title: A three component mix of thioredoxin-L2 antigens elicits broadly neutralizing responses against oncogenic human papillomaviruses.
abstract: Current human papillomavirus (HPV) vaccines based on major capsid protein L1 virus-like particles (VLP) provide potent type-specific protection against vaccine-type viruses (mainly HPV16 and 18), but cross-protect against only a small subset of the approximately 15 oncogenic HPV types. It is estimated that L1-VLP vaccines, which require a fairly complex production system and are still quite costly, fail to cover 20-30% of HPV cervical cancers worldwide, especially in low-resource countries. Alternative antigens relying on the N-terminal region of minor capsid protein L2 are intrinsically less immunogenic but capable of eliciting broadly neutralizing responses. We previously demonstrated the enhanced immunogenicity and cross-neutralization potential of an easily produced recombinant L2 antigen bearing the HPV16 L2(20-38) peptide epitope internally fused to bacterial thioredoxin (Trx). However, antibodies induced by Trx-HPV16 L2(20-38) failed to cross-neutralize notable high-risk HPV types such as HPV31. In the present work, the Trx-L2 design was modified to include L2 sequence information from the highly divergent HPV31 and HPV51 types in addition to HPV16, with the aim of extending cross-neutralization. Multivalent antigens comprising L2(20-38) peptides from all three HPV types on a single Trx scaffold molecule were compared to a mixture of the three type-specific monovalent Trx-L2 antigens. While multivalent antigens as well as the mixed antigens elicited similar anti-HPV16 neutralization titers, cross-reactive responses against HPV31 and HPV51 were of higher magnitude and more robust for the latter formulation. A mixture of monovalent Trx-L2 antigens thus represents a candidate lead for the development of a broadly cross-protective, low-cost second-generation anti-HPV vaccine.
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Seitz
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: German Cancer Research Center, Heidelberg, Germany.
authors.forename: Lis
authors.initials: L
authors.lastname: Ribeiro-Müller
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.
authors.forename: Anikó
authors.initials: A
authors.lastname: Pàlfi
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.
authors.forename: Simone
authors.initials: S
authors.lastname: Ottonello
authors.affiliation: German Cancer Research Center, Heidelberg, Germany. Electronic address: martin.mueller@dkfz.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Müller
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D036022:Capsid Proteins / Q000276:immunology*; D056738:Cross Protection; D005260:Female; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D030361:Papillomavirus Infections / Q000517:prevention & control*; D053918:Papillomavirus Vaccines / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D013879:Thioredoxins / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000956:Antigens, Viral; D036022:Capsid Proteins; C063316:L2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D053918:Papillomavirus Vaccines; D011994:Recombinant Proteins; D013879:Thioredoxins
keywords: Cross-protection; In vitro neutralization; In vivo protection; Papillomavirus minor capsid protein L2; Thioredoxin-L2