Novavax vaccine induced improved immune responses against homologous and drifted A(H3N2) viruses in older adults compared to egg-based, high-dose, influenza vaccine World Vaccine Congress April 4, 2018 2018 Novavax, Inc. All rights reserved. NASDAQ:NVAX
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 2
Why do we need a better seasonal influenza vaccine? Consistently suboptimal seasonal influenza vaccine effectiveness (VE) in recent years 1, notably in the context of: Two critical problems undermine seasonal influenza VE: 1) Classical antigenic drift (long-standing): Exemplified by poor VE during 2014-15 US flu season 2 (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 eggs 5 A(H3N2) viruses Older adults 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 WHO 6 A significant concomitant impact of egg-adaptive antigenic changes was observed 1. Russell Vaccine 2018. 2. MMWR June 2015 3. MMWR Feb 2018 4. Zost PNAS 2017 5. CDC Influenza Grand Rounds Jan 2018 6. VRBPAC Feb 2018 CAN WE DO BETTER? Broader protection? Eliminate egg-adaptive changes? 3
Playing catch-up and does one strain fit all? Rapid evolution and diversity of A(H3N2) viruses A/Singapore Most common in Australia summer 17 Most common in U.S. 17/18 season Epitope Changes 1 15 Number of significant changes to important regions of the hemagglutinin gene = Vaccine Viruses A/Hong Kong A/Switzerland 4 CDC collaboration with NextFlu. Neher, Bedford et A/Victoria A/Texas al. A/Perth 2009 2010 2011 2012 2013 2014 2015 2016 2017 Adapted from CDC Grand Rounds. January 18, 2018. https://www.cdc.gov/cdcgrandrounds/archives/2018/january2018.htm 4
Playing catch-up and does one strain fit all? Rapid evolution and diversity of A(H3N2) viruses A/Singapore Most common in Australia summer 17 Most common in U.S. 17/18 season Epitope Changes 1 15 Number of significant changes to important regions of the hemagglutinin gene = Vaccine Viruses A/Hong Kong A/Switzerland Circulating H3N2 viruses present in 2017-18 Season 5 CDC collaboration with NextFlu. Neher, Bedford et A/Victoria A/Texas al. A/Perth 2009 2010 2011 2012 2013 2014 2015 2016 2017 Adapted from CDC Grand Rounds. January 18, 2018. https://www.cdc.gov/cdcgrandrounds/archives/2018/january2018.htm 5
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
In ferrets, tniv induced broadly cross-neutralizing immune responses to drifted A(H3N2) viruses NIV + Matrix M Fluzone HD Fluzone QIV 4096 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 50% MN Titers (Log 2 ) 1024 256 64 16 4 G Smith, Y Liu, et al. Vaccine 35 (2017) 5366-5372 7
Phase 1/2 trial design 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 8 1. Clinicaltrials.gov NCT#03293498
Demographic data Variable 45µg tniv HA + MxM 180µg tniv HA + MxM IIV3-HD (Fluzone HD) N 109 111 110 Mean 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
Top-line safety data Safety events (thru 21 days) 45µg tniv HA + MxM 180µg tniv HA + MxM IIV3-HD (Fluzone HD) N 109 111 110 Counts (%) 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
HAI antibody responses (GMTs) against wild-type vaccine-homologous strains (2017-18) 250 210.0 Geometric Mean Titer (GMT) 200 150 100 50 61.0 127.0 58.0 159.0 62.0 116.0 69.0 146.0 66.0 65.0 171.0 58.0 87.0 55.0 106.0 54.0 109.0 0 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 180µg IIV3-HD 45µg 180µg IIV3-HD 45µg 180µg IIV3-HD A/HongKong H3N2 A/Michigan H1N1 B/Brisbane 11
HAI antibody response (GMFRs) against wild-type vaccine-homologous strains (2017-18) Geometric Mean Fold Titer Rise (95% CI) 4 3 2 1 0 2.1 45µg 180µg Ratio of Day 21 GMTs 47% p=0.0056 2.7 1.9 2.1 3.2 IIV3 HD 45µg 180µg 2.6 1.5 1.9 IIV3 HD 45µg 180µg IIV3 HD 2.0 A/HongKong H3N2 A/Michigan H1N1 B/Brisbane 12
HAI antibody responses (GMFRs) against 5 generations of drifted wild-type A(H3N2) strains Geometric Mean Fold Titer Rise (95% CI) 5 4 3 2 1 2.3 Ratio of Day 21 GMTs 38% p=0.0058 3.4 2.3 2.2 Ratio of Day 21 GMTs 28% p=0.036 3 2.2 2.5 Ratio of Day 21 GMTs 54% p=0.0065 3.9 2.5 2.1 Ratio of Day 21 GMTs 47% p=0.0056 2.7 1.9 2.2 Ratio of Day 21 GMTs 64% p=0.0009 3.1 1.9 0 45µg 180µg IIV3-HD 45µg 180µg IIV3-HD 45µg 180µg IIV3-HD 45µg 180µg IIV3-HD 45µg 180µg IIV3-HD A/Victoria H3N2 A/Texas H3N2 A/Switzerland H3N2 A/Hong Kong H3N2 A/Singapore H3N2 13
HAI antibody responses (GMFRs) against 5 generations of drifted wild-type A(H3N2) strains Geometric Mean Fold Titer Rise (95% CI) 5 4 3 2 1 0 2.3 45µg Ratio of Day 21 GMTs 38% p=0.0058 180µg 3.4 2.3 2.2 IIV3-HD 45µg Ratio of Day 21 GMTs 28% p=0.036 3 180µg 2.2 2.5 IIV3-HD 45µg Ratio of Day 21 GMTs 54% p=0.0065 3.9 2.5 2.1 Ratio of Day 21 GMTs 47% p=0.0056 2.7 1.9 2.2 Ratio of Day 21 GMTs 64% p=0.0009 A(H3N2) viruses currently circulating in North America 180µg IIV3-HD 45µg 180µg IIV3-HD 45µg 180µg A/Victoria H3N2 A/Texas H3N2 A/Switzerland H3N2 A/Hong Kong H3N2 A/Singapore H3N2 3.1 IIV3-HD 1.9 14
Neutralization antibody responses (GMTs) against wild-type vaccine-homologous strains (2017-18) 3000 2,079 2500 2000 1500 1,712 1,665 1,541 1,045 1000 913 764 900 1,011 500 0 253 213 210 90 144 181 91 77 213 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 180µg IIV3-HD 45µg 180µg IIV3-HD 45µg 180µg IIV3-HD A/HongKong H3N2 A/Michigan H1N1 B/Brisbane 15
Neutralization antibody responses (GMFRs) against wild-type vaccine-homologous strains (2017-18) Geometric Mean Fold Titer Rise (95% CI) 12.0 10.0 8.0 6.0 4.0 2.0 0.0 1.9 2.2 2.3 45µg 180µg 4.0 IIV3 HD 45µg 180µg 7.2 5.0 1.6 2.0 IIV3 HD 45µg 180µg IIV3 HD 2.8 A/HongKong H3N2 A/Michigan H1N1 B/Brisbane 16
Neutralization antibody responses (GMFRs) against circulating wild-type H3N2 strains Geometric Mean Fold Titer Rise (95% CI) 5.0 4.0 3.0 2.0 1.0 0.0 Vaccine Strain 2015-16 Historic Drift 2.1 2.8 45µg 180µg 2.5 Vaccine Strain 2016-17 and 17-18 Vaccine Strain 2018-19 Forward Drift 1.9 IIV3 HD 45µg 180µg 2.2 2.3 2.8 IIV3 HD 45µg 180µg Ratio of Day 21 GMTs 61% p=0.0002 A/Switzerland H3N2 A/Hong Kong H3N2 A/Singapore NFIMH H3N2 3.5 IIV3 HD 2.1 17
Neutralization antibody responses (GMFRs) against egg-adapted vs. wild-type A/Singapore H3N2 viruses Geometric Mean Fold Titer Rise (95% CI) 5.0 4.0 3.0 2.0 1.0 0.0 3.8 3.9 3.5 Ratio of Day 21 GMTs 61% p=0.0002 180µg IIV3 HD 180µg IIV3 HD A/Singapore H3N2 (egg adapted) Ratio of Day 21 GMTs 61% p=0.0002 A/Singapore H3N2 (wild type) 2.1 Nanoflu induced improved neutralization antibody responses (GMFRs) against wildtype vs. egg-adapted A/Singapore H3N2 viruses underscoring the problem of eggadaptive mutations Neutralization antibody responses against wildtype circulating viruses are the most clinically relevant 18
Discussion Avoidance of egg-adaptive antigenic changes leads to substantial improvements in vaccinehomologous 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 19
Playing catch-up and does one strain fit all? Rapid evolution and diversity of A(H3N2) viruses A/Singapore Most common in Australia summer 17 Most common in U.S. 17/18 season Epitope Changes 1 15 Number of significant changes to important regions of the hemagglutinin gene = Vaccine Viruses A/Hong Kong A/Switzerland Circulating H3N2 viruses present in 2017-18 Season 20 CDC collaboration with NextFlu. Neher, Bedford A/Victoria A/Texas et al. A/Perth 2009 2010 2011 2012 2013 2014 2015 2016 2017 Adapted from CDC Grand Rounds. January 18, 2018. https://www.cdc.gov/cdcgrandrounds/archives/2018/january2018.htm 20
Playing catch-up and does one strain fit all? Nanoflu has the potential to provider broader protection vaccine has potential to provide broader protection against antigenic drift A/Singapore Most common in Australia summer 17 Most common in U.S. this season Epitope Changes 1 15 Number of significant changes to important regions of the hemagglutinin gene = Vaccine Viruses A/Hong Kong A/Switzerland Circulating H3N2 viruses present in 2017-18 season A/Victoria A/Texas A/Perth 2009 2010 2011 2012 2013 2014 2015 2016 2017 Adapted from CDC Grand Rounds. January 18, 2018. https://www.cdc.gov/cdcgrandrounds/archives/2018/january2018.htm 21
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