The dengue vaccine dilemma: route to prevention – are we there yet?

by Nor Ilham Ainaa Muhsin

Summary:

Although the Phase III clinical studies showed that Dengvaxia® was efficacious with satisfactory safety profile, we still have to continue monitoring the vaccine for long-term adverse effect by developing suitable models and active collaborations to decipher the immunological mechanisms that might be triggered by the vaccine. We also require a thorough cost-benefit analysis to determine the best option for dengue vaccination program in Malaysia. Besides, we should not neglect other approaches such as vector control and dengue hotspot identification that can benefit other mosquito-borne diseases (e.g. malaria).

Global burden of dengue

Dengue represents a global health issue as it is endemic in over 100 countries, many with tropical and sub-tropical climate, and affects nearly 40% of the world population [1] (see Figure 1). The World Health Organization estimates 50 – 100 million infections and 22,000 deaths occur annually, commonly in children [2]. The economic burden due to diagnosis, hospital treatment, time off work, impact on tourism is difficult to quantify but likely to be very high and comparable to malaria or TB. The epidemiologic and ecologic factors affecting the spread of dengue include urbanisation trends, global warming and increased global travel, which have led to large epidemics with high mortality in Southeast Asia.

Figure 1: Distribution of global dengue risk. (image credit: www.eliminatedengue.com)
Figure 1: Distribution of global dengue risk. (image credit: www.eliminatedengue.com)

Clinical aspects of dengue

Symptoms appear 3 to 14 days after infection and can range from mild to high fever with severe headache, muscle and joint pain. Dengue Hemorrhagic Fever (DHF) is a severe form of dengue and can result in persistent vomiting, abdominal pain, bleeding and breathing difficulty. There is currently no treatment for dengue fever but the symptoms can be managed and reduced by giving intravenous fluid to counteract the fluid leak from blood vessels in the critical defervescent phase.

Dengue virus and transmission

In 1903, it was demonstrated that dengue fever was caused by a viral infection transmitted by mosquitoes during feeding [3]. The primary mosquito species is Aedes aegypti, which can also transmit the chikungunya, yellow fever and Zika virus.

The dengue virus is a single positive stranded RNA virus belonging to the Flavivirus genus of the Flaviviridae family. Albert Sabin (developer of the oral polio vaccine) identified two serologically different viruses that cause dengue in 1944 and to date, four serotypes (DENV1 – 4) have been identified. These serotypes are phylogenetically and antigenically distinct and therefore can be considered as separate viruses. Infection with one dengue serotype can provide lifelong immunity against reinfection with that particular serotype, but not against the other serotypes. Secondary infection by a different serotype contributed to the majority of DHF cases [4].

Dengue in Malaysia

Malaysia ranks in the top ten countries (see Figure 2A) with the highest dengue infection and death in the world. The dengue hotspots are predominantly found in Klang Valley (60%) followed by Johor (15%). Since 2013, Malaysia has been experiencing unprecedented outbreaks (Figure 2B and 2C). In 2015, there were 120,836 cases with 336 deaths (almost 330 cases and 1 death per day) due to dengue. This outbreak was associated with a switch in the predominant circulating serotype from DENV3 and DENV4 to DENV2 in early 2013 [5].

Figure 2A: The average annual number of dengue cases reported in the 30 most endemic countries to the WHO between 2004 to 2010. (Source: www.eliminatedengue.com)
Figure 2A: The average annual number of dengue cases reported in the 30 most endemic countries to the WHO between 2004 to 2010. (Source: www.eliminatedengue.com)
Figure 2B: Number of dengue cases in Malaysia from 1995 – 2015.
Figure 2B: Number of dengue cases in Malaysia from 1995 – 2015.
Figure 2C: Number of dengue deaths in Malaysia from 1995 – 2015.
Figure 2C: Number of dengue deaths in Malaysia from 1995 – 2015.

Overview of dengue vaccine development

Scientists have been trying to develop a vaccine for dengue since the early 1930s. There are at least three main challenges for developing an effective dengue vaccine. First, one needs to achieve immunity toward all four serotypes (i.e. a tetravalent vaccine) as secondary infection with a different serotype leads to an increased risk of DHF. Secondly, it is difficult to achieve a balanced efficacy towards all four serotypes in a tetravalent vaccine formulation due to serotype interference. Finally, the lack of an animal disease model prevents the rapid testing of candidate vaccines.

Several approaches have been tried including live attenuated (where the pathogen is made safe by mutation), inactivated (using chemical, heat or irradiation), DNA vaccines and subunit vaccines. The most advanced vaccine to date is Dengvaxia®. We will now briefly review the vaccine construction and the subsequent clinical trials before discussing the merits of implementation this vaccine in Malaysia.

Construction of Dengvaxia®  vaccine

The E and prM gene in the dengue virus have been identified as essential for dengue vaccine construction [6]. The E gene encodes the envelope glycoprotein, which stimulates the production of neutralising antibody in humans. The pre-membrane protein (encoded by the prM gene) is required to process and fold the E protein into the correct 3-dimensional structure.

In early 2000, scientists from Acambis (now acquired by Sanofi-Pasteur, a French pharmaceutical company) adopted the strategy to incorporate these two genes into a yellow fever vaccine 17D strain genomic backbone (see Figure 3) to produce a recombinant, live-attenuated, tetravalent dengue vaccine (CYD-TDV), commercially known as Dengvaxia®.

Figure 3: Construction of Dengvaxia® vaccine. The E and prM genes from all serotypes were incorporated into the yellow fever vaccine backbone. (image credit: Guy et al (2015) [8])
Figure 3: Construction of Dengvaxia® vaccine. The E and prM genes from all serotypes were incorporated into the yellow fever vaccine backbone. (image credit: Guy et al (2015) [8])
Phase III clinical trial evaluation

Dengvaxia® successfully completed two phase III clinical studies in 2014 with over 30,000 participants. Participants in both trials received three doses of the vaccine over the course of a year. These studies aim to examine the efficacy of Dengvaxia® in reducing virologically-confirmed dengue and DHF. The first trial included 10,275 children aged between 2 to 14 years recruited from 11 sites in five Asian countries. The second trial included 20,869 children aged between 9 to 16 years from 22 sites in five Central and South America countries. The volunteers were randomised to vaccine and placebo groups in a 2:1 ratio. The interim result based on 1-year-follow-up from  final dose [7] is summarised in Table 1. The data for the Asian countries was stratified into the younger cohort (< 9 years) and older cohort (> 9 years).

Table 1: Main findings of the Phase III clinical studies with CYD-TDV (Dengvaxia®)
Table 1: Main findings of the Phase III clinical studies with CYD-TDV (Dengvaxia®)

This is the first dengue vaccine to reach clinical Phase 3. The overall vaccine efficacy in the older cohort was encouraging (67.8% in Asian countries and 64.7% in Latin American countries). The most striking finding from this study is that the vaccine dramatically reduced the incidence of DHF by more than 90%.

However, there are several negative findings from the trial. First, the vaccine efficacy was low in the younger cohort (44.6%) which is the group at the highest risk. The investigators hypothesised that the low efficacy in younger cohort could be due to the ongoing development of some vascular physiology such as the capillary system in young children. Secondly, the vaccine efficacy for DENV2, the predominant circulating serotype in Malaysia, was disappointingly low (36.8% in Asian countries and 50.2% in Latin American countries) even in the older cohort. Finally, the investigators also found much higher vaccine efficacy in individuals who were seropositive at baseline, indicating previous exposure to dengue virus.

Based on the interim results, the WHO recommended introducing the vaccine in highly endemic dengue countries. As of April 2016, the vaccine has been licensed in Mexico, Brazil and the Philippines. These successful authorisations will allow collaboration with the national authorities to conduct further Phase IV studies to monitor any long-term adverse effects of the vaccine in reality and the feasibility of the vaccination programme.

Dengvaxia® dilemma in Malaysia

Upon completion of Dengvaxia®’s Phase III clinical trials, the current Deputy Health Minister, Datuk Seri Hilmi Yahya announced that the vaccine will be made free for the public by mid-2015 but the decision was reversed several months later. This is due to the fact that the overall vaccine efficacy at 60% was not convincing for larger scale usage. Besides, Dengvaxia® was shown to be not as effective against the most current prevalent serotype in Malaysia, DENV2.

Professor Emeritus Dato’ Dr. Lam Sai Kit, an eminent virologist from the University of Malaya and the Immediate Past Chairman of the Asia-Pacific Dengue Vaccine to Vaccination Steering Committee rebutted the statement. His argument is that even if ineffective, vaccines recipients will still benefit from vaccination as Dengvaxia® was shown to reduce hospitalisation and severe dengue by 80-90%. This can save our public health sector tremendous amount of money each year, as the economic burden of dengue in Malaysia is approximately RM 360 million per year.

About the Author:

Nor Ilham Ainaa Muhsin is currently in her final year of studying DPhil in Molecular Genetics at University of Oxford. She is a newbie in the scientific research field but eager to put her molecular science knowledge into translational studies, which hopefully will benefit the country. An adventurous person, she enjoys nature the most and has plans to visit Malaysia’s wonderful islands and rainforests once she submitted her thesis. She is also an avid runner.

This article first appeared in the Scientific Malaysian Magazine Issue 12. Check out other articles in Issue 12 by downloading the PDF version for free here: Scientific Malaysian Magazine Issue 12 (PDF version)

References:

[1] http://www.who.int/mediacentre/factsheets/fs117/en/

[2] http://www.cdc.gov/dengue/epidemiology/

[3] Encyclopedia of Entomology, Volume 4 by John L. Capinera

[4] Halstead, S.Á., Nimmannitya, S. and Cohen, S.N., 1970. Observations related to pathogenesis of dengue hemorrhagic fever. IV. Relation of disease severity to antibody response and virus recovered. The Yale journal of biology and medicine, 42(5), p.311.

[5] Ng, L.C., Koo, C., Mudin, R.N.B., Amin, F.M., Lee, K.S. and Kheong, C.C., 2015. 2013 dengue outbreaks in Singapore and Malaysia caused by different viral strains. The American journal of tropical medicine and hygiene, 92(6), pp.1150-1155.

[6] Mellado-Sánchez, G., García-Machorro, J., Sandoval-Montes, C., Gutiérrez-Castañeda, B., Rojo-Domínguez, A., García-Cordero, J., Santos-Argumedo, L. and Cedillo-Barrón, L., 2010. A plasmid encoding parts of the dengue virus E and NS1 proteins induces an immune response in a mouse model. Archives of virology, 155(6), pp.847-856.

[7] Hadinegoro, S.R., Arredondo-García, J.L., Capeding, M.R., Deseda, C., Chotpitayasunondh, T., Dietze, R., Hj Muhammad Ismail, H.I., Reynales, H., Limkittikul, K., Rivera-Medina, D.M. and Tran, H.N., 2015. Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. New England Journal of Medicine, 373(13), pp.1195-1206.

[8] Guy, B., Briand, O., Lang, J., Saville, M. and Jackson, N., 2015. Development of the Sanofi Pasteur tetravalent dengue vaccine: One more step forward. Vaccine, 33(50), pp.7100-7111.



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