Abstract
Currently, there are no commercially available live‐attenuated vaccines against chikungunya virus (CHIKV). Here, CHIKVs with mutations in non‐structural proteins (nsPs) were investigated for their suitability as attenuated CHIKV vaccines. R532H mutation in nsP1 caused reduced infectivity in mouse tail fibroblasts but an enhanced type‐I IFN response compared to WT‐CHIKV. Adult mice infected with this nsP‐mutant exhibited a mild joint phenotype with low‐level viremia that rapidly cleared. Mechanistically, ingenuity pathway analyses revealed a tilt in the anti‐inflammatory IL‐10 versus pro‐inflammatory IL‐1β and IL‐18 balance during CHIKV nsP‐mutant infection that modified acute antiviral and cell signaling canonical pathways. Challenging CHIKV nsP‐mutant‐infected mice with WT‐CHIKV or the closely related O'nyong‐nyong virus resulted in no detectable viremia, observable joint inflammation, or damage. Challenged mice showed high antibody titers with efficient neutralizing capacity, indicative of immunological memory. Manipulating molecular processes that govern CHIKV replication could lead to plausible vaccine candidates against alphavirus infection.
Highlights
There are no commercially available live-attenuated vaccines against chikungunya virus (CHIKV)
All three CHIKV non-structural proteins (nsPs)-mutants showed decreased virus infectivity capacity (Figs 1B and EV1A), only R to H (RH)-CHIKV and RHEV-CHIKV showed a low viral RNA titer compared to WT-CHIKV at 12 hpi (Fig EV1B), indicative of reduced viral replication
The reduced viral RNA titers produced by RH-CHIKV and RHEV-CHIKV were associated with higher soluble IFN-a and IFN-b levels (Fig EV1C and D)
Summary
There are no commercially available live-attenuated vaccines against chikungunya virus (CHIKV). CHIKVs with mutations in non-structural proteins (nsPs) were investigated for their suitability as attenuated CHIKV vaccines. R532H mutation in nsP1 caused reduced infectivity in mouse tail fibroblasts but an enhanced type-I IFN response compared to WT-CHIKV. Adult mice infected with this nsP-mutant exhibited a mild joint phenotype with low-level viremia that rapidly cleared. Ingenuity pathway analyses revealed a tilt in the anti-inflammatory IL10 versus pro-inflammatory IL-1b and IL-18 balance during CHIKV nsP-mutant infection that modified acute antiviral and cell signaling canonical pathways. Challenging CHIKV nsP-mutant-infected mice with WT-CHIKV or the closely related O’nyong-nyong virus resulted in no detectable viremia, observable joint inflammation, or damage. Manipulating molecular processes that govern CHIKV replication could lead to plausible vaccine candidates against alphavirus infection
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