Structural vaccinology for Chikungunya vaccine design

Chikungunya virus (CHIKV) has emerged as a global health concern due to its recent epidemic outbreak in 2005 in islands of the Indian Ocean and attracted the attention of the western world. The virus is transmitted from two species of mosquitoes (Aedes aegypti and Aedes albopictus) to human. Symptoms of Chikungunya fever includes non-lethal but severe and disabling effects such as rash, joint pain and polyarthralgia. Most patients feel better within a week but in some cases the joint pain may persist for months. Various efforts has been made to develop a vaccine against CHIKV. These include inactivated vaccine, live- attenuated virus vaccines, DNA vaccines, chimeric virus vaccines, subunit protein vaccines and a virus-like particle (VLP) based vaccines. Among these, majority of vaccine candidates are at preclinical stage and/or phase I trial (Ahola et al., 2015). A live-attenuated CHIKV vaccine (TSI-GSD218), developed by U.S. Army showed promising results in phase I and phase II clinical trials, however, it was not pursued further due to some side effect like arthralgia in 8% of volunteers (Hoke et al., 2012). As such, no CHIKV specific drug or vaccine is licensed for human use to date. Chikungunya virus belongs to the alphavirus genus which contain a single-stranded RNA genome that codes for four non-structural proteins and five structural proteins (Griffin et al., 2007). The non-structural proteins are required for virus replication, protein modification, and immune antagonism. The structural proteins (capsid-E3- E2-6K-E1) are synthesized as a polyprotein from a subgenomic promoter, and are cleaved post-translationally into separate proteins by an autoproteinase and signalase. The E1 glycoprotein participates in cell fusion (Lescar et al.,2001), whereas the E2 glycoprotein binds to cellular receptors (Smith et al., 1995; Zhang et al., 2005) and initiates clathrin-dependent endocytosis (Solignat et al., 2009). With the elucidation of the 2.2-A -resolution crystal structure of recombinant CHIKV E3-E2-E1 complex solved by Voss et al., 2010, and 5.3 A resolution, cryo-electron microscopy (cryoEM) map of Chikungunya VLPs with antibody bound by Sun et al., 2013, these structures have reveal the mechanisms responsible for receptor interactions, domain epitopes targeted by neutralizing antibodies, providing new ways for vaccine design. However, all the previous research has relied on injecting mouse models with VLPs for immunization to generate artificial (n)Abs as potential vaccine design. Here we propose a mature and effective methods of yeast surface display (YSD) to generate yeast libraries to obtain human antibodies from serum of CHIKV patients for a more reliable vaccine design and structural study.