Resumen de The epidemiology of malaria in mozambique: implications for malaria vaccine trials design and interpretation
Malaria continues to be the number one cause of death in young children in sub-Saharan Africa and an obstacle for economic development in endemic areas. The objective of this thesis is to improve our understanding of the epidemiology of malaria, particularly its clinical presentation and health services use, and to explore the impact of trial design on the assessment of vaccine efficacy and duration of protection. The thesis is presented as a collection of four articles published in peer-reviewed international journals on work conducted at the Barcelona Centre for International Health Research (CRESIB/Hospital Clínic) and at the Centro de Investigação em Saúde de Manhiça (CISM), in Mozambique. The first two articles are related to the burden of disease. The other two articles are related to malaria vaccine development and trial design.
Estimating the burden of disease is challenging, as health information systems in most endemic areas are weak or non-existent and a high percentage of cases and deaths occur outside health facilities. Describing malaria cases attending health services contributes to quantify the burden and describe the epidemiology and clinical presentation, giving information that may guide policy makers. The first article presents a review of the global burden of malaria, including not only the burden of disease but also the economic and social burden that malaria exerts in endemic countries. The second paper is the first study to present a comprehensive set of data on the clinical presentation and burden of disease at a rural district hospital in Mozambique. The paper presents a retrospective analysis of data collected through the morbidity surveillance system on all paediatric visits to two outpatient clinics from June 2003 to May 2005.
Anti-malarial vaccines would be a major tool to contribute to malaria control in Africa, and it is likely that the next decade will witness registration of the first one. In the third article methodological issues concerning the conduct of malaria vaccine trials and the main obstacles in the development of malaria vaccines are discussed. A summary of the different phases of a clinical development plan and a discussion on the different target populations -including children and pregnant women from endemic areas and non-immune adults- are presented.
RTS,S/AS is the most advanced candidate malaria vaccine. The pre-erythrocytic malaria vaccine RTS,S/AS02A has shown to confer protection against clinical malaria for at least 21 months in a IIb randomized controlled trial in Mozambican children aged 1 to 4 years. Efficacy varied between different endpoints, such as parasitaemia or clinical malaria; however the underlying mechanisms that determine efficacy and its duration remain unknown. In the fourth paper we performed a new, exploratory analysis, not included in the original protocol, of data from that trial to explore differences in the duration of protection among participants to better understand the protection conferred by RTS,S. It is hypothesized that the long-term protection against clinical disease observed in cohort 1 is a consequence of a partially protective vaccine-induced pre-erythrocytic immunity that lasts several weeks and limits the number of viable sporozoites and merozoites, leading to a prolonged exposure to low-dose asexual blood-stage parasites that allows the acquisition of a long-lasting asexual blood-stage immunity.
In summary, this thesis contributes to advance malaria control by providing information that may guide policy makers on the burden and age pattern of disease in southern Mozambique, and by putting forward a hypothesis that can lead to improvement in the understanding of the mechanism of action of pre-erythrocytic malaria vaccines or the design of malaria vaccine trials.
