title: Robust In Vitro and In Vivo Neutralization against Multiple High-Risk HPV Types Induced by a Thermostable Thioredoxin-L2 Vaccine.
abstract: Current prophylactic virus-like particle (VLP) human papillomavirus (HPV) vaccines are based on the L1 major capsid protein and provide robust but virus type-restricted protection. Moreover, VLP vaccines have a high production cost, require cold-chain storage, and are thus not readily implementable in developing countries, which endure 85% of the cervical cancer-related death burden worldwide. In contrast with L1, immunization with minor capsid protein L2 elicits broad cross-neutralization, and we previously showed that insertion of a peptide spanning amino acids 20-38 of L2 into bacterial thioredoxin (Trx) greatly enhances its immunogenicity. Building on this finding, we use, here, four different neutralization assays to demonstrate that low doses of a trivalent Trx-L2 vaccine, incorporating L2(20-38) epitopes from HPV16, HPV31 and HPV51, and formulated in a human-compatible adjuvant, induce broadly protective responses. Specifically, we show that this vaccine, which uses a far-divergent archaebacterial thioredoxin as scaffold and is amenable to an easy one-step thermal purification, induces robust cross-neutralization against 12 of the 13 known oncogenic HPV types. Immune performance measured with two different in vitro neutralization assays was corroborated by the results of mouse cervico-vaginal challenge and passive transfer experiments indicating robust cross-protection also in vivo. Altogether, our results attest to the potential of Trx-L2 as a thermostable second-generation HPV vaccine particularly well suited for low-resource countries.
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Seitz
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.
authors.forename: Lis
authors.initials: L
authors.lastname: Ribeiro-Müller
authors.affiliation: Department of Life Sciences, Biochemistry and Molecular Biology Unit, University of Parma, Parma, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Canali
authors.affiliation: Department of Life Sciences, Biochemistry and Molecular Biology Unit, University of Parma, Parma, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Bolchi
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Massimo
authors.initials: M
authors.lastname: Tommasino
authors.affiliation: Department of Life Sciences, Biochemistry and Molecular Biology Unit, University of Parma, Parma, Italy. martin.mueller@dkfz.de simone.ottonello@unipr.it.
authors.forename: Simone
authors.initials: S
authors.lastname: Ottonello
authors.affiliation: German Cancer Research Center, Heidelberg, Germany. martin.mueller@dkfz.de simone.ottonello@unipr.it.
authors.forename: Martin
authors.initials: M
authors.lastname: Müller
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D036022:Capsid Proteins / Q000276:immunology*; D056738:Cross Protection / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D058952:Human papillomavirus 31; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D030361:Papillomavirus Infections / Q000517:prevention & control* / Q000821:virology; D053918:Papillomavirus Vaccines / Q000276:immunology*; D013879:Thioredoxins / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D036022:Capsid Proteins; C063316:L2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D053918:Papillomavirus Vaccines; D013879:Thioredoxins