RARE DISEASE
Yellow fever
Yellow fever
Yellow fever
Synonyms: Bronze John, YF, Yellow Jack
Synonyms: Bronze John, YF, Yellow Jack
Synonyms: Bronze John, YF, Yellow Jack
Drug discovery
0
drugs
With orphan designations
Overview
Yellow fever is a mosquito-borne flavivirus infection endemic in tropical regions of Africa and South America. It presents with symptoms ranging from mild febrile illness to severe manifestations like jaundice, hemorrhage, and multi-organ failure, with a case fatality rate of 30–60% in severe cases [1][4][12]. Diagnosis relies on RT-PCR, viral culture, or serologic testing [1][13]. Prevention centers on vaccination (single dose provides lifelong immunity) and mosquito control [13][15][18]. No antiviral treatment exists; management is supportive, focusing on symptom relief and complications [1][9][17].
Population
Primarily affects 34 countries in sub-Saharan Africa and 13 countries in Central/South America [1][14][18].
Highest burden in the Democratic Republic of Congo and Brazilian Amazon due to high transmission intensity and low vaccination coverage [2][3][15].
At-risk groups include unvaccinated travelers, rural workers, and children in endemic regions (accounting for 71% of cases under age 30) [6][16].
Burden
Annual estimates: 109,000 severe cases (67,000–173,000) and 51,000 deaths (31,000–82,000) globally [2][3][11].
Africa accounts for 92% of global burden, with case fatality rates up to 12% in recent outbreaks [6][11][15].
Underreporting persists due to nonspecific symptoms and limited diagnostics; true cases may be 10–250× higher than reported [7][13].
Therapies
Supportive care: Fluid management, bleeding prophylaxis (vitamin K, H₂ blockers), and monitoring for organ failure [1][17].
Vaccination: 17D vaccine prevents >99% of cases within 30 days; mass campaigns averted 47% of deaths in Africa [3][13][15].
Outbreak response: Emergency vaccination, enhanced surveillance, and insecticide-treated bed nets [6][13][16].
Categories: rare infectious diseases
Research Papers
1,248 drug discovery papers about Yellow fever, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,248 drug discovery papers about Yellow fever, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
vaccines
2026-08-13 | Antibodies elicited by a chimeric peritrophin antigen reduce Aedes aegypti survival after blood feeding.
Vector-borne diseases transmitted by Aedes aegypti, including dengue, Zika, chikungunya, and yellow fever, represent a persistent and expanding global health threat. Limitations of conventional vector control strategies, such as insecticide use and environmental source reduction, particularly in urban settings, underscore the need for novel and complementary tools. Anti-vector vaccination offers one such strategy by inducing host-derived antibodies that are ingested during vector feeding and interfere with vector physiology or survival. Although this concept has been successfully explored in some hematophagous arthropods, it remains largely unexplored in mosquitoes. Here, we investigated mosquito peritrophins, structural components of the midgut peritrophic matrix, as potential targets for vector-directed vaccination. We designed and recombinantly expressed a chimeric antigen, PT-3, incorporating immunogenic regions from three Aedes aegypti peritrophins/peritrophin-like proteins: AAEL002495, AAEL002467, and AAEL004798. The ability of PT-3 to elicit functional antibodies was evaluated in a bovine host model. Immunization induced a robust antigen-specific humoral response, and mosquitoes fed blood supplemented with immune sera from vaccinated animals showed significantly reduced post-feeding survival compared with controls. Consistent with this functional effect, anti-PT-3 immune sera recognized native mosquito midgut components in ELISA and Western blot assays. Overall, results are consistent with antibody-mediated interference with midgut physiological processes during blood digestion, while no significant effects on oviposition or egg viability were observed among surviving females. Together, these findings provide proof-of-concept that mosquito peritrophins can serve as immunological targets for anti-vector vaccination and provide a rationale for further developing peritrophin-targeted strategies, including alternative delivery platforms, as complementary tools for arboviral control.
2026-08-11 | Yellow fever in older adults: an overlooked high-risk population in South American outbreaks.
Yellow fever (YF) remains a re-emerging public health threat in South America, with recent outbreaks reporting high case-fatality rates. Although transmission has predominantly affected rural and sylvatic populations, mounting evidence indicates that older adults experience disproportionately severe outcomes and mortality. This commentary highlights the elderly as an overlooked high-risk group in the current epidemiological landscape. Age-related immunosenescence, comorbidities, endothelial dysfunction, and reduced hepatic reserve likely amplify the pathophysiological impact of YF virus infection. At the same time, concerns about vaccine-associated adverse events in individuals ≥60 years complicate risk-benefit decision-making, contributing to under-vaccination in this vulnerable population. Delayed diagnosis and shifting eco-epidemiological patterns further exacerbate risk. As South America undergoes demographic aging alongside environmental change, targeted, age-specific strategies, including prioritized vaccination, tailored risk communication, and enhanced surveillance for older adults, are urgently needed to reduce preventable fatalities.
2026-07-11 | Formulation and stability design spaces for a new yellow fever vaccine.
Yellow fever (YF) is a life-threatening disease that is entirely preventable through vaccination. The objective of this study was to formulate a freeze-dried presentation of a live-attenuated, Vero cell-based yellow fever vaccine (vYF) with improved manufacturability and enhanced shelf-life. Considering four critical quality attributes (i.e., glass transition temperatures and infectious titers at two time points), a comprehensive formulation screening was performed to identify an optimal combination of excipients, capable of protecting the virus during lyophilization while ensuring long-term stability of the vYF infectious titer. Overall, L-proline, urea, and poloxamer 407 demonstrated a stabilizing effect, and the application of an advanced kinetic model enabled prediction of a 60-month shelf-life at 5 °C for the formulated vaccine. Machine learning models were used to build both formulation and stability design spaces that defined global stabilizing regions within the explored concentration ranges of each excipient. This study demonstrates that the combination of systematic excipient screening and advanced analytics enables the selection of robust formulations with long-term stability within an accelerated development timeframe. The developed vaccine formulation has the potential for large-scale industrial production and can address substantial market demand in the coming years, representing a significant advancement in vYF technology.
2026-07-10 | Yellow Fever Vaccination in an Individual with Confirmed Egg Protein Allergy: A Case Report
Background: Yellow fever vaccination is recommended for travelers visiting endemic regions in South America and Africa. The live-attenuated vaccine (Stamaril®, Sanofi Pasteur) is produced in embryonated chicken eggs and contains residual ovalbumin, posing a challenge for individuals with egg protein allergy. Case Presentation: We report the case of a 35-year-old male disaster relief worker with confirmed egg protein allergy and moderate sensitization but no history of anaphylaxis. Under normal circumstances, a statement confirming that vaccination is not possible would be sufficient for entry. However, due to his work-related duties and the relevant guidelines from his employer, there was an urgent need for vaccination despite his egg protein allergy. A comprehensive allergy work-up including skin prick testing, serum-specific IgE, and oral provocation testing revealed a moderate allergy without systemic reactions. Intervention: Following informed consent and risk assessment, a fractional dose (0.1 mL) of the reconstituted yellow fever vaccine was administered under close monitoring. The patient developed a localized dermal reaction without systemic symptoms. Post-vaccination neutralization testing confirmed seroconversion indicating protective immunity. Discussion: Although yellow fever vaccination is considered contraindicated in individuals with severe egg protein allergy, the literature supports its cautious use in selected cases. Fractional dosing has emerged as an effective dose-sparing strategy. Studies show that even in egg protein-allergic individuals, adverse events are rare. Conclusions: In this case, a fractional yellow fever vaccination was safe and an effective option for an egg-allergic individual in a high-risk occupational setting, supporting a personalized approach based on clinical risk assessment and current evidence.
2026-07-08 | Supplementary file 1_Breadth of neutralization induced by vYF next generation yellow fever vaccine.zip
Background A novel live-attenuated yellow fever (YF) vaccine candidate, vYF, is currently in development. Previous studies in non-human primates (NHPs) have evaluated its safety, immunogenicity, and efficacy. To further characterize the immune response, this study assessed the breadth and magnitude of neutralizing antibodies (NAbs) induced by vYF. Methods Immunogenicity was evaluated in NHPs across multiple parameters, including NAb titers against the vaccinal virus strain from 14 to 258 days post-vaccination. The breadth of neutralization was assessed using a panel of four YF virus strains selected to represent diverse phylogeny, isolation dates, and geographic origins. Titers from vYF-vaccinated NHPs were compared with those from YF-VAX–vaccinated NHPs. Two additional control strains, Stamaril® (current vaccine) and the wild-type parent strain Asibi, were included. Amino acid (AA) sequences of viral envelope residues associated with known neutralizing epitopes were analyzed to explore potential correlates with neutralization profiles. Results NAb titers from vYF-vaccinated NHPs were comparable to those obtained with the Asibi strain for two of the four wild-type strains, and 0.3 to 0.5 Log lower for the remaining two. All wild-type strains were neutralized with titers at least 3-fold higher than the established correlate of protection, indicating a broad neutralization profile. Neutralization patterns were similar between vYF- and YF-VAX–vaccinated NHP sera. Conclusion This study adds to the evidence that the vYF may elicit the same breadth of neutralizing antibody responses in NHPs, than YF-VAX reference vaccine.
small molecules
2026-08-13 | Cross-Family Mechanistic Analysis of Plant Alkaloids Against Neglected Arboviruses and Related RNA Viruses.
Neglected arboviruses dengue (DENV), Zika (ZIKV), yellow fever (YFV), Japanese encephalitis (JEV), and chikungunya collectively affect hundreds of millions of people annually, yet no specific antiviral drug has been approved for any of them. Alkaloids, nitrogen-containing specialized metabolites produced by diverse plant families, have emerged as a promising source of broad-spectrum antiviral scaffolds. This review compiles and critically analyzes over 100 alkaloid-virus pairs across several RNA virus families, providing a comparative mechanistic analysis. Lycorine, narciclasine, emetine, and berbamine, among others, exhibit potent activity against phylogenetically distant viruses, with the most potent activities reported against flaviviruses (narciclasine: EC50 0.02 µM against DENV, ZIKV, YFV, and JEV; pancratistatine: 0.0063 µM against ZIKV). Structure-activity analysis of multiple alkaloid classes identifies key pharmacophoric features, including the phenanthridine nucleus (lycorine derivatives) and the bis-benzylisoquinoline scaffold (tetrandrine, berbamine), as determinants of antiviral potency, selectivity, and broad-spectrum activity. Genetic resistance data in West Nile virus challenge the widely accepted model of lycorine as a direct nucleoside inhibitor, instead pointing toward the involvement of the membrane-associated NS4A-2K-NS4B replication complex, though direct validation remains limited for other flaviviruses. Converging structural, biochemical, and transcriptomic evidence suggests that ribosome-mediated translational stress may represent an additional host-directed antiviral mechanism for isoquinoline-type alkaloids, though the causal chain from ribosome binding to activation of the integrated stress response and to antiviral effect has not been established. The present analysis highlights that in vivo validation remains limited to a few alkaloid-virus pairs. Unbiased target deconvolution and formal testing of the ribosome/integrated stress response hypothesis stand out as essential research priorities.
2026-07-30 | Gustatory function of Aedes aegypti opsins and TRPA1 in avoiding a natural insect repellent.
The mosquito, Aedes aegypti, spreads viruses that cause dengue, yellow fever, and other devastating diseases. To identify candidate repellents that suppress blood feeding by Aedes aegypti, we conducted an in vitro screen of natural chemicals for activators of two visual opsins, Op1 and Op2, which we found are expressed at very high levels in gustatory organs. We found that Op1 and Op2 are chemical sensors since they are activated by flavonoids, including catechin. We devised an artificial membrane that mimics multiple properties of skin (VectaDerm), which we used on blood feeders, leading to the demonstration that catechin suppresses blood feeding. This behavior was disrupted in op1,op2 double mutants and in trpA1 mutants. High catechin concentrations directly activated TRPA1 and suppressed blood feeding independent of the opsins, while suppression by lower catechin levels depended on the opsins and TRPA1. Roles for opsins and TRPA1 in avoiding catechin are conserved in Drosophila. TRPA1 expressed in the tick vector for Lyme disease, Ixodes scapularis, is also activated by catechin, and I. scapularis is repelled by catechin. Since catechin is safe to humans, we propose that it could be added to repellent formulations to more effectively suppress biting by mosquitoes.
2026-07-14 | SAR exploration for 4-aminotetrahydroquinazolines with adamantyl moiety against orthoflaviviruses.
4-Aminotetrahydroquinazoline N-oxides form a prominent chemotype of orthoflavivirus reproduction inhibitors, attractive for the search of lead compounds for development as direct-action antiviral agents. Here we explored the relationship between the structure and antiviral activity within an extended series of adamantyl-containing 4-aminotetrahydroquinazolines, synthesized via SNAr reactions of 4-chlorotetrahydroquinazolines with adamantyl-containing amines. Most of the obtained compounds inhibited the reproduction of tick-borne encephalitis, yellow fever, and West Nile viruses in phenotypic assays with micromolar EC50s. The most favorable substituents at 4-amino group were 2-adamant-(1/2)-ylethyls, while the position 2 of heterocyclic core served as a toxicity switch, 2-chlorotetrahydroquinazolines being much less toxic than other analogues. Time-of-addition experiments for hit compounds against West Nile virus revealed a possibility for multi-factorial mechanism of action in the 4-aminotetrahydroquinazoline series.
2026-07-09 | Lipid peroxidation impacts orthoflavivirus infection in a virus-dependent manner.
Orthoflavivirus infection is intricately linked to host cell lipid metabolism, yet the function of bioactive lipids as regulators of infection remains to be elucidated. Here, we investigated the role of lipid mediator pathways, namely ALOX/COX enzymes and upstream lipases, in orthoflavivirus replication by comparing dengue virus (DENV), Zika virus (ZIKV), wild-type yellow fever virus (YFV-Asibi), and the live-attenuated vaccine strain YFV-17D. DENV, ZIKV, and YFV-Asibi, but not the vaccine strain, induced COX2 expression in Huh7 hepatoma cells, correlating with prostaglandin E2 (PGE2) levels in culture supernatants. All four viruses replicated more efficiently in COX2-, ALOX15-, and MGLL-deficient cells, indicating a broadly antiviral role for these enzymes. In contrast, DENV and ZIKV specifically induced ALOX12 expression and depended on ALOX12 for efficient viral RNA replication, as demonstrated by reduced genome copy numbers, altered dsRNA replication compartment morphology, and decreased infectious titers in ALOX12-depleted cells. Direct measurement of lipid peroxidation revealed that ZIKV infection markedly elevated lipid peroxide levels through both ALOX12-dependent and -independent mechanisms, whereas DENV infection did not cause detectable lipid peroxide accumulation. Consistent with this, the ferroptosis inhibitor ferrostatin impaired DENV replication, while the ferroptosis inducer erastin enhanced it; this proviral effect of erastin was fully abolished by ALOX12 knockdown, indicating that DENV depends entirely on ALOX12-driven lipid peroxidation. Iron chelation reduced both DENV and ZIKV infection, confirming a requirement for iron-dependent oxidative processes. The proviral role of lipid peroxidation extended beyond hepatoma cells, as ferrostatin treatment significantly reduced DENV and ZIKV infection in human microglia cells. Our results reveal virus-specific exploitation of lipid peroxidation pathways by orthoflaviviruses and identify ALOX12-dependent lipid peroxidation as a novel proviral mechanism that may represent a target for antiviral intervention.
2026-07-02 | Maternal instincts: a review of the role of chemosensory cues and larval habitat conditions on oviposition site choice by gravid Aedes aegypti (Diptera: Culicidae).
Aedes aegypti (Ae. aegypti) is a global vector of arboviruses, including those causing dengue, chikungunya, Zika, and yellow fever. Effective management of Ae. aegypti populations remain challenging due to their anthropophilic feeding behavior, their exploitation of urban environments, their complex oviposition behavior, and their egg physiology. The characteristics of larval habitats can influence various aspects of larval development, thereby altering adult physiology and behavior. These include differences in blood-feeding behavior, reproductive capacity, and lifespan. Gravid females select oviposition sites based on a diverse array of visual, textural, chemical, and biological cues that attract/repel females from sites and/or stimulate/inhibit oviposition, including volatile organic compounds from microorganisms, detritus, conspecific/heterospecific larvae and adults, predator activity, and environmental factors. This review focuses on the chemosensory aspects of oviposition site selection. Understanding the effects of concentration-dependent chemical cues on oviposition behavior in gravid female Ae. aegypti offers critical insights into the ecology of this species. Integrating this knowledge into vector control strategies, particularly attract-and-kill ovitraps incorporating optimized attractants and larvicides, could enhance surveillance efficacy and reduce Ae. aegypti populations. As climates become more favorable and urbanization expands, Ae. aegypti's geographic range is likely to expand, making it essential to leverage detailed behavioral and ecological insights to improve surveillance, vector management, and to mitigate arboviral disease risks globally.
proteins
2026-07-11 | Coagulopathy in viral haemorrhagic fevers and beyond: molecular mechanisms and targeted interventions.
Coagulopathy refers to any medical condition which affects the ability of the blood to clot. It can be caused due to genetic conditions like haemophilia, von Willebrand disease, or it can be caused through liver disease or deficiency of Vitamin K. It also involves a broad range of diseases affecting hemostasis as an unbalanced and even bidirectional relationship between thrombosis and bleeding. Coagulopathy can also be caused by thromboinflammation, as seen in VHFs like Ebola, Dengue, Marburg, Crimean-Congo Hemorrhagic Fever, Yellow Fever, and Hantavirus infection. The immune response and coagulation system are intricately linked in such cases. Infections from VHFs cause endothelial cell dysfunction through the immune response, monocytes/macrophages activation, and increased expression of tissue factor (TF), which in turn causes excessive thrombin production and fibrin formation. These conditions result in microvascular thrombosis, organ dysfunction, consumption of platelets and coagulation factors, causing a balanced but fragile state of hemostasis that could tip over towards either thrombosis or bleeding. New therapies have been developed that interfere with these processes, such as interference with the TF pathway (for instance, rNAPc2) and regulation of fibrinolysis (tranexamic acid). The recognition of the double-edged sword of coagulopathy is critical for the development of treatment strategies targeting coagulation disorders. This literature review discusses the molecular basis of immunothrombosis and endothelial dysfunction in VHFs.
2026-07-08 | Cellular receptors and host factors mediating orthoflavivirus entry.
Orthoflaviviruses are positive-sense, enveloped RNA viruses that include dengue virus (DENV), Zika virus (ZIKV), yellow fever virus (YFV), West Nile virus (WNV), and Japanese encephalitis virus (JEV). Viral entry is a multistep process governed by the envelope (E) glycoprotein, virion lipid composition, and host-cell molecules that act at distinct mechanistic stages. A major limitation of the current literature is that attachment factors, internalization receptors, immune-modulatory receptors, and membrane-associated cofactors are often collectively termed "receptors", which can obscure the strength and interpretation of the underlying evidence. This review therefore reorganizes reported orthoflavivirus entry-associated molecules into four functional classes: attachment factors, bona fide or candidate internalization receptors, indirect immune-modulatory receptors, and membrane-associated or post-entry cofactors. We place particular emphasis on DENV because it imposes a major clinical burden among orthoflaviviruses and has been the subject of the most extensive receptor-related research. By integrating evidence from binding assays, genetic loss-of-function studies, and in vivo models, this review highlights conserved and virus-specific entry mechanisms. This mechanism-based framework may guide the development of receptor decoys and host-targeting antivirals, although clinical translation will require rigorous validation of antiviral breadth, delivery, safety, and resistance potential.
2026-04-17 | Yellow fever virus infection in non-human primates: a systematic review and meta-analysis of prevalence, seroprevalence, and epizootic case reports (1950-2025).
Yellow fever remains a major mosquito-borne viral disease of global public health and ecological concern. Non-human primates (NHPs) are central to the sylvatic transmission cycle and serve as key sentinels of viral circulation. Yet, evidence on yellow fever virus (YFV) infection in NHPs is dispersed and has not been synthesized comprehensively. To systematically review and meta-analyze global data on the prevalence and seroprevalence of YFV infection in NHP, and to summarize molecular, clinical, and pathological findings from reported epizootic cases. We conducted a systematic search of Scopus, PubMed, Web of Science, and SciELO for studies published between 1950 and 2025, following PRISMA guidelines. Observational studies reporting YFV prevalence or seroprevalence in NHPs were included in the quantitative syntheses, and individual case reports were analyzed separately. Random-effects meta-analyses were performed, with subgroup analyses by geographic region, diagnostic method, and primate genus. Thirty-nine articles assessing 7,183 NHP met the inclusion criteria; 28 contributed to meta-analyses, and 10 provided 19 individual case reports. Pooled molecular prevalence by RT-PCR was 30.7%, and prevalence by immunohistochemistry was 43.4%, both with substantial between-study heterogeneity. Seroprevalence estimates ranged from 5.0 to 36.4% across assays and settings. Higher infection metrics were observed in howler monkeys and titi monkeys. All reported individual cases were fatal and predominantly associated with severe hepatic and multisystemic pathology. Most data originated from the Americas, particularly Brazil, with limited representation from African endemic regions. YFV infection in NHP is widespread, often severe, and epidemiologically significant. Our findings underscore the critical sentinel role of NHPs and highlight the need to strengthen integrated One Health surveillance systems to inform prevention and control strategies, particularly in the context of the current resurgence of yellow fever in Latin America and persistent data gaps in Africa.
2026-03-20 | LRP8 is a functional receptor for yellow fever virus.
Yellow fever virus (YFV) is an arbovirus causing substantial human morbidity and mortality. The live-attenuated 17D strain serves as vaccine and is one of the most successful vaccines so far. Receptor usage between attenuated and pathogenic YFV strains remains unclear. Here we performed a barcoded, genome-wide human open-reading frame library screen and identified LRP8 (also named APOER2) as a receptor for YFV. We show that LRP8 expression increases YFV infection (17D and two clinical strains, BJ01 and Asibi) in cell lines by promoting entry. Adeno-associated virus-mediated expression of human LRP8 in mouse liver aggravates infection and pathology of the clinical strain BJ01. LRP8 knockdown decreases YFV infection in brain cells, primary human hepatocytes and mosquitoes. LRP8 directly interacts with YFV 17D particles via the viral envelope protein. A soluble LRP8 decoy protein can block YFV 17D and BJ01 infection. Our findings provide insights for understanding YFV entry, tropism and pathogenesis.
2026-03-11 | Yellow fever in Latin America and the escalating risks in a changing eco-epidemiological landscape: a review.
Yellow fever (YF) remains a major public health concern in Latin America. We characterise the early-2025 outbreak, compare it with prior waves-especially Southeast Brazil (2016-2018)-and examine environmental, structural, and policy-related drivers. We reviewed regional surveillance data and mortality records from January to April 2025, comparing them to historical outbreak data. Case fatality rate (CFR), geographic spread, and population vulnerability patterns were analyzed. We also reviewed published literature and health alerts to contextualize contributing factors. In 2025, 301 confirmed cases and 124 deaths were reported (CFR 41.1%), mostly in Bolivia, Brazil, Colombia, and Peru, concentrated among unvaccinated populations at the forest-urban interface. Transmission remains sylvatic, but peri-urban spillover risk is rising. Deforestation, climate variability, cross-border migration, and political instability heighten vulnerability; surveillance is fragmented and vaccine uptake insufficient in high-risk groups. YF is re-emerging through intertwined biological, ecological, and socio-political forces. Preventing another large-scale epidemic requires strengthened, integrated surveillance, including Non-Human Primates (NHP) epizootics, equity-centred immunisation in remote areas, and coordinated regional action focused on prevention, early detection, and health-system resilience.
gene therapies
2025-09-15 | Insect-specific viruses: transmission dynamics and biological control strategies against arboviruses.
Mosquitoes are known to vector arthropod-borne viruses (arboviruses) that pose a global public health issue in the form of mosquito-borne viral diseases such as chikungunya fever, dengue fever, Japanese encephalitis, yellow fever, and Zika. Besides, mosquitoes may also carry insect-specific viruses (ISVs), which are evolutionarily alike arboviruses yet do not infect vertebrates. These ISVs have been shown to affect the ability of mosquitoes to transmit arboviruses, as well as potentially inhibit arbovirus infections in vertebrate hosts. Yet, ISVs still constitute a relatively new and little-researched area where further studies may yield new knowledge regarding their distribution, their future importance in the control of mosquito-borne viral disease and potential role in biological control of mosquitoes. This review provides insights into ISV classification, transmission, and biology, as well as historical and future aspects. It mainly focuses on the characterization of the transmission dynamics of ISVs to highlight the various potential arboviral pathogen transmission blocking mechanisms along with evolution and host tropism. The review also provides additional information on the potential use of ISVs as a method of biological control in comparison to other proposed methods as well as delving into current research into arbovirus-based vaccines and antiviral drug development.
2025-07-31 | Two mutations in NS2B are responsible for attenuation of the yellow fever virus (YFV) vaccine strain 17D.
Vaccines have done more to improve the health of humankind over the past century than almost any other technology. Among vaccines, the live-attenuated yellow fever (YF) vaccine (17D) is highly effective, providing long-lasting immunity against yellow fever virus (YFV) infection with a single dose. Developed in the 1930s through extensive serial passage of the virulent YFV-Asibi strain through mouse and chicken embryonic tissue, 17D acquired several mutations that render it attenuated in humans and non-human primates. Over the past century, 17D has become a widely studied immunogen and has also been developed into a vaccine platform for other pathogens. Despite this, most studies of 17D have focused exclusively on the host, without clearly defining the virus-intrinsic features of attenuation. Consequently, the genetic determinants of 17D attenuation remain unknown and are assumed to be multigenic. Here, we leverage the hamster host, which recapitulates many important features of human YF disease, to understand the genetic basis of 17D attenuation. We developed a YFV reverse genetics system and generated hamster-adapted Asibi/17D chimeric viruses, discovering that viruses containing 17D-derived mutations in the viral gene NS2B were significantly attenuated in the hamster. Further analysis revealed that the two non-synonymous mutations in NS2B that distinguish 17D from Asibi, I37L and I109L, act cooperatively to mediate attenuation, with both mutations required to fully prevent key features of YF disease including liver injury and coagulopathy. These findings establish NS2B as an important and unexpected determinant of YFV-17D attenuation in vivo. In addition to the implications of these findings for improving the efficacy and safety of the 17D vaccine platform, this discovery also provides a new direction for understanding more generalized principles and mechanisms of durable vaccine-induced immunity.
2025-07-09 | Amino acid changes in two viral proteins drive attenuation of the yellow fever 17D vaccine.
The live-attenuated yellow fever 17D vaccine strain differs genetically only minimally from its virulent parent. However, it remains unclear which sequence differences lead to virulence or attenuation. Here we demonstrate, using SHAPE-MaP, that these mutations do not induce global RNA structure changes and show that protein sequence mutations are mostly responsible for the phenotypic differences between 17D and virulent YFV. Using a highly modular, combinatorial genetic approach, we identified key mutations in the envelope (E) and non-structural 2A (NS2A) proteins that increase 17D's ability to spread and enhance host antiviral responses. Introducing these mutations into infectious clones of virulent YFV genomes results in viral attenuation in vitro and in two mouse models. Collectively, our results define the genetic basis for 17D attenuation and highlight a potentially general approach for creating live-attenuated vaccines by introducing mutations resulting in similar phenotypic changes in other pathogenic viruses.
2025-06-27 | Sindbis virus is suppressed in the yellow fever mosquito Aedes aegypti by Atg6/BECN1 (autophagy-related 6)-mediated activation of autophagy.
Macroautophagy/autophagy is a critical modulator of pathogen invasion response in vertebrates and invertebrates. However, how it affects mosquito-borne viral pathogens that significantly burden public health remains relatively underexplored. To address this gap, we use a genetic approach to activate autophagy in the yellow fever mosquito (Aedes aegypti) infected with a recombinant Sindbis virus (SINV) expressing an autophagy activator. We first demonstrate a 17-amino acid peptide ("AaBec-1") derived from the Ae. aegypti Atg6/BECN1 (Autophagy-related 6) gene is sufficient to induce autophagy in C6/36 mosquito cells, as marked by lipidation of Atg8 and puncta formation. Next, we engineered a recombinant SINV expressing the AaBec-1 peptide and used it to infect and induce autophagy in adult mosquitoes. We find that modulation of autophagy using this recombinant SINV negatively regulates production of infectious virus. The results from this study improve our understanding of the role of autophagy in regulating arbovirus infection in invertebrate hosts and highlight the potential for the autophagy pathway to be exploited for arbovirus control.Abberviation: C6/36- Aedesalbopictuscell line; dpi - days post-infection; FFA - focus-forming assay;MOI - multiplicity of infection; MTOR - Mechanistic target ofrapamycin kinase; PBS - phosphate-buffered saline; PCR - polymerase chain reaction; RT-PCR - reversetranscription-polymerase chain reaction; RNA - ribonucleic acid;SINV - Sindbis virus; Vero - African green monkey kidneyepithelial cells.
2025-06-26 | Performance of two low-threshold population replacement gene drives in cage populations of the yellow fever mosquito, Aedes aegypti.
Aedes aegypti is the predominant vector for arboviruses including dengue, Zika, and chikungunya viruses, which infect over 100 million people annually. Mosquito population replacement in which arbovirus-susceptible mosquitoes in the field are replaced by laboratory-engineered refractory mosquitoes represents a novel genetic control measure to interrupt arboviral disease cycles. For this approach, the engineered mosquitoes need to harbor two genetic components: an antiviral effector construct which is linked to a gene drive (GD). We tested the performance of two single-locus CRISPR/Cas9 based GD for Ae. aegypti population replacement in small cage populations for up to 16 generations. Starting from a low release threshold of 1:9 GD bearing males to wild-type males, we observed two GD constructs in which Cas9 was expressed from two different germline promoters, nanos and zpg, to increase in frequency in all cage populations. By G16, an average of 72% and 82% of individuals from the zpg-GD and nanos-GD populations, respectively, harbored at least one GD copy with corresponding increases in allele frequencies. This indicated that the two single-locus, CRISPR/Cas9-based homing GD exhibited continuous super-Mendelian inheritance in populations of Ae. aegypti. Gene drive blocking indel (GDBI, a.k.a. "resistant alleles") frequency was measured for each discrete generation in pooled samples from the six populations harboring GD. We found that populations with Cas9 expression under control of the nanos-promoter accumulated GDBI at more than twice the rate of those populations harboring the zpg-promoter driven GD. Based on preexisting data sets for homing and GDBI frequencies in addition to the cage trial observations, the relative contributions of sex-specific homing rates, maternal Cas9 deposition and potential fitness effects were modeled in MGDrivE for both GD, further explaining their divergent performance. Our study demonstrates the feasibility of low-threshold, single-locus CRISPR/Cas9 based GD for Ae. aegypti population replacement.
other
2026-07-11 | Ecological and engineered modulation of the mosquito microbiome: mechanisms, vector competence, and translational prospects for disease control.
Malaria, dengue fever, Zika, chikungunya, yellow fever, and West Nile fever are mosquito-borne diseases that collectively impose an enormous global health burden, disproportionately affecting low- and middle-income countries where vector-control tools remain limited or compromised by insecticide resistance. Over the past two decades, the characterization of mosquito-associated microbiomes has transformed our understanding of vector biology, revealing complex, ecologically contingent assemblages of bacteria, fungi, viruses, and protists that profoundly influence mosquito physiology, immunity, and pathogen transmission competence. This review synthesizes current knowledge on the composition and determinants of the mosquito microbiome across major vector genera-Aedes, Anopheles, and Culex-and critically evaluates evidence for microbiome roles in larval development, adult fitness, immune homeostasis, and pathogen-vector interactions. We examine how resident microbiota can inhibit or, in some contexts, facilitate pathogen establishment, dissemination, and transmission, and we discuss the mechanistic pathways underlying these effects, including immune priming, niche competition, antimicrobial metabolite production, and modulation of midgut barrier integrity. We then review major strategies for deliberate microbiome modulation, including Wolbachia-based pathogen blocking and population suppression, paratransgenesis, symbiont supplementation, microbiota engineering, and habitat-level manipulation, and evaluate their biological rationale, current evidence base, field feasibility, and limitations. Attention is given to the gap between laboratory proof-of-concept and operational deployment, as well as to biosafety, regulatory, ecological, and ethical challenges that must be resolved before microbiome-based interventions can be integrated into public health programs. We conclude by identifying priority research questions and the technological advances most likely to accelerate progress from descriptive microbiome science to predictive, actionable vector control.
2026-06-27 | Dissecting the host determinants of orthoflavivirus infection using QIC-seq.
Orthoflaviviruses are genetically related, yet cause distinct disease patterns ranging from hepatitis and vascular shock syndrome to encephalitis and congenital abnormalities. There is an incomplete understanding of the cellular pathways co-opted by orthoflaviviruses, and differences in host response to infection may underlie the diverse pathologies caused. We present a single-cell approach (Quantification of Infection and CRISPR guide sequencing; QIC-seq) that combines CRISPR/Cas9 knockout with virus-inclusive transcriptomics to systematically compare host factor requirements and host transcriptional response to orthoflaviviral challenge. Using a CRISPR library focused on select ER-proteostasis genes, we show that dengue and yellow fever viruses are strictly dependent on subunits of the oligosaccharyltransferase complex, while the more distantly related West Nile and Langat viruses are dependent on components of the ER-associated degradation machinery. Our data further shows virus-induced upregulation of interferon-stimulated genes, and activation of the unfolded protein response. QIC-seq enables quantitative comparisons of viral host factor utilization, which may inform development of host-directed antiviral therapies.
2026-02-10 | Potent Monoclonal Antibodies Against Circulating Yellow Fever Virus Strains from Donors Immunized with the 17D Vaccine.
Yellow fever (YF) causes approximately 50,000 deaths annually worldwide and is transmitted by infection with the yellow fever virus (YFV), which is endemic in Sub-Saharan Africa and tropical South America. The live-attenuated YFV 17D vaccine, developed in 1937, is essential to control YFV transmission, but the finite shelf life and manufacturing constraints of egg-based vaccine production, the rare but severe adverse events, and the lack of effective therapeutic options for YF disease highlight the need for new YFV vaccines and therapies. Potent YFV antibodies that neutralize circulating strains could be promising passive immunizations or treatments and guide nonreplicating YF vaccine development. In this study, we captured and screened natively paired heavy and light chain antibody libraries from two donors immunized with the YFV 17D vaccine. Yeast surface display libraries were generated and stained using YF virus-like particles purified by chromatographic techniques. Three anti-YFV antibodies were identified with potent neutralizing activity against circulating strains from Western Africa and South America, including one potent antibody with a neutralizing half-maximal inhibitory concentration of <5 ng/mL against the 17D vaccine strain. These new YFV antibodies have the potential to serve as YFV outbreak countermeasures for treatment or prevention and guide future vaccine efforts.
2026-01-29 | Human autoantibodies against type I interferons in severe viral disease.
Type I interferons (IFN-Is) are critical antiviral cytokines that restrict viral replication and limit viral disease. A remarkable recent discovery is that human autoantibodies (autoAbs) neutralizing the activities of IFN-Is phenocopy inborn errors of immunity and markedly exacerbate susceptibility to life-threatening infections. Development of these pathogenic autoAbs in humans is strongly linked to genetic and nongenetic factors affecting thymic function, and they are estimated to be present in >100 million people worldwide with a prevalence that increases with age. Here, we review major advances from the last few years that have improved our mechanistic understanding of human IFN-I autoAb development and function, as well as their association with a significant proportion of different severe viral diseases. In particular, we highlight how neutralizing IFN-I autoAbs can persist in individuals for decades, compromising IFN-I-mediated defenses, and underlying subsequent critical infections with diverse pathogens, including SARS-CoV-2, West Nile virus, tick-borne encephalitis virus, seasonal influenza viruses, herpesviruses, and rare zoonoses caused by MERS-CoV, flaviviruses, and avian H5N1 influenza A virus. Furthermore, we discuss how neutralizing IFN-I autoAbs facilitate severe adverse events with live-attenuated viral vaccines, such as the yellow fever or chikungunya virus vaccines, and suggest how implementation of IFN-I autoAb diagnostics in at-risk populations may be clinically beneficial with current prophylactic or therapeutic options. Finally, in the context of new experimental insights into how autoAbs block the ability of IFN-Is to engage with the IFNAR1/IFNAR2 receptors, we detail future opportunities to design advanced novel therapeutic strategies that might specifically mitigate IFN-I autoAb pathogenic effects.
2025-12-25 | Vertical transmission of mosquito microbiota and its effects on offspring development.
The mosquito's gut microbiota plays a crucial role in determining its capacity to transmit harmful viruses and parasites. Accordingly, manipulating mosquito gut microbiota is a promising avenue towards reducing mosquito-borne human pathogen transmission. A successful microbial control campaign will require a thorough understanding of how bacteria are transmitted through mosquito populations. Through two parallel but complementary studies using the yellow fever mosquito Aedes aegypti as a focal host species, we surveyed vertical transmission of bacteria from individual mothers to cohorts of offspring maintained in a closed system. Laboratory- and field-derived mothers deposited bacteria that support offspring development, and the relative abundance of commonly transmitted taxa correlated with offspring fitness. Maternally transmitted bacteria were detected in both larval and adult offspring, and the relative abundances of specific taxa differed between life stages. Microbiota composition in adult offspring closely resembled microbiota composition in mothers, despite dramatic shifts in the relative abundance of specific microbial community members during the larval stage. Variability in microbiota composition in offspring was also greater than variability across the population of egg-laying mothers. Eggs that underwent a period of desiccation before hatching produced larval communities dominated by endospore-forming bacteria that were rare in maternal samples. Overall, our results demonstrate the vertical transmission of mosquito-associated microbiota across generations, including bacterial taxa that could potentially be leveraged for mosquito and mosquito-borne disease control.
vaccines
2026-08-13 | Antibodies elicited by a chimeric peritrophin antigen reduce Aedes aegypti survival after blood feeding.
Vector-borne diseases transmitted by Aedes aegypti, including dengue, Zika, chikungunya, and yellow fever, represent a persistent and expanding global health threat. Limitations of conventional vector control strategies, such as insecticide use and environmental source reduction, particularly in urban settings, underscore the need for novel and complementary tools. Anti-vector vaccination offers one such strategy by inducing host-derived antibodies that are ingested during vector feeding and interfere with vector physiology or survival. Although this concept has been successfully explored in some hematophagous arthropods, it remains largely unexplored in mosquitoes. Here, we investigated mosquito peritrophins, structural components of the midgut peritrophic matrix, as potential targets for vector-directed vaccination. We designed and recombinantly expressed a chimeric antigen, PT-3, incorporating immunogenic regions from three Aedes aegypti peritrophins/peritrophin-like proteins: AAEL002495, AAEL002467, and AAEL004798. The ability of PT-3 to elicit functional antibodies was evaluated in a bovine host model. Immunization induced a robust antigen-specific humoral response, and mosquitoes fed blood supplemented with immune sera from vaccinated animals showed significantly reduced post-feeding survival compared with controls. Consistent with this functional effect, anti-PT-3 immune sera recognized native mosquito midgut components in ELISA and Western blot assays. Overall, results are consistent with antibody-mediated interference with midgut physiological processes during blood digestion, while no significant effects on oviposition or egg viability were observed among surviving females. Together, these findings provide proof-of-concept that mosquito peritrophins can serve as immunological targets for anti-vector vaccination and provide a rationale for further developing peritrophin-targeted strategies, including alternative delivery platforms, as complementary tools for arboviral control.
2026-08-11 | Yellow fever in older adults: an overlooked high-risk population in South American outbreaks.
Yellow fever (YF) remains a re-emerging public health threat in South America, with recent outbreaks reporting high case-fatality rates. Although transmission has predominantly affected rural and sylvatic populations, mounting evidence indicates that older adults experience disproportionately severe outcomes and mortality. This commentary highlights the elderly as an overlooked high-risk group in the current epidemiological landscape. Age-related immunosenescence, comorbidities, endothelial dysfunction, and reduced hepatic reserve likely amplify the pathophysiological impact of YF virus infection. At the same time, concerns about vaccine-associated adverse events in individuals ≥60 years complicate risk-benefit decision-making, contributing to under-vaccination in this vulnerable population. Delayed diagnosis and shifting eco-epidemiological patterns further exacerbate risk. As South America undergoes demographic aging alongside environmental change, targeted, age-specific strategies, including prioritized vaccination, tailored risk communication, and enhanced surveillance for older adults, are urgently needed to reduce preventable fatalities.
2026-07-11 | Formulation and stability design spaces for a new yellow fever vaccine.
Yellow fever (YF) is a life-threatening disease that is entirely preventable through vaccination. The objective of this study was to formulate a freeze-dried presentation of a live-attenuated, Vero cell-based yellow fever vaccine (vYF) with improved manufacturability and enhanced shelf-life. Considering four critical quality attributes (i.e., glass transition temperatures and infectious titers at two time points), a comprehensive formulation screening was performed to identify an optimal combination of excipients, capable of protecting the virus during lyophilization while ensuring long-term stability of the vYF infectious titer. Overall, L-proline, urea, and poloxamer 407 demonstrated a stabilizing effect, and the application of an advanced kinetic model enabled prediction of a 60-month shelf-life at 5 °C for the formulated vaccine. Machine learning models were used to build both formulation and stability design spaces that defined global stabilizing regions within the explored concentration ranges of each excipient. This study demonstrates that the combination of systematic excipient screening and advanced analytics enables the selection of robust formulations with long-term stability within an accelerated development timeframe. The developed vaccine formulation has the potential for large-scale industrial production and can address substantial market demand in the coming years, representing a significant advancement in vYF technology.
2026-07-10 | Yellow Fever Vaccination in an Individual with Confirmed Egg Protein Allergy: A Case Report
Background: Yellow fever vaccination is recommended for travelers visiting endemic regions in South America and Africa. The live-attenuated vaccine (Stamaril®, Sanofi Pasteur) is produced in embryonated chicken eggs and contains residual ovalbumin, posing a challenge for individuals with egg protein allergy. Case Presentation: We report the case of a 35-year-old male disaster relief worker with confirmed egg protein allergy and moderate sensitization but no history of anaphylaxis. Under normal circumstances, a statement confirming that vaccination is not possible would be sufficient for entry. However, due to his work-related duties and the relevant guidelines from his employer, there was an urgent need for vaccination despite his egg protein allergy. A comprehensive allergy work-up including skin prick testing, serum-specific IgE, and oral provocation testing revealed a moderate allergy without systemic reactions. Intervention: Following informed consent and risk assessment, a fractional dose (0.1 mL) of the reconstituted yellow fever vaccine was administered under close monitoring. The patient developed a localized dermal reaction without systemic symptoms. Post-vaccination neutralization testing confirmed seroconversion indicating protective immunity. Discussion: Although yellow fever vaccination is considered contraindicated in individuals with severe egg protein allergy, the literature supports its cautious use in selected cases. Fractional dosing has emerged as an effective dose-sparing strategy. Studies show that even in egg protein-allergic individuals, adverse events are rare. Conclusions: In this case, a fractional yellow fever vaccination was safe and an effective option for an egg-allergic individual in a high-risk occupational setting, supporting a personalized approach based on clinical risk assessment and current evidence.
2026-07-08 | Supplementary file 1_Breadth of neutralization induced by vYF next generation yellow fever vaccine.zip
Background A novel live-attenuated yellow fever (YF) vaccine candidate, vYF, is currently in development. Previous studies in non-human primates (NHPs) have evaluated its safety, immunogenicity, and efficacy. To further characterize the immune response, this study assessed the breadth and magnitude of neutralizing antibodies (NAbs) induced by vYF. Methods Immunogenicity was evaluated in NHPs across multiple parameters, including NAb titers against the vaccinal virus strain from 14 to 258 days post-vaccination. The breadth of neutralization was assessed using a panel of four YF virus strains selected to represent diverse phylogeny, isolation dates, and geographic origins. Titers from vYF-vaccinated NHPs were compared with those from YF-VAX–vaccinated NHPs. Two additional control strains, Stamaril® (current vaccine) and the wild-type parent strain Asibi, were included. Amino acid (AA) sequences of viral envelope residues associated with known neutralizing epitopes were analyzed to explore potential correlates with neutralization profiles. Results NAb titers from vYF-vaccinated NHPs were comparable to those obtained with the Asibi strain for two of the four wild-type strains, and 0.3 to 0.5 Log lower for the remaining two. All wild-type strains were neutralized with titers at least 3-fold higher than the established correlate of protection, indicating a broad neutralization profile. Neutralization patterns were similar between vYF- and YF-VAX–vaccinated NHP sera. Conclusion This study adds to the evidence that the vYF may elicit the same breadth of neutralizing antibody responses in NHPs, than YF-VAX reference vaccine.
small molecules
2026-08-13 | Cross-Family Mechanistic Analysis of Plant Alkaloids Against Neglected Arboviruses and Related RNA Viruses.
Neglected arboviruses dengue (DENV), Zika (ZIKV), yellow fever (YFV), Japanese encephalitis (JEV), and chikungunya collectively affect hundreds of millions of people annually, yet no specific antiviral drug has been approved for any of them. Alkaloids, nitrogen-containing specialized metabolites produced by diverse plant families, have emerged as a promising source of broad-spectrum antiviral scaffolds. This review compiles and critically analyzes over 100 alkaloid-virus pairs across several RNA virus families, providing a comparative mechanistic analysis. Lycorine, narciclasine, emetine, and berbamine, among others, exhibit potent activity against phylogenetically distant viruses, with the most potent activities reported against flaviviruses (narciclasine: EC50 0.02 µM against DENV, ZIKV, YFV, and JEV; pancratistatine: 0.0063 µM against ZIKV). Structure-activity analysis of multiple alkaloid classes identifies key pharmacophoric features, including the phenanthridine nucleus (lycorine derivatives) and the bis-benzylisoquinoline scaffold (tetrandrine, berbamine), as determinants of antiviral potency, selectivity, and broad-spectrum activity. Genetic resistance data in West Nile virus challenge the widely accepted model of lycorine as a direct nucleoside inhibitor, instead pointing toward the involvement of the membrane-associated NS4A-2K-NS4B replication complex, though direct validation remains limited for other flaviviruses. Converging structural, biochemical, and transcriptomic evidence suggests that ribosome-mediated translational stress may represent an additional host-directed antiviral mechanism for isoquinoline-type alkaloids, though the causal chain from ribosome binding to activation of the integrated stress response and to antiviral effect has not been established. The present analysis highlights that in vivo validation remains limited to a few alkaloid-virus pairs. Unbiased target deconvolution and formal testing of the ribosome/integrated stress response hypothesis stand out as essential research priorities.
2026-07-30 | Gustatory function of Aedes aegypti opsins and TRPA1 in avoiding a natural insect repellent.
The mosquito, Aedes aegypti, spreads viruses that cause dengue, yellow fever, and other devastating diseases. To identify candidate repellents that suppress blood feeding by Aedes aegypti, we conducted an in vitro screen of natural chemicals for activators of two visual opsins, Op1 and Op2, which we found are expressed at very high levels in gustatory organs. We found that Op1 and Op2 are chemical sensors since they are activated by flavonoids, including catechin. We devised an artificial membrane that mimics multiple properties of skin (VectaDerm), which we used on blood feeders, leading to the demonstration that catechin suppresses blood feeding. This behavior was disrupted in op1,op2 double mutants and in trpA1 mutants. High catechin concentrations directly activated TRPA1 and suppressed blood feeding independent of the opsins, while suppression by lower catechin levels depended on the opsins and TRPA1. Roles for opsins and TRPA1 in avoiding catechin are conserved in Drosophila. TRPA1 expressed in the tick vector for Lyme disease, Ixodes scapularis, is also activated by catechin, and I. scapularis is repelled by catechin. Since catechin is safe to humans, we propose that it could be added to repellent formulations to more effectively suppress biting by mosquitoes.
2026-07-14 | SAR exploration for 4-aminotetrahydroquinazolines with adamantyl moiety against orthoflaviviruses.
4-Aminotetrahydroquinazoline N-oxides form a prominent chemotype of orthoflavivirus reproduction inhibitors, attractive for the search of lead compounds for development as direct-action antiviral agents. Here we explored the relationship between the structure and antiviral activity within an extended series of adamantyl-containing 4-aminotetrahydroquinazolines, synthesized via SNAr reactions of 4-chlorotetrahydroquinazolines with adamantyl-containing amines. Most of the obtained compounds inhibited the reproduction of tick-borne encephalitis, yellow fever, and West Nile viruses in phenotypic assays with micromolar EC50s. The most favorable substituents at 4-amino group were 2-adamant-(1/2)-ylethyls, while the position 2 of heterocyclic core served as a toxicity switch, 2-chlorotetrahydroquinazolines being much less toxic than other analogues. Time-of-addition experiments for hit compounds against West Nile virus revealed a possibility for multi-factorial mechanism of action in the 4-aminotetrahydroquinazoline series.
2026-07-09 | Lipid peroxidation impacts orthoflavivirus infection in a virus-dependent manner.
Orthoflavivirus infection is intricately linked to host cell lipid metabolism, yet the function of bioactive lipids as regulators of infection remains to be elucidated. Here, we investigated the role of lipid mediator pathways, namely ALOX/COX enzymes and upstream lipases, in orthoflavivirus replication by comparing dengue virus (DENV), Zika virus (ZIKV), wild-type yellow fever virus (YFV-Asibi), and the live-attenuated vaccine strain YFV-17D. DENV, ZIKV, and YFV-Asibi, but not the vaccine strain, induced COX2 expression in Huh7 hepatoma cells, correlating with prostaglandin E2 (PGE2) levels in culture supernatants. All four viruses replicated more efficiently in COX2-, ALOX15-, and MGLL-deficient cells, indicating a broadly antiviral role for these enzymes. In contrast, DENV and ZIKV specifically induced ALOX12 expression and depended on ALOX12 for efficient viral RNA replication, as demonstrated by reduced genome copy numbers, altered dsRNA replication compartment morphology, and decreased infectious titers in ALOX12-depleted cells. Direct measurement of lipid peroxidation revealed that ZIKV infection markedly elevated lipid peroxide levels through both ALOX12-dependent and -independent mechanisms, whereas DENV infection did not cause detectable lipid peroxide accumulation. Consistent with this, the ferroptosis inhibitor ferrostatin impaired DENV replication, while the ferroptosis inducer erastin enhanced it; this proviral effect of erastin was fully abolished by ALOX12 knockdown, indicating that DENV depends entirely on ALOX12-driven lipid peroxidation. Iron chelation reduced both DENV and ZIKV infection, confirming a requirement for iron-dependent oxidative processes. The proviral role of lipid peroxidation extended beyond hepatoma cells, as ferrostatin treatment significantly reduced DENV and ZIKV infection in human microglia cells. Our results reveal virus-specific exploitation of lipid peroxidation pathways by orthoflaviviruses and identify ALOX12-dependent lipid peroxidation as a novel proviral mechanism that may represent a target for antiviral intervention.
2026-07-02 | Maternal instincts: a review of the role of chemosensory cues and larval habitat conditions on oviposition site choice by gravid Aedes aegypti (Diptera: Culicidae).
Aedes aegypti (Ae. aegypti) is a global vector of arboviruses, including those causing dengue, chikungunya, Zika, and yellow fever. Effective management of Ae. aegypti populations remain challenging due to their anthropophilic feeding behavior, their exploitation of urban environments, their complex oviposition behavior, and their egg physiology. The characteristics of larval habitats can influence various aspects of larval development, thereby altering adult physiology and behavior. These include differences in blood-feeding behavior, reproductive capacity, and lifespan. Gravid females select oviposition sites based on a diverse array of visual, textural, chemical, and biological cues that attract/repel females from sites and/or stimulate/inhibit oviposition, including volatile organic compounds from microorganisms, detritus, conspecific/heterospecific larvae and adults, predator activity, and environmental factors. This review focuses on the chemosensory aspects of oviposition site selection. Understanding the effects of concentration-dependent chemical cues on oviposition behavior in gravid female Ae. aegypti offers critical insights into the ecology of this species. Integrating this knowledge into vector control strategies, particularly attract-and-kill ovitraps incorporating optimized attractants and larvicides, could enhance surveillance efficacy and reduce Ae. aegypti populations. As climates become more favorable and urbanization expands, Ae. aegypti's geographic range is likely to expand, making it essential to leverage detailed behavioral and ecological insights to improve surveillance, vector management, and to mitigate arboviral disease risks globally.
proteins
2026-07-11 | Coagulopathy in viral haemorrhagic fevers and beyond: molecular mechanisms and targeted interventions.
Coagulopathy refers to any medical condition which affects the ability of the blood to clot. It can be caused due to genetic conditions like haemophilia, von Willebrand disease, or it can be caused through liver disease or deficiency of Vitamin K. It also involves a broad range of diseases affecting hemostasis as an unbalanced and even bidirectional relationship between thrombosis and bleeding. Coagulopathy can also be caused by thromboinflammation, as seen in VHFs like Ebola, Dengue, Marburg, Crimean-Congo Hemorrhagic Fever, Yellow Fever, and Hantavirus infection. The immune response and coagulation system are intricately linked in such cases. Infections from VHFs cause endothelial cell dysfunction through the immune response, monocytes/macrophages activation, and increased expression of tissue factor (TF), which in turn causes excessive thrombin production and fibrin formation. These conditions result in microvascular thrombosis, organ dysfunction, consumption of platelets and coagulation factors, causing a balanced but fragile state of hemostasis that could tip over towards either thrombosis or bleeding. New therapies have been developed that interfere with these processes, such as interference with the TF pathway (for instance, rNAPc2) and regulation of fibrinolysis (tranexamic acid). The recognition of the double-edged sword of coagulopathy is critical for the development of treatment strategies targeting coagulation disorders. This literature review discusses the molecular basis of immunothrombosis and endothelial dysfunction in VHFs.
2026-07-08 | Cellular receptors and host factors mediating orthoflavivirus entry.
Orthoflaviviruses are positive-sense, enveloped RNA viruses that include dengue virus (DENV), Zika virus (ZIKV), yellow fever virus (YFV), West Nile virus (WNV), and Japanese encephalitis virus (JEV). Viral entry is a multistep process governed by the envelope (E) glycoprotein, virion lipid composition, and host-cell molecules that act at distinct mechanistic stages. A major limitation of the current literature is that attachment factors, internalization receptors, immune-modulatory receptors, and membrane-associated cofactors are often collectively termed "receptors", which can obscure the strength and interpretation of the underlying evidence. This review therefore reorganizes reported orthoflavivirus entry-associated molecules into four functional classes: attachment factors, bona fide or candidate internalization receptors, indirect immune-modulatory receptors, and membrane-associated or post-entry cofactors. We place particular emphasis on DENV because it imposes a major clinical burden among orthoflaviviruses and has been the subject of the most extensive receptor-related research. By integrating evidence from binding assays, genetic loss-of-function studies, and in vivo models, this review highlights conserved and virus-specific entry mechanisms. This mechanism-based framework may guide the development of receptor decoys and host-targeting antivirals, although clinical translation will require rigorous validation of antiviral breadth, delivery, safety, and resistance potential.
2026-04-17 | Yellow fever virus infection in non-human primates: a systematic review and meta-analysis of prevalence, seroprevalence, and epizootic case reports (1950-2025).
Yellow fever remains a major mosquito-borne viral disease of global public health and ecological concern. Non-human primates (NHPs) are central to the sylvatic transmission cycle and serve as key sentinels of viral circulation. Yet, evidence on yellow fever virus (YFV) infection in NHPs is dispersed and has not been synthesized comprehensively. To systematically review and meta-analyze global data on the prevalence and seroprevalence of YFV infection in NHP, and to summarize molecular, clinical, and pathological findings from reported epizootic cases. We conducted a systematic search of Scopus, PubMed, Web of Science, and SciELO for studies published between 1950 and 2025, following PRISMA guidelines. Observational studies reporting YFV prevalence or seroprevalence in NHPs were included in the quantitative syntheses, and individual case reports were analyzed separately. Random-effects meta-analyses were performed, with subgroup analyses by geographic region, diagnostic method, and primate genus. Thirty-nine articles assessing 7,183 NHP met the inclusion criteria; 28 contributed to meta-analyses, and 10 provided 19 individual case reports. Pooled molecular prevalence by RT-PCR was 30.7%, and prevalence by immunohistochemistry was 43.4%, both with substantial between-study heterogeneity. Seroprevalence estimates ranged from 5.0 to 36.4% across assays and settings. Higher infection metrics were observed in howler monkeys and titi monkeys. All reported individual cases were fatal and predominantly associated with severe hepatic and multisystemic pathology. Most data originated from the Americas, particularly Brazil, with limited representation from African endemic regions. YFV infection in NHP is widespread, often severe, and epidemiologically significant. Our findings underscore the critical sentinel role of NHPs and highlight the need to strengthen integrated One Health surveillance systems to inform prevention and control strategies, particularly in the context of the current resurgence of yellow fever in Latin America and persistent data gaps in Africa.
2026-03-20 | LRP8 is a functional receptor for yellow fever virus.
Yellow fever virus (YFV) is an arbovirus causing substantial human morbidity and mortality. The live-attenuated 17D strain serves as vaccine and is one of the most successful vaccines so far. Receptor usage between attenuated and pathogenic YFV strains remains unclear. Here we performed a barcoded, genome-wide human open-reading frame library screen and identified LRP8 (also named APOER2) as a receptor for YFV. We show that LRP8 expression increases YFV infection (17D and two clinical strains, BJ01 and Asibi) in cell lines by promoting entry. Adeno-associated virus-mediated expression of human LRP8 in mouse liver aggravates infection and pathology of the clinical strain BJ01. LRP8 knockdown decreases YFV infection in brain cells, primary human hepatocytes and mosquitoes. LRP8 directly interacts with YFV 17D particles via the viral envelope protein. A soluble LRP8 decoy protein can block YFV 17D and BJ01 infection. Our findings provide insights for understanding YFV entry, tropism and pathogenesis.
2026-03-11 | Yellow fever in Latin America and the escalating risks in a changing eco-epidemiological landscape: a review.
Yellow fever (YF) remains a major public health concern in Latin America. We characterise the early-2025 outbreak, compare it with prior waves-especially Southeast Brazil (2016-2018)-and examine environmental, structural, and policy-related drivers. We reviewed regional surveillance data and mortality records from January to April 2025, comparing them to historical outbreak data. Case fatality rate (CFR), geographic spread, and population vulnerability patterns were analyzed. We also reviewed published literature and health alerts to contextualize contributing factors. In 2025, 301 confirmed cases and 124 deaths were reported (CFR 41.1%), mostly in Bolivia, Brazil, Colombia, and Peru, concentrated among unvaccinated populations at the forest-urban interface. Transmission remains sylvatic, but peri-urban spillover risk is rising. Deforestation, climate variability, cross-border migration, and political instability heighten vulnerability; surveillance is fragmented and vaccine uptake insufficient in high-risk groups. YF is re-emerging through intertwined biological, ecological, and socio-political forces. Preventing another large-scale epidemic requires strengthened, integrated surveillance, including Non-Human Primates (NHP) epizootics, equity-centred immunisation in remote areas, and coordinated regional action focused on prevention, early detection, and health-system resilience.
gene therapies
2025-09-15 | Insect-specific viruses: transmission dynamics and biological control strategies against arboviruses.
Mosquitoes are known to vector arthropod-borne viruses (arboviruses) that pose a global public health issue in the form of mosquito-borne viral diseases such as chikungunya fever, dengue fever, Japanese encephalitis, yellow fever, and Zika. Besides, mosquitoes may also carry insect-specific viruses (ISVs), which are evolutionarily alike arboviruses yet do not infect vertebrates. These ISVs have been shown to affect the ability of mosquitoes to transmit arboviruses, as well as potentially inhibit arbovirus infections in vertebrate hosts. Yet, ISVs still constitute a relatively new and little-researched area where further studies may yield new knowledge regarding their distribution, their future importance in the control of mosquito-borne viral disease and potential role in biological control of mosquitoes. This review provides insights into ISV classification, transmission, and biology, as well as historical and future aspects. It mainly focuses on the characterization of the transmission dynamics of ISVs to highlight the various potential arboviral pathogen transmission blocking mechanisms along with evolution and host tropism. The review also provides additional information on the potential use of ISVs as a method of biological control in comparison to other proposed methods as well as delving into current research into arbovirus-based vaccines and antiviral drug development.
2025-07-31 | Two mutations in NS2B are responsible for attenuation of the yellow fever virus (YFV) vaccine strain 17D.
Vaccines have done more to improve the health of humankind over the past century than almost any other technology. Among vaccines, the live-attenuated yellow fever (YF) vaccine (17D) is highly effective, providing long-lasting immunity against yellow fever virus (YFV) infection with a single dose. Developed in the 1930s through extensive serial passage of the virulent YFV-Asibi strain through mouse and chicken embryonic tissue, 17D acquired several mutations that render it attenuated in humans and non-human primates. Over the past century, 17D has become a widely studied immunogen and has also been developed into a vaccine platform for other pathogens. Despite this, most studies of 17D have focused exclusively on the host, without clearly defining the virus-intrinsic features of attenuation. Consequently, the genetic determinants of 17D attenuation remain unknown and are assumed to be multigenic. Here, we leverage the hamster host, which recapitulates many important features of human YF disease, to understand the genetic basis of 17D attenuation. We developed a YFV reverse genetics system and generated hamster-adapted Asibi/17D chimeric viruses, discovering that viruses containing 17D-derived mutations in the viral gene NS2B were significantly attenuated in the hamster. Further analysis revealed that the two non-synonymous mutations in NS2B that distinguish 17D from Asibi, I37L and I109L, act cooperatively to mediate attenuation, with both mutations required to fully prevent key features of YF disease including liver injury and coagulopathy. These findings establish NS2B as an important and unexpected determinant of YFV-17D attenuation in vivo. In addition to the implications of these findings for improving the efficacy and safety of the 17D vaccine platform, this discovery also provides a new direction for understanding more generalized principles and mechanisms of durable vaccine-induced immunity.
2025-07-09 | Amino acid changes in two viral proteins drive attenuation of the yellow fever 17D vaccine.
The live-attenuated yellow fever 17D vaccine strain differs genetically only minimally from its virulent parent. However, it remains unclear which sequence differences lead to virulence or attenuation. Here we demonstrate, using SHAPE-MaP, that these mutations do not induce global RNA structure changes and show that protein sequence mutations are mostly responsible for the phenotypic differences between 17D and virulent YFV. Using a highly modular, combinatorial genetic approach, we identified key mutations in the envelope (E) and non-structural 2A (NS2A) proteins that increase 17D's ability to spread and enhance host antiviral responses. Introducing these mutations into infectious clones of virulent YFV genomes results in viral attenuation in vitro and in two mouse models. Collectively, our results define the genetic basis for 17D attenuation and highlight a potentially general approach for creating live-attenuated vaccines by introducing mutations resulting in similar phenotypic changes in other pathogenic viruses.
2025-06-27 | Sindbis virus is suppressed in the yellow fever mosquito Aedes aegypti by Atg6/BECN1 (autophagy-related 6)-mediated activation of autophagy.
Macroautophagy/autophagy is a critical modulator of pathogen invasion response in vertebrates and invertebrates. However, how it affects mosquito-borne viral pathogens that significantly burden public health remains relatively underexplored. To address this gap, we use a genetic approach to activate autophagy in the yellow fever mosquito (Aedes aegypti) infected with a recombinant Sindbis virus (SINV) expressing an autophagy activator. We first demonstrate a 17-amino acid peptide ("AaBec-1") derived from the Ae. aegypti Atg6/BECN1 (Autophagy-related 6) gene is sufficient to induce autophagy in C6/36 mosquito cells, as marked by lipidation of Atg8 and puncta formation. Next, we engineered a recombinant SINV expressing the AaBec-1 peptide and used it to infect and induce autophagy in adult mosquitoes. We find that modulation of autophagy using this recombinant SINV negatively regulates production of infectious virus. The results from this study improve our understanding of the role of autophagy in regulating arbovirus infection in invertebrate hosts and highlight the potential for the autophagy pathway to be exploited for arbovirus control.Abberviation: C6/36- Aedesalbopictuscell line; dpi - days post-infection; FFA - focus-forming assay;MOI - multiplicity of infection; MTOR - Mechanistic target ofrapamycin kinase; PBS - phosphate-buffered saline; PCR - polymerase chain reaction; RT-PCR - reversetranscription-polymerase chain reaction; RNA - ribonucleic acid;SINV - Sindbis virus; Vero - African green monkey kidneyepithelial cells.
2025-06-26 | Performance of two low-threshold population replacement gene drives in cage populations of the yellow fever mosquito, Aedes aegypti.
Aedes aegypti is the predominant vector for arboviruses including dengue, Zika, and chikungunya viruses, which infect over 100 million people annually. Mosquito population replacement in which arbovirus-susceptible mosquitoes in the field are replaced by laboratory-engineered refractory mosquitoes represents a novel genetic control measure to interrupt arboviral disease cycles. For this approach, the engineered mosquitoes need to harbor two genetic components: an antiviral effector construct which is linked to a gene drive (GD). We tested the performance of two single-locus CRISPR/Cas9 based GD for Ae. aegypti population replacement in small cage populations for up to 16 generations. Starting from a low release threshold of 1:9 GD bearing males to wild-type males, we observed two GD constructs in which Cas9 was expressed from two different germline promoters, nanos and zpg, to increase in frequency in all cage populations. By G16, an average of 72% and 82% of individuals from the zpg-GD and nanos-GD populations, respectively, harbored at least one GD copy with corresponding increases in allele frequencies. This indicated that the two single-locus, CRISPR/Cas9-based homing GD exhibited continuous super-Mendelian inheritance in populations of Ae. aegypti. Gene drive blocking indel (GDBI, a.k.a. "resistant alleles") frequency was measured for each discrete generation in pooled samples from the six populations harboring GD. We found that populations with Cas9 expression under control of the nanos-promoter accumulated GDBI at more than twice the rate of those populations harboring the zpg-promoter driven GD. Based on preexisting data sets for homing and GDBI frequencies in addition to the cage trial observations, the relative contributions of sex-specific homing rates, maternal Cas9 deposition and potential fitness effects were modeled in MGDrivE for both GD, further explaining their divergent performance. Our study demonstrates the feasibility of low-threshold, single-locus CRISPR/Cas9 based GD for Ae. aegypti population replacement.
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2026-07-11 | Ecological and engineered modulation of the mosquito microbiome: mechanisms, vector competence, and translational prospects for disease control.
Malaria, dengue fever, Zika, chikungunya, yellow fever, and West Nile fever are mosquito-borne diseases that collectively impose an enormous global health burden, disproportionately affecting low- and middle-income countries where vector-control tools remain limited or compromised by insecticide resistance. Over the past two decades, the characterization of mosquito-associated microbiomes has transformed our understanding of vector biology, revealing complex, ecologically contingent assemblages of bacteria, fungi, viruses, and protists that profoundly influence mosquito physiology, immunity, and pathogen transmission competence. This review synthesizes current knowledge on the composition and determinants of the mosquito microbiome across major vector genera-Aedes, Anopheles, and Culex-and critically evaluates evidence for microbiome roles in larval development, adult fitness, immune homeostasis, and pathogen-vector interactions. We examine how resident microbiota can inhibit or, in some contexts, facilitate pathogen establishment, dissemination, and transmission, and we discuss the mechanistic pathways underlying these effects, including immune priming, niche competition, antimicrobial metabolite production, and modulation of midgut barrier integrity. We then review major strategies for deliberate microbiome modulation, including Wolbachia-based pathogen blocking and population suppression, paratransgenesis, symbiont supplementation, microbiota engineering, and habitat-level manipulation, and evaluate their biological rationale, current evidence base, field feasibility, and limitations. Attention is given to the gap between laboratory proof-of-concept and operational deployment, as well as to biosafety, regulatory, ecological, and ethical challenges that must be resolved before microbiome-based interventions can be integrated into public health programs. We conclude by identifying priority research questions and the technological advances most likely to accelerate progress from descriptive microbiome science to predictive, actionable vector control.
2026-06-27 | Dissecting the host determinants of orthoflavivirus infection using QIC-seq.
Orthoflaviviruses are genetically related, yet cause distinct disease patterns ranging from hepatitis and vascular shock syndrome to encephalitis and congenital abnormalities. There is an incomplete understanding of the cellular pathways co-opted by orthoflaviviruses, and differences in host response to infection may underlie the diverse pathologies caused. We present a single-cell approach (Quantification of Infection and CRISPR guide sequencing; QIC-seq) that combines CRISPR/Cas9 knockout with virus-inclusive transcriptomics to systematically compare host factor requirements and host transcriptional response to orthoflaviviral challenge. Using a CRISPR library focused on select ER-proteostasis genes, we show that dengue and yellow fever viruses are strictly dependent on subunits of the oligosaccharyltransferase complex, while the more distantly related West Nile and Langat viruses are dependent on components of the ER-associated degradation machinery. Our data further shows virus-induced upregulation of interferon-stimulated genes, and activation of the unfolded protein response. QIC-seq enables quantitative comparisons of viral host factor utilization, which may inform development of host-directed antiviral therapies.
2026-02-10 | Potent Monoclonal Antibodies Against Circulating Yellow Fever Virus Strains from Donors Immunized with the 17D Vaccine.
Yellow fever (YF) causes approximately 50,000 deaths annually worldwide and is transmitted by infection with the yellow fever virus (YFV), which is endemic in Sub-Saharan Africa and tropical South America. The live-attenuated YFV 17D vaccine, developed in 1937, is essential to control YFV transmission, but the finite shelf life and manufacturing constraints of egg-based vaccine production, the rare but severe adverse events, and the lack of effective therapeutic options for YF disease highlight the need for new YFV vaccines and therapies. Potent YFV antibodies that neutralize circulating strains could be promising passive immunizations or treatments and guide nonreplicating YF vaccine development. In this study, we captured and screened natively paired heavy and light chain antibody libraries from two donors immunized with the YFV 17D vaccine. Yeast surface display libraries were generated and stained using YF virus-like particles purified by chromatographic techniques. Three anti-YFV antibodies were identified with potent neutralizing activity against circulating strains from Western Africa and South America, including one potent antibody with a neutralizing half-maximal inhibitory concentration of <5 ng/mL against the 17D vaccine strain. These new YFV antibodies have the potential to serve as YFV outbreak countermeasures for treatment or prevention and guide future vaccine efforts.
2026-01-29 | Human autoantibodies against type I interferons in severe viral disease.
Type I interferons (IFN-Is) are critical antiviral cytokines that restrict viral replication and limit viral disease. A remarkable recent discovery is that human autoantibodies (autoAbs) neutralizing the activities of IFN-Is phenocopy inborn errors of immunity and markedly exacerbate susceptibility to life-threatening infections. Development of these pathogenic autoAbs in humans is strongly linked to genetic and nongenetic factors affecting thymic function, and they are estimated to be present in >100 million people worldwide with a prevalence that increases with age. Here, we review major advances from the last few years that have improved our mechanistic understanding of human IFN-I autoAb development and function, as well as their association with a significant proportion of different severe viral diseases. In particular, we highlight how neutralizing IFN-I autoAbs can persist in individuals for decades, compromising IFN-I-mediated defenses, and underlying subsequent critical infections with diverse pathogens, including SARS-CoV-2, West Nile virus, tick-borne encephalitis virus, seasonal influenza viruses, herpesviruses, and rare zoonoses caused by MERS-CoV, flaviviruses, and avian H5N1 influenza A virus. Furthermore, we discuss how neutralizing IFN-I autoAbs facilitate severe adverse events with live-attenuated viral vaccines, such as the yellow fever or chikungunya virus vaccines, and suggest how implementation of IFN-I autoAb diagnostics in at-risk populations may be clinically beneficial with current prophylactic or therapeutic options. Finally, in the context of new experimental insights into how autoAbs block the ability of IFN-Is to engage with the IFNAR1/IFNAR2 receptors, we detail future opportunities to design advanced novel therapeutic strategies that might specifically mitigate IFN-I autoAb pathogenic effects.
2025-12-25 | Vertical transmission of mosquito microbiota and its effects on offspring development.
The mosquito's gut microbiota plays a crucial role in determining its capacity to transmit harmful viruses and parasites. Accordingly, manipulating mosquito gut microbiota is a promising avenue towards reducing mosquito-borne human pathogen transmission. A successful microbial control campaign will require a thorough understanding of how bacteria are transmitted through mosquito populations. Through two parallel but complementary studies using the yellow fever mosquito Aedes aegypti as a focal host species, we surveyed vertical transmission of bacteria from individual mothers to cohorts of offspring maintained in a closed system. Laboratory- and field-derived mothers deposited bacteria that support offspring development, and the relative abundance of commonly transmitted taxa correlated with offspring fitness. Maternally transmitted bacteria were detected in both larval and adult offspring, and the relative abundances of specific taxa differed between life stages. Microbiota composition in adult offspring closely resembled microbiota composition in mothers, despite dramatic shifts in the relative abundance of specific microbial community members during the larval stage. Variability in microbiota composition in offspring was also greater than variability across the population of egg-laying mothers. Eggs that underwent a period of desiccation before hatching produced larval communities dominated by endospore-forming bacteria that were rare in maternal samples. Overall, our results demonstrate the vertical transmission of mosquito-associated microbiota across generations, including bacterial taxa that could potentially be leveraged for mosquito and mosquito-borne disease control.
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