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Abstract

Chikungunya virus (CHIKV) has emerged as a serious candidate for “Disease X”—the name for an unknown agent that could cause a global pandemic. This paper searches for the unique traits of CHIKV that match that designation. Critical mutations like E1-A226V and E2 L210Q have driven CHIKV’s rapid adaptability and its transmission from Aedes mosquitoes to over 110 countries around the world. Public health impact is amped because the virus can cause debilitating diseases including chronic arthritis and severe neonatal complications. Populations remain vulnerable despite a recently approved vaccine, as there is little distribution of it and no treatments for the virus. By underscoring urbanization, climate change, and global travel as ecologic and genetic factors that enable the emergence and persistence of CHIKV, this paper emphasizes that these critical enablers of CHIKV need to be addressed both in the context of host range and transmission potential. However, phylogenetic studies and surveillance data for its capacity to sustain transmission cycles show how important it is to be included in improved global health strategies. Improved early detection, improved vector control, equitable vaccine distribution, and greater international collaboration are critical to reduce the pandemic potential of CHIKV. This paper aims to explore the genetic adaptations of CHIKV that have driven its increased transmission and expanded geographic spread. It examines how key mutations enable the virus to adapt to different mosquito vectors, contributing to its pandemic potential. The paper also assesses the epidemiological and environmental factors influencing CHIKV’s emergence and persistence, alongside the public health challenges posed by limited vaccine availability and treatment options. Finally, it highlights prevention strategies and the importance of global preparedness to reduce the risk of widespread outbreaks.

Plain language summary

Chikungunya Virus (CHIKV): from genetic adaptation to pandemic risk and prevention

Chikungunya virus (CHIKV) is a strong contender for ‘Disease X,’ a term used for an unknown disease that could lead to a global pandemic. Genetic changes, such as the E1-A226V and E2-L210Q mutations, have made the virus highly adaptable and capable of spreading through Aedes mosquitoes to over 110 countries. The virus poses a serious public health risk, causing severe illnesses like chronic arthritis and complications in newborns. Despite the recent approval of a vaccine, its limited availability and the absence of treatments leave many people unprotected. Urbanization, climate change, and international travel are major factors that help the virus spread and persist. Studies on its genetic adaptability and transmission cycles highlight the need for global attention. To reduce the risk of a pandemic, we must improve early detection, strengthen mosquito control, ensure fair vaccine access, and promote international cooperation. This research paper investigates the distinct characteristics of Chikungunya virus (CHIKV), focusing on its global epidemiology, genetic mutations, transmission dynamics, pathogenesis, clinical manifestations, and current preventive strategies and management approaches. Additionally, it evaluates CHIKV as a potential candidate for causing a future global pandemic.

Keywords

chikungunya climate change disease X genetic mutations global health vector transmission

Background

The World Health Organization coined a term to name an unknown pathogen that could cause a severe international epidemic or pandemic: “Disease X.” It is not indicative of the eventual specific threat, but rather a placeholder for an as yet identified future pandemic and underscores the need for good preparedness. In 2018, the idea came to be, when it was listed on the WHO’s Blueprint list of priority disease in urgent need of research and development.^1,2 Deforestation and enhanced human–animal interactions are predicted to lead to increased opportunities for spillovers from animals to humans, also known as zoonotic spillovers, and these are a staple of the next pandemic, scientists say. It has been implicated before in past pandemics, including SARS-CoV2 and Ebola.^2,3 The most likely causative agents of Disease X are members of families of known pandemic potential viruses, including coronaviruses, filoviruses (e.g., Ebola), and paramyxoviruses (e.g., Nipah). As these pathogens are additionally respiratory, have high mutation rates, and can rapidly spread from human to human, they are particularly concerning.^2,4 Ahead of the curve, researchers and global health agencies are ramping up advanced surveillance and genetic characterization of high-risk pathogens while at the same time engaging in proactive development of adaptable medical countermeasures such as vaccines and diagnostics. The Coalition for Epidemic Preparedness Innovations’ 100 Days Mission was launched to develop pandemic vaccines within 100 days or three months after disease invasion is detected.^1,4

Chikungunya virus (CHIKV) is an arbovirus responsible for primary transmission by Aedes aegypti and Aedes albopictus mosquitoes. The meaning of the word Chikungunya is “Bent Over In Pain”-taken from the Makonde language. It refers to the debilitating joint pain, which is a feature of the disease. Other symptoms can include fever and joint pain, rash, headache, muscle pain, fatigue, and joint pain that can last months to even years. While rarely fatal, chikungunya can give rise to profound complications, especially in high risk populations, including those aged 65 years and over, infants, and those with comorbidities.^5–7 Previous to the current outbreak of the CHIKV, it has historically been confined to (and is continuously found on) a handful of locations in Africa and Asia, but has since expanded to over 110 countries across multiple continents. Its geographical spread, powered in part by intensifying global travel and urbanization as well as climate change, is a cause for concern for large scale outbreak. A vaccine has been recently made available but is only available for select at risk populations.^5,7 Chikungunya demonstrates a number of “Disease X” characteristics. Because it can cause widespread outbreaks and lacks cross immunity to related viruses such as dengue or zika and depends on efficient mosquito vectors, it is a serious contender for a future pandemic. The elevated risk of increased transmissibility or severity further elevates its evolution and potential genetic adaptation, which, in turn, requires vigilant monitoring and proactive public health measures.^5,7

Epidemiology

CHIKV, arbovirus primarily transmitted by Aedes aegypti and Aedes albopictus, exhibits unique epidemiologic patterns related to climatic factors, urbanization, and vector density. It has spread and resulted in large outbreaks worldwide. High temperatures (>25°C), which accelerate mosquito development and reduce their lifespan to around 14 days, are critical for sustaining transmission cycles. The extrinsic incubation period (EIC)—the time required for the virus to become transmissible inside the mosquito—ranges from 8 to 14 days, making temperature and mosquito survival tightly linked to outbreak potential. CHIKV has resulted in large-scale outbreaks across continents, particularly where environmental and social factors favor mosquito proliferation.

Brazil

In 2024, Brazil accounted for 84.8% of the Americas’ cumulative total, with 402,584 cases. However, since its 2014 introduction, Brazil has suffered annual outbreaks, with the northeast being hardest hit. Factors contributing to the difference are a high vector density, a tropical climate favorable to year-round transmission, and inadequate vector control measures. Nevertheless, spatial heterogeneity remains, determined by local immunity, differential socioeconomic conditions, and regional climate.^8,9 A temporal trend of annual CHIKV cases in Brazil is illustrated in Figure 1.¹⁰

Figure 1.

Temporal trend of CHIKV cases in Brazil which has experienced a significant outbreak in recent years.

India

In 2024, India reported 69,544 cases, of which a major part was from Karnataka and Maharashtra. A total of 31.6% of the cases were from Karnataka. Although these outbreaks season with the monsoon, urban waterlogging and poor waste management makes it worse. The broad geographic reach of chikungunya in India is illustrated by the fact that substantial case load was also seen in Maharashtra and Kerala.^11,12 A Map of India showing the severity of cases confirmed in 2024 based on states is illustrated in Figure 2.^12,13

Figure 2.

Heatmap of India showing confirmed cases in 2024 of chikungunya (CHIKV) based on states.

A temportal trend of CHIKV cases in the two most affected states in India—Maharashtra and Karnataka—is illustrated in Figure 3^12,13

Figure 3.

Temporal trend of confirmed chikungunya (CHIKV) cases in Maharashtra and Karnataka from 2018 to 2024.

Pakistan

In 2024, Pakistan reported 5706 cases, with the biggest outbreaks coinciding with monsoon seasons when vector breeding is at its highest. Sindh and Punjab provinces with high urban density and the insufficiency of mosquito control measures were hotspots. Although India has lower case numbers, surveillance gaps and underreporting very likely underestimate the true burden of disease.¹⁴

Malaysia

In 2024, Malaysia had 80 cases and only localized outbreaks during rainy season. The larger epidemics have been prevented by effective vector control measures. But, post flood mosquito breeding is still a concern.¹⁵

The Americas: beyond Brazil

Significant outbreaks had been reported in Paraguay (3104 cases), Argentina (768), and Bolivia (451) and other countries in the Americas. They together cover less area than Brazil but reveal circumscribed localization of chikungunya within these nations.^8,16

Africa and Southeast Asia

While lower transmission levels than the rest of the regions, Senegal reported nine cases in Africa in 2024.¹⁷ In Southeast Asia, the Maldives had 240 cases by May 2024 attributed to intermittent rains and subsequent vector proliferation.¹⁸

Trends

Outbreaks occur in periods of inundating tropical rainy season and urban centers appear disproportionately affected because of resident vector density and environmental conditions. Vectors such as Aedes aegypti continue to expand their geographical range and thus threaten non endemically regions in response to climate change.^9,19

Genetic mutation

As a single-stranded RNA virus with very high mutation rate, this virus can rapidly adapt to new vectors and hosts.^20,21 Its genome consists of three major lineages: East/Central/South African (ECSA), Asian and the West African lineage. CHIKV’s epidemic potential has been mediated in part by adaptive mutations in the envelope proteins E1 and E2.^9,22 Vectors and vertebrate hosts show enhanced infection and pathogenicity upon viral mutations like E1-M88L or E1-V156A.²⁰ CHIKV has a rapid rate of genetic change, with an estimation of about 5–10 mutations/year for its genome.⁹ First discovered in Aedes albopictus mosquitoes during the 2005–2006 Indian Ocean outbreak, the E1-A226V mutation enhanced infectivity of CHIKV in these insects by a factor as large as 5. Previously considered a secondary vector, this mutation enhanced midgut infection and dissemination in this mosquito vector through its alteration of viral dependence on cholesterol.^22,23 About 266,000 human cases of this mutation were linked to the large 2005–2006 epidemic on Reunion Island. This mutation increased the virus’s infectivity and dissemination in the laboratory settings in Aedes albopictus significantly compared with strains lacking the mutation.²³ Additional fitness advantages in Aedes albopictus were further obtained by subsequent CHIKV mutations, such as E2-L210Q, optimizing its adaptation to this vector.^22,24 A 2022 study identified additional mutations in Brazilian ECSA-lineage strains, including changes in the E1 and nsP3 regions.²⁵ These mutations may contribute to viral persistence in populations and resistance to existing vector control strategies. Evolutionary flexibility of CHIKV in response to environmental and ecological pressures is illustrated by the mutations E1-A226V and E2-L210Q. Efficient transmission cycles were established in areas of high Aedes albopictus density, through these sequential adaptations.²² Many of the Indian isolates from different locations had novel mutations like E1 patriarchal S295 rout, E1 pivotal P294 rout, and E1 virgin V322 rout, indicating the region adaptability and enhanced virulence potential of CHIKV.²⁶ This adaptive potential is of concern that the virus may be capable of generating more severe and widespread epidemics across regions in which Aedes albopictus is well established including temperate climates. Synergistic effects of double mutations, including E2-K252Q in combination with other mutations, were found for the virus adaptability and vector infection efficiency.²⁰ In Brazil, similar to what we had observed in Cuba, ECSA lineage strains devoid of E1-A226V dominated outbreaks in the face of widespread insecticide resistance caused by kdr mutations (e.g., V410L, V1016I, and F1534C), using Aedes aegypti and not Aedes albopictus, despite substitutions that confer insecticide resistance.^9,27 This multimodal vector and geographic range in CHIKV raises concerns of its potential to become “Disease X.” Its genotypic plasticity permits adaptation to environmental and anthropogenic changes, including urbanization and vector expansion in response to climate change.^9,24 Together with low immunity in naïve populations and the absence of widespread vaccination, CHIKV’s ability to adapt makes it a potential candidate for future global pandemics. Table 1 shows the location, effect, region, and advantages gained by the virus through the discussed mutations.

Table 1.

Mutation analysis table.

Mutation	Location in genome	Effect on vector/host adaptation	Outbreak regions	Advantages gained after mutation	Sources
E1-A226V	E1 glycoprotein	Enhanced infectivity in Aedes albopictus	Indian Ocean, Reunion Island	Critical for vector switching	23 and 24
E2-L210Q	E2 glycoprotein	Improved fitness in Aedes albopictus	Kerala, India	Synergistic with E1-A226V	24
E1-M88L and E1-V156A	E1 glycoprotein	Enhanced infection and pathogenicity	Rio de Janeiro, Brazil	Increases ability to spread and gains stable adaptation	20
E1-S295F, E1-P294L, E1-A316V, E1-V322A, and E1-C328W	E1 glycoprotein	Enhanced Virulence	India	Regional adaptation	26
Kdr mutations (V410L, V1016I, and F1534C)	Voltage gated sodium channel	Insecticide resistance in Aedes aegypti	Brazil	Reduced control efficacy	27
E2-K252Q	Synergy with other mutations	Enhanced binding with midgut cell	India	Increased host adaptation	20

Transmission and spread of chikungunya

The transmission of CHIKV occurs usually via bite by the species of Aedes aegypti and Aedes albopictus mosquito.^28,29 Transmission cycles include the enzootic (forest dwelling) sylvatic cycle in which the virus cycles between mosquitoes and nonhuman primates, and the urban cycle in which the virus cycles between mosquitoes and humans in densely populated areas.^28,30–32 In the sylvatic cycle, CHIKV is primarily transmitted by Aedes species that inhabit forests, such as Aedes africanus and Aedes furcifer. These mosquitoes typically feed on non-human primates, with humans being an accidental host. Human infection occurs infrequently in this cycle. In contrast, the urban cycle occurs in densely populated areas, where Aedes aegypti and Aedes albopictus mosquitoes are the primary vectors. In this cycle, humans serve as the amplification host, and the virus spreads rapidly in urban environments with high mosquito densities and limited control measures. Densely populated areas are breeding grounds for mosquitoes, which increase risks to transmission because of stagnant water and urban heat islands environmental factors.²⁸ CHIKV enters host cells via clathrin-mediated endocytosis. The virus binds to host cell surface receptors, such as heparan sulfate proteoglycans and DC-SIGN, which facilitate virus adsorption. Once inside, the virus uncoats and releases its genome into the cytoplasm. The positive-sense RNA genome directly translates viral non-structural proteins (nsps) from the 5′ open reading frame. These nsps are essential for genome replication and viral RNA synthesis. The viral replication complex assembles on intracellular membranes, such as the rough endoplasmic reticulum, where replication of the RNA genome takes place. Subsequently, viral RNA is translated into structural proteins, including the envelope glycoproteins (E1 and E2), which are incorporated into newly formed virions. The newly synthesized virions are then packaged into vesicles and are released from cells via direct budding.³³ It is the adaptation of CHIKV to a variety of mosquito vectors that permits its rapid spread. Genetic mutations in the E1 glycoprotein of the virus that enhances its ability to be efficiently transmitted by Aedes albopictus have extended its range to temperate regions.^28–30,32 Altogether, high human population density and the global travel has facilitated spread of the virus further.^29–31 In the replication process, cell damage takes place and activates an immune response, which results in inflammation, fever, and joint pain, common to the disease.28 Severe cases have high viremia levels (10⁷ pfu/mL) facilitating efficient transmission to vectors, primarily to mosquito vectors.³² Vertical transmission from mother to child is well documented; rates up to 50% are reported if the mother is viremic at the time of labor. However, severe neonatal outcome including encephalitis is one of the usual consequences of this route.^30,32,34 Most vertical transmission cases occur when the mother is infected between 15 days before delivery and 4 days post-partum.³⁰ It has been demonstrated that the virus does cross the placental barrier from amniotic fluid and fetal tissues during stillbirth cases.³⁴ Furthermore, silent transmission from asymptomatic infections complicates the control of outbreaks.^29,32 While asymptomatic infections do occur, most CHIKV infections are symptomatic, presenting with fever, rash, and severe joint pain. The symptomatic rate varies, but studies suggest that a significant proportion of infected individuals experience the characteristic symptoms of the disease, with only a small minority remaining asymptomatic.¹⁹ Successful large-scale outbreaks are enabled by the virus’ dependence on both the efficiency of the mosquito vector and adaptation to human hosts combined with low immunity in population.³² In Salvador, low seroprevalence (11.8%) indicated that there was not enough herd immunity to avert future outbreaks. In addition, viral lineage, mosquito exposure dose, and host genetic factors might influence the severity of infection as well as symptomatic rates.³¹ Figure 4 shows the transmission cycle of chikungunya.^26,29,30

Figure 4.

Illustration of the two primary transmission cycles of chikungunya virus (CHIKV): the Sylvatic cycle and the Urban cycle.

Table 2 shows vertical transmission outcomes in chikungunya.^26,28,29

Table 2.

Vertical transmission outcomes in chikungunya.

Maternal infection stage	Neonatal outcome	Percentage impact	Sources
Early pregnancy	Fetal loss, congenital abnormalities	2% fetal loss, significant congenital impact	30 and 34
Late pregnancy	High risk of encephalopathy	68.7% encephalopathy, 19.6% fetal distress	30 and 34
During birth	Sepsis-like syndrome, encephalitis	50% vertical transmission rate in viremic mothers	28 and 34

Disease pathogenesis of chikungunya

CHIKV pathogenesis involves a complex, distinct, acute-to-chronic progression, with systemic inflammation and severe symptoms, coupled with substantial long-term morbidity. CHIKV infection can be thus divided into three phases: acute, subacute and chronic phases.

Acute phase: Characterized by fever, severe arthralgia, myalgia, rash, and headache. These symptoms are present in the majority of cases. This phase may last up to 14 days.

In 75%–88% of cases the acute phase is usually 7–10 days long and characterized by fever, rash, polyarthralgia, myalgia, and fatigue.^35–37 Because the elderly and neonates are particularly vulnerable, they can develop severe symptoms ranging from encephalitis to myocarditis, gastrointestinal complications and renal dysfunction.^35–37

Subacute phase: During this phase, joint pain persists, and patients may experience ongoing fatigue. Chronic joint issues may begin to emerge, especially in those with pre-existing comorbidities. This phase may last from 15 days to 3 months.^37,38

Chronic phase: Some patients develop persistent arthritis, fatigue, and neurological disorders, with symptoms lasting months to years. Chronic chikungunya is associated with significant long-term disability, particularly joint stiffness and neuropathic pain. This phase may last for greater than 3 months.

About 30%–50% of cases will develop chronic complications including persistent joint pain, fatigue and a form of inflammatory arthritis that can persist months to years.^35,36 Neuropathic pain such as burning or stinging is common. These are known as atypical phases. The atypical phase of chikungunya infection often presents with symptoms that deviate from the classic fever-first pattern, notably joint pain appearing before fever, which is unusual and seen more in women. Patients may experience a broad range of manifestations involving multiple organ systems, including eye inflammation, oral ulcers, skin eruptions, neurological issues like memory loss, and occasional cardiovascular effects such as temporary blood pressure drops. These atypical symptoms occur across all ages, although eye problems are more common in children.³⁹ This compounds disability and limits the effectiveness of traditional treatments.³⁸ Neurological involvement was frequent; chikungunya RNA was detected in 52.9% fatal case specimens including CSF and was associated with encephalitis (21.4%).³⁷ Chronic chikungunya significantly impairs daily functionality, and 76% of infected individuals have walking disabilities one year post infection.^36,38 Chronic chikungunya symptoms last from 3 months to 5 years affecting the quality of life significantly.⁴⁰ The psychological burden of long-term disease is underscored by increased risk of depression.³⁸

The rates of hospitalization range from 2.6% to 17%, and severe forms frequently require intensive care.^36,40,41 People with comorbidities such as diabetes or other cardiovascular diseases are more vulnerable to hospitalization.³⁷ Mortality is primarily seen in the case of severe disease complicated with neurological or cardiovascular complications, with reported case fatality ratios between 0.1% and 0.7%.³⁶ However, a rare but serious outcome, Guillain-Barré syndrome, is reported in about 1.7 cases per 10,000 chikungunya infections.⁴¹ During the subacute phase, patients with diabetes had a seven fold increased risk of death (odds ratio: 7.7). Most deaths occurred during the acute phase (18 days post symptom onset) although median time from symptom onset to death was 12 days.³⁷ In outbreaks, as occurred in the 2023 Brazilian epidemic, excess mortality was vastly underreported and the observed rates were 60 times higher than officially confirmed deaths.⁴² Table 3 lists clinical manifestations of CHIKV by stage.^36,38,41

Table 3.

Clinical manifestations by stage.

Stage	Timeframe	Symptoms	Prevalence (%)	Additional notes	Sources
Acute	0–14 days	High fever, severe arthralgia, myalgia, rash, headache	88% arthralgia, 90% fever	Severe symptoms may require hospitalization	36, 38 and 41
Subacute	15 days to 90 days (3 months)	Persistent arthralgia, worsening joint symptoms, fatigue	Persistent symptoms in ~30%–40% patients	Symptoms reduce in intensity but persist in some cases
Chronic	>90 days (3 months)	Chronic arthritis, fatigue, depression, neurological disorders, stiffness	Chronic symptoms in 44% patients	May lead to significant long-term disability and reduced quality of life

Therapeutic and preventive measures of chikungunya

Symptom alleviation is the focus of current management.^43,44 Patients with acute pain are treated with paracetamol and opioids but non-steroidal anti-inflammatory drugs (NSAIDs) are avoided to control bleeding rates.^43,45 NSAIDs, corticosteroids or for severe cases disease-modifying antirheumatic drug (DMARD) such as methotrexate, hydroxychloroquine are used for chronic arthritis.^43,45,46 These DMARDs may be used for refractory conditions.⁴⁵ Critical to the mobility is physiotherapy and analgesics.^44,45

There has been emerging research on antiviral treatments for chikungunya. One such candidate is sofosbuvir, a drug primarily used for hepatitis C. A study by Ferreria et al.⁴⁷ demonstrated that sofosbuvir may inhibit CHIKV replication in vitro, suggesting that it could be a promising therapeutic approach for managing CHIKV infections in the future. Aceclofenac is a non-steroidal anti-inflammatory drug that relieves pain and inflammation. During both acute and chronic phases, a short course of corticosteroids such as prednisolone will give relief from arthritis.^45,48,49 Chronic arthritis is treated with methotrexate and hydroxychloroquine, though combined evidence shows improved results.^49,50 Some experimental therapies include the combination of 2-fluoroadenine and metyrapone, which are also active antivirally in vitro.⁵¹ Limited utility has been demonstrated in isolated studies of the use of ribavirin and interferon-α.⁴⁹ Treatment is supportive and follows a symptom based approach.

FDA approved chikungunya vaccine VLA1553 with seroprotection of 96.8% over two years in phase III trials.^52,53 It uses a live attenuated virus approach that leads to long lasting neutralizing antibody, with high efficacy.^52,54 Other vaccine candidates, MV-CHIK and mRNA-based vaccines, are still under development.^55,56 Because of the rapid advancement of the regulatory pathways, the clinical trials were conducted with immunological markers rather than conventional efficacy trials.^57,58 We still lag behind in widespread access of vaccines to endemic regions.^52,57

Chikungunya can be prevented by common people by destroying Aedes mosquito breeding site, like stagnant water in drums, flowerpots, or drains^28,59 Insect repellents containing DEET, picaridin, or oil of lemon eucalyptus, and wearing protective clothes, such as long sleeved shirts and pants, are advised.^19,29 Window screens, mosquito nets, and cleaning the environment are known to greatly lower exposure.¹⁹ As suggested by WHO, community engagement in integrated vector management reinforces the effect of single efforts.^34,59 In endemic regions, awareness campaigns and behavioral interventions are critical.^9,29 Table 4 shows various CHIKV vaccines that are available or are under development.^52,54,55

Table 4.

Chikungunya vaccine overview.

Vaccine name	Developer	Type	Phase of development	Efficacy/results	Sources
VLA1553 (Valneva)	Valneva Austria GmbH	Live-attenuated	FDA Approved (2023)	96.8% seroprotection over 2 years	52
MV-CHIK	Themis Bioscience	Measles-vectored	Phase II Completed	50%–95.9% seroconversion rates depending on dose	55
BBV87	Bharat Biotech & IVI	Inactivated	Preclinical/phase I	Preclinical stage; no human trial data	54
ChAdOx1 Chik	University of Oxford	ChAdOx1 vector	Phase I	Early trial results pending
PXVX0317	Bavarian Nordic	Virus-like particle (VLP)	Phase I	Initial immunogenicity data promising
mRNA-1388	Moderna	mRNA-based	Preclinical	Under development, data not available

Prediction of chikungunya to cause global pandemics

CHIKV is a credible candidate for future global pandemic because of its high adaptability, genetic evolution, and ability to spread broadly. The repeated emergence of CHIKV in highly populated and globally linked parts of the world is illustrated by large-scale outbreaks in the Indian Ocean islands, India, and the Americas where more than 3.7 million cases have been reported since 2013.^9,28 The virus has mutated critically, including the E1-A226V mutation, which increased its fitness in Aedes albopictus allowing for its spread in areas where Aedes aegypti was less frequent.^23,24 Moreover, epidemiologically advantageous additional mutations, such as E2-L210Q, have increased its epidemic potential, allowing the virus to establish sustained human–mosquito transmission cycles.²⁴ Its genomic plasticity and capacity to adapt to new ecological and vectorial niches emphasized the pandemic potential of CHIKV.^9,21 In addition to the high attack rates, debilitating long-term symptoms and severe disease complications such as neurodevelopmental delay of neonates and chronic arthritis increase the public health burden.^9,28 CHIKV geographical spread and local transmission are facilitated by a global distribution of Aedes vectors, along with climate change and urbanization.^20,30 Rapid geographic expansion and persistence in many different environments are supported by surveillance data and phylogenetic studies.^21,23 Hence, CHIKV meets the criteria of a potential candidate for “Disease X”: a disease that potentially can exploit an interconnected web of ecological, genetic, and social factors to cause global health crises.

Conclusion

CHIKV is a serious contender for its status as a future global health crisis as it has the remarkable capacity to adapt, spread, and survive in the different environments. Key mutations, most notably E1-A226V and E2-L210Q, have enabled it to be highly effective at infecting previously resistant mosquito species such as Aedes albopictus, which can now be found worldwide. Together with urbanization, climate change, and global travel, this adaptability has helped fuel huge outbreaks such as the more than 3.7 million cases in the Americas since 2013. Virus causes debilitating effects—chronic arthritis, severe complications in neonates, and prolonged illness—and with no widespread vaccines or effective treatments, it remains a major public health threat. Achieving control of CHIKV will need to take a new approach based on earlier detection and improved vector control strategies, along with equitable access to vaccines in the affected regions. The global “sync” that was developed to combat COVID is critical to avoid being overtaken by this adaptable virus that meets all the criteria for “Disease X,” which could utilize interconnected social, environmental, and biological factors to cause the next pandemic.

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Shoubeho Sadique Shandhi

Suprety Malaker

Ramisa Anjum

References

DISEASE X – What it is, and what it is not | CEPI, https://cepi.net//disease-x-what-it-and-what-it-not (2024, accessed 9 October 2024).

What is Disease X | Johns Hopkins | Bloomberg School of Public Health, https://publichealth.jhu.edu/2024/what-is-disease-x (2024, accessed 9 October 2024).

Eyes on Disease X: Ranking the next pandemic | Think Global Health. Council on Foreign Relations, https://www.thinkglobalhealth.org/article/eyes-disease-x-ranking-next-pandemic (2024, accessed 9 October 2024).

Episode #114 – Disease X, https://www.who.int/podcasts/series/science-in-5/episode–114—disease-x (2024, accessed 9 October 2024).

What Is Chikungunya? Cleveland clinic, https://my.clevelandclinic.org/health/diseases/25083-chikungunya (2024, accessed 25 December 2024).

Case definitions, clinical classification, and disease phases Dengue, Chikungunya, and Zika – PAHO/WHO | Pan American Health Organization, https://www.paho.org/en/documents/case-definitions-clinical-classification-and-disease-phases-dengue-chikungunya-and-zika (2023, accessed 25 December 2024).

Chikungunya – PAHO/WHO | Pan American Health Organization, https://www.paho.org/en/topics/chikungunya (2024, accessed 25 December 2024).

ECDC. Chikungunya worldwide overview, https://www.ecdc.europa.eu/en/chikungunya-monthly (2024, accessed 25 December 2024).

De Souza

Ribeiro

De Lima

STS

, et al. Chikungunya: a decade of burden in the Americas. Lancet Regional Health - Americas 2024; 30: 100673.

10.

Almeida

DDS

Santos

MVS

Cavalcanti

LDMPH

, et al. Impacto epidemiológico da Chikungunya no Brasil: casos confirmados, mortalidade e perfil dos acometidos por raça, escolaridade e região (2017–2024). Braz J Health Rev 2025; 8: e79230.

11.

National Health Mission. Weekly outbreak report disease alerts/outbreaks reported and responded to by states/UTs through Integrated Disease Surveillance Program (IDSP). Integrated Disease Surveillance Programme, National Centre for Disease Control, https://drive.google.com/file/d/1R48Z4mop81jCe8hRRq-yONUDo0y3ZRtt/view (2024, accessed 25 December 2024).

12.

National Center for Vector Borne Diseases Control (NCVBDC). Chikungunya situation in India:: National Center for Vector Borne Diseases Control (NCVBDC), https://ncvbdc.mohfw.gov.in/index4.php?lang=1&level=0&linkid=486&lid=3765 (2024, accessed 25 December 2024).

13.

The Translational Research Consortia (TRC) for Chikungunya Virus in India. Current status of chikungunya in India. Front Microbiol 2021; 12: 695173.

14.

Center of Disease Control, National Institute of Health, Islamabad. Integrated Disease Surveillance & Response (IDSR) Report. Center of Disease Control National Institute of Health, Islamabad, https://www.nih.org.pk/wp-content/uploads/2024/11/Weekly_Report-44-2024%20.pdf (2024, accessed 25 December 2024).

15.

Kementerian Kesihatan Malaysia. Situasi Semasa Demam Denggi Di Malaysia Minggu Epidemiologi 41, https://www.moh.gov.my/index.php/database_stores/store_view_page/17/2581 (2024, accessed 25 December 2024).

16.

Gutiérrez

https://www.facebook.com/pahowho. PAHO/WHO Data – Weekly Report | PAHO/WHO. Pan American Health Organization/World Health Organization, https://www3.paho.org/data/index.php/en/mnu-topics/chikv-en/550-chikv-weekly-en.html (2019, accessed 25 December 2024).

17.

Africa CDC. Africa CDC epidemic intelligence report, https://africacdc.org/download/africa-cdc-weekly-event-based-surveillance-report-august-2024/?ind=1725170707317&filename=Africa_CDC_Epidemic_Intelligence_Weekly_Report_31_August_2024-v3.pdf&wpdmdl=17080&refresh=676b094a128441735067978 (2024, accessed 25 December 2024).

18.

WHO Health Emergencies Programme, WHO Regional Office for South-East Asia. WHO South-East Asia Region Epidemiological Bulleti. 10th Edition, World Health Organization South East Asia, https://cdn.who.int/media/docs/default-source/searo/whe/wherepib/2024_10_searo_epi_bulletin.pdf (2024, accessed 25 December 2024).

19.

Chikungunya | CDC Yellow Book 2024, https://wwwnc.cdc.gov/travel/yellowbook/2024/infections-diseases/chikungunya (2024, accessed 25 December 2024).

20.

Ning

Xia

Wang

, et al. Host-adaptive mutations in chikungunya virus genome. Virulence 2024; 15: 2401985.

21.

Chevillon

Briant

Renaud

, et al. The chikungunya threat: an ecological and evolutionary perspective. Trends Microbiol 2008; 16: 80–88.

22.

Tsetsarkin

Chen

Sherman

, et al. Chikungunya virus: evolution and genetic determinants of emergence. Curr Opin Virol 2011; 1: 310–317.

23.

Tsetsarkin

Vanlandingham

McGee

, et al. A single mutation in chikungunya virus affects vector specificity and epidemic potential. PLoS Pathog 2007; 3: e201.

24.

Tsetsarkin

Weaver

SC.

Sequential adaptive mutations enhance efficient vector switching by chikungunya virus and its epidemic emergence. PLoS Pathog 2011; 7: e1002412.

25.

Mendes Dos Santos

Dias

Ramirez Pavon

, et al. Regional mutations in CHIKV-ECSA genomes and detection of other viruses in the serum of acute febrile patients by a metagenomic approach in Mato Grosso, Central-Western Brazil, 2018. Virology 2022; 576: 18–29.

26.

Singh

Tiwari

Mishra

, et al. Molecular epidemiology of chikungunya virus: mutation in E1 gene region. J Virol Methods 2012; 185: 213–220.

27.

Almeida-Souza

Oliveira

CHD

Brito

, et al. High frequencies of kdr mutation and chikungunya infection in Aedes aegypti population from Minas Gerais, Brazil. Pathogens 2024; 13: 457.

28.

Manzoor

Javed

Ejaz

, et al. The global emergence of chikungunya infection: an integrated view. Rev Med Virol 2022; 32: e2287.

29.

Mourad

Makhani

Chen

LH.

Chikungunya: an emerging public health concern. Curr Infect Dis Rep 2022; 24: 217–228.

30.

Faria

Da Silva

Avelar

CFR

, et al. Vertical transmission of chikungunya virus: a worldwide concern. Braz J Infect Dis 2024; 28: 103747.

31.

Anjos

Mugabe

Moreira

PSS

, et al. Transmission of chikungunya virus in an urban slum, Brazil. Emerg Infect Dis 2020; 26: 1364–1373.

32.

Hussien

FH.

An overview of chikungunya disease, origins, symptoms, transmission, route of infection, diagnosis, and treatment. Med J Babylon 2023; 20: 240–243.

33.

Silva

Dermody

TS.

Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies. J Clin Invest 2017; 127: 737–749.

34.

Ferreira

FCPDADM

Da Silva

ASV

Recht

, et al. Vertical transmission of chikungunya virus: a systematic review. PLoS ONE 2021; 16: e0249166.

35.

Costa

Barreto

FKDA

Barreto

MCA

, et al. Epidemiology and economic burden of chikungunya: a systematic literature review. TropicalMed 2023; 8: 301.

36.

Rama

De Roo

Louwsma

, et al. Clinical outcomes of chikungunya: a systematic literature review and meta-analysis. PLoS Negl Trop Dis 2024; 18: e0012254.

37.

De Lima

STS

De Souza

Cavalcante

, et al. Fatal outcome of chikungunya virus infection in Brazil. Clin Infect Dis 2021; 73: e2436–e2443.

38.

Dutra

JIS

Souza

MCD

Lins

CAA

, et al. Impact of chronic illness caused by chikungunya fever on quality of life and functionality. Einstein (São Paulo) 2024; 22: eAO0562.

39.

Deeba

Hasan

MdM

Al Mosabbir

, et al. Manifestations of atypical symptoms of chikungunya during the Dhaka Outbreak (2017) in Bangladesh. Am J Trop Med Hygiene 2019; 100: 1545–1548.

40.

Kang

Auzenbergs

Clapham

, et al. Chikungunya seroprevalence, force of infection, and prevalence of chronic disability after infection in endemic and epidemic settings: a systematic review, meta-analysis, and modelling study. Lancet Infect Dis 2024; 24: 488–503.

41.

Kharwadkar

Herath

Clinical manifestations of dengue, Zika and chikungunya in the Pacific Islands: a systematic review and meta-analysis. Rev Med Virol 2024; 34: e2521.

42.

Ribas Freitas

Lima Neto

Rodrigues

, et al. Excess mortality associated with chikungunya epidemic in Southeast Brazil, 2023. Front Trop Dis 2024; 5: 1466207.

43.

Millsapps

Underwood

Barr

KL.

Development and application of treatment for chikungunya fever. Res Rep Trop Med 2022; 13: 55–66.

44.

Guaraldo

Wakimoto

Ferreira

, et al. Treatment of chikungunya musculoskeletal disorders: a systematic review. Expert Rev Anti-Infect Therapy 2018; 16: 333–344.

45.

Abdelnabi

Neyts

Delang

Chikungunya virus infections: time to act, time to treat. Curr Opin Virol 2017; 24: 25–30.

46.

Kennedy Amaral Pereira

Schoen

. Management of chikungunya arthritis. Clin Rheumatol 2017; 36: 2179–2186.

47.

Ferreira

Reis

De Freitas

, et al. Beyond members of the Flaviviridae family, Sofosbuvir also inhibits chikungunya virus replication. Antimicrob Agents Chemother 2019; 63: e01389-18.

48.

Chopra

Saluja

Venugopalan

Effectiveness of chloroquine and inflammatory cytokine response in patients with early persistent musculoskeletal pain and arthritis following chikungunya virus infection. Arthritis Rheumatol 2014; 66: 319–326.

49.

Padmakumar

Jayan

Menon

, et al. Comparative evaluation of four therapeutic regimes in chikungunya arthritis: a prospective randomized parallel-group study. Indian J Rheumatol 2009; 4: 94–101.

50.

Amaral

Bingham

Taylor

, et al. Therapy for chikungunya arthritis: a study of 133 Brazilian patients. Am J Trop Med Hygiene 2023; 109: 542–547.

51.

Davuluri

Ghanghav

Ahire

, et al. Repurposed drugs in combinations exert additive anti-chikungunya virus activity: an in-vitro study. Virol J 2024; 21: 5.

52.

Chen

Fritzer

Hochreiter

, et al. From bench to clinic: the development of VLA1553/IXCHIQ, a live-attenuated chikungunya vaccine. J Travel Med 2024; 31: taae123.

53.

Marques

ETA

Dhalia

. Chikungunya vaccine VLA1553 induces sustained protective antibody concentrations. Lancet Infect Dis 2024; 24: 1298–1299.

54.

Maure

Khazhidinov

Kang

, et al. Chikungunya vaccine development, challenges, and pathway toward public health impact. Vaccine 2024; 42: 126483.

55.

Reisinger

Tschismarov

Beubler

, et al. Immunogenicity, safety, and tolerability of the measles-vectored chikungunya virus vaccine MV-CHIK: a double-blind, randomised, placebo-controlled and active-controlled phase 2 trial. Lancet 2018; 392: 2718–2727.

56.

De Lima Cavalcanti

TYV

Pereira

De Paula

, et al. A review on chikungunya virus epidemiology, pathogenesis and current vaccine development. Viruses 2022; 14: 969.

57.

Cohen

A chikungunya vaccine is likely to get approved. Who will get it?

Science 2023; 382: 503–504.

58.

Irfan

Ahmed

Advancements in chikungunya virus management: FDA approval of IXCHIQ vaccine and global perspectives. Health Sci Rep 2024; 7: e2183.

59.

World Health Organization. Launch of the WHO global arbovirus initiative. Geneva, Switzerland: World Health Organization.

Chikungunya virus: from genetic adaptation to pandemic risk and prevention

Abstract

Plain language summary

Keywords

Background

Epidemiology

Brazil

India

Pakistan

Malaysia

The Americas: beyond Brazil

Africa and Southeast Asia

Trends

Genetic mutation

Transmission and spread of chikungunya

Disease pathogenesis of chikungunya

Therapeutic and preventive measures of chikungunya

Prediction of chikungunya to cause global pandemics

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iDs

References