Vaccine for Hepatitis E virus (HEV)

28 Apr 2015 NUS scientists in collaboration with Xiamen University studied the neutralization mechanism of Hepatitis E virus infection and developed a vaccine

Infectious hepatitis viral diseases are major health problems in both developing and developed countries. Hepatitis E virus (HEV) is an important cause of severe hepatitis in humans. HEV infection causes severe liver inflammation characterized by jaundice, fever, liver enlargement and abdominal pain.The mortality rate in the general population is ~5% and ~25% in pregnant women.

A team led by Prof Jayaraman SIVARAMAN from the Department of Biological Science in NUS in collaboration with Prof Ningshao XIA from Xiamen University in China has developed a neutralization antibody strategy for HEV infection. This collaborative project between NUS and Xiamen is initiated by Prof HEW Choy Leong and he is the key person whom strongly supported this joint project. They have demonstrated that the HEV protein shell (capsid) is partially enclosed, and is consist of homodimers of the E2 domain. These dimers protrude from the viral surface and engage with the host cell to initiate infection (Li et al PLoS Pathogens 2009). They have raised several monoclonal antibodies (mAbs) against all four genotypes of HEV.

The team showed that genotype-1 HEV is preferentially neutralized by mAb 8C11 and specifically engages with the capsid protein E2 domain at the groove region (see Figure). mAb 8G12, on the other hand, interacts at the dimer interface region, neutralizes all four genotypes of HEV with ~2.53-3.45 nM binding affinity. 8G12 has a protective, neutralizing capacity that significantly blocks virus infection to host cells. Animal studies confirmed 8G12 to be a neutralizing mAb, with immune predominance in anti-HEV to effectively prevent hepatitis E infection. Using structure-based mutations and cell model assays with virus-like particle (VLP), the scientists have identified several conserved residues from all four genotypes that are essential for 8G12 neutralization and identified the key epitopes to abolish virus-host interactions.

The VLP used in these studies includes E2 domain, consist of 239 amino acids of the HEV capsid protein, which can enter the host, similar to that of an authentic virus. The HEV neutralization mechanism identified with E2 domain of capsid protein was instrumental in the development of a vaccine for HEV. His collaborators at Xiamen University conducted the pre-clinical and clinical studies and recently a vaccine for HEV (VLP-p239) was launched into the market.

These images show that genotype-1 HEV is preferentially neutralized by mAb 8C11 and specifically engages with the capsid protein E2 domain at the groove region. [Image credit: Sivaraman J and Tang X]

References

1. Gu Y, Tang X, Zhang X, Song C, Zheng M, Wang K, Zhang J, Ng MH., Hew CL, Li ., Xia N, Sivaraman J. “Structural Basis for the Neutralization of Hepatitis E Virus by a Cross-genotype Antibody.” Cell Res (2015) (In press)

2. Tang X, Yang C, Gu Y, Song C, Zhang X, Wang Y, Zhang J, Hew CL, Li S, Xia N, Sivaraman J “Structural basis for the neutralization and genotype specificity of hepatitis E virus.” PNAS (2011) 108 10266

3. Li S, Tang X, Seetharaman J, Yang C, Gu Y, Zhang J, Du H, Shih JW, Hew CL, Sivaraman J, Xia N “Dimerization of hepatitis E virus capsid protein E2s domain is essential for virus-host interaction.” PLoS Pathogens 5 (2009) e1000537