title: Protective antibody and CD8+ T-cell responses to the Plasmodium falciparum circumsporozoite protein induced by a nanoparticle vaccine.
abstract: BACKGROUND
  The worldwide burden of malaria remains a major public health problem due, in part, to the lack of an effective vaccine against the Plasmodium falciparum parasite. An effective vaccine will most likely require the induction of antigen specific CD8(+) and CD4(+) T-cells as well as long-lasting antibody responses all working in concert to eliminate the infection. We report here the effective modification of a self-assembling protein nanoparticle (SAPN) vaccine previously proven effective in control of a P. berghei infection in a rodent model to now present B- and T-cell epitopes of the human malaria parasite P. falciparum in a platform capable of being used in human subjects.
  
  
  RESULTS
  To establish the basis for a SAPN-based vaccine, B- and CD8(+) T-cell epitopes from the P. falciparum circumsporozoite protein (PfCSP) and the universal CD4 T-helper epitope PADRE were engineered into a versatile small protein (∼125 amino acids) that self-assembles into a spherical nanoparticle repetitively displaying the selected epitopes. P. falciparum epitope specific immune responses were evaluated in mice using a transgenic P. berghei malaria parasite of mice expressing the human malaria full-length P. falciparum circumsporozoite protein (Tg-Pb/PfCSP). We show that SAPN constructs, delivered in saline, can induce high-titer, long-lasting (1 year) protective antibody and poly-functional (IFNγ(+), IL-2(+)) long-lived central memory CD8(+) T-cells. Furthermore, we demonstrated that these Ab or CD8(+) T-cells can independently provide sterile protection against a lethal challenge of the transgenic parasites.
  
  
  CONCLUSIONS
  The SAPN construct induces long-lasting antibody and cellular immune responses to epitope specific sequences of the P. falciparum circumsporozoite protein (PfCSP) and prevents infection in mice by a transgenic P. berghei parasite displaying the full length PfCSP.
authors.affiliation: Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Kaba
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McCoy
authors.forename: Tais A P F
authors.initials: TA
authors.lastname: Doll
authors.forename: Clara
authors.initials: C
authors.lastname: Brando
authors.forename: Qin
authors.initials: Q
authors.lastname: Guo
authors.forename: Debleena
authors.initials: D
authors.lastname: Dasgupta
authors.forename: Yongkun
authors.initials: Y
authors.lastname: Yang
authors.forename: Christian
authors.initials: C
authors.lastname: Mittelholzer
authors.forename: Roberta
authors.initials: R
authors.lastname: Spaccapelo
authors.forename: Andrea
authors.initials: A
authors.lastname: Crisanti
authors.forename: Peter
authors.initials: P
authors.lastname: Burkhard
authors.forename: David E
authors.initials: DE
authors.lastname: Lanar
mesh_terms: D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018985:Epitopes, B-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D008288:Malaria / Q000276:immunology / Q000517:prevention & control; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D008969:Molecular Sequence Data; D053758:Nanoparticles / Q000008:administration & dosage / Q000648:ultrastructure; D010962:Plasmodium berghei / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D055503:Protein Multimerization; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000913:Antibodies, Protozoan; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D017780:Malaria Vaccines; C487838:PfCSP DNA vaccine; D015800:Protozoan Proteins; D019444:Vaccines, DNA