Development of Standard Reagents for Harmonization of EV 71 Vaccines

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Dr. Javier Martin
Principal Scientist
Division of Virology,
National Institute for Biological Standards and Control (NIBSC),
United Kingdom


Enterovirus A71 (EV71) is the major causative agent of severe and fatal hand, foot and mouth (HFMD) disease. Since EV71 was first isolated from patients in California in 1969, it has been associated with sporadic cases and outbreaks of a wide spectrum of diseases, including HFMD, herpangina, aseptic meningitis, encephalitis, cerebellar ataxia and poliomyelitis-like syndrome. From the late 1990s, outbreaks and epidemics caused by EV71, particularly in the Asia-Pacific region, have occurred more frequently with the incidence of severe HFMD cases and mortalities. Vaccine development is the best way to prevent and control infectious diseases and vaccines against EV71 are already available or under development. Three EV71 vaccine products have been approved by the China Food and Drug Administration (CFDA) since December 2015, having shown good immunogenicity and more than 90% protective efficacy in more than 30,000 infants and children.

Projects to establish WHO International Standards for anti-EV71 serum (Human) and EV71 vaccine antigen were endorsed by ECBS, WHO, in 2012.  The 1st WHO International Standard (IS) for anti-EV71 serum (Human) was established in 2015 following a collaborative study led by the National Institute for Biological Standards and Control (NIBSC, UK) and the National Institutes for Food and Drug Control (NIFDC, China). The study showed that between laboratory variations in neutralization titres were significantly reduced when values were expressed relative to those of the IS. The use of this IS will ensure that methods used to measure the serum neutralizing activity or antibody levels against EV71 are accurate, sensitive and reproducible, which will contribute to the standardized assessment of the quality and efficacy of vaccines used in immunization programs globally.

The project to establish an IS for EV-71 vaccine antigen has been initiated with an aim to harmonize methods for the measurement of the antigen content of EV71 products. Different immunochemistry assays are in use for this purpose that employ different antibody reagents and references, which results in difficulties in comparing different EV71 vaccines and in interpreting research results on virus antigenic and immunogenic properties. Being able to establish an IS with an assigned potency should facilitate comparing both EV71 vaccine products and antigen assays. We also aim at establishing both in vitro and in vivo potency assays for EV71 vaccines with good correlation between them.  In addition, it will be important to study the relative contribution of full and empty virus particles to the antigenic and immunogenic properties of the different EV-71 products including their ability to induce antibodies against EV71 isolates from different genogroups. Preliminary results on this project and the different steps required to conduct this collaborative study will be discusse.

The content is authorized by Dr. Javier Martin on October 30, 2017.