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Dengue vaccine clinical trials in India — An opportunity to inform the global response to a re-emerging disease challenge

2019; Elsevier BV; Volume: 84; Linguagem: Inglês

10.1016/j.ijid.2019.03.016

1878-3511

Anthony S. Fauci, Emily J. Erbelding, Stephen S. Whitehead, M. Cristina Cassetti, F. Gray Handley, Ranjan Gupta,

Malaria Research and Control

Dengue viral disease or dengue fever (DF) is among the most important globally re-emerging infectious diseases of the 21st century. The World Health Organization (WHO) estimates that every year 50–100 million symptomatic dengue virus (DENV) infections occur worldwide, resulting in approximately 500,000 hospitalizations, and 22,000 deaths, with most cases occurring in children (Bhatt et al., 2013Bhatt S. Gething P.W. Brady O.J. Messina J.P. Farlow A.W. Moyes C.L. et al.The global distribution and burden of dengue.Nature. 2013; 496: 504-507https://doi.org/10.1038/nature12060Crossref PubMed Scopus (5773) Google Scholar, Gubler, 2002Gubler D.J. Epidemic dengue/dengue hemorrhagic fever as a public health, social and economic problem in the 21st century.Trends Microbiol. 2002; 10: 100-103https://doi.org/10.1016/S0966-842X(01)02288-0Abstract Full Text Full Text PDF PubMed Scopus (1157) Google Scholar, Stanaway et al., 2016Stanaway J.D. Shepard D.S. Undurraga E.A. Halasa Y.A. Coffend L.E. 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Dengue viral infection can have serious clinical manifestations, such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) (Whitehead et al., 2007Whitehead S.S. Blaney J.E. Durbin A.P. Murphy B.R. Prospects for a dengue virus vaccine.Nat Rev Microbiol. 2007; 5: 518-528https://doi.org/10.1038/nrmicro1690Crossref PubMed Scopus (453) Google Scholar, World Health Organization, 1997World Health Organization Dengue haemorrhagic fever; diagnosis, treatment prevention and control.2nd ed. World Health Organization, Geneva1997Google Scholar). DHF is characterized by increased vascular permeability and plasma leakage; DSS is a more severe presentation of DHF where the plasma leakage is so extensive that the patient goes into shock (Kalayanarooj, 2011Kalayanarooj S. Clinical manifestations and management of Dengue/DHF/DSS.Trop Med Health. 2011; 39: 83-87https://doi.org/10.2149/tmh.2011-S10Crossref PubMed Scopus (101) Google Scholar). Major dengue epidemics, particularly in low-resource settings, can severely impact communities, overstretch medical and public health capacities, lower economic productivity, and strain resources on a national scale. Although dengue has been reported in Asia and Africa for hundreds of years, it has recently grown in public health importance in many regions, including the Western Hemisphere. In part, this is due to mosquito vector proliferation and dispersion, which has been linked to globalization, possibly including the earlier transport of enslaved individuals from Africa. This historic link is illustrated in the origins of the name "dengue", which is rooted in the Swahili term "Ka-dinga pepo," meaning "cramp-like seizure." In 1780, Benjamin Rush described a dengue outbreak in Philadelphia and coined a similar term: "break bone fever." Some of the earliest cases of DF and probable DHF/DSS were described in India in the 1870s (Laughlin et al., 2012Laughlin C.A. Morens D.M. Cassetti M.C. Denis A.C.S. San Martin J.L. Whitehead S.S. Fauci A.S. Dengue research opportunities in the Americas.JID. 2012; 206: 1121-1127https://doi.org/10.1093/infdis/jis351Crossref PubMed Scopus (54) Google Scholar). The global resurgence of dengue viral disease in more than 60 countries makes it a classic example of a re-emerging infectious disease with a significant and widespread public health impact. The primary vector for DENV is the Aedes aegypti mosquito, which has become well-established in tropical and sub-tropical regions while adapting well to urban environments. In addition, an alternative DENV vector, Aedes albopictus, has spread into temperate geographical regions, further expanding the global range of the virus. As witnessed throughout history, human activities including migration, travel, and urbanization, as well as climatic changes such as rising global temperatures likely have facilitated the expansion and establishment of dengue-carrying mosquito vectors. Currently, it is estimated that at least 2.5 billion people live in the tropical and contiguous temperate areas where dengue occurs, and even more people will be in harm's way as the range of DENV vectors expands (Gupta et al., 2012Gupta N. Srivastava S. Jain A. Chaturvedi U.C. Dengue in India.Indian J Med Res. 2012; 136: 373-390PubMed Google Scholar, Morens, 1994Morens D.M. Antibody-dependent enhancement of infection and the pathogenesis of viral disease.Clin Infect Dis. 1994; 19: 500-512https://doi.org/10.1093/clinids/19.3.500Crossref PubMed Scopus (248) Google Scholar, Morens and Fauci, 2008Morens D.M. Fauci A.S. Dengue and hemorrhagic fever: a potential threat to public health in the United States.JAMA. 2008; 299: 214-216https://doi.org/10.1001/jama.2007.31-aCrossref PubMed Scopus (150) Google Scholar, Morens et al., 2013Morens D.M. Folkers G.K. Fauci A.S. Dengue: the continual re-emergence of a centuries-old disease.EcoHealth. 2013; 10: 104-106https://doi.org/10.1007/s10393-013-0825-7Crossref Scopus (5) Google Scholar). DENV infection may present clinically in various ways, ranging from asymptomatic infections to more severe presentations with complications such as DHF or DSS. Much remains to be learned about the pathogenesis, immunology, and epidemiology of DENV infection and resulting disease. For example, successive heterologous infection by any of the four strains of dengue, depending on timing of exposure and host immune response, can lead to a more severe clinical presentation, a phenomenon that many attribute to antibody-dependent enhancement (ADE) (Morens, 1994Morens D.M. Antibody-dependent enhancement of infection and the pathogenesis of viral disease.Clin Infect Dis. 1994; 19: 500-512https://doi.org/10.1093/clinids/19.3.500Crossref PubMed Scopus (248) Google Scholar, Porterfield, 1982Porterfield J.S. Immunological enhancement and the pathogenesis of dengue haemorrhagic fever.J Hyg Camb. 1982; 89: 355-364https://doi.org/10.1017/S0022172400070923Crossref Scopus (21) Google Scholar). Currently, there are no licensed dengue-specific therapeutics, nor are any candidate drugs in late-stage development. Treatments such as fluid and electrolyte replacement, to mitigate the capillary leak syndrome associated with DHF and DSS, and the administration of blood or blood products during hemorrhage are often helpful; however, they can be difficult to implement in remote or resource-limited areas. Immune-mediated therapies, such as convalescent plasma or monoclonal antibodies, may not be effective because the virus is cleared from the blood by the immune system prior to the beginning of shock syndrome; furthermore, such approaches may lead to antibody-mediated immunopathogenesis. Public health measures, such as vector control, can be quite effective at preventing dengue viral infections. However, these measures remain challenging because the mosquito vectors rapidly evolve to avoid chemo-prevention and expand their ability to live in harsh environments. Given that the development of effective therapeutic interventions is unlikely in the short term, and that more reliable, long-term vector control remains elusive, the development of dengue vaccine candidates that can protect against all four dengue serotypes remains a top priority. However, vaccine development has been hindered by the lack of a reliable animal model and other technical concerns. In addition, safety concerns, such as the possibility of vaccine-induced ADE causing acute disease, have emerged in relation to one vaccine candidate, Dengvaxia™ (Whitehead et al., 2017Whitehead S.S. Durbin A.P. Pierce K.K. Elwood D. McElvany B.D. Fraser E.A. et al.In a randomized trial, the live attenuated tetravalent dengue vaccine TV003 is well-tolerated and highly immunogenic in subjects with flavivirus exposure prior to vaccination.PLoS Negl Trop Dis. 2017; 11e0005584https://doi.org/10.1371/journal.pntd.0005584Crossref Scopus (67) Google Scholar, Guy et al., 2011Guy B. Barrere B. Malinowski C. Saville M. Teyssou R. Lang J. From research to phase III: preclinical, industrial and clinical development of the Sanofi Pasteur tetravalent dengue vaccine.Vaccine. 2011; 29: 7229-7241https://doi.org/10.1016/j.vaccine.2011.06.094Crossref PubMed Scopus (249) Google Scholar, Guy and Jackson, 2016Guy B. Jackson N. Dengue vaccine: hypotheses to understand CYD-TDV-induced protection.Nat Rev Microbiol. 2016; 14: 45-54https://doi.org/10.1038/nrmicro.2015.2Crossref PubMed Scopus (135) Google Scholar, Guy et al., 2017Guy B. Noriega F. Ochiai R.L. L'azou M. Delore V. 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Protective and immunological behavior of chimeric yellow fever dengue vaccine.Vaccine. 2016; 34: 1643-1647https://doi.org/10.1016/j.vaccine.2016.02.004Crossref PubMed Scopus (128) Google Scholar, World Health Organization, 2018World Health Organization Dengue vaccine: WHO Position Paper — September 2018.Wkly Epidemiol Rec. 2018; 36 (Available at http://apps.who.int/iris/bitstream/handle/10665/274315/WER9336.pdf?ua=1): 457-476Google Scholar, Wilder-Smith et al., 2018Wilder-Smith A. Hombach J. Ferguson N. Selgelid M. O'Brien K. Vannice K. et al.Deliberations of the strategic advisory group of experts on immunization on the use of CDY-TDV dengue vaccine.Lancet Infect Dis. 2018; S1473–3099: 30494-30498https://doi.org/10.1016/S1473-3099(18)30494-8Abstract Full Text Full Text PDF Scopus (88) Google Scholar, Whitehead and Subbarao, 2018Whitehead S.S. Subbarao K. Which dengue vaccine approach is the most promising, and should we be concerned about enhanced disease after vaccination? The risks of incomplete immunity to dengue virus revealed by vaccination.Cold Spring Harb Perspect Biol. 2018; 10 (pii:a028811)https://doi.org/10.1101/cshperspect.a028811Crossref Scopus (15) Google Scholar). In India, dengue is a long-standing public health problem. In addition to the significant health impacts and loss of life, it has been estimated that dengue costs India approximately $1.11 billion annually (Shepherd et al., 2014Shepherd D.S. Halasa Y.A. Tyagi B.K. Adhish S.V. Nandan D. Karthiga K.S. et al.Economic and disease burden of dengue illness in India.Am J Trop Med Hyg. 2014; 91: 1235-1242https://doi.org/10.4269/ajtmh.14-0002Crossref Scopus (108) Google Scholar). It is also likely that these estimates are lower than the true burden, as many asymptomatic or mild symptomatic infections may not be detected or reported. To address this re-emerging threat, the Department of Biotechnology (DBT) under the Indian Ministry of Science and Technology, the Department of Health Research/Indian Council of Medical Research (DHR/ICMR) of the Indian Ministry of Health and Family Welfare, and the National Institute of Allergy and Infectious Diseases (NIAID) of the U.S. National Institutes of Health, Department of Health and Human Services have decided to prioritize collaborative research on promising dengue vaccine candidates. To foster this research, Indian and U.S. scientists and scientific leaders have launched an initiative within the Indo-U.S. Vaccine Action Program (VAP). Founded in 1987, the VAP was established based on the premise that vaccines are among the most cost-effective health technologies and their widespread use is key to controlling the burden of vaccine-preventable diseases worldwide. VAP remains a vital research support entity and has received funding from both public and private sources to facilitate research on global priorities including malaria, tuberculosis, and enteric diseases. As an example of its effectiveness, VAP facilitated research and development that resulted in India's first indigenous rotavirus vaccine, which is projected to save the lives of approximately 80,000 children per year in India (National Institute of Allergy and Infectious Diseases and Department of Biotechnology, 2012National Institute of Allergy and Infectious Diseases Department of Biotechnology Indo US vaccine action program: 25 years of partnership — 1987–2012.Commemorative silver jubilee publication. 2012Google Scholar; National Institute of Allergy and Infectious Diseases, 2019National Institute of Allergy and Infectious Diseases Indo-US vaccine action program.2019https://www.niaid.nih.gov/research/indo-us-vaccine-action-programGoogle Scholar; Travasso, 2015Travasso C. First rotavirus vaccine made in India is launched.BMJ. 2015; 350: h1475https://doi.org/10.1136/bmj.h1475Crossref Scopus (2) Google Scholar). Currently, the Indo-U.S. VAP is supporting various projects focused on dengue research. Specifically, this program has supported the development of a candidate dengue vaccine in India at the International Centre for Genetic Engineering and Biotechnology by providing expertise and research resources (Ramasamy et al., 2018Ramasamy V. Arora U. Shukla R. Poddar A. Shanmugam R.K. White L.J. et al.A tetravalent virus-like particle vaccine designed to display domain III of dengue epitope proteins induces multi-serotype neutralizing antibodies in mice and macaques which confer protection against antibody dependent enhancement in AG129 mice.PLoS Negl Trop Dis. 2018; 12e0006191https://doi.org/10.1371/journal.pntd.0006191Crossref Scopus (51) Google Scholar). Additionally, a candidate tetravalent dengue vaccine developed in an NIAID laboratory (Whitehead et al., 2017Whitehead S.S. Durbin A.P. Pierce K.K. Elwood D. McElvany B.D. Fraser E.A. et al.In a randomized trial, the live attenuated tetravalent dengue vaccine TV003 is well-tolerated and highly immunogenic in subjects with flavivirus exposure prior to vaccination.PLoS Negl Trop Dis. 2017; 11e0005584https://doi.org/10.1371/journal.pntd.0005584Crossref Scopus (67) Google Scholar), is now licensed to multiple Indian companies and under consideration for Phase II and III clinical trials in India. These trials will be supported by epidemiological studies and other related activities that also will help inform future public health interventions to address the dengue challenge in India. The publications included in this IJID Supplement provide some of the epidemiological context as currently understood, and other background information needed to plan and undertake such trials with oversight provided by the VAP's Candidate Vaccine Advisory Committee. To further develop medical countermeasures to reduce the burden of dengue in India and throughout the world, an interdisciplinary approach must be applied along with the integration of basic and clinical research informed by genomic and bioinformatic scientific tools. Viral genome sequences and host genetic factors may be expected to have an important role in addressing dengue by providing insights into host immune response, disease pathogenesis, and biomarkers for severity. Similarly, multifaceted studies will be essential for developing effective vector-control measures, diagnostics, therapeutics, and vaccines. Most importantly, extensive international collaboration is needed to bring together research data, materials, and resources from all affected regions for a comprehensive understanding of this global epidemic and the potential for control. This IJID Supplement provides valuable data and information to the global dengue research community to help inform future clinical trials of candidate dengue vaccines and other dengue studies, particularly in India. This article is part of a supplement entitled 'Dengue Fever in India' which is sponsored by the Department of Biotechnology, Government of India, and collated by the Translational Health Science and Technology Institute.