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© 2018 Novavax, Inc. All rights reserved. NASDAQ:NVAX
April 4, 2018
Novavax NanoFlu vaccine induced improved immune responses against homologous and drifted A(H3N2) viruses in older adults compared to egg-based, high-dose, influenza vaccineWorld Vaccine Congress
2
Outline
The need for an improved flu vaccine
The nanoparticle vaccine and Matrix-M adjuvant
Broadly cross-reactive A(H3N2) immune responses in ferrets
Phase 1/2 trial design
Phase 1/2 data
Conclusions
Two critical problems undermine seasonal influenza VE:1) Classical antigenic drift (long-standing):
• Exemplified by poor VE during 2014-15 US flu season2 (emergence of A/Switzerland H3N2)
2) Egg-adaptive antigenic changes (recently recognized):• Exemplified by poor A(H3N2) VE during 2017-18 US flu season in spite of an apparent “match”3
• Existence of well-characterized egg-adaptive mutations in HA antigenic epitopes (T160K)4
• Problematic given that 87% of flu vaccines deployed in the US are produced in eggs5
Compounding effect of both problems likely contributed to recent poor A(H3N2) VE noted during the 2017 influenza season in Australia
• A level of drift likely present with the emergence of A/Singapore-NFIMH (H3N2)-like viruses, though not rising to the strict definition of “drift” by WHO6
• A significant concomitant impact of egg-adaptive antigenic changes was observed
CAN WE DO BETTER?Broader protection? Eliminate egg-adaptive changes?
3
Why do we need a better seasonal influenza vaccine?
Consistently suboptimal seasonal influenza vaccine effectiveness (VE) in recent years1, notably in the context of:
A(H3N2) Older adultsviruses
1. Russell Vaccine 2018.2. MMWR June 20153. MMWR Feb 20184. Zost PNAS 20175. CDC Influenza Grand Rounds Jan 20186. VRBPAC Feb 2018
Playing catch-up and does “one strain fit all”? Rapid evolution and diversity of A(H3N2) viruses
4
Adapted from CDC Grand Rounds. January 18, 2018. https://www.cdc.gov/cdcgrandrounds/archives/2018/January2018.htm
4 CDC collaboration with NextFlu. Neher, Bedford etal.
Most common in Australia summer ‘17
2009 2010 2011 2012 2013 2014 2015 2016 2017
Epitope Changes
1 15Number of significant changes to important
regions of the hemagglutinin gene
= Vaccine Viruses
A/Singapore
A/Hong Kong
A/Switzerland
A/TexasA/Victoria
A/Perth
Most common in U.S. 17/18 season
Playing catch-up and does “one strain fit all”? Rapid evolution and diversity of A(H3N2) viruses
5
Adapted from CDC Grand Rounds. January 18, 2018. https://www.cdc.gov/cdcgrandrounds/archives/2018/January2018.htm
5 CDC collaboration with NextFlu. Neher, Bedford etal.
Most common in Australia summer ‘17
2009 2010 2011 2012 2013 2014 2015 2016 2017
Epitope Changes
1 15Number of significant changes to important
regions of the hemagglutinin gene
= Vaccine Viruses
A/Singapore
A/Hong Kong
A/Switzerland
A/TexasA/Victoria
A/Perth
Most common in U.S. 17/18 season
Circulating H3N2 viruses present in 2017-18 Season
The nanoparticle influenza vaccine and Matrix-M adjuvant
• Recombinant hemagglutinin (HA) nanoparticle vaccine• Baculovirus/Sf9 insect cell system• Express recombinant, full-length, wild-type HA that assembles into HA homotrimers• Purified HA homotrimers form higher order nanoparticle structures of 20-40 nm • 2 to 9 HA homotrimers per nanoparticle held together by hydrophobic interactions• Rapid, high-yield, high purity, production process
• Potent saponin-based Matrix-M adjuvant• Extracted from bark of Quillaja saponaria Molina• Enhancement of activated T cell, B cell, and APC
populations• Induction of functional, and broadly cross-reactive
antibodies• Induction of polyfunctional T cells, both CD4+ and CD8+• Antigen sparing in the context of pandemic influenza
6
7
In ferrets, tNIV induced broadly cross-neutralizing immune responses to drifted A(H3N2) viruses
4096
1024
256
64
16
4
50%
MN
Tite
rs (L
og2)
NIV + Matrix MFluzone HDFluzone QIV
Novel hemagglutinin nanoparticle influenza vaccine with Matrix-M™ adjuvant induces hemagglutination inhibition, neutralizing, and protective responses in ferrets against homologous and drifted A (H3N2) subtypes
G Smith, Y Liu, et al.Vaccine 35 (2017) 5366-5372
• Conducted in U.S.1 across 3 sites in North Carolina• 330 clinically-stable adults ages ≥60 years• Randomized 1:1:1, stratified by age (60-74, and 75+)• Single IM dose on day 0 of:
• tNIV: 15µg each HA (45µg total) + 50µg Matrix-M, or• tNIV: 60µg each HA (180µg total) + 50µg Matrix-M, or• Licensed egg-based high-dose (180µg total), trivalent, inactivated influenza vaccine (IIV3-HD)(Fluzone-HD)
• Day 21 rescue dose of IIV3-HD or placebo• All 3 vaccines included 2017-18 WHO recommended NH strains:
• A/Michigan (H1N1); A/Hong Kong (H3N2); B/Brisbane
• Objectives• Safety: assessed through Day 21• Immunogenicity: HAI and MN against vaccine-homologous and drifted H3N2 strains through Day 21
Phase 1/2 trial design
1. Clinicaltrials.gov NCT#03293498
8
N 109 111 110Mean age (SD) 69 (6.3) 68 (6.2) 69 (6.1)
Median age 68 67 69
Count (%) ≥65 y.o. 73 (66.9) 76 (68.4) 79 (71.8)
Count (%) ≥75 y.o. 19 (17.4) 20 (18.0) 20 (18.2)
%M / % F 46.8/53.2 45.9/54.1 48.2/51.8
Race/Ethnicity
White (%) 83.5 88.3 90.0
Black/African American (%) 15.6 11.7 8.2
All other (%) 0.9 0 0.9
Self-identified as Hispanic (%) 0.9 0.9 0.9
Flu vaccine in 2016-17 (%) 95 (87.2) 94 (84.7) 93 (84.5)
Any flu vaccine w/i 3 yrs (%) 102 (93.6) 101 (91.0) 102 (92.7)
9
Demographic data
45µg tNIV HA + MxM 180µg tNIV HA + MxM IIV3-HD (Fluzone HD)Variable
N 109 111 110Counts (%) of Subjects with Events
Any treatment emergent adverse event (TEAE)
40 (37%) 52 (47%) 51 (46%)
Any Solicited TEAE 30 (28%) 37 (33%) 38 (35%)
Local solicited 15 (14%) 26 (23%) 30 (27%)
Severe local solicited 2 (2%) 0 (0%) 1 (1%)
Systemic Solicited 23 (21%) 24 (22%) 20 (18%)
Severe systemic solicited 2 (2%) 4 (4%) 0 (0%)
Unsolicited TEAE 22 (20%) 24 (22%) 20 (18%)
Severe unsolicited 0 (0%) 2 (2%) 1 (1%)
Severe & related unsolicited 0 (0%) 0 (0%) 1 (1%)
Medically-attended unsolicited 9 (8%) 6 (5%) 2 (2%)
Serious adverse events (SAEs) 0 (0%) 1 (1%) 0 (0%)
10
Top-line safety data
45µg tNIV HA + MxM 180µg tNIV HA + MxM IIV3-HD (Fluzone HD)Safety events (thru 21 days)
61.0
127.0
58.0
159.0
62.0
116.0
69.0
146.0
66.0
210.0
65.0
171.0
58.0
87.0
55.0
106.0
54.0
109.0
0
50
100
150
200
250
Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21
HAI antibody responses (GMTs) against wild-type vaccine-homologous strains (2017-18)
Geo
met
ric M
ean
Tite
r (G
MT)
11
45µg NanoFlu 180µg NanoFlu IIV3-HD 45µg NanoFlu 180µg NanoFlu IIV3-HD 45µg NanoFlu 180µg NanoFlu IIV3-HDA/HongKong H3N2 A/Michigan H1N1 B/Brisbane
HAI antibody response (GMFRs) against wild-type vaccine-homologous strains (2017-18)
12
2.1
2.7
1.92.1
3.2
2.6
1.5
1.92.0
0
1
2
3
4
45µg NanoFlu 180µgNanoFlu
IIV3‐HD 45µg NanoFlu 180µgNanoFlu
IIV3‐HD 45µg NanoFlu 180µgNanoFlu
IIV3‐HD
A/HongKong H3N2 A/Michigan H1N1 B/Brisbane
Geo
metric
Mean Fold Tite
r Rise (95%
CI)
Ratio of Day 21 GMTs47% ↑ p=0.0056
2.3
3.4
2.3 2.2
3
2.22.5
3.9
2.5
2.1
2.7
1.92.2
3.1
1.9
0
1
2
3
4
5
HAI antibody responses (GMFRs) against 5 generations of drifted wild-type A(H3N2) strains
Ratio of Day 21 GMTs38% ↑ p=0.0058
Ratio of Day 21 GMTs28% ↑ p=0.036
Ratio of Day 21 GMTs54% ↑ p=0.0065
Ratio of Day 21 GMTs47% ↑ p=0.0056
Ratio of Day 21 GMTs64% ↑ p=0.0009
Geo
met
ric M
ean
Fold
Tite
r Ris
e (9
5% C
I)
13
45µg NanoFlu
180µg NanoFlu
IIV3-HD 45µg NanoFlu
180µg NanoFlu
IIV3-HD 45µg NanoFlu
180µg NanoFlu
IIV3-HD 45µg NanoFlu
180µg NanoFlu
IIV3-HD 45µg NanoFlu
180µg NanoFlu
IIV3-HD
A/Victoria H3N2 A/Texas H3N2 A/Switzerland H3N2 A/Hong Kong H3N2 A/Singapore H3N2
2.3
3.4
2.3 2.2
3
2.22.5
3.9
2.5
2.1
2.7
1.92.2
3.1
1.9
0
1
2
3
4
5
HAI antibody responses (GMFRs) against 5 generations of drifted wild-type A(H3N2) strains
Ratio of Day 21 GMTs38% ↑ p=0.0058
Ratio of Day 21 GMTs28% ↑ p=0.036
Ratio of Day 21 GMTs54% ↑ p=0.0065
Ratio of Day 21 GMTs47% ↑ p=0.0056
Ratio of Day 21 GMTs64% ↑ p=0.0009
Geo
met
ric M
ean
Fold
Tite
r Ris
e (9
5% C
I)
14
45µg NanoFlu
180µg NanoFlu
IIV3-HD 45µg NanoFlu
180µg NanoFlu
IIV3-HD 45µg NanoFlu
180µg NanoFlu
IIV3-HD 45µg NanoFlu
180µg NanoFlu
IIV3-HD 45µg NanoFlu
180µg NanoFlu
IIV3-HD
A/Victoria H3N2 A/Texas H3N2 A/Switzerland H3N2 A/Hong Kong H3N2 A/Singapore H3N2
A(H3N2) viruses currently circulating in North America
15
Neutralization antibody responses (GMTs) against wild-type vaccine-homologous strains (2017-18)
913
1,712
764
1,665
900
2,079
253
1,011
213
1,541
210
1,045
90 144 91 18177
213
0
500
1000
1500
2000
2500
3000
Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21
45µg NanoFlu 180µg NanoFlu IIV3-HD 45µg NanoFlu 180µg NanoFlu IIV3-HD 45µg NanoFlu 180µg NanoFlu IIV3-HD
A/HongKong H3N2 A/Michigan H1N1 B/Brisbane
Neutralization antibody responses (GMFRs) against wild-type vaccine-homologous strains (2017-18)
16
1.9 2.2 2.3
4.0
7.2
5.0
1.6 2.02.8
0.0
2.0
4.0
6.0
8.0
10.0
12.0
45µg NanoFlu 180µgNanoFlu
IIV3‐HD 45µg NanoFlu 180µgNanoFlu
IIV3‐HD 45µg NanoFlu 180µgNanoFlu
IIV3‐HD
A/HongKong H3N2 A/Michigan H1N1 B/Brisbane
Geo
metric
Mean Fold Tite
r Rise (95%
CI)
Neutralization antibody responses (GMFRs) against circulating wild-type H3N2 strains
17
2.1
2.82.5
1.92.2
2.3
2.8
3.5
2.1
0.0
1.0
2.0
3.0
4.0
5.0
45µg NanoFlu 180µgNanoFlu
IIV3‐HD 45µg NanoFlu 180µgNanoFlu
IIV3‐HD 45µg NanoFlu 180µgNanoFlu
IIV3‐HD
A/Switzerland H3N2 A/Hong Kong H3N2 A/Singapore‐NFIMH H3N2
Geo
metric
Mean Fold Tite
r Rise (95%
CI)
Vaccine Strain 2015-16Historic Drift Vaccine Strain 2016-17 and 17-18 Vaccine Strain 2018-19
Forward Drift
Ratio of Day 21 GMTs61% ↑ p=0.0002
Neutralization antibody responses (GMFRs) against egg-adapted vs. wild-type A/Singapore H3N2 viruses
Ratio of Day 21 GMTs61% ↑ p=0.0002
3.8 3.93.5
2.1
0.0
1.0
2.0
3.0
4.0
5.0
180µg NanoFlu IIV3‐HD 180µg NanoFlu IIV3‐HD
A/Singapore H3N2 (egg‐adapted) A/Singapore H3N2 (wild‐type)
18
Geo
met
ric M
ean
Fold
Tite
r Ris
e (9
5% C
I) Ratio of Day 21 GMTs61% ↑ p=0.0002
Nanoflu induced improved neutralization antibody responses (GMFRs) against wild-type vs. egg-adapted A/Singapore H3N2 viruses underscoring the problem of egg-adaptive mutations
Neutralization antibody responses against wild-type circulating viruses are the most clinically relevant
19
• Avoidance of egg-adaptive antigenic changes leads to substantial improvements in vaccine-homologous A(H3N2) HAI antibody responses
• Induction of immune responses against conserved HA head based epitopes expands cross-reactive HAI responses against a broad panel of A(H3N2) drift variants:
• 28-38% increase in HAI against distant historic drifted viruses (2012-13, 2014-15) • 54% increase in HAI against recent historic drifted viruses• 64% increase in HAI against forward drifted virus, A/Singapore
• Most substantial HAI antibody increases were observed against a “forward” drifted A(H3N2) virus, A/Singapore, offering a potential safeguard against the age-old problem of classical antigenic drift
• Broad cross-reactivity to antigenically diverse co-circulating A(H3N2) viruses ensures that “one size fits all” regardless of geography
• Next steps• Phase 2 in Fall 2018: quadrivalent formulation• Phase 3 anticipated in 2H 2019
Discussion
Playing catch-up and does “one strain fit all”? Rapid evolution and diversity of A(H3N2) viruses
20
Adapted from CDC Grand Rounds. January 18, 2018. https://www.cdc.gov/cdcgrandrounds/archives/2018/January2018.htm
20 CDC collaboration with NextFlu. Neher, Bedford et al.
Most common in Australia summer ‘17
2009 2010 2011 2012 2013 2014 2015 2016 2017
Epitope Changes
1 15Number of significant changes to important
regions of the hemagglutinin gene
= Vaccine Viruses
A/Singapore
A/Hong Kong
A/Switzerland
A/TexasA/Victoria
A/Perth
Most common in U.S. 17/18 season
Circulating H3N2 viruses present in 2017-18 Season
Playing catch-up and does “one strain fit all”? Nanoflu has the potential to provider broader protection
21
Adapted from CDC Grand Rounds. January 18, 2018. https://www.cdc.gov/cdcgrandrounds/archives/2018/January2018.htm
Most common in Australia summer ‘17
Most common in U.S. this season
2009 2010 2011 2012 2013 2014 2015 2016 2017
Epitope Changes
1 15Number of significant changes to important
regions of the hemagglutinin gene
= Vaccine Viruses
A/Singapore
A/Hong Kong
A/Switzerland
A/TexasA/Victoria
A/Perth
NanoFlu vaccine has potential to provide broader protection against antigenic drift
Circulating H3N2 viruses present in 2017-18 season