Vaccine. parasites neither boosts existing 3D7-specific T cell responses nor appears to immune divert cellular responses towards the Wellcome allele. INTRODUCTION The development of highly effective cross-strain immunity against infectious pathogens remains the universal goal for all those vaccine developers. This is no less true in the case of the apicomplexan parasite C the causative agent of the most severe and deadly form of human malaria. Like most difficult infectious pathogens, the high level of antigenic variation and polymorphism displayed by this parasite in endemic areas frequently poses a huge challenge in the context of IQ 3 effective subunit vaccine development (1, 2). Antigens expressed during the blood-stage parasite contamination, such as merozoite surface protein 1 (MSP1) (3) and apical membrane antigen 1 (AMA1) (4), remain leading targets for inclusion IQ 3 in subunit vaccine candidates. These two antigens have been associated with protective immunity in naturally-exposed individuals (5-7), as well as proving efficacious in pre-clinical vaccine studies of mice (8-10) and non-human primates (11-14). Although protective blood-stage immunity has been widely associated with antibody responses, a growing body of evidence in both animal and human studies supports a contributing role for cellular immunity (15, 16). Although infected erythrocytes lack MHC molecules with which to present parasite-derived peptides, it is thought that effector CD4+ T cells can enhance clearance of opsonized parasitized red blood cells (pRBCs) by macrophages in the spleen; orchestrate the induction of parasiticidal pro-inflammatory serum cytokine responses; and/or provide polarizing help for B cells leading to the induction of protective cytophilic IgG subclasses that may better interact with innate cellular effectors such as monocytes or neutrophils (17, 18). CD8+ T cells have been shown to be protective in the mouse model at both the liver-stage (19, 20) and blood-stage of malaria contamination (21). CD8+ T cells specific for blood-stage antigens potentially target merozoite derived antigens during the late stages of pre-erythrocytic parasite development within infected hepatocytes (20). We have thus aimed to develop clinically-relevant subunit vaccine delivery platforms that are capable of inducing antibody responses against the transgene of interest in conjunction with strong cellular immunity (22, 23), and in a recent series of Phase I/IIa clinical trials in Oxford, UK we have shown that viral vectored delivery of the MSP1 and AMA1 blood-stage malaria antigens can achieve this goal (24, 25). In these trials, the two antigens were separately delivered utilizing a heterologous IQ 3 prime-boost immunization regime consisting of a priming vaccination with a recombinant replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) vector, followed eight weeks later by a boosting vaccination with an attenuated modified vaccinia virus Ankara (MVA) vector recombinant for the same antigen (Physique S1). This regime was shown to be safe and immunogenic for both antibody Sntb1 and T cell responses in healthy adult human volunteers and, when the vectors for both antigens were co-administered, sterilizing efficacy was observed in 1/9 individuals against controlled human malaria contamination (CHMI) with vaccine homologous 3D7 strain sporozoites (26). Importantly, antibodies against MSP1 and AMA1 have been shown to elicit vaccine-strain specific IQ 3 efficacy in non-human primate studies (12, 14) as well as most recently humans, in the case of a monovalent 3D7 strain AMA1 protein/adjuvant vaccine tested in Malian children (27). Attempts to address this issue of antigenic polymorphism have involved the development of multivalent vaccine formulations made up of multiple allelic variants of the MSP1 or AMA1 target antigen (28-30) or artificial diversity covering consensus sequences (31). Similarly, both of the viral vectored vaccine transgene inserts had been previously designed to address the issues surrounding target antigen polymorphism by encoding bi-allelic vaccine inserts for AMA1 (32, 33) and MSP1 (34, 35). Although these strategies aim to confront the difficulties surrounding the induction of cross-strain humoral immunity, other reports have raised important concerns about this approach in the context of T cell immunity (36). Such studies utilizing malaria antigens have concluded that inclusion of multiple allelic variants in a vaccine may be detrimental to both the priming and re-stimulation of antigen-experienced T cells (37, 38). These immunological studies arose from questions relating to the population dynamics of natural malaria contamination, host-parasite co-evolution and how allelic dimorphisms are maintained. Although the population of parasite strains circulating in an endemic population will be influenced by host human leukocyte antigen (HLA) type and other genetic factors, studies of parasite populations have.