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Title: Models for measuring and predicting malaria vaccine efficacy
Author: White, Michael
ISNI:       0000 0004 2752 7072
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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In the past decade several candidate malaria vaccines have undergone clinical trials in artificial challenge studies and studies of natural infection under field conditions. GlaxoSmithKline’s RTS,S vaccine against Plasmodium falciparum infection has taken the lead, with Phase III trials in African children demonstrating 55.8% (97.5% CI, 51.3% - 59.8%) efficacy against clinical malaria and 34.8% (95% CI, 16.2% – 49.2%) efficacy against severe malaria. Mathematical models can contribute to multiple stages of malaria vaccine development, from measuring efficacy in clinical trials, understanding the relationship between naturally acquired and vaccine-induced immunity, identifying correlates of protection, and predicting the likely impact of vaccination programs in the field. When measuring vaccine efficacy in field trials under natural exposure to malaria, there are many factors which can bias estimates of efficacy. We demonstrate how heterogeneity in exposure can cause efficacy to be underestimated and heterogeneity in vaccine response can cause efficacy to be overestimated. Most infection-blocking vaccines rely on boosting some element of the pre-erythrocytic immune response, however the relationship between the naturally acquired pre-erythrocytic responses and protection from infection remains poorly understood. By analysing studies from a systematic of the published literature, I demonstrate that although many studies report a statistically significant relationship between cellular pre-erythrocytic immune responses and protection from infection, many studies do not have sufficient statistical power to evaluate the effects of the pre-erythrocytic immune response. Mathematical models are developed for investigating the relationship between pre-erythrocytic antibodies and protection from infection, and fitted to data from a longitudinal study of malaria infection in Kenyan adults. The relationship between antibodies to the antigens circumsporozoite protein (CSP) and thrombospondin-related adhesion protein (TRAP) and protection from infection is characterised using dose-response curves. Using data from an artificial challenge trial of the RTS,S malaria vaccine, I demonstrate that vaccine-induced protection from infection depends on both anti-CSP antibodies and CSP-specific T cells. I estimate that RTS,S causes a 97.7% (95% CI, 96.3% – 98/7%) reduction in the number of parasites entering the blood from the liver. The immune effector mechanisms determining the duration of vaccine-induced protection from infection are likely to be similar to those involved in naturally acquired immunity. Models of antibody kinetics were fitted to data from longitudinal studies of the antibody response to P. falciparum infection in Ghanaian and Gambian children, and the parameters determining the duration of antibody response are estimated. Upon licensure, a successful malaria vaccine is likely to be administered to young African children. A model of malaria transmission, extensively fitted to clinical data, is used to investigate the impact of vaccination in different transmission settings; the interaction between vaccines and other interventions such as insecticide treated nets; and the interaction between vaccination and naturally acquired immunity. Finally, the potential cost-effectiveness of vaccination is explored.
Supervisor: Ghani, Azra ; Griffin, Jamie Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral