Abstract
The capsid of human papillomavirus (HPV) spontaneously arranges into a T = 7 icosahedral particle with 72 L1 pentameric capsomeres associating via disulfide bonds between Cys175 and Cys428. Here, we design a capsomere-hybrid virus-like particle (chVLP) to accommodate multiple types of L1 pentamers by the reciprocal assembly of single C175A and C428A L1 mutants, either of which alone encumbers L1 pentamer particle self-assembly. We show that co-assembly between any pair of C175A and C428A mutants across at least nine HPV genotypes occurs at a preferred equal molar stoichiometry, irrespective of the type or number of L1 sequences. A nine-valent chVLP vaccine-formed through the structural clustering of HPV epitopes-confers neutralization titers that are comparable with that of Gardasil 9 and elicits minor cross-neutralizing antibodies against some heterologous HPV types. These findings may pave the way for a new vaccine design that targets multiple pathogenic variants or cancer cells bearing diverse neoantigens.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Neutralizing / blood
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Antibodies, Neutralizing / immunology
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Antibodies, Viral / blood
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Antibodies, Viral / immunology
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Capsid Proteins / administration & dosage
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Capsid Proteins / genetics
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Capsid Proteins / immunology*
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Drug Design
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Epitopes / genetics
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Epitopes / immunology
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Female
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Humans
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Immunogenicity, Vaccine
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Mice
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Models, Animal
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Mutation
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Neoplasms / therapy*
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Neoplasms / virology
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Neutralization Tests
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Papillomaviridae / genetics
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Papillomaviridae / immunology*
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Papillomavirus Infections / therapy*
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Papillomavirus Infections / virology
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Papillomavirus Vaccines / administration & dosage
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Papillomavirus Vaccines / genetics
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Papillomavirus Vaccines / immunology*
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Protein Multimerization / genetics
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Protein Multimerization / immunology
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Vaccines, Virus-Like Particle / administration & dosage
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Vaccines, Virus-Like Particle / genetics
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Vaccines, Virus-Like Particle / immunology
Substances
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Antibodies, Neutralizing
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Antibodies, Viral
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Capsid Proteins
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Epitopes
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Papillomavirus Vaccines
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Vaccines, Virus-Like Particle