Development of scrub typhus vaccine using an autotransporter protein of Orientia tsutsugamushi

Abstract

Introduction: Scrub typhus is an acute febrile illness caused by O. tsutsugamushi infection. Recently, the rapid increase of scrub typhus incidence and sporadic outbreaks in several countries of endemic Asian-pacific region has become a serious public health issue. Despite the wide range of preventative approaches that have been attempted in the past 70 years, all have failed to develop an effective prophylactic vaccine. Currently, the selection of the proper antigens is one of the critical barriers to generating cross-protective immunity against antigenically-variable strains of O. tsutsugamushi. Methods: Based on the functional genomic analysis, a group of genes encoding autotransporter proteins has been identified and characterized in the genome of O. tsutsugamushi. The sequences of surface cell antigen (sca) genes were compared among diverse genotypes of O. tsutsugamushi and the potential role of Sca proteins in the bacterial interaction with host cells was examined. In addition, the antigenicity of them was investigated using scrub typhus patients sera. Finally, I screened Sca antigens for vaccine development after immunization and subsequent lethal challenge of diverse strains in mice infection model. Results: Five sca genes (scaA-E) encoding autotransporter proteins were identified in the genome of O. tsutsugamushi. Among them, ScaA and ScaC have been well conserved in diverse genotype of O. tsutsugamushi. I found that these two bacterial proteins are involved in the bacterial adhesion to host cells and induced specific immune responses in scrub typhus patients. Furthermore, immunization of ScaA could provide significant protective immunity not only against to homologous strain infection but also to the lethal challenge of heterologous strains. Conclusions: Immunization of ScaA proteins provides protective immunity in mice when challenged with the homologous strain and significantly enhanced protective immunity against infection with heterologous strains. To our knowledge, this is the most promising result of scrub typhus vaccination trials against infection of heterologous strains in mouse models thus far.