title: Durable immunity to oncogenic human papillomaviruses elicited by adjuvanted recombinant Adeno-associated virus-like particle immunogen displaying L2 17-36 epitopes.
abstract: Vaccination with the minor capsid protein L2, notably the 17-36 neutralizing epitope, induces broadly protective antibodies, although the neutralizing titers attained in serum are substantially lower than for the licensed L1 VLP vaccines. Here we examine the impact of other less reactogenic adjuvants upon the induction of durable neutralizing serum antibody responses and protective immunity after vaccination with HPV16 and HPV31 L2 amino acids 17-36 inserted at positions 587 and 453 of VP3, respectively, for surface display on Adeno-Associated Virus 2-like particles [AAVLP (HPV16/31L2)]. Mice were vaccinated three times subcutaneously with AAVLP (HPV16/31L2) at two week intervals at several doses either alone or formulated with alum, alum and MPL, RIBI adjuvant or Cervarix. The use of adjuvant with AAVLP (HPV16/31L2) was necessary in mice for the induction of L2-specific neutralizing antibody and protection against vaginal challenge with HPV16. While use of alum was sufficient to elicit durable protection (>3 months after the final immunization), antibody titers were increased by addition of MPL and RIBI adjuvants. To determine the breadth of immunity, rabbits were immunized three times with AAVLP (HPV16/31L2) either alone, formulated with alum±MPL, or RIBI adjuvants, and after serum collection, the animals were concurrently challenged with HPV16/31/35/39/45/58/59 quasivirions or cottontail rabbit papillomavirus (CRPV) at 6 or 12 months post-immunization. Strong protection against all HPV types was observed at both 6 and 12 months post-immunization, including robust protection in rabbits receiving the vaccine without adjuvant. In summary, vaccination with AAVLP presenting HPV L2 17-36 epitopes at two sites on their surface induced cross-neutralizing serum antibody, immunity against HPV16 in the genital tract, and long-term protection against skin challenge with the 7 most common oncogenic HPV types when using a clinically relevant adjuvant.
authors.affiliation: Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Subhashini
authors.initials: S
authors.lastname: Jagu
authors.affiliation: Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Balusubramanyam
authors.initials: B
authors.lastname: Karanam
authors.affiliation: Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Wang
authors.affiliation: Biomedical Sciences Program, Health Sciences Department, Qatar University, PO Box 2713, Doha, Qatar.
authors.forename: Hatem
authors.initials: H
authors.lastname: Zayed
authors.affiliation: Medigene AG, Pannegg/Martinsreid, Germany.
authors.forename: Margit
authors.initials: M
authors.lastname: Weghofer
authors.affiliation: Jake Gittlen Cancer Research Foundation, Pennsylvania State University College of Medicine, Hershey, PA, USA; Department of Pathology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Brendle
authors.affiliation: Jake Gittlen Cancer Research Foundation, Pennsylvania State University College of Medicine, Hershey, PA, USA; Department of Pathology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: Karla K
authors.initials: KK
authors.lastname: Balogh
authors.affiliation: Medigene AG, Pannegg/Martinsreid, Germany.
authors.forename: Kerstin Pino
authors.initials: KP
authors.lastname: Tossi
authors.affiliation: Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins University, Baltimore, MD, USA; Department of Gynecology and Obstetrics, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Richard B S
authors.initials: RBS
authors.lastname: Roden
authors.affiliation: Jake Gittlen Cancer Research Foundation, Pennsylvania State University College of Medicine, Hershey, PA, USA; Department of Pathology, Pennsylvania State University College of Medicine, Hershey, PA, USA; Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA, USA. Electronic address: ndc1@psu.edu.
authors.forename: Neil D
authors.initials: ND
authors.lastname: Christensen
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D036022:Capsid Proteins / Q000276:immunology*; D000229:Dependovirus / Q000276:immunology; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology; D005260:Female; D052162:Human papillomavirus 16; D051379:Mice; D008807:Mice, Inbred BALB C; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D027383:Papillomaviridae / Q000276:immunology; D030361:Papillomavirus Infections / Q000517:prevention & control*; D053918:Papillomavirus Vaccines / Q000276:immunology*; D011817:Rabbits; D014614:Vaccines, Synthetic / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D036022:Capsid Proteins; D000939:Epitopes; C063316:L2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D053918:Papillomavirus Vaccines; D014614:Vaccines, Synthetic; C510352:human papillomavirus vaccine, L1 type 16, 18; C080100:oncogene viral capsid protein L2, human papillomavirus type 33
keywords: AAV2; Adeno-associated virus; Adjuvant; Challenge; Display; HPV16; HPV31; Human papillomavirus; L2; Neutralizing antibody; VLP; Vaccine