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:
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.
2026-08-13 | 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.
2026-07-30 | 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.
2026-08-13 | 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.
2026-08-13 | 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.
2026-07-30 | 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.
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