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Flaviviruses consist of significant human pathogens responsible for hundreds of millions of infections each year. Their antigenic relationships generate immune responses that are cross-reactive to multiple flaviviruses and their widespread and overlapping geographical distributions, coupled with increases in vaccination coverage, increase the likelihood of exposure to multiple flaviviruses. Depending on the antigenic properties of the viruses to which a person is exposed, flavivirus cross-reactivity can be beneficial or could promote immune pathologies. In this review we describe our knowledge of the functional immune outcomes that arise from varied flaviviral immune statuses. The cross-reactive antibody and T cell immune responses that are protective versus pathological are also addressed.

Usutu virus is a zoonotic arbovirus that causes massive mortality in blackbirds. Using a unique longitudinal dataset on the kinetics of virus-specific antibodies in naturally infected wild blackbirds (Turdus merula), we found that individual birds may remain seropositive for >1 year and that reinfection can occur despite low-level virus neutralizing antibodies.

Tembusu virus (TMUV), an emerging avian orthoflavivirus, causes severe economic losses due to egg-drop syndrome and fatal encephalitis in domestic waterfowl. To combat this threat, the host immune system plays a crucial role in controlling and eliminating TMUV infection. Understanding the mechanisms of this immune response is thus vital for developing effective strategies against the virus. In this study, we investigated the antiviral activities of duck TRIM family proteins (duTRIM) against TMUV, focusing particularly on duTRIM14 as a potent host restriction factor. We showed that overexpression of duTRIM14 significantly inhibits TMUV replication, while its deficiency leads to increased viral titers. We elucidate a novel mechanism by which duTRIM14 interacts with the TMUV NS1 protein, facilitating its K27/K29-linked polyubiquitination and subsequent proteasomal degradation. The Lys141 residue on NS1 was identified as critical for this process, with its removal significantly enhancing TMUV replication both in vitro and in vivo . Furthermore, we showed that duTRIM14 interacts with duck TBK1 (duTBK1), promoting its K63-linked polyubiquitination on Lys30 and Lys401, which substantially augments IFN-β production during TMUV infection. Taken together, these results provide a novel dual-action antiviral mechanism in which duTRIM14 suppresses TMUV replication by simultaneously promoting proteasomal degradation of NS1 and enhancing the host antiviral response by modulating duTBK1 activity.

Studies have demonstrated cross-reactivity of anti-dengue virus (DENV) antibodies in human sera against Zika virus (ZIKV), promoting increased ZIKV infection in vitro. However, the correlation between in vitro and in vivo findings is not well characterized. Thus, we evaluated the impact of heterotypic flavivirus immunity on ZIKV titers in biofluids of rhesus macaques. Animals previously infected (≥420 days) with DENV2, DENV4, or yellow fever virus were compared to flavivirus-naïve animals following infection with a Brazilian ZIKV strain. Sera from DENV-immune macaques demonstrated cross-reactivity with ZIKV by antibody-binding and neutralization assays prior to ZIKV infection, and promoted increased ZIKV infection in cell culture assays. Despite these findings, no significant differences between flavivirus-naïve and immune animals were observed in viral titers, neutralizing antibody levels, or immune cell kinetics following ZIKV infection. These results indicate that prior infection with heterologous flaviviruses neither conferred protection nor increased observed ZIKV titers in this non-human primate ZIKV infection model.

Accurate serological tools are essential for monitoring the transmission of arboviruses with pandemic potential, yet cross-reactivity between closely related viruses hampers diagnostics and surveillance. Here, we develop a high-throughput multiplex serological assay to quantify antibody responses to 28 antigens from nine arboviruses (dengue, Zika, yellow fever, West Nile, Usutu, Japanese encephalitis, chikungunya (CHIKV), Mayaro (MAYV), and O’nyong-nyong virus) and apply it to over 4000 samples from epidemiologically distinct sites on four continents. We implement a flexible analytical method based on Bayesian finite mixture models and Receiver Operating Characteristic analysis to evaluate assay performance and define seropositivity thresholds. As a case study, we resolve cross-reactive and virus-specific responses for CHIKV and the emerging MAYV by combining competitive immunoassays with mathematical modelling of multiplex serological and epidemiological data. This approach yields cross-reactivity-adjusted estimates of local transmission dynamics, in agreement with existing epidemiological evidence, and reveals that CHIKV is more prone to induce cross-reactive antibody responses than MAYV. Our results demonstrate the power of combining multiplex serology with experimental validation and modelling to disentangle exposure histories in the face of serological cross-reactivity. This integrative approach holds promise for improving arbovirus surveillance, particularly in settings with overlapping transmission of multiple viruses and limited diagnostic capacity. Arboviruses often co-circulate, but cross-reactivity hampers serological diagnostics. Here, the authors paired multiplex serology with competitive immunoassays and Bayesian modelling to quantify antibody cross-reactivity and extract virus-specific signals from exposure data, enabling reconstruction of transmission dynamics.

Mosquito-borne flaviviruses, including Dengue virus (DENV), Japanese encephalitis virus (JEV), West Nile virus (WNV), Yellow fever virus (YFV), and Zika virus (ZIKV), continue to present a significant threat to public health worldwide. In 2024, these viruses accounted for 11,717 reported cases in the United States and more than 7.6 million cases globally. As of early 2025, according to CDC data, 1830 cases of dengue had already been reported, with 1584 transmitted locally within the U.S. Despite the considerable burden that these diseases pose, no specific antiviral treatments exist. A very limited number of virus-specific vaccines have been licensed, such as those for YFV, JEV, and, with specific constraints, for DENV. To date, no pan-flavivirus vaccine is available. This review examines the potential of emerging vaccine platforms—particularly messenger RNA and virus-like particles—as promising tools in the pursuit of a broadly protective flavivirus vaccine. We analyze current strategies for inducing cross-neutralizing immune responses and discuss how these technologies could support the presentation of conserved quaternary epitope conformations, which are increasingly recognized as critical targets for establishing potent immune responses. We review key advances in virology, immune response, and immunogen delivery systems to highlight the potential for developing a pan-flavivirus vaccine.

The complement system is a key component of innate immunity which readily responds to invading microorganisms. Activation of the complement system typically occurs via three main pathways and can induce various antimicrobial effects, including: neutralization of pathogens, regulation of inflammatory responses, promotion of chemotaxis, and enhancement of the adaptive immune response. These can be vital host responses to protect against acute, chronic, and recurrent viral infections. Consequently, many viruses (including dengue virus, West Nile virus and Nipah virus) have evolved mechanisms for evasion or dysregulation of the complement system to enhance viral infectivity and even exacerbate disease symptoms. The complement system has multifaceted roles in both innate and adaptive immunity, with both intracellular and extracellular functions, that can be relevant to all stages of viral infection. A better understanding of this virus-host interplay and its contribution to pathogenesis has previously led to: the identification of genetic factors which influence viral infection and disease outcome, the development of novel antivirals, and the production of safer, more effective vaccines. This review will discuss the antiviral effects of the complement system against numerous viruses, the mechanisms employed by these viruses to then evade or manipulate this system, and how these interactions have informed vaccine/therapeutic development. Where relevant, conflicting findings and current research gaps are highlighted to aid future developments in virology and immunology, with potential applications to the current COVID-19 pandemic.

Interferon-stimulated genes (ISGs) play a pivotal role in the innate immune response to viral infection. Among them, SAMD9 and its paralog SAMD9L have recently emerged as important antiviral effectors with translation-inhibitory activity. While both proteins restrict poxvirus, rotavirus and reovirus replication, only SAMD9L has been shown to inhibit HIV and other lentiviruses. In this study, we identify human SAMD9L as a potent and broad-spectrum restriction factor that targets multiple medically relevant flaviviruses, including West Nile virus (WNV), Zika virus (ZIKV), dengue virus (DENV), and Usutu virus (USUV). Exogenous expression of SAMD9L, but not SAMD9, efficiently suppressed replication of all tested flaviviruses. Furthermore, its knockdown in human myeloid cells, including microglial cells and primary macrophages, impaired the antiviral activity of type I interferon, identifying SAMD9L as a key antiviral ISG in primary target cells of flavivirus infection. Mechanistically, we demonstrate that SAMD9L inhibits viral replication by targeting the translation of flaviviral RNA, and that this activity depends on its Schlafen-like ribonuclease domain, previously implicated in the inhibition of HIV-1 translation. Interestingly, although SAMD9 does not inhibit flavivirus replication, it is able to repress the translation of flaviviral RNA outside the context of infection, suggesting that its activation may be virus-specific or that flaviviruses have evolved mechanisms to evade or counteract SAMD9's antiviral activity. Finally, we confirm that SAMD9 and SAMD9L overexpression induces activation of the innate immune response. However, this immunostimulatory function is dispensable for SAMD9L-mediated antiviral activity, since SAMD9L is able to restrict flavivirus replication independently of innate immune activation. Together, our findings broaden the known antiviral repertoire of SAMD9L, establish its essential role in restricting flavivirus replication via translational repression, and highlight its function as a key component of the cellular defenses against flaviviruses in myeloid cells.

Due to their widespread geographic distribution and frequent outbreaks, mosquito-borne flaviviruses, such as DENV (DENV), Zika virus (ZIKV), Japanese encephalitis virus (JEV), yellow fever virus (YFV), and West Nile virus (WNV), are considered significant global public health threats and contribute to dramatic socioeconomic imbalances worldwide. The global prevalence of these viruses is largely driven by extensive international travels and ecological disruptions that create favorable conditions for the breeding of Aedes and Culex species, the mosquito vectors responsible for the spread of these pathogens. Currently, vaccines are available for only DENV, YFV, and JEV, but these face several challenges, including safety concerns, lengthy production processes, and logistical difficulties in distribution, especially in resource-limited regions, highlighting the urgent need for innovative vaccine approaches. Nucleic acid-based platforms, including DNA and mRNA vaccines, have emerged as promising alternatives due to their ability to elicit strong immune responses, facilitate rapid development, and support scalable manufacturing. This review provides a comprehensive update on the progress of DNA and mRNA vaccine development against mosquito-borne flaviviruses, detailing early efforts and current strategies that have produced candidates with remarkable protective efficacy and strong immunogenicity in preclinical models. Furthermore, we explore future directions for advancing nucleic acid vaccine candidates, which hold transformative potential for enhancing global public health.

Flaviviruses, including Dengue virus (DENV), Zika virus (ZIKV) and Japanese encephalitis virus (JEV), remain major global health threats, and currently, there are no widely available vaccines for humans. The fusion loop region of the flavivirus envelope protein plays a crucial role in eliciting neutralizing antibodies and providing protection against secondary DENV infections. However, these antibodies often exhibit dual functionalities, with both neutralizing and enhancing activities, posing a challenge for vaccine development. In this study, we focused on optimizing the fusion loop epitope as the primary immunogen and incorporated the adjacent bc loop which we had reported previously as a complementary element, aiming to enhance the immunogen capable of robust neutralization and protection without inducing the risk of antibody-dependent enhancement (ADE). This newly designed immunogen was named as muBCFL which comprises sequences spanning from amino acid 69 to 116 primarily on DENV-2 envelope protein, along with four specific mutations (T76A, W101A, G106Q, and L107D). The synthesized muBCFL peptide elicited neutralizing antibodies against all four DENV serotypes, ZIKV, and JEV, with particularly strong neutralization activity against DENV-2, ZIKV, and JEV. Besides, compared to pre-immune sera, muBCFL-immune sera significantly reduced viremia levels in DENV- or ZIKV-infected AG129 mice and increased the survival rates of JEV-challenged ICR mice. Furthermore, in vitro and in vivo ADE assays validated that muBCFL-immune sera did not induce ADE compared with the control 4G2 monoclonal antibody. These findings indicated that the muBCFL sequence holds great potential as a safe and effective immunogen for developing a flavivirus vaccine in the future.