Continuing Education Activity

This continuing education activity provides clinicians with a comprehensive review of Venezuelan equine encephalitis, a mosquito-borne arboviral disease endemic to Central and South America that can cause large-scale outbreaks affecting both equine and human populations. Despite its significant public health implications, Venezuelan equine encephalitis is frequently misdiagnosed due to its clinical overlap with other febrile arboviral illnesses and limited familiarity among clinicians outside endemic regions. This activity addresses the gap between current practice and evidence-based standards by reviewing the virology, epidemiology, clinical presentation, diagnostic approach, and supportive management of the disease. Participants develop practical skills in risk stratification, recognition of neurological complications, patient and caregiver education on mosquito avoidance, and coordination of interdisciplinary care to optimize outcomes in affected patients.

Objectives:

• Identify the epidemiologic risk factors, geographic distribution, and transmission mechanisms of Venezuelan equine encephalitis virus, including enzootic and epizootic strain differences.
• Assess patients presenting with febrile illness in endemic regions for clinical and laboratory findings consistent with Venezuelan equine encephalitis, including leukopenia, lymphopenia, and cerebrospinal fluid abnormalities.
• Implement evidence-based supportive management strategies for patients with Venezuelan equine encephalitis across the full spectrum of disease severity, from mild febrile illness to fulminant encephalitis.
• Collaborate with infectious disease specialists, neurologists, obstetricians, nurses, and other members of the interdisciplinary healthcare team to develop coordinated care plans that address the clinical, preventive, and long-term needs of patients with Venezuelan equine encephalitis.

Introduction

Venezuelan equine encephalitis virus (VEEV) is the causative viral pathogen of Venezuelan equine encephalitis. VEEV can cause disease at low, stable levels (enzootic) as well as in sudden outbreaks (epizootic), which at times have resulted in a high number of cases. Outbreaks frequently involve both equines, including horses, donkeys, mules, and zebras, and humans, and may range over a large geographic area, lasting for several months to years.[1][2] Major outbreaks occur most commonly in South and Central America, with sporadic outbreaks in Mexico and the southern United States.[3]

VEEV exists as a natural pathogen that was also developed as a biological weapon by both the United States and the former Soviet Union during the Cold War.[1] Outbreaks have been reported in several South, Central, and North American countries, including Venezuela, Colombia, Peru, Ecuador, Costa Rica, Nicaragua, Honduras, El Salvador, Guatemala, Panama, Mexico, and the United States.[3] Previous outbreaks of epizootic strains have affected tens of thousands of people during a single epidemic.[4][5]

Etiology

VEEV is a single-stranded positive-sense RNA alphavirus in the genus Alphavirus of the family Togaviridae.[1][2] Most alphaviruses, including chikungunya virus, eastern equine encephalitis virus, western equine encephalitis virus, and VEEV, are transmitted to humans and animals by mosquitoes. Arboviruses replicate in arthropod vectors before transfer to vertebrates.[6] New World alphaviruses, including VEEV, eastern equine encephalitis virus, and western equine encephalitis virus, are found in the Americas and can cause severe encephalomyelitis. Old World alphaviruses, including chikungunya virus, were historically found in Europe, Asia, and Africa but have caused significant outbreaks in the Americas since 2013. The Chikungunya virus most commonly causes fever and polyarthritis, and can rarely cause encephalitis.

VEEV was discovered in 1935 after equine outbreaks in Venezuela, Colombia, and Trinidad.[2] VEEV was not isolated from humans until 1950 during an outbreak in Colombia.[3] Six antigenic subtypes (I through VI) and many antigenic variants exist within each subtype. Within subtype I, there are 5 antigenic variants (AB through F). Strains IAB and IC are responsible for causing encephalitis in equines and humans. These subtypes of VEE are highly pathogenic and can spread quickly through equine populations. Horses are the key reservoir species and amplification hosts for epizootic viral strains.[7] 

The enzootic strains (ID, IE, and IIF within subtype I and subtypes II through VI) frequently cycle between sylvatic rodents and Culex mosquitoes, and equines and humans are considered incidental or dead-end hosts. These strains usually cause asymptomatic or mild disease in equines, but can cause severe, sometimes fatal, disease in humans. Spillover from these enzootic transmission cycles between rodents and mosquitoes may lead to human epidemics. Findings suggest that there is no clinical difference in disease caused by epizootic and enzootic strains of VEEV in humans.[3] 

Epidemiology

VEE infections primarily occur in South and Central America, especially in Venezuela, Colombia, Panama, and Ecuador.[8][9][10][11] Outbreaks have also occurred in Mexico and the southern United States.[12][13] Enzootic VEEV circulates nearly continuously in sylvatic or swamp habitats in tropical and subtropical locations in the Americas.[14] Infections are highly sporadic, ranging from rare enzootic cases to large outbreaks with tens of thousands of cases in horses and humans.

For example, an outbreak in Venezuela in 1995 resulted in at least 13,000 cases of VEE in humans. An earlier outbreak in Colombia in 1967 resulted in an estimated 220,000 human cases.[5] Risk factors for VEE outbreaks include high horse population density (which amplifies VEEV), proximity to marshy or mangrove habitats, high mosquito density, and low horse vaccination rates. Living in areas with heavy rainfall, low altitude, and human encroachment into infected enzootic areas also increases the risk for outbreaks.[15][16]

Epizootic subtypes IAB and IC can cause significant disease in both humans and equines.[1] VEE can occur in all age groups, and there is usually no sex bias during outbreaks. However, infected children are more likely than adults to develop lasting neurological sequelae and fatal encephalitis. Pregnant women infected with VEEV are at risk for congenital disabilities, spontaneous abortions, preterm deliveries, and stillbirths.[1][17]

Pathophysiology

Several species of mosquitoes can transmit both the enzootic and epizootic strains of VEEV.[3] Ochlerotatus taeniorhynchus (also known as Aedes taeniorhynchus) appears to be the primary mosquito vector during epizootic outbreaks, while Culex (subgenus Melanoconion) mosquitoes primarily transmit enzootic strains.[18] Mosquitoes feed on infected rodents or equines, infecting the mosquito midgut.

Following initial infection, the virus matures and disseminates to secondary organs, including the salivary glands. VEEV accumulates in the salivary glands, and blood-feeding releases virions through the mosquito salivary ducts into the new host. The virus then enters a host cell and replicates in the cytoplasm.[2]

Infected equines are viral amplification hosts for epizootic strains, while sylvatic rodents are the primary reservoir hosts for enzootic strains.[1] Infected equines and humans develop high viremia loads that can, in turn, serve as sources of further mosquito infections. Infected horses shed the virus in body fluids, and humans can become infected through direct contact or inhalation of aerosolized virus.

Histopathology

Examination of the spleen, gastrointestinal tract, and lymph nodes of infected equines, rodents, and humans shows a significant depletion of lymphocytes.[1] VEEV replicates in lymphoid tissue, inducing an inflammatory cell response and cellular necrosis.[19] Additional pathological findings include interstitial pneumonia and alveolar hemorrhage in the lungs and hepatocellular degeneration in the liver in fatal human cases.[18][19] As the virus clears, tissues recover.[19]

History and Physical

VEE can manifest a range of symptoms, from mild febrile flu-like illness to severe or fatal encephalitis.[6][7][18] The incubation period for VEE infection in humans is typically 2 to 5 days.[1] Based on prior outbreaks, it is estimated that around 3 percent of infected persons develop neurologic complications.[3] 

An individual with VEE typically has a brief febrile illness characterized by malaise, myalgias (most commonly in the thighs or lumbar region), an occipital or retro-orbital headache, fever, chills, nausea, and vomiting.[1] Children are more likely to develop encephalitis and have a higher rate of morbidity and mortality from fulminant disease than do adults.[6] Symptoms of more severe disease include tremors, seizures, behavioral changes, hemiparesis, hemichorea, cranial nerve palsies, ataxia, myoclonus, confusion, somnolence, and coma.[1][19] Generalized congestion, edema, hemorrhage, and vasculitis in the brain, gastrointestinal tract, and lungs are seen in lethal cases, which comprise less than 1% of human infections.[1][18] 

The physical examination may reveal conjunctival injection, pharyngeal inflammation, and muscle tenderness. Other clinical signs of VEEV infection include leukopenia, tachycardia, and fever. Patients with acute infection may develop interstitial pneumonia. Signs and symptoms of VEE may overlap with other circulating arbovirus infections.

Evaluation

Many cases of VEE are diagnosed clinically, and cases are probably frequently misdiagnosed as other, more common febrile illnesses.[3] VEE can be clinically diagnosed in the laboratory based on a reactive immunoglobulin M antibody in the cerebrospinal fluid (CSF), a 4-fold rise in serum antibody titers against VEEV, or isolation of the virus, viral antigens, or genomic sequences from tissue, blood, or CSF.[3][18] These diagnostic tests may be cost-prohibitive, especially in resource-limited countries.[3] Laboratory testing may reveal leukopenia, lymphopenia, and elevated transaminase levels.[19] A lumbar puncture to obtain CSF for analysis may be necessary, with CSF demonstrating a lymphocytic pleocytosis and elevated protein levels.

Treatment / Management

The most notable recent development is 4'-fluorouridine (4'-FlU, EIDD-2749), a broad-spectrum antiviral that shows potent activity against VEEV, with submicromolar potency in cell culture. This antiviral can treat alphavirus encephalitis even in the presence of resistance mutations.[20] Another significant antiviral drug in development is BDGR-49, a quinazolinone compound that demonstrated remarkable efficacy in preclinical studies.[21]

Most infections are self-limiting, though neurological sequelae may occur.[1] Although no United States Food and Drug Administration (FDA)-approved human vaccine is currently available, TC-83 is a live-attenuated vaccine strain that has been used in both humans and equines.[18] The vaccine is not widely available and is typically reserved for laboratory and military personnel at high risk of exposure. Up to 40% of individuals may develop flu-like symptoms following vaccination.

Approximately 80% of vaccinated individuals will seroconvert. Additionally, there is a risk that the vaccine strain may revert to a wild-type, virulent strain, potentially causing outbreaks.[2] Formalin-inactivated TC-83 has also been used in equines and humans who do not seroconvert with the live-attenuated vaccine. However, boosters are necessary to maintain immunity.[3] Postinfection, immunity to a specific serotype appears to be lifelong; however, cross-immunity between serotypes may be poor.

The development of next-generation vaccine candidates for VEEV is ongoing. A candidate vaccine against VEE, eastern equine encephalitis, and western equine encephalitis is currently in development. A single-center, phase 1, randomized, open-label, dose-escalation study to examine the safety, tolerability, and immune response of 3 doses of an experimental trivalent encephalitis vaccine (VRC-WEVVLP073-00-VP) has been completed, with results showing the candidate vaccine to be safe, well-tolerated, and immunogenic. Another phase 1, randomized, observer-blind, placebo-controlled study found the candidate vaccine pWRG/VEE to be safe, reactogenic, and immunogenic. Other studies of candidate vaccines are ongoing.

Differential Diagnosis

Several arboviruses circulate in overlapping regions throughout Central and South America. VEE clinically presents like other tropical arboviral diseases and may be indistinguishable without confirmatory testing.[3] The differential diagnosis for VEE is extensive. A thorough travel history should be obtained in patients presenting with febrile illness in endemic regions. Clinicians should elicit any exposure to ill equids. Careful history-taking and physical examination may aid in differentiating VEEV from other arbovirus infections, but laboratory diagnosis remains most specific.

• Other arboviral diseases (eg, dengue, yellow fever, Zika, chikungunya, eastern equine encephalitis, western equine encephalitis, West Nile virus, Mayaro virus)
• Bacterial meningitis
• Malaria
• Typhoid fever
• Leptospirosis
• Herpes simplex encephalitis
• Lyme disease
• Rocky Mountain spotted fever

Pertinent Studies and Ongoing Trials

As of March 2026, the following clinical trials were ongoing:

• NCT06002503, a single-center, phase 1, randomized, observer-blind trial evaluating the safety and reactogenicity of a VEE DNA vaccine candidate delivered by either intramuscular or intradermal jet injection.
• NCT03531242, a single-center, phase 2, open-label, nonrandomized study evaluating the safety and immunogenicity of the VEE vaccine, inactivated, dried, C-84, TSI-GSD 205, Lot 7, Run 1, as a booster vaccination in adults at risk of exposure to VEE virus. 
• NCT07088822, a single-center, phase 1, randomized, blind trial evaluating the safety and immunogenicity of a novel VEEV vaccine (V4020) administered subcutaneously or by intramuscular injection in humans. 

Prognosis

Equine mortality is significant and is estimated to be 19% to 83% during epizootic outbreaks. Fatality rates are much lower in humans, and less than 1% of cases are lethal. Adults are more likely to develop febrile illness. Children are at greater risk of developing neurological disease or encephalitis.[18] Symptoms of central nervous system disease may include ataxia, depression, altered mentation, coma, and seizures.[2] Children are also more likely to experience neurological sequelae following recovery from VEE.[22]

Complications

Neurological sequelae may persist following recovery from initial infection with VEEV. Though there is no specific therapy for VEEV, most patients survive with supportive care, even with encephalitic disease.[22] Some patients develop permanent neurological sequelae, which can include seizures, confusion, intellectual disabilities, and behavioral changes. The spectrum of VEEV-induced sequelae ranges from mild and manageable to life-altering. Postinfectious sequelae can develop irrespective of the severity of the preceding febrile illness.[22]

Pregnant women may be at a distinct risk of complications from arbovirus infections. VEEV was classified as the first teratogenic arbovirus. Pregnant women are at risk for congenital disabilities, miscarriage, preterm delivery, and stillbirth. Vertical transmission from mother to fetus has been documented.

Results from 10 fetal autopsies performed during an outbreak demonstrated VEEV in the brains of aborted fetuses.[3][17] Infants born to mothers with VEE may have neurological sequelae or fatal cerebral lesions. Worldwide, infectious diseases remain one of the most common causes of maternal mortality, and it is estimated that up to 90% of pregnancies occur in regions where arboviruses are endemic or epidemic.[17]

Deterrence and Patient Education

Because no specific treatment exists for VEE, avoiding mosquito bites and VEE infection is the best prevention. Outbreaks may be controlled by reducing mosquito populations, because arthropods serve as the primary vector of infection. Humans, especially those who have frequent contact with equines, should limit physical exposure to mosquitoes, wear protective clothing, and apply mosquito repellent frequently. Aerosolized insecticide applications in endemic areas will also help reduce mosquito populations.[3]

Epizootic outbreaks may also be prevented through mass vaccination of horses with the TC-83 live-attenuated vaccine.[1] TC-83 is licensed and available for equines in endemic regions.[6] Sustained vaccine programs between outbreaks may be necessary to develop herd immunity in equines to limit spillover into humans.[3]

Pearls and Other Issues

Global warming may facilitate the emergence of VEE epidemics. Climate change can lead to longer transmission seasons, changes in rainy seasons, which increase mosquito populations, and increased geographic distributions of tropical mosquito vectors.[3][23] Enzootic VEEV exists continuously in tropical regions, and the emergence of epizootic strains poses a risk of equine and human outbreaks. In endemic regions, surveillance programs for early detection and implementation of mosquito control and equine vaccination will help control outbreaks.

VEEV was developed as a biological weapon by the United States and the former Soviet Union during the Cold War. VEEV is classified as a biosafety level 3 pathogen by the Centers for Disease Control and Prevention and as a category B priority pathogen by the National Institute of Allergy and Infectious Diseases.[2] Laboratory accidents have been reported, with infections occurring from small-volume aerosolized samples.

Enhancing Healthcare Team Outcomes

The diagnosis and treatment of VEE require an interdisciplinary approach. Clinicians in endemic areas must maintain a high degree of suspicion for the diagnosis. Patients will require supportive care for any degree of disease they develop, from mild illness to fulminant encephalitis. Following recovery, some patients may experience neurological sequelae and will require continued support from clinicians and the community.

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Disclosure: Jeffrey Jenks declares no relevant financial relationships with ineligible companies.

Disclosure: Maria Crespo declares no relevant financial relationships with ineligible companies.