Impact of genetic changes, pathogenicity and antigenicity on Enterovirus- A71 vaccine development

Abstract

Enterovirus-A71 (EV-A71) is an etiological agent of the hand, foot and mouth disease (HFMD). EV-A71 infection produces high fever and ulcers in children. Some EV-A71 strains produce severe infections leading to pulmonary edema and death. Although the protective efficacy of the inactivated vaccine (IV) was ≥ 90% against mild HFMD, there was approximately 80% protection against severe HFMD. The monovalent EV-A71 IV elicits humoral immunity but lacks long-term immunogenicity. Spontaneous mutations of the EV-A71 genome could lead to antigenicity changes and the virus may not be neutralized by antibodies elicited by the IV. A better alternative would be the live attenuated vaccine (LAV) that elicits cellular and humoral immunity. The LAV induces excellent antigenicity and chances of reversion is reduced by presence of multiple mutations which could reduce pathogenicity. Besides CV-A16, outbreaks have been caused by CV-A6 and CV-A10, hence the development of bivalent and trivalent vaccines is required.

Enterovirus-Associated Hand-Foot and Mouth Disease and Neurological Complications in Japan and the Rest of the World

“…The high strain diversity in EV-A71 is attributed to a high evolutionary rate, ca. 4 × 10 −3 substitutions per site per year estimated on the VP1 [74]; such a high mutation rate is due to the lack of a proofread mechanism in the viral RNA-dependent RNA polymerase (RdRp) with overall mutation rates of 10 −3 to 10 −5 mutations per copied nucleotide per replication cycle [75]. Additionally, despite recombination events in the capsid-encoding region are considered infrequent due to structural and functional constraints, the effects of recombination in EV-A71 are considered source of diversity among strains and genogroups [73,76,77].…”

Regulation of Apoptosis by Enteroviruses

“…The symptoms of Coxsackie virus infection range from mild cold symptoms to severe myocarditis, pericarditis, meningitis, and pancreatitis (Muller et al, 2017;Qi and Xiong, 2017). EV71 infection is often characterized by hand, foot and mouth disease (Yee and Laa Poh, 2017). Thus, EV infection can severely endanger human health.…”

A decade of sustained selection pressure on two surface sites of the VP1 protein of Enterovirus A71 suggests that immune evasion may be an indirect driver for virulence

“…With several large HFMD outbreaks in east Asian countries over the last three decades, totalling several million cases and thousands of fatalities 9 , EV-A71 constitutes an emerging pathogen with epidemiological impact far beyond that of classic milder HFMD caused by other viruses. Although vaccine development for EV-A71 has been a research priority for nearly two decades 10,11 , there is no universally licensed vaccine or antiviral treatment for EV-A71 infection 12 .…”