A chimeric 18L1-45RG1 virus-like particle vaccine cross-protects against oncogenic alpha-7 human papillomavirus types.

Bettina Huber,Christina Schellenbacher,Saeed Shafti-Keramat,Reinhard Kirnbauer,Dieter Fink,Christoph Jindra,Peter C Angeletti

doi:10.1371/journal.pone.0120152

Bettina Huber, Christina Schellenbacher + Show 5 more

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https://doi.org/10.1371/journal.pone.0120152

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Abstract

Persistent infection with oncogenic human papillomaviruses (HPV) types causes all cervical and a subset of other anogenital and oropharyngeal carcinomas. Four high-risk (hr) mucosal types HPV16, 18, 45, or 59 cause almost all cervical adenocarcinomas (AC), a subset of cervical cancer (CxC). Although the incidence of cervical squamous cell carcinoma (SCC) has dramatically decreased following introduction of Papanicolaou (PAP) screening, the proportion of AC has relatively increased. Cervical SCC arise mainly from the ectocervix, whereas AC originate primarily from the endocervical canal, which is less accessible to obtain viable PAP smears. Licensed (bivalent and quadrivalent) HPV vaccines comprise virus-like particles (VLP) of the most important hr HPV16 and 18, self-assembled from the major capsid protein L1. Due to mainly type-restricted efficacy, both vaccines do not target 13 additional hr mucosal types causing 30% of CxC. The papillomavirus genus alpha species 7 (α7) includes a group of hr types of which HPV18, 45, 59 are proportionally overrepresented in cervical AC and only partially (HPV18) targeted by current vaccines. To target these types, we generated a chimeric vaccine antigen that consists of a cross-neutralizing epitope (homologue of HPV16 RG1) of the L2 minor capsid protein of HPV45 genetically inserted into a surface loop of HPV18 L1 VLP (18L1-45RG1). Vaccination of NZW rabbits with 18L1-45RG1 VLP plus alum-MPL adjuvant induced high-titer neutralizing antibodies against homologous HPV18, that cross-neutralized non-cognate hr α7 types HPV39, 45, 68, but not HPV59, and low risk HPV70 in vitro, and induced a robust L1-specific cellular immune response. Passive immunization protected mice against experimental vaginal challenge with pseudovirions of HPV18, 39, 45 and 68, but not HPV59 or the distantly related α9 type HPV16. 18L1-45RG1 VLP might be combined with our previously described 16L1-16RG1 VLP to develop a second generation bivalent vaccine with extended spectrum against hr HPV.

Highlights

High-risk mucosal human papillomaviruses (HPV) are the causative agents of practically all cervical cancers (CxC) worldwide
Expression of the recombinant fusion protein was verified by SDS-PAGE and Coomassie staining (Fig. 1A), and antigenicity by Western Blot using an anti-HPV16 L2 aa 11–200 serum (Fig. 1B), or anti-L1 Monoclonal antibodies (mAb) Camvir-1 (Fig. 1C)
Α7 HPV types are overrepresented in AC of the endocervix, which are under-diagnosed by conventional PAP smears

Summary

Introduction

High-risk (hr) mucosal human papillomaviruses (HPV) are the causative agents of practically all cervical cancers (CxC) worldwide. There are more than 15 hr mucosal HPV types known so far, the majority belonging to species α9 (HPV16, 31, 33, 35, 52, 58) and α7 (HPV18, 39, 45, 59, 68), and in addition to α5 (HPV51), α6 (both HPV56, 66), and α11 (HPV73) [1,2]. HPV16, 18 and 45 are responsible for about 77% of all CxC [3], and 94% of the subset of cervical AC cases worldwide. About 10% of the worldwide population is infected with HPV at the ano-genital site [4]. Genital HPV is the most common sexually transmitted infection (STI), with a lifetime cumulative risk of 70%

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