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REVIEW ARTICLE
Year : 2016  |  Volume : 7  |  Issue : 4  |  Page : 161-164

Trends in clinical trials of dengue vaccine


Department of Pharmacology, SRM Medical College, Kattankulathur, Kanchipuram, Tamil Nadu, India

Date of Web Publication12-Oct-2016

Correspondence Address:
Priya Marimuthu
Department of Pharmacology, SRM Medical College, Kattankulathur, Kanchipuram - 603 203, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2229-3485.192035

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   Abstract 

Dengue is one of the most important vector-borne disease and an increasing problem worldwide because of current globalization trends. Roughly, half the world's population lives in dengue endemic countries, and nearly 100 million people are infected annually with dengue. India has the highest burden of the disease with 34% of the global cases. In the context of an expanding and potentially fatal infectious disease without effective prevention or specific treatment, the public health value of a protective vaccine is clear. There is no licensed dengue vaccine is available still, but several vaccines are under development. Keeping in view the rise in dengue prevalence globally, there is a need to increase clinical drug and vaccine research on dengue. This paper briefly reviews on the development and current status of dengue vaccine to provide information to policymakers, researchers, and public health experts to design and implement appropriate vaccine for prophylactic intervention.

Keywords: Clinical trials, dengue vaccine, global perspective


How to cite this article:
Marimuthu P, Ravinder JR. Trends in clinical trials of dengue vaccine. Perspect Clin Res 2016;7:161-4

How to cite this URL:
Marimuthu P, Ravinder JR. Trends in clinical trials of dengue vaccine. Perspect Clin Res [serial online] 2016 [cited 2019 Sep 23];7:161-4. Available from: http://www.picronline.org/text.asp?2016/7/4/161/192035


   Introduction Top


Dengue is the most common arthropod-borne disease in humans. The global prevalence of dengue has grown dramatically in recent decades; the disease is now endemic in more than hundred countries. Dengue is estimated to affect 50-100 million people each year in the tropical and subtropical areas. [1],[2] Of these 500,000 develop into severe forms of the disease such as dengue hemorrhagic fever and dengue shock syndrome. [3],[4]


   Dengue virus structure Top


Dengue fever, including dengue hemorrhagic fever and dengue shock syndrome, is caused by four antigenically distinct dengue viruses DENV-1, DENV-2, DENV-3, and DENV-4 belonging to genus Flavivirus of the family Flaviviridae. [4],[5] These four dengue viruses are antigenically cross-reactive. Aedes aegypti and Aedes albopictus are the major vectors for dengue virus transmission. [6] The Flavivirus virion consists of a nucleocapsid structure surrounded by a lipid bilayer containing an envelope (E) glycoprotein and a nonglycosylated membrane (M) protein. The E protein is the major surface protein with a role in receptor binding and membrane fusion, is the major immunogen during Flavivirus infection. The M protein is found in infected cells as a glycosylated precursor, premembrane (prM) protein. The other nonstructural proteins are NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. The similarity in antigenic structure of the four types of DENV is closely related to the similar manifestations of dengue diseases. [7]


   Management of dengue fever Top


The affected patients develop high fever, headache, and muscle and joint pain, from which almost all cases recover, whereas dengue hemorrhagic fever patients develop plasma leakage and hemorrhagic manifestations, which may lead to shock. [8] Currently, management of dengue virus infections relies on control measures targeting personnel prophylactic measures, environmental management, and source reduction. [9],[10]


   Dengue vaccine research and trials Top


Vaccines are considered as one of the major contributions of the 20 th century and one of the most cost-effective public health interventions. In the situation of growing and potentially fatal infectious disease without effective prevention or specific treatment, the value of a protective vaccine is clear. There is no licensed dengue vaccine is available still, but some vaccines are under development, including live attenuated virus vaccines, live chimeric virus vaccines, inactivated virus vaccines, live recombinant, DNA, and subunit vaccines as shown in [Figure 1].
Figure 1: Types of dengue vaccine

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Sixty years back, efforts to develop a dengue vaccine was with attempts to prevent virus transmission using infectious human plasma treated with ox virus grown in live mosquitoes and inactivated with formalin. [11] Schlesinger et al. and Sabin made the first attempt to immunize using mouse-passaged live-attenuated DENV-1 and -2 viruses in 1956. [12],[13] Mahidol University and Sanofi Pasteur tried to develop live-attenuated virus dengue vaccine candidates using primary dog kidney (PDK) cell passage in 2004; the Walter Reed Army Institute of Research and GlaxoSmithKline Biologicals also used PDK passage to attenuate vaccine virus strain candidates in. [14],[15] The US National Institutes of Allergy and Infectious Diseases attenuated DENV strains by targeted mutagenesis; the resulting DENV strains served as chimeric backbones. [16],[17]


   Dengue vaccine clinical trials - Global perspectives Top


Despite intense research efforts over more than 60 years, no dengue vaccine is commercially available. [10],[18] This paper briefly gives the current status of dengue vaccine development globally to provide information to policy makers, researchers, public health experts to design and implement appropriate vaccine as a prophylactic intervention.

We used clinical drug trial registry of US and did an Analytical study of Dengue Vaccine Trials registered in clinicaltrials.gov from January 1, 2003, to July 3, 2013. Search was done using "Advanced search" at "search terms" and "conditions." Data collected were subjected to descriptive analysis using Microsoft Excel software. Results were given in percentage comparison.

A total number of study registered in clinical trial registry is 183,504. The number of studies for vaccines is 4032 which accounts for 2.5% of the total clinical trials which is shown in [Figure 2]. Out of 4032 vaccine trials, sixty studies were registered for dengue vaccine. Among it, 31 trials in are in Phase 1, 23 trials in Phase 2, and 6 trials in Phase 3 of development. The different types of dengue vaccine under clinical trials are shown in [Figure 3].
Figure 2: Percentage of vaccine trials registered in clinical trials.gov

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Figure 3: Number of dengue vaccines in clinical trials

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   Discussion Top


Live attenuated virus vaccines contain weakened viruses that can induce adaptive immune responses to both structural and nonstructural proteins. Tetravalent vaccine would be highly desirable for a safe and effective dengue vaccine as immunization with a single type of dengue virus may present a risk of increased disease severity to later infection with a different type of dengue virus. [19],[20],[21]

Live chimeric virus vaccines are the most advanced product, in which specific proteins from one virus are substituted for those of another virus. For dengue vaccine, chimeric viruses are constructed by exchanging the prM/E genes of each of DENV1-4 for homologous genes of the yellow fever virus strain 17D. In Phase 2 studies, the tetravalent CVD vaccine appeared safe. [22],[23] Sanofi Pasteur is in advanced clinical development (Phase 3) of a chimeric yellow fever dengue vaccine, to enter clinical endpoint trials. [24],[25] Currently, one chimeric dengue vaccine trial is carried out in India. [26]

Inactivated virus vaccines have two advantages over live virus vaccines; there is no possibility of reverting to virulence and can induce balanced immune responses. Recent advances in genetic engineering technology have stimulated research on dengue vaccine using live recombinant DNA and subunit vaccines. [27] The challenges in the development of dengue vaccine are the four dengue serotypes circulate globally, so the vaccine must be tetravalent. [28] Neutralizing titers to all four viruses need to be attained despite the previous immune status of the vaccinated individuals.


   Conclusion Top


The global burden of dengue is significant, and the existing clinical trials for dengue vaccines are lower in the global context. Vaccination would be an immense value and an essential tool in prevention and control of dengue. Keeping in view the rise in dengue prevalence globally, there is a great need to increase vaccine research on dengue with applications of novel technologies for vaccine development and expansion of vaccine developers with the prospective to provide clinical benefit.

Acknowledgment

We thank Prof. Dr. James Pandian, MS., M.Ch (Plastic), Dean, SRM Medical College Hospital and Research Centre, Potheri for support in the conduct of the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

1.
Dash AP, Bhatia R, Kalra NL. Dengue in South-East Asia: An appraisal of case management and vector control. Report of the World Health Organization, Regional Office for South-East Asia: Dengue Bulletin. New Delhi: WHO. 2012. Vol 36: p. 2-4.  Back to cited text no. 1
    
2.
Simmons CP, Farrar JJ, Nguyen VV, Wills B. Dengue. N Engl J Med 2012;366:1423-32.  Back to cited text no. 2
[PUBMED]    
3.
Guzman MG, Halstead SB, Artsob H, Buchy P, Farrar J, Gubler DJ, et al. Dengue: A continuing global threat. Nat Rev Microbiol 2010;8 12 Suppl: S7-16.  Back to cited text no. 3
    
4.
Halstead SB. Dengue. Lancet 2007;370:1644-52.  Back to cited text no. 4
[PUBMED]    
5.
Lindenbach BD, Thiel HJ, Rice CM. Flaviviridae: The viruses and their replication. In: Knipe DM, Howley PM, editors. Fields Virology. 5 th ed. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 1101-52.  Back to cited text no. 5
    
6.
Rodhain F, Rosen L. Mosquito vectors and dengue virus-vector relationships. In: Gubler DJ, Kuno G, editors. Dengue and Dengue Hemorrhagic Fever. London: CAB International; 1997. p. 45-60.  Back to cited text no. 6
    
7.
Konishi E. Issues related to recent dengue vaccine development. Trop Med Health 2011;39 4 Suppl: 63-71.  Back to cited text no. 7
    
8.
World Health Organization. Dengue Guidelines for Diagnosis, Treatment, Prevention and Control. Geneva: World Health Organization; 2009.  Back to cited text no. 8
    
9.
Hombach J. Vaccines against dengue: A review of current candidate vaccines at advanced development stages. Rev Panam Salud Publica 2007;21:254-60.  Back to cited text no. 9
[PUBMED]    
10.
Luz PM, Grinsztejn B, Galvani AP. Disability adjusted life years lost to dengue in Brazil. Trop Med Int Health 2009;14:237-46.  Back to cited text no. 10
[PUBMED]    
11.
Simmons JS, St John JH, Reynolds FH. Experimental studies of dengue. Philipp J Sci 1931;44:1-252.  Back to cited text no. 11
    
12.
Schlesinger RW, Gordon I, Frankel JW, Winter JW, Patterson PR, Dorrance WR. Clinical and serologic response of man to immunization with attenuated dengue and yellow fever viruses. J Immunol 1956;77:352-64.  Back to cited text no. 12
    
13.
Wisseman CL, Sweet BH, Rosenzweig EC, Eylar OR. Attenuated living type 1 dengue vaccines. Am J Trop Med Hyg 1963;12:620-3.  Back to cited text no. 13
    
14.
Sabchareon A, Lang J, Chanthavanich P, Yoksan S, Forrat R, Attanath P, et al. Safety and immunogenicity of tetravalent live-attenuated dengue vaccines in Thai adult volunteers: Role of serotype concentration, ratio, and multiple doses. Am J Trop Med Hyg 2002;66:264-72.  Back to cited text no. 14
[PUBMED]    
15.
Simasathien S, Thomas SJ, Watanaveeradej V, Nisalak A, Barberousse C, Innis BL, et al. Safety and immunogenicity of a tetravalent live-attenuated dengue vaccine in flavivirus naive children. Am J Trop Med Hyg 2008;78:426-33.  Back to cited text no. 15
[PUBMED]    
16.
Blaney JE Jr., Durbin AP, Murphy BR, Whitehead SS. Targeted mutagenesis as a rational approach to dengue virus vaccine development. Curr Top Microbiol Immunol 2010;338:145-58.  Back to cited text no. 16
    
17.
Wright PF, Durbin AP, Whitehead SS, Ikizler MR, Henderson S, Blaney JE, et al. Phase 1 trial of the dengue virus type 4 vaccine candidate rDEN4{Delta} 30-4995 in healthy adult volunteers. Am J Trop Med Hyg 2009;81:834-41.  Back to cited text no. 17
[PUBMED]    
18.
Guy 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;29:7229-41.  Back to cited text no. 18
[PUBMED]    
19.
Halstead SB, Vaughn DW. Dengue vaccines. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 5 th ed. Maryland Heights: Saunders Elsevier; 2008. p. 1155-61.  Back to cited text no. 19
    
20.
Durbin AP, Whitehead SS. Dengue vaccine candidates in development. Curr Top Microbiol Immunol 2010;338:129-43.  Back to cited text no. 20
[PUBMED]    
21.
Morrison D, Legg TJ, Billings CW, Forrat R, Yoksan S, Lang J. A novel tetravalent dengue vaccine is well tolerated and immunogenic against all 4 serotypes in flavivirus-naive adults. J Infect Dis 2010;201:370-7.  Back to cited text no. 21
[PUBMED]    
22.
Huang CY, Butrapet S, Pierro DJ, Chang GJ, Hunt AR, Bhamarapravati N, et al. Chimeric dengue type 2 (vaccine strain PDK-53)/dengue type 1 virus as a potential candidate dengue type 1 virus vaccine. J Virol 2000;74:3020-8.  Back to cited text no. 22
[PUBMED]    
23.
Sabchareon A, Wallace D, Sirivichayakul C, Limkittikul K, Chanthavanich P, Suvannadabba S, et al. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: A randomised, controlled phase 2b trial. Lancet 2012;380:1559-67.  Back to cited text no. 23
[PUBMED]    
24.
Guy B, Saville M, Lang J. Development of Sanofi Pasteur tetravalent dengue vaccine. Hum Vaccin 2010;6:9.  Back to cited text no. 24
    
25.
Thomas SJ. The necessity and quandaries of dengue vaccine development. J Infect Dis 2011;203:299-303.  Back to cited text no. 25
[PUBMED]    
26.
Available from: http://www.clinicaltrial.gov. [Last accessed on 2013 Sep 16].  Back to cited text no. 26
    
27.
Raviprakash K, Defang G, Burgess T, Porter K. Advances in dengue vaccine development. Hum Vaccin 2009;5:520-8.  Back to cited text no. 27
[PUBMED]    
28.
Mahalingam S, Herring BL, Halstead SB. Call to action for dengue vaccine failure. Emerg Infect Dis 2013;19:1335-7.  Back to cited text no. 28
[PUBMED]    


    Figures

  [Figure 1], [Figure 2], [Figure 3]


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