A Rodent Model of Chikungunya Virus Infection in RAG1 -/- Mice, with Features of Persistence, for Vaccine Safety Evaluation

Chikungunya virus (CHIKV) is a positive sense, single stranded RNA virus in the genus Alphavirus, and the etiologic agent of epidemics of severe arthralgia in Africa, Asia, Europe and, most recently, the Americas. CHIKV causes chikungunya fever (CHIK), a syndrome characterized by rash, fever, and debilitating, often chronic arthritis. In recent outbreaks, CHIKV has been recognized to manifest more neurologic signs of illness in the elderly and those with co-morbidities. The syndrome caused by CHIKV is often self-limited; however, many patients develop persistent arthralgia that can last for months or years. These characteristics make CHIKV not only important from a human health standpoint, but also from an economic standpoint. Despite its importance as a reemerging disease, there is no licensed vaccine or specific treatment to prevent CHIK. Many studies have begun to elucidate the pathogenesis of CHIKF and the mechanism of persistent arthralgia, including the role of the adaptive immune response, which is still poorly understood. In addition, the lack of an animal model for chronic infection has limited studies of CHIKV pathogenesis as well as the ability to assess the safety of vaccine candidates currently under development. To address this deficiency, we used recombination activating gene 1 (RAG1-/-) knockout mice, which are deficient in both T and B lymphocytes, to develop a chronic CHIKV infection model. Here, we describe this model as well as its use in evaluating the safety of a live-attenuated vaccine candidate.
Author Summary Chikungunya virus (CHIKV), the etiologic agent of chikungunya fever (CHIK), is a positive sense, single-stranded RNA virus in the genus Alphavirus. Chikungunya fever begins as a flu-like illness, which progresses to severe arthralgia and debilitating arthritis. This syndrome is often self-limited and rarely fatal; however many patients develop persistent arthralgia that can last from months to years. Currently there is no licensed vaccine or specific treatment for CHIKF, leaving current treatment as purely supportive in nature. The role of the adaptive immune system in disease course and viral persistence is still poorly understood. The lack of an animal model of persistent CHIKF has hindered the study of the role of the adaptive immune response and safety testing of vaccine candidates, which are under development. Due to the fact that the vaccine candidate would be deployed in areas where numerous individuals have an impaired adaptive immune system due to malnutrition or disease (HIV/AIDS); it is important to study the safety of the vaccine candidate in immunodeficient animals with no adaptive immune system. In this study we present an animal model of persistent CHIKV in adult mice, which lack an adaptive immune system and demonstrate the safety of a live-attenuated vaccine candidate.