Hybrid large hepatitis B surface protein composed of two viral genotypes C and D induces strongly cross-neutralizing antibodies

Abstract

Hepatitis B virus (HBV) vaccination is known to effectively decrease the risk of HBV infection. However, several issues need to be addressed in order to develop an improved HBV vaccine. Although the HBV vaccine has been shown to be effective, this vaccine needs to be more efficacious in defined groups, including non-responders (i.e., individuals who do not develop a protective response even after vaccination) and in health care workers and travelers who require rapid protection. Furthermore, it has been reported that universal HBV vaccination has accelerated the appearance of vaccine-escape mutants resulting from the accumulation of mutations altering the “a” determinant of the hepatitis B surface (HBs) protein. To address these problems, we have been focusing on the large HBs (LHBs) protein, which consists of three domains: pre-S1, pre-S2, and S (in N- to C-terminal order). To enhance the immunogenicity of LHBs, we developed a yeast-derived hybrid LHBs (hy-LHBs) antigen composed of the LHBs proteins from two distinct genotypes (Genotypes C and D). The levels of antibodies induced by hy-LHBs immunization were high not only against S, but also against the pre-S1 and pre-S2 domains. Additionally, hy-LHBs immunization induced significantly more strongly cross-reactive neutralizing antibodies than did small HBs (SHBs) or LHBs of any genotype alone. These findings suggested that hy-LHBs might serve as a candidate antigen for use in an improved prophylactic HBV vaccine.