Clinical Development of Enterovirus 71 (EV71) Vaccine

Since the infection of enterovirus 71 / EV71 primarily affects countries in the Asia-Pacific region, there is little incentive for vaccine companies from developed countries to develop enterovirus 71 / EV71 vaccines, and mainly the companies and institutes in Asia make efforts to take the vaccines from research to product launch. The ideal candidates for enterovirus 71 / EV71 vaccine should elicit strong cross-genotype neutralizing antibody response and have low costs of the finished products. Candidates based on synthetic peptides, recombinant subunits, virus-like particles, and chemically-inactivated virions are in consideration.

Due to their intrinsically poor immunogenic ability, neutralization epitopes-based enterovirus 71 / EV71 vaccines should be formulated in strong adjuvant such as CFA, which are not approved by FDA right now. Similar situation has been met by recombinant subunit-based enterovirus 71 / EV71 vaccine candidates. For the VLP-based EV71 vaccine candidate, neutralizing antibody responses will be induced only when high dose of them are formulated with alum; there also should be a long time for the construction of recombinant baculovirus VLP-EV71 and the GMP certification of the insect cells; in addition, the high cost of production will be an obstacle for VLP-EV71 vaccine development.

A stable and cost-effective enterovirus 71 / EV71 may be developed based on formalin-inactivated virions that can induce cross-genotype neutralizing antibody responses in mice and non-human primate models. Five inactivated enterovirus 71 / EV71 virion vaccines have been produced in China, Taiwan and Singapore, and have entered into phase 1 or 2 human clinical trials.

Manufacturing processes Clinical trials Reference (clinicaltrials. Gov Identifier)
Organizations Cell lines and EV71 strain UP-stream Down-stream Dosage (μg of EV71 antigen) Population target Current status
NHRIa (Taiwan) Vero cell and EV71 B4 subgenotype (GMP-certified) Roller-bottle (Serum-free media) Gel-filtration Chromatography 5 and 10 Young adults Phase 1 completed NCT01268787
Sinovac (China) Vero cell and EV71 C4 subgenotype Cell factory (Serum-free media) Gel-filtration Chromatography 0.25, 0.5 and 1 Young adults, young children and infants Phase 1 and 2 completed Phase 3 now NCT01273246, NCT01273233, NCT01507857
Beijing Vigoo (China) Vero cell and EV71 C4 subgenotype Cell factory (Serum-free media) Gel-filtration Chromatography 0.4, 0.8 and 1.6 Young adults, young children and infants Phase 1 and 2 completed Phase 3 now NCT01313715, NCT01399853, NCT01508247
CAMS (China) Human diploid cell KMB-17 and EV71 C4 subgenotype Cell factory (Serum-free media) Gel-filtration Chromatography Unknown Young adults, young children and infants Phase 1 and 2 completed Phase 2 now NCT01391494, NCT01512706
Inviragen (Singapore) Vero cell and EV71 B3 subgenotype Cell factory (Serum-free media) Gel-filtration Chromatography 0.3 and 3 Young adults Phase 1 completed NCT01376479

Table 2. Formalin-inactivated EV71 whole-virus vaccine candidates currently being tested in clinical trials

  1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Malaysia C1, C2, B3, B4 C1 C1 B4, C1   C1 B5, C1   B5, C1 B5        
Singapore B3, B4 B3, C1 B3 B4 B4 B4, C1       B5   B5    
Taiwan   B4, C2, C4 B4 B4 B4 B4, C4 B4, B5 C4 C4 C5 B5, C5 B5 B5 C4
Japan C2, B3, B4 C2 C2 C2, B4 C2 B4, C2, C4 C4, B5 C4   C4 C4      
China   C4   C4 C4 C4 C4 C4     C4 A, C4 C4  
Vietnam                 C1, C4, C5        
Australia   C2 B3, C2 B4, C1 B4, C1 C1 C1 C4            
Korea       C3                 C4  
The Netherlands C1, C2   C2 C2 C1 C1, C2   C1, C2 C1, C2   C1, C2 C2    
United Kingdom   C1 C1, C2 C1 C1 C1   C1   C1, C2        
Norway           C1 C1              
Austria         C1 C1 C1 C4            

Bold indicates predominant genotype.
doi: 10.1371/journal.0001737.t006

Table 1. Distribution of EV71 genotypes throughout the world from 1997 to 2010

EV71 Strain Source