title: Rhesus macaque and mouse models for down-selecting circumsporozoite protein based malaria vaccines differ significantly in immunogenicity and functional outcomes.
abstract: Non-human primates, such as the rhesus macaques, are the preferred model for down-selecting human malaria vaccine formulations, but the rhesus model is expensive and does not allow for direct efficacy testing of human malaria vaccines. Transgenic rodent parasites expressing genes of human Plasmodium are now routinely used for efficacy studies of human malaria vaccines. Mice have however rarely predicted success in human malaria trials and there is scepticism whether mouse studies alone are sufficient to move a vaccine candidate into the clinic.
  
  
  
  A comparison of immunogenicity, fine-specificity and functional activity of two Alum-adjuvanted Plasmodium falciparum circumsporozoite protein (CSP)-based vaccines was conducted in mouse and rhesus models. One vaccine was a soluble recombinant protein (CSP) and the other was the same CSP covalently conjugated to the Qβ phage particle (Qβ-CSP).
  
  
  
  Mice showed different kinetics of antibody responses and different sensitivity to the NANP-repeat and N-terminal epitopes as compared to rhesus. While mice failed to discern differences between the protective efficacy of CSP versus Qβ-CSP vaccine following direct challenge with transgenic Plasmodium berghei parasites, rhesus serum from the Qβ-CSP-vaccinated animals induced higher in vivo sporozoite neutralization activity.
  
  
  
  Despite some immunologic parallels between models, these data demonstrate that differences between the immune responses induced in the two models risk conflicting decisions regarding potential vaccine utility in humans. In combination with historical observations, the data presented here suggest that although murine models may be useful for some purposes, non-human primate models may be more likely to predict the human response to investigational vaccines.
authors.affiliation: Structural Vaccinology Laboratory, Malaria Vaccine Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Phares
authors.affiliation: Division of Veterinary Medicine, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: May
authors.affiliation: Structural Vaccinology Laboratory, Malaria Vaccine Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Genito
authors.affiliation: Division of Veterinary Medicine, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Hoyt
authors.affiliation: Structural Vaccinology Laboratory, Malaria Vaccine Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA.
authors.forename: Farhat A
authors.initials: FA
authors.lastname: Khan
authors.affiliation: Structural Vaccinology Laboratory, Malaria Vaccine Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Porter
authors.affiliation: Structural Vaccinology Laboratory, Malaria Vaccine Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA.
authors.forename: Margot
authors.initials: M
authors.lastname: DeBot
authors.affiliation: Malaria Vaccine Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA.
authors.forename: Norman C
authors.initials: NC
authors.lastname: Waters
authors.affiliation: Cytos Biotechnology, Wagistrasse 25, 8952, Schlieren, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Saudan
authors.affiliation: Structural Vaccinology Laboratory, Malaria Vaccine Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA. sheetij.dutta.civ@mail.mil.
authors.forename: Sheetij
authors.initials: S
authors.lastname: Dutta
mesh_terms: D000818:Animals; D005260:Female; D000071497:Immunogenicity, Vaccine; D008253:Macaca mulatta; D017780:Malaria Vaccines / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology
chemical_list: D017780:Malaria Vaccines; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C041595:circumsporozoite protein, Protozoan
keywords: Circumsporozoite protein; Macaque; Malaria; Mice; Rhesus; Vaccine