proteins

2026-07-28 | Low-Dose Interleukin-2 Enhances Activated Suppressor Regulatory T Cells and CTLA-4 and HLA-DR Expression in Chronic Chikungunya Arthritis.

Chronic chikungunya arthritis is a debilitating post-viral inflammatory arthritis with no established evidence-based therapy. Regulatory T cell (Treg) dysfunction may contribute to persistent inflammation, and low-dose interleukin-2 (IL-2) may restore immune regulation. We evaluated the immunomodulatory effects of low-dose IL-2 using peripheral blood mononuclear cells from adults with laboratory-confirmed chronic chikungunya arthritis in Atlántico, Colombia. Cells were treated ex vivo with recombinant IL-2 or an IL-2/anti-IL-2 monoclonal antibody complex in the presence of CD2/CD3/CD28 stimulation beads, followed by flow cytometric assessment of effector T cells and Tregs. Low-dose IL-2 treatments ex vivo did not increase total Treg frequency but selectively increased activated suppressor Tregs while decreasing activated T effector cells, enhancing Treg CTLA-4 and HLA-DR expression, and reducing Ki67 expression in effector T cells. IL-2 complex treatment decreased cytokine-secreting Tregs, and IL-10 and TGF-β were not associated with IL-2 treatment status or with Teff/Treg balance, suggesting limited utility as pharmacodynamic biomarkers of low-dose IL-2 treatments. These findings support the use of activated suppressor Tregs, Treg CTLA-4, and HLA-DR expression as candidate biologic endpoints for evaluation in future trials of low-dose IL-2 in chikungunya arthritis.

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2026-07-21 | Ewing sarcoma breakpoint region 1 (EWSR1) protein binds to nonstructural protein 2 and non-coding regions of chikungunya virus genome to inhibit virus replication.

Chikungunya virus (CHIKV) is an alphavirus with a single-stranded RNA genome. Conserved sequence elements within the 5' and 3' non-coding regions (NCRs) of the CHIKV genome interact with host proteins to regulate viral RNA replication. Electrophoretic mobility shift assays (EMSAs) and mass spectrometry identified several host RNA-binding proteins that associate with these conserved NCR elements, among which EWSR1 uniquely bound the 3' ends of both the plus-sense genomic RNA and the minus-sense replication intermediate RNA. EMSA and biolayer interferometry (BLI) demonstrated that EWSR1 binds strongly to two RNA elements: a 48-nucleotide region in the plus-strand 3'-NCR (3NCR48) and a 50-nucleotide region at the 3'-end of the minus-strand replication intermediate (5NCR-RC50), which is complementary to the genome's 5'-NCR and its adjacent sequence. RNA immunoprecipitation from CHIKV-infected cells confirmed that EWSR1 binds CHIKV RNA in vivo. Functional analyses revealed that CHIKV infection downregulates EWSR1 expression and causes its accumulation in the cytoplasm. Knockdown or knockout (KO) of EWSR1 expression increased CHIKV genomic RNA levels and viral titers, whereas its overexpression suppressed both. EWSR1 reduced the synthesis of both plus- and minus-sense CHIKV RNAs in infected cells. Additionally, EWSR1 was found to bind to CHIKV nsP2 and inhibit its helicase activity, which is critical for viral genome replication. The antiviral activity of EWSR1 extended to Ross River virus but not to Sindbis virus, consistent with conservation of the 48-nucleotide sequence in their respective 3'-NCRs. Together, these findings identify EWSR1 as a novel host restriction factor that limits CHIKV replication through specific interactions with viral RNA and the nsP2 protein.IMPORTANCEChikungunya virus (CHIKV) poses a significant medical challenge, necessitating the development of novel antiviral strategies. This study demonstrates that the host protein EWSR1 plays a key role in controlling CHIKV replication. By binding to specific regions of viral RNA and interacting with nsP2, a critical viral enzyme, EWSR1 inhibits viral RNA synthesis and reduces viral titers. In the absence of EWSR1, CHIKV replicates more efficiently, underscoring its antiviral function. These findings establish EWSR1 as an important host restriction factor that limits CHIKV replication. Understanding this interaction enhances our knowledge of host-virus dynamics and may guide the design of new antiviral approaches against CHIKV and related alphaviruses.

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2026-06-18 | Perspectives on chikungunya vaccinology: from traditional platforms to epitope-driven rational design.

Chikungunya virus (CHIKV) is an arthritogenic alphavirus transmitted mainly by female Aedes aegypti and Aedes albopictus mosquitoes. It causes significant morbidity and persistent arthralgia, with its global spread driven by Aedes vectors and viral lineage diversification. Vaccination remains the most cost-effective prevention strategy, but development is hindered by unpredictable outbreaks, undefined immune correlates of protection, and the variability of immunodominant epitopes. This review analyzes CHIKV's genomic and proteomic features, mechanisms of viral entry and transmission, immune evasion strategies, and host immune responses to inform vaccine design. It also critically assesses major vaccine platforms and their limitations. For example, the licensed vaccines Ixchiq (live-attenuated) and Vimkunya (virus-like particle) still facing limitations regarding safety in specific populations, durability of cross-protection, manufacturing complexity, and global accessibility. The review then highlights emerging epitope-based strategies informed by immunoinformatics, which have identified conserved viral epitopes to guide rational multi-epitope vaccine designs. These approaches may address limitations of conventional platforms by precisely targeting conserved protective epitopes, broadening human leukocyte antigen coverage, and reducing reactogenicity. While most epitope-based CHIKV vaccine candidates remain in computational or early preclinical stages, continued integration of immunoinformatics, structural vaccinology, and experimental validation could accelerate the development of safer and more broadly protective next-generation CHIKV vaccines.

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2026-05-27 | CHIKV-Infected Human Dermal Fibroblasts Mount an IFNβ Transcriptional Response Independent of TBK1/IKKε Signaling That Fails to Prevent Lethal Infection.

Chikungunya virus (CHIKV) is an alphavirus that infects dermal fibroblasts as a primary target cell during natural mosquito-borne transmission. While primary human dermal fibroblasts (hDFs) have been implicated as a key source of type I interferon (IFN-I) during CHIKV infection, the dynamics of this response and its sufficiency for antiviral protection remain incompletely understood. Here, we systematically characterize in vitro CHIKV infection of primary hDFs, evaluating the effects of single-passage viral stock origin (mammalian- vs. mosquito-propagated), donor variability, and multiplicity of infection (MOI) on infection kinetics and innate immune induction. We demonstrate that hDFs support high-titered CHIKV replication at both MOI 1 and 0.01, resulting in universal cell death by 72 hpi despite robust IFNβ transcript induction-reaching up to ~2800-fold over mock-and secretion of pro-inflammatory cytokines, including IFNα2, TNFα, IL-1β, and IL-8. Notably, IFNβ protein levels remained below 10 pg/mL under all infection conditions, revealing a disconnect between transcriptional and translational responses, suggesting CHIKV-mediated translational suppression. Pharmacological inhibition of TBK1/IKKε via amlexanox did not suppress IFNβ transcript induction at any tested concentration, suggesting that canonical PRR signaling through this node-including both RIG-I/MAVS and TLR3/TRIF pathways-is not the major driver of the observed transcriptional response. In contrast, co-inoculation with exogenous IFNβ as low as 20 pg/mL activated IFNAR signaling, robustly upregulated interferon-stimulated genes (ISGs), and fully rescued hDFs from otherwise lethal infection. Together, these findings demonstrate that CHIKV-infected hDFs mount a transcriptionally robust but translationally insufficient innate immune response and that the transcriptional response appears to operate independently of TBK1/IKKε. These results have direct implications for understanding how the skin microenvironment may modulate early CHIKV pathogenesis and suggest that paracrine IFNβ signaling from neighboring cell types may be critical for fibroblast survival during natural infection.

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2026-05-15 | ISG15 negatively regulates RIPK3-mediated cell death and viral pathogenesis.

Necroptosis, a form of programmed, inflammatory necrosis, plays an important role in viral-host defense and inflammation. The receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like pseudokinase (MLKL) pathway mediates necroptosis. Yet, the mechanisms that control necroptosis to limit immunopathology are poorly understood. Here, we report that interferon-stimulated gene 15 (ISG15) negatively regulates RIPK3-mediated cell death, including necroptosis, and limits immunopathology during chikungunya virus (CHIKV) infection. ISG15-deficient mice infected with CHIKV display increased levels of necroptosis, resulting in elevated proinflammatory cytokine and chemokine production, leading to increased lethality. This dysregulated host response is fully prevented when MLKL or RIPK3 is ablated in Isg15-/- mice. Mechanistically, ISG15 non-covalently associates with the RIPK3 necrosome in an RIP homotypic interaction motif (RHIM)-dependent manner, regulating necroptosis downstream of CHIKV infection, tumor necrosis factor (TNF), lipopolysaccharide (LPS), and poly(I:C) stimulation. These results demonstrate a role for ISG15 in limiting immunopathology during infection by modulating necroptosis-dependent inflammation and pathogenesis.

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small molecules

2026-08-12 | [Imported Chikungunya Infection Following Travel to Cuba: A Case with Persistent Inflammatory Arthralgia in the Subacute Phase].

Alphavirus chikungunya is an arbovirus transmitted by Aedes mosquitoes and typically presents with acute-onset fever and severe polyarthralgia. In a subset of patients, joint symptoms may persist beyond the acute phase, leading to prolonged functional impairment. With increasing international travel, imported chikungunya infections have become an important consideration in non-endemic countries. In this report, we present a 58-year-old woman who was diagnosed with imported chikungunya infection after returning from Cuba, presenting with fever and widespread joint pain. On initial evaluation, C-reactive protein levels were markedly elevated, while procalcitonin levels remained within normal limits. The diagnosis was confirmed by demonstrating chikungunya virus-specific IgM positivity and IgG seroconversion in sequential serum samples. Viral RNA was not detected in molecular assays. Dengue, Zika, and other arboviral infections, as well as rheumatologic diseases, were excluded during the differential diagnosis. Despite treatment with antipyretics and non-steroidal anti-inflammatory drugs, the patient's joint pain persisted and significantly limited daily activities, necessitating opioid analgesics. Based on the persistence of symptoms beyond the acute phase but for less than three months, the clinical picture was consistent with subacute (post-acute) chikungunya-associated inflammatory arthralgia. Systemic corticosteroid therapy was initiated, resulting in partial clinical improvement. Disease-modifying antirheumatic drugs were not started, as the criteria for chronic chikungunya arthritis were not met. This case highlights the importance of considering chikungunya infection in travelers returning from endemic regions who present with fever and persistent arthralgia, even in the absence of rash. Early recognition and appropriate management during the subacute phase are crucial to improve patient outcomes and prevent progression to chronic disease.

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2026-08-11 | Identification and characterization of anti-chikungunya virus compounds using a biosafe toolkit.

Chikungunya virus (CHIKV) is a re-emerging mosquito-borne alphavirus for which no specific antiviral therapy is currently available. During the large outbreak in Foshan, Guangdong Province, China, in July 2025, CHIKV rapidly spread to neighboring regions and caused more than 16,000 confirmed cases. In this study, the predominant outbreak strain of CHIKV was selected as the reference sequence to establish a panel of complementary biosafe tools for antiviral compound screening and mechanistic investigation. A virus replicon particle (VRP) system for CHIKV was first constructed and applied to compound library screening, resulting in the identification of three candidate antiviral compounds: MDL-12330A, bazedoxifene acetate, and anidulafungin. To further validate their antiviral activities and investigate their potential mechanisms, CHIKV functional evaluation systems were subsequently established, including vesicular stomatitis virus (VSV)- and murine leukemia virus (MLV)-based pseudovirus systems for viral entry, a replicon RNA system for post-entry replication-associated processes, a replication-defective nsP4 mutant replicon RNA system for primary translation, and a virus-like particle (VLP) system for viral particle assembly and budding assessment. Using these complementary systems, we systematically evaluated the antiviral profiles of the three candidate compounds across multiple stages of the CHIKV life cycle. This analysis revealed distinct stage-specific inhibitory patterns and provided insights into their potential antiviral mechanisms, which warrant validation using authentic CHIKV infection to assess their translational potential.

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2026-08-11 | A nanoluciferase-expressing attenuated CHIKV vaccine strain enables rapid and visual drug screening in vitro and in vivo.

Climate change has expanded the range of vectors for the chikungunya virus (CHIKV), thereby increasing its global threat. This situation underscores the urgent need for antiviral therapies. However, the development of drugs is limited by the need for Biosafety Level 3 (BSL-3) containment and the lack of tools for real-time infection monitoring. To address these challenges, we developed a replication-competent reporter virus called CHIKV-ΔnsP3-Nluc. We inserted the Nano-luciferase (Nluc) gene into the attenuation site of the FDA-approved live-attenuated vaccine strain VLA1553 (IXCHIQ). This modified virus retains an attenuated phenotype, replicating more slowly than wild-type CHIKV while maintaining high genetic stability. Nluc activity correlates well with viral titer (R2 = 0.9689), enabling precise quantification of viral replication. In interferon-deficient A6 mice, CHIKV-ΔnsP3-Nluc caused a lethal yet attenuated infection. Real-time bioluminescence imaging revealed that the spleen and kidneys were the primary replication sites, with luminescence intensity closely matching viral titers (R2 = 0.8388). We confirmed the platform's potential for rapid antiviral screening using the nucleoside analog 4'-fluorouridine (4'-FlU). This compound inhibited viral replication in vitro (EC50= 0.063 µM) and significantly reduced viremia and mortality in vivo at a dose of 10 mg/kg, resulting in 100% survival. CHIKV-ΔnsP3-Nluc is a BSL-2-compliant tool that combines the safety of a vaccine candidate with a sensitive reporter function. It has the potential to accelerate studies of CHIKV pathogenesis and assist in developing new antiviral therapies.IMPORTANCEThe expanding range of CHIKV outbreaks poses a threat to global public health, and there is currently a lack of suitable tools for the development of antiviral drugs. In this study, we developed a Nano-luciferase reporter virus based on the attenuated vaccine strain VLA1553 to track viral infection. This viral assay can effectively evaluate the inhibitory and protective effects of candidate compounds both in vitro and in vivo, and its luciferase signal reliably reflects the level of viral replication. Our research provides a safe and stable tool that serves as a suitable platform for the development of antiviral drugs targeting CHIKV.

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2026-08-10 | Repurposing tirbanibulin as an orally active E2-targeting entry inhibitor against Chikungunya virus.

Chikungunya virus (CHIKV) causes severe acute and chronic disease, yet no approved specific antiviral treatment exists. To rapidly identify potential treatments, we aimed to screen an FDA-approved drug library for inhibitors of CHIKV infection. Tirbanibulin, a dual-microtubule polymerization and Src kinase inhibitor, was assessed for its potential anti-CHIKV activity. We performed a high-throughput screen of an FDA-approved drug library. Mechanism-of-action studies included entry-step analysis, surface plasmon resonance (SPR) binding assays and molecular docking. In vivo efficacy was evaluated in lethal murine neuroinfection and CHIKV-induced arthritis models following oral administration of the candidate compound. Tirbanibulin exhibited nanomolar to low-micromolar antiviral activity (EC50 range: 0.035-75.64 μM) across multiple cell lines, with high selective indices in key target HT22 and Huh7 cells. It acted at a post-attachment entry step, inhibiting clathrin-mediated endocytosis and potentially viral fusion. Surface plasmon resonance confirmed direct, high-affinity binding to the CHIKV E1 and E2 glycoprotein complex (K_D = 73 nM). In the lethal neuroinfection model, oral tirbanibulin significantly improved survival and reduced brain viral loads; in the arthritis model, it markedly attenuated footpad swelling and inflammatory pathology. Tirbanibulin is a novel, orally bioavailable entry-stage inhibitor that directly targets the E2 glycoprotein. Multiple preclinical and clinical studies have confirmed its favourable oral bioavailability and safety. Given its established clinical safety profile, it represents a promising repurposing candidate for clinical evaluation against Chikungunya fever.

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2026-08-10 | Lethal and sublethal effects of toxic sugar baits differ among insecticide resistant and insecticide susceptible populations of Aedes aegypti.

Widespread insecticide resistance and the potential for sublethal exposures to alter mosquito fitness have increased interest in alternative approaches such as attractive toxic sugar baits (ATSBs), yet their lethal and sublethal effects in insecticide-resistant versus susceptible populations remain poorly understood. We evaluated the lethal and sublethal effects (LC25) of a novel boric acid and dinotefuran ATSB on ingestion, mortality, blood feeding, and reproductive traits in permethrin-resistant and permethrin-susceptible Aedes aegypti. Aedes aegypti is the primary global vector of dengue, Zika, chikungunya, and yellow fever viruses, placing billions at risk and underscoring the need for sustainable vector control strategies. ATSB affected ingestion, mortality, and reproductive traits in a resistance-dependent manner. Susceptible mosquitoes exhibited reduced ATSB ingestion, whereas resistant mosquitoes showed increased ingestion, suggesting that resistance status modifies feeding responses to the bait formulation. ATSB ingestion increased acute mortality in both strains, with a stronger effect in susceptible mosquitoes, and similarly shortened survival time across strains, indicating consistent sublethal toxicity regardless of resistance status. ATSB reduced blood feeding in both strains, suggesting potential downstream effects on pathogen transmission. Fertility exhibited a significant resistance × treatment interaction, with ATSB increasing fertility in resistant mosquitoes but reducing it in the susceptible strain. These findings indicate that the effects of this ATSB on mosquito fitness and arbovirus transmission-related traits are strongly influenced by permethrin resistance, highlighting the importance of incorporating resistance status into ATSB evaluations and integrated vector control strategies.

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vaccines

2026-08-13 | Antibodies elicited by a chimeric peritrophin antigen reduce Aedes aegypti survival after blood feeding.

Vector-borne diseases transmitted by Aedes aegypti, including dengue, Zika, chikungunya, and yellow fever, represent a persistent and expanding global health threat. Limitations of conventional vector control strategies, such as insecticide use and environmental source reduction, particularly in urban settings, underscore the need for novel and complementary tools. Anti-vector vaccination offers one such strategy by inducing host-derived antibodies that are ingested during vector feeding and interfere with vector physiology or survival. Although this concept has been successfully explored in some hematophagous arthropods, it remains largely unexplored in mosquitoes. Here, we investigated mosquito peritrophins, structural components of the midgut peritrophic matrix, as potential targets for vector-directed vaccination. We designed and recombinantly expressed a chimeric antigen, PT-3, incorporating immunogenic regions from three Aedes aegypti peritrophins/peritrophin-like proteins: AAEL002495, AAEL002467, and AAEL004798. The ability of PT-3 to elicit functional antibodies was evaluated in a bovine host model. Immunization induced a robust antigen-specific humoral response, and mosquitoes fed blood supplemented with immune sera from vaccinated animals showed significantly reduced post-feeding survival compared with controls. Consistent with this functional effect, anti-PT-3 immune sera recognized native mosquito midgut components in ELISA and Western blot assays. Overall, results are consistent with antibody-mediated interference with midgut physiological processes during blood digestion, while no significant effects on oviposition or egg viability were observed among surviving females. Together, these findings provide proof-of-concept that mosquito peritrophins can serve as immunological targets for anti-vector vaccination and provide a rationale for further developing peritrophin-targeted strategies, including alternative delivery platforms, as complementary tools for arboviral control.

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2026-08-06 | Chikungunya vaccine approval in Brazil: navigating through epidemiological challenges and immunisation strategies.

Chikungunya virus (CHIKV) can cause acute arboviral illness, usually accompanied by severe polyarthralgia. In 2025, live-attenuated CHIKV vaccine Ixchiq® (Valneva, Saint-Herblain, France) was authorised for use in Brazil, where CHIKV often co-circulates with other arboviruses. A central public health question emerges: how should this vaccine be optimally deployed in a country characterised by hyperendemic transmission, frequent underdiagnosis, and marked regional disparities? We conducted an epidemiological analysis using notified CHIKV cases from the Notifiable Diseases Information System (SINAN) and socioeconomic indicators from the Brazilian Human Development Atlas. This framework enabled the identification of municipal clusters with shared epidemiological and socioeconomic profiles, allowing exploration of the relationship between disease notification rate and social health determinants. Our results showed that CHIKV transmission exhibited a cyclic pattern with geographic expansion toward the Southeast/South - Brazil's most densely populated regions characterised by low population immunity. Cluster analyses showed that the greatest disease burden is concentrated in socioeconomically disadvantaged municipalities, particularly in the Northeast, where healthcare disparities may further impact diagnostic capacity. Based on the obtained results, we believe in a hybrid immunisation strategy starting from high-incidence municipalities in the northeast and reaching major urban centres in the southeast in order to prevent larger outbreaks. Implementation must account also for current vaccine contraindications in high-risk groups and be guided by real-time epidemiological and entomological surveillance.

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2026-07-10 | Chikungunya virus virus-like particle vaccine (VIMKUNYA) elicits cross-neutralization across CHIKV lineages and against other alphaviruses after just one dose.

Chikungunya virus (CHIKV) is a mosquito-borne virus that has spread widely and infected millions of people. CHIKV can cause both acute and chronic polyarthralgia that can be debilitating. The CHIKV virus-like particle (VLP) vaccine, VIMKUNYA™, is approved for use in the US, EU/EEA, UK, and Switzerland. The aim of this study was two-fold: 1) determine if a single dose of CHIKV VLP vaccine generates cross-neutralizing antibodies against diverse CHIKV strains representing major viral lineages, as well as other arthritogenic alphaviruses, and 2) determine if previous alphavirus vaccination alters the ability to generate cross-neutralizing antibodies after CHIKV VLP vaccination. In this analysis, sera from participants enrolled in a phase 2 study were assessed for neutralizing activity against multiple CHIKV strains and related alphaviruses. A single vaccination with CHIKV VLP vaccine induced cross-neutralizing antibodies against multiple lineages of CHIKV and generated measurable cross-neutralizing activity against several related arthritogenic alphaviruses. Importantly, individuals with prior history of alphavirus vaccination exhibited immune responses comparable to alphavirus-naïve participants, indicating that earlier exposure did not hinder the ability to mount a strong CHIKV-specific or cross-reactive antibody response. These results highlight the broad immunogenic potential of CHIKV VLP vaccine and support its suitability across diverse populations, including individuals with prior alphavirus exposure, as previous vaccination did not diminish the ability to generate robust CHIKV-specific or cross-neutralizing antibody responses against CHIKV and other arthritogenic alphaviruses.

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2026-07-10 | A single-dose chimeric Newcastle disease virus (NDV)/chikungunya virus (CHIKV) is an effective CHIKV vaccine candidate.

With the broad spread of the chikungunya virus (CHIKV), there is an increasing demand for more effective and protective vaccines. In this study, we first developed a Newcastle disease virus (NDV) vector vaccine candidate expressing the complete envelope (E3-E1) protein of CHIKV. The immunoelectron microscopy confirmed the presence of E2 protein in the rNDV-CHIKV virion, and the virological results showed that the expression of E1 and E2 protein was stable after 10 serial passages in embryonated chicken eggs. Moreover, we assessed its safety and immunogenicity following intramuscular (i.m.) or subcutaneous (s.c.) administration in C57BL/6 mice. The immunogenicity analyses demonstrated that a single-dose immunization elicits high titers of CHIKV E2-specific IgG antibodies, potent neutralizing activity, and T-cell immune responses. Importantly, both routes of immunization conferred complete protection against wild-type CHIKV challenge in C57BL/6 mice. These findings present a promising novel vector-based vaccine candidate with significant potential for effective CHIKV prevention.IMPORTANCEChikungunya virus (CHIKV) imposes a substantial global health burden, characterized by arthralgia that can persist for years, neurological complications, and potentially fatal outcomes in vulnerable populations. Currently, two vaccines against CHIKV have been approved: a live-attenuated vaccine (Ixchiq) and a virus-like particle (VLP) vaccine (Vimkunya). However, Ixchiq has been withdrawn from clinical use due to significant side effects, highlighting the urgent need for the development of novel vaccine strategies. Our research has successfully developed a novel vaccine candidate that utilizes Newcastle disease virus as a vector to express CHIKV antigens. This innovative strategy offers multiple advantages: cost-effectiveness, genetic stability of the inserted gene, and robust immunogenicity with effective immune protection. This approach offers a contribution in addressing the emerging threat posed by CHIKV.

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2026-07-01 | Structural and immunogenic characterisation of ChAdOx1 Chik-derived Chikungunya VLPs supports a mechanistic rationale for vaccine-induced protection.

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes severe chronic arthritis in humans and constitutes an expanding global threat. We previously reported that a single unadjuvanted dose of ChAdOx1 Chik vaccine was safe and elicited cross-protective functional antibodies against four distinctive CHIKV lineages in a Phase 1 trial. Here, we show that the CHIKV structural polyprotein encoded by ChAdOx1 Chik can assemble into CHIKV virus-like particles (VLPs) in mammalian cells. Cryo-EM derived reconstruction confirms that these CHIKV VLPs closely resemble the structure of the native virion and LC-MS demonstrates authentic E1/E2 glycosylation. In C57BL/6 mice, unadjuvanted CHIKV VLPs conferred significant protection against viremia and CHIKV-induced foot swelling. A head-to-head comparison of three adjuvant-free platforms encoding structural antigens derived from ChAdOx1 Chik showed that viral-vectors and VLPs induced similar CHIKV-neutralising antibody titres, both surpassing immunisation with soluble E2. Together, these structural and immunogenicity data support a mechanistic rationale that VLP assembly mediated by the clinically relevant ChAdOx1 Chik vaccine contributes to its vaccine-induced protection demonstrated in pre-clinical and clinical studies.

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antibodies

2026-05-23 | CONVICTION-CHIK study on the effect of convalescent plasma for mother-to-child Chikungunya infection: protocol for a multicentre, open label, single-arm, phase II trial.

Mother-to-child peripartum transmission of Chikungunya infection may induce severe illness with neonatal encephalitis/encephalopathy, leading to major neurological sequalae in offspring. There is not, at present, any licensed vaccine or treatment for Chikungunya virus (CHIKV) disease in pregnant women or neonates. However, there are a range of potential treatments, including passive immune therapies by hyperimmune antibodies or blood products, which warrant further investigation. Our study aims to determine whether the early administration of CHIKV convalescent plasma donor is effective in preventing several adverse outcomes in neonates exposed to maternal peripartum CHIKV infection. CONVICTION-CHIK is a multicentre, interventional, phase II, single-arm trial, that will be conducted in two French overseas departments in the Indian Ocean throughout 2026. Neonates with the following criteria will be included: (1) mother with a clinical and/or biological diagnosis of CHIKV infection occurring between day -2 and + 2 around delivery; (2) cared for in a 3rd level neonatal intensive care unit; (3) treatment administration possible within 12 h from diagnosis of maternal infection. The intervention consists in the transfusion of 25 mL/kg of ABO CHIKV convalescent plasma over 4 h. The primary endpoint is the proportion of newborn infants treated with CHIKV convalescent plasma who survive without encephalitis/encephalopathy in the first 5 days of life. This outcome will also be assessed in a parallel cohort of untreated newborn infants exposed to peripartum CHIKV infection. Secondary endpoints are clinical, biological, and brain imaging findings of neonatal CHIKV infection, in treated and untreated neonates. Based on an expected decrease in the primary endpoint from 25% to 3% in the intervention group, the required sample size is 30 treated neonates. A parallel cohort of 30 contemporaneous untreated neonates will be enrolled to provide exploratory context for the observed treatment effect. If successful, this research will expand the therapeutic arsenal for treating peripartum neonatal CHIKV infection, in addition to symptomatic management of organ failure. The results of this study will allow to consider the feasibility to implement the systematic collection of convalescent plasma following Chikungunya outbreaks, for the management of subsequent epidemics. NCT07190560 (registered 17 September 2025).

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2026-03-25 | E2 Protein of Chikungunya Virus: A Narrative Review of Its Potential as a Therapeutic Target.

Chikungunya Virus (CHIKV), an enveloped RNA virus transmitted by Aedes mosquitoes, has become an increasing global health concern, particularly in South America, where cases and fatalities have risen (PAHO, 2023). This review focuses on therapeutic strategies targeting the CHIKV E2 protein, including vaccines, antibodies, and antiviral approaches tested in vitro and in vivo. Literature reporting on the E2 protein, including studies on viral structure, host interactions, symptoms, and treatments under development, was analyzed. The E2 protein, a major structural component of CHIKV, is critical for viral entry and virulence, mediating interactions with host factors (Glycosaminoglycans (GAGs) and C-type lectins) and receptors (Matrix Remodeling-Associated Protein 8 (Mxra8) and Prohibitin-1 (PHB1)). It also elicits robust antibody responses, making it a key target for therapeutic intervention. The E2 protein is essential for CHIKV entry and virulence, making it a key target for vaccines, antibodies, and antivirals. While preclinical studies show promise, efficacy varies and clinical translation remains limited. Challenges include viral diversity, immune escape, and the need for integrated strategies combining different therapeutic approaches. Given the absence of licensed vaccines and antivirals for alphaviruses, the E2 protein represents a promising therapeutic target while inhibiting E2 could block viral entry and infection. However, current strategies show variable efficacy and inconclusive results, highlighting the need for further research to validate and optimize E2-targeted therapies.

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2026-01-29 | Human autoantibodies against type I interferons in severe viral disease.

Type I interferons (IFN-Is) are critical antiviral cytokines that restrict viral replication and limit viral disease. A remarkable recent discovery is that human autoantibodies (autoAbs) neutralizing the activities of IFN-Is phenocopy inborn errors of immunity and markedly exacerbate susceptibility to life-threatening infections. Development of these pathogenic autoAbs in humans is strongly linked to genetic and nongenetic factors affecting thymic function, and they are estimated to be present in >100 million people worldwide with a prevalence that increases with age. Here, we review major advances from the last few years that have improved our mechanistic understanding of human IFN-I autoAb development and function, as well as their association with a significant proportion of different severe viral diseases. In particular, we highlight how neutralizing IFN-I autoAbs can persist in individuals for decades, compromising IFN-I-mediated defenses, and underlying subsequent critical infections with diverse pathogens, including SARS-CoV-2, West Nile virus, tick-borne encephalitis virus, seasonal influenza viruses, herpesviruses, and rare zoonoses caused by MERS-CoV, flaviviruses, and avian H5N1 influenza A virus. Furthermore, we discuss how neutralizing IFN-I autoAbs facilitate severe adverse events with live-attenuated viral vaccines, such as the yellow fever or chikungunya virus vaccines, and suggest how implementation of IFN-I autoAb diagnostics in at-risk populations may be clinically beneficial with current prophylactic or therapeutic options. Finally, in the context of new experimental insights into how autoAbs block the ability of IFN-Is to engage with the IFNAR1/IFNAR2 receptors, we detail future opportunities to design advanced novel therapeutic strategies that might specifically mitigate IFN-I autoAb pathogenic effects.

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2026-01-14 | Modulating Chikungunya and Mayaro virus-induced disease severity in mice using low concentrations of anti-IFNAR1 antibodies.

The laboratory mouse (Mus musculus) is the most widely used animal model for preclinical research, with numerous wild-type and genetically modified mouse strains available. Chikungunya virus (CHIKV), a mosquito-borne arthritogenic alphavirus, has emerged in various new regions and caused several millions of cases within the last decade. Mayaro virus (MAYV), an arthritogenic alphaviruses closely related to CHIKV, remains geographically restricted to the Americas. Existing mouse models rely on immunodeficient mice, leading to lethal illness, or footpad injection, which induces localized arthropathy. We present a proof-of-concept study demonstrating how disease severity in mice can be modulated using sub-neutralizing concentrations of an interferon 1 receptor (IFNAR1) blocking monoclonal antibody (mAb). C57BL/6 mice were injected intraperitoneally with varying anti-IFNAR1 antibody doses before intraperitoneal infection with CHIKV or MAYV. For both, CHIKV and MAYV, we observed an anti-IFNAR1 mAb dose-dependent increase in blood viral loads and disease severity. A 1mg dose induced severe disease, whereas a 0.1 mg dose resulted in moderate symptoms in mice, mainly facial pain expression signs, accompanied by detectable viremia in the days preceding symptom onset. Viral loads in organs and serum concentrations of inflammatory cytokines and chemokines were also elevated in mice receiving 0.1mg anti-IFNAR1 mAb. In conclusion, we provide proof of concept that CHIKV and MAYV disease severity can be modulated using low concentrations of anti-IFNAR1 mAb. We used this approach to develop a new infection model for mild systemic disease, based on an accessible strain and a commercial antibody allowing for easy implementation and adaptation.

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2026-01-07 | Passive transfer of human sera from chikungunya virus virus-like particle vaccine (Vimkunya) recipients fully protects non-human primates from viremia.

Vimkunya, a chikungunya virus (CHIKV) virus-like particle (VLP) vaccine, is well-tolerated and induces a rapid, durable serum neutralizing antibody (SNA) response in individuals aged ≥12 years. This study evaluated the efficacy of human CHIKV VLP antisera to protect cynomolgus macaques from heterologous CHIKV challenge and determined an SNA titer that confers complete protection against viremia. Macaques receiving negative control sera had detectable viremia and RNAemia, whereas those receiving control anti-CHIKV IgG or CHIKV VLP antisera with pre-challenge NT80 ≥ 25.7 had no detectable viremia/RNAemia through 10 days post-challenge. Logistic regression showed that pre-challenge NT80s of 23.6 and 25.9 corresponded with 80% and 90% probability of protection, respectively. Data from seroepidemiology studies demonstrated that a neutralizing titer of >1:10 is protective in convalescent persons. The SNA NT80 threshold of 100 selected by US and European regulators to predict protection against CHIKV disease in humans is conservative by a factor of ~4.

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2026-07-28 | Single-stranded nucleic acid binding enhances the in vitro catalytic activity of Chikungunya virus nsP2 protease.

Chikungunya virus (CHIKV) is an emerging arbovirus whose replication relies on the multifunctional nonstructural protein 2 (nsP2), particularly its viral protease (nsP2pro), which is essential for polyprotein processing. In this study, we investigated how interactions with nucleic acids influence nsP2pro activity. Using High-Throughput Sequencing-Fluorescent Ligand Interaction Profiling (HiTS-FLIP), we identified specific single-stranded DNA aptamers that enhanced nsP2pro activity. Additionally, both random single-stranded DNA and single-stranded RNA were found to stimulate protease activity, whereas double-stranded DNA showed no such effect. Circular dichroism spectroscopy and secondary structure predictions confirmed that the identified aptamers adopt stable folded conformations. Similarly, structured RNA sequences were also capable of promoting protease activity. The observed stimulatory effect depended on the nucleic acid strand type, length, and buffer conditions, suggesting the involvement of electrostatic interactions. NMR experiments demonstrated that nsP2pro interacts with single-stranded DNA, accompanied by changes in its conformational dynamics upon binding. Molecular dynamic simulations of nsP2pro-RNA and -DNA complexes revealed that these nucleic acids interact specifically with the nsP2pro methyltransferase domain and induce an opening process in the protease active site. Our findings provide novel insights into the regulation of nsP2pro, enhancing our understanding of CHIKV replication mechanisms, and may guide future antiviral development strategies.

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2026-05-24 | Aptamers as immunomodulatory therapeutic alternatives targeting neglected tropical diseases (NTDs).

Neglected tropical diseases (NTDs) comprise a heterogeneous group of infections that disproportionately affect populations in low- and middle-income countries, where limited access to diagnostics, therapeutics, and surveillance perpetuates disease burden. Conventional strategies based on antibodies and small-molecule drugs face major challenges, including high production costs, limited stability, cross-reactivity, toxicity, and the emergence of drug resistance. In this context, aptamers, short single-stranded nucleic acids selected by SELEX, have emerged as versatile immunomodulatory tools with significant potential for the diagnosis and treatment of NTDs. This chapter provides a comprehensive overview of aptamer-based strategies targeting major NTDs, with particular emphasis on human African trypanosomiasis and arboviral infections such as dengue, Zika, and chikungunya. Aptamers directed against conserved parasite and viral epitopes demonstrate the capacity to circumvent immune evasion mechanisms, including antigenic variation and serotype diversity, while enabling highly specific recognition and internalization. In African trypanosomes, RNA aptamers targeting variant surface glycoproteins exploit the flagellar pocket for targeted drug delivery, offering a novel approach to overcome therapeutic resistance. In arboviral diseases, aptamers have been successfully integrated into advanced diagnostic platforms, including competitive ELISA, electrochemical, and capacitive biosensors, achieving high sensitivity, rapid response times, and minimal cross-reactivity among closely related flaviviruses. Beyond diagnostics, selected aptamers exhibit neutralizing activity and immunomodulatory effects by interfering with host-pathogen interactions and innate immune signaling pathways.

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2026-04-29 | The inhibition mechanism of Wolbachia on mosquito-borne RNA virus replication as seen through lipid metabolism regulation.

Mosquito-borne RNA viruses, including but not limited to the dengue virus (DENV), Zika virus (ZIKV), and chikungunya virus (CHIKV), pose serious threats to global public health. Current countermeasure approaches are frequently plagued by insufficient coverage, susceptibility to drug resistance, and poor sustainability. Wolbachia, a natural symbiont within mosquitoes, has been shown to block the replication and transmission of mosquito-borne RNA viruses. In recent years, increasing attention has focused on the mechanism of its antiviral action, which involves the regulation of host lipid metabolism. Here, we systematically reviewed the mechanisms by which mosquito-borne RNA viruses disrupt normal lipid metabolism in host cells, elucidating how these viruses rely on host lipids to achieve invasion and form replication complexes. Multiple pathways of Wolbachia disrupting lipid metabolism are highlighted, including rearranging the host lipid environment, competing with viruses for key metabolic resources, regulating mitochondrial-lipid droplet interactions, and altering membrane fluidity. The translational medicine and public health applications of Wolbachia strains were explored, holding potential for advancing novel antiviral strategies based on metabolic disruption.

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2026-02-06 | Global epidemiology and evolutionary dynamics of arboviruses: A systematic review of surveillance, control strategies, and emerging threats.

Arboviral diseases, transmitted primarily by Aedes mosquitoes, represent a growing global health challenge. The spread of dengue, Zika, chikungunya, and yellow fever has been associated with factors such as climate change, urbanization, and increased global mobility. We conducted a systematic review of the literature published between January 2000 and December 2024, screening 487 studies, of which 11 met predefined inclusion criteria and were included in the final synthesis (PROSPERO registration: CRD42021231605). The review integrates evidence from epidemiological reports, molecular surveillance studies, and evaluations of control strategies across endemic and emerging regions. Findings indicate a marked geographic expansion of major arboviruses beyond traditional endemic zones, with multiple studies reporting substantial increases in incidence in temperate regions over the past two decades. Molecular analyses consistently demonstrate high genetic diversity and ongoing viral evolution, reflecting adaptation to environmental and host pressures. The review also highlights persistent challenges in disease control, including widespread insecticide resistance, uneven surveillance capacity, and limitations in vaccine deployment. Emerging interventions such as Wolbachia-based vector control, genetically modified mosquitoes, and newer dengue and chikungunya vaccines show promise but require integration within broader surveillance, health-system, and governance frameworks. Overall, the findings underscore the need for coordinated, multisectoral approaches to strengthen early detection, improve control strategies, and mitigate the growing global burden of arboviral diseases.

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2026-01-28 | The ability of alphavirus replicases to synthesize non-viral type I interferon-inducing RNAs correlates with viral RNA synthesis and has a diverse impact on virus replication and pathogenicity.

Alphaviruses have positive-strand RNA genomes that mimic cellular mRNAs, and their translation results in the synthesis of nonstructural (ns) polyprotein, the precursor of viral replicase. The ns polyprotein is processed by its protease activity to form an early replicase complex, responsible for the synthesis of negative-strand RNA that forms a double-stranded RNA (dsRNA) replication intermediate with the RNA genome. The following processing results in the formation of a late replicase complex responsible for the synthesis of positive-strand RNAs. Replication complexes are anchored to membranes, and dsRNA is shielded from cellular pattern recognition receptors. Nevertheless, alphavirus infection triggers a type I interferon response; this is partly due to the ability of replicases to utilize cellular RNAs as templates for synthesis of specific dsRNAs (rPAMPs). Here, we demonstrate that replicases of 11 alphaviruses, representing most of the antigenic complexes of alphaviruses, are all capable of rPAMP synthesis in human cells and that some replicases also do the same in mosquito cells. The levels of rPAMPs generally correlate with the efficiency of viral RNA synthesis and are increased by mutations slowing down the processing of the ns polyprotein. For different strains of Semliki Forest virus, the elevated synthesis of rPAMPs correlates with a previously reported virulent phenotype, while for mutants of chikungunya virus, the situation is reversed. Thus, synthesis of rPAMPs is a universal property of alphavirus replicases; these molecules are used to regulate virus infection, and their functional impact depends on their amount as well as the virus species.IMPORTANCEAlphaviruses are important mosquito-borne emerging pathogens. Their ability to interact with cellular defenses, including type I IFN, is crucial for infection. Here, we found that alphavirus replicases have a universal ability to synthesize type I IFN-inducing RNAs using non-viral templates, and that their synthesis varies greatly among viruses and their strains. Production of these RNAs was increased by mutations slowing down the maturation of the viral replicase. The abundance of non-viral type I IFN-inducing RNAs correlated with neurovirulence of Semliki Forest virus, indicating their role in virus pathogenicity; however, for chikungunya virus, their excess correlated with virus attenuation. These data are important to promote the understanding of mechanisms of alphavirus pathogenesis and virus interactions with the host immune system. As alphaviruses represent promising platforms for development of advanced mRNA vaccines, the data can also be used for rational optimization of alphavirus-based vaccine candidates.

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