title: Full-length Plasmodium falciparum circumsporozoite protein administered with long-chain poly(I·C) or the Toll-like receptor 4 agonist glucopyranosyl lipid adjuvant-stable emulsion elicits potent antibody and CD4+ T cell immunity and protection in mice.
abstract: The Plasmodium falciparum circumsporozoite (CS) protein (CSP) is a major vaccine target for preventing malaria infection. Thus, developing strong and durable antibody and T cell responses against CSP with novel immunogens and potent adjuvants may improve upon the success of current approaches. Here, we compare four distinct full-length P. falciparum CS proteins expressed in Escherichia coli or Pichia pastoris for their ability to induce immunity and protection in mice when administered with long-chain poly(I · C) [poly(I · C)LC] as an adjuvant. CS proteins expressed in E. coli induced high-titer antibody responses against the NANP repeat region and potent CSP-specific CD4(+) T cell responses. Moreover, E. coli-derived CS proteins in combination with poly(I · C)LC induced potent multifunctional (interleukin 2-positive [IL-2(+)], tumor necrosis factor alpha-positive [TNF-α(+)], gamma interferon-positive [IFN-γ(+)]) CD4(+) effector T cell responses in blood, in spleen, and particularly in liver. Using transgenic Plasmodium berghei expressing the repeat region of P. falciparum CSP [Pb-CS(Pf)], we showed that there was a 1- to 4-log decrease in malaria rRNA in the liver following a high-dose challenge and ~50% sterilizing protection with a low-dose challenge compared to control levels. Protection was directly correlated with high-level antibody titers but not CD4(+) T cell responses. Finally, protective immunity was also induced using the Toll-like receptor 4 agonist glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE) as the adjuvant, which also correlated with high antibody titers yet CD4(+) T cell immunity that was significantly less potent than that with poly(I · C)LC. Overall, these data suggest that full-length CS proteins and poly(I · C)LC or GLA-SE offer a simple vaccine formulation to be used alone or in combination with other vaccines for preventing malaria infection.
authors.affiliation: Vaccine Research Center and Cellular Immunology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kastenmüller
authors.forename: Diego A
authors.initials: DA
authors.lastname: Espinosa
authors.forename: Lauren
authors.initials: L
authors.lastname: Trager
authors.forename: Cristina
authors.initials: C
authors.lastname: Stoyanov
authors.forename: Andres M
authors.initials: AM
authors.lastname: Salazar
authors.forename: Santosh
authors.initials: S
authors.lastname: Pokalwar
authors.forename: Sanjay
authors.initials: S
authors.lastname: Singh
authors.forename: Sheetij
authors.initials: S
authors.lastname: Dutta
authors.forename: Christian F
authors.initials: CF
authors.lastname: Ockenhouse
authors.forename: Fidel
authors.initials: F
authors.lastname: Zavala
authors.forename: Robert A
authors.initials: RA
authors.lastname: Seder
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D004306:Dose-Response Relationship, Immunologic; D004655:Emulsions; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D008055:Lipids / Q000737:chemistry / Q000494:pharmacology*; D008288:Malaria / Q000517:prevention & control; D017780:Malaria Vaccines / Q000276:immunology; D051379:Mice; D030781:Organisms, Genetically Modified; D010843:Pichia / Q000235:genetics / Q000378:metabolism; D010962:Plasmodium berghei / Q000235:genetics / Q000378:metabolism; D010963:Plasmodium falciparum / Q000276:immunology* / Q000502:physiology; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000819:agonists*
chemical_list: D000913:Antibodies, Protozoan; D004655:Emulsions; D008055:Lipids; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C041595:circumsporozoite protein, Protozoan