Sophie VonDobschuetz, RVC/FAO Olga Munoz, IZSVe Rowena Kosmider, AHVLA

FAO Workshop on Influenza risk assessment and risk modeling Rome, 7-9 November 2012

Introduction Methodology Literature review ◦ Results ◦ Difficulties

Modeling strategy Expert elicitation Conclusions

The FLURISK Influenza Risk Assessment Framework (IRAF) will be ranking influenza A viruses isolated from animals

according to their potential to jump the species barrier into humans at the current time period.

The model will concentrate on the initial species jump and not take into account the potential of a virus for sustained transmission in humans.

Epidemiological assessment will be combined with virological assessment.

For the virological assessment a virus chacterization score is being developed.

1. Literature review: to identify potential virological risk factors, such as genetic traits or mutations;

2. Consultation between virologists and risk assessors to select the most suitable factors;

3. Expert elicitation to weight the identified factors and rank them by importance;

4. Building the final virus characterization score.

=> Only risk factors concerning the species jump per se are

being used.

=> Only factors which have been studied and for which a consequence has been found are being considered.

Main Question: Which are the virological factors, common to all subtypes or singular to each subtype, that enable and facilitate an Influenza A virus strain (IAV) to cross the species barrier?

Aim: To identify suitable virological factors.

Categories that are likely to influence the species jump:

• Interspecies barriers

• Intramammal barriers

• Intermammal barriers

From a virological point of view, and after consultation with risk assessors, it was decided to concentrate on:

intramammal barriers

I. Attachment and entry

II. Replication: Interaction with cell factors (NP-PB1-PB2-PA)

IV. Host immune response

III. Release

Receptor preference α 2-3 α 2-6 Paradigm:

other glycan characteristics (e.g. length)

certain pattern for H1 (D225, D190 ), H3 and H2 (L226, S228 )

Mutations: 20 from AIV to humans

3 from SIV (H1N1) to humans (H1N1pdm09)

Presence of adaptive amino acid substitutions in the polymerase complex PB2: 8 mutations, among which:

E627K

D701N

G590S/Q591R SR polymorphism

PA: 6 mutations

PB1: 3 mutations

NP: 4 mutations (all studied in mice lab-adapted strains)

Increase OR decrease polymerase activity

NOT

Release and shedding

NA:

stalk deletion

e.g. all H5N1 isolates since 2007: 20 AA deletion

•

• LPAI H2N2: shift from intestinal

to respiratory viral tropism (Sorrell

et al., 2010)

• LPAI H7N1: replication in the RT

and excreted fecally at higher

titers (Hoffmann et al., 2012)

• LPAI H1N1: increases

pathogenesis and replication (Munier et al., 2010)

•HPAI H5N1: no differences

between long and short stalk, but

may contribute to a shorter death

time (Matusoka et al., 2009)

•HPAI H5N1: increases

virulence (+ less

glycolsyaltion sites:

131/158/169, H3

numbering) (Matsuoka et al.,

2009)

•HPAI H5N1-H1N1

reassortant with 20 AA

deletion: more virulent than

other or no deletion (Zhou et

al., 2009)

NA stalk deletion

Host immune response

Antigenic distance

to HA/NA of currently circulating subtypes in humans

Taken from: Yong, Nature 2012

1. Standardization

Receptor binding studies: HA; solid-phase enzyme linked assay; glycan arrays; virus

histochemestry; MD simulation; x-ray crystallography

In vitro/vivo studies: animal models; subtypes; inoculation dose/route; cell cultures;

etc.

Blixt et al., 2004

Literature Review - Difficulties

2. Interpretation of data

Reassortment: difficult to pinpoint an optimal combination Mutations: •2 categories

•different between hosts? between host switch events? Which are common to different hosts?

•Subtype or even strain dependent? Which are common to different subtypes?

•Most studied: from AIV to humans, poorly SIV to humans, None EIV or CIV

Literature Review - Difficulties

From the information generated by the literature review, broad definitions were worked out for each stage of the viral cycle (e.g. no specification of particular mutations).

Final virus characteristic score:

For the four stages: attachment, replication, release and host immune response, five main risk factors were identified (1-2 factors each).

Each factor is divided into two possible characteristics.

Stage of life cycle Factor Characteristic Attachment Receptor preference Amino acid motif typical for a2-6

sialic acid binding Amino acid motif typical for a2-3

sialic acid binding

Replication Presence of known amino acid substitutions in polymerase complex (PB1, PB2, PA, NP)

Presence of adaptive amino acid substitutions in PB2

Presence of adaptive amino acid substitutions in any of the other genes that make up the polymerase complex

Origin of the polymerase complex (PB1, PB2, PA, NP)

No reassortment Reassortment

Release and shedding Stalk deletion in the NA Full length stalk Shorter stalk

Antigenic distance Origin of NA and HA HA/NA in species it is typically associated with

HA/NA from another subtype/lineage or circulating in a different species

Modeling Strategy

Aim: to weight and prioritize identified virological risk factors

Expert elicitation ◦ On-line questionnaire asking experts which

virus is most likely to jump the species barrier into humans

Pair-wise comparison

Rank 8 virus profiles

◦ Pictorial representations of factors for virus profile

Estimate weights of factors

The FLURISK IRAF concentrates on the initial species jump of animal influenza viruses into humans and does not take into account the potential of a virus for sustained transmission in humans.

We categorize identified risk factors by the stages of the infection process: virus attachment, replication, release and host immune response. Five main risk factors have been identified within these categories, with two characteristics each.

The factors will be weighted and prioritized according to expert elicitation (currently in pilot stage).

The final virus characteristic score will be used to estimate the (intrinsic) likelihood of an animal influenza virus jumping the species barrier and infecting humans.

This will make up the virological assessment in the FLURISK IRAF, in addition to an epidemiological assessment.

The FLURISK IRAF concentrates on the initial species jump of animal influenza viruses into humans and does not take into account the potential of a virus for sustained transmission in humans.

We categorize identified risk factors by the stages of the infection process: virus attachment, replication, release and host immune response. Five main risk factors have been identified within these categories, with two characteristics each.

The factors will be weighted and prioritized according to expert elicitation (currently in pilot stage).

The final virus characteristic score will be used to estimate the (intrinsic) likelihood of an animal influenza virus jumping the species barrier and infecting humans.

This will make up the virological assessment in the FLURISK IRAF, in addition to an epidemiological assessment.

EFSA for funding the FLURISK project;

The FLURISK consortium for the active participation

in the discussions:

◦ Animal Health and Veterinary Laboratories Agency, UK (AHVLA)

◦ Istitut Pasteur, France (IP)

◦ Istituto Zooprofilattico Sperimentale delle Venezie, Italy (IZSVe)

◦ National Institute for Public Health and Environment, The

Netherlands (RIVM)

◦ Royal Veterinary College, UK (RVC)

◦ Ghent University, Belgium (Ugent)

Thank you