Therapeutic approaches against dengue virus: current status of vaccines, antivirals, and monoclonal antibodies

ABSTRACT

Dengue virus (DENV) continues to pose a major global health challenge, with widespread distribution, frequent outbreaks, and four antigenically distinct serotypes complicating efforts for effective prevention and treatment. Despite decades of research, no universally protective vaccine or widely approved therapeutic exists, and the risk of antibody-dependent enhancement further complicates intervention strategies. This review provides an integrated perspective on dengue prevention and treatment, positioning vaccines, monoclonal antibodies, antiviral drugs, and host-directed therapies along the continuum of infection. It synthesizes recent advances in dengue prophylaxis and therapy, highlighting key innovations in vaccines, monoclonal antibodies, and antiviral compounds. Live-attenuated and chimeric tetravalent vaccines have progressed from early development to advanced clinical trials, demonstrating promising immunogenicity, safety, and potential for simplified dosing regimens. Concurrently, engineered monoclonal antibodies targeting conserved viral epitopes have improved neutralization breadth and reduced enhancement risk, while combination strategies may further limit viral escape. Antiviral development has explored both direct-acting and host-directed mechanisms, revealing potent candidates in preclinical models, although clinical translation remains challenging. Together, these advances illustrate a multifaceted approach to dengue control, integrating vaccine optimization, rational antibody design, and targeted therapeutics. By contextualizing recent progress and remaining challenges, this review underscores the urgent need for coordinated efforts to develop safe, effective, and broadly deployable interventions, ultimately supporting global efforts to reduce the burden of dengue.

Trial registration: ClinicalTrials.gov identifier: NCT04722627, NCT05201794, NCT06006559, NCT05710224, NCT04273217.

Introduction

Dengue fever represents a major public health concern in tropical and subtropical regions, with the disease now emerging as a notable threat in Europe. This expansion is driven by the sustained proliferation of Aedes aegypti and Aedes albopictus mosquitoes, as well as the circulation of four antigenically distinct dengue virus serotypes (DENV-1 to DENV-4) within the Orthoflavivirus genus (family Flaviviridae) [1]. Recent decades have witnessed a marked surge in both incidence and prevalence of dengue, with global reported case numbers reaching over 6.5 million in 2023 and 1900 deaths reported in 2025 to date, and the heaviest toll observed in the Americas and Southeast Asia [2]. This upward trend is fuelled by factors such as the expansion of habitats conducive to vectors (linked in part, in some regions, to climate change), rapid urbanization, increased mobility, and the persistent immunological naivety of human populations faced with the successive emergence of different serotypes [3]. Despite these high figures, the true burden remains underestimated, particularly in regions where disease diagnosis and surveillance capacities are limited. Dengue imposes substantial socio-economic loss through morbidity, hospital admissions, and labour force disruption [4]. To date, there is no licensed, specific antiviral for dengue and patient management remains largely supportive. The vaccine approach faces significant challenges, including cross-immunity and avoiding the risk of antibody-dependent enhancement (ADE), which represent major constraints for both vaccination strategies and the use of therapeutic monoclonal antibodies [5]. Furthermore, viral genetic diversity necessitates pan-serotype and pan-genotype therapeutic solutions to ensure robust efficacy against circulating and emerging variants. Advances in structural virology, immunopathology, and biotechnological platforms have spurred development of innovative interventions. Rational drug design, informed by high-resolution structural data on viral proteins, alongside progress in monoclonal antibodies and next-generation vaccines, embody promising strategies for improving efficacy and safety in dengue therapeutics [6,7]. This review synthesizes current knowledge on dengue virus biology, pathogenesis, and immunology, with a primary focus on therapeutic and preventive strategies. This work is a narrative (non-systematic) review based on literature retrieved from PubMed and ClinicalTrials.gov up to 2025. Studies were selected based on their clinical relevance, development stage, and mechanistic insight, with an emphasis on candidates supported by peer-reviewed publications or registered clinical trials. This approach aims to provide an integrated and translational overview rather than an exhaustive systematic analysis.

Dengue virus: biological and clinical features

General characteristics

Dengue virus (DENV) is an enveloped, single-stranded, positive-sense RNA virus of the Flaviviridae family. The four serotypes (DENV-1 to DENV-4) share approximately 65% genomic homology and elicit partially distinct but cross-reactive immune responses.

The ∼10.7 kb viral genome encodes a single polyprotein, post- and co-translationally cleaved into three structural proteins: the Capsid (C), pre-Membrane (prM), and Envelope (E) proteins and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5). Structural proteins play a central role in many critical processes within the virus life cycle, including genome encapsidation (C), virion assembly and maturation (prM→M), and host cell entry (E). Non-structural proteins play an essential role, particularly in immune evasion (NS1), polyprotein processing (NS3), scaffolding of the replication complex (NS4B) and RNA synthesis (NS5) [8].

Clinical challenges and severity

Dengue typically begins after an incubation period of 4–10 days following an infective mosquito bite. It presents as an acute febrile illness with a constellation of symptoms including biphasic high fever, severe retro-orbital headache, pronounced myalgia and arthralgia (“break-bone fever”), maculopapular rash, nausea, vomiting, and marked fatigue [9]. While most infections are self-limiting, dengue can progress to severe forms. According to the 2009 WHO criteria, dengue is classified into three severity levels:

• – dengue without warning signs.

• – dengue with warning signs, such as abdominal pain, persistent vomiting, fluid accumulation, mucosal bleeding, lethargy, liver enlargement, rising haematocrit with falling platelets.

• – severe dengue, also called dengue haemorrhagic fever (DHF) or dengue shock syndrome (DSS), which is defined by severe plasma leakage and/or severe bleeding due to increased vascular permeability and/or organ failure [9]. Hospitalization is frequent, and mortality risk peaks in children and patients with prior infection by a heterologous serotype [10]. Risk factors for progression to severe disease include age, immune history, and chronic comorbidities. In particular, diabetes, obesity, hypertension, chronic kidney disease, cardiovascular disease, and haemoglobinopathies, including sickle cell disease, have been associated with a higher risk of severe clinical outcomes in cohort studies and meta-analyses [11–14]. Although case-fatality rates have declined, post-acute morbidity remains significant. Many patients experience prolonged fatigue, musculoskeletal pain, and reduced functional capacity, with persistent impairment of quality of life. In severe cases, neurological or hepatic sequelae may also occur [15].

Immunopathological mechanisms

Severe dengue is driven by dysregulated immune responses, notably antibody-dependent enhancement (ADE). During secondary infection with a serotype differing by 30–35% in the E protein, cross-reactive antibodies bind and opsonize, but fail to neutralize the viral particle, instead facilitating viral entry into Fc receptor-bearing macrophages and dendritic cells [9,13,16]. This enhances viral entry into permissive cells and increases intracellular replication efficiency, thereby amplifying viral dissemination. The magnitude of ADE is not uniform across dengue virus serotypes and is also influenced by the concentration and affinity of pre-existing antibodies. Epidemiological studies have shown that secondary infections involving DENV-2 are more frequently associated with severe disease, suggesting serotype-specific differences in viral fitness, antibody affinity, and epitope accessibility [17].

ADE leads to high viremia and triggers an exaggerated release of pro-inflammatory cytokines (“cytokine storm”), exacerbating vascular leakage and increasing risk of shock and multi-organ failure. Dysfunction of immune cells is further compounded by impaired interferon responses, dysfunctional B- and T-cell activation, and anomalies in the regulation of chemokines, all influencing clinical outcome [13].

Recent advances have also shown that neutrophil and dendritic cell dysfunction contribute to both protective and pathogenic responses. Altered Neutrophil Extracellular Trap (NET) formation, corresponding to web-like chromatin structures released by activated neutrophils to trap and neutralize pathogens, together with dendritic cell apoptosis, may amplify endothelial permeability and plasma leakage characteristic of severe dengue [18].

The broad clinical spectrum and complex immunopathology underscore the urgent need for efficacious therapeutics. While vaccination remains central in prevention, expanding therapeutic options, including monoclonal antibodies and antiviral drugs, will be pivotal to improving clinical outcomes in severe cases [13,19].

Prophylactic and therapeutic approaches for dengue

Current and future therapeutic strategies have the potential to transform dengue management by reducing morbidity, mortality, and economic burden. Major advances in the last five years include new vaccine candidates entering large-scale trials, first-in-human studies for direct acting antivirals (DAAs) and the clinical development of therapeutic monoclonal antibodies. The temporal positioning and complementary roles of these prophylactic and therapeutic approaches for dengue are summarized in Figure 1.

Figure 1.

Integrated therapeutic windows during dengue virus infection. Schematic representation of dengue virus infection kinetics and stage-specific therapeutic intervention windows. Following mosquito-mediated transmission, viremia rapidly increases during the early febrile phase before declining, while immune and inflammatory responses progressively intensify and contribute to the critical phase associated with immunopathology, vascular leakage, and severe dengue risk. Preventive and therapeutic strategies are positioned according to their expected optimal timing of administration. Vaccination acts as a pre-exposure prophylactic strategy, whereas therapeutic monoclonal antibodies and direct-acting antivirals are expected to be most effective when administered before or shortly after infection, during periods of viral replication. In contrast, host-directed therapies aimed at modulating inflammation may be more relevant during later stages characterized by dysregulated immune responses and immunopathology. This integrated framework highlights the complementary roles of vaccines, monoclonal antibodies, antivirals, and host-directed therapies across the continuum of dengue infection.

Vaccines

Efforts to develop a dengue vaccine began nearly a century ago [20], with decades of slow progress hampered by the virological complexity of dengue, including the need to ensure effective protection against all four serotypes (DENV-1 to DENV-4) and mitigation of the risks of antibody-dependent enhancement (ADE). The need for balanced tetravalent immunity, capable of protecting without priming for severe disease, has driven a stepwise scientific and technological evolution in vaccine platforms, as summarized in Table 1.

Table 1.

Dengue vaccine candidates: key characteristics and clinical outcomes.

Clinical & advanced candidates							Inactivated, DNA, subunit & VLP/mRNA candidates
Category	Dengvaxia (Sanofi)	Qdenga (TAK-003, Takeda)	TV003/TV005 (NIH/Butantan)	Butantan-DV (Butantan/NIH)	V181 (Merck)	DenguiAll (Serum Inst. of India)	TDENV-PIV (WRAIR/Sumitomo/Takeda)	EDIII-P64K (CU/MMI : subunit)	V180 (Merck)	TVDV (DNA/Vaxfectin)	prM/E mRNA	DENVLP (VLP : investigational)
Platform/Antigen Target	Live-attenuated chimeric (YF-17D : prM/E DENV1-4)	Live-attenuated (DENV-2 backbone : prM/E DENV1-4)	Live-attenuated tetravalent (prM/E DENV1-4 : TV005 higher DENV2 dose)	Live-attenuated tetravalent (TV003-derived)	Live-attenuated tetravalent candidate (three potency formulations)	Live-attenuated tetravalent (SII “Dengusiil”)	Purified inactivated tetravalent DENV1-4 (alum-adjuvanted)	Recombinant EDIII fused to carrier P64K ± capsid : alum-adjuvanted : tetravalent formulations	Truncated versions of E consisting of the N-terminal portion of E (DEN-80E) adjuvanted with ISCOMATRIX®	Tetravalent dengue DNA vaccine (prM/E DENV1-4) formulated ± Vaxfectin®	Non-replicating mRNA-LNP encoding DENV prM/E (mono- and multiserotype constructs)	Tetravalent virus-like particles displaying DENV E : non-replicating
Immunogenicity	Tetravalent nAb : titres wane over years	≥90% seroconversion to all 4 serotypes after 2 doses : durable nAb : robust B/T-cell responses	Single dose induces 90% tetravalent seroconversion with TV005 in naïve adults : durable responses in children–adults	High tetravalent nAb GMTs in phase 2 : strong plasmablast and memory B-cell responses in naïve and exposed	Dose-dependent nAb : best responses with mid/high potency : responses higher in flavivirus-experienced adults	High seroconversion and robust nAb titres in most subjects : responses boosted over time : data limited to early-phase trials	Strong nAb after 2–3 doses : titres boosted by higher antigen dose and adjuvant : good memory responses	High PRNT50 and IFN-γ secretion in mice after EDIII-P64K : durable responses ≥6 mo post-boost (Frontiers Publishing Partnerships)	Tetravalent nAb in most participants : titres wane over months	Safe : modest nAb : best GMTs in high-dose + Vaxfectin® group : overall less immunogenic than live vaccines	Robust humoral and cellular responses in mice : complete protection vs lethal DENV-2 challenge in some regimens	Very strong and durable nAb in NHP (up to 1 year) : IgG transfer protects mice : no ADE signal in vitro
Trial Phase/Population	Phase 3 : children 2–16 y : Asia/LatAm	Phase 3 (TIDES) : children 4–16 y : 8 endemic countries	Phase 1–2 : flavivirus-naïve and exposed adults : trials in US, Brazil, India : CHIM in adults	Phase 3 completed; 16,235 participants 2–59 y in multicentre Brazilian trial; vaccine now licensed in Brazil following Anvisa approval (https://butantan.gov.br/noticias/vacina-da-dengue-do-instituto-butantan-primeira-do-mundo-em-dose-unica-e-aprovada-pela-anvisa?utm_source=chatgpt.com)	Phase 1 : healthy adults 18–50 y : flavivirus-naïve and experienced	Phase 1 (60 adults 18–45 y, Australia) : phase 1/2 India ongoing	Phase 1 : 100 healthy adults 18–39 y	Preclinical : murine models only (no human trial)	Phase 1 : 98 flavivirus-naïve adults; 9 V180 formulations: ISCOMATRIX™ (2 doses), aluminium hydroxide, or unadjuvanted	Phase 1 : 40 flavivirus-naïve adults : 3 dose groups	Preclinical : mice (DENV-1 and DENV-2 prM/E mRNA-LNP)	Preclinical : non-human primates + mice
Vaccination schema.	3 doses (0/6/12 months)	2 doses (0/3 months)	Single dose (SC)	Single dose (SC)	2 doses (0/3 months) in phase 1	Single dose in phase 1	2 doses 4 weeks apart : optional 3rd dose at 6 mo in subset	Multiple doses in mice (e.g. 4 doses DV2 EDIII-P64K) (Frontiers Publishing Partnerships)	3 injections at months 0, 1, and 2.	3 IM doses (0/1/5 mo) : 1–2 mg DNA : ± Vaxfectin®	1–3 mRNA-LNP doses in mice : regimens vary by construct and study	Repeated IM doses in mice and NHP (e.g. 3-dose series)
Efficacy – VCD (%)	∼60% overall : higher in seropositives (pooled phase 3)	80.2% at 12 mo : 61.2% over 4.5 y	No field VCD efficacy : CHIM : near-complete protection vs DENV-2 and DENV-3 after single TV005 dose	79.6% overall at 2 y : 73.6% dengue-naïve : 89.2% previously exposed : follow-up ≈3.7 y	No VCD efficacy data (phase 1 only)	No VCD efficacy data (phase 1 only)	No natural VCD efficacy : immunogenicity only : human challenge data from prime-boost regimens (TDENV-PIV + LAV) shows protection vs DENV-1 (The Lancet)	No VCD efficacy : protective in mouse challenge models only	No clinical VCD efficacy : phase 1 only	No clinical VCD efficacy : phase 1 only : some neutralization but limited seroconversion	Mouse challenge : protection vs homologous DENV-1 or DENV-2 : no human VCD data	NHP challenge : ↓ viremia and protection vs all 4 DENV serotypes : no human VCD data
Efficacy – Hospitalization/Severe	↓ hospitalized/severe VCD in seropositives : ↑ risk in seronegatives over 5 years	95.4% vs hospitalized VCD at 12 mo : 84.1% over 4.5 y : protection in seronegatives maintained	No clinical hospitalization data (CHIM only)	≈89% protection vs severe dengue/dengue with warning signs (up to 5 y) (Cell)	No data (phase 1 immunogenicity/safety only)	No data (phase 1 immunogenicity/safety only)	No hospitalization/severe data (early-phase + CHIM)	None (animal only)	None (phase 1 only)	None (phase 1 only)	None (preclinical)	None (preclinical)
Serotype- and Serostatus-Specific Efficacy	Best for DENV-3/4 : weaker DENV-1/2 : benefit only in baseline seropositives	Seropositives : VE against all serotypes : seronegatives : VE vs DENV-1/2, no VE vs DENV-3 : DENV-4 incidence too low	Balanced nAb responses to all 4 serotypes : CHIM : full protection vs DENV-2/3 after TV005 : no field serotype-specific VE yet	VE 75.8% vs DENV-1 and 59.7% vs DENV-2 : no DENV-3/4 cases during follow-up : high VE in both dengue-naïve and exposed	Seroconversion rates differ by serotype and potency : higher titres for DENV-2/3 at mid/high dose : no VE data	Seroconversion to ≥3–4 serotypes in most vaccinees at higher dose : no VE or serotype-specific clinical data	Tetravalent nAb : higher titres at 4 µg : prime-boost (PIV + LAV) yields strong DENV-1 protection in CHIM : no field serotype VE	Potent EDIII-specific nAb in mice : tetravalent formulations protective against multiple serotypes : no human serotype data	ISCOMATRIX™ groups showed tetravalent responses in 71–88% at M2, 86–100% at M3, 43–72% at M8, and 0–43% at M14; ≥trivalent responses were 100% at M2–M3, 57–100% at M8, and 29–86% at M14.	Neutralizing responses modest for TVDV alone : improved breadth and titres with Vaxfectin® and higher dose : still below live vaccines	High homologous nAb to DENV-1 or DENV-2 : some cross-reactive responses : risk of ADE discussed for certain constructs (Cell)	High nAb against all 4 serotypes in 100% NHP : no ADE in vitro : protection across serotypes in challenge
Safety Profile	Good short-term safety : long-term ↑ hospitalized/severe dengue in seronegatives	Acceptable reactogenicity : SAEs similar/fewer vs placebo : no enhancement signal up to 4.5 y	Well tolerated in adults and children : mostly mild–moderate local/systemic reactions	Generally well tolerated : AE/SAE rates close to placebo in phase 2–3 : no safety signal up to ≈5 y	Well tolerated in phase 1 : AE profile similar to placebo : no vaccine-related SAEs	Acceptable safety : local pain and headache most common : no vaccine-related SAEs in 6-month follow-up	Well tolerated in adults : AE rates similar to placebo : mild local/systemic reactions	No human data : in vivo mouse safety acceptable (preclinical)	All 9 V180 formulations were generally well tolerated. Formulations with ISCOMATRIX™ adjuvant were associated with more adverse events than aluminium-adjuvanted or unadjuvanted formulations.	Good safety : no vaccine-related SAEs : reactogenicity mild : lipid adjuvant well tolerated	Acceptable tolerability in animal models : no human safety data yet	No major toxicity in NHP studies : no ADE in vitro : preclinical only
Sample Size/Localization	>30,000 : Asia + Latin America	≈20,000 : 8 countries (Brazil, Colombia, Dominican Republic, Nicaragua, Panama, Philippines, Sri Lanka, Thailand)	Hundreds of adults/children across US, Brazil, India : CHIM cohorts smaller (dozens)	16,235 participants : all Brazilian regions (multicentre phase 3)	∼300 participants across dose groups and flavivirus-status strata in phase 1 sites	60 adults in Australia : additional phase 1/2 sites in India planned/ongoing	100 adults : US sites (WRAIR/Takeda collaboration)	Preclinical mice studies in Cuba : no clinical cohorts	98 adults; Australia	40 adults : single-country phase 1 : military research setting	Preclinical in mice only (various labs) : no clinical cohorts	Preclinical in NHP in Japan : supportive mouse experiments
Limitations/Challenges	Restricted to seropositive populations; waning VE over time; 3-dose regimen with need for pre-vaccination screening; manufacturing and distribution being phased out after the manufacturer announced discontinuation because of low global demand	Lower/absent VE vs DENV-3 in seronegatives : DENV-4 data limited : VE declines over time : mainly recommended in high-transmission settings	No field VE yet : CHIM data only : regulatory path still uncertain : logistics of deployment not defined	No data for DENV-3/4 so far : VE decreases from 79.6% to ≈67% at longer follow-up : single-country trial to date; real-world data outside Brazil still pending	Programme not advanced beyond phase 1 : modest titres for some serotypes : no efficacy or long-term data	Data limited to small early-phase trials : no VCD/hospitalization data : VE and durability unknown : manufacturing/scale-up not yet public	Multiple doses : cold-chain : immunogenicity lower than live vaccines : CHIM data still limited to specific regimens	Only preclinical : no human dosing, safety, or VE : manufacturing/scale-up not evaluated	Phase 1 only: Low immunogenicity for DENV-4	Phase 1 only : modest immunogenicity : requires 3 injections : less attractive vs LAV platforms	Preclinical only : ADE risk must be controlled : no clinical dosing, safety or VE yet	Preclinical stage : no human data : durability and reactogenicity in humans unknown : manufacturing complexity of VLPs
Current regulatory status/deployment	Previously licensed in multiple endemic countries and in the USA; use restricted to seropositive individuals; Availability now limited in some settings; programmatic use constrained by implementation and supply timelines	EMA-approved since 2022 and WHO-prequalified in 2024; progressively introduced in Europe, Latin America and Asia without baseline serostatus screening	Not licensed; evaluated in phase 1–2 and human challenge trials; serves as backbone for Butantan-DV and DenguiAll	Licensed in Brazil after completion of phase 3; planned inclusion in the national immunization programme with public supply by Instituto Butantan	Development in early clinical stages (phase 1–2, including bridging trial with Butantan-DV)	Early clinical evaluation (phase 1/2 in Australia and India);	Evaluated in small phase 1 cohorts and controlled human infection models;	Preclinical subunit platform; only animal data available; no human trials yet	Vaccine tested in a phase 1 trial; no subsequent efficacy trials announced	Tetravalent DNA vaccine tested in a phase 1 trial; no subsequent efficacy trials announced	Multiple mRNA-LNP constructs with strong protection in mice or non-human primates; currently limited to preclinical development	Virus-like particle candidates at preclinical stage; clinical development has not yet started
References	[21–27]	[28–32]	[34,35]	[36,37]	[38–40]	[41]	[42]	[43]	[44]	[45]	[46,47]	[48]

This table summarizes the main dengue vaccine candidates currently licensed or under clinical development, including their platform, antigenic composition, dosing schedules, trial phases, efficacy against virologically confirmed dengue (VCD), impact on hospitalization/severe disease, serotype- and serostatus-specific performance, immunogenicity, safety profiles, and key limitations. Data are extracted exclusively from peer-reviewed publications and official trial reports. Sample sizes and geographic regions are provided where applicable.

VE: Vaccine efficacy; VCD: virologically confirmed dengue.

Live attenuated and chimeric vaccines

The first breakthrough towards clinical application emerged with the chimeric, live attenuated vaccine Dengvaxia (CYD-TDV), developed by Sanofi Pasteur. Licensed in 2015 after nearly a decade of clinical development, Dengvaxia is composed of four chimeric constructs in which the prM and E genes from each DENV serotype are inserted into a yellow fever 17D virus backbone. As a consequence of this design, the non-structural proteins, including NS1, are derived from YF-17D rather than DENV, and the vaccine does not elicit dengue-specific NS1-directed immunity, in contrast to natural infection. Pivotal Phase III trials demonstrated an overall efficacy of approximately 59.2%, but this protection varied by serotype (as low as 35% for DENV-2 and over 75% for DENV-3 and DENV-4). In 2017–2018, post-marketing analyses revealed an increased risk of severe dengue and hospitalization among seronegative recipients, attributed to ADE. Following these findings, WHO and national advisory groups recommended that Dengvaxia be used mainly in individuals with documented prior dengue infection, with additional consideration of age (≥9 years) and local epidemiological context to optimize the benefit-risk balance [21]. In the United States, the FDA approved Dengvaxia in 2019 for use in seropositive adolescents aged 9–16 years residing in endemic areas, consistent with CDC/ACIP guidance. This requirement for pre-vaccination screening and age restriction represents a major constraint for large-scale implementation [22,23]. Importantly, this increased risk was not directly related to the lower efficacy against certain serotypes, such as DENV-2, but rather to immunological mechanisms involving ADE. In seronegative individuals, Dengvaxia primes the immune system as a primary infection, and subsequent natural exposure to a different DENV serotype acts as a secondary infection, increasing the likelihood of severe disease through sub-neutralizing cross-reactive antibodies [24,25]. Despite these limitations, Dengvaxia demonstrated clinically meaningful protection in appropriately selected populations. In seropositive individuals, vaccination was associated with a reduction in severe dengue and hospitalization, supporting its value as a targeted preventive tool [26]. At the same time, Dengvaxia established proof-of-concept for tetravalent dengue immunization. The global uptake of Dengvaxia has remained limited, and the manufacturer has announced plans to discontinue its production by 2026 due to low demand. Its marketing authorization was also withdrawn in the European Union in 2025 for commercial reasons, reflecting broader challenges related to implementation, public acceptance, and its restricted indication [27].

Using a different design that has the potential to limit or overcome these limitations, Takeda has developed TAK-003 (Qdenga), a live attenuated tetravalent vaccine based on the DENV-2 PDK-53 strain, a highly attenuated virus, derived from serial passage of DENV-2 in primary dog kidney (PDK) cells. This DENV-2 backbone carries targeted mutations that reduce replication in both Aedes vectors and humans, and is used to express the prM and E genes of DENV-1, DENV-3, and DENV-4, thereby conferring tetravalent coverage [28,29]. Clinical development began in 2016, leading to the Tetravalent Immunization against Dengue Efficacy Study (TIDES) Phase III trial, which enrolled over 20,000 children in endemic areas [30]. Initial analyses from the TIDES Phase III trial demonstrated an overall vaccine efficacy of approximately 72–73% against virologically confirmed dengue after two doses in the first two years of follow-up [31]. Extended follow-up showed that efficacy against symptomatic, virologically confirmed dengue declines over time, with cumulative efficacy of around 61.2% at 4.5 years post-vaccination. By contrast, efficacy against dengue-related hospitalizations remained notably higher (≈84% at 4.5 years), indicating sustained protection against clinically significant outcomes [32,33]. Protection across serotypes was observed through extended follow-up, with differential serotype-specific efficacy: protection was better sustained for DENV-1 and DENV-2 in both baseline seropositive and seronegative individuals, whereas robust estimates for DENV-3 and DENV-4 in seronegatives could not be provided due to low case numbers. Importantly, no signal consistent with vaccine-associated enhanced disease was observed in seronegative participants during long-term follow-up, although continued surveillance remains warranted. The vaccine received European approval in 2022 and WHO prequalification in 2024, without a requirement for prior serostatus screening, which increases its potential impact in endemic settings [30].

Further, the National Institute of Allergy and Infectious Diseases (NIAID) advanced the live-attenuated tetravalent dengue vaccines TV003 and TV005. TV003 is a live-attenuated tetravalent vaccine composed of rDENV1Δ30, rDEN2/4Δ30, rDENV3Δ30/31, and rDENV4Δ30 strains, each attenuated via deletions in the 3’-non-coding region. TV005, which includes a tenfold higher dose of the DENV-2 component, corrected earlier immunogenicity limitations and, in controlled human infection models conducted in the United States (2020–2024), demonstrated complete protection against DENV-2 and DENV-3 with a balanced tetravalent response and no evidence of ADE risk. Phase I-II studies consistently demonstrated strong immunogenicity and excellent tolerability [34,35].

In parallel, the Butantan Institute in Brazil developed Butantan-DV, a vaccine based on the same strains and therefore antigenically identical to TV003 but produced locally and evaluated through an entirely independent clinical programme in an endemic population. The large Phase III trial (2016–2024), involving more than 16,000 children and adolescents, showed >80% efficacy against DENV-1 and DENV-2 with a favourable safety profile and no signal of ADE. Efficacy estimates for DENV-3 and DENV-4 remain incomplete due to limited circulation during the study period [36,37].

In addition, Merck's V181, another tetravalent, live-attenuated candidate constructed from chimeric viruses, was subjected to rigorous, advanced clinical evaluation. Its four components include attenuated DENV-1, DENV-3, and DENV-4 strains carrying a Δ30 deletion in the 3′ untranslated region, as well as a DENV-2 prM and E inserted on a DENV-4Δ30 backbone. These modifications reduce replication while preserving immunogenicity. Early-phase trials demonstrated good safety and balanced immunogenicity following a two-dose schedule, and Phase III studies in children are ongoing as of 2025 [38–40].

Finally, the Serum Institute of India has developed the DenguiAll live attenuated tetravalent dengue vaccine. It is composed of four independently attenuated recombinant virus strains (rDEN-1Δ30, rDEN-2/4Δ30, rDEN-3Δ30/31, and rDEN-4Δ30) originally developed by the National Institute of Allergy and Infectious Diseases (NIAID) and manufactured in India. Initial Phase I/II studies data indicate robust seroconversion across all four DENV types and a favourable safety profile, though definitive evaluation will require larger, late-phase trials [41].

Beyond clinical efficacy, the large-scale implementation of dengue vaccines faces important logistical and economic challenges. Dengvaxia, for example, requires a three-dose schedule over 12 months, which complicates adherence and increases programmatic costs in endemic settings. In addition, although formulated as a lyophilized vaccine, it still requires cold-chain storage, limiting deployment in resource-constrained regions. Market uptake has also been variable, reflecting challenges in public acceptance and implementation. While cost-effectiveness analyses have been performed for Dengvaxia, comparable economic and implementation data for newer vaccine candidates remain limited. Ensuring equitable access will require simplified dosing regimens, improved thermostability, and scalable production strategies adapted to endemic regions.

In addition to logistical considerations, important differences in policy and implementation must be considered across dengue vaccines. For example, CYD-TDV (Dengvaxia) requires prior serostatus screening and is restricted to specific age groups, which increases programmatic complexity and limits large-scale deployment. In contrast, TAK-003 (Qdenga) does not require pre-vaccination screening, offering a more straightforward implementation strategy in endemic settings.

Moreover, the genetic diversity and ongoing evolution of dengue virus highlight the importance of genomic surveillance to monitor vaccine effectiveness and anticipate major changes in circulating strains.

Inactivated, subunit, and emerging platforms

Recognizing the challenges posed by live vaccines, alternative platforms have advanced, aiming to optimize safety, broaden immunogenicity, and streamline manufacturing.

In the early 2010s, focus shifted to purified inactivated vaccines (PIV), like TDENV-PIV (DPIV), developed by the U.S. Army Medical Research Institute of Infectious Diseases. Phase I trials in 2013 established neutralizing antibody responses across serotypes and an acceptable safety profile in naïve adults [42]. In the same decade, subunit vaccines targeting EDIII (envelope domain III), such as EDIII-P64 K, a recombinant fusion protein in which the dengue EDIII domain is coupled to the Neisseria meningitidis P64 K carrier protein to enhance immunogenicity, displayed strong preclinical immunogenicity and attenuated ADE risk. However, progress to human trials has been modest due to technical and translational challenges [43].

Merck has also developed V180, a tetravalent recombinant dengue subunit vaccine (DEN-80E) composed of truncated envelope (E) proteins corresponding to the N-terminal portion of E and adjuvanted with ISCOMATRIX®. This formulation was evaluated in a Phase I dose-escalation trial in flavivirus-naive adults, with ISCOMATRIX™-adjuvanted formulations showing the strongest immunogenicity. All formulations were generally well tolerated. However, some patients had antibodies against only three of the four serotypes, and in every case the missing serotype was the fourth [44].

DNA vaccination entered clinical testing with TVDV (Vaxfectin®-adjuvanted DNA vaccine) between 2014 and 2018. Phase I studies yielded encouraging neutralization responses and solid safety, but development remains cautious, pending further efficacy data [45].

By the late 2010s and early 2020s, nanoparticle and mRNA-based vaccines represented new frontiers. The COVID-19 era further catalyzed mRNA vaccine development, with prM/E-encoding LNP-mRNA candidates achieving robust protection in animal models as of 2021–2025 [46,47]. Virus-like particle (VLP) vaccines (DENVLPs) demonstrated durable, multivalent neutralization and no ADE in preclinical primate studies (2024) [48]. These platforms promise modular design, rapid scalability, and enhanced safety profiles, critical for pandemic and endemic response adaptability.

Beyond immunogenicity and safety, these platforms must also be considered in terms of feasibility, including dose number, duration of protection, and economic cost. Evidence from cost-effectiveness analyses of CYD-TDV shows that programmatic costs may be substantial, with estimates of ≈72 USD per vaccinated child in Indonesia and ≈380 USD per fully vaccinated child in Puerto Rico, depending on viral transmission intensity, screening strategy, and country-dependent vaccine pricing [49,50]. These observations highlight that price, logistical constraints, and durability of protection are critical factors when comparing current and next-generation dengue vaccines, alongside clinical efficacy and safety.

Antiviral molecules

Antiviral molecules can be classified into direct-acting antivirals (DAAs), which target viral proteins involved in replication, and host-directed antivirals (HDAs), which interfere with host cellular pathways required for viral replication. This review focuses primarily on direct-acting antivirals, whose development stages and main characteristics are summarized in Table 2.

Table 2.

Antiviral candidates against dengue: development stage and main features.

Category	Terminated/Stopped candidates			Ongoing Clinical Development (Phase I–III)
Molecule	Balapiravir	Ribavirin	Sofosbuvir	AT-752	JNJ-1802 (Mosnodenvir)	NITD-688 (EYU-688)
Target/Mechanism	NS5 RNA-dependent RNA polymerase inhibitor : prodrug of R1479	Broad-spectrum nucleoside analogue : inhibits viral RNA synthesis/MTase in vitro	NS5 polymerase inhibitor repurposed from HCV : blocks DENV RNA replication	Guanosine nucleotide prodrug targeting the viral RNA-dependent RNA polymerase	Direct-acting NS4B inhibitor : blocks replication complex assembly	NS4B-binding inhibitor : disrupts NS3–NS4B interaction, blocks replication
Trial Phase/Population	Phase II randomized trial in hospitalized adult males with early dengue (<48 h fever), Vietnam. Development stopped (no efficacy)	Preclinical : rhesus prophylaxis study infected with DENV-1	Preclinical : in vitro + mouse models, no dengue clinical trial	phase 1 safety, tolerability, and pharmacokinetics of ascending single and multiple oral doses in healthy subjects.	Phase 1 completed in healthy adults Phase 2 stopped due to change in the strategic development of the enterprise.	Phase II clinical trials ongoing in dengue patients (EYU-688) : strong preclinical package
Therapeutic Regimen	Oral : 1500–3000 mg BID for 5 days in trial	Parenteral/oral prophylaxis in rhesus monkeys (single and multiple doses)	Oral : standard HCV doses suggested for humans dosing in µM-equivalent or mg/kg in mice	Oal : single ascending doses: 250,500,100 and 1500 mg and multiple ascending doses :100mg DQ and 750 mg BID	Oral : Phase 2a low dose 40-mg loading dose followed by 10-mg maintenance dose, medium dose 200 mg followed by 50 mg, and high dose 600 mg followed by 200 mg	Oral : once- or twice-daily dosing predicted from PK and modelling : clinical trial uses oral tablets
Efficacy/Key Results	Strong in vitro inhibition : no reduction in viremia, NS1, cytokines or fever vs placebo	In rhesus monkeys, prophylactic dosing did not prevent viremia or disease	Potent suppression of DENV replication in vitro : reduced DENV1 RNA in mouse liver and serum	Preclinical Active in vitro and in PBMCs and In vivo(viremia reduction and survival increased).Phase I favourable safety and pharmacokinetic.	Potent pan-serotype inhibition, good Phase I safety Effective in Phase 2a in a controlled infection setting at high dose	Potent pan-serotype activity in cells : decreased viremia and improved survival in multiple animal models : Phase II aims to show viral-load reduction in patients
Benefits	Early benchmark dengue polymerase inhibitor : defined trial framework for future antivirals	Broad-spectrum antiviral : historical experience and known PK	Strong preclinical potency : oral drug with established human safety in HCV	Oral drug with a robust mechanism of action.	First-in-class, pan-serotype small molecule : strong antiviral effect : favourable safety and PK in Phase 1	Pan-serotype, high barrier to resistance : favourable PK and safety in animals : oral candidate already in Phase II
Limitations/Challenges	Well tolerated but no clinical benefit : limited intracellular activation in activated PBMCs : dengue programme stopped	Ineffective prophylactic agent in NHP : known toxicity (e.g. haemolytic anaemia, teratogenicity) limits dengue use	Only preclinical dengue data : possibility of resistance : clinical dosing for dengue not defined	Few preclinical data: one serotype in vivo and two in vitro. human efficacy not yet proven	Resistance via NS4B mutations possible : long-term safety and effectiveness in endemic use still unknown	Clinical resistance monitoring needed : human efficacy not yet proven : long-term safety in patients under evaluation
References	[51]	[54,55]	[52,53]	[58,59]	[60–67]	[68–70]

This table provides an overview of antiviral molecules evaluated for dengue treatment or prophylaxis, spanning terminated clinical programmes and agents currently in clinical development. Mechanisms of action, therapeutic regimens, study populations, key efficacy findings, benefits, and limitations are summarized based on published experimental and clinical evidence. Only dengue-specific data from peer-reviewed studies and registered clinical trials are included.

Terminated/Stopped candidates

Balapiravir, a cytidine analogue and prodrug of the 4′-azidocytidine (R1479), was among the first direct-acting antivirals repurposed for dengue treatment. Developed initially for hepatitis C, Balapiravir demonstrated potent inhibition of dengue viral replication across all four serotypes in vitro. These promising preclinical findings led to a Phase II clinical trial in Thailand between 2007 and 2009 enrolling 64 adult patients with acute dengue infection within 48 h of fever onset [51]. Oral administration of 1500 or 3000 mg twice daily for five days was well tolerated without major safety concerns. Despite achieving plasma concentrations exceeding the in vitro EC₅₀ (maximum serum concentrations surpassing 6 μM), Balapiravir did not reduce viremia (mean peak viral RNA load ∼6.1 log10 copies/mL vs. 6.3 log10 in placebo), NS1 antigenemia, or fever duration. Mechanistic studies revealed that dengue virus infection causes impaired intracellular conversion of R1479 to its active triphosphate metabolites within peripheral blood mononuclear cells, markedly diminishing antiviral potency, a host-virus interaction not predicted by in vitro assays. Furthermore, in vivo mouse models confirmed a lack of significant viremia reduction even at high dosing. Consequently, Balapiravir’s clinical development in dengue was halted, but the trial established a valuable proof of concept and trial framework for future antiviral testing [51].

The HCV polymerase inhibitor Sofosbuvir was evaluated for dengue between 2016 and 2018 and demonstrated consistent in vitro inhibition of DENV replication in several studies; more recent work also showed suppression of DENV-1 replication in human hepatic (Huh7) cells. However, robust peer-reviewed in vivo efficacy data are scarce, and no clinical trials have been conducted [52,53]. Ribavirin, another broad-spectrum nucleoside analogue, revealed minimal anti-dengue activity in vitro and failed to reduce viremia in non-human primate models, leading to deprioritization for dengue [54,55]. By contrast, the adenosine analogue NITD-008 robustly inhibited flaviviruses in vitro and reproducibly reduced viremia and mortality in multiple mouse models, thereby demonstrating the potential for nucleoside chain terminators against DENV. However, NITD-008 was not advanced clinically because of toxicity signals in extended toxicology studies [56,57].

Ongoing clinical development

AT-752, an orally available double prodrug of a guanosine nucleotide targeting the viral RNA-dependent RNA polymerase, represents a more conventional antiviral strategy under clinical evaluation. This compound developed by ATEA Pharmaceuticals showed potent in vitro activity against DENV-2 and DENV-3, as well as other flaviviruses, with minimal cytotoxicity. In vivo, oral dosing generated the active triphosphate AT-9010 in blood cells and significantly reduced viremia, morbidity, and mortality in DENV-2-infected AG129 mice [58]. These promising results led to a Phase I first-in-human study (NCT04722627). The compound was well tolerated up to 1500 mg as a single dose and 750 mg TID as multiple doses, with no serious adverse events. The active metabolite AT-273 showed dose-dependent plasma exposure, a long half-life, and reached the target EC90 at 750 mg TID, supporting further clinical development for dengue [59].

Among viral targets, the NS3-NS4B interaction has emerged as critical for dengue virus replication. The relevance of this interface is supported by the identification of small-molecule inhibitors such as JNJ-A07, which disrupts this interaction and has demonstrated potent pan-serotype antiviral activity in both mouse models and mosquito transmission systems, highlighting this strategy as a validated antiviral target [60,61].

JNJ-1802 (Mosnodenvir, also known as JNJ-64281802), a more potent analogue of JNJ-A07, has emerged as a promising clinical candidate with a distinct mechanism of action.

Preclinical studies demonstrated in vitro nanomolar inhibition across all four DENV serotypes and 2–3 log10 viremia reduction in AG129 mouse models and efficacy in NHPs [62]. Phase I trials (2019–2020) involving 80 healthy adult volunteers confirmed dose-proportional pharmacokinetics and excellent tolerability [63]. A subsequent Phase II trial (2021–2024, NCT05201794) enrolled 1595 adult participants, including household contacts (HHC) of laboratory confirmed dengue cases in Asia and South America. While the study confirmed that prolonged prophylactic administration of JNJ-1802 was feasible and well tolerated, peer-reviewed efficacy data remain limited [64]. In a Phase IIa daily prophylaxis trial with Mosnodenvir in a controlled human infection model, high-dose Mosnodenvir reduced the incidence of DENV-3 infection and overall viral RNA compared with placebo. These findings were observed in a small-scale challenge study, and no serious adverse events were reported. Levels of the drug remained consistent until day 21, and some recipients of the sequenced DENV showed emergent NS4B mutations, indicating antiviral pressure [65]. Regarding NS4B mutations, it should be noted that the French Caribbean has witnessed the emergence of naturally resistant DENV-2 variants from epidemic lineages, independently of Mosnodenvir exposure, underscoring the imperative for continuous genomic surveillance before and after antiviral deployment [66]. In October 2024, Janssen discontinued the Phase II field study of JNJ-1802. The decision was linked to strategic portfolio reprioritization, and not to safety or efficacy concerns [67]. The compound continues to show strong preclinical and early-phase clinical signals. Its further development remains possible, potentially through other companies, charitable foundations, or non-governmental organizations.

NITD-688, a compound also targeting the NS3-NS4B interaction and first reported in 2017, showed potent pan-serotype activity in vitro (EC₅₀ 0.15 μM against DENV-2) and achieved 2–3 log10 reductions in viremia in mouse models [68]. While preclinical data are promising, no clinical trial results in dengue patients have been published to date. A first-in-human study (NCT06006559) evaluating the safety and pharmacokinetics of EYU-688, the clinical formulation of NITD-688, was initiated in 2024. NITD-688’s oral bioavailability and long half-life support manageable dosing regimens, highlighting its potential as a candidate for future dengue therapeutic development [69,70].

Despite setbacks, current candidates like JNJ-1802 and NITD-688 exemplify the success of phenotypic screening in identifying new viral targets and support the development of direct-acting antivirals as a cornerstone of future dengue therapeutic development.

In addition to monotherapy approaches, combination strategies are increasingly being considered. To our knowledge, no clinical studies have evaluated the combined use of antiviral drugs and therapeutic monoclonal antibodies for dengue. However, such combination strategies may offer complementary mechanisms of action, potentially enhancing antiviral potency, reducing toxicity, and limiting the emergence of resistance mutations. This approach remains an area for future investigation.

From a translational perspective, direct-acting antivirals targeting viral proteins, such as NS4B or the RNA-dependent RNA polymerase, are expected to be most effective when administered early during the febrile phase, when viral replication is at its peak, with the primary objective of reducing viremia and preventing progression to severe dengue (Figure 1).

Therapeutic monoclonal antibodies

The development of monoclonal antibodies (mAbs) as therapeutic interventions against dengue virus (DENV) has progressed significantly over the past two decades, driven by the urgent need for targeted antivirals capable of reducing viremia, preventing antibody-dependent enhancement (ADE), and mitigating severe disease outcomes. This section summarizes the major advances in antibody discovery and development, organized chronologically to illustrate the scientific rationale, preclinical findings, and clinical evaluations of key candidate antibodies, whose characteristics and development status are summarized in Table 3.

Table 3.

Therapeutic monoclonal antibodies against dengue: characteristics and development status.

Category	4E11	VIS513 (Dengushield)	EDE1-C10	AV-1
Epitope	E protein Domain III (DIII), strands A–G : type-specific epitope (journals.asm.org)	Domain III of E protein : engineered to bind DIII of all four DENV serotypes	Envelope dimer epitope 1 (EDE1) : quaternary epitope spanning two E monomers, near fusion loop/prM site	Epitope not publicly disclosed : Human IgG against DENV envelope
Therapeutic Target/Mechanism of Action	Viral entry and attachment : blocks virion attachment/entry. strongest for DENV-1/3	Viral attachment and entry Potent pan-serotype neutralization : neutralizes even in ADE conditions :	Viral fusion and entry : prevents E dimer rearrangement, blocks fusion and M-E interactions cross-neutralizes ZIKV in vitro	Human IgG against DENV envelope
Trial Phase/Population	Preclinical only : Immunodeficient mouse models (AG129) and cell lines no human trials published	Phase 1 in healthy adults in (Australia/India) observer-blind, randomized IV study completed. Phase 2 adults with acute dengue in trial ongoing (India : CTRI/2021/07/035290, ADAPT platform)	Preclinical only : mouse models, in vitro DENV1-4 and ZIKV neutralization assays	Phase 1:healthy adult volunteers in single-ascending-dose completed (NCT04273217): Phase 2 DENV-3 CHIM trial ongoing (NCT06799741)
Formulation/Dosing	Recombinant IgG1 : tested as single or repeated doses in mouse models	Humanized IgG1 Phase 1 : single IV infusion Phase 2: single-dose IV in dose-ranging	Fully human IgG1 : single or multiple IV doses in preclinical	Recombinant human IgG Phase 1 : single ascending IV doses Phase 2 :multiple-dose regimens in ongoing CHIM/
Efficacy (Neutralization & Clinical)	Moderate in vitro neutralization : type-restricted : partial protection in mice : no clinical efficacy data (journals.asm.org)	In NHPs, single VIS513 dose given 24 h or 5 d post-infection reduces viraemia without impairing endogenous responses : protects mice in ADE model : human antiviral efficacy still under evaluation	Very potent pan-serotype neutralization at low ng/mL : protects mice from lethal challenge : also neutralizes ZIKV	Preclinical data indicate strong neutralization : Phase 1 results not yet fully published : Phase 2 CHIM designed to test reduction in viremia and symptoms vs placebo
Safety/ADE Risk	ADE observed at sub-neutralizing titres in vitro and in mice : concern for unmodified DIII-specific mAbs (journals.asm.org)	Phase 1 trial: VIS513 safe and well tolerated with dose-proportionate PK : preclinical ADE models show VIS513 can neutralize antibody-enhanced infection rather than amplify it	Broad neutralization predicted to limit ADE : some in vitro work suggests lower enhancement than many E-directed mAbs : no human safety data	Phase 1a safety reports indicate acceptable tolerability and standard IgG AE profile : ADE risk monitored but not yet fully characterized
Pharmacokinetics/Immunogenicity	Not clinically evaluated : PK inferred from generic IgG1 in animals	Phase 1: linear PK, long half-life (∼32–36 days), no anti-drug antibodies : supports single-dose therapy in adults	No clinical PK : expected long half-life as human IgG1 in vivo	Phase 1a shows dose-proportionate exposure and long half-life typical of human IgG : no anti-drug antibodies reported
Limitations/Challenges	Limited breadth : ADE risk : no clinical development : mainly of historical/structural interest	Phase 2 results awaited : IV infusion, likely expensive : impact on hard clinical endpoints (hospitalization, severe dengue) not yet proven	High manufacturing cost : IV administration : preclinical stage only : real-world ADE risk and escape not yet defined	Clinical efficacy data still pending : cost and access issues : optimal timing (prophylaxis vs treatment) and serostatus effects not yet known
References	[71,72]	[73–75]	[77–79]	[80]

This table compiles the main monoclonal antibody (mAb) candidates targeting dengue virus, including epitope specificity, mechanisms of action, dosing strategies, clinical phases, sample sizes, neutralization profiles, safety considerations, and major development challenges. Both preclinical and clinical-stage mAbs are represented, along with Fc-modified and bispecific antibody formats. All information is derived from peer-reviewed studies and official clinical trial documentation.

Initial antibody discovery efforts focused primarily on the dengue virus envelope (E) protein, particularly domain III (DIII), which plays a central role in receptor engagement and viral entry. One of the first candidates, 4E11, recognizes a conformational epitope spanning the A and G strands of DIII and exhibited cross-reactive but incomplete neutralization across serotypes [71,72]. Structural studies later showed that 4E11 can induce premature exposure of the fusion loop, thereby destabilizing the viral particle. However, its limited potency, especially against DENV-4, and the potential for antibody-dependent enhancement (ADE) at sub-neutralizing concentrations highlighted the constraints of early DIII-directed antibodies [73].

These insights motivated rational antibody engineering efforts to improve the breadth and affinity of 4E11. Using structure-guided mutagenesis and computational design, several key residues within the paratope were modified, markedly enhancing affinity for DENV-4 and overall pan-serotype potency. This optimized variant ultimately led to the development of VIS513 (Dengushield), a humanized derivative retaining a DIII-targeting mechanism but exhibiting substantially improved neutralization capacity in vitro and protective efficacy in murine models [74,75]. VIS513 entered Phase I clinical evaluation, where it demonstrated a favourable safety profile [76]. Together, 4E11 and VIS513 illustrate how iterative engineering of an initially modest DIII-specific antibody can yield a clinically advanced candidate with broadened efficacy and reduced ADE liability.

A major advance emerged with the discovery of envelope dimer epitopes (EDEs). Structural studies revealed that human antibodies like EDE1-C10, isolated from convalescent patients, recognized conserved quaternary motifs spanning E protein dimers. EDE1-C10 achieved potent cross-serotype neutralization at nanomolar concentrations and conferred robust protection against lethal DENV challenge in mouse models [77–79]. Mechanistically, it blocks viral fusion within endosomes, establishing EDEs as superior antibody targets compared to DIII.

Building on these advances, AV-1 (AbViro) became the first dengue-specific monoclonal antibody to enter human clinical evaluation. It is currently being evaluated in a Phase II trial enrolling approximately 42 patients. A Phase I trial demonstrated safety and tolerability, and the Phase II study is ongoing; no efficacy results have yet been released [80].

Beyond their dengue-specific neutralizing activity, a growing body of evidence suggests that they may exhibit broader cross-reactivity with flaviviruses. Notably, several dengue-targeting monoclonal antibodies and vaccine-induced immune responses have been shown to exhibit cross-reactivity with other flaviviruses, particularly Zika virus. This cross-neutralization is primarily mediated by conserved epitopes within the envelope protein, especially at quaternary structural interfaces. While such cross-reactivity may confer partial protective immunity, it also raises concerns regarding antibody-dependent enhancement across flaviviruses, highlighting the need for careful evaluation in vaccine and antibody development [81,82].

From a clinical perspective, therapeutic monoclonal antibodies are likely to occupy specific niches in dengue management rather than serving as broad population-level interventions. Their potential applications include post-exposure prophylaxis in high-risk contacts, early treatment in individuals with confirmed infection, and targeted use in populations at increased risk of severe disease, such as children, elderly individuals, or patients with comorbidities.

However, their implementation in endemic, resource-limited settings raises important challenges. The need for intravenous administration, high production costs, and cold-chain requirements may limit large-scale deployment. These constraints suggest that monoclonal antibodies may be best positioned as targeted interventions complementing vaccines and antiviral drugs within integrated dengue control strategies.

Conclusion

Dengue virus remains a major global health challenge driven by the co-circulation of four antigenically distinct serotypes, ongoing genotype turnover, and complex host-virus immunological interactions [1,9,10]. Antibody-dependent enhancement continues to shape natural immunity and remains a central constraint for prophylactic and therapeutic innovation [10,16]. These features place dengue at the interface between virology, immunology, and population-level epidemiology, and explain why the development of durable and broadly protective countermeasures remains particularly challenging [3,13].

In the vaccine field, recent progress has expanded the range of available strategies, but key scientific and operational questions persist. Live-attenuated and chimeric tetravalent vaccines have demonstrated clinically meaningful protection and acceptable safety profiles in large trials [25,32,36,37], while next-generation DNA, VLP and mRNA platforms extend antigen design possibilities and may better accommodate antigenic diversity [46,47,83,48,45]. However, durability of protection, serotype- and genotype-dependent variations in efficacy, and the immunological balance between neutralizing and cross-reactive antibodies remain unresolved issues [5,30,32,35]. Key questions remain regarding the feasibility of achieving lifelong immunity in endemic settings, the identification of target populations, and the potential for deployment during outbreaks. Due to the decline in antibody titres and the subsequent risk of ADE, booster schedules should be discussed, with indications that may be different in the presence or absence of exposure to natural re-immunization. Furthermore, given the genetic diversity of DENV and the frequent replacement of serotypes or genotypes, vaccine formulations may need to be updated periodically in response to viral evolution, as with the flu virus or SARS-CoV-2. Close integration of immunological correlates of protection, genomic surveillance and real-world effectiveness data will be required to achieve this.

These considerations highlight the potential need for adaptive vaccine strategies informed by genomic surveillance, particularly in the context of ongoing genotype replacement. In the longer term, the development of pan-arboviral vaccines targeting multiple flaviviruses may represent a promising but complex direction, given the challenges associated with cross-reactive immunity and antibody-dependent enhancement.

In parallel, antiviral development has identified both direct-acting and host-targeted candidates that disrupt essential viral processes, but translation from preclinical efficacy to clinical benefit remains difficult because dengue pathogenesis reflects both viral replication and host-driven immunopathology. Using antivirals could raise significant scientific and public health questions about resistance. It is important to distinguish between drug-induced escape mutations and naturally occurring variants. With naturally occurring variants, we can monitor their emergence and transmission by gathering genomic data, which allows us to assess their spread and fitness. However, we must consider, study and anticipate the fitness cost of drug-induced mutations across human and mosquito hosts, and their potential for regional spread within transmission networks [65,66,69]. The therapeutic positioning of these antivirals must also be clarified: preventive administration in exposed contacts, early curative treatment in symptomatic infection, or targeted deployment to reduce progression to severe disease in specific populations. These scenarios imply different expectations in terms of speed of action, treatment adherence, and impact on community-level transmission but also on the cost of the treatment [62,65].

Therapeutic monoclonal antibodies have emerged as a complementary approach that can bridge prophylaxis and early intervention. Broadly neutralizing antibodies directed against conserved epitopes, including EDE-targeting antibodies, have demonstrated potent cross-serotype activity in preclinical and early clinical studies [76–80]. Fc-engineered, bispecific and combination formats may reduce enhancement risk and constrain the emergence of escape variants, yet important mechanistic and clinical questions remain [84–86].

The optimal use and clinical positioning of these therapeutic tools remain to be defined, including their relative value as preventive or curative interventions and the populations most likely to benefit. Furthermore, in the context of dengue virus infection, the use of antibodies is inextricably linked to the risk of ADE. This raises important questions regarding residual antibody concentrations following preventive administration or curative treatment. Additionally, advances in antibody engineering, such as YTE and LALA Fc modifications, raise important questions regarding half-life extension and effector-function modulation. While these modifications could be beneficial in preventive treatment, subsequent doses would need to be administered within a strict time window to limit the risk of ADE. Moreover, increasing the serum half-life of antibodies would reduce the number of injections required, and therefore the cost of treatment. Another consideration is whether to add the TM mutation to the Fc fragment, which reduces effector function. This could be beneficial for preventive treatment, as it would minimize the risk of ADE. However, in the context of both preventive and curative treatment, it could reduce the antibody's antiviral activity, particularly against a strain that is not well neutralized due to the genetic variability of DENV.

A key contribution of this review is the integration of preventive and therapeutic strategies within a unified framework spanning the full course of dengue infection, from pre-exposure vaccination to early antiviral treatment. Taken together, advances across vaccines, antiviral molecules, and monoclonal antibodies indicate that dengue control is unlikely to rely on a single technology, but rather on coordinated and complementary strategies [30,32,36,62,80].

Access to various tools that can contribute to both the prevention and treatment of dengue will rapidly raise the question of their potential contribution to global public health. The realistic objectives for the coming decade are to reduce severe disease and hospitalization, protect high-risk populations, and mitigate outbreak amplification in endemic regions [9]. Achieving these outcomes will require sustained mechanistic research, adaptive trial designs, strengthened genomic and immunological surveillance, and closer alignment between biomedical innovation and public-health implementation [13,30,32]. Their implementation will also require substantial financial investment to support the deployment of vaccines and antivirals, which remains challenging in many endemic countries. A global effort, particularly on the part of countries with the financial means to do so, will therefore be necessary, notably through charitable or non-governmental organizations. Similar international initiatives have previously been implemented for other infectious diseases and could serve as a model for dengue.

In the long term, the question of the contribution of these therapeutic tools to the eradication of dengue will arise. Global eradication currently appears unrealistic, due to the vastness of the areas where the disease is present, the limited resources of some of them, the existence of sylvatic cycles, and the possibility of retro-zoonotic cycles. However, local eradication can be considered, particularly if human therapies, which limit the existence, the duration or intensity of viremia (and therefore the risk of infection of new mosquitoes), are combined with emerging vector control techniques that can either limit mosquito populations (e.g. sterile insect technologies) or render them poorly competent for dengue transmission (e.g. Wolbachia-based technologies). Future progress will likely depend on such combined approaches to provide effective protection for exposed populations.

Disclosure statement

Figure elements and graphical layout were created using BioRender artificial intelligence-assisted tools (DeepL (26.1.1.19426 + f5541b2b2a326680f620ca50469b08abfda5acc1) and ChatGPT/OpenAI GPT-5.5), which were used exclusively for language editing, figure refinement, and visual optimization under full author supervision. All scientific content, interpretation, and final editorial decisions were performed and validated by the authors. No potential conflict of interest was reported by the author(s).