Search Results (82)

Background: Respiratory syncytial virus (RSV) poses a significant health burden in children, being the major cause of lower respiratory tract infection (LRTI), including bronchiolitis. During the 2023–2024 RSV season, Spain introduced nirsevimab, a monoclonal antibody for universal RSV prophylaxis in infants. This study reviews the safety of nirsevimab through post-marketing surveillance. Material and Methods: A descriptive pharmacovigilance study was made based on spontaneous reporting data of suspected adverse events (SAEs) from the Spanish Pharmacovigilance System for Medicinal Products for Human Use (SEFV-H) and industry reports. SAEs reported between September 2023 and May 2024 were extracted from the Spanish Pharmacovigilance Adverse Reactions Data (FEDRA) database. Cases were analysed by sex, age, severity, and SAEs classification using the Preferred Terms (PT) level of the Medical Dictionary for Regulatory Activities (MedDRA). Reporting rates were estimated based on immunization coverage and birth data. Results: Sixty-seven cases reported 141 SAEs, yielding an overall rate of 23.1 cases per 100,000 doses. Common events included rash (8.51%), drug ineffectiveness (7.09%), and pyrexia (7.09%). Serious events constituted 53.70% of reports, including two fatalities (3.00%). No new safety signals or unexpected risks, such as antibody-dependent enhancement (ADE), were identified. Discussion: SAEs reported peaked early in the campaign, reflecting heightened reporting in new immunization programs. The safety profile aligns with clinical trial findings and regulatory expectations, confirming nirsevimab’s benefit–risk balance. Continued pharmacovigilance is critical for maintaining public trust in RSV prophylaxis. Nirsevimab demonstrated a favorable safety profile during Spain’s initial universal RSV immunization campaign in infants, supporting its continued use in reducing RSV-related morbidity. Full article

Antibody-dependent enhancement (ADE) is a well-established mechanism of pathology in several viral diseases, but its relevance in COVID-19 is not yet recognized. Although several studies in humans have shown an association between antibody responses and disease severity, long term studies addressing the presence of antibodies before infection and their neutralization capacity are needed to establish ADE. Mechanistic studies have determined that the entry of SARS-CoV-2 into host cells can be mediated by immune complexes through Fcγ receptors or by favoring ACE2 conformation. However, the impact on viral replication is not clear. There is evidence for enhancing effects of immune complexes on Fcγ receptor-mediated effector mechanisms and cytokine secretion after modulation of cell signaling in immune cells, specially by antibodies with altered glycosylation, which points to ADE that can contribute to COVID-19 pathology. However, more studies are needed to determine the impact of antibodies both in naturally infected and vaccinated subjects, which can lead to their use as a prognostic marker and increase vaccine safety. Full article

Dengue virus (DENV) threatens public health, especially in regions with tropical and subtropical climates. In 2024, the World Health Organisation reported 3.4 million confirmed dengue cases, with 16,000 severe cases and 3000 dengue-associated fatalities. The first licensed dengue vaccine, CYD-TDV (Dengvaxia^®,Sanofi-Pasteur, Paris, France), is recommended by the WHO only for individuals aged 9–45 years with a prior history of dengue infection. However, being vaccinated with Dengvaxia^® increases the risk of developing severe dengue infections in seronegative individuals. Recently, a second licensed dengue vaccine, Qdenga^®,Takeda, Singen, Germany), was approved and recommended by the WHO to be administered only in highly dengue-endemic countries, as it was not shown to elicit a robust immune response against DENV-3 and DENV-4 serotypes in dengue seronegative individuals. Due to an imbalance in immune response against all four DENV serotypes, there is a higher risk of developing the antibody-dependent enhancement (ADE) effect, which could lead to severe dengue. This review has identified mutations throughout the DENV genome that were demonstrated to attenuate the virulence of DENV in either in vitro or in vivo studies. Several amino acid residues within the DENV prM and E proteins were identified to play important roles in ADE and modifying these ADE-linked residues is important in the rational design of novel live-attenuated dengue vaccine candidates. This review provides current insights to guide the development of a novel live-attenuated tetravalent dengue vaccine candidate that is effective against all DENV serotypes and safe from ADE. The efficacy and safety of the live-attenuated vaccine candidate should be further validated in in vivo studies. Full article

VEGF-A₁₆₅-induced persistent dysfunction of the barrier formed by immortalized bovine retinal endothelial cells (iBREC) is only transiently reverted by inhibition of VEGF-A-driven signaling. As angiopoietin-2 (Ang-2) enhances the detrimental action of VEGF-A₁₆₅, we studied if binding of both growth factors by the bi-specific antibody faricimab sustainably reverts barrier impairment. Confluent monolayers of iBREC were exposed to VEGF-A₁₆₅ for one day before 10–1000 µg/mL faricimab was added for additional five days. To assess barrier function, we performed continuous electric cell–substrate impedance, i.e., cell index, measurements. VEGF-A₁₆₅ significantly lowered the cell index values which recovered to normal values within hours after the addition of faricimab. Stabilization lasted for two to five days, depending on the antagonist’s concentration. As determined by Western blotting, only ≥100 µg/mL faricimab efficiently normalized altered expression of claudin-1 and claudin-5, but all concentrations prevented further increase in plasmalemma vesicle-associated protein induced by VEGF-A₁₆₅; these proteins are involved in barrier stability. Secretion of Ang-2 by iBREC was significantly higher after exposure to VEGF-A₁₆₅, and strongly reduced by faricimab even below basal levels; aflibercept was significantly less efficient. Taken together, faricimab sustainably reverts VEGF-A₁₆₅-induced barrier impairment and protects against detrimental actions of Ang-2 by lowering its secretion. Full article

Background/Objectives: The antibody-dependent enhancement (ADE) of viral entry has been documented for SARS-CoV-2 infection both in vitro and in vivo. However, the potential for the SARS-CoV-2 vaccination to elicit similar ADE effects remains unclear. Methods: In this study, we assessed the in vitro ADE potential of monoclonal antibodies (mAbs) derived from individuals vaccinated with the inactivated SARS-CoV-2 vaccine and compared them to those from one convalescent donor. Results: Our analysis revealed no significant difference in binding affinity or neutralizing capacity between the vaccinated and convalescent mAbs. However, the inactivated SARS-CoV-2 vaccination induced fewer ADE-inducing mAbs, particularly those targeting the Class III epitope on the receptor-binding domain (RBD) compared to those from the convalescent individual. Moreover, no significant in vitro ADE was detected in either vaccinated or convalescent sera, indicating low levels of ADE-inducing antibodies in the sera. Conclusions: An inactivated SARS-CoV-2 vaccination induces fewer ADE-inducing antibodies compared to natural infection, further emphasizing the safety of inactivated SARS-CoV-2 vaccines. Full article

Virus-induced antibodies represent a dual-edged sword in the immune response to viral infections. While antibodies are critical for neutralizing pathogens, some can paradoxically exacerbate disease severity through mechanisms such as antibody-dependent enhancement (ADE), autoantibody, and prolonged inflammation. Long coronavirus disease (COVID) and dengue hemorrhagic fever (DHF) exemplify conditions where pathogenic antibodies play a pivotal role in disease progression. Long COVID is associated with persistent immune dysregulation and autoantibody production, leading to chronic symptoms and tissue damage. In DHF, pre-existing antibodies against dengue virus contribute to ADE, amplifying viral replication, immune activation, and vascular permeability. This review explores the mechanisms underlying these pathogenic antibody responses, highlighting the shared pathways of immune dysregulation and comparing the distinct features of both conditions. By examining these studies, we identify key lessons for therapeutic strategies, vaccine design, and future research aimed at mitigating the severe outcomes of viral infections. Full article

Receptors for the immunoglobulin G constant fraction (FcγRs) are widely expressed in cells of the immune system. Complement-independent phagocytosis prompted FcγR research to show that the engagement of IgG immune complexes with FcγRs triggers a variety of cell host immune responses, such as phagocytosis, antibody-dependent cell cytotoxicity, and NETosis, among others. However, variants of these receptors have been implicated in the development of and susceptibility to autoimmune diseases such as systemic lupus erythematosus. Currently, the knowledge of FcγR variants is a required field of antibody therapeutics, which includes the engineering of recombinant soluble human Fc gamma receptors, enhancing the inhibitory and blocking the activating FcγRs function, vaccines, and organ transplantation. Importantly, recent interest in FcγRs is the antibody-dependent enhancement (ADE), a mechanism by which the pathogenesis of certain viral infections is enhanced. ADEs may be responsible for the severity of the SARS-CoV-2 infection. Therefore, FcγRs have become a current research topic. Therefore, this review briefly describes some of the historical knowledge about the FcγR type I family in humans, including the structure, affinity, and mechanism of ligand binding, FcγRs in diseases such as systemic lupus erythematosus (SLE), and the potential therapeutic approaches related to these receptors in SLE. Full article

Dengue is a growing global public health challenge, with rising incidence and case fatality rates fueled by urbanization and climate change. The substantial mortality, morbidity, and economic burden associated with the disease underscore the need for effective prevention strategies, including vector control, personal protective measures, and vaccination. This narrative review provides a practical guide for clinicians to ensure the appropriate administration of dengue vaccines to at-risk groups, such as individuals in endemic regions and travelers to these areas. Live-attenuated tetravalent dengue vaccines, including Dengvaxia^®, Qdenga^®, and Butantan-DV, have demonstrated efficacy in clinical trials but require careful use due to the risk of antibody-dependent enhancement (ADE). To mitigate this risk, guidelines recommend vaccination primarily for individuals with prior confirmed dengue infection, emphasizing the importance of accessible and affordable point-of-care rapid testing. Co-administration of dengue vaccines with other live-attenuated or inactivated vaccines has been shown to be safe and immunogenic, broadening their potential application. However, live-attenuated vaccines are contraindicated for immunocompromised individuals and pregnant women. Enhancing clinician awareness, expanding diagnostic capabilities, and prioritizing high-risk populations are critical steps to optimize vaccination strategies. Combined with robust prevention programs, these efforts are essential to reducing the global burden of dengue and mitigating its impact. Full article

Antibody-dependent enhancement (ADE) is a phenomenon in which antibodies enhance subsequent viral infections rather than preventing them. Sub-optimal levels of neutralizing antibodies in individuals infected with dengue virus are known to be associated with severe disease upon reinfection with a different dengue virus serotype. For Severe Acute Respiratory Syndrome Coronavirus type-2 infection, three types of ADE have been proposed: (1) Fc receptor-dependent ADE of infection in cells expressing Fc receptors, such as macrophages by anti-spike antibodies, (2) Fc receptor-independent ADE of infection in epithelial cells by anti-spike antibodies, and (3) Fc receptor-dependent ADE of cytokine production in cells expressing Fc receptors, such as macrophages by anti-nucleocapsid antibodies. This review focuses on the Fc receptor-dependent ADE of cytokine production induced by anti-nucleocapsid antibodies, examining its potential role in severe COVID-19 during reinfection and its contribution to the post-acute sequelae of COVID-19, i.e., prolonged symptoms lasting at least three months after the acute phase of the disease. We also discuss the protective effects of recently identified anti-spike antibodies that neutralize Omicron variants. Full article

DENV belongs to the Flaviviridae family and possesses a single-stranded RNA genome of positive polarity. DENV infection manifests in mild subclinical forms or severe forms that may be dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Despite a lot of effort worldwide, the exact mechanism underlying the pathogenesis of severe DENV infection remains elusive. It is believed that both host and viral factors contribute to the outcome of dengue disease. The host factors are age at the time of infection, sex, nutrition, and immune status, including the presence of pre-existing antibodies or reactive T cells. Viral factors include the serotype, genotype, and mutation(s) due to error-prone RNA-dependent polymerase leading to the development of quasispecies. Accumulating bodies of literature have depicted that DENV has many ways to invade and escape the immune system of the host. These invading strategies are directed to overcome innate and adaptive immune responses. Like other viruses, once the infection is established, the host also mounts a series of antiviral responses to combat and eliminate the virus replication. Nevertheless, DENV has evolved a variety of mechanisms to evade the immune system. In this review, we have emphasized the strategies that DENV employs to hijack the host innate (interferon, IFN; toll-like receptors, TLR; major histocompatibility complex, MHC; autophagy; complement; apoptosis; RNAi) and adaptive (antibody-dependent enhancement, ADE; T cell immunity) immune responses, which contribute to the severity of DENV disease. Full article

Extensive research has been conducted on the SARS-CoV-2 virus in association with various infectious diseases to understand the pathophysiology of the infection and potential co-infections. In tropical countries, exposure to local viruses may alter the course of SARS-CoV-2 infection and coinfection. Notably, only a portion of the antibodies produced against SARS-CoV-2 proteins demonstrate neutralizing properties, and the immune response following natural infection tends to be temporary. In contrast, long-lasting IgG antibodies are common after dengue virus infections. In cases where preexisting antibodies from an initial dengue virus infection bind to a different dengue serotype during a subsequent infection, there is a potential for antibody-dependent enhancement (ADE) and the formation of immune complexes associated with disease severity. Both SARS-CoV-2 and dengue infections can result in immunodeficiency. Viral proteins of both viruses interfere with the host’s IFN-I signaling. Additionally, a cytokine storm can occur after viral infection, impairing a proper response, and autoantibodies against a wide array of proteins can appear during convalescence. Most of the reported autoantibodies are typically short-lived. Vaccines against both viruses alter the immune response, affecting the course of viral infection and enhancing clearance. A comprehensive analysis of both viral infections and pathogenicity is revisited to prevent infection, severity, and mortality. Full article

Respiratory infections with respiratory syncytial virus (RSV) account for an important part of hospital admissions for acute respiratory infections. Nirsevimab has been developed to reduce the hospital burden of RSV infections. Compared with the product previously used, it has a stronger binding capacity to RSV F protein and a high affinity for FcRn (neonatal receptor for the Fc fragment of IgG), which extends its lifespan. Nirsevimab has been shown to be highly effective in reducing hospitalization rates of RSV infections but a large or unknown number of treated subjects have been excluded in clinical and post-marketing studies. However, analysis of these studies cannot exclude that, in rare cases, nirsevimab facilitates and worsens RSV infection (or other respiratory infections). This could be attributable to antibody-dependent enhancement (ADE) which has been observed with RSV F protein antibodies in inactivated vaccine trials. This risk has been incompletely assessed in pre-clinical and clinical trials (incomplete exploration of nirsevimab effector functions and pharmacokinetics). ADE by disruption of the immune system (not studied and due to FcRn binding) could explain why there is no reduction in all-cause hospital admissions in treated age groups. Given the high price of nirsevimab, the cost-effectiveness of mass immunization campaigns may therefore be debated from an economic as well as a scientific point of view. Full article

Declared as a Public Health Emergency in 2016 by the World Health Organization (WHO), the Zika virus (ZIKV) continues to cause outbreaks that are linked to increased neurological complications. Transmitted mainly by Aedes mosquitoes, the virus is spread mostly amongst several tropical regions with the potential of territorial expansion due to environmental and ecological changes. The ZIKV envelope protein’s domain III, crucial for vaccine development due to its role in receptor binding and neutralizing antibody targeting, was integrated into sterically optimized AP205 VLPs to create an EDIII-based VLP vaccine. To increase the potential size of domains that can be accommodated by AP205, two AP205 monomers were fused into a dimer, resulting in 90 rather than 180 N-/C- termini amenable for fusion. EDIII displayed on AP205 VLPs has several immunological advantages, like a repetitive surface, a size of 20–200 nm (another PASP), and packaged bacterial RNA as adjuvants (a natural toll-like receptor 7/8 ligand). In this study, we evaluated a novel vaccine candidate for safety and immunogenicity in mice, demonstrating its ability to induce high-affinity, ZIKV-neutralizing antibodies without significant disease-enhancing properties. Due to the close genetical and structural characteristics, the same mosquito vectors, and the same ecological niche of the dengue virus and Zika virus, a vaccine covering all four Dengue viruses (DENV) serotypes as well as ZIKV would be of significant interest. We co-formulated the ZIKV vaccine with recently developed DENV vaccines based on the same AP205 VLP platform and tested the vaccine mix in a murine model. This combinatory vaccine effectively induced a strong humoral immune response and neutralized all five targeted viruses after two doses, with no significant antibody-dependent enhancement (ADE) observed. Overall, these findings highlight the potential of the AP205 VLP-based combinatory vaccine as a promising approach for providing broad protection against DENV and ZIKV infections. Further investigations and preclinical studies are required to advance this vaccine candidate toward potential use in human populations. Full article

Dengue virus poses a significant global health challenge, particularly in tropical and subtropical regions. Despite the urgent demand for vaccines in the control of the disease, the two approved vaccines, Dengvaxia and TV003/TV005, there are current questions regarding their effectiveness due to an increased risk of antibody-dependent enhancement (ADE) and reduced protection. These challenges have underscored the need for further development of improved vaccines for Dengue Virus. This study presents a new design using an in silico approach to generate a more effective dengue vaccine. Initially, our design process began with the collection of Dengue polyprotein sequences from 10 representative countries worldwide. And then conserved fragments of viral proteins were retrieved as the bases for epitope screening. The selection of epitopes was then carried out with criteria such as antigenicity, immunogenicity, and binding affinity with MHC molecules, while the exclusion criteria were according to their allergenicity, toxicity, and potential for antibody-dependent enhancement. We then constructed a core antigen with the selected epitopes and linked the outcomes with distinct adjuvant proteins, resulting in three candidate vaccines: PSDV-1, PSDV-2, and PSDV-3. Among these, PSDV-2 was selected for further validation due to its superior physicochemical and structural properties. Extensive simulations demonstrated that PSDV-2 exhibited strong binding to pattern recognition receptors, high stability, and robust immune induction, confirming its potential as a high-quality vaccine candidate. For its recombinant expression, a plasmid was subsequently designed. Our new vaccine design offers a promising additional option for Dengue virus protection. Further experimental validations will be conducted to confirm its protective efficacy and safety. Full article

Chikungunya virus (CHIKV) is a pathogenic arthritogenic alphavirus responsible for large-scale human epidemics for which a vaccine was recently approved for use. Mayaro virus (MAYV) is a related emerging alphavirus with epidemic potential with circulation overlap potential with CHIKV. We previously reported the ability of a non-replicating human adenovirus (AdV)-vectored vaccine expressing the MAYV structural polyprotein to protect against disease in mice following challenge with MAYV, CHIKV and UNAV. Herein, we evaluated mouse immunity and protective efficacy for an AdV-CHIKV full structural polyprotein vaccine in combination with heterologous AdV-MAYV prime/boost regimens versus vaccine coadministration. Heterologous prime/boost regimens skewed immunity toward the prime vaccine antigen but allowed for a boost of cross-neutralizing antibodies, while vaccine co-administration elicited robust, balanced responses capable of boosting. All immunization strategies protected against disease from homologous virus infection, but reciprocal protective immunity differences were revealed upon challenge with heterologous viruses. In vivo passive transfer experiments reproduced the inequity in reciprocal cross-protection after heterologous MAYV challenge. We detected in vitro antibody-dependent enhancement of MAYV replication, suggesting a potential mechanism for the lack of cross-protection. Our findings provide important insights into rational alphavirus vaccine design that may have important implications for the evolving alphavirus vaccine landscape. Full article