Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS


OPTIMUNISE Berichtzusammenfassung

Project ID: 261375
Gefördert unter: FP7-HEALTH
Land: Denmark

Periodic Report Summary 3 - OPTIMUNISE (Optimising the impact and cost-effectiveness of child health intervention programmes of vaccines and micronutrients in low-income countries)

Project Context and Objectives:
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 ( 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
2. Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ 2000;321:1435-8
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
5. 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
6. 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
7. 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

Project Results:
Consortium coordination (WP10). The first consortium meeting was held in Navrongo in April 2011. The meeting reviewed the scientific background and the management of the consortium. Partner 7 has set up a webpage to cover the scientific background and to report results (Deliverable 10). Subsequent consortium meetings were held in Nouna (March 2012) with focus on the measles vaccine (MV) trials (WP5-7); Bandim Health Project (January 2013) which focused on the need to submit an amendment request (Deliverable 12); Navrongo (January 2014) discussing the progress of the MV RCT; and Nouna (February 2015) which planned the last year of the project.

Routine data collection on childhood interventions (WP1-3). The project started with a workshop (Bissau, 2011) on collecting routine data on health interventions for work package (WP) 1-3 (Partners 1-5). The scientific background for the non-specific effects (NSE) of childhood interventions was reviewed. Partner 1 provided an introduction to statistical analysis in Stata and survival analysis which is the main instrument for assessing effects of interventions. The current data collection systems were discussed and agreement was reached on how data should be collected for the main outcomes, including child mortality, hospitalisations, consultations and growth, and the main exposures, including all vaccinations, micronutrient supplementations and preventive drug treatment. Data collection is ongoing (WP1-3) since early 2011. The number of children followed in the three sites is around 7,600 in urban Guinea-Bissau, 18,000 in rural Guinea-Bissau, 11,900 in Nouna, and 11,200 in Navrongo. Experiences from the first rounds were discussed at a workshop in Guinea-Bissau in August 2012 and summarised in a guide for routine data collection (Deliverable 1)
Analysis of data gathered in WP1-3 and paper writing (WP4). We have organised statistical workshops with the University of Ghana (January, 2012), on data analysis at the Bandim Health Project (January 2013) (Deliverable 2), on statistical methods for HDSS in Nouna (June, 2013), and on the determinants of the fully immunized child (Accra, March 2014; Copenhagen, August-September 2014). The PhD candidates have had extended visits to Heidelberg and Copenhagen for analysis and write up.

Analyses have been presented at the INDEPTH conference in Maputo (2013) and will be presented at the INDEPTH conference in Addis Ababa (2015). All three sites have submitted a large number of papers related to vaccination coverage, implementation of programs, non-specific effects of vaccines and consequences for child survival. Data from both Ghana and Guinea-Bissau suggest that it is better for child survival to have MV than DTP as the most recent vaccination (Deliverable 3). The observations on the beneficial NSEs of MV, BCG and OPV and the negative effects of DTP are supported by these findings. The NSEs have also been shown in high-income settings.

Measles vaccine trials (WP5-7). A protocol for early MV at 4 and 9 months of age and a risk assessment was developed in 2011 and finalized in Nouna in March 2012. The protocol was subsequently translated to Portuguese and French and submitted to the respective national committees and ministries of health. The protocol was approved by the ethical committees in Guinea-Bissau, Burkina Faso, Denmark, and Germany (Deliverable 5). The MV trials were pilot tested successfully in both Guinea-Bissau and Burkina Faso (Deliverable 6). The trial will end in December 2015-January 2016 (Deliverables 7 and 8).

We have been delayed because protocol writing and obtaining ethical and political approval took longer than originally planned, but the consortium is functioning well.
Potential applications: SAGE has reviewed and recommended further studies of the NSEs of BCG, MV and DTP. Monitoring the NSEs of vaccines can lead to large savings and major reductions in mortality in high-mortality areas.

Potential Impact:
OPTIMUNISE consortium is collaborating with a DANIDA-sponsored project including three other INDEPTH sites which also monitor the most common vaccines and micronutrient supplementation to measure the real life effects.
The current vaccination programme focuses entirely on specific effects of vaccines. The OPTIMUNISE data is likely to establish a series of generalisations which will fundamentally question the basis for the current paradigm for vaccinations. This may have major policy implications. These generalisations will include at least:
• Live vaccines, including BCG, OPV and MV, have beneficial NSEs.
• Early BCG vaccination is associated with a major reduction in neonatal mortality. Randomised trials (RCT) among low-birth weight children in Guinea-Bissau, who normally do not receive BCG at birth, have shown reductions of more than 40% in neonatal mortality.
• OPV has major beneficial NSEs in RCTs and in campaigns. The withdrawal of OPV in the endgame for polio eradication is likely to lead to increases in child mortality.
• Early MV is associated with reduced morbidity and mortality. It is current WHO policy that the age of MV should increase to 12 months once measles infection is under control. It will therefore be very important to establish that early MV before 9 months of age followed by a later dose has an even better effect on child survival than current policy.
• MV should receive more attention in vaccination programs. The current vaccination programmes focus on increasing the coverage for DTP3 rather than for MV; hence, more children are now missing MV than DTP3. Not being fully vaccinated (i.e. lacking MV) is associated with 25% higher mortality through childhood. To improve child survival, MV should be given much higher priority.
• Vaccination in the presence of maternal antibodies may enhance the beneficial NSEs.
• Boosting with live vaccines, including BCG, OPV and MV enhances the beneficial NSEs.
• In contrast to the beneficial effects of live vaccines, inactivated vaccines, including DTP, HBV, IPV and H1N1, may have negative overall effects (including increased mortality) even though they protect against the targeted disease.
• DTP is associated with higher female than male mortality whereas the opposite is true after MV.
• Receiving DTP with MV or after MV is associated with increased child mortality compared to having MV as the most recent vaccination. Hence, vaccination programmes should ensure that DTP is administered timely and not with or after MV. Live-vaccine-last should be the guiding principle.
• Vitamin A supplementation (VAS) may affect the NSEs of vaccines. Both observational studies and RCTs in Navrongo and Guinea-Bissau have found that VAS enhances the NSE of vaccines in a sex-differential manner. Hence, additional studies to establish the optimal way of using VAS are needed.
• The MDG4 has been reached to a very large extent due to the NSEs of live vaccines even in poorly organised health care systems.
The beneficial NSEs will strongly modify the cost-effectiveness of the current programme and will point to several problems in the way the programme is implemented. The international health authorities have tended to dismiss the NSEs as biologically implausible but this is changing as an increasing number of immunological studies are showing that both innate and adaptive immune mechanism may enhance/diminish protection against unrelated infections. WHO’s SAGE has recommended further studies of the NSEs of vaccines. Hence, the observations of OPTIMUNISE may help to shape the future global immunisation programmes to the benefit of children in low-income countries.

Verwandte Informationen


Torben Theilmann, (Financial director)
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