Paul-Ehrlich-Institut
Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel

A Morbillivirus Vaccine Vector
Expre...
Influenza Virus Epidemiology
 Influenza A viruses infect swine,
horses, seals, and a large variety of
birds as well as hu...
Ferret Model for Respiratory
Viruses
• Signs and severity of disease closely resemble
human disease
• Strong similarities ...
Seasonal H1N1 Pre-Infection
Protects Ferrets at Least as
Well as an Inactivated H5N1
Vaccine
Groups:
1. control:
2. H1N1in...
l

1i

nf

ac

ro

1v
1N

5N

H

H

day 3

l

1i

nf

ac

ro
1v
1N

5N
H

H

nt

10

co

nf

nf

ac
1i

1v

l

nf

ro

1i
...
Can we design a vaccine
reproducing this cross-protection?
Expectations:
Milder and shorter disease.
Reduced viral load ...
Live-Attenuated Morbillivirus Vaccines
Induce Long-Lasting Protection
Morbilliviruses as Vaccine Platforms
Introduction of...
Generation of a CDV Vaccine
Carrying Influenza Antigens
CDV Vaccine Strain Onderstepoort (OS)

OS expressing NP and HA fro...
Experimental Design
Immunization

Challenge
Sacrifice

E

E

E

ELISpot
serum

0

7

10

14

21

28

31

days after vaccin...
Both Viruses Induce a Robust
Immune Response Against CDV

SFC/106 MNCs

VN Titer

Day 0

Day 10

Day 28
Only OS NPHA Elicits Also a
Response Against Influenza

SFC/106 MNCs

HAI Titer

Day 0

Day 10

Day 28
Vaccination with OS NPHA Reduces
Viral Load after Homologous and
Heterologous Challenge
H1N1-matched

Nasal Turbinate Tite...
How Does This Relate to One
Health?
• Influenza is a prototypical zoonotic disease –
successful control will involve addre...
Acknowledgements
INRS-Institut ArmandFrappier, Laval

National Microbiology
Laboratory, Winnipeg

Ronan Rouxel
Isabelle Me...
Skin Rash
CDV Spreads Through the Host

von Messling et al., PNAS 2004
Viral Take-Over of Lymphatic Tissues
Precedes Epithelium Invasion
Thymus

Spleen
10x

Bladder
10x

Oesphagus
10x

10x

4 d...
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A Morbillivirus Vaccine Vector Expressing Influenza HA and NP Proteins Induces Robust Humoral and Cellular Immune Responses

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GRF 2nd One Health Summit 2013: Presentation by Veronika Von Messling, Paul-Ehrlich-Institute

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A Morbillivirus Vaccine Vector Expressing Influenza HA and NP Proteins Induces Robust Humoral and Cellular Immune Responses

  1. 1. Paul-Ehrlich-Institut Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel A Morbillivirus Vaccine Vector Expressing Influenza HA and NP Proteins Induces Robust Humoral and Cellular Immune Responses Veronika von Messling, DVM, PhD One Health Summit, Davos, November 20, 2013
  2. 2. Influenza Virus Epidemiology  Influenza A viruses infect swine, horses, seals, and a large variety of birds as well as humans => Eradication is not feasible  All subtypes of influenza A viruses (1-17 HA and 1-10 NA) are found in aquatic birds.  A pandemic occurs when a “new” subtype adapts to humans. Challenge: Lakadamyali et al., PNAS 2003 Currently available HA/NA based vaccines only protect against antigenetically matched viruses.
  3. 3. Ferret Model for Respiratory Viruses • Signs and severity of disease closely resemble human disease • Strong similarities to humans in lung physiology, airway morphology and cell types present in the respiratory tract • Sialic acids are predominantly -2,6-linked (influenza) • Small animal model that can be accommodated by most animal facilities • Immunological reagents are being developed • Ferret genome project is ongoing
  4. 4. Seasonal H1N1 Pre-Infection Protects Ferrets at Least as Well as an Inactivated H5N1 Vaccine Groups: 1. control: 2. H1N1inf: PBS - 2 x i.m. injection (n=3 per time point) intranasal infection with 105 infectious doses of H1N1 USSR/90/77 (n=5-6 per time point) 3. H5N1vac: Formalin-inactivated H5N1 vaccine - 2 x i.m. injections (4 µg H5 HA equiv.; Viet Nam 1203/04; n=5-6 per time point)
  5. 5. l 1i nf ac ro 1v 1N 5N H H day 3 l 1i nf ac ro 1v 1N 5N H H nt 10 co nf nf ac 1i 1v l nf ro 1i nt 1N 5N H H co 1N ac l nf ro 1v l ac ro 1i nt 1N 5N H H nt 1v co H 5N * nt nf 1i ac l nf ro 1v nt 1N 5N H H co 1i ac H co 1000 co l ac 1i 1v 1N 5N nf ro 1i 1N 1v l * H H day 1 * nt 1N 5N H H ro 1000 co H ac l nt 10000 1v ro 10000 co 1 100000 5N nt 1 100000 H co log10 TCID50 100000 10000 * 6 months 100 10 100 * 1000 100 10 1 * day 6 12 months * 18 months
  6. 6. Can we design a vaccine reproducing this cross-protection? Expectations: Milder and shorter disease. Reduced viral load = less transmission. Requirements: Induction of humoral and cellular immune responses. Immune responses against HA as well as conserved viral proteins.
  7. 7. Live-Attenuated Morbillivirus Vaccines Induce Long-Lasting Protection Morbilliviruses as Vaccine Platforms Introduction of immunogenic proteins from other pathogens in the morbillivirus genome Expression of the “foreign” protein in the highly immunogenic morbillivirus context Cellular and humoral immune response to the morbillivirus + “foreign” antigen
  8. 8. Generation of a CDV Vaccine Carrying Influenza Antigens CDV Vaccine Strain Onderstepoort (OS) OS expressing NP and HA from H1N1 USSR/90/77 (OS NPHA) OS OS NPHA
  9. 9. Experimental Design Immunization Challenge Sacrifice E E E ELISpot serum 0 7 10 14 21 28 31 days after vaccination Immunization: 5x105 infectious doses of OS or OS NPHA, i.m. injection (n=9/virus) Challenge: intranasal infection with 105 infectious doses of n=3 of each group/virus): a) H1N1 USSR/90/77 (homologous virus) b) pH1N1 Mx/09 (heterologous – same subtype) c) H3N2 Port Chalmers/1/71 (heterologous – different subtype Sacrifice: 3 days post-challenge to collect nasal turbinate and lung tissues for titration
  10. 10. Both Viruses Induce a Robust Immune Response Against CDV SFC/106 MNCs VN Titer Day 0 Day 10 Day 28
  11. 11. Only OS NPHA Elicits Also a Response Against Influenza SFC/106 MNCs HAI Titer Day 0 Day 10 Day 28
  12. 12. Vaccination with OS NPHA Reduces Viral Load after Homologous and Heterologous Challenge H1N1-matched Nasal Turbinate Titer Day 3 H1N1-mismatched TCID50/mg tissue Body temperature C H3N2 Days post-infection * ** **
  13. 13. How Does This Relate to One Health? • Influenza is a prototypical zoonotic disease – successful control will involve addressing human and animal hosts • Vaccination is the most cost-effective and efficient public health measure against infectious diseases. • Reverse engineering of vaccines – i.e. identifying correlates of immunity and designing a vaccine that induces this response – allows the development of tailor-made vaccines.
  14. 14. Acknowledgements INRS-Institut ArmandFrappier, Laval National Microbiology Laboratory, Winnipeg Ronan Rouxel Isabelle Meunier Xiao Xiang Wong Darwyn Kobasa Michael Gray Jason Gren Shane Jones Betty Luy Gary Kobinger Funding CIHR, CFI, Armand-Frappier Foundation, Duke-NUS
  15. 15. Skin Rash
  16. 16. CDV Spreads Through the Host von Messling et al., PNAS 2004
  17. 17. Viral Take-Over of Lymphatic Tissues Precedes Epithelium Invasion Thymus Spleen 10x Bladder 10x Oesphagus 10x 10x 4 d.p.i. 8 d.p.i. 14 d.p.i. lymphatic cells epithelial cells Rudd et al., JVI 2005

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