Abstract
BackgroundChikungunya virus (CHIKV) and other alphaviruses are the etiologic agents of numerous diseases in both humans and animals. Despite this, the viral mediators of protective immunity against alphaviruses are poorly understood, highlighted by the lack of a licensed human vaccine for any member of this virus genus. The alphavirus E2, the receptor-binding envelope protein, is considered to be the predominant target of the protective host immune response. Although envelope protein domains have been studied for vaccine and neutralization in flaviviruses, their role in alphaviruses is less characterized. Here, we describe the role of the alphavirus E2 domains in neutralization and protection through the use of chimeric viruses.Methodology/Principal FindingsFour chimeric viruses were constructed in which individual E2 domains of CHIKV were replaced with the corresponding domain from Semliki Forest virus (SFV) (ΔDomA/ΔDomB/ΔDomC/ ΔDomA+B). Vaccination studies in mice (both live and inactivated virus) revealed that domain B was the primary determinant of neutralization. Neutralization studies with CHIKV immune serum from humans were consistent with mouse studies, as ΔDomB was poorly neutralized.Conclusions/SignificanceUsing chimeric viruses, it was determined that the alphavirus E2 domain B was the critical target of neutralizing antibodies in both mice and humans. Therefore, chimeric viruses may have more relevance for vaccine discovery than peptide-based approaches, which only detect linear epitopes. This study provides new insight into the role of alphavirus E2 domains on neutralization determinants and may be useful for the design of novel therapeutic technologies.
Highlights
Alphaviruses are a diverse group of arthropod-borne viruses that are distributed worldwide [1]
Related alphaviruses cause human/animal disease globally, yet no vaccines or antivirals exist for human use
Numerous candidate vaccines and therapies are being developed, little is known about the specific viral targets of an effective host immune response
Summary
Alphaviruses are a diverse group of arthropod-borne viruses (arbovirus) that are distributed worldwide [1]. Recent work studying CHIKV evolution has shown that emergence of adaptive mutations, which increase transmissibility in Ae. albopictus can occur in just one passage [7] putting more temperate countries, like the United States, at considerable risk. Other alphaviruses such as the equine encephalitis viruses (eastern, western and Venezuelan), O’nyong nyong (ONNV), Sindbis (SINV) and Semliki Forest (SFV) viruses, pose a considerable threat to human and animal health around the globe [8]. We describe the role of the alphavirus E2 domains in neutralization and protection through the use of chimeric viruses
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