Travel-Related Challenges of Chikungunya Virus and Vaccination Options

Abstract

Chikungunya is a febrile illness caused by an arbovirus transmitted by Aedes spp. mosquitoes, which are abundant worldwide and can easily establish new habitats. With urbanization and climate change, the vector has spread to new areas. Chikungunya has caused multiple outbreaks worldwide in most continents. Molecular evidence suggests that a single mutation in the chikungunya virus can influence vector specificity, enhancing its potential to cause explosive outbreaks. The infection commonly presents with a triad of fever, rash, and arthritis. The latter symptom occurs in more than 90% of sufferers and may persist for many months to years, causing significant morbidity. Currently, no antiviral therapy is available, and management is primarily supportive. Several cases of Chikungunya acquired through international travel have been reported. Travel-associated viremic cases can drive introduction and local transmission in new geographical areas where the mosquito vector is abundant. Awareness of the disease among both travelers and healthcare providers remains poor. A global one health approach, with strengthened public health policies, enhanced surveillance, and travel-related prevention, is currently the most effective way to curb the reemerging threat of the disease. Two vaccines are currently available and are durable for at least 2 years; though they lack efficacy data, they have both been approved. First, VLA1553, trade-named IXCHIQ, is a live-attenuated vaccine with nearly 99% seroprotection; however, it has many safety concerns, including Chikungunya-like illness (CLI), and has recently been paused for use in persons older than 60 years. Second, PXVX0317, trade-named Vimkunya, is a virus-like particle with nearly 98% seroprotection, but it does not cause CLI. Both vaccines are currently recommended for travelers visiting areas with a CDC-declared outbreak.

Introduction

Chikungunya (CHIK) is a self-limiting infection caused by the Chikungunya virus (CHIKV), an arbovirus transmitted by Aedes spp. Humans are the main reservoirs, but other vertebrates can carry the virus. Vertical transmission is also well described [1].

CHIKV was first discovered in 1952 in Tanzania. The term “chikungunya” is derived from the native Kimakonde language, which means “to become contorted” due to the severe stooped appearance of sufferers with arthritis that is characteristic of this disease [2]. An evolutionary timescale whole genome study determined that CHIKV might have first evolved 300 years ago [3].

CHIK is a re-emerging infectious disease that has caused multiple outbreaks. The World Health Organization (WHO) designated the disease as a major public health concern due to its high morbidity, causing chronic debilitating illness in sufferers and high mortality risk in neonates and the elderly.

There have been multiple outbreaks worldwide, and several Indian Ocean islands have experienced explosive outbreaks [4]. In addition, over the past few years, the risk of infection among international travelers has increased, with numerous imported cases reported [5].

With the global threat of CHIKV emergence, an effective and durable vaccine was urgently needed. A live-attenuated vaccine was fast-tracked and approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2023–2024, respectively. A second vaccine, a non-live virus-like particle (VLP), was also approved by the FDA and EMA in 2025.

This narrative reviews the chikungunya virus and its pathogenesis, including epidemiology and outbreaks; the role of the mosquito vector in transmission; clinical presentation and diagnosis; and the two currently licensed vaccines, with an emphasis on travel-related challenges and implications.

Virology

CHIKV is a positive-sense single-stranded RNA Alphavirus of the Togaviridae family. It is an arbovirus, similar to Dengue, Zika, and Yellow Fever viruses. However, all the latter viruses are Orthoflaviviruses of the Flaviviridae family. Hence, CHIKV is more closely related to other alphaviruses, including Ross River, Mayaro, Una, Semliki Forest, and O’nyong’nyong viruses.

The CHIKV genome encodes structural proteins, including the capsid and envelope proteins (C-E3-E2-6 K-E1), which encapsulate the genome and facilitate the assembly of new viruses and their entry into host cells. The genome also contains two open reading frames (ORFs) encoding non-structural proteins (nsP1-4), which are responsible for viral replication, translation, and immune evasion. The genome has three distinct genotypes: West African, East/Central/South African (ECSA), and Asian. The latter has two clades, the Indian Ocean and South-East Asian [6]. The CHIKV replicase complex replicates genomic RNA for incorporation into new virus particles. It has transcriptase activity that produces mRNA from a subgenomic promoter, which encodes the structural proteins [7]. Mature virions bud from the plasma membranes of infected cells and carry 240 copies of E2-E1 glycoproteins that are arranged into 80 heterotrimeric spike complexes. E2 protein is the receptor-binding moiety, and E1 protein is involved in the fusion of the virion envelope within the target cell membranes [8]. The spike complex, especially the E2 envelope protein, is the target for neutralizing antibodies [9].

Pathogenesis

In non-human primates, long-term infection with CHIKV was detected in joints, and macrophages were the main cellular reservoir [10]. In mice, CHIKV RNA persisted specifically in joint tissue for at least 16 weeks, and viral replication was detected in chondrocytes in metatarsal joints, with evidence of focal erosion and periarticular inflammation, and within human chondrocytes, CHIKV induced apoptosis, cartilage remodeling, and cytokine production [11].

Animal studies utilizing plasma from humans naturally infected with CHIKV, containing neutralizing antibodies (NAb), demonstrated protective effects [12]. In vitro, selective expression of the virus’s structural proteins produced virus-like particles (VLPs). When these VLPs were injected into non-human primates, they induced neutralizing antibodies that protected against viral bloodstream infection. These antibodies were then transferred into immunodeficient mice, which were exposed to lethal doses of CHIKV, and the antibodies provided adequate protection against the infection [13].

Epidemiology

CHIK has caused multiple outbreaks over the past two decades. Currently, more than 75% of the world’s population lives in areas at risk of CHIKV transmission. Between 2015 and 2020, the cumulative number of confirmed cases reported to the WHO worldwide was 3,076,220 (Fig. 1). In 2024, worldwide, there have been more than 240,000 cases. A higher number of reported chikungunya cases in the Americas may be attributed to enhanced surveillance, diagnosis, and reporting systems compared to those in Africa, which may explain the underreporting of the disease. In addition, large outbreaks in the Americas may be driven by previously unexposed populations. The differences also highlight the true burden of disease when enhanced surveillance is implemented, as many cases remain unreported. However, the overall global pattern highlights the widespread occurrence of CHIK worldwide, and the numerous explosive outbreaks reported over the past two decades further showcase the rapid evolution and spread of the virus both locally and internationally.

Fig. 1.

World distribution of cumulative confirmed cases of chikungunya reported to the WHO, 2015–2020

With the spread of Chikungunya worldwide, the role of international travelers who may be viremic can further spread the infection to new areas where the disease has not been previously documented. Several imported cases to Europe and the Middle East, following travel to Thailand and Myanmar in 2019 [5, 14] and to Bali in 2022 [15], have been reported. These outbreaks showed a significantly increased risk of infection among international travelers, again highlighting the potential for the virus to spread beyond endemic regions through travel. The growing geographical spread of CHIKV is driven in part by increasing global mobility and climate change, which enhance vector habitats [16, 17]. Thus, there is a critical role of traveler education and vector control in endemic and at-risk regions. Awareness of CHIK remains low among both travelers and healthcare providers, contributing to underdiagnosis and underreporting. The WHO 2024 update on Chikungunya surveillance underscores the rising incidence of imported cases, such as travel-associated viremic cases, which can further drive introduction and local transmission in geographical areas with competent Aedes vectors. The report emphasizes integrating surveillance data with travel advisories to link imported cases to the initiation of outbreaks and to enhance protection for travelers and public health systems.

Transmission

CHIKV is readily transmitted by Aedes spp., and their eggs have been known to spread through the international tyre trade [18]. The two primary species responsible for transmitting these viruses are Aedes aegypti and Aedes albopictus. A single mutation within CHIKV can alter vector specificity, thereby enhancing its potential for explosive outbreaks. Mutations in E1 and E2 can confer higher fitness for adaptation to A. aegypti, increasing infectivity, dissemination, and transmission [19]. Furthermore, the growth of the human population, driven by urbanization and globalization, together with global climate change that is causing warmer temperatures and changes in rainfall patterns, is allowing mosquito vectors to thrive at higher altitudes and in new locations [20].

Clinical Manifestations

After a mosquito bite, CHIKV initially replicates in dermal fibroblasts, then spreads to the lymph nodes and enters the bloodstream, allowing dissemination throughout the body. This tissue replication results in extremely high levels of viremia, often exceeding 10⁹ virus particles per milliliter of blood. During this phase, if an Aedes mosquito takes a blood meal, it can acquire the virus and facilitate further transmission [21]. The incubation period ranges from 1 to 12 days, with an average of 2 to 7 days. The clinical illness generally persists for one to three weeks before resolving on its own. The classic clinical triad typically includes high-grade fever (usually > 39 °C), polyarthralgia or arthritis (usually symmetrical and often affecting the hands and feet), and a maculopapular morbilliform rash (Fig. 2) [22]. CHIK can cause significant chronic morbidity, causing incapacitating symptoms with debilitating joint pain, which can last months to years in 30–40% of cases, especially among those older than 35 years [23]. Case fatality is almost 1 in 1,000, and is usually in those older than 75 years or neonates, but can increase to 10.7% if complicated disease is present [24].

Fig. 2.

Main clinical triad of Chikungunya disease

Diagnosis and Management

Serological diagnosis of CHIKV infection is primarily performed using IgM- and IgG-specific ELISA. Diagnosis is typically based on the detection of anti-CHIKV IgM antibodies, which become detectable at the end of the first week of illness, peak at 3–5 weeks and may persist for up to two months [25]. Detection of CHIKV RNA through nucleic acid amplification tests (NAAT) is an effective method for diagnosing infection. Viral RNA can typically be detected in serum for up to 6 to 8 days after the onset of symptoms. To maximize diagnostic accuracy, it is recommended to perform both molecular testing and serological assays on samples collected during the first week of illness [25]. Currently, there is no specific antiviral therapy for CHIK, and the management is mainly supportive. Purified human polyvalent CHIKV immunoglobulins from donors in the convalescent phase of CHIK infection resulted in inhibition of viral amplification in tissue and prevented viremia in animal models [12]. A phase 1 trial of mRNA-1944, a lipid nanoparticle-encapsulated mRNA encoding the heavy and light chains of a CHIKV-specific monoclonal neutralizing antibody in healthy participants, demonstrated neutralization of CHIKV and therapeutically relevant concentrations [26].

Vaccines

Currently, two approved chikungunya vaccines are in use. The first, VLA1553—marketed as IXCHIQ—is a live-attenuated vaccine derived from the La Réunion strain LR2006-OPY1 of the ECSA genotype. A significant 61-amino-acid deletion in the nsP3 gene, which encodes part of the viral replicase complex, attenuates CHIKV in vivo. In a Phase 1 clinical trial, this live-attenuated vaccine demonstrated 100% seroconversion. All participants developed CHIKV-specific neutralizing antibodies that persisted for 1 year [27, 28]. A Phase 3 clinical trial selected a dose of 1 × 10⁴ 50% Tissue Culture Infectious Dose (TCID50) per 0.5mL, administered as a single intramuscular dose. The trial was conducted in non-endemic areas due to the unpredictability of CHIKV epidemiology and outbreaks, which made efficacy trials unfeasible [29]. The primary endpoint was the proportion of baseline-negative participants with a seroprotective CHIKV antibody level, defined as a 50% plaque reduction in a microplaque reduction neutralization test (µPRNT), with a µPRNT50 titer of at least 150 geometric mean antibody titers (GMTs). The Phase 3 study included 4,128 participants randomized at a 3:1 ratio for VLA1553 or placebo and were stratified by age into two groups: 18 to 64 years and 65 years and older [30]. The immunogenicity analysis was conducted in a subset population. This comprised 362 participants: 266 in the vaccine arm and 96 in the placebo arm. The seroprotection rate was 98.9% on day 28 and 96.3% on day 180 (6 months). No difference was observed between the two stratified age groups [30]. A 2-year single-arm Phase 3b follow-up study of 362 vaccine recipients found persistence of seroprotection with an efficacy of 96.8% and no difference across stratified age groups [31]. Chikungunya-like illness (CLI), defined as fever plus symptoms such as arthralgia, myalgia, back pain, rash, lymphadenopathy, or certain neurological, cardiac, or ocular symptoms within 30 days of vaccination, was a key safety concern. CLI occurred in 11.7% of vaccine recipients (361/3,082) and 0.6% of placebo recipients (6/1,033), with most cases being mild to moderate, and there was no increased risk in those aged 65 or older. Severe CLI, which interfered with daily activities or required medical care, was reported in 1.5% of the vaccine group (46 cases) and 0.8% of the placebo group (8 cases). Prolonged reactions lasting 30 days or more occurred in 0.5% (14 cases) of the vaccine group [30].

The FDA granted IXCHIQ accelerated approval in 2023 [32]. This was the first time a vaccine for a new disease was approved with a surrogate marker and no vaccine efficacy data. In 2024, the EMA and Health Canada both granted IXCHIQ their approval [33, 34]. However, In May 2025, the FDA and CDC recommended pausing IXCHIQ use in individuals aged 60 and older due to reports of serious post-marketing adverse events, including cardiac and neurological events among recipients aged 62 to 89 [35].

The second vaccine, PXVX0317, marketed as Vimkunya, is a non-live recombinant Virus-like Particle (VLP) CHIKV vaccine. The recumbence includes structural proteins capsid, E1-3, 6 K from CHIKV strain 37,997 of the West African genotype, which lacks a viral genome, preventing its replication [13]. In the Phase 1 trial, high NAb levels were maintained [28].

A phase 2 study assessed the safety and tolerability of the CHIK VLP [36]. Overall, 29% developed mild local reactions in the vaccine arm. All but one of the vaccine recipients responded positively (99.5%). At week 72, 96% of the vaccine recipients remained seropositive, and none of the study participants developed CHIK infection [36].

The second Phase 2 study was a safety and immunogenicity study [37]. The PXVX0317 used in this study was adjuvanted with aluminium hydroxide, intended to elicit an earlier, higher, and longer-lasting response. The most common AEs were injection-site pain, reported in 23% of participants who received the unadjuvanted vaccine and 31% who received the adjuvanted vaccine. No serious AEs were reported, concluding that the vaccine was well-tolerated and induced a robust, durable immune response, and recommended a single 40 µg dose of the adjuvanted vaccine [37].

Following the Phase 2 studies, an animal model study was conducted, and monoclonal antibodies (mAbs) were generated from peripheral blood B cells of three PXVX0317-vaccinated individuals of the phase 2 study on day 57 of immunization and was shown to neutralize CHIKV infection potently, and a subset of these inhibited multiple related arthritogenic alphaviruses in the descending order: O’nyong nyong, Mayaro, Una, and Ross River viruses. These results demonstrate the inhibitory breadth and activity of the human B cell response induced by the PXVX0317 vaccine against CHIKV and potentially other related alphaviruses [38].

The Phase 3 trial was conducted in the USA [39]. The study included 2,790 participants in the vaccine arm and 464 in the placebo arm. At day 22 of inoculation, the immunoreponse was 97.8% in all vaccine groups (GMTs 1618) compared to 1.2% (GMTs 7.9) in the placebo group. The vaccine was safe and tolerable, the most common AEs were injection site pain (23·7%) [39]. In 2025, the FDA, the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) and EMA granted Vimkunya accelerated approval [40–42]. Vaccine efficacy trials are to be done for both vaccines in phase 4 clinical trials, with readouts expected by 2029–2030. For the indications of both vaccines, the WHO Strategic Advisory Group of Experts on Immunization (SAGE) policy does not allow for the development of guidelines without vaccine efficacy data; however, guidelines for endemic populations are expected by 2026 [43].

Currently, both vaccines are recommended for laboratory workers with potential exposure to CHIKV. However, the main recommendation for both vaccines is for travelers to areas with CDC-declared outbreaks. The vaccines can be considered for certain persons traveling to non-outbreak countries with transmission among humans within the past five years for persons with long-stay travel of 6 months or more, and in all persons age above 65 years (Vimkunya only) especially if they have comorbidities, who might have at least two or more weeks cumulative exposure to mosquitoes in indoor or outdoor settings, excluding those traveling for business and likely to be mainly in mosquito protected indoor settings [44].

Although both vaccine indications and seroprotectivity are similar, there are differences between the two vaccines (Table 1). Many questions regarding the two vaccines still remain, including the impacts of pre-existing CHIKV immunity on vaccine safety and immunogenicity, long-term immunity of vaccines and if a booster would be required, safety in children aged 12 and under for Vimkunya, 17 and under for IXCHIQ, the use in pregnant and breastfeeding women, the use in immunocompromised individuals, and the overall efficacy in individuals previously exposed or infected to other alphaviruses [45]. Moreover, no validated immune marker currently exists that predicts clinical protection. The two vaccines are not interchangeable, and with the development of viremia with IXCHIQ, it may be possible that healthy young persons may suffer from subclinical CLI, causing virus-induced arthritis or encephalopathy that may go undetected; however, these are still theoretical risks, not currently supported by clinical efficacy or postmarketing data. Given this, in addition to the contraindication of live attenuated vaccines in immunocompromised and pregnant women, Vimkunya may be a better choice for travel clinics to offer to their travelers.

Table 1.

Comparison between the two currently licensed vaccines

	IXCHIQ (Valneva)	Vimkunya (Bavarian Nordic)
Vaccine type	Live-attenuated virus	Virus-like particle
CHIKV strain	LR2006-OPY1	37,997 West Africa
Durability	2 years	2 years
Age	> 18 yrs (May 2025: pause on use in persons age > 60 years)	> 12 yrs
Dosage	Single dose 0.5 ml IM	Single dose 0.8 ml IM
Indications	Certain laboratory workers. Travelers aged 18–60 traveling to areas with a declared outbreak.	Certain laboratory workers. Travelers aged 12 and above traveling to areas with a declared outbreak.
Seroprotection	98.9%	97.8%
Efficacy data available	No	No
Vaccine-associated viremia	Yes	No
Chikungunya-like illness	Yes	No

Concluding Remarks

Chikungunya is an emerging global threat that continues to cause multiple outbreaks worldwide. The Chikungunya virus can readily mutate, facilitating its potential spread through the ever-expanding mosquito vectors with direct implications on global health. Introduction of strict public health policies for surveillance and prevention of Chikungunya should be continued and further upscaled in underreporting countries, with greater emphasis on the role of international travel in its spread. Awareness among travelers and their healthcare providers of the risk of the disease is crucial. Healthcare and travel-related clinics should provide necessary counseling on the symptoms of chikungunya and its long-lasting sequelae, mosquito-bite prevention measures with arthropod repellents, including diethyltoluamide (DEET), picaridin, or permethrin, and review of full travel itinerary for potential travel to areas with declared- or previously declared- chikungunya outbreaks, with comprehensive counseling on the disease to be integrated in all travel medicine clinics, and the introduction of the two vaccines within these clinics, recommending them to eligible travelers visiting regions and countries with outbreaks.

Abbreviations

CHIK

Chikungunya

CHIKV

Chikungunya virus

VLP

Virus-like particle

CLI

Chikungunya-like illness

Author Contributions

MB, MT, JT, ZM: Conceptualization, methodology, software, validation, investigation, resources, writing-original draft, writing-review and editing, visualization, supervision, project administration.

Funding

Not applicable.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Ethics Approval and Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Clinical Trial Number

Not applicable.

Competing Interests

The authors declare no competing interests.