Pandemic vaccination: constraining a moving target

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Pandemic vaccinationconstraining a moving target

• ESWI
• TEIC, Vilamoura, 16-09-08

Albert Osterhaus
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Human influenza three appearances

• Seasonal influenza
• (A H3N2, H1N1 B)
• Avian influenza
• (A H7N7, H5N1)
• Pandemic influenza
• (A H1N1, H2N2, H3N2?)

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INFLUENZA A VIRUS
Recent zoönotic transmissions
Subtype H7N7 H5N1 H9N2 H5N1 H7N7 H7N2 H7N3 H5N1
Country UK Hongkong SE-Asia Hongkong Netherlands
USA Canada SE-Asia/M-East/ Europe/W-Africa
Year 1996 1997 1999 2003 2003 2003 2004 2003-8
Cases 1 18 gt2 2? 89 1 2 gt360
Deaths 0 6 0 1 1 0 0 gt240
CFR gt 60
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Areas reporting confirmed occurrence of H5N1
avian influenza in poultry and wild birds since
2003
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Experimental infection of six wild duck species
with highly pathogenic avian influenza virus
(H5N1) Emerging Infectious Diseases, 2008
Juthatip Keawcharoen, D.V.M. Thijs Kuiken, DVM,
PhD Department of Virology National Influenza
Center Erasmus MC Rotterdam
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Highly pathogenic H5N1 influenza virus in
smuggled Thai eagles, BelgiumVan Borm et al,
Emerg Infect Dis. 2005
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Pandemic preparednessMedical (and veterinary)
interventions

• Surveillance in humans (WHO system) and animals
• early warning
  and rapid response

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Surveillance of AH1/N1 H274Y in the Netherlands
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INFLUENZA- medical interventions NB societal
interventions

• Surveillance
• in humans and animals seasonal
  surveillance is the basis for pandemic
  surveillance
• early warning
  and rapid response
• Antiviral therapy
• is the treatment option for influenza and
  can also be used for prevention.
• increase of seasonal treatment will
  facilitate pandemic availability
• Vaccination
• is the corner stone of influenza
  prevention.
• increase of seasonal vaccination will
  enhance pandemic preparedness

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Cumulative Number of Confirmed Human Cases of
Avian Influenza A/(H5N1) Reported to WHO 10
September 2008
Total number of cases includes number of
deaths.WHO reports only laboratory-confirmed
cases. All dates refer to onset of illness.
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Current seasonal flu vaccines
1 dose (trivalent) 1 chicken egg!
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seasonal influenza vaccine formulations

• Source IFPMA website 2008

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HIGH RISK GROUPS chronic cardiovascular
disease chronic airway disease diabetes
mellitus chronic renal dysfunction
immune-compromised elderly (? 60 years)
Doses of influenza vaccine distributed / 1000
population
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Pandemic influenza vaccines
- Key issues -

• Response time
• (currently gt6 months)
• Production capacity
• (currently 400 million
  doses world-wide)
• Efficacy/Safety
• (human trials with prototype
  vaccines)
• NB Regulatory preparedness

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Pandemic influenza vaccines
- Improvements in production systems -
Production systems
Cell culture MDCK, Vero, PERC-6, others
Continuous availability of production substrate
Flexibility in optimizing production (GMO cell
lines, substrate, carriers, continuous flow
systems, etc)

• Cell culture MDCK, Vero, PERC-6, others
• Continuous availability of production substrate
• Flexibility in optimizing production
• (GMO cell lines, substrate, carriers,
  continuous flow systems, etc)

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Pandemic influenza vaccines
- Improvements in seed strain preparation 1 -
Seed-strain preparation
Reverse Genetics
Reverse Genetics
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Available H5 RG vaccine strains

• Clade 1 A/Vietnam/1194/2004
  NIBRG-14) (1
• A/Vietnam/1203/2004 2,3
• Clade 1' A/Hong Kong/213/2003 (NIBRG-12)1
• Clade 2
• Subclade 2-1 A/Indonesia/5/2005 3
• Subclade 2-2 A/turkey/Turkey/1/2005 (NIBRG-23) 1
• A/bar headed goose/Qinghai/1A/2005 2
• A/whooping swan/Mongolia/244/2005 2
• Subclade 2-3 A/Anhui/1/2005 3
• 1 - NIBSC, UK 2 - St Judes, USA 3 - CDC, USA

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Pandemic influenza vaccines
- Improvements in vaccine strain selection -
Strain selection
Influenza A virus surveillance in wild birds
database of LPAI viruses Bypass the
necessity of reverse genetics (e.g. LPAI H7N7
from ducks) (V.J. Munster et al., EID., 2006)
Antigenic mapping to determine best HA/NA
vaccine candidates (D.J. Smith, A.S. Lapedes et
al., Science 305371-376, 2004)

• Influenza A virus surveillance in wild birds
  database of LPAI viruses.
• Bypass the necessity of reverse genetics (e.g.
  LPAI H7N7 from ducks)
• (V.J. Munster et al., EID., 2006)

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Avian influenza A virus surveillance - Sampling
sites 1998-present -
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Avian influenza A virus surveillance - HA and NA
subtypes -
Fouchier et al., J Virol., 2005 Munster et al.,
Emerg Inf Dis., 2005 Olsen et al., Science.,
2006
Subtypes detected in wild birds globally
Subtypes detected in wild birds in our own
studies (Northern Europe)
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Antigenic cartography
- Human H3N2 1968-present -
Antigenic cartographyQuantitative analysis and
visualisation of antigenic properties HI titers
represented as distances
Science 305, 371-376, 2004
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Pandemic influenza vaccines
- Room for improvement -
Strain selection
small changes easy to incorporate
Seed-strain preparation
Production systems
New targets identify correlates of
protection
New targets identify correlates of protection
Improve efficacy novel adjuvants delivery
systems
larger changes long path before implementation?
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Structure of Influenza A Virus
Orthomyxovirus
Neuraminidase (9 subtypes)
Viral RNA
M2protein
M1 protein
Haemagglutinin (16 subtypes)
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Pandemic influenza vaccines
- Identification of new targets,correlates of
protection -

• Targeting M2 a universal influenza vaccine ?

• Role of antibodies to NA in protection upon
  vaccination?
• Only 9 NA subtypes, versus 16 HA subtypes
• Less drift in NA as compared to HA?

• Role of cellular immunity in protection?
• Identify targets (conserved internal proteins,
  epitopes!)
• Identify modes of antigen delivery (vectors,
  LAIV, DNA vac)

- Cross-protective immunity between virus
subtypes?
Clinical protection rather than sterile immunity?
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Pandemic influenza vaccines
- Room for improvement -
Strain selection
small changes easy to incorporate
Seed-strain preparation
Production systems
New targets identify correlates of protection
Improve efficacy adjuvants delivery systems
Improve efficacy adjuvants delivery systems
larger changes long path before implementation?
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Avian influenza A (H5N1) - Expanding host range? -

• Field H5N1 virus infection
• Poultry
• Wild birds (gt60 species)
• Humans
• Pigs
• Leopards
• Tigers
• Domestic cats
• Domestic dogs
• Owstons palm civet
• Stone marten
• Mink

• Experimental H5N1 virus infection
• Domestic cat
• Ferret
• Mice
• Macaque
• Other carnivore species at risk?
• Fox
• Mustelids
• Phocids

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Ferrets are widely accepted to be a good animal
model for influenza virus (H5N1)

• Ferrets are susceptible to infection with human
  and avian influenza viruses
• Highly pathogenic strains replicate in upper and
  lower respiratory tracts
• Infection with most HPAI H5N1viruses results in
• Severe systemic disease spleen, intestine,
  liver, brain
• Mortality
• H5N1 human isolates from 2004 outbreak more
  severe than those from 1997 outbreak

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Pathology experimentally H5N1 infected cats
Rimmelzwaan et al. Am. J. Pathol. (2006) Kuiken
et al., Science 2004

• Severe necrosis and inflammation in
• Lung
• Brain
• Heart
• Kidney
• Liver
• Small intestine
• Adrenal gland
• Influenza virus expression closely associated
  with lesions

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Virus titers in organs of infected macaques, day
4 p.i. A/Hong Kong/156/97 (H5N1)
Cerebellum
Cerebrum
Kidney
Liver
Organ
Heart
Spleen
TBLN
Lung
Trachea
lt1
1
2
3
4
5
6
7
Log TCID50/gram tissue
Rimmelzwaan et al., J.Virol. 2001 Kuiken et al.,
J.Vet Pathol 2003
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Adjuvants for pandemic influenza vaccines
Most important candidates

• Aluminum salts (ALOH, ALPO4, ALOH-PO4, ...)
• Oil-in-water emulsions (MF59, AS03, )
• Novel approaches
• Virosomes
• Iscoms

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ADJUVANTS AND FLU VACCINES

• Seasonal flu-vaccine does not require adjuvant
• Boosting
• Yearly administration of alum may carry risks
• FLUAD (MF59, Novartis) for elderly
• Pandemic flu-vaccine does require adjuvant
• Priming
• Without adjuvant larger doses of antigen
  required (90 ug)
• Adjuvant can enhance breadth of protection

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Assessment of pre-pandemic H5N1 clinical trials
Data presented at WHO meeting, February
2007 (Sanofi Pasteur, 4 Companies in Jp, CSL,
Microgen, Sinovac, GSK, Novartis,Baxter)
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MF59 - o/w emulsion adjuvant (Novartis)
Appearance milky white oil in water (o/w
emulsion)
Composition
0.5 Polysorbate 80 water-soluble
surfactant 0.5 Sorbitan Triolate oil-soluble
surfactant 4.3 Squalene -oil Water for
injection 10 nM Na-citrate buffer
Density 0.9963 g/ml
Viscosity close to water, easy to inject
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AS-03 from GSK

• Oil-in-water emulsion (cf MF59) metaboliseable
  oil
• sterol (alpha-tocopherol)
• emulsifying agent
• Strong dose-reduction for pandemic vaccine

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The three CHMP criteria are exceeded by all the
adjuvanted doses seroconversion rates
3.8µg H5
100
7.5µg H5
15µg H5
30µg H5
75
3.8µg H5 AS
7.5µg H5 AS
15µg H5 AS
30µg H5 AS
Seroconversion rate ()
50
CHMP criteria
40
25
0
Post first dose
Post second dose
IX International Symposium on Respiratory Viral
Infections March 3 6, 2007, Hong Kong
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Vaccine discovered against H5N1 bird flu
OK., lets start spreading the H5N2 virus
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Using the neutralisation assay, all 3 CHMP
criteria were met with all adjuvanted doses in
heterologous testing
H5N1-A/Indonesia/5/05 Seroconversion rates
Vaccinated with Vietnam strain / testing with
Indonesia strain
IX International Symposium on Respiratory Viral
Infections March 3 6, 2007, Hong Kong
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Ferrets vaccinated with GSK AS-adjuvanted H5N1
split candidate vaccine

• 2 immunisations of ferrets at D0 and D21 (H5N1
  A/Vietnam/1194/04 split virus / AS)
• Heterologous challenge (wild-type virus
  A/Indonesia/5/05, 105 TCID50) at D49
• Post challenge results at D5

Full cross-protection (against mortality) with
AS-adjuvanted H5N1 split candidate vaccine 3.8
µg
Baras et al., PLoS One 2008
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Pandemic influenza vaccines
- Key issues Role of adjuvanted vaccines-

• Response time
• (currently gt6 months)
• Production capacity
• (currently 400 million doses world-wide)
• Efficacy/Safety
• (human trials with prototype vaccines)
• NB Regulatory
  preparednes

Novel adjuvants
Stockpile adjuvant and antigen Replace Ag subtype
if required
Ag sparing, broad activity, safe
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Vectors For Viral Antigen Delivery

• Retroviruses
• Poxviruses
• Adenoviruses
• Adeno-associated viruses
• Herpesviruses
• Alphaviruses
• VLPs (HPV, rotavirus, parvovirus, HBV.)
• Bacterial vectors
• Plasmid DNA
  NB LAIV !!!
• DCs and exosomes

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• Cynomolgus Macaques (Macaca fascicularis)
• 1-2 years of age

Kreitz et al., JID in press
0
28
56
60

• Vaccines
• MVA-HA (A/Vietnam/1194/04)1
• MVA (wildtype)1
• PBS
• Viruses
• A/Vietnam/1194/04
• A/Indonesia/5/05

• Read-out
• Serology
• Clinical signs
• Virus titers
• Pathology

• 1ml PBS divided over both legs (intramuscular)
• (dose 108.5 PFU)
  Blood was drawn on day 0, 28, 56
  and 60

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Challenge viruses

• A/Vietnam/1194/04 (A/VN/1194/04)
• A/Indonesia/5/05 (A/IND/5/05)

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Serology MVA-HA immunized animals
HI
VN
influenza virus A/Vietnam/1194/04
influenza virus A/Indonesia/5/05
Kreitz et al., JID in press
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Lung virus titers
influenza virus A/Vietnam/1194/04
influenza virus A/Indonesia/5/05
Kreitz et al., JID in press
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Gross pathology
Kreitz et al., JID in press
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CONCLUSIONS development of pandemic influenza
vaccines

• Several novel generations of influenza vaccines
  are being developed
• (adjuvanted, DNA, LAIV, vectored, VLP, and
  peptide-based vaccines)
• Novel adjuvants have led to seasonal flu vaccine
  and vaccine candidates against
• avian influenza (H5,H9) that are Ag-sparing
  and broadly active
• Vectored vaccines are promising influenza vaccine
  candidates
• LAIV is used for seasonal vaccination and is a
  promising pandemic vaccine candidate

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Vaccination strategies for an
influenza pandemic
PRE-PANDEMIC
PANDEMIC
Only planning for manufacturing duringpandemic
Protection
3-6 months
3-4 weeks
Manufacturing of pre-pandemic vaccine
Protection
3-6 months
CROSS PROTECTION
Manufacturing of pre-pandemic vaccine
?
Direct protection
3-4 weeks
Months or years
Pandemic influenza vaccine stockpiling
Pandemic vaccine
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Acknowledgements
Dept. Virology, Erasmus MC Vincent Munster Emmie
de Wit Debby van Riel Theo Bestebroer Ger van der
Water Brigitte van Uden Geert van
Amerongen Robert Dias dUllois Joost Kreitz Jan
de Jong Bart Haagmans Thijs Kuiken Ron
Fouchier Guus Rimmelzwaan
ViroNovative BV James Simon Viroclinics BV Koert
Stittelaar NIBSC John Wood PEI Langen Gerd
Sutter Sanofi Pasteur GSK Solvay