Chikungunya Virus Strains Show Lineage-Specific Variations in Virulence and Cross-Protective Ability in Murine and Nonhuman Primate Models

Abstract

Chikungunya virus (CHIKV) is a reemerging arbovirus capable of causing explosive outbreaks of febrile illness, polyarthritis, and polyarthralgia, inflicting severe morbidity on affected populations. CHIKV can be genetically classified into 3 major lineages: West African (WA); East, Central, and South African (ECSA); Indian Ocean (IOL); and Asian. Additionally, the Indian Ocean (IOL) sublineage emerged within the ECSA clade and the Asian/American sublineage emerged within the Asian clade. While differences in epidemiological and pathological characteristics among outbreaks involving different CHIKV lineages and sublineages have been suggested, few targeted investigations comparing lineage virulence levels have been reported. We compared the virulence levels of CHIKV isolates representing all major lineages and sublineages in the type I interferon receptor-knockout A129 mouse model and found lineage-specific differences in virulence. We also evaluated the cross-protective efficacy of the IOL-derived, live-attenuated vaccine strain CHIKV/IRESv1 against the Asian/American CHIKV isolate YO123223 in both murine and nonhuman primate models, as well as the WA strain SH2830 in a murine model. The CHIKV/IRES vaccine provided protection both in mice and in nonhuman primate cohorts against Caribbean strain challenge and protected mice against WA challenge. Taken together, our data suggest that Asian/American CHIKV strains are less virulent than those in the Asian, ECSA, and WA lineages and that despite differences in virulence, IOL-based vaccine strains offer robust cross-protection against strains from other lineages. Further research is needed to elucidate the genetic basis for variation in CHIKV virulence in the A129 mouse model and to corroborate this variation with human pathogenicity.

A Single and Un-Adjuvanted Dose of a Chimpanzee Adenovirus-Vectored Vaccine against Chikungunya Virus Fully Protects Mice from Lethal Disease

“…Previous studies have shown that viremia in A129 mice occurs on days 1-3 [15]. Therefore, to determine if the vaccine could protect against viremia, blood was taken from all mice on day 2 post challenge, which corresponds to the predicted day of peak viremia [15]. Consistent with survival and foot swelling, only the mice that were PBS-treated or ChAdOx1 Zika-vaccinated had a viremia of approximately 6 log10 pfu/mL ( Figure 5).…”

“…All ChAdOx1 CHIKV-vaccinated mice were protected in this model, even at a high challenge dose, highlighting the robustness of the single-dose vaccination. Furthermore, high titer viremias are produced from CHIKV infection in A129 mice [15], and ChAdOx1 CHIKV vaccines were able to reduce challenge viremia levels to undetectable levels on the day of highest anticipated titer. This feature is critical for arbovirus vaccines as it decreases the potential for mosquito transmission.…”

“…The most commonly used strain to perform in vivo vaccine efficacy studies is the LR strain. However, multiple lineages of CHIKV are found worldwide and have slightly different phenotypes in the A129 mouse [15]. Regardless, all known CHIKVs are comprised of one serotype and antibody immunity against one lineage can be cross-neutralized by another [29].…”

“…There was no significant swelling seen in ChAdOx1 Chik, ChAdOx1 Chik ∆Cap, or 181/25-vaccinated mice, in either foot (Figure 4a,b). Previous studies have shown that viremia in A129 mice occurs on days 1-3 [15]. Therefore, to determine if the vaccine could protect against viremia, blood was taken from all mice on day 2 post challenge, which corresponds to the predicted day of peak viremia [15].…”

“…All virus and sera titrations were performed on Vero cell monolayers in 12-well plates as described previously [15]. Briefly, samples underwent 10-fold serial dilutions in media and were used to infect confluent Vero cell monolayers, after which a semisolid overlay containing 0.4% agarose was added and allowed to solidify.…”