The World Health Organization (WHO) reports that approximately 150 million
individuals worldwide are afflicted with a chronic hepatitis C viral (HCV) infection. Although HCV can cause acute infections that are spontaneously cleared within a short time period, chronically infected individuals are at serious risk of developing liver-related disease. The WHO estimates that around 700,000 individuals die every year due to complications arising from HCV-related infection. With the new direct acting antiviral (DAA) therapy, the HCV treatment landscape is sure to change, with a potential decrease in the mortality and morbidity associated with HCV infections. Nonetheless, there is a dire need for a prophylactic measure in the form of an HCV vaccine, which has proven elusive thus far.
A group based at the Johns Hopkins University School of Medicine, led by principal investigator Dr. Justin Bailey, MD, PhD, has published an article
in PLOS Pathogens
that provides insight on how HCV evades the human immune response and why developing an HCV vaccine has been difficult. Per the authors, to develop a successful vaccine against a virus that is as genetically diverse as HCV, the vaccine must be able to elicit an immune response that targets a large range of viral forms.
The authors generated a library of E1 and E2 genes, which code for viral envelope glycoproteins
, to examine the link between sequence and sensitivity to two powerful, broadly neutralizing antibodies (bNAbs), HC33.4 and AR4A. The library consisted of naturally occurring HCV E1E2 genes, of which 113 produced viable HCV pseudoparticles (HCVpp) which were used for further study. The authors utilized the library to first examine any variations in the HCVpp library in the binding region of the two bNAbs examined. Results showed that the HC33.4 antibody show some variability at one position examined while the AR4A antibody showed no variability in the epitopes examined.
Dr. Bailey and his colleagues then measured if the HCVpp library can mediate successful cell entry when incubated with either of the two bNAbs. Results showed that HC33.4 neutralized 88% of the HCVpp library while AR4A neutralized 85.8%. The authors were surprised to find large variability in each bNAb’s ability to neutralize the HCVpp library. In a press release
, Ramy El-Diwany, lead investigator on the study, is quoted saying, “We discovered that there was a lot of naturally occurring resistance, meaning we may need to greatly expand the set of viruses we use to evaluate potential vaccines.”