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. 1. Eight of the PEVA candidates identified from previous antigen discovery efforts using transcriptomic data are being examined side by side with five PEVA candidates identified by GenVec, a local Biotech company. All the antigens are being immunized along with CSP to examine their ability to enhance CSP mediated protection. Both DNA prime Ad5 boost and protein prime Ad5 boost immunization regiments are being tried out, followed by challenge with sporozoites to examine the sterile protective ability of the CSP combinations. Data generated from these studies will help in down selection of antigens for further evaluation. 2. To discover Pre-erythrocytic Vaccine Antigens, Phage display libraries were generated using RNA extracted from fresh and axenically cultured Plasmodium falciparum NF54 sporozoites. 3. Human Sera from protected and non-protected individuals from Mali PfSPZ vaccine trial is currently being used to screen the libraries. Using the above two libraries and negative panning with non-protected individual sera and positive panning with sera from protected individuals, it will be possible to isolate both sporozoite specific and liver stage specific PE vaccine antigens.
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