Development of enterovirus 71 vaccines: from the lab bench to Phase III clinical trials

Abstract

The widespread epidemics of enterovirus 71 (EV71) seriously affected the Western Pacific Region. Young children, especially those younger than 3 years are the most susceptible population to the EV71-associated diseases. Several Asian countries have begun to focus on the research and development of EV71 vaccines. Five inactivated whole-virus EV71 candidate vaccines (three were manufactured in mainland China based on a C4 genotype strain, one in Taiwan based on a B4 genotype strain and one in Singapore based on a B2 genotype strain) have been assessed in clinical trials. Three candidate vaccines developed in mainland China have already completed Phase III clinical trials recently. The tested EV71 vaccine could provide good efficacy, satisfactory safety, and high immunogenicity. Thus, inactivated EV71 vaccines are expected to become the first available vaccines against EV71 in the near future.

Keywords::

• clinical trial
• efficacy
• EV71 vaccine
• hand, foot and mouth disease
• immunogenicity
• safety
• seroprevalences
• vaccine strain

Financial & competing interests disclosure

This manuscript was supported by China’s 12–5 National Major Infectious Disease Program (2012ZX10004703). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The widespread epidemics of enterovirus 71 (EV71) seriously affected the Western Pacific Region, but outside of the Asia-Pacific region few severe cases and deaths associated with EV71 were observed. The reason why EV71 were circulating predominantly in Asia and caused a large number of deaths in this region has not yet been understood completely.

• There is a need to develop and improve the monitoring system for molecular epidemiology in epidemic areas and to evaluate evolutionary trends and the variation extent of EV71 virus.

• As EV71 candidate vaccines developed in different countries or regions were based on different genotype strains in accordance with the predominant genotype circulated in the local areas, concerns on the cross-protection capability of vaccine against different genotype strains were raised.

• Preclinical studies indicated that immunization of EV71 strain could elicit both cellular and humoral immunity to neutralize EV71 in vivo and in vitro, block the cytopathic effect and decrease the animal morbidity or mortality.

• Five EV71 candidate vaccines were assessed in clinical trials. Early clinical trials have shown good safety and immunogenicity of the alum-adjuvant inactivated EV71 vaccines.

• In Phase III clinical trials, the alum-adjuvant inactivated EV71 vaccines could provide significant protection against EV71-associated disease, especially EV71-associated HFMD in children for 1 year. But a booster dose of EV71 vaccine may be needed for persistent protection.

• After the approval in the market, the EV71 vaccine may face some practical issues and an optimized immunization strategy would be needed. And the protective efficacy of EV71 vaccine could be challenged by both the newly generated genotypes of EV71 and other predominant enterovirues such as CA16.