1. Challenges, Consideration, and Progress
Dengue Virus
Challenges, Consideration, and Progress
Michaela Nickol
14 March 2019

2. Overview Dengue Virus Disease Progression
Antibody-Dependent Enhancement
Vaccine Development
Alternative Approaches

3. Dengue Transmitted by Aedes aegypti
Endemic in more than 100 countries throughout Africa, Asia, and America
million individuals infected each year
Ranges from asymptomatic to life-threatening disease
Simmons et al. Viruses

4. Genome Organization Enveloped, positive-sense RNA virus
Perera and Kuhn. Current Opinions in Microbiology

5. Serotypes DENV-1 DENV-2 DENV-3 DENV-4 5 genotypes 6 genotypes
nature.com

6. Serotypes Error prone RNA-dependent polymerase
Homologous recombination
Increase in migration

7. Dengue Infection Ranges from asymptomatic to life-threatening
500 million individuals infected each year
100 million symptomatic infections
20 million cases result in severe disease
20,000 deaths each year

8. Dengue Fever Acute fever Headache Myalgia Arthalgia Vomiting Weakness
Maculopapular rash
Self-limiting
tabletsmanual.com

9. Severe Disease – Dengue Hemorrhagic Fever
Similar to Dengue Fever
Decline in platelets
Vascular leakage
Abdominal pain
Hypotension
dengueuta.weebly.com

10. Severe Disease – Dengue Shock Syndrome
Similar to Dengue Hemorrhagic Fever
Severe bleeding
Multi-organ involvement
Hypovalaemic shock
eJmanager.com

11. Disease Progression Unknown why some infections progress to DHF/DSS
Mix of factors
Gender
Genetic characteristics
Immunological status
Epidemiological factors
Viral strain
Secondary infection with a heterologous serotype

12. Antibody-Dependent Enhancement
Whitehead et al. Nature Reviews Microbiology

13. Antibody-Dependent Enhancement - Cuba
1977
DENV-1 epidemic
1981
DENV-2 epidemic
1997
DENV-2 epidemic
2001
DENV-3 epidemic
1975
~2.6% of Cubans had antibodies

14. Vaccine Development No approved vaccine
Immune functions are not well-understood
No sufficient animal models
Accessible to resource-poor countries
freeiconspng.com
theconversation.com

15. Vaccine Development - ChimeriVax
Live recombinant attenuated vaccine
E and prM genes cloned into yellow fever 17D vaccine
Guy et al. Vaccine

16. Vaccine Development - ChimeriVax
Licensed in 20 countries
Administered in 3 doses (0, 6, and 12 months)
Safe for individuals between 9 and 45 years old

17. Vaccine Development - ChimeriVax
Viral interference has been observed
Efficiency higher in serotypes 3 and 4
Performs differently in seropositive and seronegative individuals
Increased risk of severe disease in seronegative individuals
“pre-vaccination screening strategy”

18. Vaccine Development – NIH/Butantan
Live attenuated vaccine
Site-directed mutagenesis to delete nucleotides in the 3’ UTR
Induction of T-cell and antibody response
Response raised against structural and nonstructural proteins
Bos et al. Pathogens and Global Health

19. Vaccine Development - Takeda
Live attenuated recombinant chimeric vaccine
Attenuated DENV-2 backbone
E and prM genes of other serotypes expressed on backbone
Osorio et al. Vaccine

20. Alternative Approaches - Mesocyclops
Trialed in Vietnam
Reduction in A. aegypti mosquitoes
Reduction in DENV incidence over several years

21. Alternative Approaches - Wolbachia
A. aegypti infected with Wolbachia bacterium
Induces resistance to arboviruses
Reduces lifespan by 50%
Wikipedia.com

22. Questions?