7/14/2014

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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E

Elicitation of broadly-reactive HA head antibodies to seasonal and pandemic viruses by COBRA vaccines

Second WHO Integrated Meeting on development and clinical trials of Influenza vaccines that induce broadly

protective and long-lasting immune responses 5th – 7th May 2014

Geneva, Suisse

1 V A C C I N E & G E N E T H E R A P Y I N S T I T U T E

Program Hypothesis

Universal influenza vaccines can be rationally engineered

to elicit broadly cross-neutralizing epitopes Universal antigens can be used in pre-immune hosts to re-focus the immune response,

preferentially recalling broadly neutralizing antibodies that provides breadth against multiple

strains within a subtype

Universal antigens can also be delivered with appropriate technologies to stimulate durable

and long-lasting immunity

Antigen

Selection

Production & Delivery System

Adjuvant

(Formulation)

V A C C I N E & G E N E T H E R A P Y I N S T I T U T E

HA as the Principal Component of a Universal Influenza Vaccine

Immune-refocusing of HA to increase breadth

Promote immunogenicity of the known broadly neutralizing stem epitopes

Identify head sequences which stimulate broadly neutralizing Abs

Benefits: Anti-head response against receptor binding site potent and MOA of current vaccine Accepted surrogate marker (HAI) Risks: Breadth may be narrower than anti-stem approaches

Benefits: Breadth may reach across groups of influenza Risks: Not as potent as anti-head, higher amount of functional anti-stem Abs needed Disease modulating? No surrogate marker identified

HEAD:

STEM:

V A C C I N E & G E N E T H E R A P Y I N S T I T U T E

Influenza Vaccine Program

Vaccines: A goal of influenza vaccine development is the elicitation of cross-protective immunity. It is currently impossible to predict which antigenic variants may emerge and therefore an ideal vaccine will elicit immunity to most potential variants.

Pandemic Influenza: H5N1, H7N9, H2N2

Broadly-reactive HA immunogens

Seasonal Influenza: H1N1, H3N2, and B Broadly-reactive HA immunogens/ Universal influenza platforms

100 µm

HA M1 NA

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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E

H5N1 Background

• Initially emerged in poultry and humans in 1997

• Diversity within subtype

– 10 phylogenetic clades

– Geographically distinct

– Human infections from

clades 0, 1, 2 and 7

Total Clade Distribution

0 1

2 3

4 5

6 7

8 9

1

2

0

Giles et al. 2012. J. Inf. Dis. 205(10):1562-70.

Giles et al. 2012. Clin Vacc Immunol. 19(2):128-39. Giles et al.. 2011. J. Virol. 86:1500-1513. Giles BM and Ross TM. 2011. Vaccine. 29:3043-54.

5 V A C C I N E & G E N E T H E R A P Y I N S T I T U T E

Antigen Design

• Computationally Optimized Broadly Reactive Antigen (COBRA) – Align amino acid sequences from Clade 2 human isolates – Assemble ‘Layered’ Consensus – Limit sampling bias

• Confirm presence of conserved linear epitopes – (Immune epitope database; www.immuneepitope.org)

Giles and Ross. 2011. Vaccine. 29:3043-54

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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E

Mouse Antibody Responses

0 3 5 6

V V B C

8-12 week

BALB/c 3ug HA + Alum

Giles and Ross. 2011. Vaccine. 29:3043-54

7 V A C C I N E & G E N E T H E R A P Y I N S T I T U T E

NHP Immunogenicity Breadth (HAI)

Receptor Blocking Antibody(HAI Titers)

Clade 0

(HK/4

83/97)

Clade 1

(HK/2

13/03)

Clade 1

(VN/1

203/04)

Clade 2

.1.1

(Dk/H

U/02)

Clade 2

.1.3

(IN/0

5/05)

Clade 2

.2.1

(Eg/3

21/07)

Clade 2

.2.1

(Eg/3

300/08)

Clade 2

.2.2

(Tk/E

G/0

7)

Clade 2

.2.2

(Tk/T

k/05)

Clade 2

.2.2

(WS/0

5)

Clade 2

.2.2

(BHG

/1/0

5)

Clade 2

.3.2

(CM

P/HK/0

7)

Clade 2

.3.2

(Buz/

Bul/10)

Clade 2

.3.4

(JW

E/1038/0

6)

Clade 2

.3.4

(AN/1

/05)

Clade 4

(Gs/1

175/06)

Clade 7

(Ck/V

N/08)

Clade 2

.0 C

OBRA

3

4

5

6

7

8

9

10

Whooper Swan Clade 2.2 VLP

COBRA VLP

Mock (Alum Only)

*** p<0.001

** p<0.01

* p<0.05

0 1 2.1 2.2 2.3 4 7

** ***

***

****

****

*** **

******

**

Virus

HA

I GM

T (

Lo

g2)

Giles et al. 2012. Clin Vaccine Immunol.19:128-39.

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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E

Part I: COBRA 1st Generation

0 3 5 6

V V B C

Challenged with A/Whooper Swan/Mongolia/244/2005; Clade 2.2.

Day 3 post-infection

Giles et al. 2012. J. Inf. Dis. 205(10):1562-70.

9 V A C C I N E & G E N E T H E R A P Y I N S T I T U T E

Human COBRA-2 Human/Avian COBRA-2 All H5 COBRA

SiteASiteBSiteCSiteDSiteE

Globular Head (HA1)

Stem (HA2)

Hemagglutinin Structure • 5-10% diversity between

clades • COBRA diversity 1.5% • Receptor binding antibody (similar yet different)

• Can we utilize empirical

data and sequence information to structurally design antigens for increased breadth and viral coverage?

Crevar et al. Manuscript in progress.

Second Generation H5N1 COBRA Vaccines

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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E

H5N1 COBRA Ferret Experiments using human/avian H5N1 COBRA-2

and All H5N1 COBRA vaccines

Second Generation

H5N1 COBRA Hemagglutination Inhibition Titers to H5N1

Clade 1

(VN/1

203/04)

Clade 1

.1 (C

am/V

0813302/11

Clade 2

.1.3

(IN/0

5/05)

Clade 2

.1.3

.2 (I

N/NIH

RD1949/12)

Clade 2

.2 (W

S/244/0

5)

Clade 2

.2 (T

k/Tk/0

5)

Clade 2

.2.1

(Egy/3

21/07)

Clade 2

.2.1

(Egy/3

300/08)

Clade 2

.2.1

(Hubei/1

/10

Clade 2

.2.1

.1 (T

k/Isr/3

62/11)

Clade 2

.2.2

(Bng/3

233/11)

Clade 2

.3.4

(AN/1

/05)

Clade 2

.3.4

(JW

E/1038/0

6

Clade 2

.3.2

.1 (E

gy/N02038/1

0

Clade 2

.3.2

.1 (D

k/VN/L

BM140/1

2)

Clade 7

(Ck/V

N/08)

4

5

6

7

8

9

10

Human COBRA-2

Human-Avian COBRA-2

All H5 COBRA

V iral Strain

Lo

g 2

HA

I Tit

er Whooper Swan

*

*

**

* *

*

*

**

*

*

*

*

*

*

* p<0.05

Ferret Immunogenicity Breadth of HAI

V A C C I N E & G E N E T H E R A P Y I N S T I T U T E

Summary

• An HA head-based approach has potential to replace SOC – Induces protection (vaccine efficacy) to a level comparable to SOC vaccines against

WHO recommended strains, AND – Demonstrates breath of protection by providing consistent efficacy across

types/subtypes against drifted/mismatched strains

• New approaches for re-engineering HA have been

demonstrated to increase breadth of neutralizing antibody response in pre-clinical studies – COBRA antigens increase breadth of Ab response over wild-type HA

• Determining clinical POC in human translational studies is

feasible – Progress into clinic with COBRA split-INV for POC – Assess whether or not COBRA antigens stimulate breath of immune response in

humans as expected from pre-clinical animal model data

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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E

Acknowledgements

• VGTI Florida –Donald Carter –Corey Crevar

–Greg Kirchenbaum

–Terianne Wong –Chalise Bloom

–Bradford Lefoley –Chris Darby

–Neha Reddy –Kevin Lee

–Rayleigh Chan

• University of Pittsburgh –Dilhari DeAlmeida –Kirsten Schneider-Orhum

–Brendan Giles

–Xian-Chun Tang –Brooke Pierce

Department of NeuroPathology Clayton Wiley Stephanie Bissel

New York University Elodie Ghedin

Icahn Mt. Sinai School of Medicine Florian Krammer

UPMC Shanta Zimmer Rick Zimmerman Kerry Empey

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Influenza Projects Supported by:

NIH/NIAID NSF DoD PATH Vaccine Solutions Sanofi-Pasteur