title: Broad Cross-Protection Is Induced in Preclinical Models by a Human Papillomavirus Vaccine Composed of L1/L2 Chimeric Virus-Like Particles.
abstract: At least 15 high-risk human papillomaviruses (HPVs) are linked to anogenital preneoplastic lesions and cancer. Currently, there are three licensed prophylactic HPV vaccines based on virus-like particles (VLPs) of the L1 major capsid protein from HPV-2, -4, or -9, including the AS04-adjuvanted HPV-16/18 L1 vaccine. The L2 minor capsid protein contains HPV-neutralizing epitopes that are well conserved across numerous high-risk HPVs. Therefore, the objective of our study was to assess the capacity to broaden vaccine-mediated protection using AS04-adjuvanted vaccines based on VLP chimeras of L1 with one or two L2 epitopes. Several chimeric VLPs were constructed by inserting L2 epitopes within the DE loop and/or C terminus of L1. Based on the shape, yield, size, and immunogenicity, one of seven chimeras was selected for further evaluation in mouse and rabbit challenge models. The chimeric VLP consisted of HPV-18 L1 with insertions of HPV-33 L2 (amino acid residues 17 to 36; L1 DE loop) and HPV-58 L2 (amino acid residues 56 to 75; L1 C terminus). This chimeric L1/L2 VLP vaccine induced persistent immune responses and protected against all of the different HPVs evaluated (HPV-6, -11, -16, -31, -35, -39, -45, -58, and -59 as pseudovirions or quasivirions) in both mouse and rabbit challenge models. The degree and breadth of protection in the rabbit were further enhanced when the chimeric L1/L2 VLP was formulated with the L1 VLPs from the HPV-16/18 L1 vaccine. Therefore, the novel HPV-18 L1/L2 chimeric VLP (alone or in combination with HPV-16 and HPV-18 L1 VLPs) formulated with AS04 has the potential to provide broad protective efficacy in human subjects.
  
  
  
  From evaluations in human papillomavirus (HPV) protection models in rabbits and mice, our study has identified a prophylactic vaccine with the potential to target a wide range of HPVs linked to anogenital cancer. The three currently licensed vaccines contain virus-like particles (VLPs) of the L1 major capsid protein from two, four, or nine different HPVs. Rather than increasing the diversity of L1 VLPs, this vaccine contains VLPs based on a recombinant chimera of two highly conserved neutralizing epitopes from the L2 capsid protein inserted into L1. Our study demonstrated that the chimeric L1/L2 VLP is an effective vehicle for displaying two different L2 epitopes and can be used in a quantity equivalent to what is used in the licensed vaccines. Hence, using the chimeric L1/L2 VLP may be a more cost-effective approach for vaccine formulation than adding different VLPs for each HPV.
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Boxus
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: Michel
authors.initials: M
authors.lastname: Fochesato
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: Agnès
authors.initials: A
authors.lastname: Miseur
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mertens
authors.affiliation: GSK Vaccines, Rixensart, Belgium.
authors.forename: Najoua
authors.initials: N
authors.lastname: Dendouga
authors.affiliation: Department of Pathology, Penn State Hershey Medical Center, College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Brendle
authors.affiliation: Department of Pathology, Penn State Hershey Medical Center, College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Karla K
authors.initials: KK
authors.lastname: Balogh
authors.affiliation: Department of Pathology, Penn State Hershey Medical Center, College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Neil D
authors.initials: ND
authors.lastname: Christensen
authors.affiliation: GSK Vaccines, Rixensart, Belgium sandra.giannini@gsk.com.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Giannini
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D036022:Capsid Proteins / Q000276:immunology; D056738:Cross Protection / Q000276:immunology*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D009856:Oncogene Proteins, Viral / Q000276:immunology; D027383:Papillomaviridae / Q000276:immunology*; D030361:Papillomavirus Infections / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D053918:Papillomavirus Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D017386:Sequence Homology, Amino Acid; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D036022:Capsid Proteins; C063316:L2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D053918:Papillomavirus Vaccines; D011993:Recombinant Fusion Proteins; D058425:Vaccines, Virus-Like Particle; C063317:L1 protein, Human papillomavirus type 16