Climate change driving the global burden of Dengue:why the arrival of a vaccine could not come soon
Speculated by some to be coined from the Swahili phrase ‘Ka-dinga pepo’ – loosely translated as ‘cramp-like seizure caused by an evil spirit’ – the etymology of ‘Dengue‘ is uncertain. However, the fear that has plagued communities as Dengue epidemics wax and wane over the centuries is not. Since its first historical record, in a Chinese encyclopaedia dated between 265–420 AD, Dengue has persisted through the ages with relatively infrequent, but nevertheless devastating, outbreaks till the latter half of the 20th century.  From then on Dengue enjoyed a frightening resurgence and re-emergence; to become possibly the most important human vector-borne viral disease, affecting an estimated 390 million people per year.  Indeed, over the past five decades, the incidence of dengue fever has increased 30-fold with some 50–100 million new infections estimated to occur annually in more than 100 endemic countries .
So what is responsible for this viral renaissance? Undoubtedly, it is down to a combination of factors – unprecedented population growth, uncontrolled urbanisation and sluggish mosquito control measures in endemic areas are some of the present contributors to a situation which is only exacerbated by climate change. Global warming has increased the geographical range of the mosquito vectors Aedes albopictus and Aedes aegypti, which is also responsible for transmitting the Zika virus. As such, dengue is encroaching on territories where the virus was once unheard of – Aedes albopictus is now well established in 16 European countries. Reports in 2010 of isolated indigenous infections in France and Croatia were followed two years later by Europe’s first Dengue epidemic in Madeira – an event which may not be so rare in the future, with some proposing that seasonal outbreaks in Europe may occur be the end of the century as climate change extends the spatial and temporal vector window. [4, 5, 6]
Indeed it is feared that 2016 will see a record number of cases due to the current El Niño, a climatic phenomenon every 5 years originating from the Pacific Ocean which disrupts weather patterns worldwide. Abnormally high atmospheric temperatures and unseasonal heavy rainfall drive up mosquito populations across Asia and South America by improving vector breeding conditions, which favour stagnant water in warm climates.   A recent study analysing 18 years of monthly dengue fever reports from eight countries in South-East Asia revealed that the period of highest incidence, occurring in the years 1997-1998, coincided with the most intense El Niño event of the 20th Century.  To the researchers, the correlation between the two was unmistakeable. With 2015 reaching the hottest temperatures ever recorded, it is undeniable that global warming itself, with or without the El Niño phenomenon, may have the propensity to mimic or compound nature’s cyclical forecast of dengue epidemics with increasing frequency and severity.
The clinical spectrum of dengue disease ranges from the asymptomatic to severe dengue haemorrhagic fever and dengue shock syndrome, which can be fatal. There is no cure. Unlike chicken pox or measles, those infected by dengue virus are vulnerable to re-infection. Furthermore, the risk of severe disease is actually increased in patients infected for a second time because of the existence of multiple closely related virus serotypes (DENV1 – 4). A previous infection with DENV-1 will only grant life-long immunity against DENV-1, and not against the other forms which have different foreign molecules, known as antigens, on their surface. In fact, previous exposure to DENV-1 exacerbates the severity of a future infection by a different serotype, with a greater risk of hospitalisation and death.  Historically, only a few places had more than one serotype circulating in an area.  However, with long-distance travel and urbanisation it is more common to have multiple serotypes co-existing in a location, and with that, the need to protect a growing population at risk is even more pressing.
Dengvaxia®, the world’s first vaccine against dengue fever, is the product of 20 years of development at the French pharmaceutical giant Sanofi Pasteur. A recombinant live-attenuated vaccine, it is composed of four genetically engineered viruses, each expressing the structural genes of one of the four DENV serotypes, inserted into a yellow fever DNA backbone. Thus, the vaccine viruses all express the structural antigens of the four DENV serotypes; enabling the host immune response to develop resistance against the antigenic targets of all known DENV strains, without the dangers associated with developing the disease itself.   Phase III trials suggest the vaccine may have a profound impact in reducing disease burden in people aged 9 years and older in areas with high endemicity – with significant reduction in dengue cases among both seropositive and seronegative individuals within this age group. However, the benefits of the vaccine in those younger than 9 years is unclear with trial dating suggesting an apparent increase in the risk of hospitalisation post-vaccination. 
The Philippine’s approval of Dengvaxia® in people aged 9 to 45 years and its launch in April 2016 of the world’s first public dengue vaccination programme will help clarify, as of yet, unanswered questions around the vaccine including duration of protection, cost-effectiveness and effect on overall transmission of the virus, particularly in age groups not vaccinated. [14, 15] Hence, the impact of the vaccine is yet to be fully established and endemic countries looking to follow suit will be observing closely. Maintaining efforts in the realms of surveillance, early detection of outbreaks and effective mosquito-control will continue to be critical players in a multi-pronged approach to fighting the disease. While the approval of the vaccine for public use has been hailed as ‘a major milestone in the global fight against Dengue’, cautious optimism may be wise – unlike Polio, the vaccine is unlikely to eradicate the disease completely.  In addition, the vaccine necessitates three doses: at baseline, 6 months and 12 months, which may pose a logistical challenge for many public health systems in endemic areas.  Thus, from community-based initiatives for vigilant vector control to sophisticated early warning systems and vaccine development, integration of multiple defence systems will have a synergistic effect to most efficaciously protect populations in areas with endemic disease.
With five other dengue vaccine candidates currently in clinical development, Dengvaxia® may have been the first to break new ground in the battle against Dengue but will most certainly not be the last.  As public health systems strain under the burden of Dengue fever, the advent of new, effective vaccines will be welcomed regardless of the continued challenges in mitigating the transmission and morbidity of Dengue disease.
Su Ling Yeoh is a 4th year medical student at Sidney Sussex College, University of Cambridge. Hollie French is a 2nd year undergraduate reading Biological Natural Sciences at the University of Cambridge. As a researcher on Polygeia’s Climate Change and Health Systems project, she aims to promote the One Health concept, and to complement her upcoming research project as a student at VigiLab (Vector Immunogenomics and Infection Laboratory).
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Climate change and the emergence of vector-borne diseases in Europe: case study of dengue fever. Bouzid, M; Colón-González, F J et al. (2014) BMC public health vol. 14 (1) p. 781
The 2012 Madeira Dengue Outbreak: Epidemiological Determinants and Future Epidemic Potential Lourenço J, Recker M (2014) The 2012 Madeira Dengue Outbreak: Epidemiological Determinants and Future Epidemic Potential. PLoS Negl Trop Dis 8(8): e3083.
Region-wide synchrony and travelling waves of dengue across eight countries in Southeast Asia. van Panhuis, W G; Marc, C et al. (2015) PNAS 112 (42) 13069-13074.
Dengue vaccine: hypotheses to understand CYD-TDV-induced protection. Guy, Bruno; Jackson, Nicholas (2016) Nature Reviews Microbiology 14, 45–54
“Will Dengue Vaccines Be Used in the Public Sector and If So, How? Findings from an 8-Country Survey of Policymakers and Opinion Leaders.” Douglas, D L. et al. (2013) PLoS Neglected Tropical Diseases 7.3: e2127.
Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. Hadinegoro, Sri R et al. (2015) N Engl J Med; 373:1195-1206