Glycoprotein engineering for hemorrhagic fever virus vaccines

Scientists stabilized the Crimean-Congo hemorrhagic fever virus glycoprotein complex to study its structure and develop a potential vaccine. This complex elicits an immune response and sheds light on the virus's entry mechanism.

Background

Crimean-Congo hemorrhagic fever virus (CCHFV) is a serious threat to human health, with mortality rates ranging from 10% to 40%. The virus is primarily transmitted through tick bites or contact with infected livestock, and its range is expanding due to factors like climate change and livestock trade. The lack of approved vaccines or treatments for CCHFV infection underscores the urgent need for effective medical countermeasures. Current approaches to understanding CCHFV entry mechanisms and developing vaccines have been limited by the complex organization and processing of the virus's glycoproteins. Specifically, the structure of the glycoprotein Gn and its interactions with other viral glycoproteins, GP38 and Gc, have remained elusive. This lack of structural information has hindered efforts to design stable glycoprotein complexes suitable for vaccine development and has limited our understanding of the virus's entry process into host cells.

Technology description

The Crimean-Congo hemorrhagic fever virus (CCHFV) is a serious threat to human health, and no approved vaccines or treatments are currently available. This technology describes engineering of a stabilized heterotrimeric glycoprotein complex from CCHFV, consisting of GP38, Gn, and Gc proteins. This complex mimics the pre-fusion state of viral glycoproteins, essential for viral entry into host cells. The complex is stabilized by a disulfide bond and polar interactions, enhancing its stability and expression levels. Structural analysis revealed the intricate interactions between the three proteins and highlighted the role of an N-linked glycan on Gn in stabilizing the Gc fusion loops.

This technology is differentiated because it provides the first structural understanding of a stabilized, pre-fusion heterotrimeric glycoprotein complex for CCHFV. Previous studies have only reported structures of individual CCHFV glycoproteins or complexes in their post-fusion state. This breakthrough offers crucial insights into the virus's entry mechanism and facilitates the development of novel vaccines and therapeutics. Immunization studies in mice demonstrated that this complex elicits a protective immune response, making it a promising candidate for vaccine development against CCHFV.

Benefits

Provides a detailed understanding of the Crimean-Congo hemorrhagic fever virus (CCHFV) entry mechanism
Offers a potential template for vaccine development against CCHFV
Presents a stabilized heterotrimeric glycoprotein complex (GP38-Gn-Gc) that elicits a protective immune response in mice