title: Head-to-Head Comparison of Soluble vs. Qβ VLP Circumsporozoite Protein Vaccines Reveals Selective Enhancement of NANP Repeat Responses.
abstract: Circumsporozoite protein (CSP) of Plasmodium falciparum is a promising malaria vaccine target. RTS,S, the most advanced malaria vaccine candidate consists of the central NANP repeat and carboxy-terminal region of CSP displayed on a hepatitis B virus-like particle (VLP). To build upon the success of RTS,S, we produced a near full-length Plasmodium falciparum CSP that also includes the conserved amino-terminal region of CSP. We recently showed that this soluble CSP, combined with a synthetic Toll-like-receptor-4 (TLR4) agonist in stable oil-in-water emulsion (GLA/SE), induces a potent and protective immune response in mice against transgenic parasite challenge. Here we have investigated whether the immunogenicity of soluble CSP could be further augmented by presentation on a VLP. Bacteriophage Qβ VLPs can be readily produced in E.coli, they have a diameter of 25 nm and contain packaged E. coli RNA which serves as a built in adjuvant through the activation of TLR7/8. CSP was chemically conjugated to Qβ and the CSP-Qβ vaccine immunogenicity and efficacy were compared to adjuvanted soluble CSP in the C57Bl/6 mouse model. When formulated with adjuvants lacking a TLR4 agonist (Alum, SE and Montanide) the Qβ-CSP induced higher anti-NANP repeat titers, higher levels of cytophilic IgG2b/c antibodies and a trend towards higher protection against transgenic parasite challenge as compared to soluble CSP formulated in the same adjuvant. The VLP and soluble CSP immunogenicity difference was most pronounced at low antigen dose, and within the CSP molecule, the titers against the NANP repeats were preferentially enhanced by Qβ presentation. While a TLR4 agonist enhanced the immunogenicity of soluble CSP to levels comparable to the VLP vaccine, the TLR4 agonist did not further improve the immunogenicity of the Qβ-CSP vaccine. The data presented here pave the way for further improvement in the Qβ conjugation chemistry and evaluation of both the Qβ-CSP and soluble CSP vaccines in the non-human primate model.
authors.affiliation: Structural Vaccinology Laboratory, Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States of America.
authors.forename: Farhat
authors.initials: F
authors.lastname: Khan
authors.affiliation: Structural Vaccinology Laboratory, Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States of America.
authors.forename: Mike
authors.initials: M
authors.lastname: Porter
authors.affiliation: Structural Vaccinology Laboratory, Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Schwenk
authors.affiliation: Structural Vaccinology Laboratory, Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States of America.
authors.forename: Margot
authors.initials: M
authors.lastname: DeBot
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, Silver Spring, MD 20910, United States of America.
authors.forename: Sheetij
authors.initials: S
authors.lastname: Dutta
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry; D017908:Allolevivirus / Q000378:metabolism; D000534:Alum Compounds / Q000737:chemistry; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry; D004926:Escherichia coli / Q000235:genetics; D005260:Female; D007107:Immune System; D007074:Immunoglobulin G / Q000276:immunology; D008070:Lipopolysaccharides / Q000737:chemistry; D008288:Malaria / Q000517:prevention & control; D017780:Malaria Vaccines / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D018512:Parasitemia / Q000469:parasitology; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics; D012329:RNA, Bacterial / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry; D034101:Sporozoites / Q000737:chemistry; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014614:Vaccines, Synthetic / Q000737:chemistry*; D058425:Vaccines, Virus-Like Particle / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000913:Antibodies, Protozoan; D000939:Epitopes; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D012329:RNA, Bacterial; D011994:Recombinant Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014614:Vaccines, Synthetic; D058425:Vaccines, Virus-Like Particle; C041595:circumsporozoite protein, Protozoan; C041524:aluminum sulfate