Research Article: Identifying the Role of E2 Domains on Alphavirus Neutralization and Protective Immune Responses

Date Published: October 16, 2015

Publisher: Public Library of Science

Author(s): James Weger-Lucarelli, Matthew T. Aliota, Attapon Kamlangdee, Jorge E. Osorio, Scott C. Weaver.

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.

Partial Text: Alphaviruses are a diverse group of arthropod-borne viruses (arbovirus) that are distributed worldwide [1]. Chikungunya virus (CHIKV) has been the cause of several recent outbreaks of arthritic disease and has now spread into the Caribbean and Central/South America, with at least 44 countries in the Americas having reported locally acquired cases, including the United States [2]. The disease caused by CHIKV is characterized by high fever and painful arthralgia, which can last for months or even years after infection [3]. The primary mosquito vector for CHIKV transmission is Aedes aegypti; however, recent evolution of certain lineages of the virus has allowed increased transmission by the more temperate Aedes albopictus [4, 5]. While this adaptation has facilitated recent outbreaks of CHIKV in Europe and southeast Asia, the virus circulating in the Americas does not possess this mutation [6]. Still, 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, also pose a considerable threat to human and animal health around the globe [8].

The massive ongoing outbreak and global spread of CHIKV has highlighted the need for a vaccine against this virus. The development of a vaccine is hampered by the lack of knowledge of specific domains of protection that can assist in designing rationale vaccines that are safe and highly effective. Recombinant live-attenuated (LAV) or sub-unit vaccines that target a particular domain of CHIKV might represent the best option for a vaccine candidate. We have previously shown that an attenuated poxvirus, modified vaccinia Ankara (MVA), expressing only CHIKV E3 and E2 proteins was a safe and effective vaccine candidate [21]. Other groups have shown that E2 or peptides within E2 can produce a protective immune response in mice [13, 37, 38]. A recent study showed that neutralizing antibodies and protection could be induced by vaccination with sub-unit antigens consisting of either domain B or domains A and B together, suggesting individual domains of the receptor binding protein are sufficient to produce a neutralizing antibody response [39].



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