Identification of novel pre-erythrocytic malaria antigen candidates for combination vaccines with circumsporozoite protein

Cate Speake, Alexander Pichugin, Tejram Sahu, Vlad Malkov, Robert Morrison, Ying Pei, Laure Juompan, Neta Milman, Stasya Zarling, Charles Anderson, Sharon Wong-Madden, Jason Wendler, Andrew Ishizuka, Zachary W. MacMillen, Valentino Garcia, Stefan H.I. Kappe, Urszula Krzych, Patrick E. Duffy

Research output: Contribution to journalArticle

Abstract

Malaria vaccine development has been hampered by the limited availability of antigens identified through conventional discovery approaches, and improvements are needed to enhance the efficacy of the leading vaccine candidate RTS,S that targets the circumsporozoite protein (CSP) of the infective sporozoite. Here we report a transcriptome-based approach to identify novel pre-erythrocytic vaccine antigens that could potentially be used in combination with CSP. We hypothesized that stage-specific upregulated genes would enrich for protective vaccine targets, and used tiling microarray to identify P. falciparum genes transcribed at higher levels during liver stage versus sporozoite or blood stages of development. We prepared DNA vaccines for 21 genes using the predicted orthologues in P. yoelii and P. berghei and tested their efficacy using different delivery methods against pre-erythrocytic malaria in rodent models. In our primary screen using P. yoelii in BALB/c mice, we found that 16 antigens significantly reduced liver stage parasite burden. In our confirmatory screen using P. berghei in C57Bl/6 mice, we confirmed 6 antigens that were protective in both models. Two antigens, when combined with CSP, provided significantly greater protection than CSP alone in both models. Based on the observations reported here, transcriptional patterns of Plasmodium genes can be useful in identifying novel pre-erythrocytic antigens that induce protective immunity alone or in combination with CSP.

Original languageEnglish (US)
Article numbere0159449
JournalPloS one
Volume11
Issue number7
DOIs
StatePublished - Jul 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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