Chikungunya Virus and Prospects for a Vaccine

Scott C Weaver; Jorge E Osorio; Jill A Livengood; Rubing Chen; Dan T Stinchcomb


Expert Rev Vaccines. 2012;11(9):1087-1101. 

In This Article

Evolution & Emergence Mechanisms

The historical accounts of CHIKV spread from Africa to Asia and perhaps the Americas were supported by the first phylogenetic studies of the virus.[33] These studies concluded that CHIKV originated in Africa, where two major enzootic lineages circulate principally in West and East/Central/South Africa (ECSA), respectively. The oldest Asian CHIKV isolates, dating from the late 1950s or earlier, fell within the ECSA lineage, indicating emergence and transport from this region of Africa. By contrast, the West African lineage was not associated with any CHIKV strains isolated during major epidemics outside of Africa.

More recent phylogenetic analyses using complete genomic sequences (Figure 4) largely confirm these earlier results and place more precise dates on CHIKV divergence events. Although the accuracy of ancient divergence estimates using coalescent methods is difficult to verify, these studies conclude that all CHIKV strains sampled to date evolved from a common ancestor during the past 500 years, and that the endemic/epidemic lineage first sampled in Asia during the late 1950s was introduced from East Africa at least 70 years ago.[34] The ECSA CHIKV lineage was also identified in West Africa (a bat isolate from Senegal), indicating that the two main enzootic clades overlap spatially, at least on occasion.

Figure 4.

Phylogenetic tree of chikungunya virus strains derived from complete concatenated open reading frames for the nonstructural and structural polyproteins.
Key E1 amino acid substitutions that facilitated (Indian Ocean lineage) or prevented (Asian lineage) adaptation to Aedes albopictus are shown on the right.
CAR: Central African republic; ECSA: East/Central/South Africa.

In 2004, a CHIK epidemic began in East Africa that resulted in its emergence both in the literal sense and in the figurative sense from relative obscurity. Initially, epidemics were observed in coastal Kenya, first in Lamu and then in Mombasa,[37,38] followed by spread to Comoros, La Réunion and other islands in the Indian Ocean during 2005 (Figure 5).[39] Many tourists returning to Europe from vacations in this region were afflicted, raising awareness of the epidemic.[26] Then, in late 2005, epidemics ensued in India,[40] followed by exportation via infected travelers to nearly all regions of the world including the USA.[41] Autochthonous transmission of these new epidemic strains subsequently occurred in Southeast Asia[42] and Europe,[43,44] but fortunately not in the Americas. Many of these epidemics in the Indian Ocean Basin, India and Southeast Asia continued into 2012.

Figure 5.

Distribution of chikungunya virus strains and movement of outbreaks inferred from the phylogenetic analysis depicted in Figure 4.
CHIK: Chikungunya fever; CHIKV: Chikungunya virus.
Reproduced with permission from [24].

The source of the 2005 Indian Ocean Basin epidemic was first traced by Schuffenecker et al. to the ECSA enzootic lineage, like the earlier Asian emergence before 1958.[45] The Indian epidemic was later shown to have resulted from an independent emergence from the mainland of East Africa.[34] The first CHIKV isolates from the La Réunion epidemic exhibited an alanine at E1 envelope glycoprotein residue 226, but later isolates showed an A226V substitution near the fusion peptide that mediates viral entry via endosomes. On the basis of earlier studies implicating this residue in cholesterol dependence for replication of a closely related alphavirus, Semliki Forest virus,[46] Schuffenecker et al. hypothesized that this CHIKV E1 substitution affected infection of mosquitoes, which are cholesterol auxotrophs.[45] This hypothesis was later supported by experimental infections of A. albopictus, which demonstrated that this mutation caused a dramatic increase in CHIKV infectivity.[28,31] The A226V substitution, which confers an approximate 100-fold reduction in the infectious dose 50% for A. albopictus but has little or no effect on infection of A. aegypti,[28,30] appeared to result in highly efficient transmission in regions where the latter mosquito, previously considered the only principal vector, was not abundant. This substitution was shown to have occurred independently or convergently in several locations of India and in La Réunion and Gabon,[47] and was consistently found in locations where A. albopictus was the predominant vector, consistent with convergent selection by vector susceptibility.[34,48]

Finally, beginning in 2009, an additional envelope glycoprotein substitution, L210Q in the E2 protein, was detected in regions of India where A. albopictus was the main vector.[49] This mutation has been shown to further increase infectivity for A. albopictus, albeit to a lesser extent that E1-A226V, but again has no effect on infectivity for A. aegypti.[30] This additional adaptive mutation suggests even more efficient transmission of current Indian strains, with major public health implications not only for that country but also due to the threat of CHIKV exportation to other regions. Since 1985, A. albopictus has colonized many parts of the world from its native Asia and, unlike A. aegypti, it can survive winters in temperate climates.[50] Thus, the adaptation of CHIKV to this vector puts many new temperate regions of the world, including the Americas, at risk for epidemics and endemicity.

A surprising finding of recent CHIKV sequencing efforts was the lack of either of the A. albopictus-adaptive envelope glycoprotein mutations in strains of the old endemic/epidemic Asian lineage. This CHIKV genotype has been circulating in regions native to A. albopictus for at least 64 years yet did not undergo comparable adaptive selection for more efficient infection of this vector. This was particularly surprising because these mutations, while conferring a strong fitness advantage in A. albopictus, have little or no effect on infection of A. aegypti, assumed to be the principal vector in Southeast Asia. Aedes albopictus tends to be more common in rural and forested areas while A. aegypti predominates in urban settings of many tropical regions.[51–53] In India, A. aegypti predominates in many regions during the dry season, but A. albopictus populations in the South are highest during the rainy season.[54,55] Tsetsarkin et al. hypothesized that the E1-A226V substitutions had CHIKV lineage-specific penetrance, and showed that, in the genetic background of the old Asian strains, they had no effect on infectivity for either urban vector.[56] An additional E1 substitution, already present in ECSA strains but not in the old Asian lineage, was required for E1-226V to exert its effect on A. albopictus infection. Thus, a single mutation with an apparently neutral phenotype prevented the Asian CHIKV strain from adapting to A. albopictus for decades, underscoring the dramatic impact of epistatic effects on CHIKV phenotypes.[32,56]