Vaccination with a chikungunya virus-like particle vaccine exacerbates disease in aged mice

Introduction Chikungunya virus (CHIKV) is a re-emerging pathogen responsible for causing outbreaks of febrile disease accompanied with debilitating joint pain. Symptoms typically persist for two weeks, but more severe and chronic chikungunya illnesses have been reported, especially in the elderly. Currently, there are no licensed vaccines or antivirals against CHIKV available. In this study, we combined a CHIK virus-like particle (VLP) vaccine with different adjuvants to enhance immunogenicity and protection in both, adult and aged mice. Methods CHIK VLP-based vaccines were tested in 6-8-week-old (adult) and 18-24-month-old (aged) female C57BL/6J mice. Formulations contained CHIK VLP alone or adjuvants: QuilA, R848, or Imject Alum. Mice were vaccinated three times via intramuscular injections. CHIKV-specific antibody responses were characterized by IgG subclass using ELISA, and by microneutralization assays. In addition, CHIKV infections were characterized in vaccinated and non-vaccinated adult mice and compared to aged mice. Results In adult mice, CHIKV infection of the right hind foot induced significant swelling, which peaked by day 7 post-infection at approximately 170% of initial size. Viral titers peaked at 2.53 x 10(10) CCID50/ml on day 2 post-infection. Mice vaccinated with CHIK VLP-based vaccines developed robust anti-CHIKV-specific IgG antibody responses that were capable of neutralizing CHIKV in vitro. CHIK VLP alone or CHIK plus QuilA administered by IM injections protected 100% of mice against CHIKV. In contrast, the antibody responses elicited by the VLP-based vaccines were attenuated in aged mice, with negligible neutralizing antibody titers detected. Unvaccinated, aged mice were resistant to CHIKV infection, while vaccination with CHIKV VLPs exacerbated disease. Conclusions Unadjuvanted CHIK VLP vaccination elicits immune responses that protect 100% of adult mice against CHIKV infection. However, an improved vaccine/adjuvant combination is still necessary to enhance the protective immunity against CHIKV in the aged. Author summary Chikungunya virus is responsible for outbreaks of febrile illnesses accompanied with debilitating join pain in subtropical and tropical regions of the world. The disease caused by chikungunya virus typically resolves itself within weeks, but may be persistent and more severe in elderly individuals. Currently, there are no licensed vaccines, although a virus-like particle vaccine is currently being tested in Phase II clinical trials. In this study, we formulated chikungunya virus-like particles with adjuvants to skew and enhance the immune responses against chikungunya, and vaccinated adult and aged mice. Our aim was to identify a vaccine formulation that would protect adult and elderly populations. Results showed that the unadjuvanted vaccine was very effective in adult mice, eliciting strong virus-neutralizing antibody titers, and protecting mice against chikungunya infection and disease. In contrast, chikungunya disease was exacerbated in mice vaccinated with the virus-like particle vaccine alone or with QuilA adjuvant. This study highlights the need for an improved vaccine approach to safely and effectively vaccinate the elderly against chikungunya viral infections.