Abstract
Chikungunya virus (CHIKV) is the causative pathogen of chikungunya fever, a mosquito-borne viral disease causing highly debilitating arthralgia that can persist for months and progress to chronic arthritis. Our previous studies have identified the CHIKV live-attenuated vaccine candidate CHIKV-NoLS. Like most live-attenuated vaccines, attenuated replication of CHIKV-NoLS has the potential to limit scalable production. To overcome production limits, as well as other drawbacks of live-attenuated vaccines, we developed an in vivo liposome RNA delivery system to deliver the self-replicating RNA genome of CHIKV-NoLS directly into mice, allowing the recipients' body to produce the live-attenuated vaccine particles. CAF01 liposomes were able to deliver replication-competent CHIKV-NoLS RNA in vitro. Immunodeficient AG129 mice inoculated with liposome-delivered CHIKV-NoLS RNA developed viremia and disease signs representative of this lethal model of CHIKV infection, demonstrating de novo vaccine particle production in vivo. In immunocompetent C57BL/6 mice, liposome-delivered CHIKV-NoLS RNA inoculation was associated with reduced IgM and IgG levels with low antibody CHIKV-neutralizing capacity, compared to vaccination with the original live-attenuated vaccine CHIKV-NoLS. One dose of liposome-delivered CHIKV-NoLS RNA did not provide systemic protection from CHIKV wild-type (WT) challenge but was found to promote an early onset of severe CHIKV-induced footpad swelling. Liposome-delivered CHIKV-NoLS RNA inoculation did, however, provide local protection from CHIKV-WT challenge in the ipsilateral foot after one dose. Results suggest that in the presence of low CHIKV-specific neutralizing antibody levels, local inflammatory responses, likely brought on by liposome adjuvants, have a role in the protection of CHIKV-induced footpad swelling in the ipsilateral foot of mice inoculated with liposome-delivered CHIKV-NoLS RNA. Low IgG and CHIKV-specific neutralizing antibody levels may be responsible for early onset of severe swelling in the feet of CHIKV-WT-challenged mice. These results support previous studies that suggest CHIKV is vulnerable to antibody-mediated enhancement of disease. Further studies using booster regimes aim to demonstrate the potential for liposomes to deliver the self-replicating RNA genome of live-attenuated vaccines and offer a novel immunization strategy.
Highlights
Chikungunya fever is a mosquito-borne viral disease caused by the chikungunya virus (CHIKV)
To overcome potential production limits for our CHIKV vaccine candidate (CHIKV-nucleolar localization sequence (NoLS)), we developed a liposomal approach to deliver the replication-competent RNA genome of the liveattenuated vaccine
CHIKV-NoLS RNA inoculation did not produce any PRNT50 antibodies. The use of this novel liposome delivery system has a number of potential benefits over a traditional live-attenuated vaccine: [1] CHIKV-NoLS is currently passaged in Vero cells, an acceptable vaccine substrate, using virus production serum-free medium (VP-SFM), a serumfree, ultra-low-protein medium, and administered in vivo as a live-attenuated virus particle
Summary
Chikungunya fever is a mosquito-borne viral disease caused by the chikungunya virus (CHIKV). CHIKV has recently become established in the Americas, infecting over 1.5 million people in just 2 years [4]. The majority of individuals infected with CHIKV develop disease [5, 6]. Symptoms of chikungunya disease are characterized by the acute onset of fever and joint pain lasting 7–10 days. A high proportion of patients experience prolonged articular pain and arthritis lasting several weeks to years [7]. This chronic form of CHIKV disease contributes considerably to disease burden.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have