Rift Valley fever: Unanswered questions and unmet needs. Jeroen Kortekaas, 11 th EPIZONE meeting September 20 th, Paris, France

Transcription

1 Rift Valley fever: Unanswered questions and unmet needs Jeroen Kortekaas, 11 th EPIZONE meeting September 20 th, Paris, France

2 Wageningen Bioveterinary Research, Lelystad

3 Wageningen Bioveterinary Research, Lelystad Picture: Adolfo Ibáñez, CMV

4 Presentation objectives Introduction of the Order Bunyavirales Rift Valley fever: Susceptible species Molecular virology History Epidemiology Pathology Vaccines

5 The order Bunyavirales Largest group of RNA viruses affecting mammals Nine families: Feraviridae Fimoviridae Jonviridae Phasmaviridae Tospoviridae Nairoviridae Peribunyaviridae Hantaviridae Phenuiviridae

6 Rift Valley fever: Susceptible species

7 Biosafety level-3 Animal facility Laboratory

8 The RVFV virion Enveloped virus with icosahedral symmetry ( nm) Segmented single-strand negative-sense RNA genome Large (L), Medium (M), Small (S) One serotype NSs is the major virulence determinant

9 RVFV replication

10 Class II fusion proteins (alphaviruses) Kielian et al., Viruses 2010

11 RVFV Gc is a class-ii fusion protein De Boer et al., J Virol 2012 Dessau and Modis PNAS 2013

12 Structure of Gn (ectodomain) Yan Wu et al. PNAS 2017 Dessau and Modis PNAS 2013

13 RVFV replication Le May et al., PLoS Path 2008

14 RVFV replication Piper et al., PLoS ONE hpi S M L Wichgers Schreur et al., PLoS Path 2016

15 The Great Rift Valley

16 History 1930: Virus isolated during outbreak among European-breed sheep in the Rift Valley, Kenya 3500 lambs and 1200 ewes died from acute necrosis of the liver, also cattle and goats affected Mosquito transmission suggested Robert Daubney

17 Virus circulation between <

18 First incursion South Africa Kenya 1930 South Africa 1950

19 First incursion Madagascar Kenya 1930 Madagascar 1973 South Africa 1950

20 First incursion Egypt Egypt 1977 Kenya 1930 Madagascar 1973 South Africa 1950

21 First incursion Mauritania and Senegal Mauritania Senegal 1987 Egypt 1977 Kenya 1930 Madagascar 1973 South Africa 1950

22 First incursions Saudi Arabia and Yemen Mauritania Senegal 1987 Egypt 1977 Saudi Arabia 2000 Yemen Kenya 1930 Madagascar 1973 South Africa 1950

23 Current situation

24 RVFV in Turkey?

25

26 Widespread virus movement, few reassortment events

27 RVFV isolated from 30 species, 10 genera a b c Aedes Culex Anopheles Aedes mcintoshi

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29 Transmission of RVFV from European breed lambs to Culex pipiens mosquitoes Vloet et al., submitted

30 Ecology Bird & McElroy Antiviral Res 2016

31 Rift Valley fever animal a b c Mice Sheep Cattle % Survival Day 1 0 l o g R N A c o p i e s / m l D P I ~20% Fatality 1 0 l o g R N A c o p i e s / m l D P I

32 Liver: The major target organ

33 Fatal cases Necrotic foci

34 Mononuclear phagocytic cells Lozach et al., Cell Host & Microbe 2011

35 Commercially available RVF vaccines Inactivated vaccine: Requires booster and yearly revaccinations Smithburn vaccine: Highly effective, but not safe for pregnant animals

36 Clone 13 Plaque-purified from a human case Bouloy et al, % deletion NSs gene Shown to be safe in mice, sheep and cattle Highly effective in sheep and cattle Since 2010, more than 19 million doses used in the field Registered in South Africa, Namibia and Botswana

37 CASTELLUM A public-private partnership to protect humans and animals from emerging zoonoses

38 1 0 lo g R N A c o p ie s /o rg a n Clone 13 is neurovirulent in mice after intranasal administration M o c k In f e c t e d Clone 13 Negative control Cerebellum Hippocampus Cerebral cortex

39 Clone 13 is safe for lambs No viremia No disease No dissemination No shedding No spreading

40 Fetal malformations and stillbirths after inoculation of an overdose of Clone 13 Makoschey et al., PLoS Negl Trop Dis. 2016

41 Next-generation vaccines MP-12 MP-12 NSm ZH501 NSs- NSm (DDvax) ChAdOx-1-GnGc RVFV-4s

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43 % S u r v i v a l Four-segmented RVFV ( NSs) R V F V - 4 s C l Intranasal D P I Wichgers Shreur et al., Vaccine 2014,2017

44 Efficacy and safety of RVFV-4s Sterile immunity, single vaccination Overdose is safe for fetus Wichgers Shreur et al., Vaccine 2015 Wichgers Shreur et al., Vaccine 2017

45 Major conclusions RVFV has affected millions of animals and tens- to hundreds of thousands of humans in single outbreaks RVFV has a demonstrated ability to spread across large geographical areas Susceptible livestock, wildlife and mosquito species are globally prevalent Outbreaks are difficult to predict Vaccines (human and veterinary) and diagnostics to control large future outbreaks are not (readily) available

46 Unaswered questions and unmet needs Unanswered questions (a few of many): Epidemiology: Transmission and sylvatic cycle Immunology: Role of immune cells Pathogenesis: Severe cases Unmet needs: More and better diagnostic capablility Vaccine that optimally combines efficacy with safety Vaccine stockpile or incentive to vaccinate (combination vaccines!)

47 No longer neglected...

48 Acknowledgements