Lack of allele-specific efficacy of a bivalent AMA1 malaria vaccine

<p>Abstract</p> <p>Background</p> <p>Extensive genetic diversity in vaccine antigens may contribute to the lack of efficacy of blood stage malaria vaccines. Apical membrane antigen-1 (AMA1) is a leading blood stage malaria vaccine candidate with extreme diversity, potentially limiting its efficacy against infection and disease caused by <it>Plasmodium falciparum </it>parasites with diverse forms of AMA1.</p> <p>Methods</p> <p>Three hundred Malian children participated in a Phase 2 clinical trial of a bivalent malaria vaccine that found no protective efficacy. The vaccine consists of recombinant AMA1 based on the 3D7 and FVO strains of <it>P. falciparum </it>adjuvanted with aluminum hydroxide (AMA1-C1). The gene encoding AMA1 was sequenced from <it>P. falciparum </it>infections experienced before and after immunization with the study vaccine or a control vaccine. Sequences of <it>ama1 </it>from infections in the malaria vaccine and control groups were compared with regard to similarity to the vaccine antigens using several measures of genetic diversity. Time to infection with parasites carrying AMA1 haplotypes similar to the vaccine strains with respect to immunologically important polymorphisms and the risk of infection with vaccine strain haplotypes were compared.</p> <p>Results</p> <p>Based on 62 polymorphic AMA1 residues, 186 unique <it>ama1 </it>haplotypes were identified among 315 <it>ama1 </it>sequences that were included in the analysis. Eight infections had <it>ama1 </it>sequences identical to 3D7 while none were identical to FVO. Several measures of genetic diversity showed that <it>ama1 </it>sequences in the malaria vaccine and control groups were comparable both at baseline and during follow up period. Pre- and post-immunization <it>ama1 </it>sequences in both groups all had a similar degree of genetic distance from FVO and 3D7 <it>ama1</it>. No differences were found in the time of first clinical episode or risk of infection with an AMA1 haplotype similar to 3D7 or FVO with respect to a limited set of immunologically important polymorphisms found in the cluster 1 loop of domain I of AMA1.</p> <p>Conclusion</p> <p>This Phase 2 trial of a bivalent AMA1 malaria vaccine found no evidence of vaccine selection or strain-specific efficacy, suggesting that the extreme genetic diversity of AMA1 did not account for failure of the vaccine to provide protection.</p

Anaemia in a phase 2 study of a blood stage falciparum malaria vaccine

<p>Abstract</p> <p>Background</p> <p>A Phase 1-2b study of the blood stage malaria vaccine AMA1-C1/Alhydrogel was conducted in 336 children in Donéguébougou and Bancoumana, Mali. In the Phase 2 portion of the study (n = 300), no impact on parasite density or clinical malaria was seen; however, children who received the study vaccine had a higher frequency of anaemia (defined as haemoglobin < 8.5 g/dL) compared to those who received the comparator vaccine (Hiberix). This effect was one of many tested and was not significant after adjusting for multiple comparisons.</p> <p>Methods</p> <p>To further investigate the possible impact of vaccination on anaemia, additional analyses were conducted including patients from the Phase 1 portion of the study and controlling for baseline haemoglobin, haemoglobin types S or C, alpha-thalassaemia, G6PD deficiency, and age. A multiplicative intensity model was used, which generalizes Cox regression to allow for multiple events. Frailty effects for each subject were used to account for correlation of multiple anaemia events within the same subject. Intensity rates were calculated with reference to calendar time instead of time after randomization in order to account for staggered enrollment and seasonal effects of malaria incidence. Associations of anaemia with anti-AMA1 antibody were further explored using a similar analysis.</p> <p>Results</p> <p>A strong effect of vaccine on the incidence of anaemia (risk ratio [AMA1-C1 to comparator (Hiberix)]= 2.01, 95% confidence interval [1.26,3.20]) was demonstrated even after adjusting for baseline haemoglobin, haemoglobinopathies, and age, and using more sophisticated statistical models. Anti-AMA1 antibody levels were not associated with this effect.</p> <p>Conclusions</p> <p>While these additional analyses show a robust effect of vaccination on anaemia, this is an intensive exploration of secondary results and should, therefore, be interpreted with caution. Possible mechanisms of the apparent adverse effect on haemoglobin of vaccination with AMA1-C1/Alhydrogel and implications for blood stage vaccine development are discussed. The potential impact on malaria-associated anaemia should be closely evaluated in clinical trials of AMA1 and other blood stage vaccines in malaria-exposed populations.</p

Space-time clustering of childhood malaria at the household level: a dynamic cohort in a Mali village

BACKGROUND: Spatial and temporal heterogeneities in the risk of malaria have led the WHO to recommend fine-scale stratification of the epidemiological situation, making it possible to set up actions and clinical or basic researches targeting high-risk zones. Before initiating such studies it is necessary to define local patterns of malaria transmission and infection (in time and in space) in order to facilitate selection of the appropriate study population and the intervention allocation. The aim of this study was to identify, spatially and temporally, high-risk zones of malaria, at the household level (resolution of 1 to 3 m). METHODS: This study took place in a Malian village with hyperendemic seasonal transmission as part of Mali-Tulane Tropical Medicine Research Center (NIAID/NIH). The study design was a dynamic cohort (22 surveys, from June 1996 to June 2001) on about 1300 children (<12 years) distributed between 173 households localized by GPS. We used the computed parasitological data to analyzed levels of Plasmodium falciparum, P. malariae and P. ovale infection and P. falciparum gametocyte carriage by means of time series and Kulldorff's scan statistic for space-time cluster detection. RESULTS: The time series analysis determined that malaria parasitemia (primarily P. falciparum) was persistently present throughout the population with the expected seasonal variability pattern and a downward temporal trend. We identified six high-risk clusters of P. falciparum infection, some of which persisted despite an overall tendency towards a decrease in risk. The first high-risk cluster of P. falciparum infection (rate ratio = 14.161) was detected from September 1996 to October 1996, in the north of the village. CONCLUSION: This study showed that, although infection proportions tended to decrease, high-risk zones persisted in the village particularly near temporal backwaters. Analysis of this heterogeneity at the household scale by GIS methods lead to target preventive actions more accurately on the high-risk zones identified. This mapping of malaria risk makes it possible to orient control programs, treating the high-risk zones identified as a matter of priority, and to improve the planning of intervention trials or research studies on malaria

Risques climatiques et agriculture en Afrique de l’Ouest

Le futur de l’Afrique de l’Ouest dépend de la capacité du secteur de l’agriculture à s’adapter pour garantir la sécurité alimentaire dans un contexte de changement climatique et de croissance démographique. Pour faciliter cette adaptation, la recherche a déployé d’importants efforts pour améliorer les connaissances sur les mécanismes climatiques et leurs impacts sur les systèmes agropastoraux. Or, ces avancées issues de la recherche ne sont que rarement prises en compte dans la planification et la prise de décision. Partant de ce constat, un projet de recherche « Agriculture et gestion des risques climatiques : outils et recherches en Afrique », soutenu par le ministère français des Affaires étrangères et du Développement international est mené entre 2016 et 2018 dans plusieurs pays d’Afrique de l’Ouest. Il a pour objectif d’élaborer des outils efficaces de gestion du risque climatique pour les agriculteurs, en co-construisant avec des réseaux de chercheurs et d’acteurs directement impliqués dans l’accompagnement de l’agriculture des stratégies innovantes basées sur les résultats de la recherche. Cet ouvrage restitue les principales avancées de cette recherche-action sur trois thématiques prioritaires : les services climatiques pour l’agriculture, la gestion des ressources en eau et l’intensification écologique. Il permet aux acteurs du secteur agricole (organisations paysannes, filières, secteur privé agricole, banques de développement agricole, fournisseurs d’intrants, services agricoles et de météorologie) de s’approprier de nouvelles connaissances et de nouveaux outils pour une meilleure prise en compte des risques climatiques dans la gestion des systèmes de production