Towards a novel and safe EVA71 VLP vaccine: Enhancing capsid stability with thermal selection

Abstract

Enterovirus A71 (EVA71) is an important etiological agent of hand, foot, and mouth disease (HFMD), especially among infants and young children. HFMD caused by EVA71 can vary from mild and self-limited disease to severe and complicated illness. Severe symptoms or neurological complications such as brainstem encephalitis or acute flaccid paralysis can be fatal. Currently, none of the antiviral therapies against EVA71 has reached clinical trials. Therefore, preventive vaccines are crucial to tackling this disease. Different types of vaccines have been developed against EVA71, such as inactivated vaccines, subunit vaccines, recombinant vaccines, or virus-like particles (VLPs). However, except the inactivated vaccines, all of them are in the early stages of development. The inactivated vaccines, based on formaldehyde-inactivated viruses, were licensed and used effectively in China, the country that suffers the most from cyclic outbreaks of HFMD caused by EVA71. However, these vaccines have not been approved internationally yet due to some issues in safety and quality of production. The production of an inactivated virus is hazardous as there is the risk of an escape of the live virus into the environment. In contrast, the VLP vaccine would produce a cost-effective virus-free vaccine. Empty capsids (ECs) that are produced during the lifecycle of EVA71, along with mature infectious particles, offer the potential to be developed as a safe and effective VLP vaccine. The reasons are that these particles are antigenically indistinguishable from virus particles, and unable to replicate as they are devoid of the RNA genome. Indeed, it was shown that VLPs based on ECs are alternative virus-free vaccine candidates for poliovirus, which is a related picornavirus. However, our studies with poliovirus have shown that native ECs are antigenically unstable and can be easily converted to an expanded conformation (HAg) at moderate temperatures. This instability results in the loss of native antigenic conformation (NAg) or the appropriate display of epitopes essential to elicit a long-lived protective immune response. Thus, it was essential to stabilise VLPs to maintain the native form of antigenicity. Whether this is true for EVA71 or not is yet to be confirmed.