Dengue hemorrhagic fever is a severe health issue in many regions worldwide, caused by the dengue virus (DENV), which is primarily transmitted by Aedes aegypti, Aedes albopictus, and Aedes polynesiensis mosquitoes. According to the World Health Organization (WHO), dengue disease affect nearly 390 million people per year, with approximately 96 million experiencing clinical manifestations. The disease has expanded in terms of its geographical coverage, involving over 100 countries in tropical and subtropical regions (Bhatt et al., 2013, Cattarino et al., 2020). Severe cases of dengue, including dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), cause significant morbidity and mortality, particularly where health care is inaccessible (WHO, 2019). The recent epidemics have highlighted the growing burden on public health, underscoring the need for effective responses to these challenges.

A crucial aspect of dengue is the complex interaction between the disease and the human immune system. Initial infections with any of the four serotypes of DENV often result in mild illness and immunity to the specific serotype; subsequent infections with serotypes different from the initial one often have more severe implications. The paradoxical nature of the immune response, which can either protect against disease or exacerbate it, underscores the importance of understanding immune-mediated pathogenesis (Thomas and Yoon, 2019). The pathways involved in the development of severe dengue are antibody-dependent enhancement (ADE) mechanisms, dysregulated T-cell responses, and cytokine storms. This research paper examines the pathways and their research implications for enhancing vaccine development and future treatment procedures to mitigate dengue worldwide.

Although substantial clinical evidence exists, the mechanisms of ADE, T-cell original antigenic sin, and cytokine-mediated vascular leakage remain difficult to investigate in humans due to ethical and practical considerations. Small animal and non-human primate (NHPs) models have gained an important role. AG129 IFN-receptor-deficient mice enabled researchers to perform controlled antibody-transfer experiments, which correctly reproduced ADE-enhanced viremia and hemodynamic collapse. Humanized NSG-BLT (NOD scid gamma mice engrafted with human bone marrow, liver, and thymus) mice have enabled researchers to examine human T-cell clonotypes in vivo, and cynomolgus macaques have the capacity to recapitulate the tetravalent immune environment required for studying vaccines (Kayesh and Tsukiyama-Kohara, 2022, Keeler and Fox, 2021, Khanam et al., 2022). The importance of such models lies in their ability to consider clinically relevant factors, such as neonatal immunity, aging, obesity, and diabetes mellitus, thereby providing more accurate predictions. In this review, we integrate observations from human studies with information from other animal systems, providing standardized methodological recommendations consistent with ARRIVE (Animal Research: Reporting of in Vivo Experiments) to ensure the findings are reproducible and comply with guidelines from Human and Animal Ethics Committees.

Treatment of dengue is based on how these immune responses work, especially in relation to vaccine production and treatment regimens (Graham, 2020). With an emphasis on critical processes such as antibody-dependent enhancement (ADE) and T-cell-mediated pathogenesis, as well as the subsequent effects of these processes on the clinical management of the disease, this paper will explore the theoretical background of immunological responses to the dengue virus. The discussion of these immunological processes can provide insight into the development of effective vaccines and therapies against dengue (Petrilli et al., 2020, Villar et al., 2015). In Fig. 1, the definition of the classification of symptomatic dengue infection is provided by the WHO.

The review has linked clinical dengue immunopathology to validated animal models, providing mechanistic evidence to enhance vaccine and therapeutic design. The immunopathogenesis of dengue needs to be integrated with clinical and experimental data. This review demonstrates how proven animal models accurately replicate human immune responses, including ADE, cytokine-mediated vascular leakage, and T-cell-mediated pathology, thereby enhancing the predictive capability and safety of vaccines and therapeutics. Other integrative models have also expedited the process of discovering dengue biomarkers and preclinical vaccine studies (Hegde and Bhat, 2022, Hegde et al., 2024).