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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.

► ChimeriVax-WN02 is a live attenuated vaccine for protection against West Nile virus. ► We assessed the immunogenicity and safety of ChimeriVax-WN02 in subjects aged ≥50. ► Subjects were randomized in 3 groups to receive 1 dose of a different formulation. ► Seroconversion was achieved at day 28 by >92% of subjects in each of the groups. ► ChimeriVax-WN02 was well tolerated in subjects in all groups. ChimeriVax-WN02 is a live, attenuated chimeric vaccine for protection against West Nile virus (WNV) produced by insertion of the genes encoding the pre-membrane (prM) and envelope (E) proteins of WNV (strain NY99) into the yellow fever 7D vaccine virus. This Phase II, randomized, double-blind, placebo-controlled, multi-center study in the US assessed the immunogenicity, viremia, and safety of the ChimeriVax-WN02 vaccine. The study included adults in general good health. Subjects aged ≥50 years were randomized to one of four treatment groups: ChimeriVax-WN02 4×103 plaque-forming units (pfu) (n=122), 4×104pfu (n=124), 4×105pfu (n=113), or placebo (n=120). A subset of subjects was randomized to assess viremia after vaccination at three different dose levels. Subjects were followed for safety up to 6 months after vaccination. A total of 121subjects for WN024×103, 122 for WN02 4×104, 110 for WN02 4×105, and 120 for the placebo group completed the study up to the 6-month safety follow-up. Seroconversion, as measured by plaque reduction neutralization test (PRNT), was achieved at Day 28 by 92.1%, 93.2%, and 95.4% of subjects in the WN02 4×103, the WN02 4×104, and the WN02 4×105 groups, respectively. Viremia was transient, detected between Days 2 and 14 but not at Day 28, and in most cases did not reach the quantification threshold. The percentage of subjects reporting at least one event of reactogenicity was similar in the placebo and active vaccine groups and showed no dose relationship. The ChimeriVax-WN02 vaccine was highly immunogenic and well tolerated among subjects ≥50 years old at all dose levels.

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.

West Nile Virus (WNV) and Usutu Virus (USUV) are both neurotropic mosquito-borne viruses belonging to the Flaviviridae family. These closely related viruses mainly follow an enzootic cycle involving mosquitoes as vectors and birds as amplifying hosts, but humans and other mammals can also be infected through mosquito bites. WNV was first identified in Uganda in 1937 and has since spread globally, notably in Europe, causing periodic outbreaks associated with severe cases of neuroinvasive diseases such as meningitis and encephalitis. USUV was initially isolated in 1959 in Swaziland and has also spread to Europe, primarily affecting birds and having a limited impact on human health. There has been a recent expansion of these viruses’ geographic range in Europe, facilitated by factors such as climate change, leading to increased human exposure. While sharing similar biological traits, ecology, and epidemiology, there are significant distinctions in their pathogenicity and their impact on both human and animal health. While WNV has been more extensively studied and is a significant public health concern in many regions, USUV has recently been gaining attention due to its emergence in Europe and the diversity of its circulating lineages. Understanding the pathophysiology, ecology, and transmission dynamics of these viruses is important to the implementation of effective surveillance and control measures. This perspective provides a brief overview of the current situation of these two viruses in Europe and outlines the significant challenges that need to be addressed in the coming years.

It has been 20 years since West Nile virus first emerged in the Americas, and since then, little progress has been made to control outbreaks caused by this virus. After its first detection in New York in 1999, West Nile virus quickly spread across the continent, causing an epidemic of human disease and massive bird die-offs. Now the virus has become endemic to the United States, where an estimated 7 million human infections have occurred, making it the leading mosquito-borne virus infection and the most common cause of viral encephalitis in the country. To bring new attention to one of the most important mosquito-borne viruses in the Americas, we provide an interactive review using Nextstrain: a visualization tool for real-time tracking of pathogen evolution (nextstrain.org/WNV/NA). Nextstrain utilizes a growing database of more than 2,000 West Nile virus genomes and harnesses the power of phylogenetics for students, educators, public health workers, and researchers to visualize key aspects of virus spread and evolution. Using Nextstrain, we use virus genomics to investigate the emergence of West Nile virus in the U S, followed by its rapid spread, evolution in a new environment, establishment of endemic transmission, and subsequent international spread. For each figure, we include a link to Nextstrain to allow the readers to directly interact with and explore the underlying data in new ways. We also provide a brief online narrative that parallels this review to further explain the data and highlight key epidemiological and evolutionary features (nextstrain.org/narratives/twenty-years-of-WNV). Mirroring the dynamic nature of outbreaks, the Nextstrain links provided within this paper are constantly updated as new West Nile virus genomes are shared publicly, helping to stay current with the research. Overall, our review showcases how genomics can track West Nile virus spread and evolution, as well as potentially uncover novel targeted control measures to help alleviate its public health burden.

The West Nile virus (WNV), isolated in 1937, is an arbovirus (arthropod-borne virus) that infects thousands of people each year. Despite its burden on global health, little is known about the virus' biological and evolutionary dynamics. As several lineages are endemic in West Africa, we obtained the complete polyprotein sequence from three isolates from the early 1990s, each representing a different lineage. We then investigated differences in growth behavior and pathogenicity for four distinct West African lineages in arthropod (Ap61) and primate (Vero) cell lines, and in mice. We found that genetic differences, as well as viral-host interactions, could play a role in the biological properties in different WNV isolates in vitro, such as: (i) genome replication, (ii) protein translation, (iii) particle release, and (iv) virulence. Our findings demonstrate the endemic diversity of West African WNV strains and support future investigations into (i) the nature of WNV emergence, (ii) neurological tropism, and (iii) host adaptation.

Evasion of host antiviral mechanisms Many cellular messenger RNAs and viral RNAs are methylated at the 2′- O position of the 5′ guanosine cap. The role of this modification in virus infection has been unclear. Michael Diamond and colleagues now show that this form of methylation enables several unrelated viruses to evade innate host antiviral responses through escape from suppression by interferon-stimulated genes. This suggests an evolutionary explanation for 2′- O methylation of cellular mRNA: it may distinguish self from non-self RNA under conditions of infection. Novel classes of pharmacological agents that specifically inhibit cytoplasmic viral 2′- O methyltransferases may be expected to have broad-spectrum antiviral activity. Many cellular and virus messenger RNAs are methylated at the 2′- O positions of the 5′ guanosine cap. The role of 2′- O methylation in virus infection has been unclear. These authors show that this form of methylation enables several unrelated viruses to evade the antiviral effects of genes stimulated by type I interferon. Cellular messenger RNA (mRNA) of higher eukaryotes and many viral RNAs are methylated at the N-7 and 2′- O positions of the 5′ guanosine cap by specific nuclear and cytoplasmic methyltransferases (MTases), respectively. Whereas N-7 methylation is essential for RNA translation and stability 1 , the function of 2′- O methylation has remained uncertain since its discovery 35 years ago 2 , 3 , 4 . Here we show that a West Nile virus (WNV) mutant (E218A) that lacks 2′- O MTase activity was attenuated in wild-type primary cells and mice but was pathogenic in the absence of type I interferon (IFN) signalling. 2′- O methylation of viral RNA did not affect IFN induction in WNV-infected fibroblasts but instead modulated the antiviral effects of IFN-induced proteins with tetratricopeptide repeats (IFIT), which are interferon-stimulated genes (ISGs) implicated in regulation of protein translation. Poxvirus and coronavirus mutants that lacked 2′- O MTase activity similarly showed enhanced sensitivity to the antiviral actions of IFN and, specifically, IFIT proteins. Our results demonstrate that the 2′- O methylation of the 5′ cap of viral RNA functions to subvert innate host antiviral responses through escape of IFIT-mediated suppression, and suggest an evolutionary explanation for 2′- O methylation of cellular mRNA: to distinguish self from non-self RNA. Differential methylation of cytoplasmic RNA probably serves as an example for pattern recognition and restriction of propagation of foreign viral RNA in host cells.

West Nile virus (WNV), the most common mosquito-borne disease in the continental United States, is vectored by Culex spp. mosquitoes. Since its introduction to New York State (NYS) in 1999, WNV has become endemic. NYS temperatures have risen by 0.14 °C per decade since 1900, with larger increases linked to increased WNV transmission. In this study, we asked if increases in temperature in NYS influence virus diversification and adaptation, leading to shifts in thermal sensitivity. More specifically, do contemporary WNV strains have increased transmission potential at higher temperatures compared to historic strains? Using surveillance and sequencing data of WNV isolated from mosquitoes in NYS, we found a significant correlation between rising temperatures, increased WNV genetic diversity, and higher prevalence. We then analyzed genetically distinct WNV strains from mosquitoes collected during recent warm summers (2017 and 2018) and cooler historic summers (2003 and 2004). Assessing Culex pipiens dissemination efficiency and calculating the relative R₀ at 20 °C, 24 °C, and 28 °C, we found that contemporary strains exhibit higher transmission potential at increased temperatures. Our results show that contemporary WNV strains possess greater phenotypic and genotypic diversity, suggesting that climate warming in concert with viral adaptation may facilitate the emergence of strains with enhanced transmission potential.

People infected with West Nile virus often experience cognitive side effects including memory loss through unknown mechanisms; mice and humans infected with the virus experience a loss in hippocampal presynaptic terminals, which can be reversed by disrupting complement or microglia in mice. Cognitive abnormalities associated with West Nile virus A majority of West Nile virus (WNV) sufferers experience cognitive signs and symptoms, including memory dysfunction, but the mechanisms driving these impairments are largely unknown. Robyn Klein and colleagues demonstrate an enhancement of complement-mediated synaptic pruning in the hippocampus following WNV infection. This pruning required microglia and resembled developmental pruning by the same mechanism. Disruption of complement or microglia during infection protected animals from the WNV-induced memory deficits. Over 50% of patients who survive neuroinvasive infection with West Nile virus (WNV) exhibit chronic cognitive sequelae 1 , 2 . Although thousands of cases of WNV-mediated memory dysfunction accrue annually 3 , the mechanisms responsible for these impairments are unknown. The classical complement cascade, a key component of innate immune pathogen defence, mediates synaptic pruning by microglia during early postnatal development 4 , 5 . Here we show that viral infection of adult hippocampal neurons induces complement-mediated elimination of presynaptic terminals in a murine WNV neuroinvasive disease model. Inoculation of WNV-NS5-E218A, a WNV with a mutant NS5(E218A) protein 6 , 7 leads to survival rates and cognitive dysfunction that mirror human WNV neuroinvasive disease. WNV-NS5-E218A-recovered mice (recovery defined as survival after acute infection) display impaired spatial learning and persistence of phagocytic microglia without loss of hippocampal neurons or volume. Hippocampi from WNV-NS5-E218A-recovered mice with poor spatial learning show increased expression of genes that drive synaptic remodelling by microglia via complement. C1QA was upregulated and localized to microglia, infected neurons and presynaptic terminals during WNV neuroinvasive disease. Murine and human WNV neuroinvasive disease post-mortem samples exhibit loss of hippocampal CA3 presynaptic terminals, and murine studies revealed microglial engulfment of presynaptic terminals during acute infection and after recovery. Mice with fewer microglia ( Il34 −/− mice with a deficiency in IL-34 production) or deficiency in complement C3 or C3a receptor were protected from WNV-induced synaptic terminal loss. Our study provides a new murine model of WNV-induced spatial memory impairment, and identifies a potential mechanism underlying neurocognitive impairment in patients recovering from WNV neuroinvasive disease.

Computational analyses of pathogen genomes are increasingly used to unravel the dispersal history and transmission dynamics of epidemics. Here, we show how to go beyond historical reconstructions and use spatially-explicit phylogeographic and phylodynamic approaches to formally test epidemiological hypotheses. We illustrate our approach by focusing on the West Nile virus (WNV) spread in North America that has substantially impacted public, veterinary, and wildlife health. We apply an analytical workflow to a comprehensive WNV genome collection to test the impact of environmental factors on the dispersal of viral lineages and on viral population genetic diversity through time. We find that WNV lineages tend to disperse faster in areas with higher temperatures and we identify temporal variation in temperature as a main predictor of viral genetic diversity through time. By contrasting inference with simulation, we find no evidence for viral lineages to preferentially circulate within the same migratory bird flyway, suggesting a substantial role for non-migratory birds or mosquito dispersal along the longitudinal gradient. Classical epidemiological approaches have been limited in their ability to formally test hypotheses. Here, Dellicour et al. illustrate how phylodynamic and phylogeographic analyses can be leveraged for hypothesis testing in molecular epidemiology using West Nile virus in North America as an example.