Enterovirus 71

Hand, foot and mouth disease (HFMD) was first reported in New Zealand in 1957 and occurs mostly in young children, with a peak incidence at about 2 years of age. The causative agents of HFMD are picornaviruses, most often of human enterovirus species A, chiefly the Coxsackie A viruses and Enterovirus A71 (EV71). The picornaviruses belong to the Picornaviridae, a family of small non-enveloped viruses with a single-stranded positive-sense RNA genome of about 7500 nucleotides.

EV71 was first isolated from the faeces of a female suffering from encephalitis in 1969 in California. However, a retrospective study conducted in the Netherlands indicated that the virus could have emerged as early as 1963; a finding consistent with reports of possible worldwide EV71 epidemics in the late twentieth century, throughout the world and with epidemics in Asia, Europe and the Americas. EV71 virus causes a range of effects from asymptomatic infection and mild HFMD to neurological disease with severe central nervous system complications and cardiopulmonary failure. In severe cases mortality rates can be high, especially in children aged 5 years and younger. EV71 is considered to be the most severe neurotoxic enterovirus and severe EV71 disease has become a major public health problem in China.

EV71 isolates can be clustered according to their genomic sequence into at least eight genogroups (A–H) but belong to one serotype. Genogroups B and C have been of greatest interest because of their frequency of isolation and implication in disease in Eastern Asia, and can each be sub-classified into five subgenogroups (C1–C5 and B1–B5). C4 is by far the major genogroup circulating in China, while B4, B5 and C5 are found in other Asian countries. In contrast, strains of genogroups C1 and C2 are predominantly found in Europe where severe disease is uncommon. In 2011, the WHO Regional Office for the Western Pacific issued A guide to clinical management and public health response for hand, foot and mouth disease (HFMD) to support the treatment, prevention and control of HFMD.

Enterovirus 71 vaccines

To date three vaccines against EV71 have been licensed in China, all using C4 genogroup strains. The efficacy of these three vaccines after two doses immunization ranges from 90.0% to 97.4% after one year of surveillance to 95.1% after two-year follow-up. Candidate vaccines containing B4 and B5 genogroups are in development elsewhere but have not yet reached the licensing stage. Other vaccines such as recombinant and other forms of subunit vaccines, vectored vaccines, virus-like particle vaccines are in the early stage of development. In addition, the development of vaccines against Coxsackie A16, A6 and A10 is being considered with a view to developing combination/multivalent vaccines.

Enterovirus vaccine standardization

Written standards

In 2019 and 2020 WHO organized a working group meeting and an informal consultation to review the current status of development and regulation of enterovirus 71 vaccines and developed WHO Recommendations to assure the quality, safety and efficacy of enterovirus 71 vaccines (inactivated). This document provides guidance to NRAs and manufacturers on the manufacturing process, and on nonclinical and clinical aspects, to assure the quality, safety and efficacy of enterovirus 71 vaccines (inactivated) for prophylactic use.

Recommendations to assure the quality, safety and efficacy of enterovirus 71 vaccines (inactivated), Annex 3, TRS No 1030.

Reference materials

International reference materials have been established by WHO ECBS and available to qualified applicants:

• The first WHO International Standard for anti-EV71 serum (human) (NIBSC code 14/140) with an assigned value of 1000 IU/ampoule for the standardization of diagnostic tests for use in seroprevalence studies and for assessing immunity.
• The First WHO International Reference Reagent for EV71 neutralization assays (NIBSC code 13/238) with an assigned value of 300 IU/ampoule for use in the standardization of virus neutralization assays.
• The First WHO International Standard for EV71 inactivated vaccine (NIBSC code 18/116) with an assigned unitage of 3625 IU/ampoule for use in in vitro assays to measure the antigen content of vaccine products through the calibration of secondary reference preparations.
• WHO international reference reagents for EV71 genogroups C4 and B4 inactivated vaccine
• WHO international reference reagents for EV71 genogroups C4 and B4 inactivated vaccine (NIBSC codes 18/120 and 18/156 respectively) with assigned unitages of 300 and 250 IU/ampoule respectively for use in in vitro assays to measure the antigen content of vaccine products through the calibration of secondary reference preparations.

International Reference Preparations catalogue