Dengue: The next vaccine preventable disease? Prof John McBride James Cook University

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1 Dengue: The next vaccine preventable disease? Prof John McBride James Cook University

2 Dengue viruses A flavivirus ~11kb genome, ~50nm diameter, lipid envelope. Gene order 5 C-prM-E-NS1 Four serotypes (1-4) NS5 Different serotypes have 60-80% amino acid homology (D1 and D3 closest, D4 most dissimilar)

3 Dengue fever Aedes aegypti Mosquito

4 Aedes aegypti Breeding Sites

5 Transmission of Dengue Virus by Aedes aegypti Mosquito feeds / acquires virus Mosquito refeeds / transmits virus Viremia Extrinsic incubation period Intrinsic incubation period Viremia Days Illness Human #1 Human #2 Illness

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7 Dengue fever - diagnosis Early (up to 7 days) - Culture, PCR or NS1 ELISA IgM 80% + by day 5, 99% by d10 IgM attenuated in 2ndary infection ELISA IgG appears a few days later and stays + for life. Anamnestic response in 2ndary infection Secondary infection implied by presence of IgG in first 5 days Card tests IgM/G, NS1

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10 DHF PATHOGENESIS Roles for Anamnestic antibody Increased viral load Cytokines, TNF DC-SIGN expression Anaphylotoxins NO Endothelial function

11 Global distribution of Dengue Bhatt, S., et al. (2013). "The global distribution and burden of dengue." Nature 496(7446):

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13 Imported dengue: Reflects the international epidemic Number of Imported Dengue Cases

14 Live attenuated vaccines

15 Wallace, D., et al. (2013). "Challenges in the clinical development of a dengue vaccine." Curr Opin Virol 3(3):

16 Vaccine challenges Prior flavivirus exposure could make vaccines more reactogenic Vaccine antibodies could sensitize individuals when antibody response suboptimal (ADE) Neither observed in clinical trials to date

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20 Methods 3 doses 0,6 & 12 months Comparator initially rabies then placebo (IDMC mandated) Febrile episodes Ix with RT-PCR and NS1 300 children in immunogenicity subset Efficacy was clinical endpoint post 3 rd dose (VE = 100 (1 IDCYD / IDControl)

21 Results - VE Safety

22 Other findings Severity of illness no differences in vaccinated vs control group Immunogenicity Vaccine Control

23 Author obsevations The observed lack of efficacy against DENV2 despite satisfactory immunogenicity is surprising and will need further investigation Ongoing phase 3 efficacy studies in more than volunteers in ten countries in Latin America and Asia will provide pivotal data for this candidate vaccine s efficacy

24 Further clues on breakthroughs CYD-TDV in 401, placebo 199 in Latin America High immunogenicity 95% in flavi immunes, 78% in flavi naïve Some evidence of a different genotype 2 response than that see in SEA Villar et al. (2013). Safety and Immunogenicity of a Recombinant Tetravalent Dengue Vaccine in 9-16 Year Olds: A Randomized, Controlled, Phase II Trial in Latin America. Pediatr Infect Dis J, 32(10),

25 Do we need to do human protection studies? D1 protective D3 less so (3/5 infected and had LFTs)

26 Immunogenicity of a LATV 113 flavivirus naïve subjects NIH vaccine Tri or quadrivalent response in >75% subjects Asymptomatic rash in 64% vaccines Low level viraemia (~10 PFU) in most subjects Durbin et al(2013). A single dose of any of four different live attenuated tetravalent dengue vaccines is safe and immunogenic in flavivirus-naive adults: a randomized, double-blind clinical trial. J Infect Dis, 207(6),

27 Conclusions Dengue pandemic worsening Leading vaccine candidate safe and immunogenic, but clinical efficacy disappointed (but further studies pending) Neutralising assays are not predictive of clinical efficacy Dengue Human Challenge Model (DHCM) may be needed. The effort continues!

28 Thankyou for your attention