Clinical development of RTS,S as a vaccine for the prevention of malaria in Mozambican children

  1. Sacarlal, Jahit
Dirigida por:
  1. Carlos Ascaso Terrén Director/a
  2. Pedro L. Alonso Director/a

Universidad de defensa: Universitat de Barcelona

Fecha de defensa: 13 de julio de 2009

Tribunal:
  1. Mª Teresa Jiménez de Anta Presidente/a
  2. Xavier Carné Secretario/a
  3. Ángel Gil de Miguel Vocal

Tipo: Tesis

Teseo: 285047 DIALNET lock_openTDX editor

Resumen

Malaria is caused by protozoan parasites of the genus Plasmodium, Plasmodiidae family, transmitted to humans through the bite of infected female Anopheles.spp mosquitoes. It is one of the major global public health problems and an important cause of death in young children in Subsaharian Africa.Malaria is both a cause and a consequence of poverty. It best represents the paradigm of the vicious circle of disease and poverty. Recent estimates suggest that malaria alone costs about 12 billion US dollars to the endemic countries of Africa, and therefore represents a major constraint to economic progress. Today, Africa continues to carry the brunt of the global malaria burden with around 350-550 million clinical episodes and between 700.000 and 1.6 million deaths annually, representing 80-90% of the all malaria deaths in the world, mostly in children younger than five years and pregnant women. Estimates of malaria mortality are rather imprecise. However, describing the contribution of malaria to under five mortality is a very important and relevant objective. It improves the precision of our burden estimate, and helps prioritize and guide control efforts, as well as evaluate its impact. However in rural areas of Africa such as Mozambique, many children are born and die without ever being registered, and a significant proportion of all deaths take place outside health facilities. In this scenario, the only way of estimating the likely cause of death is through an interview of a witness of the final illness. This is called a verbal autopsy (VA).The last decades have witnessed the establishment of a network of centres throughout the continent that include continuous demographic surveillance of defined populations, the so called Demographic Surveillance Sites (DSS). The DSS have been established to record prospectively demographic information, including births and deaths, to investigate epidemiological and social determinants, and to provide a platform on which to undertake large-scale community interventions trials.The first article of this thesis describes 10 year data from the Manhiça DSS on the most frequent causes of mortality in children under 15 years of age, between 1997 and 2006. During this period, 10037 deaths were recorded, of which 3730 were recorded in children under 15 years old. Verbal autopsy interviews were conducted for 3002 (80.4%) of these deaths. According to respondents, 54% of deaths occurred outside a health facility. Overall, malaria accounted for 22% of all deaths, but the relative frequency was highest in children 1 to 4 years of age, accounting for 34% of all deaths corresponding to a mortality rate of 6.1 deaths/1000 pyrs.The last decade has witnessed a renewed effort in the study and control of this disease. New tools are becoming available, and the development of a vaccine is considered a potentially key component for improved control.GlaxoSmithKline (GSK) Biological's RTS,S,AS02A is a currently the world's most clinically-advanced malaria vaccine candidate. RTS,S/AS02A specifically targets the pre-erythrocytic stage of P. falciparum, and has been shown to confer protection against P. falciparum infection, delivered via laboratory-reared infected mosquitoes, in immunised malaria naive volunteers and against natural infection in semi-immune adult and immune children.As part of the clinical development plan, we conducted a Proof of Concept randomised, controlled, phase IIb trial of RTS,S/AS02A in 2022 Mozambican children aged 1-4 years living in a rural endemic area of Mozambique. The initial double blind phase included study months 0 to 8.5 and the single blind phase from study months 8.5 to 21. The open phase included study months 21 to 45. Children were randomised in a 1:1 ratio to receive RTS,S/AS02A or the control vaccines. The RTS,S/AS02A was administered intramuscularly in the deltoid region according to a 0, 1, and 2 month schedule. Children aged 24 months and older in the control group received three paediatric doses (0.5 ml) of Engerix-B . Children under 24 months received two paediatric doses of Prevenar , administered at the first and third vaccinations and one dose of Hiberix , at the second vaccination. Good safety profile and immunogenicity has been confirmed. Considering the entire follow up period of 45 months, Vaccine Efficacy (VE)(2.5-45) against first or only episode of clinical malaria disease was 30.5% (95% CI 18.9-40.4; p=<0.001), and VE against severe malaria was 38.3% (95% CI 3.4 to 61.3; p=0.045).These results highlight the feasibility of developing a malaria vaccine that may protect children against malaria, and may therefore be a useful component of the strategies to improve malaria control.