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Why we need a Global Dengue Alliance

Half of the world’s population is now at risk of dengue infection. There is a pressing need for an integrated approach to effectively address this growing threat to public health. While new tools for combating dengue fever have recently been developed in the field of vector control and vaccines, there is no treatment for dengue fever other than early detection and treatment of complications. The Drugs for Neglected Diseases initiative (DNDi) has recently contributed to the establishment of the Global Dengue Alliance with research institutions from dengue-endemic countries. The Alliance’s goal is to deliver a new treatment for dengue, with repurposed drugs or drug combinations, within a five-year timeframe. This initiative represents a significant leap forward by ensuring active engagement, scientific leadership, clinical guidance, and political interest from endemic countries. However, challenges persist, including the alignment of diverse partners and stakeholders, addressing knowledge gaps, leveraging information from different geographies and epidemiological settings, and securing adequate funding. Overcoming these challenges is crucial for the success of the Alliance and the development of an effective dengue treatment.

Dengue is the fastest-growing vector-borne infection in the world, caused by an arbovirus, and transmitted to humans through the bite of infected mosquitos of the Aedes species, which also transmits other flaviviruses such as Zika, chikungunya, and yellow fever. With an estimated 100–400 million infections occurring each year, half of the world’s population is now at risk of becoming infected1,2. The World Health Organization named it as one of the top ten threats to global health in 20193.

Autores:

Belén Pedrique, Terín Beca Y Neelika Malavige

Global burden of dengue

Dengue predominantly affects low- and middle-income countries (LMICs) in tropical and sub-tropical climates worldwide, mostly in urban and semi-urban areas1. The highest infection rates are found in South Asia, Southeast Asia, and Latin America, with Asia accounting for 70% of the disease burden. The incidence of dengue has continued to rise in many endemic countries in Asia and Latin America in recent years, with co-circulation of all four dengue virus serotypes (DENV1-4) reported2.

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Figure 1. A mother in Colombo, Sri Lanka, watches over her son after several family members became severely ill with dengue. Photo credit: Xabier Vahed-DNDi

Higher global temperatures increase the biting frequency and the competence of mosquitoes in transmitting dengue4. Climate change, rapid urbanization, improper waste disposal, and international travel are leading to a significant increase in the burden of dengue, overwhelming health-care system in endemic countries, and an expansion of this infection to new geographical locations. Climate change has also facilitated the spread of Aedes in temperate countries, with regular outbreaks recently documented in areas in which it was not previously common, such as the Middle East and Africa, and with small outbreaks also reported in Southern Europe and USA2.

Although all individuals in dengue-endemic regions are equally susceptible, marginalized populations bear a disproportionate burden given the cost of treating dengue and the loss of wages due to inability to work5.

Figure 2. Dr. Wanatpreeya Phongsamar with a recovering dengue patient at Siriraj Hospital in Bangkok Thailand. Sriraj is one of the Dengue Allianc

Figure 2. Dr. Wanatpreeya Phongsamar with a recovering dengue patient at Siriraj Hospital in Bangkok, Thailand. Sriraj is one of the Dengue Alliance Members. Photo credit: Luke Duggleby-DNDi.

Understanding pathogenesis for diagnosis

Most dengue infections are asymptomatic or result in mild illness, but in some people, they can lead to severe complications such as shock, severe bleeding or organ dysfunction that can be fatal1. Patients need to be closely monitored during the first days of fever to promptly identify vascular leakage and provide adequate fluid replacement to prevent complications in the critical phase, such as hypotension, shock, and fluid overload6.

Historically, dengue fever mainly affected children in endemic countries, but the current trend is towards an increase in the number of cases among adults. Young children, pregnant women, and individuals with comorbidities or presenting a secondary dengue infection experience higher incidence rates of severe disease and mortality1. Investigation of inflammatory mediators and early biomarkers to identify individuals prone to having endothelial dysfunction is essential to provide early treatment to patients progressing to vascular leakage, and to identify therapeutic targets.

Antibody dependent enhancement (ADE) has been suggested to be an important mechanism in the development of severe dengue during a secondary dengue infection. Following a primary infection, individuals develop serotype-specific neutralizing antibodies that usually provide lifelong protection. While higher levels of neutralizing antibodies protect against infection and severe disease to all serotypes, intermediate levels appear to lead to more symptomatic and severe manifestations when a new infection occurs7.

Reliable, affordable, and highly sensitive point-of-care diagnostics are essential for diagnosing dengue at the time of presentation to a healthcare facility. Diagnosing dengue fever is challenging because of the similarities between the clinical symptoms at onset of the disease and common infections such as COVID-19, influenza, or malaria; and because of the low sensitivity and specificity of existing point-of-care diagnostic tests. Serological assays face interpretation challenges due to the presence of cross-reactive IgG in regions with co-circulating flaviviruses1,8.

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Figure 3. Dengue researchers at Sri Jayawardenepura University in Colombo, Sri Lanka. Photo credit: Xavier Vahed-DNDi

Vector control

The main strategy adopted until now to reduce the burden of dengue is vector control. Traditional methods have relied on preventing contact between the vector and host at the household level, with measures such as mosquito nets, repellents, and insecticide spraying. However, implementing these methods is difficult and costly, and mosquitoes can develop resistance to insecticides. An innovative strategy involves releasing Wolbachia infected mosquitoes. Wolbachia is a bacterium that hampers the virus’s ability to replicate in the vector, thereby reducing dengue transmission by Aedes mosquitoes. Although these techniques hold promise for reducing the incidence of dengue, it is unlikely that vector control alone will be sufficient to reduce the overall burden of dengue9.

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Figure 4: Village Health Volunteer adds temefos powder to water containers and all potential breeding zone of the larvae in a house, teaching residents how to use the product, in the Klong Toey community in Bangkok, 2022. Temefos is a larvicide that is administered to standing water that kills the aedes larvae by inhibiting their nervous system. Photo credit: Luke Duggleby-DNDi

Dengue vaccines

The existing dengue vaccines, namely CYD-TDV (Dengvaxia) and TAK-003 (QDENGA), have demonstrated effectiveness in reducing hospitalizations, particularly in individuals already seropositive for dengue. However, both vaccines exhibit some degree of waning immunity over time, particularly in seronegative individuals and their efficacy is limited against certain DENV serotypes.

These two dengue vaccines are in the process of registration in different countries, and another vaccine candidate (TV003) is undergoing phase 3 trial. All current vaccine candidates are tetravalent live attenuated vaccines. Therefore, it is crucial to assess whether mRNA vaccines could elicit a DENV-specific immune response of higher magnitude and longer duration10.

Treatment for dengue and challenges

There is no specific treatment for dengue, and the management of patients is limited to symptomatic relief and close monitoring for warning signs that may indicate progression to severe dengue, and early treatment of complications1.

Dengue infections are associated with a relatively short viremia, with viral loads decreasing after 72 hours, particularly in secondary dengue infections. Therefore, novel direct-acting antiviral agents to reduce or inhibit viral replication should be administered very early to prevent progression to severe disease. Ongoing research also includes drugs inhibiting host mediators, like mast cell products, that play a substantial role in disease progression. Specific monoclonal antibodies are also being investigated as potential therapies administered early in the illness.

There is an urgent need to discover safe, effective, affordable, and accessible treatments for dengue to prevent disease progression and potentially reduce hospitalizations and the substantial costs associated with outpatient monitoring of patients. Given that patients typically seek medical attention after 72 hours of fever, a combination of antiviral and host-directed therapy holds the potential for the most effective therapeutic outcome11.

Global Dengue Alliance

The Drugs for Neglected Diseases initiative (DNDi), a not-for-profit research organization created in 2003 to develop new treatments for neglected patients, has recently supported the constitution of the Global Dengue Alliance. This alliance, formed by institutions from dengue-endemic countries such as the Faculty of Medicine at Siriraj Hospital, Mahidol University in Thailand; the Ministry of Health in Malaysia; the Translational Health Science and Technology Institute in India; the Oswaldo Cruz Foundation in Brazil; and the Federal University of Minas Gerais in Brazil, aims to expedite research and development and deliver dengue therapeutics through a collaborative partnership model. The mission is to provide a new treatment for dengue within five years by exploring repurposed drugs, drug combinations, and novel antivirals in development by pharmaceutical companies. The Alliance is co-created, co-owned, and co-funded by research institutions from dengue-endemic countries, with a governance mechanism for collaborative decision-making at different levels11-13.

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Figure 5. Dengue Alliance Meeting. Photo credit:
Sumit Sharma-DNDi

The Alliance has established a preclinical working group, a clinical working group, and a translational working group to facilitate effective communication and scientific planning. These groups contribute to the Joint Steering Committee, responsible for realizing the vision and mission of the Alliance. Through the collaboration of partners, existing knowledge, experience, technologies, and capabilities are shared to jointly validate preclinical assays. The initial focus is on identifying currently available drugs for repurposing as dengue therapeutics. Simultaneously, clinicians from endemic countries, with extensive experience in treating dengue patients, contribute to clinical trials design with selected drug candidates. The first trials are expected to be launched in 202411.

The creation of the Global Dengue Alliance is a significant step toward developing a dengue treatment that is adapted to the specific needs of LMICs by bringing together resources from endemic countries, and ensuring their engagement, scientific leadership, clinical guidance, and political interest. The working groups and steering committee coordinate efforts to address knowledge gaps in epidemiology, biomarkers, diagnostics, clinical trials, and regulatory frameworks while promoting open science11-13.

Although the Alliance currently has a limited number of partners, it is open to collaborations with new groups and key stakeholders in therapeutics and diagnostics. Its collaborative model faces some challenges, such as in aligning diverse members and addressing knowledge gaps across different geographies and epidemiological settings. In addition, conducting clinical trials for dengue treatment can be challenging due to the seasonal nature of the disease, exacerbated by climate change, making disease patterns more unpredictable.

Climate change represents an increasing threat to human health and over half of infectious diseases are aggravated by climatic hazards, according to a 2022 study published by Nature14. There is therefore a growing interest by donor organizations in understanding the true burden of dengue, and the devastating impact it has on health systems and patients in endemic countries. However, securing funding to support the development of new treatments for dengue remains a significant obstacle.

Most efforts to control dengue are currently focusing on vectors control and vaccines; but we also need an effective treatment. An integrated approach that encompasses these three elements is essential to confront the escalating challenges posed by dengue infection globally11-13.

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Autores:

Belén Pedrique 
Epidemiologist and Senior Medical Manager. Drugs for Neglected Diseases initiative.
bpedrique@dndi.org

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Neelika Malavige
Head of Global Dengue Program. Drugs for Neglected Diseases initiative.
Professor at the Department of Immunology and Molecular Medicine, University of Sri Jayewardenepura, Sri Lanka.

Tel: +94772443193
gnmalavige@dndi.org
@GMalavige

Investigacion firma Terin

Terín Beca
Medical doctor in Preventive Medicine and Public Health.
Consultant at Drugs for Neglected Diseases initiative.
Associate Professor at the Camilo Jose Cela University.

tbeca@extern.dndi.org
@tblue1916

Referencias:

  1. World Health Organization. Dengue and severe dengue [Internet]. 2023. Available from: https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue
  2. World Health Organization. Geographical expansion of cases of dengue and chikungunya beyond the historical areas of transmission in the Region of the Americas [Internet]. 2023. Available from: https://www.who.int/emergencies/disease-outbreak-news/item/2023-DON448
  3. World Health Organizaton. Ten threats to global health in 2019 [Internet]. Available from: https://www.who.int/news-room/spotlight/ten-threats-to-global-health-in-2019
  4. Ryan SJ, Carlson CJ, Mordecai EA, Johnson LR. Global expansion and redistribution of Aedes-borne virus transmission risk with climate change. Han BA, editor. PLoS Negl Trop Dis [Internet]. 2019 Mar 28;13(3):e0007213. Available from: https://dx.plos.org/10.1371/journal.pntd.0007213
  5. Mulligan K, Dixon J, Joanna Sinn C-L, Elliott SJ. Is dengue a disease of poverty? A systematic review. Pathog Glob Health [Internet]. 2015 Feb;109(1):10–8. Available from: http://www.tandfonline.com/doi/full/10.1179/2047773214Y.0000000168
  6. Yacoub S, Lam PK, Vu LHM, Le TL, Ha NT, Toan TT, et al. Association of Microvascular Function and Endothelial Biomarkers With Clinical Outcome in Dengue: An Observational Study. J Infect Dis [Internet]. 2016 Sep 1;214(5):697–706. Available from: https://academic.oup.com/jid/article-lookup/doi/10.1093/infdis/jiw220
  7. Katzelnick LC, Gresh L, Halloran ME, Mercado JC, Kuan G, Gordon A, et al. Antibody-dependent enhancement of severe dengue disease in humans. Science (80- ) [Internet]. 2017 Nov 17;358(6365):929–32. Available from: https://www.science.org/doi/10.1126/science.aan6836
  8. Simo FBN, Bigna JJ, Kenmoe S, Ndangang MS, Temfack E, Moundipa PF, et al. Dengue virus infection in people residing in Africa: a systematic review and meta-analysis of prevalence studies. Sci Rep [Internet]. 2019 Sep 20;9(1):13626. Available from: https://www.nature.com/articles/s41598-019-50135-x
  9. Utarini A, Indriani C, Ahmad RA, Tantowijoyo W, Arguni E, Ansari MR, et al. Efficacy of Wolbachia-Infected Mosquito Deployments for the Control of Dengue. N Engl J Med [Internet]. 2021 Jun 10;384(23):2177–86. Available from: http://www.nejm.org/doi/10.1056/NEJMoa2030243
  10. Thomas SJ. Is new dengue vaccine efficacy data a relief or cause for concern? npj Vaccines [Internet]. 2023 Apr 15;8(1):55. Available from: https://www.nature.com/articles/s41541-023-00658-2
  11. Science TH. Treatments for dengue: a Global Dengue Alliance to address unmet needs. Lancet Glob Heal. 2023;(23):1680–1.
  12. DNDi. Dengue Alliance [Internet]. 2022. Available from: https://dndi.org/global-networks/dengue-alliance/No Title
  13. Malavige GN, Sjö P, Singh K, Piedagnel J-M, Mowbray C, Estani S, et al. Facing the escalating burden of dengue: Challenges and perspectives. Sulis G, editor. PLOS Glob Public Heal [Internet]. 2023 Dec 15;3(12):e0002598. Available from: https://dx.plos.org/10.1371/journal.pgph.0002598
  14. Mora C, McKenzie T, Gaw IM, Dean JM, von Hammerstein H, Knudson TA, et al. Over half of known human pathogenic diseases can be aggravated by climate change. Nat Clim Chang [Internet]. 2022 Sep 8;12(9):869–75. Available from: https://www.nature.com/articles/s41558-022-01426-1

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