Rational design of a multi-valent human papillomavirus vaccine by capsomere-hybrid co-assembly of virus-like particles

Daning Wang,Tingting Li,Shaowei Li,Yurou Yang,Yingbin Wang,Jie Chen,Qinjian Zhao,Ningshao Xia,Ciying Qian,Jun Zhang,Xiaosa Chi ,Qiang Xu ,Shunlin Huang ,Zhiping Wang,Xinlin Liu,Qingbing Zheng,Maozhou He,Shuo Song,Minxi Wei,Zhibo Kong,Hai Yu,Ying Gu

doi:10.1038/s41467-020-16639-1

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.

Highlights

The capsid of human papillomavirus (HPV) spontaneously arranges into a T = 7 icosahedral particle with 72 L1 pentameric capsomeres associating via disulfide bonds between Cys[175] and Cys[428]
Using L1 proteins harboring either a Cys175Ala or a Cys428Ala (HPV16 numbering) mutation, we confirmed an inhibition of capsid formation, with the proteins folding as star-shaped pentamers that were incapable of selfassembling into HPV L1 virus-like particles (VLPs)
We found that HPVL1-C175A and -C428A mutants can pair-wise assemble for each of the three HPV types when combined (Fig. 1a, e, i)

Summary

Introduction

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. The HPV virion is delivered into the host away from bodily fluids, resulting in a lower immune response by the host against the neutralization epitope of the capsid In terms of this lower immune pressure and type-restricted neutralization mostly evoked in human antiviral immunity, the phylogenetics of HPV is complex, and there has been a gradual accumulation of more than 200 distinct genotypes[1].

Methods

Results

Conclusion