Goals 4 (MDG4), but the impact on child survival is rarely measured. This approach is not reliable. Vaccines and micronutrients may have beneficial or negative non-specific effects (NSE) on overall child mortality; effects, which are not explained by prevention of targeted diseases or deficiencies.

Main objectives and progress:

OPTIMUNISE takes advantage of the Health and Demographic Surveillance System (HDSS) sites in the INDEPTH Network (www.indepeth-net.org(link is external)) to test the real life impact of child interventions on overall mortaliaty. OPTIMUNISE is being implemented at three INDEPTH sites in Guinea-Bissau (Bandim Health Project), Burkina Faso (Nouna), and Ghana (Navrongo). As a basis for the studies, OPTIMUNISE has modified the HDSS data collection systems to include information on all interventions in childhood.

In the period 01/03/2014 to 31/08/2015 OPTIMUNISE nearly completed enrolment and blood sample collection in two randomised controlled trials (RCT) of early measles vaccination (MV) in Burkina Faso and Guinea-Bissau to test whether early MV at 4.5 and 9 months compared with MV at 9 months of age reduces child mortality by 50%. The RCTs will end in the last months of 2015.

In the period 01/03/2014 to 31/08/2015 OPTIMUNISE has continued the observational studies of the NSEs of vaccines. Several cross-site workshops have standardises data cleaning of the HDSS data and analysis of the determinants of the fully immunized child (FIC) by 12 months of age. The main conclusions are: low coverage for MV at all sites prevents children from being FIC and not being FIC is associated with 20-25% higher child mortality than being FIC.

In the period 01/03/2014 to 31/08/2015 OPTIMUNISE has confirmed previous work showing beneficial NSEs of the live vaccines BCG and MV but also extended it to apply to the live oral polio vaccine (OPV). The mortality impact of eradication campaigns with MV and OPV has not been studied previously. However, one major observation made by OPTIMUNISE in the current period is that there are major effects on survival of these campaigns. The mortality rate has been around 20% lower after-campaign compared with before-campaign levels for both OPV and MV. Hence, the numerous campaigns with OPV and MV have been major drivers towards MDG4. Two sites have reached MDG4 and the third site has almost done it. A surprising aspect is that boosting enhances the beneficial NSEs of live vaccines. Hence, repeated campaigns with OPV and MV have had much larger effects than expected.

OPTIMUNISE has also studied the impact of the routine vaccination coverage and sequence of vaccinations on the decline towards MDG4. It has been shown in the current period that the dramatic increase in routine MV coverage in some sites may have contributed to the marked decline in mortality, since we have found consistently that measles-vaccinated children have lower mortality than non-measles vaccinated children, and this difference cannot be explained by prevention of measles infection since there has been virtually no measles infection for a long-time.

Hence, OPTIMUNISE has shown major beneficial NSEs of routine vaccination with OPV, MV and BCG and of campaigns with MV and OPV. These observations will modify the cost-effectiveness of immunisation programs in the analyses currently conducted by the consortium. Unfortunately, in current practice, both BCG and MV vaccinations are often delayed in order not to waste vaccine doses by opening a multi-dose vial for just a few children; given the large effect on survival of these vaccines, this is not a cost-effective policy.

In the period 01/03/2014 to 31/08/2015 OPTIMUNISE has also shown that some non-live vaccines may have negative effects for over-all survival, the deleterious effects being particularly marked for girls. Diphtheria-tetanus-pertussis DTP vaccination is associated with 50% (95% CI: 21-85%) higher mortality for girls than for boys in the 16 available studies. This negative effect for females has also been found for the new combination vaccine pentavalent vaccine (DTP+HBV+Hib). While the disease-specific effects may be more or less constant throughout childhood, the NSEs are linked most strongly to the most recent vaccine and the sequence of vaccination is therefore important. According to current policy, missing vaccines should be given whenever possible and there is no restriction on the sequence of these vaccinations. OPTIMUNISE has found repeatedly that getting a non-live vaccine after MV has a negative effect on child survival. In northern Ghana 86% of the children got DTP after MV when the immunisation programme started 25 years ago; today only <1% get these vaccines in the wrong order. This change is the sequence of vaccinations has had a major beneficial impact on overall survival levels.

More than 35 papers have been produced since the beginning of OPTIMUNISE and another 29 are in preparation or planned.

Potential applications:

WHO’s Strategic Advisory Group of Experts on immunization (SAGE) has conducted an independent review in 2013-2014 of the NSEs of BCG, DTP and MV  showing strong beneficial effects of BCG and MV, whereas the majority of studies  (7/10) showed a negative effect of DTP (1-7). SAGE recommended further studies of the NSEs.

Studies showing a negative effect of DTP

1. Velema JP, Alihonou EJ, Gandaho T, Hounye FH. Childhood mortality among users and non- users of primary health care in a rural West African community. Int J EpidemioI 1991;20:474- 479

1. Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ 2000;321:1435-8
2. Aaby P, Vessari H, Nielsen J, Maleta K, Benn CS, Jensen H, Ashorn P. Sex differential effects of routine immunizations and childhood survival in rural Malawi. PIDJ 2006;25:721-727
3. Aaby P, Ravn H, Roth A, Rodrigues A, Lisse IM, Diness BR, Lausch KR, Lund N, Biering-Sørensen S, Whittle H, Benn CS. Early diphtheria-tetanus-pertussis vaccination associated with higher female mortality and no difference in male mortality in a cohort of low birthweight children: an observational study within a randomised trial. Arch Dis Child 2012: doi:10.1136/archdischild-2011-300646
4. Aaby P, Nielsen J, Benn CS, Trape JF. Sex-differential and non-targeted effects of routine vaccinations in a rural area with low vaccination coverage: Observational study from Senegal. Trans Roy Soc Trop Med Hyg  2015;109:77-85

3. 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 2004,33:374-80
4. Moulton LH, Rahmathullah L, Halsey NA, Thulasiraj RD, Katz J, Tielsch JM. Evaluation of non-specific effects of infant immunizations on early infant mortality in a southern Indian population. Trop Med Int Health 2005;10:947-55