RARE DISEASE
Rift valley fever
Rift valley fever
Rift valley fever
Drug discovery
0
drugs
With orphan designations
Overview
Rift Valley fever (RVF) is a zoonotic Phlebovirus transmitted via mosquito bites or contact with infected livestock fluids/tissues. Most human cases present as self-limited febrile illness, but severe manifestations include hemorrhagic fever (50% mortality), encephalitis, or ocular complications (1–10% permanent vision loss). Endemic in sub-Saharan Africa and the Arabian Peninsula, outbreaks peak during heavy rainfall linked to mosquito proliferation [1][6][11][15][16].
Burden
Human: Case fatality rate (CFR) averages <1% overall but reaches 27.5% in severe cases. Outbreaks infect thousands (e.g., 90,000 cases in East Africa, 1997) [5][16][20].
Economic: Livestock abortions/mortality cause trade restrictions and income loss, disproportionately affecting pastoralist communities [9][14][16].
Long-term: Ocular sequelae in 1–10% of survivors; miscarriage in 54% of febrile pregnant women [7][11][15].
Therapies
Supportive care: Fluid/electrolyte management, analgesia, and blood product transfusion for hemorrhage [3][6][15][19].
Antivirals: No approved therapeutics; ribavirin is contraindicated due to worsened outcomes. Experimental agents (e.g., favipiravir, monoclonal antibodies) show preclinical promise [1][3][13][17].
Categories: rare infectious diseases
Research Papers
648 drug discovery papers about Rift valley fever, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
648 drug discovery papers about Rift valley fever, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-28 | Repurposing Small-molecule Inhibitors against Bunyaviruses: Advances, Mechanisms, and Therapeutic Prospects.
Bunyaviricetes, including highly pathogenic members such as Severe Fever with Thrombocytopenia Syndrome Virus, Crimean-Congo Hemorrhagic Fever Virus, and Rift Valley Fever Virus, pose significant global health threats characterized by high mortality rates and a lack of approved specific therapeutics. Drug repurposing provides pharmaceutical companies with cost-effective and expedited strategies to discover innovative treatment options for patients. Given the issue of antiviral drug resistance and the high cost of developing new antiviral drugs, drug repurposing offers enormous potential for expanding the repertoire of available therapeutics. This paper reviews the progress made in developing candidate drugs against bunyaviruses through high-throughput screening and drug repurposing methods, summarizes the mechanisms of action of candidate drugs targeting viruses and host cells, and looks ahead to future trends in the development of small-molecule antiviral drugs, with the aim of providing a reference for promoting the development of new bunyavirus drugs.
2026-05-14 | LRP-1 as Target of Broad-Specific Antivirals: Benefits, Risks and Challenges.
Low-density lipoprotein receptor-related protein 1 (LRP-1) is a highly pleiotropic protein involved in the regulation of numerous signalling pathways and interacts with more than 70 different ligands, including viral particles. Recent studies have shown that LRP-1 is the receptor for a spectrum of viruses of great relevance to human and animal health. Rift Valley fever virus (RVFV), Oropouche virus (OROV), Severe fever with thrombocytopaenia syndrome virus (SFTSV), Dengue virus (DENV), Sicilian sandfly fever virus (SFSV), La Crosse virus (LACV), Jamestown Canyon virus (JCV), and Chandipura virus (CHPV) interact with LRP-1 for their infection in mammalian hosts cells. They are included in the arbovirus group, provoke acute disease with significant health implications and present a high risk of transmission from their endemic regions. Currently, none of these viruses have a specific antiviral or vaccine for the treatment of the disease, therefore the development of an antiviral blocking LRP-1 functions would have great scope and potential. In this review, we searched for the current evidence of the validation of LRP-1 as a cellular target for a wide range of RNA genome viruses, highlighting common features of these viruses and the regulation of LRP-1 mediated intracellular signalling in different cell types. In addition, the advantages of an antiviral using LRP-1 as molecular target are discussed, along with the risks and challenges involved in blocking its activity.
2026-04-06 | Preclinical efficacy of a favipiravir and nitazoxanide combination against Rift Valley Fever Virus.
Emerging and re-emerging viruses represent a major global health challenge. To address this, the WHO encourages the development of broad-spectrum medical countermeasures. This study evaluated the efficacy of repurposed broad-spectrum molecules against Bunyaviricetes viruses and more specifically Rift Valley fever virus (RVFV). In vitro, favipiravir and nitazoxanide showed low effective doses with an additive effect in combination against several viruses, including RVFV, Crimean-Congo hemorrhagic fever virus and Hantaan virus. In a murine model of severe RVFV infection, combination treatment reduced viral replication and increased time to death. Pharmacokinetic analyses revealed favorable inhibitory quotients for favipiravir, whereas nitazoxanide displayed low exposure in mice. Favipiravir-induced viral mutagenesis was confirmed, and nitazoxanide targeted late replication steps. Additionally, no resistant variants emerged after serial passages in vitro. Despite the need for further studies in other animal models, these findings underscore the potential of this broad-spectrum compound combination against RVFV and other Bunyaviricetes viruses.
2026-04-06 | The RNA helicase eIF4A as a novel target in insect cells to combat arboviral infections.
Arthropod-borne viruses cause major global health burdens, yet few vaccines or antivirals exist. Targeting host factors required for viral replication offers a promising approach. The DEAD-box RNA helicase eIF4A, a core component of the translation initiation complex eIF4F, unwinds structured 5' UTRs and is therefore critical also for the translation of many viral RNAs. The compound classes rocaglates and pateamines are potent eIF4A inhibitors in mammalian cells. Here we show that the natural rocaglate silvestrol strongly inhibits Rift Valley fever virus replication (RVFV) in human cells without cytotoxicity, expanding the list of eIF4A-dependent arboviruses. Moreover, we studied eIF4A function and rocaglate/pateamine sensitivity in insects, specifically in the arboviral vector Aedes aegypti and the fruit flies Anastrepha suspensa and Drosophila melanogaster. Sequence analysis showed conservation of the rocaglate-binding motif between the human eIF4A and all three insects. Dual luciferase assays in insect cell lines confirmed selective translation inhibition from purine-rich reporters by silvestrol below cytotoxic thresholds. Purified eIF4A variants from all three insect species retained helicase activity, allowing direct testing of inhibitor interactions. Thermal shift assays demonstrated robust stabilization of eIF4A-RNA complexes by both compound classes in the wildtype proteins, with unexpected rocaglate sensitivity of the putatively insensitive Ae. aegypti H161L mutant, indicating a unique binding pocket geometry of the mosquito protein. In summary, our results present RVFV as another drug target for eIF4A inhibitors and highlight comparative biochemistry studies providing insights into distinctive eIF4A inhibitor binding site architecture, with the prospect of exploring informed design to develop species-specific inhibitors.
2026-02-10 | Microbial pigments as potential anti-rift valley fever virus drugs
Abstract Rift valley fever virus (RVFV) is among the WHO list of priority diseases, yet no effective vaccine or treatment is currently available. Microbial pigments (MPs) represent a promising small-molecules library which can be exploited for the drug discovery of anti-RVFV compound. In this study, thirteen MPs were in silico screened to identify candidates with acceptable drug-likeness and possible ability to cross the blood brain barrier. Next, the binding interaction of the filtered molecules were compared against key RVFV proteins for the selection of the optimum inhibitor. Molecular dynamics simulations were performed (200 ns) to further evaluate the interactions. The selected candidate (pyocyanin; PCN) was produced, purified and analytically characterized in-house. Finally, the antiviral potential of PCN was tested in vitro against RVFV using the tissue culture infection dose 50% (TCID50) method. In silico screening studies revealed that prodigiosin and PCN exhibit ideal drug-likeness properties. PCN exerted a promising in silico interaction with the key RVFV proteins as revealed by the molecular docking and dynamic studies. Results showed that PCN may be effectively produced and purified from bacterial cultures. Its cell-safe concentration (0.49 μg/mL) demonstrated a promising 2.89 log10 reduction in TCID50 when incubated with RVFV infected cells. A lower effect was observed (2.00 log10 reduction) in cells treated with PCN prior to RVFV infection. These results suggest that PCN may represent a potential effective low-cost molecule to combat RVFV.
vaccines
2026-08-17 | Opportunities and challenges for countermeasures against Rift Valley fever virus: A quintessential One Health pathogen.
Rift Valley fever virus (RVFV) is a zoonotic arbovirus transmitted by a wide range of mosquito vectors present across the African continent. RVFV has resulted in large-scale epidemics in East, West, southern, and northern Africa with additional epidemics affecting the Arabian Peninsula, Mayotte, and Comoros. In some areas, rather than large-scale isolated outbreaks, RVFV causes a fluctuating low-level endemic burden affecting livestock populations by resulting in pregnancy loss and significant production losses. RVFV risk extends into the human population when it is transmitted either by vector-borne transmission or direct contact with infected animals or animal products such as blood, meat, or milk. Following infection, 2%-3% of humans can develop severe disease manifestations including encephalitis/meningitis, hemorrhagic fever, and retinitis, with visual deficits commonly reported among survivors. While RVF cases in animals and humans have been spatially linked, the proportion and risk associated with spillover events is poorly classified. Given RVFV's dual threat to human and livestock health, it has been designated a priority pathogen by WHO for development of countermeasures. This review aims to summarize current knowledge of RVFV epidemiology, infection, and control as well as highlight key recent advances in the understanding of epidemiology and vaccine development. Multiple next-generation vaccine candidates have advanced to phase two clinical trials which offer hope for approved and commercially available human vaccines in the coming decades. However, despite these promising advancements, key gaps in knowledge remain, particularly regarding the total burden and geographic distributions of endemic and epidemic infections, shifting epidemiologic patterns, optimal vaccine use cases, and the effects of RVFV infection on pregnancy in humans living in hyperendemic regions. Many gaps in understanding persist, and RVFV remains a quintessential One Health pathogen requiring coordinated human, animal, and environmental investigation and collaboration to translate scientific advances into effective national public health strategies.
2026-08-04 | Rift Valley fever immuno-epidemiology, disease severity, and vaccine response among human populations in Uganda
BACKGROUND: Rift Valley fever (RVF) is a mosquito-borne viral infection of ruminants and humans in Africa and the Arabian Peninsula with potential for global spread. Knowledge gaps exist on the burden of RVF and disease manifestations, and currently no licensed vaccines exist for humans. This projectstudied the RVF seroprevalence, risk factors and disease manifestations, and assessed the response to the ChAdOx1 RVF candidate vaccine among humans in Uganda. METHODS: This research project involved four studies. Study 1 was a systematic review and meta-analysis of the RVF clinical manifestations in humans. Study 2 was a cross-sectional seroprevalence and risk factor assessment survey that analysed data and tested stored plasma specimens for RVF antibodies in Uganda. Study 3 analysed cross-sectional data and enrolled into 1 year follow up a cohort of RVF survivors to study the clinical manifestations and immune response to the wildtype virus infection in Uganda. Study 4 was a phase 1 safety and immunogenicity clinical trial of the novel ChAdOx1RVF vaccine among healthy adults in Uganda. RESULTS: RVF seroprevalence was high (10.2%; 95% confidence interval (CI) 8.6 - 12.1) and associated with age, ethnicity, and owning cattle and poultry. The systematic review and meta-analysis established nine clinical syndromes and that RVF causes 21% (95% CI 14 - 29) mortality, mostly among hospitalised patients. However, among cases reported to the Uganda health care system during the Uganda outbreaks of November 2017 to March 2020, 70% (n=28/40) were hospitalised, out of whom 64% (n=18/28) died. Survivors recovered without sequalae and developed high wellsustained IgG antibodies. Healthy adults administered the ChAdOx1RVF vaccine showed no safety concern and robust humoral and cellular immune responses were elicited. CONCLUSION: This PhD project provides insight into the exposure burden of RVF among populations at risk, the high mortality among hospitalised patients, and immune response among survivors in Uganda. It also provides encouraging results on the safety and immunogenicity of the ChAdOx1 RVF vaccine among humans. Interventions should be developed to prevent infections and improve patient outcomes.
2026-07-27 | Emerging Viral Zoonoses: Epidemiology, Vaccination Strategies, and Implications for Global Public Health.
Background/Objectives: Emerging viral zoonoses represent a growing threat to global public health, with most newly emerging infectious diseases originating from animal reservoirs. Recent outbreaks of monkeypox, Ebola virus disease, Marburg virus disease, Rift Valley fever, and avian influenza highlight the capacity of zoonotic viruses to cross species barriers, spread internationally, and generate substantial health, social, and economic consequences. This review examines the ecological, epidemiological, and biological determinants of viral zoonotic emergence and transmission, with particular emphasis on vaccination and outbreak prevention strategies. Methods: A structured narrative review was conducted using a predefined literature search strategy across major scientific databases. Peer-reviewed epidemiological, clinical, and public health publications published between January 2000 and February 2026 were screened and selected according to predefined relevance criteria. Results: The emergence of viral zoonoses is driven by complex interactions among animal reservoirs, environmental and climatic changes, human behavior, and viral adaptation. Although transmission pathways and clinical outcomes differ among pathogens, common determinants of spillover and outbreak amplification were identified. Current evidence supports the importance of integrated surveillance, genomic monitoring, vaccination strategies, and community engagement as key components of preparedness and response. Emerging preventive approaches targeting pathogen transmission, including transmission-blocking strategies and vector-associated microbiota interventions, may provide additional opportunities for disease control. Conclusions: Strengthening preparedness for emerging viral zoonoses requires coordinated One Health approaches integrating human, animal, and environmental health. Future priorities include the development of next-generation vaccines, expansion of digital and genomic surveillance systems, improved equitable access to vaccines, and innovative interventions aimed at reducing zoonotic spillover and interrupting pathogen transmission.
2026-06-22 | Maternal vaccination protects dams and prevents in utero transmission of Rift Valley fever virus in rats.
In utero transmission and spontaneous fetal death are hallmarks of Rift Valley fever virus (RVFV) infection in pregnant animals. Compounding evidence indicates pregnant individuals are particularly vulnerable to RVFV, as in utero transmission and increased rates of miscarriage have been reported in people infected during pregnancy. Further, human placenta explants are permissive to RVFV infection. Viable vaccine candidates intended for veterinary or human use must protect vulnerable populations, including pregnant individuals and fetuses. Using a pregnant rat model, we show that maternal vaccination with a live-attenuated RVFV lacking the non-structural proteins NSs and NSm (RVFV-delNSs/NSm) is immunogenic, safe, and protective. Dams vaccinated either prior to or during pregnancy were protected from virulent challenge during pregnancy, and we found no evidence of infectious virus in the placentas and fetuses of challenged animals. These studies offer important pre-clinical data in a tractable pregnancy model and serve as a blueprint for evaluating future vaccine approaches designed to protect pregnant individuals and their fetuses. Rift Valley fever virus (RVFV) poses a formidable threat to pregnant animals and potentially to pregnant individuals and their developing fetuses. Despite this risk, pregnant individuals are rarely included in vaccine trials, leaving this potentially vulnerable population unprotected. Using a live-attenuated RVFV vaccine, we demonstrate that maternal vaccination is safe and protects both pregnant rats and their fetuses from congenital Rift Valley fever. Because live-attenuated vaccines are often contraindicated during pregnancy due to theoretical safety concerns, we further show that vaccination prior to pregnancy provides equivalent protection throughout future pregnancy. Taken together, these findings provide a blueprint for the preclinical evaluation of RVFV vaccines during pregnancy.
2026-06-15 | Evolutionary dynamics and molecular adaptation of Rift Valley fever virus across human and non-human outbreaks in Africa.
Rift Valley fever virus (RVFV) is an emerging zoonotic virus of major public health and veterinary concern across Africa. Although past genomic studies have focused on outbreak response and lineage classification, the molecular mechanisms driving viral persistence and adaptation remain poorly understood. This study aimed to identify RVFV protein-coding mutations and adaptive signatures across multiple epidemics and epizootics in Africa. This retrospective genomic analysis examined 596 RVFV segment sequences retrieved from the NCBI Virus database, including L (n = 173), M (n = 196) and S (n = 227) sequences from 13 African countries across human and non-human hosts between 1944 and 2022. Following the identification of protein-coding mutations via Genome Detective and custom scripts, we performed phylogenetic reconstruction using IQ-TREE and host-state reconstruction to map cross-species transmission patterns and selection pressure analyses were conducted using codon-based models implemented in the Datamonkey platform. All data analyses and visualizations were performed using R software. A total of 7,339 protein-coding mutations were identified, ranging from 2-20 per isolate. RVFV isolates collected in South Africa, Kenya and Madagascar exhibited the highest genomic diversity. Comparative analysis revealed higher mutation burdens in the L and S segments than in the M segment, with broader diversity among non-human hosts. Phylogenetic reconstruction showed that human-derived sequences clustered within livestock and vector lineages, a pattern consistent with significant genetic bottlenecks during spillovers. Notably, host-state reconstruction identified livestock lineages as the primary source of human outbreaks. We identified seven recurrent amino acid mutations across the genome: N277S, N277D and S278N in the polymerase (L); I442S, I442V, V659A in the glycoproteins (M); and N133S in the NSs protein (S). FUBAR-supported signals consistent with diversifying selection were identified at corresponding codon sites, particularly within the polymerase and glycoprotein regions, highlighting candidate residues potentially associated with adaptive processes affecting replication efficiency and immune evasion. Our findings demonstrate that RVFV evolution across Africa is geographically and temporally heterogeneous, with livestock infections identified as the primary driver of human outbreaks. While RVFV evolution is largely shaped by purifying selection, FUBAR analysis revealed a limited number of candidate codon sites under diversifying selection that may facilitate host-specific adaptation. These host-specific pressures likely contribute to adaptive substitutions that fine-tune polymerase function, alter glycoprotein antigenicity and enhance immune escape. Collectively, these results reveal the molecular mechanisms underpinning viral persistence and provide information to support the design of cross-protective vaccines.
oligonucleotides
2026-01-28 | LRP1 Interacts with the Rift Valley Fever Virus Glycoprotein Gn via a Calcium-Dependent Multivalent Electrostatic Mechanism.
The Rift Valley fever virus (RVFV) is a highly pathogenic, mosquito-borne zoonotic virus that poses a significant risk to livestock, human health, and global public health security. Although RVFV is classified by the World Health Organization (WHO) as a priority pathogen with epidemic potential, no licensed vaccines or effective antiviral therapies are currently available. A limited understanding of the molecular mechanisms of RVFV entry has hindered therapeutic development. Here, we elucidate the molecular basis by which the RVFV envelope glycoprotein Gn recognizes its receptor, low-density lipoprotein receptor-related protein 1 (LRP1). Bio-layer interferometry (BLI) demonstrates that full-length LRP1 directly binds the head domain of Gn with nanomolar affinity in a Ca2+-dependent manner. Both LRP1 clusters II (CL II) and IV (CL IV) independently interact with Gn, with CL IV exhibiting stronger affinity, indicating a multivalent recognition mode. Structural modeling using AlphaFold 3 reveals pronounced charge complementarity between basic residues on Gn and acidic, Ca2+-coordinated pockets within LRP1. Mutations in key acidic residues in CL IV greatly reduced Gn binding, confirming the essential roles of Ca2+ coordination and electrostatic interactions. Collectively, our findings define a Ca2+-stabilized, electrostatically driven mechanism for RVFV Gn recognition by LRP1, providing molecular insight into viral entry and a structural framework for the rational design of vaccines and antiviral therapeutics.
2025-11-03 | MRNA innovation: preparing for arboviruses and the next global outbreak.
Aedes-borne arboviruses, including dengue, Zika, chikungunya, yellow fever, Japanese encephalitis, Rift Valley fever, and Venezuelan equine encephalitis, are rapidly expanding their global reach, with recent outbreaks occurring in non-endemic regions such as southern Europe and the southern United States. Environmental suitability in parts of South America, Asia, and Africa supports continued high transmission potential, while re-emerging pathogens like Oropouche fever further highlight the threat. Current vaccines-though effective in specific contexts-face significant limitations in coverage, safety, and adaptability, underscoring the urgent need for innovative approaches. Advances in mRNA technology, including multivalent self-amplifying RNA platforms, offer a rapid, flexible solution with strong preclinical efficacy against multiple arboviruses. By synthesizing recent epidemiological data, vaccine developments, and translational research, this work calls for accelerated investment, global collaboration, and preparedness strategies to enable timely deployment of next-generation vaccines before the next major outbreak.
2025-09-08 | Limiting viral replication in hematopoietic cells delays Rift Valley fever virus disease progression in C57BL/6 mice.
Rift Valley fever virus (RVFV) causes mild to severe disease in livestock and humans. It was first identified in 1931 during an epizootic in Kenya and has spread across Africa and into the Middle East. Hematopoietic cells are one of the major targets of RVFV in vivo; however, their contribution to RVFV pathogenesis remains poorly understood. To address this, we generated a recombinant miRNA-targeted virus, RVFVmiR-142, to limit viral replication in hematopoietic cells and evaluated the consequences on RVFV disease manifestations in C57BL/6 mice. MicroRNAs are evolutionarily conserved non-coding RNAs that regulate mRNA expression. RVFVmiR-142 includes an insertion of four repeated sequences targeted by hematopoietic-specific miRNA-142. RVFVmiR-MM, which contains four repeats of sequences that are not targets of any known miRNA, was generated as a control. RVFVmiR-142 showed restricted replication in vitro compared to RVFVmiR-MM. C57BL/6 mice infected with 2 TCID50 of RVFVmiR-142 had delayed disease progression vs RVFVmiR-MM-infected mice, the phenotype of which was overcome by higher infection doses. The difference in disease progression at low dose was eliminated in MiR-142 KO mice, confirming the specificity of the phenotype. A timed euthanasia study showed delayed viral replication of RVFVmiR-142 compared to RVFVmiR-MM in infected mice, most notably in tissues largely composed of hematopoietic cells. Furthermore, control of RVFVmiR-142 replication in the popliteal lymph nodes correlated with an increased type I IFN response, which was lacking in the liver tissue where RVFVmiR-142 replication continued to increase. These data suggest that RVFV replication in hematopoietic cells contributes to viral amplification and/or spread.IMPORTANCERVFV is a segmented, single-stranded, negative-sense RNA virus vectored by diverse genera of mosquitoes and can infect a variety of wild animals, domesticated livestock, and humans. Despite the increase in both the range and frequency of RVFV outbreaks over the years, there is currently no vaccine or treatment available for human use against RVFV. Mononuclear phagocytic cells (MPCs) are one of the major targets of RVFV in vivo; however, the contribution of RVFV replication in these cells to its pathogenesis has not been well characterized. In this study, we generated a recombinant miRNA-targeted virus with restricted replication in hematopoietic cells and examined its pathogenesis in C57BL/6 mice. This study demonstrates that hematopoietic cell infection contributes to viral pathogenesis by augmenting viral amplification and/or spread.
2025-08-26 | A DNA vaccine candidate provides protection against Rift Valley Fever virus in sheep under natural field conditions
Rift Valley Fever virus (RVFV) is a mosquito-borne zoonotic pathogen, that causes significant morbidity and mortality in livestock, including high abortion rates in pregnant animals and elevated case fatality in neonates, representing a major threat to both animal and human health. Vaccination is the most effective countermeasure to reduce RVFV’s impact. In this study, we designed a veterinary DNA vaccine encoding a consensus RVFV glycoprotein precursor (GPC), optimized for expression in sheep. The construct was evaluated for immunogenicity in mice and sheep and for protective efficacy in sheep raised under natural field conditions in Senegal, West Africa. The vaccine induced robust humoral responses characterized by high neutralizing antibody titers in both mice and sheep. Under natural exposure, vaccinated sheep showed reduced infection rates (3.2%) compared with controls (14.3%), and neutralizing antibody responses persisted for more than one year. Importantly, the vaccine was well tolerated, including in pregnant animals, with no adverse outcomes such as abortions or fetal abnormalities. These findings demonstrate that a DNA-based RVFV vaccine can elicit durable immunity and provide protection in livestock under real-world conditions. This study highlights the potential of DNA vaccines as a safe, effective, and affordable alternative to existing veterinary vaccines and supports their further development as a key strategy to reduce RVFV transmission and improve animal and human health outcomes in endemic regions.
2025-01-21 | Research progress of mosquito-borne virus mRNA vaccines.
In recent years, mRNA vaccines have emerged as a leading technology for preventing infectious diseases due to their rapid development and high immunogenicity. These vaccines encode viral antigens, which are translated into antigenic proteins within host cells, inducing both humoral and cellular immune responses. This review systematically examines the progress in mRNA vaccine research for major mosquito-borne viruses, including dengue virus, Zika virus, Japanese encephalitis virus, Chikungunya virus, yellow fever virus, Rift Valley fever virus, and Venezuelan equine encephalitis virus. Enhancements in mRNA vaccine design, such as improvements to the 5' cap structure, 5'UTR, open reading frame, 3'UTR, and polyadenylation tail, have significantly increased mRNA stability and translation efficiency. Additionally, the use of lipid nanoparticles and polymer nanoparticles has greatly improved the delivery efficiency of mRNA vaccines. Currently, mRNA vaccines against mosquito-borne viruses are under development and clinical trials, showing promising protective effects. Future research should continue to optimize vaccine design and delivery systems to achieve broad-spectrum and long-lasting protection against various mosquito-borne virus infections.
proteins
2026-06-10 | Biochemical Basis for LRP1 Interaction With Rift Valley Fever Virus Glycoprotein and Its Role in Viral Entry.
The LDL receptor related protein 1 (LRP1) is a host entry factor for Rift Valley fever virus (RVFV), a negative sense RNA virus in the Bunyaviricetes class within the Phenuiviridae family. Previous studies revealed that RVFV glycoproteins (Gn and Gc; GnGc) primarily interact with LRP1 clusters II (CLII) and IV (CLIV) to promote viral entry. However, the mechanism of RVFV GnGc binding to LRP1 is not fully characterized. In this study, we have successfully mapped the roles of individual LRP1 ligand binding regions, known as CR domains, and identified CR25 to be sufficient for high affinity RVFV GnGc binding. Analysis of LRP1 multi-CR binding to RVFV GnGc also revealed redundant modes of binding for LRP1. Mutation of a key aromatic residue within CR25 resulted in near complete loss of binding to RVFV GnGc, suggesting a critical role for CR25 in binding to GnGc in vitro. We further assessed the capacity of these CR domains to inhibit RVFV-MP12GFP infection and determined that more than two contiguous LRP1 CR domains are necessary for in vitro neutralization. Together, these results provide a biochemical basis for LRP1 binding with RVFV GnGc and suggest that a similar mechanism may be at play in LRP1-mediated infection by emerging and re-emerging viruses, including bunyaviruses, alphaviruses, and flaviviruses. These results also highlight that truncated LRP1 ectodomains can be used for immunogen design and therapeutic targeting.
2026-06-01 | IFN-β signaling plays an important role in the prevention of Rift Valley Fever Encephalitis
Introduction Rift Valley fever (RVF) is a zoonotic disease caused by the Bunyavirus RVF Virus (RVFV). Most infected humans develop self-limiting febrile illness, while in rare cases RVFV infections result in severe symptoms, such as encephalitis (RVFE). The present study aimed at investigating the role of type I interferon (IFN-I) signaling in the RVF disease progression in the central nervous system (CNS). Material and Methods C57BL/6 (WT), IFNAR-/-, and IFN-β-/- mice (n = 10 for each group) were intranasally infected with 103 plaque forming units of the attenuated strain RVFV MP12. The mice were clinically evaluated twice daily for 7 or 21 days and then sacrificed. Organ samples were histologically examined and analyzed by immunohistochemistry, immunofluorescence and quantitative RT-PCR. Results WT mice did not develop histological lesions and RVFV RNA was not detected in brain and liver. One exception was a single WT mouse that developed meningoencephalitis at 14 dpi, which was associated with high viral load in the brain. All IFNAR-/- mice developed fatal hepatocellular necrosis at 4-5 dpi with a high amount of viral antigen and RNA in the liver but no CNS lesions. Five out of ten IFN-β-/- mice developed lymphohistiocytic meningoencephalitis at 8-14 dpi with high viral load in the brain. At 7 dpi, 90 % IFN-β-/- mice manifested mild to moderate hepatitis, while in the brain only mild meningitis was found. Immunofluorescence demonstrated RVFV antigen in neurons. Conclusion The results indicate that IFN-β signaling plays an important role in the prevention of a late onset RVFE, and IFN-β-/--mice are still able to manage the infection in the liver. RVFV MP12 has a neuronal tropism in the brain. Publication History Article published online: 01 July 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-04-23 | Dissecting placental host-pathogen interactions: Rift Valley fever virus infection in early human trophoblast stem cells.
Rift Valley fever virus (RVFV) is a mosquito-borne Phlebovirus and zoonotic pathogen affecting maternal-fetal health. Vertical transmission is linked to miscarriage and severe fetal outcomes, but mechanisms of placental pathogenesis remain unclear. We used first-trimester human trophoblast stem cells (hTSCs) to model infection at the maternal-fetal interface. Immunofluorescence, qRT-PCR, western blotting, and single-cell transcriptomics showed that hTSCs are highly susceptible to RVFV. Strand-specific viral transcriptomics confirmed the ambisense S segment and revealed preferential transcription of the M and S segments over L. RVFV induced G1 arrest, impairing trophoblast proliferation and differentiation, and drove widespread transcriptional reprogramming, including strong interferon lambda 1 (IFNL1) but modest type I interferon responses, and dysregulation of inflammatory and preeclampsia-associated genes such as RUNX1 and TGFBRAP1. Recombinant IFN-λ pretreatment reduced RVFV protein expression, highlighting hTSCs as a robust model and IFN-λ as a promising antiviral strategy.
2025-01-27 | Atypical hyperendemicity of Rift Valley fever in Southwestern Uganda associated with the rapidly evolving lineage C viruses.
Recent Rift Valley fever (RVF) epidemiology in eastern Africa region is characterized by widening geographic range and increasing frequency of small disease clusters. Here we conducted studies in southwestern (SW) Uganda region that has since 2016 reported increasing RVF activities. A 22-month long hospital-based study in three districts of SW Uganda targeting patients with acute febrile illness (AFI) or unexplained bleeding was followed by a cross-sectional population-based human-animal survey. We then estimated RVFV force of infection (FOI) and yearly cases using the age-structured seroprevalence data and conducted genomic phylodynamic modelling of RVFV isolates. Overall RVF prevalence was 10.5% (205 of 1,968) among febrile or hemorrhagic cases, including 5% with acute (PCR or IgM positive) infection, averaging 5 cases per month. Community-based serosurvey recorded prevalence of 11.8% (88 of 743) among humans and 14.6% (347 of 2,383) in livestock. Expected yearly human RVF cases were 314-2,111 per 1,369 km 2 in SW Uganda versus 0-711 in comparable regions of Kenya and Tanzania. Viral genomic studies identified RVFV lineage C, sub-clade C.2.2, as the circulating strain in SW Uganda since 2019. Lineage C strain has undergone recent rapid evolution and clonal expansion resulting in four sub-clades, C.1.1, C.1.2, C.2.1, and C.2.2, that are more adept at establishing endemicity in new territories. We demonstrate an atypical RVF hyperendemic region in SW Uganda characterized by sustained human clinical RVF cases, unusually high population prevalence, and high number of expected yearly human cases, associated in part with emergence of new RVFV sub-lineages. Rift Valley fever (RVF) studies in SW Uganda found atypical sustained human cases averaging 5 cases/month, >10% population prevalence, and expected yearly cases >3-fold higher (314-2,111 vs 0-711) than comparable regions in East Africa, associated with emerging RVFV sub-lineages.
2024-11-04 | Tissue specific innate immune responses impact viral infection in Drosophila.
All organisms sense and respond to pathogenic challenge. Tissue-specific responses are required to combat pathogens infecting distinct cell types. Cyclic dinucleotides (CDNs) are produced endogenously downstream of pathogen recognition or by pathogens themselves which bind to STING to activate NF-kB-dependent antimicrobial gene expression programs. It remains unknown whether there are distinct immune responses to CDNs in Drosophila tissues. Here, we investigated tissue specific CDN-STING responses and uncovered differences in gene-induction patterns across tissues that play important roles in viral infections. Using tissue-and cell-specific genetic studies we found that dSTING in the fat body controls CDN-induced expression of dSTING-regulated gene 1 (Srg1) but not dSTING-regulated gene 2 (Srg2) or 3 (Srg3). In contrast, the gastrointestinal tract largely controls expression of Srg2 and Srg3. We found that Srg3 is antiviral against the natural fly pathogen Drosophila C virus and the human arthropod-borne Rift Valley Fever virus (RVFV), but not other arthropod-borne viruses including Sindbis virus and dengue virus. Furthermore, we found that Srg3 has an important role in controlling RVFV infection of the ovary which has important implications in understanding vertical transmission of viruses and RVFV in mosquitoes. Overall, our study underscores the importance of tissue-specific responses in antiviral immunity and highlights the complex tissue regulation of the CDN-STING pathway.
other
2026-06-25 | Neutralizing Antibodies Against Rift Valley Fever Virus: Current Status and Advances.
Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen that has caused repeated epidemics across Africa and the Arabian Peninsula, posing a severe and growing threat to public health and livestock. Infection in ruminants causes high neonatal mortality and catastrophic abortion storms; human disease ranges from self-limiting febrile illness to hemorrhagic fever, encephalitis, and permanent blindness. No licensed human vaccines or specific antiviral therapeutics are available, creating an urgent unmet medical need. We systematically reviewed the peer-reviewed literature on RVFV neutralizing antibodies (NAbs), extracting and synthesizing data on antibody sources, epitope specificity, in vitro neutralizing potency, in vivo protective efficacy, and molecular mechanisms of action. A growing body of work has identified potent NAbs from immunized rodents, rabbits, alpacas, non-human primates, and convalescent patients. These NAbs predominantly target the Gn and Gc envelope glycoproteins. Their mechanisms include blocking host receptor (LRP1) binding, preventing the pH-dependent conformational rearrangement of the Gn-Gc complex, and directly inhibiting viral membrane fusion. Lead candidates, such as RVFV-268 and RVFV-140, achieve sub-nanogram neutralization and confer robust protection in rodent models against lethal challenge, aerosol exposure, and vertical transmission. Bispecific antibodies and combination strategies further enhance potency and the genetic barrier to viral escape. Substantial progress has illuminated the epitope landscape and neutralization mechanisms of RVFV, yielding promising clinical candidates. Translational challenges remain, including viral immune escape, antibody thermostability, and the need for rigorous preclinical evaluation. Future efforts should prioritize structure-guided engineering, rational antibody combinations, and testing in clinically predictive animal models.
2026-02-12 | Arboviruses in Cancer therapy: pros and cons.
Arboviruses, arthropod-borne RNA viruses, are increasingly being recognized not only as causative agents of infectious diseases but also as promising tools in cancer therapy. Recent studies have demonstrated that certain arboviruses possess inherent oncolytic properties and can stimulate potent antitumor immune responses. This review critically examines the therapeutic potential of arboviruses in oncology alongside the key biosafety and translational challenges they present. Several members of the Flaviviridae, Reoviridae, Togaviridae, and Bunyaviridae families, such as Zika virus (ZIKV), Dengue virus (DENV), Yellow Fever virus (YFV), West Nile virus (WNV), Reovirus, Alphavirus, and Rift Valley Fever virus (RVFV), have shown tumor-selective cytotoxicity and strong immunogenicity. ZIKV targets glioblastoma stem-like cells via CD24/SOX2-integrin αvβ5 signaling, while DENV enhances cytotoxic T lymphocyte activity through TRAIL and cytokine induction. These viruses can reprogram the tumor microenvironment by promoting innate and adaptive immune activation, making them attractive candidates for combination with immune checkpoint inhibitors. Despite these advantages, major concerns remain, including viral neurotropism, off-target effects, environmental transmission via vectors, and the impact of pre-existing immunity in endemic regions. In immunocompromised patients, even attenuated strains may pose safety risks. To unlock the full clinical potential of arboviruses in cancer treatment, future strategies must focus on improving tumor specificity through genetic engineering and mitigating biosafety risks. Arbovirus-based virotherapy offers a novel immunotherapeutic avenue capable of turning immunologically “cold” tumors into “hot” ones, thus enhancing cancer immunotherapy outcomes.
2026-01-01 | Potent neutralization of Rift Valley fever virus mediated by monoclonal antibodies via concurrent inhibition of attachment and fusion
Rift Valley fever virus (RVFV) is one of the most important mosquito-borne pathogens that causes substantial morbidity and mortality in livestock and humans. Despite its public health and economic impact, no licenced vaccines or therapeutics are currently available for human use. Here, we report the isolation of a panel of Gn-specific monoclonal antibodies (mAbs) from the memory B cells of rhesus macaques immunized with Ad4-GnGc or Ad5-GnGc. 20 mAbs with neutralizing activity were identified and divided into two groups, targeting subdomain I and subdomain III of the Gn protein, respectively. In murine infection models, representative nAbs A38 and A13 demonstrated efficacious protection against RVFV infection in both prophylactic and therapeutic settings. Research on the neutralizing mechanisms of antibodies revealed that A13 mainly mediates neutralization by inhibiting RVFV fusion to cells, while A38 disrupts multiple stages of the viral entry process by blocking both virus attachment and membrane fusion. To gain deeper insights into these mechanisms, we predicted the variable regions of antibodies and performed molecular docking with RVFV Gn head domain. Structural analysis showed that A38 binds to the DI and DIII subdomains, while A13 binds to an epitope spanning three subdomains of Gn, likely preventing the structural rearrangements required for membrane fusion. This study identifies multiple promising therapeutic candidates against RVFV and elucidates the structural mechanisms by which neutralizing antibodies inhibit various stages of the viral life cycle. These findings deepen our understanding of RVFV pathogenesis and will facilitate the development of novel therapeutic strategies.
2025-12-16 | Cryo-EM structure of the Rift Valley fever virus envelope protein in complex with a potent neutralization antibody.
Entry of Rift Valley fever virus (RVFV) into host cells is mediated by the viral glycoproteins Gn and Gc. Structural details and assembly mechanism of Gn and Gc on the surface of RVFV remain unclear. Here, we stabilized the GnGc with the neutralizing monoclonal antibody RVFV-140 and determined a near-atomic resolution structure of the GnGc hexamer in complex with the fragment antigen binding (Fab) domain of RVFV-140 (Fab140). Our structure showed that RVFV-140 recognizes a ternary epitope and crosslinks two adjacent Gn heads within the hexamer, thus preventing the prefusion to postfusion transition of the glycoproteins. The intraglycoprotein and interglycoprotein interactions within the GnGc hexamer involve van der Waals forces and hydrogen bonds, which are mainly located between Gn heads, and Gn domain C and Gc domain III. Assembly of the GnGc hexamer requires dramatic conformational changes in the loops L231-L244, D280-Q286, Q380-D386, and A427-Y429 of Gn and the hinge region between domains I and II of Gc. The construction of viral capsomeres with the hexameric structure of recombinant GnGc shows that the capsomeres interact primarily through residues 693 to 713 in domain I of Gc. These interactions vary depending on the local environment of each capsomere.
2025-12-01 | Generation of a replication-defective rift valley fever virus and development of a single-virus quantum dot tracking platform
A replication- defective strain of Rift Valley fever virus was developed, facilitating safe investigation under BSL-2 laboratory conditions. Establishment of a single-virus tracking system for Rift Valley fever virus. Live imaging revealed that Rift Valley fever virus undergoes intracellular transport via microtubules and endocytic vesicles. Rift Valley fever virus (RVFV) is a highly virulent zoonotic pathogen posing substantial risks to global public health and livestock industries. Classified by the WHO as a priority pathogen with high pandemic potential, RVFV underscores the critical need for fundamental research to accelerate the development of vaccines and antiviral agents. In this study, we engineered a replication-defective RVFV system that preserves the capacity for host cell infection and a single round of genomic replication. Targeted deletion of the envelope glycoprotein genes Gn and Gc, together with the non-structural protein NSm resulted in a replication-incompetent virus capable of producing infectious particles only in trans-complementing cell lines engineered to express the missing components. This system enables safe experimentation under BSL-2 containment. By incorporating a biotin acceptor peptide (AP) tag into the viral L protein and leveraging biotin-streptavidin bridging for quantum dot conjugation, we developed a highly specific, protein-level labeling platform for single-virus tracking of RVFV. This advanced methodology permits real-time visualization of the viral life cycle from the point of cellular entry. Using this system, we have obtained the first live-cell imaging evidence that RVFV undergoes microtubule-dependent transport via endocytic vesicles during infection. Our findings provide unprecedented insight into the dynamic post-entry trafficking of RVFV and establish a versatile and safe strategy applicable to the study of other high-containment pathogens.
small molecules
2026-07-28 | Repurposing Small-molecule Inhibitors against Bunyaviruses: Advances, Mechanisms, and Therapeutic Prospects.
Bunyaviricetes, including highly pathogenic members such as Severe Fever with Thrombocytopenia Syndrome Virus, Crimean-Congo Hemorrhagic Fever Virus, and Rift Valley Fever Virus, pose significant global health threats characterized by high mortality rates and a lack of approved specific therapeutics. Drug repurposing provides pharmaceutical companies with cost-effective and expedited strategies to discover innovative treatment options for patients. Given the issue of antiviral drug resistance and the high cost of developing new antiviral drugs, drug repurposing offers enormous potential for expanding the repertoire of available therapeutics. This paper reviews the progress made in developing candidate drugs against bunyaviruses through high-throughput screening and drug repurposing methods, summarizes the mechanisms of action of candidate drugs targeting viruses and host cells, and looks ahead to future trends in the development of small-molecule antiviral drugs, with the aim of providing a reference for promoting the development of new bunyavirus drugs.
2026-05-14 | LRP-1 as Target of Broad-Specific Antivirals: Benefits, Risks and Challenges.
Low-density lipoprotein receptor-related protein 1 (LRP-1) is a highly pleiotropic protein involved in the regulation of numerous signalling pathways and interacts with more than 70 different ligands, including viral particles. Recent studies have shown that LRP-1 is the receptor for a spectrum of viruses of great relevance to human and animal health. Rift Valley fever virus (RVFV), Oropouche virus (OROV), Severe fever with thrombocytopaenia syndrome virus (SFTSV), Dengue virus (DENV), Sicilian sandfly fever virus (SFSV), La Crosse virus (LACV), Jamestown Canyon virus (JCV), and Chandipura virus (CHPV) interact with LRP-1 for their infection in mammalian hosts cells. They are included in the arbovirus group, provoke acute disease with significant health implications and present a high risk of transmission from their endemic regions. Currently, none of these viruses have a specific antiviral or vaccine for the treatment of the disease, therefore the development of an antiviral blocking LRP-1 functions would have great scope and potential. In this review, we searched for the current evidence of the validation of LRP-1 as a cellular target for a wide range of RNA genome viruses, highlighting common features of these viruses and the regulation of LRP-1 mediated intracellular signalling in different cell types. In addition, the advantages of an antiviral using LRP-1 as molecular target are discussed, along with the risks and challenges involved in blocking its activity.
2026-04-06 | Preclinical efficacy of a favipiravir and nitazoxanide combination against Rift Valley Fever Virus.
Emerging and re-emerging viruses represent a major global health challenge. To address this, the WHO encourages the development of broad-spectrum medical countermeasures. This study evaluated the efficacy of repurposed broad-spectrum molecules against Bunyaviricetes viruses and more specifically Rift Valley fever virus (RVFV). In vitro, favipiravir and nitazoxanide showed low effective doses with an additive effect in combination against several viruses, including RVFV, Crimean-Congo hemorrhagic fever virus and Hantaan virus. In a murine model of severe RVFV infection, combination treatment reduced viral replication and increased time to death. Pharmacokinetic analyses revealed favorable inhibitory quotients for favipiravir, whereas nitazoxanide displayed low exposure in mice. Favipiravir-induced viral mutagenesis was confirmed, and nitazoxanide targeted late replication steps. Additionally, no resistant variants emerged after serial passages in vitro. Despite the need for further studies in other animal models, these findings underscore the potential of this broad-spectrum compound combination against RVFV and other Bunyaviricetes viruses.
2026-04-06 | The RNA helicase eIF4A as a novel target in insect cells to combat arboviral infections.
Arthropod-borne viruses cause major global health burdens, yet few vaccines or antivirals exist. Targeting host factors required for viral replication offers a promising approach. The DEAD-box RNA helicase eIF4A, a core component of the translation initiation complex eIF4F, unwinds structured 5' UTRs and is therefore critical also for the translation of many viral RNAs. The compound classes rocaglates and pateamines are potent eIF4A inhibitors in mammalian cells. Here we show that the natural rocaglate silvestrol strongly inhibits Rift Valley fever virus replication (RVFV) in human cells without cytotoxicity, expanding the list of eIF4A-dependent arboviruses. Moreover, we studied eIF4A function and rocaglate/pateamine sensitivity in insects, specifically in the arboviral vector Aedes aegypti and the fruit flies Anastrepha suspensa and Drosophila melanogaster. Sequence analysis showed conservation of the rocaglate-binding motif between the human eIF4A and all three insects. Dual luciferase assays in insect cell lines confirmed selective translation inhibition from purine-rich reporters by silvestrol below cytotoxic thresholds. Purified eIF4A variants from all three insect species retained helicase activity, allowing direct testing of inhibitor interactions. Thermal shift assays demonstrated robust stabilization of eIF4A-RNA complexes by both compound classes in the wildtype proteins, with unexpected rocaglate sensitivity of the putatively insensitive Ae. aegypti H161L mutant, indicating a unique binding pocket geometry of the mosquito protein. In summary, our results present RVFV as another drug target for eIF4A inhibitors and highlight comparative biochemistry studies providing insights into distinctive eIF4A inhibitor binding site architecture, with the prospect of exploring informed design to develop species-specific inhibitors.
2026-02-10 | Microbial pigments as potential anti-rift valley fever virus drugs
Abstract Rift valley fever virus (RVFV) is among the WHO list of priority diseases, yet no effective vaccine or treatment is currently available. Microbial pigments (MPs) represent a promising small-molecules library which can be exploited for the drug discovery of anti-RVFV compound. In this study, thirteen MPs were in silico screened to identify candidates with acceptable drug-likeness and possible ability to cross the blood brain barrier. Next, the binding interaction of the filtered molecules were compared against key RVFV proteins for the selection of the optimum inhibitor. Molecular dynamics simulations were performed (200 ns) to further evaluate the interactions. The selected candidate (pyocyanin; PCN) was produced, purified and analytically characterized in-house. Finally, the antiviral potential of PCN was tested in vitro against RVFV using the tissue culture infection dose 50% (TCID50) method. In silico screening studies revealed that prodigiosin and PCN exhibit ideal drug-likeness properties. PCN exerted a promising in silico interaction with the key RVFV proteins as revealed by the molecular docking and dynamic studies. Results showed that PCN may be effectively produced and purified from bacterial cultures. Its cell-safe concentration (0.49 μg/mL) demonstrated a promising 2.89 log10 reduction in TCID50 when incubated with RVFV infected cells. A lower effect was observed (2.00 log10 reduction) in cells treated with PCN prior to RVFV infection. These results suggest that PCN may represent a potential effective low-cost molecule to combat RVFV.
vaccines
2026-08-17 | Opportunities and challenges for countermeasures against Rift Valley fever virus: A quintessential One Health pathogen.
Rift Valley fever virus (RVFV) is a zoonotic arbovirus transmitted by a wide range of mosquito vectors present across the African continent. RVFV has resulted in large-scale epidemics in East, West, southern, and northern Africa with additional epidemics affecting the Arabian Peninsula, Mayotte, and Comoros. In some areas, rather than large-scale isolated outbreaks, RVFV causes a fluctuating low-level endemic burden affecting livestock populations by resulting in pregnancy loss and significant production losses. RVFV risk extends into the human population when it is transmitted either by vector-borne transmission or direct contact with infected animals or animal products such as blood, meat, or milk. Following infection, 2%-3% of humans can develop severe disease manifestations including encephalitis/meningitis, hemorrhagic fever, and retinitis, with visual deficits commonly reported among survivors. While RVF cases in animals and humans have been spatially linked, the proportion and risk associated with spillover events is poorly classified. Given RVFV's dual threat to human and livestock health, it has been designated a priority pathogen by WHO for development of countermeasures. This review aims to summarize current knowledge of RVFV epidemiology, infection, and control as well as highlight key recent advances in the understanding of epidemiology and vaccine development. Multiple next-generation vaccine candidates have advanced to phase two clinical trials which offer hope for approved and commercially available human vaccines in the coming decades. However, despite these promising advancements, key gaps in knowledge remain, particularly regarding the total burden and geographic distributions of endemic and epidemic infections, shifting epidemiologic patterns, optimal vaccine use cases, and the effects of RVFV infection on pregnancy in humans living in hyperendemic regions. Many gaps in understanding persist, and RVFV remains a quintessential One Health pathogen requiring coordinated human, animal, and environmental investigation and collaboration to translate scientific advances into effective national public health strategies.
2026-08-04 | Rift Valley fever immuno-epidemiology, disease severity, and vaccine response among human populations in Uganda
BACKGROUND: Rift Valley fever (RVF) is a mosquito-borne viral infection of ruminants and humans in Africa and the Arabian Peninsula with potential for global spread. Knowledge gaps exist on the burden of RVF and disease manifestations, and currently no licensed vaccines exist for humans. This projectstudied the RVF seroprevalence, risk factors and disease manifestations, and assessed the response to the ChAdOx1 RVF candidate vaccine among humans in Uganda. METHODS: This research project involved four studies. Study 1 was a systematic review and meta-analysis of the RVF clinical manifestations in humans. Study 2 was a cross-sectional seroprevalence and risk factor assessment survey that analysed data and tested stored plasma specimens for RVF antibodies in Uganda. Study 3 analysed cross-sectional data and enrolled into 1 year follow up a cohort of RVF survivors to study the clinical manifestations and immune response to the wildtype virus infection in Uganda. Study 4 was a phase 1 safety and immunogenicity clinical trial of the novel ChAdOx1RVF vaccine among healthy adults in Uganda. RESULTS: RVF seroprevalence was high (10.2%; 95% confidence interval (CI) 8.6 - 12.1) and associated with age, ethnicity, and owning cattle and poultry. The systematic review and meta-analysis established nine clinical syndromes and that RVF causes 21% (95% CI 14 - 29) mortality, mostly among hospitalised patients. However, among cases reported to the Uganda health care system during the Uganda outbreaks of November 2017 to March 2020, 70% (n=28/40) were hospitalised, out of whom 64% (n=18/28) died. Survivors recovered without sequalae and developed high wellsustained IgG antibodies. Healthy adults administered the ChAdOx1RVF vaccine showed no safety concern and robust humoral and cellular immune responses were elicited. CONCLUSION: This PhD project provides insight into the exposure burden of RVF among populations at risk, the high mortality among hospitalised patients, and immune response among survivors in Uganda. It also provides encouraging results on the safety and immunogenicity of the ChAdOx1 RVF vaccine among humans. Interventions should be developed to prevent infections and improve patient outcomes.
2026-07-27 | Emerging Viral Zoonoses: Epidemiology, Vaccination Strategies, and Implications for Global Public Health.
Background/Objectives: Emerging viral zoonoses represent a growing threat to global public health, with most newly emerging infectious diseases originating from animal reservoirs. Recent outbreaks of monkeypox, Ebola virus disease, Marburg virus disease, Rift Valley fever, and avian influenza highlight the capacity of zoonotic viruses to cross species barriers, spread internationally, and generate substantial health, social, and economic consequences. This review examines the ecological, epidemiological, and biological determinants of viral zoonotic emergence and transmission, with particular emphasis on vaccination and outbreak prevention strategies. Methods: A structured narrative review was conducted using a predefined literature search strategy across major scientific databases. Peer-reviewed epidemiological, clinical, and public health publications published between January 2000 and February 2026 were screened and selected according to predefined relevance criteria. Results: The emergence of viral zoonoses is driven by complex interactions among animal reservoirs, environmental and climatic changes, human behavior, and viral adaptation. Although transmission pathways and clinical outcomes differ among pathogens, common determinants of spillover and outbreak amplification were identified. Current evidence supports the importance of integrated surveillance, genomic monitoring, vaccination strategies, and community engagement as key components of preparedness and response. Emerging preventive approaches targeting pathogen transmission, including transmission-blocking strategies and vector-associated microbiota interventions, may provide additional opportunities for disease control. Conclusions: Strengthening preparedness for emerging viral zoonoses requires coordinated One Health approaches integrating human, animal, and environmental health. Future priorities include the development of next-generation vaccines, expansion of digital and genomic surveillance systems, improved equitable access to vaccines, and innovative interventions aimed at reducing zoonotic spillover and interrupting pathogen transmission.
2026-06-22 | Maternal vaccination protects dams and prevents in utero transmission of Rift Valley fever virus in rats.
In utero transmission and spontaneous fetal death are hallmarks of Rift Valley fever virus (RVFV) infection in pregnant animals. Compounding evidence indicates pregnant individuals are particularly vulnerable to RVFV, as in utero transmission and increased rates of miscarriage have been reported in people infected during pregnancy. Further, human placenta explants are permissive to RVFV infection. Viable vaccine candidates intended for veterinary or human use must protect vulnerable populations, including pregnant individuals and fetuses. Using a pregnant rat model, we show that maternal vaccination with a live-attenuated RVFV lacking the non-structural proteins NSs and NSm (RVFV-delNSs/NSm) is immunogenic, safe, and protective. Dams vaccinated either prior to or during pregnancy were protected from virulent challenge during pregnancy, and we found no evidence of infectious virus in the placentas and fetuses of challenged animals. These studies offer important pre-clinical data in a tractable pregnancy model and serve as a blueprint for evaluating future vaccine approaches designed to protect pregnant individuals and their fetuses. Rift Valley fever virus (RVFV) poses a formidable threat to pregnant animals and potentially to pregnant individuals and their developing fetuses. Despite this risk, pregnant individuals are rarely included in vaccine trials, leaving this potentially vulnerable population unprotected. Using a live-attenuated RVFV vaccine, we demonstrate that maternal vaccination is safe and protects both pregnant rats and their fetuses from congenital Rift Valley fever. Because live-attenuated vaccines are often contraindicated during pregnancy due to theoretical safety concerns, we further show that vaccination prior to pregnancy provides equivalent protection throughout future pregnancy. Taken together, these findings provide a blueprint for the preclinical evaluation of RVFV vaccines during pregnancy.
2026-06-15 | Evolutionary dynamics and molecular adaptation of Rift Valley fever virus across human and non-human outbreaks in Africa.
Rift Valley fever virus (RVFV) is an emerging zoonotic virus of major public health and veterinary concern across Africa. Although past genomic studies have focused on outbreak response and lineage classification, the molecular mechanisms driving viral persistence and adaptation remain poorly understood. This study aimed to identify RVFV protein-coding mutations and adaptive signatures across multiple epidemics and epizootics in Africa. This retrospective genomic analysis examined 596 RVFV segment sequences retrieved from the NCBI Virus database, including L (n = 173), M (n = 196) and S (n = 227) sequences from 13 African countries across human and non-human hosts between 1944 and 2022. Following the identification of protein-coding mutations via Genome Detective and custom scripts, we performed phylogenetic reconstruction using IQ-TREE and host-state reconstruction to map cross-species transmission patterns and selection pressure analyses were conducted using codon-based models implemented in the Datamonkey platform. All data analyses and visualizations were performed using R software. A total of 7,339 protein-coding mutations were identified, ranging from 2-20 per isolate. RVFV isolates collected in South Africa, Kenya and Madagascar exhibited the highest genomic diversity. Comparative analysis revealed higher mutation burdens in the L and S segments than in the M segment, with broader diversity among non-human hosts. Phylogenetic reconstruction showed that human-derived sequences clustered within livestock and vector lineages, a pattern consistent with significant genetic bottlenecks during spillovers. Notably, host-state reconstruction identified livestock lineages as the primary source of human outbreaks. We identified seven recurrent amino acid mutations across the genome: N277S, N277D and S278N in the polymerase (L); I442S, I442V, V659A in the glycoproteins (M); and N133S in the NSs protein (S). FUBAR-supported signals consistent with diversifying selection were identified at corresponding codon sites, particularly within the polymerase and glycoprotein regions, highlighting candidate residues potentially associated with adaptive processes affecting replication efficiency and immune evasion. Our findings demonstrate that RVFV evolution across Africa is geographically and temporally heterogeneous, with livestock infections identified as the primary driver of human outbreaks. While RVFV evolution is largely shaped by purifying selection, FUBAR analysis revealed a limited number of candidate codon sites under diversifying selection that may facilitate host-specific adaptation. These host-specific pressures likely contribute to adaptive substitutions that fine-tune polymerase function, alter glycoprotein antigenicity and enhance immune escape. Collectively, these results reveal the molecular mechanisms underpinning viral persistence and provide information to support the design of cross-protective vaccines.
oligonucleotides
2026-01-28 | LRP1 Interacts with the Rift Valley Fever Virus Glycoprotein Gn via a Calcium-Dependent Multivalent Electrostatic Mechanism.
The Rift Valley fever virus (RVFV) is a highly pathogenic, mosquito-borne zoonotic virus that poses a significant risk to livestock, human health, and global public health security. Although RVFV is classified by the World Health Organization (WHO) as a priority pathogen with epidemic potential, no licensed vaccines or effective antiviral therapies are currently available. A limited understanding of the molecular mechanisms of RVFV entry has hindered therapeutic development. Here, we elucidate the molecular basis by which the RVFV envelope glycoprotein Gn recognizes its receptor, low-density lipoprotein receptor-related protein 1 (LRP1). Bio-layer interferometry (BLI) demonstrates that full-length LRP1 directly binds the head domain of Gn with nanomolar affinity in a Ca2+-dependent manner. Both LRP1 clusters II (CL II) and IV (CL IV) independently interact with Gn, with CL IV exhibiting stronger affinity, indicating a multivalent recognition mode. Structural modeling using AlphaFold 3 reveals pronounced charge complementarity between basic residues on Gn and acidic, Ca2+-coordinated pockets within LRP1. Mutations in key acidic residues in CL IV greatly reduced Gn binding, confirming the essential roles of Ca2+ coordination and electrostatic interactions. Collectively, our findings define a Ca2+-stabilized, electrostatically driven mechanism for RVFV Gn recognition by LRP1, providing molecular insight into viral entry and a structural framework for the rational design of vaccines and antiviral therapeutics.
2025-11-03 | MRNA innovation: preparing for arboviruses and the next global outbreak.
Aedes-borne arboviruses, including dengue, Zika, chikungunya, yellow fever, Japanese encephalitis, Rift Valley fever, and Venezuelan equine encephalitis, are rapidly expanding their global reach, with recent outbreaks occurring in non-endemic regions such as southern Europe and the southern United States. Environmental suitability in parts of South America, Asia, and Africa supports continued high transmission potential, while re-emerging pathogens like Oropouche fever further highlight the threat. Current vaccines-though effective in specific contexts-face significant limitations in coverage, safety, and adaptability, underscoring the urgent need for innovative approaches. Advances in mRNA technology, including multivalent self-amplifying RNA platforms, offer a rapid, flexible solution with strong preclinical efficacy against multiple arboviruses. By synthesizing recent epidemiological data, vaccine developments, and translational research, this work calls for accelerated investment, global collaboration, and preparedness strategies to enable timely deployment of next-generation vaccines before the next major outbreak.
2025-09-08 | Limiting viral replication in hematopoietic cells delays Rift Valley fever virus disease progression in C57BL/6 mice.
Rift Valley fever virus (RVFV) causes mild to severe disease in livestock and humans. It was first identified in 1931 during an epizootic in Kenya and has spread across Africa and into the Middle East. Hematopoietic cells are one of the major targets of RVFV in vivo; however, their contribution to RVFV pathogenesis remains poorly understood. To address this, we generated a recombinant miRNA-targeted virus, RVFVmiR-142, to limit viral replication in hematopoietic cells and evaluated the consequences on RVFV disease manifestations in C57BL/6 mice. MicroRNAs are evolutionarily conserved non-coding RNAs that regulate mRNA expression. RVFVmiR-142 includes an insertion of four repeated sequences targeted by hematopoietic-specific miRNA-142. RVFVmiR-MM, which contains four repeats of sequences that are not targets of any known miRNA, was generated as a control. RVFVmiR-142 showed restricted replication in vitro compared to RVFVmiR-MM. C57BL/6 mice infected with 2 TCID50 of RVFVmiR-142 had delayed disease progression vs RVFVmiR-MM-infected mice, the phenotype of which was overcome by higher infection doses. The difference in disease progression at low dose was eliminated in MiR-142 KO mice, confirming the specificity of the phenotype. A timed euthanasia study showed delayed viral replication of RVFVmiR-142 compared to RVFVmiR-MM in infected mice, most notably in tissues largely composed of hematopoietic cells. Furthermore, control of RVFVmiR-142 replication in the popliteal lymph nodes correlated with an increased type I IFN response, which was lacking in the liver tissue where RVFVmiR-142 replication continued to increase. These data suggest that RVFV replication in hematopoietic cells contributes to viral amplification and/or spread.IMPORTANCERVFV is a segmented, single-stranded, negative-sense RNA virus vectored by diverse genera of mosquitoes and can infect a variety of wild animals, domesticated livestock, and humans. Despite the increase in both the range and frequency of RVFV outbreaks over the years, there is currently no vaccine or treatment available for human use against RVFV. Mononuclear phagocytic cells (MPCs) are one of the major targets of RVFV in vivo; however, the contribution of RVFV replication in these cells to its pathogenesis has not been well characterized. In this study, we generated a recombinant miRNA-targeted virus with restricted replication in hematopoietic cells and examined its pathogenesis in C57BL/6 mice. This study demonstrates that hematopoietic cell infection contributes to viral pathogenesis by augmenting viral amplification and/or spread.
2025-08-26 | A DNA vaccine candidate provides protection against Rift Valley Fever virus in sheep under natural field conditions
Rift Valley Fever virus (RVFV) is a mosquito-borne zoonotic pathogen, that causes significant morbidity and mortality in livestock, including high abortion rates in pregnant animals and elevated case fatality in neonates, representing a major threat to both animal and human health. Vaccination is the most effective countermeasure to reduce RVFV’s impact. In this study, we designed a veterinary DNA vaccine encoding a consensus RVFV glycoprotein precursor (GPC), optimized for expression in sheep. The construct was evaluated for immunogenicity in mice and sheep and for protective efficacy in sheep raised under natural field conditions in Senegal, West Africa. The vaccine induced robust humoral responses characterized by high neutralizing antibody titers in both mice and sheep. Under natural exposure, vaccinated sheep showed reduced infection rates (3.2%) compared with controls (14.3%), and neutralizing antibody responses persisted for more than one year. Importantly, the vaccine was well tolerated, including in pregnant animals, with no adverse outcomes such as abortions or fetal abnormalities. These findings demonstrate that a DNA-based RVFV vaccine can elicit durable immunity and provide protection in livestock under real-world conditions. This study highlights the potential of DNA vaccines as a safe, effective, and affordable alternative to existing veterinary vaccines and supports their further development as a key strategy to reduce RVFV transmission and improve animal and human health outcomes in endemic regions.
2025-01-21 | Research progress of mosquito-borne virus mRNA vaccines.
In recent years, mRNA vaccines have emerged as a leading technology for preventing infectious diseases due to their rapid development and high immunogenicity. These vaccines encode viral antigens, which are translated into antigenic proteins within host cells, inducing both humoral and cellular immune responses. This review systematically examines the progress in mRNA vaccine research for major mosquito-borne viruses, including dengue virus, Zika virus, Japanese encephalitis virus, Chikungunya virus, yellow fever virus, Rift Valley fever virus, and Venezuelan equine encephalitis virus. Enhancements in mRNA vaccine design, such as improvements to the 5' cap structure, 5'UTR, open reading frame, 3'UTR, and polyadenylation tail, have significantly increased mRNA stability and translation efficiency. Additionally, the use of lipid nanoparticles and polymer nanoparticles has greatly improved the delivery efficiency of mRNA vaccines. Currently, mRNA vaccines against mosquito-borne viruses are under development and clinical trials, showing promising protective effects. Future research should continue to optimize vaccine design and delivery systems to achieve broad-spectrum and long-lasting protection against various mosquito-borne virus infections.
proteins
2026-06-10 | Biochemical Basis for LRP1 Interaction With Rift Valley Fever Virus Glycoprotein and Its Role in Viral Entry.
The LDL receptor related protein 1 (LRP1) is a host entry factor for Rift Valley fever virus (RVFV), a negative sense RNA virus in the Bunyaviricetes class within the Phenuiviridae family. Previous studies revealed that RVFV glycoproteins (Gn and Gc; GnGc) primarily interact with LRP1 clusters II (CLII) and IV (CLIV) to promote viral entry. However, the mechanism of RVFV GnGc binding to LRP1 is not fully characterized. In this study, we have successfully mapped the roles of individual LRP1 ligand binding regions, known as CR domains, and identified CR25 to be sufficient for high affinity RVFV GnGc binding. Analysis of LRP1 multi-CR binding to RVFV GnGc also revealed redundant modes of binding for LRP1. Mutation of a key aromatic residue within CR25 resulted in near complete loss of binding to RVFV GnGc, suggesting a critical role for CR25 in binding to GnGc in vitro. We further assessed the capacity of these CR domains to inhibit RVFV-MP12GFP infection and determined that more than two contiguous LRP1 CR domains are necessary for in vitro neutralization. Together, these results provide a biochemical basis for LRP1 binding with RVFV GnGc and suggest that a similar mechanism may be at play in LRP1-mediated infection by emerging and re-emerging viruses, including bunyaviruses, alphaviruses, and flaviviruses. These results also highlight that truncated LRP1 ectodomains can be used for immunogen design and therapeutic targeting.
2026-06-01 | IFN-β signaling plays an important role in the prevention of Rift Valley Fever Encephalitis
Introduction Rift Valley fever (RVF) is a zoonotic disease caused by the Bunyavirus RVF Virus (RVFV). Most infected humans develop self-limiting febrile illness, while in rare cases RVFV infections result in severe symptoms, such as encephalitis (RVFE). The present study aimed at investigating the role of type I interferon (IFN-I) signaling in the RVF disease progression in the central nervous system (CNS). Material and Methods C57BL/6 (WT), IFNAR-/-, and IFN-β-/- mice (n = 10 for each group) were intranasally infected with 103 plaque forming units of the attenuated strain RVFV MP12. The mice were clinically evaluated twice daily for 7 or 21 days and then sacrificed. Organ samples were histologically examined and analyzed by immunohistochemistry, immunofluorescence and quantitative RT-PCR. Results WT mice did not develop histological lesions and RVFV RNA was not detected in brain and liver. One exception was a single WT mouse that developed meningoencephalitis at 14 dpi, which was associated with high viral load in the brain. All IFNAR-/- mice developed fatal hepatocellular necrosis at 4-5 dpi with a high amount of viral antigen and RNA in the liver but no CNS lesions. Five out of ten IFN-β-/- mice developed lymphohistiocytic meningoencephalitis at 8-14 dpi with high viral load in the brain. At 7 dpi, 90 % IFN-β-/- mice manifested mild to moderate hepatitis, while in the brain only mild meningitis was found. Immunofluorescence demonstrated RVFV antigen in neurons. Conclusion The results indicate that IFN-β signaling plays an important role in the prevention of a late onset RVFE, and IFN-β-/--mice are still able to manage the infection in the liver. RVFV MP12 has a neuronal tropism in the brain. Publication History Article published online: 01 July 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-04-23 | Dissecting placental host-pathogen interactions: Rift Valley fever virus infection in early human trophoblast stem cells.
Rift Valley fever virus (RVFV) is a mosquito-borne Phlebovirus and zoonotic pathogen affecting maternal-fetal health. Vertical transmission is linked to miscarriage and severe fetal outcomes, but mechanisms of placental pathogenesis remain unclear. We used first-trimester human trophoblast stem cells (hTSCs) to model infection at the maternal-fetal interface. Immunofluorescence, qRT-PCR, western blotting, and single-cell transcriptomics showed that hTSCs are highly susceptible to RVFV. Strand-specific viral transcriptomics confirmed the ambisense S segment and revealed preferential transcription of the M and S segments over L. RVFV induced G1 arrest, impairing trophoblast proliferation and differentiation, and drove widespread transcriptional reprogramming, including strong interferon lambda 1 (IFNL1) but modest type I interferon responses, and dysregulation of inflammatory and preeclampsia-associated genes such as RUNX1 and TGFBRAP1. Recombinant IFN-λ pretreatment reduced RVFV protein expression, highlighting hTSCs as a robust model and IFN-λ as a promising antiviral strategy.
2025-01-27 | Atypical hyperendemicity of Rift Valley fever in Southwestern Uganda associated with the rapidly evolving lineage C viruses.
Recent Rift Valley fever (RVF) epidemiology in eastern Africa region is characterized by widening geographic range and increasing frequency of small disease clusters. Here we conducted studies in southwestern (SW) Uganda region that has since 2016 reported increasing RVF activities. A 22-month long hospital-based study in three districts of SW Uganda targeting patients with acute febrile illness (AFI) or unexplained bleeding was followed by a cross-sectional population-based human-animal survey. We then estimated RVFV force of infection (FOI) and yearly cases using the age-structured seroprevalence data and conducted genomic phylodynamic modelling of RVFV isolates. Overall RVF prevalence was 10.5% (205 of 1,968) among febrile or hemorrhagic cases, including 5% with acute (PCR or IgM positive) infection, averaging 5 cases per month. Community-based serosurvey recorded prevalence of 11.8% (88 of 743) among humans and 14.6% (347 of 2,383) in livestock. Expected yearly human RVF cases were 314-2,111 per 1,369 km 2 in SW Uganda versus 0-711 in comparable regions of Kenya and Tanzania. Viral genomic studies identified RVFV lineage C, sub-clade C.2.2, as the circulating strain in SW Uganda since 2019. Lineage C strain has undergone recent rapid evolution and clonal expansion resulting in four sub-clades, C.1.1, C.1.2, C.2.1, and C.2.2, that are more adept at establishing endemicity in new territories. We demonstrate an atypical RVF hyperendemic region in SW Uganda characterized by sustained human clinical RVF cases, unusually high population prevalence, and high number of expected yearly human cases, associated in part with emergence of new RVFV sub-lineages. Rift Valley fever (RVF) studies in SW Uganda found atypical sustained human cases averaging 5 cases/month, >10% population prevalence, and expected yearly cases >3-fold higher (314-2,111 vs 0-711) than comparable regions in East Africa, associated with emerging RVFV sub-lineages.
2024-11-04 | Tissue specific innate immune responses impact viral infection in Drosophila.
All organisms sense and respond to pathogenic challenge. Tissue-specific responses are required to combat pathogens infecting distinct cell types. Cyclic dinucleotides (CDNs) are produced endogenously downstream of pathogen recognition or by pathogens themselves which bind to STING to activate NF-kB-dependent antimicrobial gene expression programs. It remains unknown whether there are distinct immune responses to CDNs in Drosophila tissues. Here, we investigated tissue specific CDN-STING responses and uncovered differences in gene-induction patterns across tissues that play important roles in viral infections. Using tissue-and cell-specific genetic studies we found that dSTING in the fat body controls CDN-induced expression of dSTING-regulated gene 1 (Srg1) but not dSTING-regulated gene 2 (Srg2) or 3 (Srg3). In contrast, the gastrointestinal tract largely controls expression of Srg2 and Srg3. We found that Srg3 is antiviral against the natural fly pathogen Drosophila C virus and the human arthropod-borne Rift Valley Fever virus (RVFV), but not other arthropod-borne viruses including Sindbis virus and dengue virus. Furthermore, we found that Srg3 has an important role in controlling RVFV infection of the ovary which has important implications in understanding vertical transmission of viruses and RVFV in mosquitoes. Overall, our study underscores the importance of tissue-specific responses in antiviral immunity and highlights the complex tissue regulation of the CDN-STING pathway.
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2026-06-25 | Neutralizing Antibodies Against Rift Valley Fever Virus: Current Status and Advances.
Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen that has caused repeated epidemics across Africa and the Arabian Peninsula, posing a severe and growing threat to public health and livestock. Infection in ruminants causes high neonatal mortality and catastrophic abortion storms; human disease ranges from self-limiting febrile illness to hemorrhagic fever, encephalitis, and permanent blindness. No licensed human vaccines or specific antiviral therapeutics are available, creating an urgent unmet medical need. We systematically reviewed the peer-reviewed literature on RVFV neutralizing antibodies (NAbs), extracting and synthesizing data on antibody sources, epitope specificity, in vitro neutralizing potency, in vivo protective efficacy, and molecular mechanisms of action. A growing body of work has identified potent NAbs from immunized rodents, rabbits, alpacas, non-human primates, and convalescent patients. These NAbs predominantly target the Gn and Gc envelope glycoproteins. Their mechanisms include blocking host receptor (LRP1) binding, preventing the pH-dependent conformational rearrangement of the Gn-Gc complex, and directly inhibiting viral membrane fusion. Lead candidates, such as RVFV-268 and RVFV-140, achieve sub-nanogram neutralization and confer robust protection in rodent models against lethal challenge, aerosol exposure, and vertical transmission. Bispecific antibodies and combination strategies further enhance potency and the genetic barrier to viral escape. Substantial progress has illuminated the epitope landscape and neutralization mechanisms of RVFV, yielding promising clinical candidates. Translational challenges remain, including viral immune escape, antibody thermostability, and the need for rigorous preclinical evaluation. Future efforts should prioritize structure-guided engineering, rational antibody combinations, and testing in clinically predictive animal models.
2026-02-12 | Arboviruses in Cancer therapy: pros and cons.
Arboviruses, arthropod-borne RNA viruses, are increasingly being recognized not only as causative agents of infectious diseases but also as promising tools in cancer therapy. Recent studies have demonstrated that certain arboviruses possess inherent oncolytic properties and can stimulate potent antitumor immune responses. This review critically examines the therapeutic potential of arboviruses in oncology alongside the key biosafety and translational challenges they present. Several members of the Flaviviridae, Reoviridae, Togaviridae, and Bunyaviridae families, such as Zika virus (ZIKV), Dengue virus (DENV), Yellow Fever virus (YFV), West Nile virus (WNV), Reovirus, Alphavirus, and Rift Valley Fever virus (RVFV), have shown tumor-selective cytotoxicity and strong immunogenicity. ZIKV targets glioblastoma stem-like cells via CD24/SOX2-integrin αvβ5 signaling, while DENV enhances cytotoxic T lymphocyte activity through TRAIL and cytokine induction. These viruses can reprogram the tumor microenvironment by promoting innate and adaptive immune activation, making them attractive candidates for combination with immune checkpoint inhibitors. Despite these advantages, major concerns remain, including viral neurotropism, off-target effects, environmental transmission via vectors, and the impact of pre-existing immunity in endemic regions. In immunocompromised patients, even attenuated strains may pose safety risks. To unlock the full clinical potential of arboviruses in cancer treatment, future strategies must focus on improving tumor specificity through genetic engineering and mitigating biosafety risks. Arbovirus-based virotherapy offers a novel immunotherapeutic avenue capable of turning immunologically “cold” tumors into “hot” ones, thus enhancing cancer immunotherapy outcomes.
2026-01-01 | Potent neutralization of Rift Valley fever virus mediated by monoclonal antibodies via concurrent inhibition of attachment and fusion
Rift Valley fever virus (RVFV) is one of the most important mosquito-borne pathogens that causes substantial morbidity and mortality in livestock and humans. Despite its public health and economic impact, no licenced vaccines or therapeutics are currently available for human use. Here, we report the isolation of a panel of Gn-specific monoclonal antibodies (mAbs) from the memory B cells of rhesus macaques immunized with Ad4-GnGc or Ad5-GnGc. 20 mAbs with neutralizing activity were identified and divided into two groups, targeting subdomain I and subdomain III of the Gn protein, respectively. In murine infection models, representative nAbs A38 and A13 demonstrated efficacious protection against RVFV infection in both prophylactic and therapeutic settings. Research on the neutralizing mechanisms of antibodies revealed that A13 mainly mediates neutralization by inhibiting RVFV fusion to cells, while A38 disrupts multiple stages of the viral entry process by blocking both virus attachment and membrane fusion. To gain deeper insights into these mechanisms, we predicted the variable regions of antibodies and performed molecular docking with RVFV Gn head domain. Structural analysis showed that A38 binds to the DI and DIII subdomains, while A13 binds to an epitope spanning three subdomains of Gn, likely preventing the structural rearrangements required for membrane fusion. This study identifies multiple promising therapeutic candidates against RVFV and elucidates the structural mechanisms by which neutralizing antibodies inhibit various stages of the viral life cycle. These findings deepen our understanding of RVFV pathogenesis and will facilitate the development of novel therapeutic strategies.
2025-12-16 | Cryo-EM structure of the Rift Valley fever virus envelope protein in complex with a potent neutralization antibody.
Entry of Rift Valley fever virus (RVFV) into host cells is mediated by the viral glycoproteins Gn and Gc. Structural details and assembly mechanism of Gn and Gc on the surface of RVFV remain unclear. Here, we stabilized the GnGc with the neutralizing monoclonal antibody RVFV-140 and determined a near-atomic resolution structure of the GnGc hexamer in complex with the fragment antigen binding (Fab) domain of RVFV-140 (Fab140). Our structure showed that RVFV-140 recognizes a ternary epitope and crosslinks two adjacent Gn heads within the hexamer, thus preventing the prefusion to postfusion transition of the glycoproteins. The intraglycoprotein and interglycoprotein interactions within the GnGc hexamer involve van der Waals forces and hydrogen bonds, which are mainly located between Gn heads, and Gn domain C and Gc domain III. Assembly of the GnGc hexamer requires dramatic conformational changes in the loops L231-L244, D280-Q286, Q380-D386, and A427-Y429 of Gn and the hinge region between domains I and II of Gc. The construction of viral capsomeres with the hexameric structure of recombinant GnGc shows that the capsomeres interact primarily through residues 693 to 713 in domain I of Gc. These interactions vary depending on the local environment of each capsomere.
2025-12-01 | Generation of a replication-defective rift valley fever virus and development of a single-virus quantum dot tracking platform
A replication- defective strain of Rift Valley fever virus was developed, facilitating safe investigation under BSL-2 laboratory conditions. Establishment of a single-virus tracking system for Rift Valley fever virus. Live imaging revealed that Rift Valley fever virus undergoes intracellular transport via microtubules and endocytic vesicles. Rift Valley fever virus (RVFV) is a highly virulent zoonotic pathogen posing substantial risks to global public health and livestock industries. Classified by the WHO as a priority pathogen with high pandemic potential, RVFV underscores the critical need for fundamental research to accelerate the development of vaccines and antiviral agents. In this study, we engineered a replication-defective RVFV system that preserves the capacity for host cell infection and a single round of genomic replication. Targeted deletion of the envelope glycoprotein genes Gn and Gc, together with the non-structural protein NSm resulted in a replication-incompetent virus capable of producing infectious particles only in trans-complementing cell lines engineered to express the missing components. This system enables safe experimentation under BSL-2 containment. By incorporating a biotin acceptor peptide (AP) tag into the viral L protein and leveraging biotin-streptavidin bridging for quantum dot conjugation, we developed a highly specific, protein-level labeling platform for single-virus tracking of RVFV. This advanced methodology permits real-time visualization of the viral life cycle from the point of cellular entry. Using this system, we have obtained the first live-cell imaging evidence that RVFV undergoes microtubule-dependent transport via endocytic vesicles during infection. Our findings provide unprecedented insight into the dynamic post-entry trafficking of RVFV and establish a versatile and safe strategy applicable to the study of other high-containment pathogens.
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