title: Amino acid sequence diversity of the major human papillomavirus capsid protein: implications for current and next generation vaccines.
abstract: Despite the fidelity of host cell polymerases, the human papillomavirus (HPV) displays a degree of genomic polymorphism resulting in distinct genotypes and intra-type variants. The current HPV vaccines target the most prevalent genotypes associated with cervical cancer (HPV16/18) and genital warts (HPV6/11). Although these vaccines confer some measure of cross-protection, a multivalent HPV vaccine is in the pipeline that aims to broaden vaccine protection against other cervical cancer-associated genotypes including HPV31, HPV33, HPV45, HPV52 and HPV58. Both current and next generation vaccines comprise virus-like particles, based upon the major capsid protein, L1, and vaccine-induced, type-specific protection is likely mediated by neutralizing antibodies targeting L1 surface-exposed domains. The aim of this study was to perform an in silico analysis of existing full length L1 sequences representing vaccine-relevant HPV genotypes in order to address the degree of naturally-occurring, intra-type polymorphisms. In total, 1281 sequences from the Americas, Africa, Asia and Europe were assembled. Intra-type entropy was low and/or limited to non-surface-exposed residues for HPV6, HPV11 and HPV52 suggesting a minimal effect on vaccine antibodies for these genotypes. For HPV16, intra-type entropy was high but the present analysis did not reveal any significant polymorphisms not previously identified. For HPV31, HPV33, HPV58, however, intra-type entropy was high, mostly mapped to surface-exposed domains and in some cases within known neutralizing antibody epitopes. For HPV18 and HPV45 there were too few sequences for a definitive analysis, but HPV45 displayed some degree of surface-exposed residue diversity. In most cases, the reference sequence for each genotype represented a minority variant and the consensus L1 sequences for HPV18, HPV31, HPV45 and HPV58 did not reflect the L1 sequence of the currently available HPV pseudoviruses. These data highlight a number of variant amino acid residues that warrant further investigation for vaccine and natural history studies of HPV.
authors.affiliation: Virus Reference Department, Public Health England, London, UK.
authors.forename: Amina I
authors.initials: AI
authors.lastname: Ahmed
authors.forename: Sara L
authors.initials: SL
authors.lastname: Bissett
authors.forename: Simon
authors.initials: S
authors.lastname: Beddows
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D036022:Capsid Proteins / Q000235:genetics; D019295:Computational Biology; D003198:Computer Simulation; D030541:Databases, Genetic; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000235:genetics; D027383:Papillomaviridae / Q000145:classification / Q000235:genetics* / Q000276:immunology*; D030361:Papillomavirus Infections / Q000517:prevention & control / Q000821:virology*; D053918:Papillomavirus Vaccines / Q000235:genetics*
chemical_list: D036022:Capsid Proteins; D009856:Oncogene Proteins, Viral; D053918:Papillomavirus Vaccines
keywords: Diversity; Entropy; HPV; L1; Papillomavirus