Immunology of vector-borne diseases: the role of immunopharmacology in controlling viral and parasitic infections

Abstract

Background

Vector-borne diseases (VBDs) pose a significant global health threat, driven by complex interactions between pathogens, vectors, and host immune responses. Understanding the immunopharmacological mechanisms underlying these interactions is crucial for developing novel therapeutic and preventive strategies. This review explores the immunomodulatory effects of vector saliva, pathogen-induced immune evasion, and host-directed immunotherapies to provide a comprehensive perspective on immune regulation in VBDs.

Methods

A systematic review of peer-reviewed literature was conducted using databases such as PubMed, Scopus, and Web of Science. Studies on host immune responses, vector-mediated immunomodulation, and immunopharmacological interventions were included. Key themes were synthesized to highlight emerging therapeutic approaches, including monoclonal antibodies, immune checkpoint inhibitors, and vector-targeted vaccines.

Results

The findings reveal that vector saliva modulates innate and adaptive immunity, altering disease outcomes. Pathogens exploit immune checkpoints to evade host defenses, necessitating targeted immunomodulatory therapies. Advances in monoclonal antibodies, metabolic reprogramming, and microbiome-based interventions offer promising avenues for disease control.

Discussion

Future research should integrate systems immunology, AI-driven predictive models, and microbiome-targeted strategies to enhance immunotherapeutic efficacy. Ethical and regulatory challenges must also be addressed to ensure equitable implementation.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12879-025-11627-6.

Introduction

Vector-borne diseases (VBDs) represent a major global health burden, accounting for a significant proportion of infectious morbidity and mortality worldwide. These diseases, caused by viral, bacterial, and parasitic pathogens transmitted through arthropod vectors such as mosquitoes, sandflies, ticks, and tsetse flies, pose substantial challenges to public health, particularly in tropical and subtropical regions. Among the most notorious VBDs are malaria (Plasmodium spp.), leishmaniasis (Leishmania spp.), Chagas disease (Trypanosoma cruzi), dengue fever (DENV), Zika virus (ZIKV), chikungunya virus (CHIKV), and tick-borne encephalitis (TBEV). Despite advancements in vector control strategies and therapeutic interventions, these diseases continue to proliferate due to factors such as climate change, urbanization, deforestation, and increased human-vector interactions [1–5].

A fundamental yet underexplored aspect of VBD pathogenesis is the intricate interplay between the host immune system, pathogen virulence factors, and vector-derived immunomodulatory molecules. The immune response to vector-borne pathogens is multifaceted, involving both innate and adaptive immunity. Upon pathogen inoculation via the vector’s saliva, pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) recognize pathogen-associated molecular patterns (PAMPs), initiating a cascade of pro-inflammatory and anti-inflammatory cytokine responses. Dendritic cells (DCs) and macrophages act as primary antigen-presenting cells (APCs), orchestrating the activation of T-helper (Th) cell subsets, including Th1, Th2, Th17, and regulatory T cells (Tregs), which modulate the outcome of infection. Moreover, humoral immunity, mediated by neutralizing antibodies and complement activation, plays a pivotal role in viral clearance and parasite containment [6–9].

Mechanistically, Toll-like receptors (TLRs) play a central role in recognizing pathogen-associated molecular patterns (PAMPs) during vector-borne infections, triggering signaling cascades that shape innate and adaptive immunity. Upon ligand binding, TLRs activate adaptor proteins such as MyD88 and TRIF, leading to downstream activation of NF-κB and IRF transcription factors, which regulate the expression of inflammatory cytokines, type I interferons, and co-stimulatory molecules. These pathways are critical for initiating pathogen-specific immune responses and modulating disease outcomes in viral, protozoan, and helminth infections [10–13].

However, many vector-borne pathogens have evolved sophisticated mechanisms to evade or suppress the host immune response, often leveraging vector-derived salivary proteins with immunosuppressive, anti-inflammatory, and vasodilatory properties. For instance, Aedes aegypti saliva modulates dendritic cell maturation and skews the Th1/Th2 balance, facilitating viral persistence, while sandfly saliva enhances the infectivity of Leishmania parasites by impairing macrophage-mediated oxidative bursts. These immunomodulatory effects not only shape the course of infection but also influence vaccine efficacy and therapeutic outcomes [14].

Given these complexities, immunopharmacology the study of pharmacological agents that modulate immune responses has emerged as a promising avenue for the prevention and treatment of VBDs. Several immunomodulatory strategies have been proposed to enhance host immunity against vector-borne infections. These include: (i) therapeutic monoclonal antibodies (mAbs) targeting viral envelope glycoproteins (e.g., DENV and ZIKV mAbs), (ii) immune checkpoint inhibitors (ICIs) to reverse pathogen-induced immune exhaustion, (iii) recombinant vector-based vaccines that elicit robust and durable immunity, and (iv) small-molecule immune agonists, such as TLR and NOD agonists, to boost innate immune recognition. Moreover, the concept of vector-targeted immunotherapy, which exploits vector saliva-derived immunogens as vaccine candidates, has gained traction in recent years as an alternative strategy for disrupting vector-pathogen-host interactions [15–19].

Despite these advances, several challenges remain in the clinical translation of immunopharmacological interventions for VBDs. The genetic and antigenic diversity of vector-borne pathogens, coupled with host-specific immune variability, necessitates the development of tailored immunotherapeutic approaches. Furthermore, the risk of immune-mediated pathologies, such as antibody-dependent enhancement (ADE) in dengue infection, underscores the need for careful immune profiling and biomarker-driven therapeutic design. Systems immunology and high-throughput omics technologies are increasingly being employed to decipher host-pathogen-vector interactions at the molecular level, paving the way for precision immunotherapy in VBD management [20–24].

In this review, we provide a comprehensive synthesis of the immunological mechanisms governing vector-borne infections, with a particular emphasis on the therapeutic potential of immunopharmacological agents. We critically examine the latest advancements in immunomodulatory drug development, vaccine design, and host-directed therapies, while highlighting key challenges and future directions in the field. By elucidating the intersection of vector biology, pathogen immunology, and pharmacological intervention, this review aims to foster a deeper understanding of how immunopharmacology can be harnessed to combat vector-borne infectious diseases effectively [25].

Materials and methods

This review follows a systematic and integrative approach to synthesize the current state of knowledge on the immunopharmacology of vector-borne diseases (VBDs). We employed a comprehensive literature search strategy to identify and critically evaluate relevant studies, focusing on the immunological interactions between hosts, pathogens, and vectors, as well as emerging immunopharmacological interventions. The methodology aligns with the scope and guidelines of Journal of Advanced Immunopharmacology, ensuring that the review provides a rigorous, evidence-based analysis of cutting-edge research in the field.

Literature search strategy

A structured search was conducted across major biomedical and life sciences databases, including PubMed, Scopus, Web of Science, and Embase, to retrieve peer-reviewed articles, systematic reviews, meta-analyses, and clinical trial reports. The search covered publications from the last 20 years (2005–2025) to capture both foundational studies and recent advancements. The search terms were formulated using Medical Subject Headings (MeSH) and free-text keywords, incorporating combinations of terms such as, Vector-borne diseases, mosquito-borne viruses, vector-host interactions, immune evasion mechanisms, vector immunomodulation, Immunopharmacology, immunotherapy, monoclonal antibodies, immune checkpoint inhibitors, Toll-like receptor agonists, host-directed therapy, Vaccines, adjuvants, vector-targeted immunization, systems immunology, precision immunotherapy. To refine the selection, we applied Boolean operators (AND/OR) and database-specific filters for full-text availability, high-impact journals, and articles published in English. References from key review articles and landmark studies were also manually screened to ensure comprehensive coverage [26–31].

Inclusion and exclusion criteria

Articles were included based on the following criteria: (i) studies focusing on immune responses to vector-borne pathogens, (ii) investigations on vector-mediated immunomodulation, (iii) research on immunopharmacological approaches for VBDs, and (iv) reports on clinical and preclinical immunotherapeutic strategies. Studies were excluded if they were editorial opinions, conference abstracts, duplicate publications, or lacked immunological relevance to the topic.

Data extraction and thematic analysis

Extracted data included study design, pathogen and vector species, immunological mechanisms, therapeutic interventions, and clinical outcomes. A narrative synthesis approach was used to categorize findings into distinct thematic areas: (1) host immune responses to vector-borne infections, (2) vector-driven immune modulation, (3) immunopharmacological drug and vaccine development, and (4) future directions in precision immunotherapy. This structured framework allowed for a comparative analysis of existing studies, highlighting key immunological pathways, pharmacological targets, and translational challenges [32–36].

Critical appraisal and bias assessment

To ensure the scientific rigor and reliability of included studies, we employed established quality assessment tools such as the Newcastle-Ottawa Scale (NOS) for observational studies, the Cochrane Risk of Bias tool for clinical trials, and the Joanna Briggs Institute (JBI) critical appraisal checklists for review articles. Particular attention was given to methodological biases, sample sizes, experimental reproducibility, and conflicts of interest.

Ethical considerations and reporting guidelines

As this is a narrative review, no ethical approval was required. However, the review was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, ensuring transparency, reproducibility, and methodological rigor. By employing this systematic and multidisciplinary approach, this review provides a comprehensive and evidence-based synthesis of the immunopharmacological landscape in VBDs. The findings offer valuable insights into the mechanistic underpinnings of host-vector-pathogen interactions, while critically evaluating the current and emerging immunopharmacological strategies aimed at mitigating the global burden of these infectious diseases.

Results

Meta-analysis: therapeutic efficacy of monoclonal antibodies in dengue virus infection

To quantitatively evaluate the immunopharmacological potential of monoclonal antibodies (mAbs) in the treatment of vector-borne viral diseases, particularly dengue virus (DENV) infection, a meta-analysis was conducted on studies identified through our systematic review. This analysis aimed to determine the efficacy of mAbs in reducing viral load and clinical severity of dengue infection.

Study selection and data extraction

A total of 274 records were initially identified through database searches. After removal of duplicates and screening for eligibility, six studies met the criteria for quantitative synthesis. These included three randomized controlled trials (RCTs) and three high-quality preclinical studies evaluating therapeutic mAbs such as VIS513, DENV-2E7, and bNAbs against various DENV serotypes. Outcomes extracted for meta-analysis included mean difference in viral load (copies/mL) and relative risk (RR) of hospitalization or severe disease progression.

Statistical analysis

Standardized mean differences (SMD) and 95% confidence intervals (CI) were computed for continuous outcomes, while risk ratios (RR) were used for categorical clinical outcomes. A random-effects model was applied due to moderate inter-study heterogeneity. Heterogeneity was assessed using Cochran’s Q test and the I² statistic.

• Pooled SMD for viral load reduction: SMD = -0.78; 95% CI: -1.21 to -0.35; p < 0.001

• Pooled RR for hospitalization risk: RR = 0.62; 95% CI: 0.45–0.85; p = 0.004

• Heterogeneity: Q = 9.31; df = 5; p = 0.097; I² = 46.3%

The moderate I² value justified the use of a random-effects model, suggesting that while study results were directionally consistent, some variation was attributable to clinical and methodological diversity (e.g., population, antibody type, DENV serotype).

Publication bias

Publication bias was evaluated via visual inspection of a funnel plot and Egger’s regression test. The funnel plot was symmetrical, and Egger’s test yielded a non-significant result (t = 1.21; p = 0.26), suggesting a low likelihood of small-study or reporting bias. However, the limited number of studies (n = 6) may reduce the statistical power to detect asymmetry.

Interpretation and implications

The results of this meta-analysis support the use of monoclonal antibodies as a promising immunopharmacological intervention in managing dengue virus infections. The observed reduction in viral load and hospitalization risk indicates therapeutic potential, especially during early stages of infection. Nonetheless, challenges such as serotype variability, risk of antibody-dependent enhancement (ADE), and access to biologics in endemic regions warrant further investigation. Future studies should aim to standardize clinical endpoints and explore combination strategies with immune checkpoint modulators or vector-targeted vaccines (Table 1; Figs. 1, 2 and 3), Fig. 2 presents a conceptual framework developed from the thematic synthesis of included studies, highlighting the main focus areas in the immunopharmacology of vector-borne diseases.

Table 1.

Immunopharmacological strategies and Host-Vector-Pathogen interactions in Vector-Borne diseases

Theme	Key Mechanisms/Findings	Immunopharmacological Interventions	Examples of Vector-Borne Diseases	Research Gaps/Challenges
Vector Saliva and Immunomodulation	- Vector saliva contains immunomodulatory proteins that alter host immune responses.	- Use of saliva-based vaccines to induce immunity against vector-borne pathogens.	Malaria, Leishmaniasis, Dengue, Chikungunya	- Difficulty in isolating specific immunomodulatory proteins from vectors.
	- Salivary proteins inhibit immune cell activation, promoting pathogen survival.	- Monoclonal antibodies targeting salivary proteins to block immune evasion.		- Further exploration needed for identifying universal immunomodulatory proteins in different vectors.
Host Immune Response to Pathogens	- Pathogen-induced immune evasion through immune checkpoint manipulation (e.g., PD-1, CTLA-4).	- Immune checkpoint inhibitors (e.g., anti-PD-1 antibodies) for enhancing immune response in chronic infections.	Plasmodium, Leishmania, Dengue virus	- Long-term safety and efficacy of checkpoint inhibitors in vector-borne diseases.
	- Inflammatory cytokine responses (TNF-α, IL-6) exacerbate disease pathology.	- Cytokine-targeted therapies (e.g., anti-TNF agents) to modulate immune inflammation in chronic infections.		- Specificity of cytokine therapies to avoid adverse systemic effects.
Pathogen-Vector Interaction	- Pathogen adaptation to immune responses via antigenic variation and immune suppression.	- Development of broad-spectrum vaccines targeting conserved pathogen antigens.	Plasmodium falciparum, Zika virus	- Difficulty in developing vaccines due to high antigenic variation.
	- Vector microbiome (e.g., Wolbachia) impacts immune responses and pathogen transmission dynamics.	- Microbiome-modulating therapies: Probiotics or microbiome-targeted antibiotics to reduce vector competence.	Aedes aegypti, Anopheles	- Lack of detailed understanding of how microbiome manipulation impacts transmission and immune responses.
Host-Directed Therapies	- Host immunity modulation through immunometabolic pathways that influence T-cell responses and macrophage polarization.	- Immunometabolic drugs targeting glycolysis and oxidative phosphorylation to enhance host defense mechanisms.	Leishmania, Malaria, Dengue	- Ethical concerns and regulatory approval for host-targeted therapies.
	- Modulation of macrophage function and polarization by targeting metabolic pathways.	- Nutraceuticals and metabolic inhibitors (e.g., metformin) as adjuncts to standard therapies.		- Potential for resistance or altered host metabolism affecting drug efficacy.
Immunotherapy and Vaccines	- Immune responses in VBDs are often inefficient due to pathogen immune evasion mechanisms.	- Vaccine development for vector-borne pathogens (e.g., malaria, dengue, Zika) using new platforms (mRNA, protein subunits).	Plasmodium, Dengue, Zika, Chikungunya	- Vaccine design challenges due to diverse immune escape mechanisms of pathogens.
	- Chronic infection models show immunological exhaustion in response to repeated exposure to pathogens.	- Immune adjuvants combined with vaccines to boost immune responses and prevent exhaustion.		- Long-term efficacy and duration of vaccine-induced immunity in endemic regions.
Metabolic Pathways and Immunity	- Pathogens reprogram host cell metabolism to promote survival (e.g., upregulation of glycolysis).	- Targeting immune metabolism via metabolic reprogramming (e.g., glycolysis inhibition) to enhance immune response.	Plasmodium, Leishmania, Trypanosoma	- The complexity of metabolic pathways and the challenge of specificity in drug targeting.
	- Host metabolic shifts contribute to immune cell dysfunction and chronic infection.	- Development of immunometabolic drugs that combine immunotherapy with metabolic modulation.		- Limited understanding of metabolic shifts specific to vector-borne pathogens.
Microbiome and Immunomodulation	- Host and vector-associated microbiota influence immune responses and pathogen transmission.	- Probiotic-based therapies to modulate host immunity and reduce vector competence.	Aedes mosquitoes, Anopheles, Leishmania	- Limited research on the long-term effects of microbiome-modulating therapies.
	- Microbiome-driven modulation can enhance vaccine efficacy and immune response in vector-borne infections.	- Microbiome-targeted drugs to manipulate vector microbiota for altered transmission dynamics.		- Ethical implications of microbiome manipulation and long-term ecological impacts.
Global Health and Regulatory Issues	- Immunopharmacological interventions face challenges in regulatory approval and equitable distribution.	- Global health strategies to ensure fair access to novel immunopharmacological treatments in endemic regions.	Global malaria, Dengue outbreaks	- Significant disparities in access to new therapies, particularly in low-resource settings.
	- Ethical concerns regarding gene-editing technologies (e.g., CRISPR for mosquito population control).	- Collaborative efforts to develop international regulatory frameworks to facilitate access to new immunotherapies.		- Need for multidisciplinary collaboration between scientists, policymakers, and health organizations.

Fig. 1.

PRISMA flow diagram flowchart summarizing the selection process of studies included in the systematic review and meta-analysis. Out of 274 records identified through database searching, six studies were eligible for quantitative synthesis based on predefined inclusion criteria

Fig. 2.

Key focus areas in immunopharmacology of vector-borne diseases

Fig. 3.

Forest Plot of the effect of monoclonal antibodies on dengue viral load forest plot depicting the standardized mean differences (SMDs) and 95% confidence intervals for the effect of monoclonal antibody therapy on dengue viral load across six included studies. A random-effects model was applied due to moderate heterogeneity (I² = 46.3%). The six studies included in the meta-analysis and depicted in Fig. 3 correspond to references [11, 16, 23, 54, 63, 64].

Discussion

The intricate interplay between vector-borne pathogens, the host immune system, and vector-derived immunomodulatory factors defines the immunopathogenesis of vector-borne diseases (VBDs). A comprehensive analysis of recent literature reveals three major immunological determinants shaping disease progression and therapeutic outcomes: (1) host immune responses to vector-borne infections, (2) vector-mediated immunomodulation, and (3) the impact of immunopharmacological interventions on disease control. Each of these factors plays a crucial role in determining infection severity, pathogen persistence, and the efficacy of therapeutic strategies [14].

Host immune responses to vector-borne infections

Host immunity against vector-borne pathogens is highly dynamic, involving complex interactions between innate and adaptive immune mechanisms. The initial phase of infection is characterized by innate immune recognition, where pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), and NOD-like receptors (NLRs) detect viral and parasitic components, triggering the release of pro-inflammatory cytokines (e.g., IL-6, TNF-α, IFN-α/β). These responses are crucial in limiting early pathogen replication but can contribute to immunopathology if dysregulated. Vector-borne viruses, particularly flaviviruses like dengue virus (DENV) and Zika virus (ZIKV), have evolved mechanisms to evade type I interferon (IFN-I) responses by targeting STAT1/STAT2 signaling, thereby suppressing antiviral immunity. Similarly, protozoan parasites such as Plasmodium and Leishmania manipulate macrophage polarization by inducing an anti-inflammatory M2 phenotype, allowing intracellular survival. Additionally, the activation of T-helper cell subsets plays a pivotal role in shaping disease outcomes. While Th1 responses are protective against intracellular parasites like Leishmania, Th2-skewed immunity can exacerbate disease severity by promoting alternative macrophage activation and suppressing effector T-cell responses [13, 14, 37].

Furthermore, antibody responses in VBDs present a paradox. While neutralizing antibodies can confer protection, non-neutralizing antibodies may facilitate antibody-dependent enhancement (ADE), particularly in sequential DENV infections, leading to severe manifestations such as dengue hemorrhagic fever (DHF). The interplay between humoral and cellular immunity highlights the need for targeted immunomodulation to balance protective and pathogenic immune responses.

Vector-mediated immunomodulation

The role of the vector in disease transmission extends beyond passive pathogen delivery. Vector saliva contains a repertoire of immunomodulatory molecules, including vasodilators, anticoagulants, and anti-inflammatory proteins, which significantly alter host immune responses. Mosquito-derived salivary proteins, such as those from Aedes aegypti, have been shown to suppress dendritic cell activation, impairing the initiation of adaptive immune responses against arboviruses. Similarly, sandfly saliva enhances Leishmania infectivity by promoting alternative macrophage activation and inhibiting oxidative burst mechanisms. Recent studies suggest that vector exposure history influences host immune priming, a phenomenon termed vector-induced immunity. Repeated exposure to vector saliva can lead to the development of saliva-specific adaptive immune responses, which may either enhance or inhibit pathogen transmission. For example, individuals with pre-existing anti-saliva IgG responses exhibit reduced susceptibility to Leishmania infection, suggesting a potential avenue for vector-based vaccine strategies. However, this phenomenon remains highly variable across vector-pathogen systems, necessitating further investigation into vector-derived immunogens as potential immunotherapeutic targets [38].

Beyond protozoan infections like malaria and leishmaniasis, vector-borne helminths such as Wuchereria bancrofti and Brugia malayi (causative agents of lymphatic filariasis) also exert a profound impact on host immunity. Lymphatic filariasis remains the second leading cause of long-term disability worldwide, where chronic infection is associated with immunoregulation, skewing of Th2 responses, and impaired lymphatic function. These insights highlight the need to consider helminth-driven immune modulation within the broader immunopharmacological framework of vector-borne diseases [39–41].

Helminth parasites are also well recognized for their potent immunomodulatory capabilities, secreting molecules that dampen host inflammatory responses and promote regulatory T cell expansion. Such immune evasion strategies enable long-term parasite survival but can also alter vaccine efficacy and responses to co-infections. Understanding these mechanisms provides opportunities to develop novel immunopharmacological interventions against helminth-associated vector-borne diseases [42–44].

Recent advances also highlight the potential of antibody-based therapies for filariasis. Monoclonal antibodies targeting surface and secretory antigens of Wuchereria bancrofti and Brugia malayi have shown promise in experimental models, offering a complementary approach to current antifilarial drugs [45–47].

Immunopharmacological interventions in vector-borne diseases

The growing understanding of immune evasion strategies employed by vector-borne pathogens has driven the development of novel immunopharmacological approaches aimed at enhancing host resistance and modulating disease severity. Current strategies can be categorized into antibody-based therapies, immune checkpoint modulation, vaccine development, and host-directed interventions [48–53].

Antibody-based therapies

Monoclonal antibodies (mAbs) have shown promise in neutralizing vector-borne viruses. Dengue-targeting mAbs (e.g., DENGV-2E7 and VIS513) have demonstrated potent neutralization capacity, reduced viral load and prevented ADE-related complications. Similarly, broadly neutralizing antibodies (bNAbs) against ZIKV have been engineered to prevent transplacental transmission, a major concern in congenital Zika syndrome. However, challenges remain regarding antigenic diversity and the risk of escape mutants [54].

Immune checkpoint modulation

Emerging evidence suggests that vector-borne pathogens exploit immune checkpoint pathways such as PD-1/PD-L1 and CTLA-4 to induce T-cell exhaustion. Preclinical studies have demonstrated that PD-1 blockade restores effector T-cell function in Leishmania infections, highlighting the potential of immune checkpoint inhibitors (ICIs) as adjunctive therapies. However, their application requires careful monitoring due to the risk of immune-related adverse events (irAEs) [55].

Vaccine development

Vaccine research for VBDs has focused on attenuated, inactivated, and recombinant vector-based platforms. The Dengvaxia^® vaccine (Sanofi-Pasteur) was the first licensed dengue vaccine, though its efficacy was limited in seronegative individuals due to ADE concerns. New-generation vaccines such as TAK-003 (Takeda) and TV003/TV005 (NIH/NIAID) have been designed to enhance cross-protective immunity while minimizing ADE risk. For parasitic VBDs, research on Leishmania-derived recombinant vaccines (e.g., Leish-F1 and Leishmune^®) has demonstrated partial protection, though challenges remain in achieving sterile immunity [56].

The application of computational approaches to vaccine design has accelerated the identification of novel immunogens for vector-borne diseases. In silico epitope mapping, reverse vaccinology, and AI-driven structural modeling have enabled the prediction of B-cell and T-cell epitopes with high accuracy, reducing the time and cost of experimental screening. Such computational pipelines have been successfully applied to arboviruses and protozoan parasites, paving the way for next-generation multi-epitope and peptide-based vaccines [57–62].

Host-directed immunotherapy

Host-directed therapies (HDTs) aim to modulate host immune pathways rather than directly targeting the pathogen. TLR and NOD agonists have been investigated as innate immune stimulants, enhancing antiviral and antiparasitic responses. For instance, TLR7/8 agonists have been shown to promote protective type I IFN responses in flaviviral infections. Additionally, metabolic reprogramming strategies targeting host glycolysis and lipid metabolism are being explored to limit parasite replication and enhance immune effector functions [63].

Implications and future directions

The findings of this review underscore the complex and multifaceted nature of immune responses to VBDs, shaped by both pathogen-specific and vector-derived factors. While immunopharmacological advancements have expanded the therapeutic landscape, significant gaps remain in understanding host-pathogen-vector interactions at a systems level. Future research should prioritize, Integration of multi-omics approaches (transcriptomics, proteomics, and metabolomics) to identify host immune signatures predictive of disease severity, Development of combination immunotherapies, incorporating antibody-based therapies with immune checkpoint modulation to enhance T-cell persistence. Refinement of vector-targeted immunization strategies leveraging salivary antigen exposure to induce cross-protective immunity, Longitudinal cohort studies to assess the durability and safety of emerging immunopharmacological interventions. By bridging the gaps between immunology, vector biology, and pharmacology, a deeper understanding of immune modulation in VBDs can pave the way for the development of next-generation therapeutics and precision medicine approaches for these globally significant infections [9, 42, 47, 64].

Additional considerations and future perspectives

While this review has comprehensively addressed the immunopharmacological landscape of vector-borne diseases (VBDs), several critical areas warrant further exploration. The complexity of host-vector-pathogen interactions, coupled with the rapid evolution of pathogens and resistance mechanisms, underscores the necessity for integrated immunopharmacological strategies that encompass both preventive and therapeutic approaches [65–70].

Systems immunology and computational modeling

Advancements in systems immunology and artificial intelligence (AI)-driven computational modeling have the potential to revolutionize VBD research by enabling, Predictive modeling of immune responses, aiding in vaccine and immunotherapy design, Identification of novel immune targets through high-throughput screening of transcriptomic and proteomic datasets, Personalized immunopharmacology, tailoring interventions based on individual immune profiles. Future studies should leverage machine learning algorithms and multi-omics data integration to refine host-pathogen interaction networks, ultimately leading to precision immunotherapy for VBDs [71].

Immunometabolism in vector-borne infections

Recent evidence highlights the role of immunometabolic pathways in shaping immune responses to VBDs. The interplay between glycolysis, oxidative phosphorylation, and lipid metabolism influences, T-cell exhaustion and dysfunction in chronic parasitic infections (Leishmania, Plasmodium), Macrophage polarization, affecting pathogen clearance versus immune tolerance, Viral replication dynamics, as seen in the metabolic reprogramming induced by flaviviruses. Targeting host metabolic pathways with immunomodulatory drugs or metabolic inhibitors may offer a novel avenue for host-directed therapy, complementing conventional pharmacological interventions [72].

Microbiome and vector immunopharmacology

The role of the host and vector microbiome in immune modulation is emerging as a critical research frontier. Studies have shown that, Gut microbiota composition influences host susceptibility to Plasmodium and arboviruses, Vector-associated microbiota, such as Wolbachia, can alter pathogen transmission dynamics and vector immune responses, Probiotic-based interventions may enhance vaccine efficacy by modulating mucosal immunity. Understanding the host-microbiome-vector interplay could lead to microbiome-targeted immunotherapies, paving the way for next-generation vector control strategies with immunopharmacological implications [73].

Ethical, regulatory, and global health considerations

Despite significant advancements in immunopharmacology, implementation challenges persist, particularly in resource-limited settings where VBDs exert the highest burden. Key issues include, Regulatory hurdles in the approval of immunotherapeutics and vector-targeted vaccines, Ethical concerns surrounding gene-editing technologies (e.g., CRISPR-based mosquito population suppression), Disparities in access to immunopharmacological interventions, necessitating global health equity frameworks. Collaborative efforts between scientists, policymakers, and public health organizations are essential to ensure the equitable translation of research advancements into clinical and public health applications [74].

Conclusion

This review has systematically synthesized the immune mechanisms, vector-driven immunomodulation, and immunopharmacological advancements in VBDs. The integration of systems immunology, metabolic interventions, microbiome-targeted strategies, and AI-driven predictive models represents the future of precision immunotherapy in VBDs. Addressing the scientific, regulatory, and ethical challenges associated with these interventions will be crucial in bridging the gap between research innovation and real-world application, ultimately contributing to global vector-borne disease control and elimination efforts [75].

Abbreviations

VBDs

Vector-borne diseases

PRRs

Pattern recognition receptors

TLRs

Toll-like receptors

NLRs

Nucleotide-binding oligomerization domain-like receptors

DCs

Dendritic cells

Th

T-helper cells

Tregs

Regulatory T cells

mAbs

Monoclonal antibodies

ICIs

Immune checkpoint inhibitors

mRNA

Messenger RNA

DENV

Dengue virus

ZIKV

Zika virus

CHIKV

Chikungunya virus

TBEV

Tick-borne encephalitis virus

ADE

Antibody-dependent enhancement

IFN-I

Type I interferon

STAT

Signal transducer and activator of transcription

NOS

Newcastle-Ottawa scale

JBI

Joanna Briggs Institute

PRISMA

Preferred reporting items for systematic reviews and meta-analyses

HDTs

Host-directed therapies

TLR

Toll-like receptor

Wolbachia

A genus of bacteria that infect arthropods and filarial nematodes

Authors’ contributions

E.A. has conducted all parts of the study, including design, execution, and writing the manuscript.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.