On June 5, Nature Communications published online an article by Prof. Ningshao Xia's team, entitled "Rational design of a multi-valent human papillomavirus vaccine by capsomere-hybrid co-assembly of virus-like particles". Based on the insights into the viral-like particle (VLP) assembly mechanism of human papillomavirus (HPV), the study has designed a capsomere-hybrid VLP (chVLP) that is capable of simultaneously generating protective effects against multiple HPV types. This study has paved the way for the development of a new generation of multivalent cervical cancer vaccine with a broader spectrum covering all high-risk HPV types, and provided new thoughts for the design of vaccines for other highly mutated virus and vaccines for targeting tumor neoantigens.

The research found that 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. The research team designed 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. The study showed 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.

Complementary assembly design of VLP based on pentamers and the immunoprotection effect of heterodimerized nine-valent HPV vaccine

Prof. Ningshao Xia's team has been conducting basic and applied research on prophylactic HPV vaccines. The team has shed light on the mechanisms of HPV VLPs assembly based on E. coli (Structure, 2016), provided insights into the structural basis of antibody-mediated neutralization of HPV type specificity (mBio, 2017), and developed the first-generation HPV vaccine of China (HPV 16/18 bivalent, Cecolin®. Hum Vacc & Immunother, 2014. Vaccine, 2015. Vaccine, 2017. Sci China Life Sci, 2019. JNCI, 2020). Besides, the second-generation HPV vaccine developed by the team is about to start phase III clinical trial (Nine-valent. Emerg Microbes Infec, 2018. They have signed a global alliance partnership agreement with GlaxoSmithKline (GSK) to develop a next-generation HPV vaccine, and pioneered the development of third-generation HPV vaccine on the strength of their structural vaccinology design. This published work is a further effort to design a novel HPV multivalent vaccine based on the improved understanding of the HPV VLP assembly mechanism.

Wang Daning, a post-doc fellow and two Ph.D students Liu Xinlin and Wei Minxi co-first authored this article. Prof. Li Shaowei, Assoc. Prof. Gu Ying and Prof. Xia Ningshao are co-corresponding authors of the paper. The research has been funded by the National Natural Science Foundation of China Major Program; Key Program; Taiwan Straits Joint Program; General Program) and National Major Scientific and Technological Special Project for "Significant New Drugs Development".

Link to the paper: www.nature.com/articles/s41467-020-16639-1

Source: School of Public Health