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1

Safety and Immunogenicity of a Recombinant

Virus-Like Particle Influenza A(H7N9) Vaccine

With and Without a Saponin-based Adjuvant

06 May 2014

Louis Fries, MD

Vice President, Chief Medical Officer

Novavax, Inc.

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Influenza Virus Vaccine VLPs

HA and NA spikes

M1 internal

RNA genome

No influenza genetic material

VLPs Mimic Influenza Virus, but are Non-Infectious

Lipid bilayer

3 3

Recombinant Baculovirus VLP Vaccine

Generation of baculovirus cell-based VLPs

Genes are synthesized based on GISAID sequence data

• Condon-optimized for expression in insect cells

• HA

– Exact amino acid match to human isolates

– Expressed as HA0

• NA

– Expressed in a 1:3 to 5 ratio to HA, enzymatically-active

• M1

– Avian M1 used for all strains

– Supports maximal productivity in insect cells

VLPs bud from Sf9 cell membrane lipid rafts

No amino acid changes resulting from egg passage

Ready generation of purified HA and NA reagents

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Minutes

13 14 15 16 17 18 19 20 21 22 23 24

AU

0.000

0.005

0.010

0.015Before Deglycosylation

HA

M1

HA,NA

M1

NA

Minutes

13 14 15 16 17 18 19 20 21 22 23 24

AU

0.0000

0.0002

0.0004

0.0006

0.0008

0.0010 After Deglycosylation HA~34% M1

PNGase F NA~8%

Reducing the Complexity of Capillary Gel Electrophoresis

by Deglycosylation

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5

Minutes

21.6 21.7 21.8 21.9 22.0 22.1 22.2 22.3 22.4 22.5 22.6 22.7 22.8 22.9 23.0 23.1 23.2 23.3 23.4 23.5 23.6 23.7 23.8 23.9 24.0 24.1 24.2 24.3 24.4

AU

-0.001

0.000

0.001

0.002

0.003

0.004

0.005

0.006

0.007

0.008

AU

-0.001

0.000

0.001

0.002

0.003

0.004

0.005

0.006

0.007

0.008PDA - 220nm

01-100 µgmL HA

Current

01-100 µgmL HA

PDA - 220nm

05-500 µgmL HA

PDA - 220nm

02-200 µgmL HA

PDA - 220nm

03-300 µgmL HA

PDA - 220nm

04-400 µgmL HA

R² = 0.9989

0.0

100.0

200.0

300.0

400.0

500.0

600.0

700.0

0 20 40 60 80 100

VLP HA Curve

Purified HA Curve

R² = 0.9979

0

200

400

600

800

1000

1200

0 200 400 600

CGE Calibrated with Purified HA for Initial HA Quantitation

Resultant formulations within 10% of target

using CBER SRID reagents when these became available.

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Genetic Sequence to GMP Batch Release

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Mouse Protection by H7N9 and H7N3 VLP Vaccines with and

w/o Saponin Adjuvant

Mice were immunized with VLP

vaccines containing HA and NA :

1) A(H7N9) A/Anhui/1/13, or

2) An A(H7N3), or

3) An A(H5N1) VLP

After 2 vaccine doses, the mice were

challenged with a lethal dose of A(Anhui

virus.

Both H7 vaccines, but not the H5

vaccine, protected the mice from:

• weight loss (panel A)

• death (panel B)

Even without adjuvant, H7 VLP vaccines

were cross-protective among H7 strains.

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Induction of A/Anhui/1/2013 Antibody Responses in Ferrets

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NVX900.PH7.101 Phase I Trial

• Primary objectives:

‒ Describe the safety of A/Anhui/1/2013 VLP vaccine in healthy adults

with and without saponin-based (ISCOMATRIX®) adjuvant (CSL).

‒ Assess the adjuvant effect and capacity of adjuvant to provide

dose-sparing at two dose levels

‒ Describe the performance of various formulations in terms of seroconversion rates and proportion of population with post-

immunization reciprocal HAI titers ≥ 40.

• Secondary objectives;

‒ Assess NAI responses

• Population:

‒ Target enrollment of 280 healthy adults ≥ 18 y.o. stratified on age

18-49 and ≥ 50 y.o.

‒ Males and non-pregnant females

‒ Recruited in Australia

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NVX900.PH7.101

• Randomized, observer-blind, saline placebo-controlled

• Two identical doses at Days 0 and 21

• Key serology: Days 0, 21 and 35, with later follow-up to assess

antibody persistence

• Safety follow-up for one year post dose 2.

ISCOMATRIX® Adjuvant Doses

Groups Antigen Dose (µg HA) 0 30 units 60 units

A 0 (Placebo) 40

B 45 40

C 15 40

D 15 40

E 5 40

F 15 40

G 5 40

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Safety Summary through Day 35

Counts of Subjects with AEs (%) by Treatment Groups

Antigen 0 15µg HA 45µg HA 5µg HA 15µg HA 5µg HA 15µg HA

Adjuvant 0 0 0 30 units 30 units 60 units 60 units

N treated (≥ 1 dose) 41 40 41 40 42 40 40

Any AE 1 29 (70.7) 29 (72.5) 36 (87.8) 35 (87.5) 36 (85.7) 40 (100) 39 (97.5)

Solicited 1, 2 Any 23 (56.1) 22 (55.0) 28 (68.3) 32 (80.0) 34 (81.0) 37 (92.5) 37 (92.5)

Any severe 0 2 (5.0) 1 (2.4) 4 (10.0) 2 (4.8) 7 (17.5) 0

Local 6 (14.6) 16 (40.0) 24 (58.5) 30 (75.0) 28 (66.7) 34 (85.0) 33 (82.5)

Systemic 21 (51.2) 19 (47.5) 24 (58.5) 29 (72.5) 28 (66.7) 34 (85.0) 33 (82.5)

Unsolicited 1 Any 21 (51.2) 20 (50.0) 21 (51.2) 16 (40.0) 21 (50.0) 27 (67.5) 25 (62.5)

Severe 1 (2.4) 1 (2.5) 1 (2.4) 2 (5.0) 1 (2.4) 0 2 (5.0)

Related 8 (19.5) 7 (17.5) 7 (17.1) 8 (20.0) 6 (14.3) 8 (20.0) 14 (35.0)

Sev & Rel 1 (2.4) 0 1 (2.4) 0 0 1 (2.5) 0

Serious 0 0 0 1 (2.5) 0 0 0

Medically-attended AEs 1 0 6 (15.0) 4 (9.8) 5 (12.5) 4 (9.5) 3 (7.5) 3 (7.5)

Grade 2 or 3 lab abnml. 1 3 (7.3) 1 (2.5) 2 (4.9) 1 (2.5) 1 (2.4) 4 (10.0) 2 (5.0)

1: Count and percentage of the Safety population

2: Common post-vaccinal events solicited by diary for 7 days after each dose; each subject enters the analysis here at his/her worst severity grade after either dose.

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Additional Safety Data

• Local solicited adverse events were primarily mild to moderate

injection site pain, which did not escalate in frequency or

severity after the second dose.

• Transient myalgia, arthralgia, headache and fatigue are the

major contributors to systemic reactogenicity.

‒ Overall, the rate of severe complaints is low, and the few oral

temperature elevations reported are <38.5⁰C.

• Clinical laboratory abnormalities typically transient, with no clear

temporal relation to treatment.

• Since Day 35, there have been 5 additional SAEs

‒ Span placebo, unadjuvanted, and adjuvanted vaccines groups

‒ Various body systems, none deemed related.

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A/Anhui/1/2013 HAI Titer Responses at Days 21 and 35

(Turkey RBC, egg-propagated A/Anhui/1/12013 NIBRG-268)

5.7%

15.9%

64.9%

36.8%

80.6%

64.8%

% = seroconversion rates

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Shift in Distribution of A/Anhui/1/2013 HAI Titers

1:40

5µg HA +

ISCOMATRIX®

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H7 Proves a Harder Target than H5

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Virus Antigen vs. VLP HAI Titers

95% CI

Concordance Slope 1.19 1.17 1.22

Concordance Intercept -0.22 -0.31 -0.13

Average Difference (%) 47.31 38.72 56.44

R2 = 0.89

p<0.001

• HA (and NA) sequence of egg-grown A/Anhui/1/13 virus used in HAI, based on amplified RNA

extract, is 100% identical to sequence specified by construct used to create VLPs

• Ability to use VLP reagents in HAI assay useful for rapid screening of serologic responses against

new viral variants without high security or containment facilities.

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NAI Responses by N9 ELLA (N9+M1 VLPs)

57.1%

71.9%

91.9% 92.1%

97.2%

97.1%

Black % = sero-response rates

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Summary:

o A/Anhui/1/2013 vaccine was manufactured, tested, and released for

human dosing in < 12 weeks

o Rate-limiting critical path steps:

o Gene synthesis – 9 days

o Cloning – 2.5 weeks

o MVS – 5 days

o GMP manufacturing of VLPs – not on the critical path to first vaccine doses

o Product release (potency, sterility, adventitious agent testing) – 7 weeks

o A/Anhui/1/12013 VLP vaccine in humans

o Was well-tolerated with a saponin adjuvant,

o >80% HAI antibody responses after a second IM dose with adjuvant with as

little as 5 µg of HA antigen, and

o >97% NAI antibody responses after a second IM dose with adjuvant with as

little as 5 µg of HA antigen.

o Phase II in progress currently with Novavax’ Matrix-M saponin adjuvant

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Acknowledgments

• Discovery • Gale Smith

• Mike Massare

• Ye Liu

• David Flyer

• Rama Raghunandan

• Process Development • Erica Shane

• Hua Jiang

• Margret Nathan

• Kwan-Ho Ro

• John Higgins

• Ziping Wei

• John Burd

• Diana Chinchilla-Olszar

• Monique Malou-Williams

• Manufacturing • Tim Hahn

• Malek Masoud

• Mervyn Hamer

• Cast of thousands

• Quality Systems • Jody Hatch

• Mike Sowers

• James Wong

• Konnie Taylor

• Analysts TNTC

• Clinical Development • Greg Glenn

• Nigel Thomas

• Eloi Kpamegan

• Somia Hickman

• Judy Wen

• Dewal Jani

• The clinical assay team

• Regulatory Affairs • Kathleen Callahan & the team

• Project Management • Denise Courbron

Novavax seasonal and pandemic influenza

vaccine development programs are

supported by the US Department of Health

and Human Services, BARDA