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es de,en,es,fr,it,pl 92763 A través de una iniciativa amparada por la UE se evaluaron los efectos combinados de varias vacunas infantiles en la salud general de la población en África. Ello contribuirá a modificar las políticas sanitarias vigentes de modo que se mejore la eficacia de la vacunación.

Las intervenciones sanitarias a cargo de la Organización Mundial de la Salud o de UNICEF en los países de rentas bajas (PRB) se evalúan a partir de ciertos indicadores de rendimiento, como la cobertura de vacunación. No obstante, estos indicadores sólo ofrecen suposiciones relativas a la eficacia de las intervenciones y a la carga que representa una enfermedad, pero no muestran el impacto real sobre la salud. Además, las vacunas y los micronutrientes pueden efectos no específicos (NSE, non-specific effects) tanto positivos como negativos y además interactuar con otras intervenciones. Resulta necesario disponer de datos individualizados referentes a la implantación y los resultados de las intervenciones sanitarias. Teniendo esto presente, el proyecto http://www.indepth-network.org/projects/optimunise (OPTIMUNISE) (Optimising the impact and cost-effectiveness of child health intervention programmes of vaccines and micronutrients in low-income countries), financiado por la Unión Europea, se sirvió de la base brindada por los «sistemas de vigilancia demográfica y sanitaria» (HDSS) para llevar a cabo estudios de observación y aleatorizados sobre los efectos reales totales de las intervenciones concretas. Los socios del proyecto examinaron los NSE de las vacunas integradas en el programa de vacunas infantiles y de suplementos de vitamina A en tres lugares de África occidental. Se observó a más de 90 600 niños menores de 3 años que residían en zonas rurales y urbanas. Se desarrolló una herramienta abierta al público para la recopilación y el análisis de datos y se formó a investigadores jóvenes de cada emplazamiento para que supiesen usar sus funciones con vistas a evaluar el efecto sanitario real y global de estas intervenciones. El ensayo aleatorizado sobre la administración precoz de la vacuna contra el sarampión no mostró ningún beneficio en la tasa de supervivencia infantil en general, aunque sí que producía niveles protectores de anticuerpos a partir de los cuatro o cinco meses. También se obtuvieron indicios de que la vacuna oral contra la polio en vivo podría ocasionar NSE beneficiosos, mientras que las vacunas penta y las vacunas contra difteria-tétanos-tos ferina podrían provocar NSE negativos en las mujeres. Los efectos diferenciales según el sexo eran mucho más frecuentes de lo que se creía. La combinación y la secuencia de las vacunas eran muy importantes de cara a su efecto en la supervivencia. La investigación puso de relieve la importancia de las campañas contra la polio y el sarampión de cara a reducir la tasa de mortalidad en África. OPTIMUNISE consiguió demostrar que, en los PRB, los emplazamientos HDSS pueden desempeñar un papel muy destacado en el seguimiento y la evaluación continuos de las intervenciones sanitarias. A largo plazo, esto incrementará la protección inmunológica frente a enfermedades potencialmente mortales de los niños en PRB.

2017-07-26 13:05:22 de,en,es,fr,it,pl health de,en,es,fr,it,pl society de,en,es,fr,it,pl funda de,en,es,fr,it,pl ict en brief en 98247 261375 OPTIMUNISE de,en,es,fr,it,pl 852 FP7-HEALTH http://ec.europa.eu/research/health/index_en.html 846 FP7-COOPERATION 1401 EC 837 FP7 en 12586 HEALTH.2010.3.4-6 10252 HEALTH-2007-3.4 10249 HEALTH-2007-3 11416 HEALTH 852 FP7-HEALTH 846 FP7-COOPERATION 1401 EC 837 FP7 de,en,es,fr,it,pl ECO de,en,es,fr,it,pl MED de,en,es,fr,it,pl MBI en 197115 de,en,es,fr,it,pl pubsum en report de,en,es,fr,it,pl sesam es en,any /docs/results/261/261375/final1-final-report-optimunise-31-10-2016-version2-publishable-summary.pdf es de,en,es,fr,it,pl,any /docs/results/images/2017-07/92763.jpg Dinamarca DK 223513128 de de,en,es,fr,it,pl 92763 Eine EU-Initiative bewertete kombinatorische Effekte mehrerer Impfstoffe für Kinder auf die Bevölkerungsgesundheit in Afrika, um gesundheitspolitische Maßnahmen für einen besseren Impfungserfolg anzupassen.

Um den Erfolg medizinischer Interventionen zu bewerten, die die Weltgesundheitsorganisation (WHO) oder das Kinderhilfswerk der Vereinten Nationen in LIC (Ländern mit niedrigem Einkommen) initiiert, werden bestimmte Leistungsindikatoren herangezogen, etwa die Durchimpfungsrate. Solche Indikatoren lassen allerdings nur Vermutungen über die Wirksamkeit von Interventionen und die Krankheitslast zu, statt den tatsächlichen Effekt auf die Bevölkerungsgesundheit darzulegen. Weiterhin haben Impfstoffe und Mikronährstoffe mitunter auch positive oder negative unspezifische Effekte (non-specific effects, NSE) oder interagieren mit anderen Interventionen. So werden individuelle Daten benötigt, die Effekte medizinischer Interventionen auf die Bevölkerungsgesundheit aufzeigen. Hierzu führte das EU-finanzierte Projekt http://www.indepth-network.org/projects/optimunise (OPTIMUNISE) (Optimising the impact and cost-effectiveness of child health intervention programmes of vaccines and micronutrients in low-income countries) mit Unterstützung durch das Gesundheitsüberwachungssystem HDSS (Health and Demographic Surveillance System) als einer Plattform des INDEPTH-Netzwerks Beobachtungs- und randomisierte Studien zum tatsächlichen Gesamteffekt spezifischer Interventionen auf die Bevölkerungsgesundheit durch. Die Projektpartner testeten an drei westafrikanischen Standorten NSE von Vakzinen zur Impfung von Kindern wie auch NSE von Vitamin-A-Präparaten. Aus diesen ländlichen und städtischen Regionen wurden mehr als 90.600 Kinder unter drei Jahren in die Beobachtungsstudie aufgenommen. Hierfür wurde ein öffentlich zugängliches Tool zur Datenerhebung und –analyse entwickelt, und an jedem Standort wurden mehrere Nachwuchsforscher im Umgang mit Methoden geschult, um Gesamteffekte dieser Maßnahmen auf die Gesundheit bewerten zu können. Eine randomisierte Studie zu einem Masernimpfstoff (MV) für Kinder zeigte, dass dieser zwar nicht die Gesamtüberlebensrate, aber die Bildung protektiver Antikörper bei Kindern im Alter zwischen vier und fünf Monaten verbesserte. Weitere Ergebnisse zeigen, dass der NSE beim Lebendimpfstoff OPV (oral polio vaccine) positiv, beim Totimpfstoff DTP (Diphtherie-Tetanus-Pertussis) sowie bei Penta-Impfstoffen für Frauen jedoch negativ sein kann. Weit häufiger als vermutet spielen wiederum geschlechtsspezifische Unterschiede eine Rolle. Für die Überlebensrate waren vor allem Kombination und Zeitplan der Impfungen wichtig, und die Forschung belegte mit der sinkenden afrikanischen Sterblichkeitsrate den Erfolg von OPV- und MV-Kampagnen. OPTIMUNISE hat damit demonstriert, dass HDSS-Einrichtungen in LIC-Ländern für die kontinuierliche Überwachung und Bewertung von Gesundheitsinterventionen von großer Bedeutung sind. Langfristig kann damit Kindern in LIC ein besserer Impfschutz gegen lebensbedrohliche Krankheiten vermittelt werden.

2017-07-26 13:05:23 de,en,es,fr,it,pl health de,en,es,fr,it,pl society de,en,es,fr,it,pl funda de,en,es,fr,it,pl ict en brief en 98247 261375 OPTIMUNISE de,en,es,fr,it,pl 852 FP7-HEALTH http://ec.europa.eu/research/health/index_en.html 846 FP7-COOPERATION 1401 EC 837 FP7 en 12586 HEALTH.2010.3.4-6 10252 HEALTH-2007-3.4 10249 HEALTH-2007-3 11416 HEALTH 852 FP7-HEALTH 846 FP7-COOPERATION 1401 EC 837 FP7 de,en,es,fr,it,pl ECO de,en,es,fr,it,pl MED de,en,es,fr,it,pl MBI en 197115 de,en,es,fr,it,pl pubsum en report de,en,es,fr,it,pl sesam de en,any /docs/results/261/261375/final1-final-report-optimunise-31-10-2016-version2-publishable-summary.pdf de de,en,es,fr,any /docs/results/images/2017-07/92763.jpg Dänemark DK 223513128 en de,en,es,fr,it,pl 92763 An EU initiative evaluated the combinatorial effects of a number of childhood vaccines on overall health in Africa. This will contribute to modifying existing health policies so as to improve vaccination outcomes.

Health interventions undertaken by the World Health Organization (WHO) or the United Nations Children’s Fund in low-income countries (LICs) are assessed based on certain performance indicators such as vaccination coverage. However, these indicators offer only an assumption about intervention efficacy and burden of disease and not the real-life impact on health. In addition, vaccines and micronutrients may have either beneficial or negative non-specific effects (NSEs) and may interact with other interventions. Individual-based data on health intervention uptake and health outcomes are necessary. With this in mind, the EU-funded http://www.indepth-network.org/projects/optimunise (OPTIMUNISE) (Optimising the impact and cost-effectiveness of child health intervention programmes of vaccines and micronutrients in low-income countries) project used the platform of the Health and Demographic Surveillance Systems (HDSSs) of the INDEPTH Network to perform observational studies and randomised trials on the real-life overall health effect of specific interventions. Project partners tested the NSEs of vaccines in use in the childhood vaccination programme and vitamin A supplements in three west African sites. Over 90 600 children below the age of three years were observed in these rural and urban areas. They developed a publicly available tool for data collection and analysis, and trained several young researchers in each site to use these tools to evaluate the overall real-life health impact of interventions. A randomised trial of an early measles vaccine (MV) found no beneficial effect on overall child survival but demonstrated that MV could produce protective antibody levels from four to five months of age. Further findings show that the live oral polio vaccine (OPV) may have beneficial NSEs, whereas the non-live diphtheria-tetanus-pertussis (DTP) and penta vaccines may have negative NSEs for females. Sex-differential effects were far more common than previously believed. The combination and sequence of vaccinations were very important for the effect on survival. Research revealed the importance of OPV and MV campaigns in declining African mortality rates. OPTIMUNISE successfully demonstrated that in LICs, HDSS sites can play a major role in the continuous monitoring and evaluation of health interventions. Long term, this will improve immune protection of children in LICs against life-threatening diseases

2017-07-26 13:05:22 de,en,es,fr,it,pl health de,en,es,fr,it,pl society de,en,es,fr,it,pl funda de,en,es,fr,it,pl ict en brief en 98247 261375 OPTIMUNISE de,en,es,fr,it,pl 852 FP7-HEALTH http://ec.europa.eu/research/health/index_en.html 846 FP7-COOPERATION 1401 EC 837 FP7 en 12586 HEALTH.2010.3.4-6 10252 HEALTH-2007-3.4 10249 HEALTH-2007-3 11416 HEALTH 852 FP7-HEALTH 846 FP7-COOPERATION 1401 EC 837 FP7 de,en,es,fr,it,pl ECO de,en,es,fr,it,pl MED de,en,es,fr,it,pl MBI en 197115 Project Final Report (261375 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 Executive... 2017-04-10 10:37:16 de,en,es,fr,it,pl pubsum en report de,en,es,fr,it,pl sesam en en,any /docs/results/261/261375/final1-final-report-optimunise-31-10-2016-version2-publishable-summary.pdf en de,en,es,fr,it,pl,any /docs/results/images/2017-07/92763.jpg Denmark DK 223513128 fr de,en,es,fr,it,pl 92763 Une initiative de l'UE a évalué les effets combinatoires d'un certain nombre de vaccins destinés aux enfants sur la santé globale en Afrique. Cela contribuera à modifier les politiques de la santé existantes afin d'améliorer les résultats de la vaccination.

Les interventions dans le domaine de la santé menées par l'Organisation mondiale de la santé (OMS) ou le Fonds des Nations Unies pour l'enfance dans les pays à faibles revenus (PFR) sont évaluées en fonction de certains indicateurs de performance tels que la couverture de la vaccination. Néanmoins, ces indicateurs n'offrent qu'une hypothèse quant à l'efficacité de l'intervention et au fardeau de la maladie et pas sur le réel impact sur la santé. Par ailleurs, les vaccins et les micronutriments peuvent avoir des effets non-spécifiques (ENS) bénéfiques ou négatifs et peuvent interagir avec d'autres interventions. Les données individuelles sur l'adoption de l'intervention sur la santé et les résultats de la santé sont nécessaires. Ceci étant, le projet http://www.indepth-network.org/projects/optimunise (OPTIMUNISE) (Optimising the impact and cost-effectiveness of child health intervention programmes of vaccines and micronutrients in low-income countries), financé par l'UE, a utilisé la plateforme des Health and Demographic Surveillance Systems (HDSS) du réseau INDEPTH pour effectuer des études d'observation et des essais aléatoires sur l'effet réel sur la santé d'interventions spécifiques. Les partenaires du projet ont testé les ENS des vaccins utilisé dans les programmes de vaccination des enfants et les suppléments de vitamine A dans trois sites d'Afrique occidentale. Plus de 90 600 enfants âgés de moins de trois ans ont été observés dans ces zones rurales et urbaines. Ils ont développé un outil accessible au public pour la collecte et l'analyse des données et formé plusieurs jeunes chercheurs dans chaque site à l'utilisation de ces outils pour évaluer l'impact général sur la santé et les interventions. Un essai randomisé d'un vaccin contre la rougeole (VR) n'a pas donné d'effet bénéfique sur la survie globale de l'enfant, mais a démontré que le VR peut produire des niveaux d'anticorps protecteurs de quatre à cinq mois d'âge. D'autres résultats montrent que le vaccin antipoliomyélitique oral direct (VPO) peut avoir des ENS utiles, alors que le vaccin diphtérie-tétanos-coqueluche (DTP) non vivant peut avoir des effets non spécifiques négatifs pour les femmes. Les effets différentiels au niveau du sexe étaient beaucoup plus fréquents qu'on ne le pensait précédemment. La combinaison et la séquence des vaccinations étaient très importantes pour l'effet sur la survie. La recherche a révélé l'importance des campagnes de VPO et VR dans la baisse des taux de mortalité africains. OPTIMUNISE a démontré avec succès que dans les pays à faibles revenus, les sites HDSS peuvent jouer un rôle majeur dans le contrôle et l'évaluation continus des interventions dans le domaine de la santé. À long terme, cela permettra d'améliorer la protection immunitaire des enfants dans les pays à faibles revenus contre les maladies mortelles.

2017-07-26 13:05:19 de,en,es,fr,it,pl health de,en,es,fr,it,pl society de,en,es,fr,it,pl funda de,en,es,fr,it,pl ict en brief en 98247 261375 OPTIMUNISE de,en,es,fr,it,pl 852 FP7-HEALTH http://ec.europa.eu/research/health/index_en.html 846 FP7-COOPERATION 1401 EC 837 FP7 en 12586 HEALTH.2010.3.4-6 10252 HEALTH-2007-3.4 10249 HEALTH-2007-3 11416 HEALTH 852 FP7-HEALTH 846 FP7-COOPERATION 1401 EC 837 FP7 de,en,es,fr,it,pl ECO de,en,es,fr,it,pl MED de,en,es,fr,it,pl MBI en 197115 de,en,es,fr,it,pl pubsum en report de,en,es,fr,it,pl sesam fr en,any /docs/results/261/261375/final1-final-report-optimunise-31-10-2016-version2-publishable-summary.pdf fr de,en,es,fr,it,pl,any /docs/results/images/2017-07/92763.jpg Danemark DK 223513128 it de,en,es,fr,it,pl 92763 Un’iniziativa dell’UE ha valutato gli effetti combinatori di un certo numero di vaccini pediatrici sulla salute generale in Africa. Tale operazione contribuirà a modificare le attuali politiche sanitarie in modo da migliorare gli esiti delle vaccinazioni.

Gli interventi sanitari intrapresi dall’Organizzazione mondiale della sanità (OMS) o dal Fondo delle Nazioni Unite per l’infanzia nei paesi a basso reddito (LIC) sono valutati sulla base di determinati indicatori di performance, ad esempio la copertura vaccinale. Tali indicatori presentano solo una supposizione circa l’efficacia dell’intervento e l’onere imposto dalla malattia e non gli effetti concreti sulla salute. Inoltre, vaccini e micronutrienti possono procurare effetti non specifici (NSE) positivi o negativi e interagire con altri interventi. Sono necessari dati su base individuale sull’adozione di interventi sanitari e gli esiti sulla salute. Su tali premesse, il progetto http://www.indepth-network.org/projects/optimunise (OPTIMUNISE) (Optimising the impact and cost-effectiveness of child health intervention programmes of vaccines and micronutrients in low-income countries), finanziato dall’UE, si è servito della piattaforma degli Health and Demographic Surveillance Systems (HDSS, sistemi di sorveglianza sanitaria e demografica) della rete INDEPTH, per effettuare studi osservazionali e sperimentazioni randomizzate sugli effetti concreti generali sulla salute, dovuti a specifici interventi. I partner del progetto hanno testato gli NSE di vaccini in uso nel programma di vaccinazione dell’infanzia e integratori di vitamina A in tre siti dell’Africa occidentale. In tali zone rurali e urbane, sono stati sottoposti a osservazione oltre 90 600 bambini di età inferiore a tre anni. I partner hanno sviluppato uno strumento pubblicamente disponibile per la raccolta e l’analisi dei dati e hanno formato in ciascun sito vari giovani ricercatori riguardo all’impiego di tali strumenti, al fine di valutare gli effetti sanitari concreti generali degli interventi. Una sperimentazione randomizzata di un vaccino antimorbillo (MV) precoce non ha riscontrato alcun effetto positivo sulla sopravvivenza generale dei bambini, ma ha dimostrato che il MV potrebbe produrre livelli anticorpali protettivi da quattro a cinque mesi d’età. Ulteriori scoperte indicano che il vaccino antipolio orale vivo (OPV) può determinare NSE positivi, laddove i vaccini antidifterite e antitetano e antipertosse (DTP) non vivo e i vaccini pentavalenti possono determinare NSE negativi per le bambine. Gli effetti differenziati per sesso sono stati molto più frequenti di quanto si credesse. La combinazione e la sequenza delle vaccinazioni sono risultate molto importanti per gli effetti sulla sopravvivenza. I ricercatori hanno rivelato l’importanza di campagne OPV e MV sul declino dei tassi di mortalità africani. OPTIMUNISE è riuscito a dimostrare che nei LIC, i siti HDSS possono svolgere un ruolo rilevantissimo nel monitoraggio costante e nella valutazione degli interventi sanitari. Sul lungo periodo, ne deriverà una maggiore protezione immunitaria dei bambini nei LIC rispetto a malattie potenzialmente letali.

2017-07-26 13:05:20 de,en,es,fr,it,pl health de,en,es,fr,it,pl society de,en,es,fr,it,pl funda de,en,es,fr,it,pl ict en brief en 98247 261375 OPTIMUNISE de,en,es,fr,it,pl 852 FP7-HEALTH http://ec.europa.eu/research/health/index_en.html 846 FP7-COOPERATION 1401 EC 837 FP7 en 12586 HEALTH.2010.3.4-6 10252 HEALTH-2007-3.4 10249 HEALTH-2007-3 11416 HEALTH 852 FP7-HEALTH 846 FP7-COOPERATION 1401 EC 837 FP7 de,en,es,fr,it,pl ECO de,en,es,fr,it,pl MED de,en,es,fr,it,pl MBI en 197115 de,en,es,fr,it,pl pubsum en report de,en,es,fr,it,pl sesam it en,any /docs/results/261/261375/final1-final-report-optimunise-31-10-2016-version2-publishable-summary.pdf it de,en,es,fr,it,pl,any /docs/results/images/2017-07/92763.jpg Danimarca DK 223513128 en en 98247 261375 OPTIMUNISE International child health programmes in low-income countries are justified in term of their impact on child survival. However, the effect estimates are usually calculated from performance indicators and assumptions about efficacy based on small-scale target-specific studies.... 2011-03-01 2016-08-31 2011-03-01 2016-08-31 2017-05-26 01:38:43 96688 FP7-HEALTH-2010-single-stage en 2084979 998874282 CENTRE DE RECHERCHE EN SANTE DE NOUNA

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DK www.ssi.dk

en REC en 3632955 Denmark DK 223513128 en 2084977 998306250 GHANA HEALTH SERVICE

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en PUB en 3632958 Ghana GH 273058344 en 1905799 999991431 RIJKSINSTITUUT VOOR VOLKSGEZONDHEID EN MILIEU

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DE www.klinikum.uni-heidelberg.de

en OTH en HES en 3632960 Germany DE 221940264 de,en,es,fr,it,pl 852 FP7-HEALTH http://ec.europa.eu/research/health/index_en.html 846 FP7-COOPERATION 1401 EC 837 FP7 en 12586 HEALTH.2010.3.4-6 10252 HEALTH-2007-3.4 10249 HEALTH-2007-3 11416 HEALTH 852 FP7-HEALTH 846 FP7-COOPERATION 1401 EC 837 FP7 de,en,es,fr,it,pl ECO de,en,es,fr,it,pl MED de,en,es,fr,it,pl MBI en 197115 Project Final Report (261375 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 Executive... 2017-04-10 10:37:16 de,en,es,fr,it,pl pubsum en report de,en,es,fr,it,pl sesam en en,any /docs/results/261/261375/final1-final-report-optimunise-31-10-2016-version2-publishable-summary.pdf en 164994 The many vertical health interventions led by WHO, UNICEF and other international organisations are undertaken with little attempt to assess their real life impact on health. Child health programmes in low-income countries are... 2015-05-25 11:16:30 en report en sesam de,en,es,fr,it,pl sesam http://www.indepth-network.org/index.php de,en,es,fr,it,pl 92763 An EU initiative evaluated the combinatorial effects of a number of childhood vaccines on overall health in Africa. This will contribute to modifying existing health policies so as to improve vaccination outcomes. 2017-07-26 13:05:22 de,en,es,fr,it,pl health de,en,es,fr,it,pl society de,en,es,fr,it,pl funda de,en,es,fr,it,pl ict en brief en de,en,es,fr,it,pl,any /docs/results/images/2017-07/92763.jpg en 59015 The many vertical health interventions led by WHO, UNICEF or other international organisations are undertaken with little attempt to assess their real life impact on health. Child health programmes in low-income countries are justified by their... 2014-07-18 09:41:19 en report en sesam de,en,es,fr,it,pl sesam en en,any /docs/results/261375/periodic1-optimunise-18-month-publishable-summary-revised-clean.pdf http://www.indepth-network.org/index.php en 184307 Project Context and Objectives:1. Publishable summaryProject 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)... 2016-06-16 12:39:54 en report en sesam de,en,es,fr,it,pl sesam en en,any /docs/results/261/261375/periodic3-optimunise-54-month-report-main-section-version-3-first-part.pdf en CP-FP-SICA pl de,en,es,fr,it,pl 92763 Międzynarodowe konsorcjum przeprowadza ocenę połączonych skutków kilku szczepionek dziecięcych w Afryce. W ramach oceny planuje się zmodyfikowanie istniejących polityk zdrowotnych tak, aby programy szczepień były bardziej skuteczne.

Interwencje medyczne podejmowane przez Światową Organizację Zdrowia lub UNICEF w krajach o niskich dochodach poddano ocenie w oparciu o określone wskaźniki wydajności, np. zasięg programów szczepień. Jednak na podstawie takich wskaźników specjaliści mogą tylko wysuwać hipotezy na temat skuteczności interwencji i obciążenia chorobą, ale nie są w stanie ustalić rzeczywistego wpływu na zdrowie. Ponadto szczepionki i mikroskładniki odżywcze mogą mieć działanie korzystne lub niespecyficzne działanie niekorzystne, a także mogą wchodzić w interakcję z innymi interwencjami. Konieczne jest zebranie danych dotyczących częstotliwości interwencji medycznych oraz skutków interwencji u indywidualnych osób. W tym celu w ramach finansowanego ze środków UE projektu OPTIMUNISE (Optimising the impact and cost-effectiveness of child health intervention programmes of vaccines and micronutrients in low-income countries) wykorzystano platformę systemu do nadzoru zdrowotnego i demograficznego (HDSS), aby przeprowadzić badania obserwacyjne na temat rzeczywistych skutków określonych interwencji. W trzech http://www.indepth-network.org/ (placówkach INDEPTH) (Burkina Faso, Ghana i Gwinea Bissau) partnerzy projektu zbadają niespecyficzne działanie niekorzystne szczepionki na odrę (MV), szczepionki na błonicę (DTP) oraz suplementów zawierających witaminę A. Zespół projektowy zebrał informacje na temat wszystkich rutynowych i programowych interwencji prowadzanych w dzieciństwie. Pomoże to określić rzeczywisty wpływ stosowanych obecnie metod prowadzenia programów szczepień oraz powiązanych z nimi problemów. Wstępne wyniki pokazują, że w ostatnich latach nastąpiła znaczna poprawa w przestrzeganiu terminów szczepień. Aby zwiększyć szanse dziecka na przeżycie, należy podać szczepionkę MV po szczepieniu na DTP. Wynika to z faktu, że szczepionka na DTP powiązana jest z wysoką umieralnością wśród kobiet, gdy jest podawana jako ostatnia. Ponadto dzięki monitorowaniu rezultatów stosowania wczesnych szczepionek BCG wiadomo, że wiążą się on z 40% obniżeniem umieralności noworodków. Zastosowanie suplementów z witaminą A może również zwiększyć niespecyficzne działanie niekorzystne szczepionek w zależności od płci. Wyniki projektu OPTIMUNISE pomogą w zidentyfikowaniu korzystnego i niekorzystnego działania istniejących programów szczepień, a także, w razie potrzeby, umożliwią ponowną analizę istniejących polityk w tym zakresie. W dłuższej perspektywie umożliwi to poprawę ogólnej ochrony organizmu dzieci w krajach o niskich dochodach przed zagrażającymi życiu chorobami.

2015-11-23 15:16:16 de,en,es,fr,it,pl health de,en,es,fr,it,pl society de,en,es,fr,it,pl funda de,en,es,fr,it,pl ict en brief en 98247 261375 OPTIMUNISE de,en,es,fr,it,pl 852 FP7-HEALTH http://ec.europa.eu/research/health/index_en.html 846 FP7-COOPERATION 1401 EC 837 FP7 en 12586 HEALTH.2010.3.4-6 10252 HEALTH-2007-3.4 10249 HEALTH-2007-3 11416 HEALTH 852 FP7-HEALTH 846 FP7-COOPERATION 1401 EC 837 FP7 de,en,es,fr,it,pl ECO de,en,es,fr,it,pl MED de,en,es,fr,it,pl MBI en 197115 de,en,es,fr,it,pl pubsum en report de,en,es,fr,it,pl sesam pl en,any /docs/results/261/261375/final1-final-report-optimunise-31-10-2016-version2-publishable-summary.pdf pl de,en,es,fr,any /docs/results/images/2017-07/92763.jpg Dania DK 223513128 en en 197115 261375-345-4 Project Final Report (261375 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 Executive...

Executive Summary: Project Final Report (261375 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 Executive summary (max 1 page) With OPTIMUNISE we have demonstrated that in low- and middle income countries, health and demographic surveillance systems (HDSS) sites can play a major role in the continuous monitoring and evaluation of health interventions. We have developed a publicly available free tool for data collection and data analysis. We have trained a number of young researchers in Guinea-Bissau, Ghana and Burkina Faso in using these tools to evaluate the overall real-life health impact of health interventions. We are also in the process of establishing other markers of a good health than mortality, which can be used as outcomes in the continued evaluation of health interventions in the future. Building on this platform, we have corroborated many of our previous observations of non-specific effects of BCG, measles vaccine (MV), diphtheria-tetanus-pertussis (DTP) and vitamin A supplementation (VAS), helped also by the fact that WHO carried out a review, which supported many of the conclusions. We have discovered that several other interventions have NSEs, confirming the patterns we had already established: the live oral polio vaccine (OPV) has beneficial NSEs, whereas the non-live penta and the new RTS,S malaria vaccine have negative NSEs for females. Sex-differential effects were far more common than usually assumed and we confirmed the predefined hypotheses about DTP having a negative effect for female survival. Vaccines and micronutrients interacted and combination and sequence of vaccinations were very important for the effect on survival. The potential effects of campaigns on child survival has not been assessed before but we have shown that the beneficial NSEs of OPV and the many campaigns with OPV during the last 15 years go a long way in explaining why mortality has decreased so incredibly in Africa. Similarly, we have shown that general MV campaigns also have major beneficial NSEs. There have been far more OPV campaigns than MV campaigns, so OPV campaigns may have been a major driver in explaining why two of the three HDSS sites have reached the Millennium Development Goal 4 (MDG4). We have furthermore discovered that vaccination in the presence of pre-existing immunity, from the mother or from previous vaccinations, confers additional beneficial NSEs, thus adding to the evidence for the importance of the OPV and MV campaigns for the decline in mortality. We did not, in a randomised controlled trial (RCT), confirm the finding from previous studies of a particularly beneficial effect of providing an early MV at 4-6 months of age. This could be due to the low power of the studies because the mortality rate was much lower than expected but we find it more likely that it could be due to the many OPV campaigns carried out during the trial, which tended to blur any effect of early MV. The RCT revealed that children in both Burkina Faso and Guinea-Bissau are susceptible to measles infection much earlier than hitherto anticipated, and an early MV could establish protective immunity and be an effective tool in the eradication of measles infection. We are in the process of documenting how taking into account both the NSEs and the overall real-life effect of health interventions, rather than their assumed effects, can refine the cost-effectiveness analyses and lead to completely different conclusions about which interventions to prioritise. The first analyses have shown that MV campaigns are highly cost-effective and that the restrictive vial policy to reduce wastage of vaccines in multi-dose vial (BCG, MV) is not cost-effective if the effect of these vaccines on overall child survival is taken into consideration. Project Context and Objectives: Project Final Report (261375 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 Final report: 31-08-2016 Project context and the main objectives (max 4 pages) Context: the non-specific effects of interventions Child health programmes in low-income countries are usually justified in term of their impact on child survival and how they may contribute to reaching the Millennium Development Goals. The international news and the scientific policy debate are therefore also filled with assessments indicating that particular programmes saved the lives of a certain number of children. For example, the vaccination programme is said to have saved over 20 million lives in the last two decades and the vitamin A programme over a quarter of a million lives each year (http://www.child-survival.org/childsurvival/whatiscs.php). Such assessments are mostly based on measurements of performance indicators for a particular programme, e.g. vaccination coverage, assumptions about the burden of the particular health problem (disease or deficiency), and assumptions about efficacy of the intervention, which are often based on results from small-scale pilot studies. There is no consideration of unintended positive or negative health side-effects of the common health interventions. Possible sex-differences in response to the interventions are not assessed. The possibility that health interventions may interact because they all affect the immune system is also not considered. The approach to assess performance indicators and use these to calculate the effect on mortality based on assumed burden of disease and assumed effect of the intervention on the target disease is deemed sufficient. So far, it has been the general understanding - the paradigm - that the intervention programme has only a specific effect; for example, measles vaccine prevents measles infection and vitamin A supplementation (VAS) prevents vitamin A deficiency. Once the effect is established, for example, that VAS reduces mortality with around 25% as found in the 1980s, it is assumed that this effect is constant. It is now becoming increasingly clear that this approach is insufficient. Observational studies and randomised trials conducted in several African and Asian countries have consistently shown that when it comes to assessment of real life effects of an intervention on mortality, the assumptions about the effect on mortality are 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. Second, these non-specific effects are frequently sex-differential. Third, interventions may interact producing stronger beneficial or negative non-specific effects; for example, vitamin A given together with DTP may increase mortality for girls. To the extent there are interactions between interventions, it also means that some intervention, which once reduced mortality by 25%, may now have a totally different effect because it also interacts negatively with some other intervention. The implication is that we need to continue to monitor the effect of our main interventions to continue to be sure that they have the intended overall (beneficial) effects. Hence, there is a need to assess the real life impact of the existing child health intervention programmes in the places where they are being used, taking into account the variability in programme implementation, that vaccines and micronutrients can have non-specific sex-differential effects on mortality, and that interventions may interact. Only real-life estimates of effects can lead to valid assessment of cost-effectiveness and thereby to sound evidence-based policy making. A prerequisite for testing the real life impact and cost-effectiveness of our child health interventions is to have individual-level data on health intervention uptake as well as on health status. Most low-income countries do not collect individual data on health interventions and morbidity and mortality. However, many countries have Health and Demographic Surveillance Systems (HDSS) sites. The INDEPTH Network is a network of such HDSS sites in Africa and Asia. These sites have typically been initiated as demographic surveillance sites, collecting data on births, deaths, and migration, but in recent years, many sites have integrated collection of health data into the routine data collection. The research from the Bandim Health Project HDSS has proved that HDSS sites can be extremely valuable tools for monitoring and testing the real life effects of health interventions. The present project involved three HDSS sites in West Africa, the Bandim Health Project in urban and rural Guinea-Bissau, Centre Recherche en Sante deNouna, Burkina Faso, and Navrongo Health Research Centre, Ghana. Based on a few modifications of the current data collection at these sites, including the routine collection of information on all interventions in childhood, such as vaccines, micronutrient supplementation, de-worming, bed-net distribution and bed-net impregnation, given at the health centres or in campaigns, we show that these HDSS sites can provide the platform for 1) assessing the real life effect and cost-effectiveness of child health intervention programs in observational studies; 2) testing modifications of the current health intervention programs in randomised controlled trials (RCTs), and 3) testing new interventions and their potential interactions with existing interventions in RCTs. The long-term hope is that the method will be adapted by other HDSS sites in Africa and Asia. Already implemented health interventions can generally only be evaluated in observational studies, because once a WHO-recommended intervention has been established in collaboration with international donors, it would be considered unethical to conduct a randomised controlled trial (RCT) of its “real life effect”, since it would imply withholding an intervention considered beneficial from some children. Hence, when it comes to testing the real life effect of the current child health program we must rely on observational studies for assessing impact and cost-effectiveness of health programmes. Such studies are prone to bias and the hypotheses need to be formulated in ways that minimise the risk of bias. A paper in Tropical Medicine and International Health (TMIH) formulated four testable hypotheses regarding the potential non-specific effects of the currently used diphtheria-tetanus-pertussis (DTP) and measles vaccines and their potential sex-differential effects (Fine and Smith, TMIH 2007). Using the HDSSs as a platform we aimed to test these hypotheses: first, that DTP vaccination after BCG vaccination is associated with an increase of at least 25-50% in female mortality (TMIH-hypothesis-I); second, among BCG-vaccinated children there is an increase in the female to male (F/M) mortality ratio when DTP vaccinations are given (TMIH-hypothesis-II); third, among DTP-vaccinated children there is a decrease in the F/M mortality ratio following measles vaccination (TMIH-hypothesis-III); fourth, in both boys and girls, measles vaccine (MV) given with DTP is associated with at least 50% higher mortality than that associated with MV given alone (TMIH-hypothesis-IV). The comparison of children who get an intervention with children who did not get the intervention is likely to be affected by different forms of bias. To account for this in our analyses, we emphasised the assessment of the determinants of programme adherence - from socio-economic factors to health related determinants like nutritional status or previous history of infections - and controlled for these factors in the analyses. In some situations it is 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. This may be useful because it evaluates the impact of possible modifications in an unbiased way. The HDSS platform is ideal for conducting such RCTs and we aimed to utilize this possibility in the present project. Specifically, we wanted to test a recent finding from an RCT in Guinea-Bissau: providing early measles vaccine at 4.5 and 9 months of age compared with the recommended measles vaccine at 9 months of age reduced overall mortality between 4.5 and 36 months of age by 30% in the per-protocol analysis and 22% in the intention-to-treat analysis, the effects being even stronger if the children had not received neonatal VAS (NVAS). The HDSS sites already collect data on mortality, and mortality was the main outcome in the present evaluation. 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. We therefore also aimed to identify the best relevant comparable outcome parameters, e.g. hospitalisation or growth, which correlate with child mortality/survival, and which can be used to assess the overall health impact of interventions in future assessments. Overall objective The OPTIMUNISE project had as it overall objective to develop the capacity of existing Health and Demographic Surveillance Systems (HDSS) in Africa to monitor the real life effects, including mortality, morbidity and growth, of our routine child health intervention programs in order to promote evidencebased policy which leads to the much needed reduction in the still unacceptable high child mortality. Hence, the context was that the work should contribute to reducing child mortality, to facilitate reaching the Millennium Development Goal 4 (MDG4) of reducing under-five mortality with 2/3 between 1990 and 2015. The specific objectives were defined as 1) To develop HDSS sites into a platform for monitoring real life effects of current child health programmes with the aim to assess the specific and non-specific, sex-differential effects of child health intervention programmes, as well as intervention interactions. This implies collection of routine data on all health interventions in childhood (WP1-3,WP7). A manual should be developed during the first year and will be updated based on the experience with implementing routine surveillance. The manual should be available through the INDEPTH Network. Based on this platform: 2) To measure the health impact and cost-effectiveness of the existing major child health programmes with vaccines and vitamin A controlling for known determinants of programme compliance (WP4, WP7). At least five papers were planned to be submitted during the 3rd to the 6th year of the project. 3) To evaluate in an RCT a specific modification of the current child health programme: To provide an additional measles vaccine at age 4.5 months, in addition to the recommended measles vaccine at age 9 months (WP5-6, WP8). Separate analyses from the two sites and a pooled analysis were to be available in the last year of the study. 4) To assess the relevance of different health outcomes parameters for the evaluation of the real life effect of child health programmes (WP9). This analysis was to be available in the last year of the study. The proposal was related to a call for assessment of the “Impact and cost-effectiveness of existing major health programmes”. First, it emphasised collaborative health research within Africa to ensure better health for Africans. Second, it emphasised capacity building in Africa. Third, it directly addressed the quest for reliable evidence on the overall impact and cost-effectiveness of major health programmes and more impact research, thereby contributing directly to evidence-based policy making. Fourth, it would result in a new methodology for measuring the real life effect on health of our child health programmes. Fifth, along with an emphasis on the most important outcome mortality, it would identify other reliable comparable outcome parameters. Sixth, as a key feature it would help to identify possible unintended positive and negative health side-effects beyond the targeted condition, with potentially very large implications for child health. Seventh, the testing of a specific modification in programme could potentially contribute significantly to improving child survival in low-income countries. Eight, the developed methodology and the identified outcome parameters would be easy to adapt to a wider range of health programs and to other geographical settings. Consortium The partners in the consortium were: Participant no. Participant organisation name Country 1 Statens Serum Institut Denmark 2 Bandim Health Project Guinea-Bissau 3 Centre de Recherche en Sante de Nouna Burkina Faso 4 Navrongo Health Research Centre Ghana 5 Heidelberg University Germany 6 Medical Research Council, The Gambia United Kingdom 7 INDEPTH Network Ghana 8 Rijksinstituut voor Volksgezondheid en Milieu (RIVM) The Netherlands Note: Partner 6 withdrew from the consortium because they no longer had the measles antibody assay available. For references see Final Report Foreground Project Results: Description of the main S & T results/foregrounds (max 25 pages) This report summarises what has happened within each of the objectives defined in the application. I. The platform for monitoring real life effects on morbidity and mortality of health interventions (WP1-3) Objective: To develop HDSS sites into a platform for monitoring real life effects and cost-effectiveness of our current child health programmes with the aim to assess the overall effect of the interventions on mortality, including the specific and non-specific and sex-differential effects of the interventions and their potential interactions. This implies collection of routine data on all health interventions and campaigns in infancy and childhood, as well as collection of data on health care use and health care cost. At the three HDSS sites - Nouna, Burkina Faso, Navrongo, Ghana, and Bandim, Guinea-Bissau – we developed a method for routine monitoring of health interventions, growth, morbidity and survival (WP1-3,WP7, Deliverable 1). The monitoring system is built on regular home visits to all families in the study areas at least every 4 months. At these home visits we collect information on pregnancies, deliveries, information on interventions from vaccination cards (immunisations, vitamin A supplementation (VAS) and campaigns), on growth (arm-circumference), on morbidity (hospital admissions, consultations), and on survival. The method is described on the web-page of the INDEPTH Network (Deliverable 1): http://indepth-network.org/projects/optimunise/optimunise-key-activities The work was done by Partners 2-4 and with help from Partners 1,5, and 7. Work packages (WP) 1-3: Building the platform Over the 66 months the OPTIMUNISE project has lasted we have established and consolidated this platform. For WP1 the work was done by Partners 2 and 1, for WP2 by Partners 3 and 5, and for WP3 by Partner 4. Since the beginning of the OPTIMUNISE project, 90,609 children below the age of 3 year have been under surveillance in the three sites: The average annual birth cohort for the three sites was 11,800. A total of 34,791 children below 3 years of age in Ghana, 21,866 in Burkina Faso and 33,952 in Guinea-Bissau. We saw vaccination card for 84% (75,888) of these children: 30,105 (87%) in Ghana; 15,314 (70%) in Burkina Faso; and 30,469 (90%) in Guinea-Bissau. While the core of the vaccination programme has been common in the three sites, many new vaccines have been introduced during the OPTIMUNISE project. The core of the vaccination programme has been BCG+Oral Polio Vaccine (OPV) at birth; Pentavalent + OPV at 6, 10, 14 weeks of age in Ghana and Guinea-Bissau but 2, 3, 4 months in Burkina Faso; Measles and Yellow fever at 9 months of age in all three countries. During the course of the project Pneumococcal vaccine was introduced at 6, 10, 14 w since May 2012 in Ghana, at 2, 3, 4 months: since November 2013 in Burkina Faso, and at 6, 10, 14 w: since June 2015 in Guinea-Bissau. Rubella vaccine was introduced from 9 months of age in Ghana since September 2013 and since May 2015 in Burkina Faso. Inactivated polio vaccine was introduced at 14 w since July 2016 in Guinea-Bissau but not yet in the other countries. A second dose of measles vaccine was introduced at 18 months since May 2012 in Ghana and at 15 months since October 2014 in Burkina Faso. It is not yet introduced in Guinea-Bissau. In addition to the routine vaccinations, the OPTIMUNISE sites have also been collecting data on all the child health campaigns which have been implemented in the three sites. A very large number of campaigns have been conducted during the project: OPV campaigns: 9 in Ghana, 28 in Burkina Faso, and 9 in Guinea-Bissau. Vitamin A supplementation (VAS) campaigns: 1 in Ghana, 10 in Burkina Faso, and 11 in Guinea-Bissau. Measles vaccination campaigns: 1 in Burkina Faso and 2 in Guinea-Bissau. Measles and rubella vaccination campaigns: 1 in Ghana and 1 in Burkina Faso. MDG4 context: Monitoring child survival The ultimate goal for EU FP7 sponsored research projects in low-income countries was that they should support the process of reaching the MDG4. Over the project period from 2011-2016 under-five child mortality has declined remarkably. Bandim and Navrongo have data going back more than 20 years; followup started a bit later in Nouna. MDG4 was reached in both the urban and the rural HDSS of the Bandim Health Project (Bandim) and in Navrongo. There has been a 68% reduction in mortality between 1995 (241/1000) and 2014 (76/1000) in the rural areas followed by Bandim. In the urban areas data goes back to 1979; between 1990 (227/1000) and 2014 (65/1000) mortality decline was 71%. In Navrongo the decline was 78% between 1996 (235/1000) to 2015 (52/1000). Based on extrapolation of the data from 1990 to 2015, the under-5 mortality rate has decline with 54% in Nouna. Given the experiences and expectations when we wrote the OPTIMUNISE proposal this marked decline is surprising; the process may have been particularly surprising in Guinea-Bissau which has had a decade which started with a large part of the national health staff fleeing to Europe in the aftermath of the civil war (1998-1999), and continued with numerous military coups, political instability, repeated changes in government, donor fatigue and no major economic progress. It has been of utmost interest for all Partners (1-8) in the OPTIMUNISE project to understand the background for this enormous decline in mortality. As discussed below, the beneficial non-specific effects (NSEs) of vaccines and vaccine campaigns with measles vaccine (MV) and oral polio vaccine (OPV) may have been far more important than usually assumed (see Section II). The decline in the mortality has obviously also affected our statistical power to assess effects of interventions, very specifically in relation to the randomised control trial (RCT) of early measles vaccination (see section III). II. Measure the impact and cost-effectiveness of the existing major child health programmes with vaccines and vitamin A controlling for known determinants of programme compliance (WP4, WP7). Objectives: To describe the real life implementation of child health programs in West Africa. To assess the overall impact on health of these programs. To test the four hypotheses regarding non-specific and sex-differential effects on mortality of vaccines published in 2007 (WP4). Estimate the effect on overall morbidity and mortality of changes in programme implementation over time and of the introduction of new vaccines and their potential interactions with other interventions (WP7). The basis for OPTIMUNISE was the observation that vaccines and micronutrient programmes have nonspecific effects (NSEs) because they affect the immune system and may induce immune training, which affect susceptibility to unrelated infections and may therefore affect overall morbidity and mortality. Since the process may reduce or enhance susceptibility, NSEs can be both beneficial and deleterious. The effects are often sex-differential and different health interventions may interact with each other. The data processing and communication of results for WP4 was done by Partners 1-5 and 7 and for WP7 by Partner 4 with some help from Partner 1. This area of research has grown much faster than initially anticipated. In this respect, it was very important that WHO’s Strategic Advisory Group of Experts on Immunisation (SAGE) in 2012 decided to conduct a thorough review of the NSEs of BCG, diphtheria-tetanus-pertussis (DTP) and measles vaccine (MV) on mortality for children less than five years of age. The review was conducted during 2013 and presented to SAGE in April 2014. SAGE recommended further research into the NSEs of vaccines and delegated the IVIRAC (Immunization and Vaccines related Implementation Research) committee to develop protocols and conduct such research. During the OPTIMUNISE project a paradigm conflict has developed between the current “specific solution” paradigm and the “systemic effects” paradigm that we have emphasized. In the “specific solution” paradigm vaccines have only specific effects and their overall benefit on survival is determined by the effect on the specific disease; vaccines have same effect for boys and girls; the specific effect of a vaccine is rarely modified by other health interventions; maternal immunity reduces the specific response to vaccination; the first dose of live vaccines is usually protective and little additional effect is anticipated from repeated doses; vaccination may be terminated once the target disease pathogen is eradicated; vaccines may induce long-term adaptive immune memory against the specific disease pathogen; the specific effects are mediated through development of specific memory B- and T-cells. When the OPTIMUNISE proposal was developed we emphasized the following principles of a “systemic effects” paradigm: first, live vaccines have beneficial NSEs, which have marked beneficial effects on general health (Principle 1); second, non-live vaccines have harmful NSEs, which have marked negative effect on general health in spite of specific disease protection (Principle 2); third, NSEs are sex-differential and girls are most affected by harmful NSEs (Principle 3), and fourth, NSEs are strongest for the most recent vaccination, but vaccines interact with other vaccines and vitamins, so sequence and combination are important (Principle 4). During the course of OPTIMUNISE we have developed at least 5 new principles: fifth, maternal immunity enhances the beneficial NSEs of live vaccines (Principle 5); sixth, repeated doses of live vaccines enhance their beneficial NSEs (Principle 6); seventh, termination of live vaccines may lead to increases in morbidity and mortality (Principle 7); eighth, vaccines may have long-term imprinting effect on the host, including both the innate and adaptive immune system (Principle 8); and ninth, live vaccines and non-live vaccines have different effects on the innate immune system as live vaccines induce innate immune training whereas non-live vaccines induce innate tolerance (Principle 9). Below we summarized the results which have been obtained for these principles during the implementation of WP4 and WP7 in the OPTIMUNISE project. Principle 1(P1): Live attenuated vaccines have beneficial NSEs Partners 1 and 2 had previously shown that BCG, MV, and smallpox vaccine (Vaccinia) had beneficial NSEs. Several studies during OPTIMUNISE have strengthened these observations and furthermore we have added that oral polio vaccine (OPV) apparently also has beneficial NSEs, something which has not been emphasized previously. Routine measles vaccine (MV). Due to GAVI’s interest in knowing more about the determinants of the fully immunized child (FIC) and the consequences of being FIC for subsequent child survival, Partners 1-4 and 7 obtained funding from GAVI for additional data workshops and analyses. We used data from the three West African OPTIMUNISE sites as well as from three other INDEPTH sites (Kintampo, Ghana; Nairobi, Kenya; Chakaria, Bangladesh) being part of a parallel research training project sponsored by DANIDA. The observed patterns were consistent over the 6 sites and the results can be summarized as follows: Vaccination data collected between 2001-14 from 109,473 12-23-month-old children at five African and one Asian INDEPTH HDSS sites was used to analyse the trend over time and determinants of being “fully immunized children” (FIC) and the consequence for subsequent child mortality of being FIC compared to not being FIC. There was an upward trend over time in the proportion being FIC at all centres except one, the coverage in 2013 ranging between 71% and 88%. As expected, cultural and socio-economic factors indicating better conditions were positively associated with FIC. However, encouragingly with increasing coverage the differences in FIC associated with education and wealth tended to disappear. None of the centres found differences in the proportion of being FIC among females and males. While the age of DTP-containing vaccines and OPV went down over time at all centres, the patterns were more variable for BCG and measles vaccine (MV). For MV, several centres showed slight increases in the age of vaccination. This is unfortunate since there is a limited time-window from 274-365 days of age to get MV and become a FIC. The predominant cause of not being FIC was lack of MV, explaining from 75% to 100% of not being FIC at the six centres. Controlling for back-ground factors, being FIC was associated with 22% lower mortality (95% confidence interval: 12-31%) than not being FIC. The main reason for not being FIC was lack of MV, and our analyses indicated that lack of MV is associated with 28% (14-45%) higher mortality (25). None of the centres with cause-specific mortality data reported measles epidemics, suggesting that the effect of MV is likely to be non-specific. This has been analysed specifically by Partner 4 in Navrongo that has the largest data set; the higher mortality of children who have not had MV is not explained by more measles deaths (42,51) In conclusion, to improve FIC coverage and child survival, a stronger emphasis should be given to ensure that all children are measles vaccinated on time. Hence, the key messages were: ▪ FIC coverage has increased over time and ranged between 71% and 88% in year 2013 ▪ No difference in FIC coverage between boys and girls ▪ Place of residence and delivery, and maternal education are important factors for FIC ▪ Increasing FIC coverage diminishes importance of education and wealth for being FIC ▪ BCG age at vaccination decreased very significantly in Navrongo but is still a challenge in other sites ▪ Lacking measles vaccination is the main cause for not being FIC ▪ Being FIC is associated with 22% lower mortality Measles vaccine campaigns. Partners 1 and 2 also conducted two epidemiological studies of the effect of MV campaigns in Guinea-Bissau. First, in an after-before comparison of the general mortality rate for children aged 6 months to 5 years in rural Guinea-Bissau, mortality was reduced by 20% after the general campaign in 2006 (22). Second, in urban Bissau, participation-versus-non-participation in the MV campaign in 2012 was associated with 72% lower mortality in the following year (54). The regular 3-yearly MV campaigns are conducted to eradicate/control measles infection to assure that everybody is reached. One should therefore expect that the strongest effects for children who had not previously received routine MV. However, in both studies the beneficial effect of campaign MV was much stronger for those who had previously received routine MV (22,54). Navrongo data also suggests that the MV campaigns have had a major effect on child survival reducing the mortality rate after these campaigns (67). BCG. Between 2002 and now, Bandim (Partners 1 and 2) has conducted 3 RCTs of BCG among low-birthweight (LBW) children because they are not normally given BCG at birth. Two trials have previously been published (Aaby JID 2011; Beiring-Sørensen PIDJ 2012) and a third has now been submitted (46,60). In the first two trials randomization to BCG reduced neonatal mortality with 48% (95% CI 18-67%). Over the period neonatal has declined dramatically and the reduction in the third trial was 30%. In a combined analysis of the three trials, early BCG-vaccination was associated with a 38% (95% CI 17-54%) reduction in neonatal mortality, most of the reduction being due to less neonatal sepsis and respiratory infections (46). Though BCG vaccine is recommended at birth the vaccination is often delayed. Given the beneficial effects of the vaccines it is very unfortunate that there are such delays in administration of this vaccine. An important reason is that the 20-dose vials of BCG (which have to be discarded 4-6 hours after opening) are not opened unless at least ten children are present for vaccination; therefore many contacts with the health system are not used to vaccinate. BCG coverage is usually reported as the coverage at 12 months of age, not disclosing the delay in vaccination. Within OPTIMUNISE we showed that among children born in 2010 in rural Guinea-Bissau BCG coverage by 1 week of age was 11%, 38% by 1 month, and 92% by 12 months. If BCG had been given at first contact with the health system, 1-week coverage would have been 35% and 1-month coverage 54%. After the introduction of the monthly visits (July 2012-June 2013), 1 month coverage increased to 88%. A risk factor analysis identified many factors associated with delay of BCG vaccination, including a number of socioeconomic factors, but these factors were not strongly associated with BCG vaccination when BCG-vaccination became available during the monthly visits (16). As a case study within WP7, Navrongo (Partner 4) has examined how the median age of BCG vaccination has changed over time and how neonatal mortality has developed. BCG vaccination age declined from 46 days in 1996 to 4 days in 2012. Similarly, neonatal mortality rates also declined from 46/1000 livebirths in 1996 to 12/1000 livebirths in 2012. In the 1990s and early 2000s, the reduction in the age of BCG vaccination was linked to the experiment with community nurses in the Navrongo area, both the coverage and the age of vaccination being much lower in the communities, which had community nurses than in control community. The further reduction in the late 2000s is linked to decisions by local public health authorities to always open a 20-dose vial of BCG even though there might only be one child present for vaccination (65). Routine OPV: In an RCT in Guinea-Bissau (conducted by Partners 2 and 1), OPV-at-birth was associated with 32% (0-57%) reduction in infant mortality when the effect of the many additional OPV campaigns was controlled by censoring at the time of subsequent OPV campaigns (105). Partner 1 has verified this striking observation in Denmark, which used OPV until 2001. In a nation-wide study, being OPV vaccinated was associated with a 27% (13-39%) lower risk of admissions for lower respiratory infections (106). OPV campaigns. As mentioned in the beginning, there have been a very large number of campaigns in low-income countries in the last two decades. Due to the plans to eradicate polio infection globally, the largest number of campaigns has been with OPV. The recurrent outbreaks of polio infection in Northern Nigeria have meant that new OPV campaigns have been organized. Surprisingly there has been virtually no analysis of whether these campaigns with OPV had an effect on survival. From a disease-specific perspective they should have no effect because polio is rarely a killing disease and the infection has virtually been eliminated from West Africa for the last many years. However, when the first general OPV campaign was implemented in Guinea-Bissau in 1998, Bandim (Partners 1 and 2) conducted a study which suggested that participants in the campaigns had significantly lower mortality than the non-participants (117). Within OPTIMUNISE, using the HDSS data we have now tried to estimate how OPV campaigns affect the general mortality rate by comparing the mortality rate after-campaign with the mortality rate before campaign. Participation has been very high in these campaigns (>90%) and we have therefore assumed that all eligible children received the campaign OPV. We first conducted this kind of analysis within all the randomised trials we have conducted in Bandim between 2002 and 2014 (Partners 1 and 2). The analyses have controlled for age, season, time trend and other campaigns (52). In the first analysis (52) the mortality rate for children aged less than 3 years was 19% (5-32%) lower after the campaigns than before. With each additional dose of campaign-OPV the mortality rate declined 13% (421%) per dose (test for trend, p=0.005). We have subsequently extended the analysis to include all children in the HDSS. In Bandim Partners 1 and 2 analysed the period 2002-2014 and the reduction in mortality rate was 25% (15-33%) and again there was significant beneficial effect with each additional dose of OPV (58). In Navrongo (Partner 4) mortality for the period 1996-2014 was analysed and the effect was a 12% (4-19%) reduction in mortality rate and beneficial effects for each additional dose. When the effects were estimated in a simulation model with random dates for hypothetical campaigns no effect was seen (52) so the effect cannot be explained as a result of a time trend in mortality. Interestingly, VAS campaigns were not associated with a positive effect on the mortality rate. Hence, the benefits of OPV campaigns did not seem to represent merely a beneficial effect of the additional attention during campaigns. Measuring the effects of interventions: The role of campaigns. As a consequence of these observations, we discovered that OPV campaigns can change the effect of other interventions or the time-trend being studied. Intervention RCTs usually test the standard treatment versus a proposed modification assumed to be better. However, if OPV campaigns are implemented during the conduct of the intervention trial and given to all participants, OPV is likely to reduce the difference between the groups being compared in the RCTs. We have shown this several times during conducts of trials of MV (45), BCG (46), OPV-at-birth (105), and VAS (49): • In the conduct of a RCT of an additional MV at 4½ months, measuring mortality from 4 to 36 months, the overall mortality reduction was 30% (6-48%); but if we censored at the time of the OPV campaigns, the effect of early MV was 47% (13-68%). • In an RCT of OPV at birth (OPV0) vs no OPV0, infant mortality was reduced with 17% (-13-39%); but if we censored at the time of the OPV campaigns, the effect of OPV0 was 32% (0-57%) (105) • Likewise in two trials of BCG-at birth to LBW children, infant mortality and neonatal mortality was reduced with 17% (-8-37%) and 30% (-4-53%), respectively; but if we censored at the time of the OPV campaigns, the effect of BCG-at-birth 20% (-6-40%) and 34% (0-56%), respectively (46) It has therefore become more difficult to show that an intervention has a significant beneficial effect as long as OPV campaigns are being conducted. OPV campaigns may also reduce differences between other groups; for example we have examined as one of the objectives of the OPTIMUNISE project the effect of out-of-sequence vaccinations with MV and DTP (TMIH-hypothesis-IV). As part of WP7 Partners 4 tested in Navrongo the potentially negative effects of getting MV and DTP out-of-sequence (OOS), i.e. DTP with or after MV. In the adjusted analysis, the overall result was 30% (6-47%) lower mortality for those who had the recommended sequence of MV-after-DTP3 compared with OOS vaccinations (42). However, the beneficial effect of MV-after-DTP3 was much stronger before campaigns, the reduction in mortality being 63% (12-83%); after the campaigns were implemented the reduction in mortality associated with MV-after-DTP3 was only 27% (2-46%) (42,51). Similarly in another study from Navrongo, the reduction in mortality linked to being MV versus not being measles vaccinated was 28% (13-39%), but if we censored follow-up at the time of OPV campaigns the benefit associated with MV was a 39% (19-54%) reduction in mortality. In both RCTs and observational studies, the mortality rate declines after the OPV campaigns and this reduces the differences between the groups being compared. Hence, these examples strongly indicate that OPV has beneficial NSEs. If the effects of campaigns are not taken into consideration we may fundamentally misinterpret the time trends in mortality (49,57). Specific and non-specific effects of live vaccines on mortality. In the RCTs with live vaccines, which had a beneficial effect on overall survival, we examined how much of the reduction in mortality was due to the specific effect and much to the non-specific effect: • In a meta-analysis of three RCTs of BCG at birth and with censoring for OPV-campaigns, the reduction in neonatal mortality was 41% (19-57%). None of this reduction was due to specific disease protections and hence the non-specific effect was 41% (19-57%)(46) • In an RCT, censoring for OPV-campaigns, OPV0 was associated a reduction in Infant mortality of 32% (0-57%). None of this reduction was due to specific disease protections and hence the non-specific effect was 32% (0-57%) (105) • In an RCT of early MV, the intervention was associated a 30% (6-48%) in mortality between 4-36 months of age. 4% of this reduction was due to the specific prevention of measles infection and 26% (0-45%) was due to beneficial non-specific effect (107). Hence, the reduction in mortality due to NSEs was much greater than the reduction due to specific-disease prevention. P2: Non-live vaccines - though protective against target diseases - have harmful NSEs Partners 1-5 and 7 have strengthened the evidence considerably for deleterious effects of non-live vaccines during the OPTIMUNISE project (1,6,10,23,24,32,34,35,39,40,42,43,48,53,57,59,63,73). We have only been able to test the DTP danger-signal in natural experiments (43,59) since it is difficult to get ethical permission to test WHO-recommended vaccines in RCTs. However, new RCTs have tested the non-live RTS,S malaria vaccine (24,32), and we have actively pursued the outcome. The SAGE review and the impact of DTP on child survival. The SAGE review found that BCG and MV were associated with nearly a halving of the mortality rate compared with not being vaccinated with these vaccines (see below). However, the review found a 38% (-8-108%) increase in mortality associated with DTP. Though not significant in its own right it was clearly significantly different from the effects of BCG and MV in the same studies and from standard expectations as normally the healthiest children who are vaccinated first. Nonetheless, the reviewers concluded that the literature was inconsistent since two studies had found a beneficial effect of DTP. We have subsequently shown that the WHO-SAGE analysis of DTP was flawed due to inclusion of several studies with survival bias and frailty bias. If only studies with prospective follow-up are included, the available studies suggest 2-fold higher mortality for DTP vaccinated children, the MRR being 2.00 (1.50-2.67) (34). The WHO-SAGE review concluded that though there were sex-differential effects of MV (better for girls) (109-110), there was no sex-differential effect of DTP. Since sex-differential effects were one of the focus areas for OPTIMUNISE, we reviewed the literature. Again this was a flawed conclusion because the SAGE reviewers included studies with major survival bias (34). If these studies were excluded, DTP was associated with a strongly negative effect for girls (48); among DTP vaccinated children girls had 53% higher mortality than boys (15 studies) (48). A new study from Nouna (Partner 3 and 5) has also found that DTP-containing vaccine is associated with higher mortality for girls than for boys (63). Likewise, Partners 1 and 2 found that Pentavalent vaccine (DTP+HBV+Hib) was associated with increased female mortality (39). Introduction of DTP-vaccination in 1981 associated with increased mortality: The SAGE review emphasised that it is difficult to assess the “true” effect of DTP because it is always given with OPV. Furthermore, it was emphasised that there were herd immunity to pertussis while the studies were conducted, and one would therefore not see the benefit of preventing pertussis. Given the continuing discussion of the true effects of DTP, Partners 1 and 2 went back to examine what happened when DTP was introduced in Bissau in the early 1980s. In studies of both infants and older children, we found that DTP (+/- OPV) was associated with 4-5 times higher mortality than not being DTP-vaccinated (43, 59). Since it is the healthiest children who are vaccinated first (34), the effects of DTP may be difficult to see in many studies because most studies compare healthier DTP-vaccinated children with frail DTP-unvaccinated children. However, when the vaccines were introduced the situation resembled a natural experiment and it was clear that there was a very marked negative effect of DTP (43,59). Vaccines were provided in connection with nutritional examinations from 3 months of age in Guinea-Bissau. Children were called for examinations every 3 months. Hence, due to variation in date at birth some children were vaccinated shortly after age 3 months, whereas others were nearly 6 months old. In this natural experiment, the children who received DTP early had an age-adjusted hazard ratio (HR) for mortality of 5.00 (1.53-16.3) between 3-6 months of age compared with not yet DTP-vaccinated children. In children aged 12-35 months, the HR was 4.13 (0.93-18.40) for DTP-vaccination compared with no DTP vaccination even though the DTP-vaccinated children had better nutritional status than the not DTP-vaccinated children (59). The effect was significantly negative for girls (59). Malaria vaccine associated with increased mortality: The GSK malaria vaccine RTS,S was tested in two RCTs. When the first results were published, the RTS,S group had slightly higher mortality. This made little sense if RTS,S prevented malaria infection. Hence, we asked for results to be reported by sex, from the hypothesis that if malaria vaccine, apart from protecting against malaria, also had negative NSEs, then it might be reflected in higher female mortality as seen for other non-live vaccines. In the final report (2015), the mortality data indicated 24% (-3-58%) higher mortality and a significant long-term negative effect; but data was not reported by sex. We wrote to Lancet (24) and WHO, requesting that data be presented by sex, as the increased mortality could represent negative NSEs in females. After request from SAGE members, GSK released the data by sex. As we had hypothesised, RTS,S was associated with 2-fold higher mortality for girls in both RCTs, but made no difference for boys (32). Hence, the pattern is similar to what we have seen for other non-live vaccines (see P3). P3: NSEs are sex-differential; girls are most affected by harmful NSEs Potential sex-differential effect of interventions were emphasised as part of the original OPTIMUNISE protocol and we specifically planned to test the TMIH-hypotheses about NSEs. Using the SAGE review as a basis, we have reviewed the existing literature on DTP. In the 7 available studies, DTP given after BCG was associated with 2.54-fold higher mortality for girls but not for boys (TMIH-hypothesis I). In 15 available studies, among DTP vaccinated children girls had 53% (21-93%) higher mortality than the boys (TMIH-hypothesis-II) (48). As described above, the malaria vaccine was associated with two-fold higher female mortality in RCTs. Hence, so far we have now shown increased female mortality for all the non-live vaccines we have examined: • DTP vaccinated versus DTP unvaccinated was associated with a MRR of 2.00 (1.50-2.67) in 8 studies; in 7 studies comparing DTP-vaccinated female with DTP-unvaccinated females the MRR 2.54 (1.68-3.86) and in 15 studies comparing the mortality of female and male DTP-vaccinated children the MRR was 1.53 (1.21-1.93) (34, 48). • In 3 trials of IPV comparing the mortality of female and male IPV-vaccinated children the MRR was 1.52 (1.02-2.28). • In a natural experiment with HBV, HBV-vaccinated versus not HBV-vaccinated was associated with a MRR 1.81 (1.19-2.75); comparing female HBV vaccinated versus HBV-unvaccinated females the MRR was 2.27 (1.31-3.94) and the female/male MRR among HBV children was 2.20 (1.07-4.54). • In a natural experiment with H1N1 vaccine (51), H1N1-vaccinated versus not H1N1-vaccinated children was associated with a MRR 1.86 (1.02-3.42); comparing female H1N1-vaccinated versus H1N1-unvaccinated females the MRR was 2.32 (1.19-4.52) and the female/male MRR among H1N1 children was 2.68 (0.44-16.4). • In two RCTs of RTS,S malaria vaccine, RTS,S-vaccinated versus RTS,S-unvaccinated had a MRR of 1.24 (0.97-1.58); in the two trials the MRR for female RTS,S vaccinated versus controls were 1.81 (1.04-3.14) and 2.00 (1.18-3.39), respectively. The female/mala MRR among RTS,S-vaccinated children was 1.33 (1.02-1.74) (24,32). • In the only study of Penta, the female/male MRR was 1.73 (1.11-2.70) (39) The SAGE review concluded that MV was associated with a stronger beneficial effect for girls than for boys and thereby confirmed TMIH-hypothesis III (109,110). A stronger beneficial effect of MV for girls have also been confirmed in several consortium studies (7,39,57) P4: NSEs are strongest while the vaccine is the most recent vaccination; vaccines interact with other vaccines and vitamins, so sequence and combination are important DTP with or after MV have negative effects on child survival. The observation that a non-live vaccine given after a live vaccine changes the overall effect from beneficial to negative, at least for girls, has been strengthened during the OPTIMUNISE period. The SAGE review (109) summarized the current evidence: MV+DTP compared with MV-only was associated with a HR of 2.30 (1.56-3.39); for DTP after MV compared with MV-only, the HR was 2.16 (1.25-3.74). Partner 4 subsequently corroborated these trends in a large study in northern Ghana; receiving MV and DTP out-of-sequence (i.e. DTP with or after MV) was associated with a HR of 2.58 (1.14-5.84) as long as the children had not yet received OPV campaigns (42). In a smaller study from Guinea-Bissau (Partners 1 and 2), the HR of death was higher among children with DTP>=MV (HR=1.44 (0.97-2.15)) (57). These studies do not separate the effects of DTP given after MV and DTP given with MV but they support the TMIH-hypothesis IV that DTP given with MV is associated with higher mortality than MV given alone. In a study from Guinea-Bissau which specifically studied the effect of coadministration of DTP/pentavalent vaccine with MV, the adjusted HR was 3.24 (1.20-8.73) compared with MV given alone or MV given with Yellow Fever vaccine (6). DTP given after MV has also been found to have a negative effect, for girls, in 5 RCTs from Guinea-Bissau, Senegal, The Gambia and Sudan (35). Combined BCG and DTP reduce the negative effects of DTP: WHO recommends BCG at birth and DTP at weeks 6, 10 and 14. However, many children receive BCG later, often with DTP. In a large dataset from Bangladesh, Partner 1 showed that children who received BCG+DTP1 simultaneously had an adjusted-HR from 6 weeks to 9 months of age of 0.52 (0.38-0.70) compared with children who followed the WHO-schedule of BCG-first-then-DTP (53). We have found similar trends in smaller studies from India, Senegal (23, 40) and Guinea-Bissau. Combined DTP and OPV vaccinations reduce the negative effects of DTP. Interestingly the studies of the introduction of DTP and OPV in urban (43, 59) and rural (113) Guinea-Bissau showed that giving OPV together with DTP reduced the negative effects of DTP compared with DTP-unvaccinated children (43): In urban Bissau where DTP was introduced in 1981 (43), the HR DTP-only vs unvaccinated was 10.0 (2.6-39) but “only” 3.52 (1.0-12.9) if DTP had been administered with OPV. In another study from rural Bissau where DTP was introduced in 1984 (113), the HR DTP-only vs unvaccinated was 5.00 (0.6-40) but “only” 1.90 (0.9-4.0) if DTP had been administered with OPV. In a meta-analysis of these two studies, the HR for DTP-only vs unvaccinated was 8.1 (2.6-25) but “only” 2.2 (1.2-4.2) if DTP had been administered with OPV, suggesting a significant modifying effect of co-administering DTP and OPV. To the extent this is true it might suggest that the negative effect of DTP may increase once OPV has been removed from the vaccination programme in 2020. Vitamin A supplementation (VAS) is a two-edged sword: Bandim (Partner 1 and 2) completed the first RCT testing the WHO-policy to administer VAS with vaccines to children after 6 months of age. Contrary to current beliefs, VAS did not reduce mortality by 25%. We found no overall effect, but a strong sex-differential effect; VAS halved mortality for girls yet doubled it for boys. We corroborated previous observations of a beneficial effect of repeated VAS in females. Currently there is a heated debate regarding whether VAS should continue; we are arguing that large-scale RCTs should be done to ensure that VAS is provided to those who benefit, but not those harmed (29). There has been much work to extend the assumed benefit of VAS to younger ages. In the 2000s, our RCTs showed 10-15% increased mortality after neonatal VAS (NVAS). WHO-Gates sponsored three NVAS trials with >100,000 children. The two African trials found slightly increased mortality, supporting our RCTs. We have posited that the negative effect of NVAS may be linked to NVAS enhancing female mortality after DTP vaccination (29). WHO has not made the final decision, but it is unlikely that NVAS will become policy, as it may be harmful under some circumstances. P5: Maternal immunity enhances the beneficial NSEs of receiving live vaccines One new insight in the OPTIMUNISE period has been the importance of maternal immunity in priming for positive NSEs of live vaccines in her offspring. Consistent with an enhancing effect of maternal immunity, vaccination earlier in life, when maternal immunity is more likely to be present, is associated with a much stronger beneficial effect for both OPV(45,105) and BCG(17). Maternal antibodies enhance the beneficial NSEs of MV: We examined whether maternal antibodies enhance the NSEs of MV. In two RCTs of early MV, Partners 1 and 2 measured measles antibody levels at vaccination. In contrast to current thinking that it is best to use MV after maternal antibody has disappeared, being vaccinated with MV in presence of maternal measles antibody enhanced the beneficial NSEs (12). This was not explained by confounding. Combining both RCTs, MV in the presence of maternal measles antibodies compared with no maternal measles antibody was associated with a 78% (36-93%) reduction in mortality between 4 months and 5 years of age (12). Maternal BCG-vaccination may enhance the NSEs of BCG: In a study from Guinea-Bissau, the reduction in mortality between 4 months and 3 years of age associated with having a BCG-scar was 46% (13-67%) when the mother also had a BCG-scar but only 24% (-17-51%) when the mother did not have a BCG-scar (81). [In a RCT in Denmark, BCG at birth had no overall effect on hospital admissions for infectious disease. However, among children of BCG-vaccinated mothers, randomisation to BCG-at-birth was associated with 35% (6-55%) lower risk of admission with an infectious disease, 23% (-1-42%) lower risk of atopic dermatitis, less parental-reported morbidity and fewer GP-visits up to 3 months of age] P6: Repeated doses of live vaccines enhance their beneficial NSEs Since the effect of primary MV and BCG seemed to depend on the existence of maternal immunity, we hypothesised that repeated doses of live vaccines (i.e. second and subsequent doses given in the presence of existing immunity) would enhance the NSEs. This turned out to be the case. Partner 1 reviewed available evidence for MV, BCG, OPV and Vaccinia. Repeated doses enhanced the beneficial effect on survival for all four vaccines (37). Since the first dose is protective or because there is no threat from the specific infection, these effects are clearly non-specific. MV: Two RCTs of early MV allowed comparison of two versus one dose of MV; two doses versus one dose reduced all-cause mortality by 63% (23-83%). CVIVA conducted the first studies of MV-campaigns and child survival. In both studies campaign-MV had a beneficial effect (HR=0.80 (0.64-0.96); HR=0.28 (0.10-0.77)); this effect was stronger among those who had previously received MV (HR=0.59 (0.36-0.99); HR=0.15 (0.04-0.63)). BCG: Two RCTs showed that BCG revaccination enhanced BCG’s protective effect against child mortality significantly. OPV: In campaigns in Guinea-Bissau, each additional dose of OPV reduced mortality by 13% (4-21%). In Denmark, the protective effect of OPV on admissions for infections increased with additional doses. Vaccinia: The protective effect of Vaccinia on survival and HIV-1 increased with the number of Vaccinia scars. The beneficial non-specific effects of live vaccines and the beneficial effect of boosting during campaigns could be a major reason for the development towards MDG4. The boosting mechanism (which needs to be studied mechanistically) may provide a large part of the explanation for why mortality has dropped so dramatically in the last 15-20 years in low-income countries. Since there has been far more OPV campaigns than MV campaigns, the largest part of the reduction is probably due to the OPV campaigns. This clearly raises the issue of what will happen when the OPV campaigns are stopped because polio has been eradicated. P7: Termination of live vaccines may lead to increases in morbidity and mortality One of the implications of the NSEs is that if a vaccine with beneficial NSEs is stopped after eradication, then one may do more harm by depriving all people of beneficial immune training than the good one did by protecting a few individuals from dying of the disease. Since polio, measles and rubella are likely to be eradicated in the coming decades and vaccinations may be stopped we examined what happened when smallpox was eradicated (1977) and vaccinia vaccine stopped (1980). From this perspective Partners 1 and 2 have been able to show both in Guinea-Bissau (115) and Denmark (116) that smallpox vaccination apparently had long-term beneficial effects on survival. Individuals in Denmark who were Vaccinia and BCG vaccinated in the 1970s had 46% (19-64%) lower mortality between school entry and 45 years of age from natural causes of death, whereas there was no association with accidents and suicides (116). We have also shown in Guinea-Bissau and Denmark that smallpox vaccination was associated with 35% lower risk of being HIV-1 infected (56). This experience may be critical now that we are about to stop OPV in 2020, and measles and rubella vaccines may be the next to follow. Partners 1 and 2 are about to start a cluster RCT of OPV and MV to document whether these campaigns have an impact on child survival and health in general. P8: Vaccines may have long-term imprinting effect on the immune system NSEs from a specific vaccine have been most pronounced while that vaccine is the most recent vaccination, and may change with the receipt of a new vaccine of a different type (see P4). However, some vaccines may also have long-term NSEs on health. Indications of this are the observations on beneficial NSEs of Vaccinia, which were seen even decades after smallpox vaccination was stopped (56). Another indication relates to BCG: Among BCG-vaccinated children a BCG-scar is a marker of beneficial long-term NSEs reducing mortality also after other vaccines have been given. There is no real indication that in the majority of cases BCG-scarring depends on the prior immunological status of the child. If BCG is administered by an experienced administrator 95-98% get a BCG scar (16, 38, 72). In rural Guinea-Bissau, only half of BCG-vaccinated children had a scar, most likely due to poor vaccination technique (17). Mortality at 0-4 years of age was 26% (4-44%) lower and hospital admissions were 26% (8-40%) lower for children with a BCG-scar compared with BCG-vaccinated children without a scar (17). In a meta-analysis of the effect of BCG-scar versus no BCG-scar among BCG vaccinated children, having a BCG-scar was associated with 46% (32-57%) lower mortality in the first year of life (17; 103; Roth 2005; Roth 2006; Garly 2003). The direct implication of this finding is that BCG-scarring could be used to monitor the quality of BCG vaccinations; increasing the proportion having a BCG-scar might have a strong impact on child survival. P9: Live and non-live vaccines have different effects on the innate immune system While OPTIMUNISE did not directly fund immunological studies, there has been a parallel research agenda where we have conducted immunological studies to find possible explanation for the non-specific effects. The suggestion so far is that live vaccines, BCG, vaccinia and Yellow Fever, induce innate immune training. In contrast, the non-live trivalent influenza vaccine (TIV) had opposite effects of BCG and induced innate tolerance; the same was the case for the non-live typhoid fever vaccine (TFV). Cost-effectiveness of health interventions Taking the NSEs into consideration will have major consequences for the estimated cost-effectiveness of intervention programmes. We have evaluated the cost effectiveness of the “restrictive vial opening policy” in Guinea-Bissau (14). In brief, the “restrictive vial opening policy” refers to the principles implemented in many low-income countries of only opening a vial of live BCG or MV, if there are a certain number of children present to be vaccinated. The reason is that these vaccines, once opened and dissolved, need to be used within 4-6 hours. Hence, opening a bottle for just one child will lead to high wastage rates. Countries are under pressure from donors to reduce wastage. Thus, in Guinea-Bissau and Burkina Faso, a 20-dose vial of BCG is only opened if there are 10-12 children present to be vaccinated with BCG, and a 10-dose vial of MV is only opened if there are 6-7 children present. In addition, for MV, since children only count in the statistics if vaccinated before 12 months of age, it is often required that 6-7 children between 9-11 months of age be present before a vial is opened. One OPTIMUNSE paper addressed the incremental cost-effectiveness of abandoning the restrictive MV policy, and providing MV to all children regardless of age and number of children present. Since 2011, the BHP has conducted a cluster-randomized trial, assigning children to either receive MV according to “the restrictive MV policy” or to receive MV regardless of age and number of children present (MV-for-all policy), in rural Guinea-Bissau. We used MV coverage estimates from this study to calculate the effect of the MV-for-all policy. We estimated the costs of delivering MV taking into account its positive non-specific effects and using different MV wastage scenarios; 40% wastage under the restrictive MV policy (at least 6 children vaccinated per vial) and 90% wastage under the MV for all policy. In the villages followed by Partner 2, MV coverage was 84% under the restrictive MV policy and 97% under the MV-for-all policy. Among 54,573 children born in Guinea-Bissau in 2011 and alive at 9 months of age, at 90% wastage, the MV-for-all policy was cost-effective at USD 10.7 per life year gained (LYG) and USD 282 per death averted. At 87% wastage, the MV-for-all policy was cost-saving (55). Information on household costs of seeking measles vaccination in Guinea-Bissau has been collected. Based on interviews with 1308 mothers of children aged 9-21 months living in rural Guinea-Bissau, on their experiences with seeking MV, we calculated the costs of- and time spent on seeking MV. We assessed the MV status of the children through the HDSS: 34% of children who were measles unvaccinated at time of interview had sought MV at least once and 19% of children already measles vaccinated had been taken for MV more than once. In total, 80% had gone for MV but the coverage was only 70%. Mothers on average took their child for MV 1.4 times, the cost of one time being USD 1.33 (41). Hence, with a restrictive vial policy, we may save some doses of vaccines, but we are also transferring the cost of going in vain to the parents. Furthermore, the result of the restrictive vial policy is lower coverage. The two first papers are focusing on different cost-implication of the restrictive vial policy (41,55). Further papers regarding the cost-effectiveness of measles vaccination campaigns, rotavirus vaccination and pneumococcal vaccination are in preparation by Partners 4, 1 and 2 (68-70,76). III. To evaluate in a randomised trial a specific modification of the current child health programme: To provide an additional measles vaccine at age 4.5 months, in addition to the recommended measles vaccine at age 9 months (WP5,WP6,WP8) Objective: To evaluate in a randomised controlled trial the effect on child survival and other health indicators of providing an additional dose of EZ measles vaccine as soon as possible after 4 months of age and before the standard measles vaccine at 9 months of age for children who have received DTP3 at least 4 weeks before (WP5,WP6). Within the early measles vaccination RCT (WP5-6) we planned to measure measles-specific antibody levels and test the effect of age and maternal measles-specific antibody levels at the time of the primary measles vaccination for the long-term measles-specific antibody level. The RCT of early two-dose MV strategies was conducted in Burkina Faso and Guinea-Bissau by Partners 1-3 and 5 (WP5,WP6). Partner 8 analysed the measles antibody samples in connection with these RCTs (WP8). WHO recommends the first dose of measles vaccination at 9 months of age in areas with measles transmission. The vaccination age is based on a compromise between the age at which the child is expected to lose its maternal measles antibodies (and therefore becomes susceptible) and avoiding vaccination in the presence of high levels of maternal antibodies (which blunt the antibody response to measles vaccine). However, the rationale behind this policy is based on numerous assumptions and extrapolations, rather than real data. When the current measles vaccination strategy was defined in the 1970s, most mothers had experienced measles infection. Mothers naturally infected with measles transmit higher levels of maternal antibodies to their children. However, most children are now born to mothers who have not had natural measles infection but received MV in childhood. They therefore transmit less measles antibodies to their children and the children may become susceptible to measles infection already by 3-4 months of age. For example, during an epidemic in Bissau, 4-5% of the children had had measles infection before they were enrolled in a trial of early MV at 4 to 5 months of age. Hence, the children are susceptible to measles infection much earlier now than when the policy was defined. In addition to protecting against measles infection, accumulating evidence both from observational studies and randomised trials indicates that MV has beneficial NSEs, lowering all-cause mortality due to other infectious diseases (see P1 above). In contrast, the non-live DTP vaccine is associated with increased mortality. The most recent vaccine profiles the immune system (35), hence by providing a live MV the negative effect of DTP may be abrogated. An early additional dose of MV may also have beneficial effects later, after the control group received MV. Accumulating evidence from observational studies suggest that additional doses of MV may lower all-cause mortality. In a trial of early MV from Guinea-Bissau, early MV was associated with 29% (-1-50%) lower mortality between 9 months and 3 years of age (119). To test these prior findings that an additional early MV dose could reduce all-cause mortality up to 3 years of age by 30-50% (119), OPTIMUNISE conducted an RCT. The RCT took place between July 2012 and May 2016 and tested the effect of an additional early dose of MV given 4 weeks after the third dose of pentavalent vaccine. It was conducted in the Nouna HDSS in Burkina Faso (Partners 3 and 5) and in three regions of the rural Bandim HDSS in Guinea-Bissau (Partners 2 and 1). In both countries BCG is recommended at birth together with oral polio vaccine (OPV), and 3 doses of pentavalent (DTP, hepatitis B and H. influenza type B) with OPV are recommended with 4 weeks intervals starting from age 6 weeks in Guinea-Bissau and age 2 months in Burkina Faso. At age 9 months children are scheduled to received MV and yellow fever vaccine (YF). A 13-valent pneumococcal vaccine was added to be given with pentavalent vaccine 1, 2 and 3 in Burkina Faso in November 2013 and in June 2015 in Guinea-Bissau. Rota virus vaccines were added to the vaccination programme in Burkina Faso in November 2013 (3 doses with pentavalent vaccine 1, 2 and 3) and in November 2015 (2 doses with pentavalent vaccines 1 and 2) in Guinea-Bissau. In October 2014 Burkina Faso introduced a second dose of MV at 15 months of age. In the RCT the children were enrolled and randomised at 4-6 months of age, 4 weeks after Penta3 scheduled at 14 weeks (Guinea-Bissau) or 4 months (Burkina Faso). To ensure timely vaccination and that children would be eligible to enter the study before 215 days, all children were visited at home every month to remind the mother to seek age appropriate vaccinations. Children aged 121-215 days were eligible for enrolment 4 weeks after Penta3 provided that they were registered as residents of the HDSSs. Potentially eligible children were visited at home. Mothers/guardians were explained that we were investigating whether an additional early dose of MV had beneficial effects on child mortality. Following the explanation of the study, mothers interested in participating were asked to seek the health centre/vaccination post on the same or subsequent day depending on site. At the vaccination post/health centre the mother/guardian was given information about the study orally and in writing. After the opportunity to ask and receive answers to questions, the mother/guardian was asked if she wanted her child to participate in the study and provided consent, she would sign the consent sheet. After consent the mother was interviewed on past hospital admissions and the health status of the child documented. Children were randomised 1:1 to early MV or no early MV in blocks stratified by sex. Following randomisation the child received either a standard dose of Edmonston-Zagreb measles vaccine (Serum Institute of India) or no vaccine. Since we were interested in testing the non-specific effects of the vaccine, we did not use a placebo vaccine which could also have had NSEs. The early MV dose was recorded on study forms, but the information was not transferred to the child’s vaccination card to ensure that it would not be mistaken as a 9 months MV or affect the health care of the child. All children were followed through the HDSS routines and at the first visit after 9 months of age the child was invited back to the vaccination post to receive the routine measles vaccine. In a subgroup of trial participants, we collected blood samples at enrolment, just prior to the 9 months vaccination and at 15 months (Burkina Faso) /24 months (Guinea-Bissau). Serum was analysed for measles antibody concentration using a multiplex assay by Partner 8. Prior studies have indicated that early measles vaccination is safe (47). Every third month the data safety and monitoring board received and reviewed extracted data containing the randomisation table, the identification numbers and dates of all registered deaths, hospital admissions and consultations within the first month after enrolment. A total of 8309 children were enrolled, 4559 in Burkina Faso and 3750 in Guinea-Bissau. 104 children were excluded due to protocol violations and all the remaining 8205 children were followed in the trial. The mortality rate in the trial was much lower than expected in Guinea-Bissau and slightly lower in Burkina Faso. We registered 145 deaths in the per-protocol analysis whereas the sample size calculation was based on 300 deaths. Mortality was similar in the intervention and control groups, the Hazard Ratio (HR) comparing the mortality rate in the intervention group versus the control group being 1.05 (0.75-1.46). The intention-to-treat analysis included 243 deaths and the HR was 1.12 (0.87-1.44). The results did not differ by sex. Blood samples were collected and analysed for 869 children and their mothers at enrolment. Antibody concentrations were described by geometric mean concentration and the log-transformed concentrations compared by group using Students t-test. Furthermore, we compared the proportion of samples with concentrations indicating protective levels using a cut-off of >=125 mIU/ml. Pre-vaccination antibody levels in children were low, only 21% (90/422) of children in Guinea-Bissau and 4% (16/447) of children in Burkina Faso had protective antibody levels at enrolment. At 9 months of age, there were only 14 children in the two control groups who had a protective measles antibody level. All of these children, except one, had an increase in antibody level between 4 and 9 months; presumably they had had an unregistered measles vaccination elsewhere or a measles vaccination in a campaign. Hence, with one exception, all children in both Burkina Faso and Guinea-Bissau had lost protective maternal antibody levels before 9 months of age. In both sites, early vaccinated children responded well to the vaccine and >=90% had protective antibody levels at 9 months of age. At final follow-up at 15/24 months, 97-100% was protected in both groups in both Bandim and Nouna. In Bandim 97% (96/99) had protective antibody levels after 2 doses of MV and 97% (102/105) after one dose at 9 months of age. In Nouna 100% (90/90) and 97% (94/97) had protective antibody levels after 2 and 1 dose of MV. The findings did not support that early MV reduces all-cause mortality. This could potentially be explained by the low mortality in the trial and by the frequent OPV campaigns with beneficial NSEs targeting all study children, potentially preventing the deaths, which the early MV would otherwise prevent. An interference and interaction between OPV campaigns and early MV was seen in the previous trial of early two-dose MV (45). Most children were susceptible to measles infection at 4-6 months and almost all children in the control group were susceptible at age 9 months. Children responded well to the early MV with high antibody levels. Since early MV did not seem to hamper the induction of lasting protective levels, a two-dose MV strategy with an early MV followed by MV at 9 months would improve measles immunity for the population. IV. To assess the relevance of different health outcomes parameters for the evaluation of the real life effect of child health programmes (WP9) Objective: To assess consistency and cost-effectiveness of different health outcomes for the evaluation of child health programmes in order to produce relevant comparable outcome parameters. Mortality is fortunately decreasing in Africa and it is becoming increasingly difficult and costly to measure the impact of health interventions on mortality. Hence, there is a need to identify reliable markers which are indicators of a good health and which are cheap and easy to measure, and can be used in future evaluations to assess whether current and new interventions are likely to have a positive effect (specific and non-specific) on health. The HDSSs collects different health outcomes as a part of the routine data collection: • Mortality. Reliable data on child mortality are available from all the HDSSs. • Morbidity. Mothers/caretakers are interviewed at home visits about medical consultations and hospitalisations. Routine data on consultations and hospitalisations are collected at the health care institutions where possible. • BCG-scarring. BCG-scars are registered and measured during the home visits. • Growth. Arm-circumference data are collected during the home visits. Partners 1 and 2 had the main responsibility for WP9 but other partners have and will contribute to WP9. This data has been used to assess the association between various morbidity outcomes (hospitalisation/consultations) and growth in relation to mortality. In addition, some immunological markers have been assessed as part of specific studies. Using this data, we have identified that hospitalisations to a limited extent overlap with mortality; hence, in a situation with decreasing mortality, a composite outcome of hospitalisations and mortality will be a powerful indicator of “bad health”. Furthermore, having a BCG scar is very closely linked with lower mortality, and in line with this observation, having a high IFN-gamma response to in vitro stimulation with PPD is associated with lower mortality. Hospital admissions. Previously, using data from an RCT of early MV (at 4.5 months of age) in Guinea-Bissau, Partners 1 and 2 have published that the effect of MV on mortality and hospital admissions are similar (7, 61, 107). OPTIMUNISE investigated these unique data on MV, hospitalization, and mortality more closely using event history analysis, competing risk methods, and mediation analysis techniques. It was found that effect of early MV on hospitalisation is not only another way of measuring mortality as many hospitalised children do not die. By dividing event of hospitalisation into severe and mild (with and without fatality), very equivalent effects of MV were found; MV reduced both type of events by around 30% in the interval 4.5 to 9-10 months of age. This clearly indicates that a composite outcome measure of hospitalisation and mortality is useful in future trials of NSEs of MV and possibly also other vaccines. BCG-scarring. We have confirmed previous observations that not having a BCG scar is a very strong marker of mortality (17,103). Since the same effect is found irrespective of whether 50% or 5% do not have a scar, it is unlikely that this effect mostly reflects that some children are immunologically “weaker” and therefore do not make a scar (as this proportion would not vary between 50% or 5%). In line with this, our studies confirmed that non-scarring is predominantly an issue of vaccination technique and strain of BCG vaccine (17,38). Hence, factors which affect BCG-scarring (strain, vaccination technique, amount of BCG injected intra-dermally (wheal size)) are per se determinants of mortality. The interesting implication, which has grown out of this project and was highly emphasised at the final stakeholder meeting is that it would be worthwhile to monitor BCG-scarring as an indicator of the quality of BCG vaccinations, which is a major determinant of mortality in its own right. As a consequence the OPTIMUNISE consortium has submitted a letter of intent (LOI) to EDCTP to further study how to optimize the use and monitoring of BCG vaccine to reduce infant mortality. Growth monitoring (50). Partners 1-3 and 5 intend to use the RCT and the careful monitoring of the growth of the children within the RCT to assess whether anthropometry is still a strong marker of severe morbidity/mortality. Most of the studies, which have been used to justify the focus on anthropometry, are from the period where mortality was still very high in low-income countries. Hence, we will use data from the current situation with low mortality to assess whether anthropometry is still a strong marker. Given the delay in finishing the RCT, these analyses are delayed. WE expect to be able to conduct the analysis in the beginning of 2017. Cytokine levels. Partners 1 and 2 have used immunological data obtained from subgroup studies to assess the correlation between in vitro cytokine production after stimulation with specific and non-specific antigens and mitogens and mortality, with the hope to identify immunological markers of a good survival probability. Unfortunately, we were not able to identify simple immunological markers. Maybe not surprisingly, the analyses showed that for most cytokines there was a U-shaped association with mortality – the risk was increased for both very high and very low cytokine responses (9). The only clear linear association was seen for the IFN-gamma response to PPD – the higher the response, the lower the mortality. The finding corroborates the observation that among BCG vaccinated children, developing a BCG scar and a large PPD response in vivo is associated with reduced all-cause mortality. It remains to be tested whether a strong response reflects an underlying stronger immune system or whether the association reflects that the children who were vaccinated correctly had better survival, i.e. a beneficial nonspecific effect of BCG. V. Conclusions: The NSEs of vaccines: Evidence and implications (WP11) Objective: To communicate more broadly the premises of the study in order to encourage more such studies, to disseminate the results of the study, to ensure all the major stakeholders are reached and engaged in the discussion of the results, and to the extent possible to assure that results are utilized through changes in policy. It was intended that the results of the studies conducted by OPTIMUNISE should be disseminated as widely as possible through conference presentations and publications. The final meeting of the consortium was therefore also a stakeholder meeting in which all Partners participated as well as several international agencies, national health authorities and industry. The OPTIMUNISE project has strengthened the evidence for the importance of NSEs: • We have corroborated that the live vaccines (BCG, MV and vaccinia) have strong beneficial effects for survival, the NSEs likely being more important than the specific effects. We have added information that the same is the case for OPV. • We have corroborated that the non-live DTP vaccine is associated with higher mortality, particularly for girls. We have shown that the same is the case for Penta and the new malaria vaccine RTS,S. • We have corroborated that vaccines and micronutrients very often have sex-differential effects; studies should not report only for “children” but for girls, boys and overall. • We have corroborated that vaccines and micronutrients very often interact; combinations and sequence have major consequence for survival. It cannot be assumed that specific interventions continue to have the same overall effect. Hence, continuing monitoring of efficacy is needed when new interventions are being introduced, as they are continuously. • We have discovered that priming from the mother is critical essential for stimulating the beneficial NSEs in the child. • We have discovered that boosting enhances the beneficial effects of live vaccines and may go a long way to explain the strong beneficial effects of the campaigns to eradicate polio and measles infections. Removing a live vaccine with beneficial NSEs after eradication could have major negative effects for child health in low-income countries. This problem may be important in relation to the approaching eradication of polio, measles and rubella infections. • There are also long-term programming effects of vaccination, which are only starting to be studied. Implications: The OPTIMUNISE project has shown that NSEs have numerous implications for evaluation of vaccination practices, cost-effectiveness assessments, research practices, and policy planning. Many practices for vaccinations, micronutrients and other interventions acquire a new meaning when they are seen from the perspective of NSEs. First, wastage and restrictive vial policy. To limit wastage of vaccine doses it has become policy in many national vaccination programmes to only open a multi-dose vial if a sufficient number children are present, usually 10-12 for BCG (20-dose vial) and 6-7 for MV (10-dose vial) (14). This will delay the age of vaccination and will ultimately lead to lower coverage as we have shown in several studies. Since BCG and MV have the strongest beneficial effect on mortality it is obviously unfortunate that these vaccines are delayed (or not given). The study by Partner 4 of the age of BCG vaccination in Navrongo clearly suggested benefits from always opening a vial of BCG (65). Second, combination and sequence of vaccinations interact. In the current programme missing vaccines are recommended to be given whenever there is an opportunity and there is no consideration of whether altered combinations or sequences have an effect. We have shown consistently that sequence matters. In general it would be advisable to have a live-vaccine-last policy. Until now MV has often been the last vaccine the children received. It is therefore of concern that WHO is planning a 2nd year of life platform for further vaccinations with several non-live vaccines, including booster DTP, Meningococcal vaccine, and possibly RTS,S malaria vaccine. Third, micronutrients and vaccine interact. The possible interactions between micronutrients and vaccines have been ignored but OPTIMUNISE has shown that vitamin A supplementation may have beneficial effects in some situations but also major negative effects in other situation (29). Fourth, sex-differential effects. We have repeatedly found sex-differential effects so all programmes should assess the intervention effect for both sexes. Fifth, quality of vaccines and vaccinations. Normally a vaccine is just considered given when it is administered according to the vaccination card. There may be a few children who have not responded with a protective antibody level but this has no general consequences for immunization practice. However, the data for BCG-scarring suggest that this is not correct for BCG. There is a major difference in survival depending on whether the child developed a scar or not. Hence, it would be logical to consider revaccination and to use BCG-scarring to monitor the quality of BCG-vaccination. Both vaccination technique and to lesser extent strain of BCG appears to have an effect (17,37). Sixth, monitoring indicators. Currently DTP3/penta3 is the most commonly used indicator for programme performance. Programme markers will naturally affect how the programme is performing and where it focuses (14). Given that DTP3 is associated with increased female mortality (48) this may have unfortunate consequences. The focus on DTP3 has deemphasized the importance of MV. The study of the fully immunized child (FIC) showed that delaying/not giving MV has strong negative effects for child survival (25). It would make much more sense to emphasize the vaccine indicators which are positively associated with survival, e.g. the age of and scarification after BCG vacation and the age and coverage for MV. The NSEs Endgame: WHO and the SAGE review The NSEs are not new products or new methods which can be assesses independently for their contribution to survival. If they were they would have been “sold” a long time ago and have improved child survival. NSEs are about how immune training or immune misdirection may affect child survival. The NSEs therefore also pose a major critique of assumptions underlying the current programmes for childhood interventions; because interventions interact, and may have negative effects, it becomes far more complex to find the optimal strategies. The NSEs question many WHO policies but since it is WHO which decide global health policies it also WHO which will decide how and to which extent it will use the NSEs. This is the basis for an ambivalent position. The WHO-SAGE review of the potential NSEs of BCG, DTP and MV on the survival of children under-five years of age has been a first major step by acknowledging that there are probably important NSEs. In this review there were strong beneficial effects of BCG and DTP the reduction in mortality being 47% (28-60%) and 46% (35-55%), respectively. However, the estimate for DTP went in the other direction being a 38% (-8-108%) increase in mortality. Hence, the effects of different vaccines were highly significantly different (P for the same effect of all vaccines<0.001; BCG versus MV p=0.92; BCG versus DTP, p<0.001; DTP versus MV, p<0.001. ) SAGE recommended further studies of the potential NSEs of vaccines and delegated the responsibility of prioritising further studies and protocol development to the IVIR-AC committee. Though two years have passed it has not been revealed which studies will be prioritised. So though the SAGE review does indicate an acknowledgement that NSEs may be important, it is still unclear how this perspective will be used by WHO. Perspectives In a world where NSEs are now increasingly acknowledged there are at least two different approaches. The WHO has requested more studies of NSEs of vaccines, but also emphasised that these studies should be randomised studies, as observational studies are prone to bias. RCTs are seen as the gold standard for assessing effects of interventions. This might be true in a “single solution” paradigm. However, if the NSEs perspective is pursued to its logical implications, the global health community needs to get beyond the “single solution” paradigm. From the perspective of OPTIMUNISE we need to assess the contextual conditions of interventions (45). We also need to recognise that effects are not necessarily constant, but may change with implementation or removal of other health interventions. Hence, we need not only other methods for determining the contextual conditions, but we need some form of continuous monitoring to assess whether intervention programmes continue to have the same effects. With OPTIMUNISE we have taken the first steps in demonstrating how this can be done through HDSSs within the INDEPTH Network. These sites provide a good platform for combining monitoring of real-life effects with research training of the next generations. Potential Impact: OPTIMUNISE: Potential impact Please provide a description of the potential impact (including the socio-economic impact and the wider societal implications of the project so far) and the main dissemination activities and the exploitation of results. The length of this part cannot exceed 10 pages. Potential impact: socio-economic impact – and wider societal implications The subject of OPTIMUNISE was how to reduce child mortality in the best and most cost-efficient way in resource-poor countries. An impact in this area could come from working with specific populations partially managing the health care system, from working with health policy makers at different levels to introduce new policies or change existing ones, and from working with other researchers and changing their perceptions of how evaluations of childhood interventions should be done. Study populations As described in the previous section, there has been a surprisingly sharp decline in under-five child mortality during the last 15-20 years. Though the three HDSS institutions in Burkina Faso, Ghana and Guinea-Bissau are not the main responsible for health care delivery to the affected populations, they have undoubtedly contributed to the process by maintaining focus and monitoring key indicators. OPTIMUNISE has also contributed to direct health care as part of the interventions studies going on in the study areas. The fact that OPTIMUNISE documented that we had actually reached MDG4 in two sites is important. It came as a total surprise in Guinea-Bissau and has given an empowering “feeling” that it is possible to do much more than is usually assumed. It has been discussed with INASA, the national institute of health in Bissau, to speed up the process of suggesting evidence-based policy changes to the ministry of health (MOH). [The process has slowed due to repeated changes of government]. It was also quite clear during the Stakeholder meeting in Ghana that it was the marked decline in mortality in Navrongo which caught the Ghanaian media attention. Showing this marked decline will also entail a responsibility to follow future changes when new interventions are introduced (e.g. IPV, RTS,S malaria vaccine, meningococcal vaccine) or existing ones are removed (e.g. OPV). Having documented the marked decline in specific populations provides an opportunity to study the process in greater details. The speed of the change fits poorly with current expectations about effects of different interventions. Hence, there is the possibility of obtaining a better understanding of the driving forces behind reaching MDG4 and we hope to use that opportunity in future research. Policy implications As described in the result section OPTIMUNISE has defined a whole series of areas where health intervention policies to reduce child mortality could be improved and which should therefore be taken into consideration in health policy planning and assessment. Some of these relate to changes in policy which could be implemented now and some relate to how assessment of interventions with vaccines and micronutrients should be carried out generally. The most important changes which could be done now with existing knowledge or a little bit of additional research are: • Live vaccines should be given earlier in life and with higher coverage since these vaccines tend to have beneficial non-specific effects (NSEs). • As far as possible it should be a live-vaccine-last policy, or in other words non-live vaccines should not be given with measles vaccine (MV) or after MV. • Live vaccines with beneficial NSEs should not be stopped because the targeted disease has been eradicated. • BCG-scarring could be used to monitor the quality of BCG vaccinations. • The restrictive vial policy for BCG and MV should be abandoned as it increases the age of vaccination and reduces the vaccination coverage. • DTP, the most commonly used non-live vaccine, may have an overall negative effect on child survival. This has not been contradicted by any study with assessment of vaccination status and prospective follow-up. Hence, ways should be found to minimize those negative effects, e.g. by co-administering a live vaccine or using a live vaccine shortly after the non-live vaccine. • The fact that we have documented declining maternal measles antibodies level and therefore a widening gap of measles susceptibility may help to test earlier measles vaccination. Principles for assessing the impact of health interventions • Non-live vaccine may have an overall negative effect on survival. Hence, every time a new non-live vaccine is introduced it should be examined that it is not associated with an overall negative effect. For example, this did not happen when RTS,S malaria vaccine was tested and we could document a long-term negative effect for girls (24,32). • Girls and boys react very differently to immuno-modulatory interventions. Possible sexdifferential effects of new (and old) interventions should therefore always be assessed • Interventions which act through the immune system may easily interact. Hence, it is necessary to always assess possible changes in effects due to interaction between existing and new interventions. • Interaction between interventions may also mean that intervention effects which were measured at one point in time may no longer be valid if important other interventions are implemented or stopped. Vitamin A supplementation (VAS) may no longer have the strong beneficial effect it was believed to have (29) and we were not able to confirm a major reduction in mortality with early measles vaccination. There is therefore also a need for trying to understand how different interactions may change the overall effects, e.g. DTP coverage for the effect of VAS and neonatal VAS (29) or the OPV campaigns for the effects of early measles vaccination (45). As a consequence we also need to continue to monitor the main interventions to assure that they still have the assumed effects. • The intervention programmes should use program indicators which are positively linked to the desired outcome, i.e. enhances child survival. The current situation in which the international programmes use DTP3 as main performance indicator is indefensible since DTP3 is linked to increased mortality, in particular female mortality (34,43,48,59). These policy implications are far-reaching given existing modes of implementing health interventions. As discussed briefly below, there are even wider implications of the OPTIMUNISE work. We are summarizing how far the OPTIMUNISE consortium has come in relation to health policy makers and the research community. Health policy makers Since NSEs of vaccines were first documented in 1990 in connection with the trials of high-titre measles vaccine (HTMV), it has been the headquarters of WHO and various WHO committees which have dealt with the possible NSEs of vaccines. The HTMV trials showed that a protective measles vaccine (HTMV) was associated with two-fold higher mortality for girls but not for boys, thus contradicting key assumptions in the immunization programme (35). WHO-experts initially maintained that it was impossible; the studies from Guinea-Bissau and Senegal had not been planned and there was no plausible biological mechanism. However, when the same trend was observed by American researchers on Haiti WHO withdrew HTMV. This experience generated the research which has led to more and more NSEs being detected for different vaccines, their sequence, their combinations and their interactions with micronutrients. The OPTIMUNISE consortium has moved this research agenda considerably forward as presented in the previous section on results. It has been important that WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) established a working group on the NSEs in 2012-2013 and commissioned a review of the NSEs of vaccines which was presented to SAGE in Geneva in April 2014. The review suggested that BCG and MV may have major beneficial effects halving mortality which is not related to tuberculosis and measles infections whereas the majority of studies suggested that DTP is associated with increased mortality. For MV the review recognized that there were clear indications of sexdifferential effects. Furthermore, out-of-sequence vaccinations had NSEs for survival. SAGE recommended further studies of the NSEs. Professor Benn from Partner 1 was a member of the SAGE’s working group; contributing to the review took a considerable part of partner 1’s time in 2013-2014. Though the SAGE review recognized several of our key observations, the review was still fraught with methodological problems particularly in relation to the analysis of the NSEs of DTP. The SAGE review said that though the majority of studies showed a detrimental effect of DTP (7/10) the studies were inconsistent because two studies showed a positive effect. SAGE also claimed that there was no sex-differential effect of DTP. The SAGE review included several studies with major survival or frailty bias. Due to lack of information some children get classified as “unvaccinated” because there is no information on their vaccination status. However, one of the key reasons for “lacking information” is that the child has already died. Due to such misclassification the mortality rate in the “unvaccinated” group becomes unnaturally high and as a result the estimated effect of DTP becomes very favorable. However, if we use only studies with registration of vaccination status as vaccinated or unvaccinated and prospective follow-up, then all studies show a negative effect of DTP, around two-fold higher mortality (34). These studies show also that DTP is associated with around 50% higher mortality for girls than for boys (48). Hence, OPTIMUNISE played a major role in pointing out these shortcomings in the SAGE review. It is obvious that the international organisations which are involved with general delivery of vaccines (WHO, GAVI, UNICEF) have major problems with the NSEs because the NSEs question many basic assumptions on which the current system is based. We have had contact with GAVI and UNICEF but both organisations refer all decisions regarding general policy to WHO-SAGE. This means that potential policy implications of OPTIMUNISE’s work have to be directed to WHO-SAGE. We have tried to maintain this discussion by writing brief reports about selected subjects, e.g. the beneficial NSEs of OPV, the potential increase in mortality associated with RTS,S malaria vaccine, and the faulty analysis of the impact of DTP (WHO-Letters-I to V). SAGE recommended further studies of the NSEs and transferred the matter to WHO’s implementation research committee (IVIR-AC) in April 2014. There have apparently been ongoing discussions in IVIR-AC about prioritization of the NSEs research question and the development of research protocols. However, OPTIMUNISE has not been made part of that process and the results of the discussions have not been made public so it is difficult to say at the moment to which extent OPTIMUNISE has influenced the WHO prioritization. As documented in WHO-Letters-II to IV, the new RTS,S malaria vaccine which is moderately effective against malaria may in fact be associated with higher overall long-term mortality (24) and in particular higher female mortality (32). The Global Advisory Committee on Vaccine Safety (GACVS) has defined female mortality as a danger-signal for the RTS,S malaria vaccine. Until now this may be our most specific immediate impact within the WHO system. The research we conducted before the OPTIMUNISE project showed that neonatal vitamin A supplementation was likely to have negative effects for female survival in areas with high vaccination coverage, possibly due to a negative interaction between NVAS and DTP (29). The subsequent trials conducted in Ghana and Tanzania with Gates and WHO funding supported no overall beneficial effect. In the meta-analysis of the African studies (where vaccination coverage is high) NVAS was associated with significant excess mortality (29). Though a final decision has not been made yet, it seems likely that NVAS will not become global policy. The work on the NSEs of vaccines will have contributed importantly to NVAS not becoming policy. We will keep SAGE, GACVS and WHO/UNICEF Steering Committee for Guidelines on vitamin A supplementation informed about new developments in the area of NSEs of vaccines and micronutrients. WHO did send a representative to the OPTIMUNISE stakeholder meeting in Accra August 2016. However, given that WHO has been ambivalent and reluctant to discuss priorities, we have to base future work on the assumption, that policy implications will have to be enacted through research networks showing consistent patterns which could entail major health benefits. Other researchers There has been considerably more interest among other researchers in terms of utilizing the potential implications of OPTIMUNISE’s work on the non-specific effects. Global health authorities have tended to dismiss the NSEs as biologically implausible but an increasing number of immunological studies are showing that both innate and adaptive immune mechanisms may enhance/diminish protection against unrelated infections. Several groups of immunologists in USA, Canada, Australia, Uganda, and Holland are working actively on possible mechanisms which would explain why vaccines have other effects than merely inducing specific-disease immunity (15). Research done in collaboration with the Dutch group has shown that live vaccines, like BCG and vaccinia, induce innate immune training. In contrast the non-live trivalent influenza vaccine (TIV) may have opposite effects and induced innate tolerance; the same was the case for the non-live typhoid fever vaccine (TFV). A network has been created for immunologists and epidemiologists who are interested in exploring the mechanisms of NSEs: the Optimmunize network (http://cviva.dk/Optimmunize.aspx). A group of researchers working with vaccines in the national public health institute in the Nordic countries (Finland, Sweden, Norway and Denmark) are seeking funding to study the possible NSEs of vaccines in high-income countries which have good vaccines registers and good registers for hospital admissions. Researchers from Holland and UK are also examining the possible NSEs of vaccines in high-income settings. Given the huge costs of health care in high-income settings it might have wide implications if it could be shown that changes in age of vaccination or sequence of vaccinations had implications for hospital admissions. It would be ironic if it was the health care costs in high-income countries – rather than the child mortality implications in low-income countries - that meant that the NSEs were taken into consideration because they were cost-effective. The OPTIMUNISE consortium is seeking funding to continue its work and a LOI has been submitted to EDCTP. The focus will be on how to optimize the beneficial effect of BCG studying such issues as the age of vaccination, the possibility of monitoring the quality of BCG vaccinations as measured by BCG scaring, and revaccination with BCG. A small network of PhD researchers and students within the INDEPTH has also been made and has shown excellent work documenting NSEs of vaccination in Ghana, Kenya, Bangladesh and Burkina Faso. It is expected that this group will continue and explore the potential NSEs of vaccines. Other activities are also planned within the INDEPTH Network. Since the HDSS sites have timely data from study populations sometimes 10 or 30 years back it is possible to trace the decline in mortality so we will seek collaboration to examine the road to MDG4, the effects of campaigns and what happen when the campaigns stops. Industry may also become interested. Sanofi and Merieux organized a meeting on the off-targeted effects of vaccination in June 2015 which Partner 1 helped to plan (33). GSK has organized a task force on the non-specific of vaccines which took part in the final stakeholder meeting in Accra August 2016. Wider implications The OPTIMUNISE work questions many basic assumptions for current childhood intervention programmes, for example, that there are only specific effects, that any vaccine with a protective effect is beneficial, that effects are the same for girls and boys, and that interactions between the interventions do not affect their main outcomes. We have maintained for a long-time that these assumptions are flawed and we have not been disproven. This may sound surprising but is actually fairly simple: The current public health paradigm for childhood interventions only examined the specific effects, e.g. that DTP protects against whooping cough, but not the wider health implication, e.g. that DTP enhance susceptibility to unrelated infections. Hence, it is actually possible – as supported by all data (34,35,43,48,59) – that DTP protects against whooping cough but also increases mortality from unrelated infections. Hence, the OPTIMUNISE work is part of a paradigm shift. Public health agendas should be defined based on solid data and health policies should be defined so that they optimize health. But the agendas are also part of bureaucracies which will defend the current system. OPTIMUNISE has strengthened the claim that the current policies are not the best, and with what we know at present, we could improve health. However, we also question basic assumptions and this is likely to be met by resistance. How one measures ‘potential impact’ in the middle of a paradigm shift is not self-evident. As described in the result section, the OPTIMUNISE emphasis on the NSEs of vaccines and micronutrients have generated many consistent patterns which will have far-reaching implications, for example, that non-live vaccines have negative effects for girls, that live vaccines usually have beneficial effects, that eradication campaigns with MV and OPV have had major beneficial effect on child survival and that stopping vaccination after eradication may be dangerous. Assuming these ideas are right they will presumably eventually win but it may take a long time. Main dissemination activities Conferences: Results from the OPTIMUNISE project have first been presented at scientific meetings at the local institutions and then at the annual meeting of INDEPTH Network to reach a wider audience of researchers working at HDSS sites and who would have the possibility of implementing studies in similar settings. Dr. A. Rodrigues from Partner 1 represented the consortium at the European Tropical Medicine Congress meeting in Basel September 2015. The European Commission had organized the meeting to discuss how research is utilised in policy. Christine Benn, Ane Fisker and Peter Aaby were invited as keynote speakers at several international meetings. Several members of the consortium have made presentations on the non-specific effects of vaccines and the work of the consortium in Geneva (September 2015), Paris (September 2015), Copenhagen (September 2015), Basel (September 2015), Bissau for EDCTP visit (October 2015), Bissau (October-November 2015), Addis Ababa (November 2015), Stockholm (November 2015), Copenhagen (March 2016), Leiden (May 2016), Johannesburg (August 2016), Accra (August 2016), Cape Town (August 2016), Cambridge (September 2016). Peter Aaby received an honorary doctorate from Universidade Nova de Lisboa in June 2015 for the work on the non-specific effects of vaccines. Publications: So far OPTIMUNISE has submitted 64 papers for publication in leading international journals: • 50 are published or accepted for publication, • 6 are in revision, • 9 are under review, • 17 papers are at various stages of being drafted Key results were presented the final stakeholder meeting held in the end of August 2016 in Accra. The power point presentations are available: http://indepthnetwork.org/projects/optimunise/optimunise-stakeholder-meeting (Deliverable 11) The consortium partners have within the last project period had invitations to write editorials or review articles for PNAS, Lancet, Trends in Immunology, Expert Reviews of Vaccines, Nature Immunology, and Tropical Medicine and International Health. Transactions of the Royal Society of Tropical Medicine published a special issue on the NSEs of vaccines. Other dissemination activities. We have used the press, radio or film to communicate the message that non-specific effects are important and that policy needs to take these effects into consideration. A Danish crime novel by Sissel Jo Gazan is based on our research about the nonspecific effects of vaccines. (http://salomonssonagency.se/php/book.ph p?lang=en&bookid=261). The book won the readers’ prize in Denmark in 2014 and has also been published in English (The Arc of the Swallow), American, German, and French. An Austrian and a German film team are currently making films about vaccines and have included the theme of non-specific effects of vaccines. Exploitation of results Intellectual property rights: There should no intellectual property rights in the form of patents in relation to the ideas presented here. The research results should become public domain. The data collected by the consortium will gradually be made available as data sharing once the results have been analysed by the consortium scientists. List of Websites: http://www.indepth-network.org/projects/optimunise

2017-04-10 10:37:16 de,en,es,fr,it,pl pubsum en report de,en,es,fr,it,pl sesam en 2923196 STATENS SERUM INSTITUT

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en 3548707 en 98247 261375 OPTIMUNISE de,en,es,fr,it,pl 852 FP7-HEALTH http://ec.europa.eu/research/health/index_en.html 846 FP7-COOPERATION 1401 EC 837 FP7 en 12586 HEALTH.2010.3.4-6 10252 HEALTH-2007-3.4 10249 HEALTH-2007-3 11416 HEALTH 852 FP7-HEALTH 846 FP7-COOPERATION 1401 EC 837 FP7 de,en,es,fr,it,pl ECO de,en,es,fr,it,pl MED de,en,es,fr,it,pl MBI en en,any /docs/results/261/261375/final1-final-report-optimunise-31-10-2016-version2-publishable-summary.pdf Denmark DK 223513128 en en 184307 261375-320-3 Project Context and Objectives:1. Publishable summaryProject 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)...

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 (www.indepeth-net.org) 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.

2016-06-16 12:39:54 en 2847846 STATENS SERUM INSTITUT

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en 3533877 en 98247 261375 OPTIMUNISE de,en,es,fr,it,pl 852 FP7-HEALTH http://ec.europa.eu/research/health/index_en.html 846 FP7-COOPERATION 1401 EC 837 FP7 en 12586 HEALTH.2010.3.4-6 10252 HEALTH-2007-3.4 10249 HEALTH-2007-3 11416 HEALTH 852 FP7-HEALTH 846 FP7-COOPERATION 1401 EC 837 FP7 de,en,es,fr,it,pl ECO de,en,es,fr,it,pl MED de,en,es,fr,it,pl MBI en en,any /docs/results/261/261375/periodic3-optimunise-54-month-report-main-section-version-3-first-part.pdf Denmark DK 223513128 en report en sesam de,en,es,fr,it,pl sesam en en 59015 261375-320-1 The many vertical health interventions led by WHO, UNICEF or other international organisations are undertaken with little attempt to assess their real life impact on health. Child health programmes in low-income countries are justified by their...

Project Context and Objectives: The many vertical health interventions led by WHO, UNICEF or other international organisations are undertaken with little attempt to assess their real life impact on health. Child health programmes in low-income countries are justified by their assumed impact on child survival and how they may contribute to reaching the Millennium Development Goals. However, the impact assessment is based on measurements of performance indicators, e.g. vaccination coverage, and assumptions about intervention efficacy and burden of disease. These assumptions are based only on studies of the target condition; e.g., a vaccine is evaluated for clinical protection against a specific disease. Correspondingly, assessments of cost-effectiveness are confined to disease-specific costs and savings. Observational studies and randomised controlled trials (RCTs) in several African countries have shown that this procedure is not reliable. First, vaccines and micronutrients may have either beneficial or negative non-specific effects (NSE), i.e. effects not explained by prevention of disease or deficiency. Second, NSE are frequently sex-differential. Third, interventions may interact producing stronger beneficial or negative effects; e.g., vitamin A given with diphtheria-tetanus-pertussis (DTP) may increase mortality for girls. Main objectives and progress: To test the real life impact and cost effectiveness of child health interventions, individual-based data on health intervention uptake and health outcomes are necessary. OPTIMUNISE takes advantage of the Health and Demographic Surveillance System (HDSS) sites in the INDEPTH Network. The HDSS sites can provide a platform for 1) assessing the real life effect and cost-effectiveness of interventions in observational studies; 2) testing modifications of current programs in RCTs, and 3) testing new interventions and interactions with existing interventions in RCTs. OPTIMUNISE is being implemented at three sites in Guinea-Bissau, Burkina Faso, and Ghana. OPTIMUNISE will test four hypotheses formulated in a recent paper about the beneficial NSE of measles vaccine (MV) about the negative non-specific and sex-differential effects of DTP vaccine. It is usually not considered ethical to test a health intervention recommended by WHO in randomised control trial which would mean withholding or delaying the intervention for some individuals. Hence, already recommended interventions can usually only be evaluated in observational studies. Hence, OPTIMUNISE has modified the current data collection systems at the 3 sites to include information on all routine and campaign interventions in childhood to conduct observational studies. Ongoing data collection will measure the effect of major child health programmes with vaccines (BCG, DTP, OPV, and MV) and vitamin A controlling for determinants of compliance. The first studies are submitted/published. It is hypothesized that OPTIMUNISE will show major beneficial effects of MV and BCG which will modify the cost-effectiveness of the current programme and will point to problems in the way the programme is currently implemented. It may be justified to test modifications of programs in RCTs and obtain unbiased estimates of the effect of certain aspects of a programme. Thus OPTIMUNISE has initiated a multi-centre trial to test an observation from a recent RCT: providing early MV at 4.5 and 9 months compared with MV at 9 months of age reduced overall mortality between 4.5 and 36 months of age by 50% for children who had not received vitamin A at birth. The Ghana Health Service Ethical Review Committee did not approve the trial in Ghana as they have recently introduced 3 new vaccines in the routine vaccination programme. The trial will therefore be conducted in rural areas of Burkina Faso and Guinea-Bissau with an enlarged sample size to compensate for the loss. The Ghanaian partner will extend their observational studies to examine the effect of the three new vaccines. Fortunately, mortality has declined in Africa and it may become more difficult to measure the impact of interventions. OPTIMUNISE intends to identify outcome parameters like hospitalisation which correlate with child mortality and which can be used to assess the overall health impact of interventions in future assessments. Potential applications: WHO is currently reviewing the non-specific effects of BCG, DTP and measles vaccine and it is therefore likely that more will happen in this area in the coming years. If the non-specific effects of vaccines are confirmed in our studies, it would imply large savings and major reductions in mortality in high-mortality areas. For example, this could be obtained by vaccinating earlier with BCG and measles vaccine, by giving several doses of BCG and measles vaccine, and by reducing the time that children are exposed to DTP as the most recent vaccination. Project Results: Consortium coordination (WP10). The first consortium meeting was held in Navrongo in April 2011. The meeting reviewed the scientific background and the scopes for the project and the management of the consortium. The second meeting was held in Nouna, Burkina Faso, in March 2012. This meeting covered all aspects of the project and with focus on the measles vaccine (MV) trials in WP5-7. Most partners were also present for the INDEPTH annual conference in Maputo in October 2011. Partner 7 has set up a webpage to cover the scientific background and to report the results (Deliverable 10). Routine data collection on childhood interventions (WP1-3). The project started with a workshop in Bissau in early 2011. The participants collecting routine data on health interventions for work package (WP) 1-3 were present (Partners 1-5). The scientific background related to the non-specific effects (NSE) of childhood interventions was reviewed. An initial introduction to survival analysis and statistical analysis in Stata was provided by partner 1 since survival analysis is the main instrument for assessing the relationship between interventions and health outcomes. There was a focus on preventing survival bias since many previous analyses are flawed by survival bias. The current data collection systems related to interventions at the 3 sites were reviewed and it was discussed how to standardise methodology. Agreement was reached on key features about 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. There have been 7 data collections rounds in urban Guinea-Bissau, 4 in rural Guinea-Bissau (WP1), 5 in Nouna (WP2) and 5 in Navrongo (WP3). 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). A workshop on “Logistic and survival regression analysis of epidemiologic data using Stata” was organised with the University of Ghana in January, 2012 (Henrik Ravn, Partner 1). The first analyses were presented at the conference in Maputo. All three sites have published/submitted papers related to vaccination coverage, implementation of programmes and consequences for child survival. Timeliness of vaccinations has improved considerably in recent years, particularly in Burkina Faso and Ghana. Data from both Ghana and Guinea-Bissau suggest that it is better for child survival to have MV than diphtheria-tetanus-pertussis (DTP) as the last vaccination. 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 finalised 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 has been approved by the respective ethical committees in Guinea-Bissau, Burkina Faso, Denmark, and Germany (Deliverable 5). However, the Ghanaian Health Services did not approve the study, partly because three new vaccines are currently being introduced in Ghana. The MV has been pilot tested successfully in Guinea-Bissau (Deliverable 6). Enrolment has been easier than initially thought. To cover the loss of enrolment in Ghana, we propose to increase enrolment in Burkina Faso and Guinea-Bissau. We have been delayed because the protocol writing and obtaining ethical and political approval took longer than originally planned, but the consortium is functioning well. Potential Impact: OPTIMUNISE consortium in collaboration with a DANIDA sponsored project will involve six sites in the monitoring of routine childhood interventions to measure the real life effects of the most common vaccines and micronutrient supplementation. It is expected that this will result in many studies supporting that non-specific effects (NSE) of these interventions are considerably more important than usually assumed and that these effects are often sex-differential. The current vaccination programme is not taking NSE into consideration focusing entirely on the specific effects of vaccines and the assumed disease burden. The data collected by the OPTIMUNISE is likely to establish a series of generalisations with potential major policy implications. These generalisations will probably include at least: • It is better for child survival to have measles vaccine (MV) rather than diphtheria-tetanus-pertussis (DTP) vaccine as the last vaccination. The first studies from Ghana and Guinea-Bissau have already supported this. The current vaccination programmes focus on increasing the coverage for DTP3 rather than for MV; hence, more children are now missing MV than DTP3. To improve child survival, MV should be given priority in the vaccination programmes. • Having DTP as the most recent vaccination 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 it is not permitted to administer DTP with or after MV. • 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. We expect that that the planned study will show that early BCG is also important for normal birth weight children. BCG vaccination is very often delayed in Africa because there is little focus on delivering BCG early and because most immunisation programmes have restrictions on using multi-dose vials of BCG for just a few children. • Vitamin A supplementation (VAS) may enhance the NSE 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. • Early MV at 4 month of age is associated with reduced morbidity and mortality. It is current WHO policy that the age of MV should increase to 12 months once measles 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. It is expected that OPTIMUNISE will show major beneficial NSE of MV 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. So far the official health care system has tended to dismiss the NSE as biologically implausible. However, this may be changing as an increasing number of immunological studies are showing that both innate and adaptive immune mechanism may provide protection (or enhance susceptibility) to unrelated infections (Trends in Immunology, requested review). Furthermore, the SAGE (Scientific Advisory Group of Experts) of the WHO immunisation programme is currently conducting a review of the non-specific effects of vaccines. Hence, the observations of OPTIMUNISE on the NSE may carry greater weight in the future and may help to shape the future global immunisation programmes to the benefit of children in low-income countries, helping to reach the MDG4 if not in 2015 then at least slightly later. List of Websites: http://www.indepth-network.org/index.php?option=com_content&amp;task=view&amp;id=1216&amp;Itemid=1074

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en 3513970 en 98247 261375 OPTIMUNISE de,en,es,fr,it,pl 852 FP7-HEALTH http://ec.europa.eu/research/health/index_en.html 846 FP7-COOPERATION 1401 EC 837 FP7 en 12586 HEALTH.2010.3.4-6 10252 HEALTH-2007-3.4 10249 HEALTH-2007-3 11416 HEALTH 852 FP7-HEALTH 846 FP7-COOPERATION 1401 EC 837 FP7 de,en,es,fr,it,pl ECO de,en,es,fr,it,pl MED de,en,es,fr,it,pl MBI en en,any /docs/results/261375/periodic1-optimunise-18-month-publishable-summary-revised-clean.pdf http://www.indepth-network.org/index.php Denmark DK 223513128 en report en sesam de,en,es,fr,it,pl sesam