Inactivated Enterovirus 71 Vaccine Produced by 200-L Scale Serum-Free Microcarrier Bioreactor System Provides Cross-Protective Efficacy in Human SCARB2 Transgenic Mouse

Wu, Chia-Ying; Lin, Yi‐Wen; Chia-Ho, Kuo; Liu, Wan–Hsin; Hsiu-Fen, Tai; Chien-Hung, Pan; Chen, Yung-Tsung; Hsiao, Pei-Wen; Chan, Chi-Hsien; Chang, C.; Liu, Chung-Cheng; Chow, Yen‐Hung; Chen, Juine-Ruey

doi:10.1371/journal.pone.0136420

Cited by 24 publications

(22 citation statements)

References 47 publications

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“…Moreover, the VP1–104 residue encoded two different amino acids (Asn and Asp) in the wild-type EV-V, but these were mutated into the unique residue Asn in EV-R (Table 1 ). We sequenced another genotype, B4 of EV71 E59, which has been used as a vaccine strain 48 , and found that the VP1–145 residue encoding Gly remained the same after passage in RD and Vero cells. These phenomena have been observed in previous studies; substitution of residue 145 from E to G while passage of EV71 in RD was observed 49 , 50 .…”

Section: Discussionmentioning

confidence: 99%

Mutations in VP1 and 5′-UTR affect enterovirus 71 virulence

Chang

Chen

et al. 2018

Sci Rep

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Enterovirus 71 (EV71) is a major cause of hand, foot and mouth disease (HFMD). The current EV71 propagating in Vero (EV-V) or sub-passaged in RD (EV-R) cells was used as a pathogen. Interestingly, EV-R exhibited differential virulence; challenging human scavenger receptor class B2-expressing (hSCARB2-Tg) mice with EV71 revealed that EV-V was more virulent than EV-R: 100% of mice that received lethal amounts of EV-V died, while all the mice that received EV-R survived. Severe pathogenesis correlated with viral burdens and proinflammatory cytokine levels were observed in EV-V-challenged mice, but controversy in EV-R-challenged mice. Consensus sequence analysis revealed EV-R rapidly acquired complete mutations at E145G and S241L and partial mutations at V146I of VP1, and acquired a T to C substitution at nucleotide 494 of the 5′-UTR. EV-R exhibited higher binding affinity for another EV71 receptor, human P-selectin glycoprotein ligand-1 (hPSGL-1), than EV-V. Both EV71s exhibited no significant difference in binding to hSCARB2. The molecular modelling indicate that these mutations might influence EV71 engagement with PSGL-1 and in vivo virulence.

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Section: Discussionmentioning

confidence: 99%

Mutations in VP1 and 5′-UTR affect enterovirus 71 virulence

Chang

Chen

et al. 2018

Sci Rep

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“…Consistent with EV71 replication in natural systems, the production of EV71 virus vaccine in bioreactors with a suspended microcarrier system yields both FP and EP particles [20]. A previous mouse vaccination study showed that FPs derived from the B4(E59) strain are more potent antigens than EPs and confer superior immunogenic efficacy in the neutralization of homologous virus [21].…”

Section: Introductionmentioning

confidence: 99%

The mature EV71 virion induced a broadly cross-neutralizing VP1 antibody against subtypes of the EV71 virus

Wu¹,

Yung-Tsung³

et al. 2019

PLoS ONE

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Enterovirus 71 (EV71) has emerged as a neurological virus causing life-threatening diseases in young children and infants. Although EV71 vaccines in development have presented promising results in several clinical trials, the identified key antigen for improving the broad protective efficacy of EV71 vaccines has not been well investigated. In this report, we show that different multiplicities of infection (MOIs) of the B4(E59) virus significantly affect EV71 vaccine production in a serum-free microcarrier bioreactor system. The antigens produced from high MOIs of 10−1 and 10−2 exhibited higher yield and more infectious full particle (FP) contents in the EV71 vaccines than those produced with low MOIs of 10−4 and 10−6, leading to better cross-neutralizing efficacy. The C4(E36) neutralization results showed that only antisera raised from EV71 FPs provided substantial neutralizing titers against C4(E36), whereas empty particles (EPs) of EV71 conferred no efficacy. Competitive ELISA showed that anti-FP mainly binds to FPs and that 20% of antibodies bind to EPs, whereas most anti-EP binds EPs, with only 10% antibodies binding to FPs. VP1-adsorbed anti-FP lost most of the virus neutralization efficiency, suggesting that the VP1 subunit of FP is the major immunogenic antigen determining the ability of the EV71 vaccine to elicit cross-neutralizing antibodies against EV71 virus subtypes. These findings demonstrate that the high-MOI production approach is significantly correlated with FP productivity, thereby improving the cross-neutralization efficacy of an EV71 vaccine and providing the basis for a better vaccine design against widespread EV71 viruses.

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“…To solve this problem, numerous studies have focused on vaccine development in the past decade [45][46][47][48][49], and inactivated EV71 vaccines, providing an invaluable gift for children, were developed successfully [11,12,50]. Several EV71 genotypes such as C4a, B5, C2 were circulating in the Asia-Pacific Region in the past decade and EV71 genotypes might be the key factor to affect vaccine cross-neutralization [51][52][53][54][55]. Hence, it would be further investigated whether EV71 vaccines developed using a single EV71 strain could provide strong cross-protection against other EV71 strains.…”

Section: Discussionmentioning

confidence: 99%

Enterovirus 71 Infection Shapes Host T Cell Receptor Repertoire and Presumably Expands VP1-Specific TCRβ CDR3 Cluster

Liao

Chen

et al. 2020

Pathogens

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Enterovirus 71 (EV71) has become an important public health problem in the Asia-Pacific region in the past decades. EV71 infection might cause neurological and psychiatric complications and even death. Although an EV71 vaccine has been currently approved, there is no effective therapy for treating EV71-infected patients. Virus infections have been reported to shape host T cell receptor (TCR) repertoire. Therefore, understanding of host TCR repertoire in EV71 infection could better the knowledge in viral pathogenesis and further benefit the anti-viral therapy development. In this study, we used a mouse-adapted EV71 (mEV71) model to observe changes of host TCR repertoire in an EV71-infected central nervous system. Neonate mice were infected with mEV71 and mouse brainstem TCRβ repertoires were explored. Here, we reported that mEV71 infection impacted host brainstem TCRβ repertoire, where mEV71 infection skewed TCRβ diversity, changed VJ combination usages, and further expanded specific TCRβ CDR3 clones. Using bioinformatics analysis and ligand-binding prediction, we speculated the expanded TCRβ CDR3 clone harboring CASSLGANSDYTF sequence was capable of binding cleaved EV71 VP1 peptides in concert with major histocompatibility complex (MHC) molecules. We observed that mEV71 infection shaped host TCRβ repertoire and presumably expanded VP1-specific TCRβ CDR3 in mEV71-infected mouse brainstem that integrated EV71 pathogenesis in central nervous system.

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Inactivated Enterovirus 71 Vaccine Produced by 200-L Scale Serum-Free Microcarrier Bioreactor System Provides Cross-Protective Efficacy in Human SCARB2 Transgenic Mouse

Cited by 24 publications

References 47 publications

Mutations in VP1 and 5′-UTR affect enterovirus 71 virulence

Mutations in VP1 and 5′-UTR affect enterovirus 71 virulence

The mature EV71 virion induced a broadly cross-neutralizing VP1 antibody against subtypes of the EV71 virus

Enterovirus 71 Infection Shapes Host T Cell Receptor Repertoire and Presumably Expands VP1-Specific TCRβ CDR3 Cluster

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