A chikungunya fever vaccine utilizing an insect-specific virus platform

Abstract

Traditionally, vaccine development involves tradeoffs between immunogenicity and safety. Live-attenuated vaccines typically offer rapid and durable immunity but reduced safety, while the inability of inactivated vaccines to replicate enhances safety at the expense of immunogenicity, often necessitating multiple doses and boosters. To overcome these tradeoffs, we developed the insect-specific alphavirus, Eilat virus (EILV), as a vaccine platform. To address the chikungunya virus (CHIKV) pandemic, we used an EILV cDNA clone to design a chimeric virus containing the CHIKV structural proteins. The recombinant EILV/CHIKV virus was structurally identical at 10Å to wild-type CHIKV by single particle cryoelectron microscopy, mimicked the early stages of CHIKV replication in vertebrate cells from attachment and entry to viral RNA delivery, yet remained completely defective for productive replication, providing a high degree of safety. A single dose of EILV/CHIKV produced in mosquito cells elicited rapid (within 4 days) and long-lasting (>290 days) neutralizing antibodies that provided complete protection in two different mouse models. In nonhuman primates, EILV/CHIKV elicited rapid and robust immunity that protected against viremia and telemetrically-monitored fever. Our EILV platform represents the first structurally native application of an insect-specific virus in preclinical vaccine development and highlights the potential application of such viruses in vaccinology.

The neurological complications of chikungunya virus: A systematic review

“…Two phase 1 clinical trials have shown a good safety and immunogenicity profile to date . A recent study that tested an insect‐specific alphavirus as the vaccine platform found promising results in mice and macaques, including immunogenicity after a single dose …”

A scoping review of Chikungunya virus infection: epidemiology, clinical characteristics, viral co-circulation complications, and control

“…Several distinct vaccine approaches are currently under development, however, no vaccine has been licensed. Anti-CHIKV candidates that have been already tested in humans and/or animals include inactivated-, attenuated-, virus like particle-(VLP), DNA-and chimeric vaccines (Eckels et al, 1970;Levitt et al, 1986;Muthumani et al, 2008;Wang et al, 2008;Tiwari et al, 2009;Sharma et al, 2012Akahata et al, 2010Plante et al, 2011;Wang et al, 2011;Gorchakov et al, 2012;Brandler et al, 2013;Chang et al, 2014;García-Arriaza et al, 2014;Tretyakova et al, 2014;van den Doel et al, 2014;Erasmus et al, 2017).…”

“…In addition to classical attenuation via serial viral passage in cells, reverse genetics strategies have been employed as platforms for construction of recombinant attenuated viruses or vaccine chimeras (Wang et al, 2008;Plante et al, 2011;Wang et al, 2011;García-Arriaza et al, 2014;van den Doel et al, 2014;Erasmus et al, 2017). An anti-CHIKV strategy involves the development of an attenuated chimeric vaccine using the Internal Ribosome Entry Site (IRES) of the Encephalomyocarditis virus (ECMV).…”

“…Most recently, a promising vaccine based on a chimera of Eilat virus (EILV) and CHIKV has been reported (Erasmus et al, 2017). The ELIV/ CHIKV possesses non-structural proteins of EILV and structural and accessory proteins of 99659 CHIKV strain (Asian lineage).…”

“…Since the EILV is an alphavirus specific for insects, the EILV/CHIKV was unable to replicate in vertebrate hosts, thereby providing a high degree of safety. In NHP, ELIV/CHIKV stimulated immune response and guaranteed protection against viremia (Erasmus et al, 2017).…”