Pre-erythrocytic vaccine antigen (PEVA) candidates are transcribed during liver stage (LS) development. PEVA immunogens are recognized by CD8+ and CD4+ T cells in protected rodents and naturally exposed humans. The LMIV Pathogenesis and Immunity Section and SBRI have assessed the protective efficacy of some of these immunogens after DNA vaccination in rodent models of malaria. Our next objective is to establish the nonhuman primate and human models of protective pre-erythocytic immunity for further studies, to identify additional antigens that may be contributing to protective pre-erythrocytic immunity, and to assess the efficacy of leading immunogens in animals models that can guide the prioritization of those antigens to be tested in humans. During the past fiscal year, LMIV scientists have accomplished the following: 1. Completed pilot studies of nonhuman primate models of pre-erythrocytic malaria immunity, using whole organism and subunit vaccine strategies. We have determined that rhesus monkeys can be protected against P. knowlesi infection by whole organism vaccination, and also that CD8 T cell responses against 2 of our novel PEVA antigens are associated with reduced blood stage burden of malaria after sporozoite challenge. 2. Identified 2 additional candidate pre-erythrocytic antigens that confer protection against liver stage malaria in rodent models. 3. Determined that naturally exposed African children who develop CD8 T cell interferon gamma responses against leading PEVA antigens, demonstrate reduced risk of malaria infection during followup. This observation is being confirmed in another season of followup. 4. Established a flow cytometry based method to measure the effect of antibodies to block malaria parasites from infecting liver cells.

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Speake, Cate; Pichugin, Alexander; Sahu, Tejram et al. (2016) Identification of Novel Pre-Erythrocytic Malaria Antigen Candidates for Combination Vaccines with Circumsporozoite Protein. PLoS One 11:e0159449
Davies, D Huw; Duffy, Patrick; Bodmer, Jean-Luc et al. (2015) Large screen approaches to identify novel malaria vaccine candidates. Vaccine 33:7496-505
Sahu, Tejram; Lambert, Lynn; Herrod, Jessica et al. (2015) Chloroquine neither eliminates liver stage parasites nor delays their development in a murine Chemoprophylaxis Vaccination model. Front Microbiol 6:283
Herrera, Raul; Anderson, Charles; Kumar, Krishan et al. (2015) Reversible conformational change in the Plasmodium falciparum circumsporozoite protein masks its adhesion domains. Infect Immun :
Hobbs, Charlotte V; Neal, Jillian; Conteh, Solomon et al. (2014) HIV treatments reduce malaria liver stage burden in a non-human primate model of malaria infection at clinically relevant concentrations in vivo. PLoS One 9:e100138
Murphy, Jittawadee R; Weiss, Walter R; Fryauff, David et al. (2014) Using infective mosquitoes to challenge monkeys with Plasmodium knowlesi in malaria vaccine studies. Malar J 13:215
Hobbs, Charlotte V; Dixit, Saurabh; Penzak, Scott R et al. (2014) Neither the HIV protease inhibitor lopinavir-ritonavir nor the antimicrobial trimethoprim-sulfamethoxazole prevent malaria relapse in plasmodium cynomolgi-infected non-human primates. PLoS One 9:e115506
Talley, Angela K; Healy, Sara A; Finney, Olivia C et al. (2014) Safety and comparability of controlled human Plasmodium falciparum infection by mosquito bite in malaria-naïve subjects at a new facility for sporozoite challenge. PLoS One 9:e109654
Hobbs, Charlotte V; De La Vega, Patricia; Penzak, Scott R et al. (2013) The effect of antiretrovirals on Plasmodium falciparum liver stages. AIDS 27:1674-7
Hobbs, Charlotte V; Voza, Tatiana; De La Vega, Patricia et al. (2012) HIV nonnucleoside reverse transcriptase inhibitors and trimethoprim-sulfamethoxazole inhibit plasmodium liver stages. J Infect Dis 206:1706-14

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