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The current understanding of malaria burden in Africa relies on modelled estimates based on incomplete and outdated data. The WHO defines malaria disease surveillance as a central pillar of its Global Technical Strategy. The thesis examines the precision of existing models to predict malaria burden changes and interrogation of malaria metrics from health facility and community surveys on the Kenyan coast. Geostatistical, epidemiological models provide approximations of malaria disease burden but are rarely tested against empirical data. A systematic review included 93 health facility sites across Africa with a minimum of 5 complete years of temporal data. There was a broad congruence in the matched changes at 70 sites, but significant discordance at 23 sites which showed stagnated or upward trends. Data on the pathway from infection to death, necessary to parametrise models of morbidity and mortality risk are rare. Prospective 12-month surveillance at six health facilities, the county hospital and repeat surveys among 36 matched communities was used to describe the epidemiology of malaria in all age groups. Despite conditions of declining transmission intensity, immunity to disease and the fatal consequences of infection continue to be acquired in early childhood, faster than anti-parasitic immunity and without evidence of emerging burdens of severe malaria or mortality among young-older non-pregnant adults. The value of routinely collected data from health facilities to define malaria risk was explored at 36 health facility-community pairs. There was a direct non-linear polynomial relationship between passively detected fever test-positivity and traditional community-based parasite prevalence. Information obtained through routine testing of febrile patients for malaria was able to identify spatial and temporal heterogeneities of malaria risk. Routine data offers important insights into local malaria transmission patterns, disease burdens and changing patterns of disease. An increased effort is required to replace malaria burden models with empirical data.

Malaria remains an important cause of morbidity and mortality among children in sub-Saharan Africa despite recent reductions in malaria incidence in some parts of Africa. Current control tools face threats such as the emergence of drug resistant parasites and insecticide resistant mosquitoes. A malaria vaccine is needed to complement and/or replace existing tools in order to achieve better malaria control and eventually eliminate the disease. RTS,S/AS01E is the most clinically advanced pre-erythrocytic malaria vaccine candidate and is currently being tested in a phase III trial. The short-term efficacy of RTS,S/AS01E is known but the duration of protection is unknown. Furthermore, although RTS,S is protective, it is unclear which immunological assays predict efficacy: hence there are no known correlates of vaccine-induced protection against clinical malaria. In a randomized controlled trial, I assessed the efficacy of RTS,S/AS01E in children (5-17 months old) residing in Kilifi, Kenya, over 4 years of follow-up and determined the correlates of protection against clinical malaria. In order to examine the effect of variations in malaria exposure on vaccine efficacy, I developed an individual marker of malaria exposure calculated as distance-weighted prevalence of malaria infection within 1 km radius of every child. Over 4 years of follow-up, RTS,S/AS01E had an efficacy of 29.9% (95%CI: 10.3% to 45.3%, p=0.005) and 16.8% (95%CI: -8.6% to 36.3% p=0.18) against first and all malaria episodes, respectively (by intention to treat analysis). Vaccine efficacy waned over time and with increasing malaria exposure. RTS,S/AS01E efficacy was 43.6% (95% CI, 15.5 to 62.3) in the first year but was -0.4% (95% CI, -32.1 to 45.3) in the fourth year. Vaccine efficacy was 45.1% (95%CI 11.3% to 66.0%) among children with lower than average malaria exposure index, but 15.9% (95%CI -11.0 to 36.4%) among children with higher than average malaria exposure index. Despite waning in efficacy, RTS,S/AS01E averted 65 cases of malaria per 100 vaccinated children, with more cases averted among the children in the higher malaria-exposure cohort (78 cases per 100 vaccinated children) than those the low exposure cohort (62 cases per 100 vaccinated children). RTS,S/AS01E induced high titres of anti-CS protein antibodies and CD4+ T cell but not CD8+ T cell responses. Anti-CS antibody titres and the frequency of TNF-α producing CD4+ T cell responses were independently associated with protection from clinical malaria, and the combination of both anti-CS titers and TNF-α producing CD4+ T cell response satisfied the Prentice criteria for surrogate markers of protection. There was no association between avidity of RTS,S-induced anti-CS protein antibodies and protection from clinical malaria. Conclusions: RTS,S/AS01E efficacy against all episodes is 16.8% over the 4 years of follow-up. The vaccine efficacy wanes over time and with increasing malaria exposure. RTS,S/AS01E-induced TNF-α producing CD4 T cell and anti-CS protein antibody responses were independently associated with protection from clinical malaria. Anti-CS avidity did not predict protection from clinical malaria. Long-term follow-ups of malaria vaccine trials are essential in the evaluation of the longevity of vaccine efficacy.