Development of a Live Attenuated Tetravalent Dengue Vaccine
Project Completed
Please click to see the final report.
  • Awarded Year
    2014
  • Awarded Amount
    $3,450,276
  • Disease
    NTDs Dengue fever
  • Intervention
    Vaccine
  • Development Stage
    Preclinical Development
  • Collaboration Partners
    The Chemo-Sero-Therapeutic Research Institute (KAKETSUKEN), Mahidol University

Introduction and Background of the Project

Dengue is a mosquito-borne infectious disease caused by four serotypes of dengue virus (DENV1-4). Dengue is endemic in over one hundred tropical and sub-tropical countries, and WHO estimates that 100 million people are infected every year. Of these, an estimated 500,000 people, mainly children, are hospitalized, and 12,500 die each year. In 2010, 390 million cases of dengue infection were estimated1). Despite an increase in the incidence of dengue, there is currently no effective treatment or vaccine. Dengue virus poses a threat to both residents and travelers to endemic regions, and is a major public health issue. For this reason there are high hopes for a safe and effective vaccine. In the past, several tetravalent vaccine candidates were developed using recombinant technologies and host range mutation, however, there is still no effective vaccine.

How can your partnership (project) address global health challenges?

The goal of the global strategy provided by the World Health Organization (WHO) is to reduce the burden of dengue, specifically to reduce mortality and morbidity by at least 50% and 25% respectively from 2010 figures by 2020.  Promising advances in vector control technology interventions, diagnostics, prognostic systems for triage, evidence-based clinical interventions and candidate vaccine developments can be employed in the prevention and management of dengue2).

Mahidol University’s live attenuated tetravalent dengue vaccine development begun in the 1980s. The well-balanced immune response of the experimental vaccine was recently confirmed in non-human primate studies. KAKETSUKEN initiated the development of this vaccine candidate in order to obtain licensure from the regulatory authorities of endemic countries with support from Mahidol University3).This project supports the WHO global strategy for dengue through the candidate vaccine development.

What sort of innovation are you bringing in your project?

Despite dengue’s status as a major public health issue, there is currently no safe and effective vaccine. The aim of this project is to provide a safe and effective dengue vaccine.

Our live attenuated tetravalent dengue vaccine has been developed using a classical host range mutation strategy, the same strategy used for the proven live virus smallpox, polio, MMR, varicella and yellow fever vaccines. Our vaccine is expected to be able to mimic natural dengue virus infection, as it has all the dengue viral components, including both structural and non-structural proteins. Therefore, our vaccine is also expected to be able to induce more solid and comprehensive immune responses against pathogenic dengue viruses compared to the other vaccine candidates in development.

 

Others (including references if necessary)

References;

1)    Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI. The global distribution and burden of dengue. Nature. 2013; 496(7446): 504-7.

2)    http://www.who.int/denguecontrol/9789241504034_executive_summary.pdf

3)    http://www.kaketsuken.or.jp/en/press-release/47.html

Final Report

1. Project objective 

 

Dengue is a mosquito-borne infectious disease caused by four serotypes of dengue virus (DENV1-4). The disease is endemic in over one hundred tropical and sub-tropical countries, and infects over 100 million people every year1). Despite an increase in the incidence of the disease there is currently no effective treatment. Although a new dengue vaccine, Dengvaxia®, has been licensed in several countries, clinical observations from the third year of Dengvaxia® trials document both low efficacy (16.7%) against hospitalization2) and “vaccine-enhanced” dengue disease among vaccine recipients3). For these reasons there are high expectations for a safer and more effective vaccine.

 

2. Project design 

 

This project aims to provide a safe and effective dengue vaccine.

Our live attenuated tetravalent dengue vaccine (KD-382) has been developed using a classical host range mutation strategy, the same strategy used for the proven live virus smallpox, polio and MMR vaccines. KD-382 is expected to mimic natural dengue virus infection, as it can provide all the dengue viral components, including both structural and nonstructural proteins. Therefore, KD-382 is also expected to induce more solid and comprehensive immune responses against pathogenic dengue viruses compared to genetically-modified vaccines such as the licensed Dengvaxia® and those currently undergoing Phase 3 clinical studies.

 

3. Results, lessons learned 

 

This GLP compliant study evaluated the dose-responsive immunogenicity and protective ability of our live attenuated tetravalent dengue vaccine (KD-382) in dengue virus naïve male and female cynomolgus macaques. On Day 0, monkeys in the KD-382 groups (Groups 1-3, 24 monkeys/group) received a single subcutaneous dose of one of the three kinds of 10-fold serial diluted tetravalent admixture formulations. Monkeys in the control group (Group 4) were subcutaneously administered the vehicle only.

All KD-382 inoculated monkeys seroconverted (1:>10) to all four dengue virus serotypes (DENV1-4) as early as 14 days post-vaccination and were conferred complete viremia protection against the wild type parental virus challenge at 60 days post-vaccination. In contrast, all control animals given the vehicle developed viremia after challenge. Regardless of dose formulation, KD-382 elicited well-balanced and adequately high (1:>100) neutralizing antibody (Nab) titer with a single subcutaneous immunization. Dose effect on the magnitude of Nab induced by each tetravalent admixture formulation was not observed in this study. The KD-382 was well tolerated at all dose levels, and there were no clinical signs suggesting dengue associated morbidity such as fever, body weight loss, or rash. Furthermore, during the vaccination phase (Days 0 to 60), no viremia was detected in any serum samples from KD-382 immunized monkeys through dengue standard plaque assay.

In conclusion, in a single-dose regimen, all three dose formulations of KD-382 induced well-balanced Nab responses for all four serotypes and conferred complete protection after challenge with the wild type parental virus. Therefore, the results satisfied primary immunological and virological endpoints. This GLP immunogenicity/protection study result provided robust evidence for KD-382 to advance to a Phase I clinical study, in addition to the good safety profile demonstrated in toxicity studies such as repeated dose toxicity, safety pharmacology, developmental reproductive toxicity and neurovirulence by using dengue virus naïve cynomolgus macaques.

 

1)       Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI. The global distribution and burden of dengue. Nature. 2013; 496(7446): 504-7.

2)       Halstead SB., Licensed Dengue Vaccine: Public Health Conundrum and Scientific Challenge. The American Journal of Tropical Medicine and Hygiene. 2016; 95(4): 741-745.

3)       Halstead SB, Russell PK., 2016. Protective and immunological behavior of chimeric yellow fever dengue vaccine. Vaccine 34(14): 1643-7.