title: Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents preexisting immunity to adenovirus in mice.
abstract: Although adenovirus (Ad) has been regarded as an excellent vaccine vector, there are 2 major drawbacks to using this platform: (a) Ad-based vaccines induce a relatively weak humoral response against encoded transgenes, and (b) preexisting immunity to Ad is highly prevalent among the general population. To overcome these obstacles, we constructed an Ad-based malaria vaccine by inserting a B cell epitope derived from a Plasmodium yoelii circumsporozoite (CS) protein (referred to as the PyCS-B epitope) into the capsid proteins of WT/CS-GFP, a recombinant Ad expressing P. yoelii CS protein and GFP as its transgene. Multiple vaccinations with the capsid-modified Ad induced a substantially increased level of protection against subsequent malaria challenge in mice when compared with that of unmodified WT/CS-GFP. Increased protection correlated with augmented antibody responses against the PyCS-B epitope expressed in the capsid. Furthermore, replacement of hypervariable region 1 (HVR1) of the Ad capsid proteins with the PyCS-B epitope circumvented neutralization of the modified Ad by preexisting Ad-specific antibody, both in vivo and in vitro. Importantly, the immunogenicity of the Ad-containing PyCS-B epitope in the HVR1 and a P. yoelii CS transgene was maintained. Overall, this study demonstrates that the HVR1-modifed Ad vastly improves upon Ad as a promising malaria vaccine platform candidate.
authors.affiliation: HIV and Malaria Vaccine Program, Aaron Diamond AIDS Research Center, New York, New York 10016, USA.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shiratsuchi
authors.forename: Urvashi
authors.initials: U
authors.lastname: Rai
authors.forename: Anja
authors.initials: A
authors.lastname: Krause
authors.forename: Stefan
authors.initials: S
authors.lastname: Worgall
authors.forename: Moriya
authors.initials: M
authors.lastname: Tsuji
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D001483:Base Sequence; D036022:Capsid Proteins / Q000276:immunology*; D045744:Cell Line, Tumor; D018985:Epitopes, B-Lymphocyte / Q000276:immunology*; D005260:Female; D005822:Genetic Vectors / Q000276:immunology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010967:Plasmodium yoelii / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology*
chemical_list: D000913:Antibodies, Protozoan; D036022:Capsid Proteins; D018985:Epitopes, B-Lymphocyte; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan
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