EMR acknowledges funding from MVI/PATH, the MRC and the EviMalaR network (EU FP7)

EMR acknowledges funding from MVI/PATH, the MRC and the EviMalaR network (EU FP7). (95% CI, 93.4%C97.8%) reduction in the liver-to-blood parasite inoculum, indicating that in volunteers who developed infection, a small number of parasites (often the progeny of a single surviving sporozoite) are responsible for breakthrough blood-stage infections. Introduction Malaria continues to pose a serious public health challenge, with an estimated 655,000 malaria associated deaths every year [1], despite the large scale roll out of insecticide treated nets across the globe [2] and the switch to treatment with highly efficacious artemisinin combination therapies [3]. An efficacious malaria vaccine would be an invaluable addition to the range of currently available malaria control interventions. The malaria vaccine candidate RTS,S, targeting the pre-erythrocytic stages of has been shown to prevent malaria infection and clinical disease in Phase 2b field trials in infants [4]C[6], children [7], [8] and adults [9], [10] as well as more recently in a large Phase 3 trial underway in Africa [11]. RTS,S targets the circumsporozoite protein (CSP) and has been formulated with either of two different adjuvant systems; AS02 or AS01. In field trials where RTS,S/AS01 and RTS, S/AS02 have been directly compared, RTS,S/AS01 has been found to be more immunogenic [9], [12], [13]. Sporozoites inoculated into the skin via mosquito bite can be opsonised and immobilised by vaccine-induced anti-CSP antibodies as they migrate through tissue [14]. Sporozoites that reach the liver will invade hepatocytes where they undergo hepatic development. Hepatocyte invasion could potentially be prevented by anti-CSP antibodies [15]. Intracellular parasites can be targeted by vaccine-induced CSP-specific CD4+ T cells leading to Geldanamycin killing of the infected hepatocyte [16], [17]. After approximately 6.5 days of hepatic development [18], [19], merozoites will be released into the blood circulation to begin the erythrocytic stage of infection. When released from the RFC37 liver, merozoites undergo blood-stage replication causing an exponential increase in parasite numbers. Studies of early blood-stage infection in human volunteers have demonstrated that the smaller the liver-to blood inoculum, the longer the time taken for parasite density to reach a given threshold [20], [21]. Vaccination with RTS,S induces anti-CSP antibodies and CSP-specific CD4+ T cells that produce a mixture of cytokines (such as IL-2, TNF-, IFN-) and may also express the co-stimulatory molecule CD40L [17], [22]. Protection from infection and clinical disease has been shown to be associated with both naturally-acquired and RTS,S induced anti-CSP antibodies [23], [24]. CSP-specific CD4+ T cells have been associated with protection from infection in RTS,S vaccinated children [25] and in children with naturally-acquired immunity [26]. Characterising precise immunological surrogates of protection in field trials is, however, complicated by heterogeneous exposure to malaria, temporal changes in immune markers, and interactions with naturally-acquired immunity [27], [28]. Geldanamycin In contrast, challenge trials in malaria-na?ve adults provide an ideal opportunity to investigate the dose-response relationship between immune markers and protection from infection as the infectious dose can be controlled and the timing known, there is no naturally-acquired immunity, and immune markers can be measured on the day of challenge. Kester infectious mosquitoes [30]. The efficacy of Geldanamycin RTS,S/AS01 and RTS,S/AS02 against infection was estimated to be 50% (95% CI, 32.9%C67.1%) and 32% (95% CI, 17.6%C47.6%), respectively. Protected vaccine recipients had higher anti-CSP antibody titres (mean, 188 vs. 73 g/mL; P<0.001), and higher numbers of CSP-specific CD4+ T cells per million CD4+ T cells (median, 963 vs. 308 CSP-specific CD4+ T cells; P<0.001) than unprotected vaccine recipients. The study also demonstrated significantly higher levels of anti-CSP antibody titres and numbers of CSP-specific CD4+ T cells in those vaccinated with RTS,S/AS01 compared to RTS,S/AS02. Here we re-analyze the data to investigate in detail the association between RTS,S-induced anti-CSP Geldanamycin antibodies, CD4+ T cells and protection from infection using a biologically-motivated mathematical model of sprorozoite inoculation to estimate the probability of infection and the delay in onset of parasitemia due to vaccination. Our results provide insights into the likely mechanism of action of the RTS,S vaccine as well as providing a more generalised framework for assessing the efficiency of vaccines in early stage.