Global Outbreaks and Origins of a Chikungunya Virus Variant Carrying Mutations Which May Increase Fitness for Aedes aegypti: Revelations from the 2016 Mandera, Kenya Outbreak

In May 2016, the Kenyan Ministry of Health (KMoH) reported an outbreak of chikungunya virus (CHIKV) in Mandera County on the border with Somalia. During this time in Somalia, outbreaks of CHIKV were occurring in the neighboring Bula Hawa region, originating from Mogadishu. In Mandera town, 1,792 cases were detected, and an estimated 50% of the health work force was affected by this virus. A cross-border joint response was coordinated between Kenya and Somalia to control the outbreak.1 This was the first reported outbreak of CHIKV in Kenya since 2004. The previous large CHIKV outbreak in Kenya occurred in Lamu Island in 2004, with an estimated 75% of the population infected.2 The disease also spread to the coastal city of Mombasa by the end of 2004, and further to the Comoros and La Reunion islands, causing large outbreaks in 2005–2006. On La Reunion island, unusual clinical complications were reported in association with CHIKV infection, and viral isolate sequences revealed the presence of an alanine-to-valine mutation in the E1 glycoprotein at position 226 (E1:A226V).3 This specific mutation was shown to confer significant increase in CHIKV infectivity for the Aedes albopictus vector, which was also the dominant mosquito species suspected to be responsible for the transmission of CHIKV on the island of La Reunion.4,5 Since then, the E1:A226V mutation has been observed in many of the genomes in the CHIKV lineage, spreading in the East, Central, and South African region (ECSA lineage), and has been shown to have emerged through convergent evolution in at least four different occasions.6 The remarkable emergence and spread of CHIKV adaptation to the Ae. albopictus vector prompted additional studies on the genetic plasticity of this virus, looking for additional biomarkers associated with virus transmission capacity, fitness, and pathogenicity.6–8 Mutations with the ability to enhance infection in this vector are of increased importance, as Ae. albopictus is rapidly expanding throughout the world.9 The Ae. albopictus mosquito is believed to have originated in Asia and is today most commonly found in east Asia. Aedes albopictus is also common in some parts of South and Southeast Asia, India, and Africa, and it has shown increased spread to regions with lower temperatures, such as southern Europe, southern Brazil, northern China, and the northern United States.9 In Europe, this vector has been associated with autochthonous transmission of CHIKV.10 Although some of the more recent CHIKV outbreaks have been transmitted by Ae. albopictus, most of the CHIKV transmissions in the world are associated with Aedes aegypti. Aedes aegypti is a container-breeding, domesticated mosquito mainly found in urban areas and feeding largely on humans during early and late daytime hours. Aedes aegypti originated from the ancestral zoophilic Ae. aegypti formosus native to Africa. Aedes aegypti now is most common in tropical and subtropical regions, such as Africa, India, Southeast Asia, and Australia.9 Recently, two mutations, E1:K211E and E2:V264A, have been reported in the CHIKV to be associated with increased fitness to Ae. aegypti vectors.11 These two mutations, in the background of the wild-type E1:226A, are believed to increase virus infectivity, dissemination, and transmission in Ae. aegypti, with no impact on virus fitness for the Ae. albopictus vector.6,11 E1:K211E was first observed in genomes sampled in 2006 from the Kerala and Puducherry regions, India, and simultaneous presence of both mutations was first observed in 2009–2010 in Tamil Nadu and Andhra Pradesh, India.12,13 In Kenya, the predominant CHIKV vector is Ae. aegypti, and vector competence studies using local vector populations have shown it is capable of transmitting the virus in this region.14 Given the recent large outbreak of CHIKV in the rural setting of Mandera County, Kenya, we analyzed CHIKV genomes sequenced from this outbreak for the presence of adaptive mutations associated with both Ae. albopictus and Ae. aegypti. Along with estimating origins and the time of emergence of a variant that carried two of these previously reported mutations, we also estimated time and origins of the Mandera CHIKV outbreak. Our results indicate the spread of a CHIKV that carries mutations previously associated with increased fitness for Ae. aegypti in Kenya. We also show that this variant is now connected with new large outbreaks in other regions of the world.