title: Enhancing immunogenicity and transmission-blocking activity of malaria vaccines by fusing Pfs25 to IMX313 multimerization technology.
abstract: Transmission-blocking vaccines (TBV) target the sexual-stages of the malaria parasite in the mosquito midgut and are widely considered to be an essential tool for malaria elimination. High-titer functional antibodies are required against target antigens to achieve effective transmission-blocking activity. We have fused Pfs25, the leading malaria TBV candidate antigen to IMX313, a molecular adjuvant and expressed it both in ChAd63 and MVA viral vectors and as a secreted protein-nanoparticle. Pfs25-IMX313 expressed from viral vectors or as a protein-nanoparticle is significantly more immunogenic and gives significantly better transmission-reducing activity than monomeric Pfs25. In addition, we demonstrate that the Pfs25-IMX313 protein-nanoparticle leads to a qualitatively improved antibody response in comparison to soluble Pfs25, as well as to significantly higher germinal centre (GC) responses. These results demonstrate that antigen multimerization using IMX313 is a very promising strategy to enhance antibody responses against Pfs25, and that Pfs25-IMX313 is a highly promising TBV candidate vaccine.
authors.affiliation: Jenner Institute, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Jenner Institute, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Darren B
authors.initials: DB
authors.lastname: Leneghan
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious. Disease/National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Miura
authors.affiliation: Jenner Institute, University of Oxford, Oxford, OX3 7DQ, UK.|Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious. Disease/National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Daria
authors.initials: D
authors.lastname: Nikolaeva
authors.affiliation: Jenner Institute, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Iona J
authors.initials: IJ
authors.lastname: Brian
authors.affiliation: Jenner Institute, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Matthew D J
authors.initials: MD
authors.lastname: Dicks
authors.affiliation: Jenner Institute, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Fyfe
authors.affiliation: Jenner Institute, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Zakutansky
authors.affiliation: Jenner Institute, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Simone
authors.initials: S
authors.lastname: de Cassan
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious. Disease/National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Carole A
authors.initials: CA
authors.lastname: Long
authors.affiliation: Jenner Institute, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Draper
authors.affiliation: Jenner Institute, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.affiliation: IMAXIO, 69007 Lyon, France.
authors.forename: Fergal
authors.initials: F
authors.lastname: Hill
authors.affiliation: Jenner Institute, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Sumi
authors.initials: S
authors.lastname: Biswas
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics*; D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis*; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology; D009033:Culicidae / Q000187:drug effects / Q000469:parasitology; D015870:Gene Expression; D005822:Genetic Vectors / Q000737:chemistry / Q000276:immunology; D018858:Germinal Center / Q000187:drug effects / Q000276:immunology; D006801:Humans; D000071497:Immunogenicity, Vaccine; D007303:Insect Vectors / Q000187:drug effects / Q000469:parasitology; D008018:Life Cycle Stages / Q000187:drug effects / Q000276:immunology; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D010843:Pichia / Q000235:genetics / Q000378:metabolism; D010957:Plasmids / Q000737:chemistry / Q000276:immunology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology; D015800:Protozoan Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014611:Vaccination; D014614:Vaccines, Synthetic
chemical_list: D000276:Adjuvants, Immunologic; D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D017780:Malaria Vaccines; C071284:Pfs25 protein, Plasmodium falciparum; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic