MEEGID XII. Ebola viruses: from the wild to humans

Transcription

1 MEEGID XII Bangkok, December 2014 Ebola viruses: from the wild to humans Jean-Claude Piffaretti Interlifescience, Massagno, Switzerland

2 1. Animal viruses jumping to humans 2. Influenza virus A 3. Filoviruses 4. Ebola: epidemiological situation 5. Biology and pathogenicity of Ebola virus 6. Antiviral drugs and vaccines 7. Molecular dating of Ebola outbreaks

3 Routes of transmission Droplets: land directly on mucosal lining of nose, mouth, eyes of nearby persons or can be inhaled. (Highest exposures within 1-2 meters) Airborne: aerosols become smaller by evaporation; small aerosols particles ( 10 microns) remain suspended for longer periods, if inhaled travel deep into the lungs Direct physical contact: sex, body fluids Indirect physical contact: fomites Faeca-oral Food, water

4 Animal viruses jumping the human species barrier and causing disease Virus Reservoir Disease Influenza viruses Birds Flu Measles virus Cattle Measles SARS-CoV Bats Severe Acute Respiratory Syndrome MERS-CoV Camels? Bats? Middle East Respiratory Syndrome HIV Chimpanzees Acquired Immuno-Deficiency Syndrome

5 Divergence of measles virus from rinderpest virus 11 th 12 th centuries Furuse Y et al, Virology J, 7: 52 (2010)

6 Jumping of a virus out of its natural host Dead end Ø Spillover infection Limited transmission Adaptation

7 Zoonotic transmission dynamics Lloyd-Smith JO et al, Science, 326: 362 (2010)

8 Animal viruses: obstacles to bypass human species barrier Receptors on human cells Host temperature Immune system Differences in replication and synthesis machineries Humans: α(2,6), [α(2,3)] Aquatic birds: α(2,3) Pigs: α(2,6), α(2,3)

9 Animal viruses: properties fostering jumping to human hosts High mutation rate Significant recombination, ressortment, rate Large population size Short generation time Restoration of fitness Escape of host immunity Transmission capability

10 Influenza A viruses

11 Tropism of Influenza A virus Medina RA & García-Sastre A, Nature Rev. Microbiol. 9: 590 (2011)

12 Emergence of the influenza A(H 1 N 1 )pdm09 virus

13 Middle East Respiratory Syndrome CoV De Groot RJ et al, J Virol 87: 7790 (2014) Coleman C, J Virol 88: 5209 (2014)

14 Characterization of dromedary camel MERS-CoV genome sequences Haagmans BL et al, Lancet Infect Dis 14:140 (2014) Nowotni N, Kolodziejek J, Euro Surveill 19: pii=20781 (2014)

15 Ebolavirus Zaire ebolavirus Sudan ebolavirus Bundibugyo ebolavirus Reston ebolavirus Taï Forest ebolavirus Filoviridae Marburgvirus Cuevavirus Ebola virus budding from a kidney cell (credit NIAID)

16 Clinical course - Incubation: 8-10 days (range, 2-21) - Fever, headache, chills, myalgia, malaise, (maculopapular rash) - Abdominal pain, diarrhoea, vomiting - Haemorrhage (bleeding, bruising) days after symptom onset - Recovery: antibodies that last for at least 10 years Transmission to humans - Initial infection: contact with infected animal (bat or monkey) - Subsequent infections: contact of mucous membranes or broken skin with blood or body fluids of an infected person (or infected objects, needles, syringes) - Contagiousness: ill, symptomatic patients (no transmission during incubation) - Cave: Health care workers (amplification), household care providers; family Diagnostic tests available - Polymerase chain reaction (PCR) - IgM ELISA - Antigen-capture enzyme-linked immunosorbent assay (ELISA) testing - Virus isolation (BSL 4)

17 Ebola and respiratory transmission Ebola virus is mainly transmitted by close contacts with body fluids Transmission by droplets is very likely to occur, particularly when taking care of an infected individual However, Ebola virus cannot be considered a respiratory virus Can evolution make Ebola virus a respiratory virus?

18 Tosh PK & Sampathkumar P, Mayo Clin Proc, 89: 1710 (2014)

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20 Cumulative reported cases of Ebola virus disease in Guinea, Liberia, and Sierra Leone, March 25, 2014 December 3, 2014

21 Choi JH & Croyle MA, BioDrugs; 27: 565 (2013)

22 Cascade of pathological events The impact of sgp in Ebola pathogenesis Ansari A.A. et al, J Autoimmun, 55: 1 (2014) De La Vega M-A et al, Viral Immunol, 28: 1 (2014)

23 Examples of potential treatments Treatment Mechanism of action Route Comments Plasma ZMapp Antibodies from convalescent patients Combination of three humanised monoclonal antibodies targeting GP; expressed in N. benthamiana IV IV Emergency use Emergency use Brincidofovir Inhibition of RNA synthesis Oral Derivative of cidofovir Favipiravir TKM-Ebola Inhibition of viral RNA polymerase; lethal mutagenesis sirna affecting L, VP24, VP35 expression Oral Oral Primary for influenza treatment Compassionate use Adapted from Bishop BM, Ann Pharmacother,

24 Ebola vaccines on trial Vaccine Manufacturer Target Phase of development Concerns cad3 GSK/US NIAID GP I/II rvsv-ebola Newlink Genetics/PHAC GP* I/II Pre-existing immunity Safety (replication competent) Adenovirus Vesicular Stomatitis Virus

25 Ebola Vaccine cad3-eboz Developed by NIH in collaboration with GSK/Okairos Vector: Adenovirus serotype 3 (cad3 or ChAd3) Insert: full-length wild-type GP of EBOV Zaire Non replicating recombinant virus Objective: test the safety of the vaccine and its capacity to provide an immune response N: 120 healthy adults Countries involved: USA, the UK, Switzerland and Mali

26 Ledgerwood JE et al, NEJM, 26 November 2014

27 Ebola Vaccine rvsvδg-zeboz-gp Developed by developed by the Canadian National Microbiology Laboratory Vector: Vesicular Stomatitis Virus (VSV) Insert: Ebolavirus Zaire envelope glycoprotein Replicating recombinant virus Objective: test the safety of the vaccine and its capacity to provide an immune response N: 115 healthy adults Countries involved: Germany, Switzerland, Kenya and Gabon

28 Molecular dating of the Ebola 2014 outbreak Gire SK et al, Science, 345: 1369 (2014)

29 Viral dynamics during the 2014 outbreak Gire SK et al, Science, 345: 1369 (2014)