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West Nile (WN) virus is an important cause of febrile exanthem and encephalitis. Since it invaded the U.S. in 1999, >19,000 human cases have been reported. The threat of continued epidemics has spurred efforts to develop vaccines. ChimeriVax-WNO2 is a live, attenuated recombinant vaccine constructed from an infectious clone of yellow fever (YF) 17D virus in which the premembrane and envelope genes of 17D have been replaced by the corresponding genes of WN virus. Preclinical tests in monkeys defined sites of vaccine virus replication in vivo. ChimeriVax-WNO2 and YF 17D had similar biodistribution but different multiplication kinetics. Prominent sites of replication were skin and lymphoid tissues, generally sparing vital organs. Viruses were cleared from blood by day 7 and from tissues around day 14. In a clinical study, healthy adults were inoculated with 5.0$log_{10}$plaque-forming units (PFU) (n = 30) or 3.0$log_{10}$PFU (n = 15) of ChimeriVax-WNO2, commercial YF vaccine (YF-VAX, n = 5), or placebo (n = 30). The incidence of adverse events in subjects receiving the vaccine was similar to that in the placebo group. Transient viremia was detected in 42 of 45 (93%) of ChimeriVax-WNO2 subjects, and four of five (80%) of YF-VAX subjects. All subjects developed neutralizing antibodies to WN or YF, respectively, and the majority developed specific T cell responses. ChimeriVax-WNO2 rapidly elicits strong immune responses after a single dose, and is a promising candidate warranting further evaluation for prevention of WN disease.

Objectives Arboviruses pose a significant global health challenge. This study investigated the seroprevalence of major human arboviral infections, including yellow fever (YFV), dengue (DENV), Crimean-Congo hemorrhagic fever (CCHF), Rift Valley fever (RVF), West Nile virus (WNV), and chikungunya (CHIK), in Darfur region from September to December 2018. ELISA-IgM was used to detect antibodies. RT‒PCR was used to differentiate YFV infection from vaccine-immuno-response in IgM samples. Results A total of 152 blood samples were collected, with 123 (80.9%) from males and 29 (19.1%) from females. The participants were grouped by age: 50 (32.9%) were under 20 years, 96 (63.2%) were aged 20–45 years, and 6 (3.9%) were over 45 years. The seroprevalence rates for YFV, DENV, and CHIKV were 68 (44.7%), 23 (15.1%), and 5 (3.3%), respectively. There were 11 molecularly-confirmed YFV cases (7.2%). Among these, 3/11 were positive for DENV-IgM, and 1/11 was positive for CHIKV-IgM. Among the 68 YFV-positive individuals, 15 (22.1%) had been exposed to DENV, and 2 (2.9%) had been exposed to CHIKV. Co-exposure to DENV and CHIKV was detected in 3 (1.9%) patients, while 2 (1.3%) patients had triple exposure to YFV, CHIKV, or DENV. No exposure to CCHF, RVFV, or WNV was detected.

Humans and equines are two dead-end hosts of the mosquito-borne West Nile virus (WNV) with similar susceptibility and pathogenesis. Since the introduction of WNV vaccines into equine populations of the United States of America (USA) in late 2002, there have been only sporadic cases of WNV infection in equines. These cases are generally attributed to unvaccinated and under-vaccinated equines. In contrast, due to the lack of a human WNV vaccine, WNV cases in humans have remained steadily high. An average of 115 deaths have been reported per year in the USA since the first reported case in 1999. Therefore, the characterization of protective immune responses to WNV and the identification of immune correlates of protection in vaccinated equines will provide new fundamental information about the successful development and evaluation of WNV vaccines in humans. This review discusses the comparative epidemiology, transmission, susceptibility to infection and disease, clinical manifestation and pathogenesis, and immune responses of WNV in humans and equines. Furthermore, prophylactic and therapeutic strategies that are currently available and under development are described. In addition, the successful vaccination of equines against WNV and the potential lessons for human vaccine development are discussed.

West Nile Virus (WNV), first identified in Uganda in 1937, remains a significant global health threat, adapting across diverse ecosystems and expanding geographically, particularly into temperate regions of Europe and North America. This review provides a comprehensive exploration of the latest insights and challenges in WNV management, focusing on epidemiological trends, molecular advancements, and public health implications. Recent data highlight WNV's expansion, driven by climate changes such as milder winters and longer warm seasons that increase mosquito activity and enable the virus to overwinter within mosquito populations. This facilitates year-round transmission and challenges current control strategies. Molecularly, advancements in genomic and proteomic technologies have deepened our understanding of WNV's replication and pathogenesis, identifying new therapeutic targets and improving diagnostic methods. However, the absence of an approved human vaccine leaves management dependent on supportive care, particularly for severe neurological cases. Effective vector control remains crucial, with innovative strategies including genetically modified mosquitoes and novel insecticides being pivotal. Furthermore, environmental factors like climate change and urbanization are altering vector behaviors and WNV transmission dynamics, necessitating adaptive public health strategies to manage these evolving threats. The review underscores the need for ongoing research, vaccine and therapeutic development, and enhanced public health infrastructures to better respond to WNV challenges. It stresses the critical role of integrating scientific research, public health policy, and community engagement to effectively address the persistent threat of WNV.

Although West Nile virus (WNV) has been a prominent mosquito-transmitted infection in North America for twenty years, no human vaccine has been licensed. With a cumulative number of 24,714 neurological disease cases and 2314 deaths in the U.S. since 1999, plus a large outbreak in Europe in 2018 involving over 2000 human cases in 15 countries, a vaccine is essential to prevent continued morbidity, mortality, and economic burden. Currently, four veterinary vaccines are licensed, and six vaccines have progressed into clinical trials in humans. All four veterinary vaccines require multiple primary doses and annual boosters, but for a human vaccine to be protective and cost effective in the most vulnerable older age population, it is ideal that the vaccine be strongly immunogenic with only a single dose and without subsequent annual boosters. Of six human vaccine candidates, the two live, attenuated vaccines were the only ones that elicited strong immunity after a single dose. As none of these candidates have yet progressed beyond phase II clinical trials, development of new candidate vaccines and improvement of vaccination strategies remains an important area of research.

Combating West Nile Virus DiseaseWNV remains a public health threat in many areas of the world, and current approaches to primary prevention have limitations. It is time to revisit the need for human WNV vaccines.

West Nile virus (WNV) is a neurotropic mosquito-borne virus that re-emerged in the last 25 years to cause substantial short- and long-term morbidity and mortality, particularly in the United States and Europe. Attempts to mitigate the impact of WNV by vector control have been largely unsuccessful. A WNV vaccine could be effective in decreasing disease burden. To identify and address important barriers to licensing human WNV vaccines, U.S. Centers for Disease Control and Prevention convened a meeting of key stakeholders from the U.S. federal and municipal governments, industry, academia, and regulatory agencies in April 2024. Topics discussed included epidemiology, impact of outbreaks, rationale for human vaccines, animal models and correlates of protection, diagnostic considerations, candidate human vaccines in clinical development, and regulatory considerations for vaccine development. Several barriers to human WNV vaccine licensure were identified, including 1) episodic transmission with substantial geographic and temporal variability in disease occurrence impeding the feasibility of phase III clinical trials evaluating vaccine efficacy against WNV disease, 2) high asymptomatic attack rate affecting potential clinical trial endpoint considerations, 3) lack of a surrogate endpoint to predict clinical benefit, 4) need for standardized reagents and assays to quantitate antibodies, and 5) minimal economic support for vaccine development and commercial manufacturing. Future activities to support advancing WNV vaccine development and licensure involve developing a target product profile, establishing suitable animal models and surrogate endpoints to predict clinical benefit, developing a diagnostic test to differentiate immunologic response to infection versus vaccination, conducting a sales forecast analysis, exploring partnerships that could advance vaccine development and licensure, and considering alternative approaches for licensure such as the accelerated approval pathway. We need to work collaboratively as a public health and scientific community to ensure human vaccines are available to decrease the ongoing morbidity and mortality caused by WNV.

•Flavivirus diseases are vaccine-preventable.•Flavivirus vaccines can provide individual and social protection.•Vaccines against YF, JE, and TBE are currently available.•Cost effectiveness and inconsistent prevalence are obstacles for West Nile vaccine.•Highly effective tetravalent dengue vaccines are required. Genus flavivirus comprises many important human pathogens causing public health problems worldwide. Some flavivirus infections are characterized by a relatively high mortality rate and/or high sequelae rate in survivors. Because most flavivirus life cycles are maintained between arthropod vectors and amplifying/reservoir hosts in the absence of humans, eradication of flaviviruses might be extremely difficult. Flavivirus vaccine development is considered a reasonable method to prevent flavivirus infections. Some vaccines have been successfully developed, but others have not, regardless of much effort. This review article describes currently available flavivirus vaccines against yellow fever, Japanese encephalitis, and tick-borne encephalitis. In addition, the current status of dengue and West Nile virus vaccine development is reviewed and problems regarding their development are discussed.

Roadside stormwater catch basins are frequently treated with larvicides in metropolitan areas because they are ideal larval growth sites for West Nile virus (WNV) vector species Culex pipiens Linnaeus and Cx. restuans (Theobald) . Despite the wide-spread implementation of catch basin treatments in integrated vector management programs, there is little entomological evidence to suggest catch basin larvicide treatments reduce adult mosquito abundance and thereby impact WNV risk. We evaluated the impact of treating catch basins at three of four sites (700–1000 basins each) with a formulation of Lysinibacillus sphaericus using a stepped-wedge cluster trial approach in metropolitan areas in Wisconsin, U.S.A in 2019. Treatment effects were measured by evaluating immature stage mosquito abundance in catch basins and general additive models (GAM) to analyze changes of the integrated adult female Culex spp. abundance and population stability sampled from host-seeking and gravid mosquito traps. We observed catch basin treatments to effectively suppress immature stages in catch basins (94% reduction of pupae). The GAM found catch basin treatment duration to significantly reduce the integrated abundance of gravid Culex spp. mosquitoes, with a total mean percent reduction of 37% at treated sites. Treatment duration was also observed to impact the stability of the gravid Culex spp. integrated abundance, with differences between untreated and treated sites, and among sites that differed in treatment duration. These results support the treatment of catch basins with biorational larvicides as a mosquito management tool for WNV vector species in similar metropolitan habitats provided adequate suppression of immature stage mosquitoes.

While global interest in mpox may be waning, outbreaks, illness, and death continue across Africa and the world. Ending transmission requires a sustained global response that moves beyond reactive measures.