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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.

In 2016, a chikungunya virus (CHIKV) outbreak was reported in Mandera, Kenya. This was the first major CHIKV outbreak in the country since the global reemergence of this virus in Kenya in 2004. We collected samples and sequenced viral genomes from this outbreak. All Kenyan genomes contained two mutations, E1:K211E and E2:V264A, recently reported to have an association with increased infectivity, dissemination, and transmission in the

BackgroundIn 2016, a chikungunya virus (CHIKV) outbreak was reported in Mandera, Kenya. This was the first major CHIKV outbreak in the country since the global re-emergence of this virus, which arose as an initial outbreak in Kenya in 2004. Therefore, we collected samples and sequenced viral genomes from the 2016 Mandera outbreak.Methodology/Principal FindingsAll Kenyan genomes contained two mutations, E1:K211E and E2:V264A, recently reported to have an association with increased infectivity, dissemination and transmission in the Aedes aegypti (Ae. aegypti) vector. Phylogeographic inference of temporal and spatial virus relationships using Bayesian approaches showed that this Ae. aegypti adapted strain emerged within the East, Central, and South African (ECSA) lineage of CHIKV between 2005 and 2008, most probably in India. It was also in India where the first large outbreak caused by this strain appeared, in New Delhi, 2010. More importantly, our results also showed that this strain is no longer contained to India, and that it has more recently caused several major outbreaks of CHIKV, including the 2016 outbreaks in India, Pakistan and Kenya, and the 2017 outbreak in Bangladesh. In addition to its capability to cause large outbreaks in different regions of the world, this CHIKV strain has the capacity to replace less adapted wild type strains in Ae. aegypti-rich regions. Indeed, all the latest full CHIKV genomes of the ECSA Indian Ocean Lineage (IOL), from the regions of high Ae. aegypti prevalence, carry these two mutations, including samples collected in Japan, Australia, and China.Conclusions/SignificanceOur results point to the importance of continued genomic-based surveillance of this strain’s global spread, and they prompt urgent vector competence studies in Asian and African countries, in order to assess the level of vector receptiveness, virus transmission, and the impact this might have on this strain’s ability to cause major outbreaks.Author summaryChikungunya virus (CHIKV) causes a debilitating infection with high fever, intense muscle and bone pain, rash, nausea, vomiting and headaches, and persistent and/or recurrent joint pains for months or years after contracting the virus. CHIKV is spread by two mosquito vectors, Aedes albopictus and Aedes aegypti, with increased presence around the globe. In this study, we report global spread of a CHIKV strain that carries two mutations that have been suggested to increase this virus’ ability to infect the Aedes aegypti mosquito, as well as to increase CHIKV’s ability to be transmitted by this vector. We show that this strain appeared sometime between 2005 and 2008, most probably in India, and has now spread to Africa, Asia, and Australia. We show that this strain is capable of driving large outbreaks of CHIKV in the human population, causing recent major outbreaks in Kenya, Pakistan, India and Bangladesh. Thus, our results stress the importance of monitoring this strain’s global spread, as well as the need of improved vector control strategies in the areas of Aedes aegypti prevalence.