Malaria is one of the major global public health concerns with 1.24 million deaths worldwide in 2010 (Murray, Rosenfeld et al. 2012). Sterile protection against malaria infection can be induced by multiple exposures to radiation-attenuated sporozoite (RAS) parasite forms in mice (Nussenzweig, Vanderberg et al. 1967) and humans (Clyde, Most et al. 1973), if the RAS remain sufficiently viable to invade hepatocytes (Nussenzweig, Vanderberg et al. 1967). Manufacturing of RAS has several technical hurdles to overcome to allow mass immunization (Seder, Chang et al. 2013), and therefore subunit vaccines have been the primary focus of development in recent decades. RTS,S, based on Pf circumsporozoite protein (PfCSP), the predominant sporozoite surface antigen, is the most advanced subunit candidate, but has shown only 31% efficacy against malaria episodes in Phase III testing (Agnandji, Tsassa et al. 2012), and therefore new subunit vaccine strategies are needed. CSP tolerant transgenic mice are also protected after RAS immunization, implicating additional pre-erythrocytic antigens as targets of sterile immunity (Gruner, Mauduit et al. 2007), (Mauduit, Tewari et al. 2010). We therefore sought to identify novel candidate pre-erythrocytic vaccine antigens (PEVA) that could add to the level of protection achieved with CSP immunogens alone. We assume that PEVA candidates are transcribed during liver stage (LS) development, and have used transcripomic data developed in our lab to identify such candidate antigens. LMIV has assessed the protective efficacy of some of these immunogens by DNA vaccination in rodent models of malaria. Our Primary Objective has been to down-select and prioritize the PEVA antigens that had emerged from our transcriptomic studies of liver stage (LS) parasites, and to transition an antigen or antigen combination superior to circumsporozoite surface protein (CSP) alone for evaluation as a PE vaccine antigen (PEVA) candidate in humans. We have achieved this goal by demonstrating significant superiority of CSP in combination with two of our novel antigens, over that of CSP alone, when delivered as DNA vaccinations in our two rodent models: P. yoelii in Balb/c and P. berghei in C57BL/6. We also have found that candidate PEVA antigens are recognized by CD8+ and CD4+ T cells in protected rodents and naturally exposed humans, and hypothesize that these cellular responses are critical for mediating protection. During the past year, we have shown that protection conferred by several of our novel PEVA antigens in mice is dependent on CD8+ T cells, because protection in these mice is lost or redcued when CD8+ T cells are depleted. During the past year, we have conducted extensive immunization and infection studies with African thicket rats, using different parasite rodent species (P. berghei, P. yoelii, P. chabaudi). These studies have demonstrated that it is more difficult to protect thicket rats than it is to protect laboratory rodents by immunization with whole sporozoite vaccines. Thus, thicket rats are more similar to humans, and as the natural host of P. berghei may be a more informative and rigorous model for determing which vaccines should proceed to testing in humans.
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