A virus-like particle-based tetravalent vaccine for hand, foot, and mouth disease elicits broad and balanced protective immunity

Wei Zhang,Wenlong Dai,Chao Zhang,Yu Zhou,Pei Xiong,Shuxia Wang,Xiaohua Ye,Qingwei Liu,Dongming Zhou,Zhong Huang

doi:10.1038/s41426-018-0094-1

Wei Zhang, Wenlong Dai + Show 8 more

Open Access

https://doi.org/10.1038/s41426-018-0094-1

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Abstract

Hand, foot, and mouth disease (HFMD) is an infectious disease that mainly affects infants and children, causing considerable morbidity and mortality worldwide. HFMD is commonly caused by enterovirus 71 (EV71) and coxsackieviruses A16 (CVA16), A6 (CVA6), and A10 (CVA10). Formalin-inactivated EV71 vaccines are currently available in China; however, these vaccines fail to confer cross-protection against infections by other HFMD-causing enteroviruses, highlighting the necessity of developing a multivalent HFMD vaccine. Our previous studies demonstrated that recombinant virus-like particles (VLP) of EV71, CVA16, and CVA6 are capable of inducing protective immunity against homologous virus challenges in mice. In this study, we generated CVA10-VLP using a baculovirus-insect cell expression system and then combined CVA10-VLP with EV71-VLP, CVA16-VLP, and CVA6-VLP to formulate a tetravalent VLP vaccine. Immunogenicity and protective efficacy of tetravalent VLP vaccine was compared with that of monovalent VLP vaccines. Mouse immunization studies revealed that the tetravalent vaccine elicited antigen-specific and long-lasting serum antibody responses comparable to those elicited by its corresponding monovalent vaccines. Moreover, tetravalent vaccine immune sera strongly neutralized EV71, CVA16, CVA10, and CVA6 strains with neutralization titers similar to those of their monovalent counterparts, indicating a good compatibility among the four antigens in the combination vaccine. Importantly, passively transferred tetravalent vaccine-immunized sera conferred efficient protection against single or mixed infections with EV71, CVA16, CVA10, and CVA6 viruses in mice, whereas the monovalent vaccines could only protect mice against homotypic virus infections but not heterotypic challenges. These results demonstrate that the tetravalent VLP vaccine represents a promising broad-spectrum HFMD vaccine candidate.

Highlights

Hand, foot, and mouth disease (HFMD) is a highly contagious viral disease worldwide, especially in the Asia-Pacific region, and has led to significant morbidity and mortality[1,2]
Our results showed that the tetravalent virus-like particles (VLP) vaccine can confer efficient and broad protection against enterovirus 71 (EV71), coxsackievirus A16 (CVA16), coxsackievirus A10 (CVA10), and coxsackievirus A6 (CVA6) viral infections, representing a promising broad-spectrum HFMD vaccine candidate
P1 precursor proteins and 3CD proteases of EV71, CVA16, or CVA6 in insect cells leads to the cleavage of P1 by 3CD into three capsid subunit proteins, namely, VP0, VP1 and VP3, all of which can spontaneously assemble into VLPs27,29,35

Summary

Introduction

Foot, and mouth disease (HFMD) is a highly contagious viral disease worldwide, especially in the Asia-Pacific region, and has led to significant morbidity and mortality[1,2]. Foot, and mouth disease (HFMD) is a highly contagious viral disease worldwide, especially in the Asia-. HFMD is generally a mild and self-limiting disease characterized by fever, rashes on the hands and feet, and mouth sores. (EV71) and coxsackievirus A16 (CVA16);[3,4,5] in recent years, a large number of HFMD cases were found to be associated with coxsackievirus A6 (CVA6) and coxsackievirus A10 (CVA10) infections[6,7]. CVA6 and/or CVA10 have been responsible for the recent and numerous HFMD outbreaks in many countries, such as Finland[8], France[9,10], Singapore[11], Japan[12,13], Spain[14], Thailand[15], and China[16,17]. CVA6 and CVA10 have emerged as two major causative agents of HFMD

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