An Advax-Adjuvanted Inactivated Cell-Culture Derived Japanese Encephalitis Vaccine Induces Broadly Neutralising Anti-Flavivirus Antibodies, Robust Cellular Immunity and Provides Single Dose Protection.

Tomoyoshi Komiya,Yoshikazu Honda-Okubo,Nikolai Petrovsky,Jeremy Baldwin

doi:10.3390/vaccines9111235

Tomoyoshi Komiya, Yoshikazu Honda-Okubo + Show 2 more

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https://doi.org/10.3390/vaccines9111235

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Abstract

ccJE+Advax is an inactivated cell culture Japanese encephalitis (JE) vaccine formulated with Advax, a novel polysaccharide adjuvant based on delta inulin. This vaccine has previously shown promise in murine and equine studies and the current study sought to better understand its mechanism of action and assess the feasibility of single dose vaccine protection. Mice immunised with ccJE+Advax had higher serum neutralisation titres than those immunised with ccJE alone or with alum adjuvant. ccJE+Advax induced extraordinarily broad cross-neutralising antibodies against multiple flaviviruses including West Nile virus (WNV), Murray Valley encephalitis virus (MVEV), St Louis encephalitis virus (SLEV) and Dengue virus-1 and -2 (DENV-1 and -2). Notably, the DENV-2 cross-neutralising antibodies from ccJE+Advax immunised mice uniquely had no DENV-2 antibody-dependent infection enhancement (ADIE) activity, in contrast to high ADIE activity seen with DENV-1 cross-reactive antibodies induced by mbJE or ccJE alone or with alum adjuvant. JEV-stimulated splenocytes from ccJE+Advax immunised mice showed increased IL-17 and IFN-γ production, consistent with a mixed Th1 and Th17 response, whereas ccJE-alum was associated with production of mainly Th2 cytokines. In a mouse lethal challenge study against highly virulent JaTH160 JEV strain, ccJE+Advax conferred complete protection in a two-dose schedule with 50 ng of vaccine antigen and near complete protection after a single 200 ng dose of vaccine antigen. There is an ongoing lack of human vaccines against particular flaviviruses, including WNV, SLEV and MVEV. Given its ability to provide single-dose JEV protection and induce broadly neutralising antibodies devoid of ADIE activity, ccJE+Advax vaccine could be useful in situations where rapid protection is desirable, e.g., during a local outbreak or for use in travellers or armies requiring rapid deployment to JEV endemic regions.

Highlights

Japanese encephalitis virus (JEV) is a flavivirus that is one of the leading causes of viral encephalitis in Asia with over 3 billion people living in JEV endemic regions [1]
Advax is a novel polysaccharide adjuvant based on microparticles of delta inulin, which potently stimulates vaccine immunogenicity whilst being safe and non-reactogenic [24]
The current study explored the mechanisms behind how Advax enhances culture-grown inactivated JE vaccines (ccJE) vaccine responses including assessing the breadth of cross-reactivity against other flavivirus family members, potential for such antibodies to induce antibodydependent infection enhancement (ADIE) and tested whether Advax adjuvant would allow single-dose vaccine protection against a high virulence JEV strain

Summary

Introduction

Japanese encephalitis virus (JEV) is a flavivirus that is one of the leading causes of viral encephalitis in Asia with over 3 billion people living in JEV endemic regions [1]. JEV is transmitted by Culex mosquitoes primarily to birds and pigs which act as natural reservoir for the virus, and secondarily to humans. An estimated 68,000 human cases of Japanese encephalitis (JE) occur annually resulting in about 16,000 deaths [2]. The virus causes acute inflammation in the central nervous system, and a significant portion of survivors (>30%) suffer from permanent neurological, behavioural and cognitive sequelae [3]. A recent study found that 81% of cases occur in areas with JEV vaccination programs which could suggest current JEV vaccines provide less than ideal protection [2]

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