Valneva Se · EURONEXT:VLA

Valneva — Investor Day (July 2019)

127 slides from Valneva's investor day presentation, Jul 9, 2019

1. Slide 1: R&D Investor Day 2019

   WM valneva R&D INVESTOR DAY 2019 NEW YORK, JULY 9

2. Slide 2: Disclaimer

   Disclaimer This presentation does not contain or constitute an offer of, or the solicitation of an offer to buy or subscribe for, Valneva SE shares to any person in the USA or in any jurisdiction to whom or in which such offer or solicitation is unlawful. The Valneva shares may not be offered or sol

3. Slide 3: Today's Speakers

   Today’s Speakers Thomas David Wolfgang Stanley A. LINGELBACH LAWRENCE BENDER, MD, PhD, MPH, PLOTKIN, MD MHA, DTMP Chief Executive Officer Chief Financial Officer Chief Medical Officer Emeritus Professor, Valneva Valneva Valneva Wistar Institute University of Pennsylvania Valneva - R&D Investor Day J

4. Slide 4: Agenda

   Agenda 1 Introduction – Thomas Lingelbach 2 Company Strategy – David Lawrence 3 Lyme disease and VLA15 › Lyme disease – Dr. Stanley A. Plotkin › Valneva’s vaccine candidate, VLA15 – Thomas Lingelbach 4 Chikungunya and VLA1553 › Chikungunya – Dr. Stanley A. Plotkin › Valneva’s vaccine candidate, VLA1

5. Slide 5: Introduction

   INTRODUCTION THOMAS LINGELBACH CHIEF EXECUTIVE OFFICER Valneva - R&D Investor Day July 9, 2019 5

6. Slide 6: Valneva – Highlights and key information

   Valneva – Highlights and key information + Valneva is a biotech company developing and commercializing vaccines for infectious diseases with major unmet needs › > €100m product sales revenues1 › Cash flow positive1 + Specializes in important, high value niches › Travel vaccines › Technological compe

7. Slide 7: Valneva's R&D pipeline

   Valneva’s R&D pipeline Focusing on vaccines with major unmet need Product Discovery Pre- IND Phase 1 Phase 2 Phase 3 Market research clinical enabling research Japanese Marketed vaccines encephalitis Cholera (ETEC)1 Lyme disease Clinical candidates Chikungunya Zika Clostridium difficile 1 Indication

8. Slide 8: Company Strategy

   COMPANY STRATEGY DAVID LAWRENCE CHIEF FINANCIAL OFFICER Valneva - R&D Investor Day July 9, 2019 8

9. Slide 9: Valneva's mid-term strategy

   Valneva’s mid-term strategy To become the leading commercial stage vaccine biotech R&D Commercial Products Investing in innovative R&D Growing product sales programs to address major revenues to €200m and unmet needs beyond Financial Strategic Growth Use proceeds from Organic growth commercial busin

10. Slide 10: Capital Formation Strategy

    Capital Formation Strategy Access Best Capital Market to Fund Lyme Vaccine Development Step 1 - Strengthen Shareholder Base; add Blue Chip US Investors  How? PIPE (€50m September 2018) Step 2 – Raise R&D Funding  How? Potential NASDAQ Listing (>€100m) Key Enablers – +Lyme: +Business: › Execute dev

11. Slide 11: Strengthening institutional shareholder base with blue-chip healthcare investors

    VLA continuously strengthening its institutional shareholder base with blue-chip healthcare investors January 2018 October 2018 May 2019 + Number of ordinary shares:77.6m + Number of ordinary shares:90.9m + Number of ordinary shares: 90.9m + Shareholder structure1: + Shareholder structure1: + Shareh

12. Slide 12: Lyme Disease

    LYME DISEASE STANLEY A. PLOTKIN, MD Professor Emeritus Wistar Institute University of Pennsylvania Valneva - R&D Investor Day July 9, 2019 12

13. Slide 13: Prospects for a New (or old) Vaccine Against Lyme Disease

    Prospects for a New (or old) Vaccine Against Lyme Disease by Stanley A. Plotkin Valneva NY 2019 July 9, 2019

14. Slide 14: No financial interest statement

    I have no financial interest in new Lyme Disease or Chikungunya vaccines and receive no honoraria from Valneva. 14

15. Slide 15: Case History of Alec P. (1)

    Case History of Alec P. (1)  35 yr. old living in Chester Co., PA  Walks his dog  Developed an erythematous rash behind knee  Physician called it cellulitis, treated it locally 15 15

16. Slide 16: Case History of Alec P. (2)

    Case History of Alec P. (2)  Out with his dog one day, Alec collapsed and was unresponsive  Neighbor called 911  Med-tech measured heart rate of 35/minute  Experienced cardiologist at local hospital suspected Lyme  Put in cardiac pacemaker and started intravenous cephalosporin 16 16

17. Slide 17: Lyme Disease

    Lyme Disease  Tickborne disease – Ixodes scapularis predominant in Eastern U.S. Ixodes ricinus in Europe  Caused by Borrelia burgdorferii spirochete – resides in gut of tick, migrates to salivary gland and enters host during tick feeding  Early symptoms – fever, headache, fatigue, erythema migran

18. Slide 18: Lyme Borrelia

    Lyme Borrelia 18

19. Slide 19: Skin Lesions Caused by Lyme

    Skin Lesions Caused by Lyme 19

20. Slide 20: Life cycle of Ixodes ticks

    Fig 1. Life cycle of Lvodes ticks. Illustration courtesy of Chinmoy Bhate, MD. o™== ¢ eccs “ a XN Year 2 — Fall \ Year 1 — Spring Year 2 — Summer Year 2 — Spring J Am Acad Dermatol. 2011 Apr;64(4):619-36; quiz 637-8. doi: 10.1016/jjaad.2010.03.046. Lyme disease: Part |. Advances and perspectives. Bh

21. Slide 21: Advice to Avoid Lyme Disease

    Advice to Avoid Lyme Disease (Philadelphia Inquirer)  Avoid wooded areas with high grass  Walk on trails only  Use DEET repellents  Treat clothing with permethrin  Shower within two hours after walk  Full body tick check  Check pets for ticks  Dry clothes in high heat 21

22. Slide 22: Lyme Disease reported cases

    Lyme Disease Reported cases, per 100,000 population, United States and territories, 1996 22

23. Slide 23: Age Distribution of Lyme in the US

    Age Distribution of Lyme in the US Insurance Claims Comparison of trends in the age and sex distribution of persons with Lyme disease in MarketScan with US surveillance, 2005–2010. Incidence is per 100,000 persons. Age distribution of persons with Lyme disease in MarketScan did not differ from those

24. Slide 24: Lyme Disease in Europe: Current State of Knowledge

    Lyme Disease in Europe: Current State of Knowledge 24

25. Slide 25: Borrelia Strains in U.S. and Europe

    Borrelia Strains in U.S. and Europe US Europe burgdorferii burgdorferii (ST1) mayoni afzelii (ST2) garinii (ST3,5,6) bavariensis (ST4) 25

26. Slide 26: We Should Have a Lyme Disease Vaccine Because

    We Should Have a Lyme Disease Vaccine Because:  Infection is prevalent in the US (300,000 per year) and in Europe (200,000 per year)  Vaccination with OspA was proven to work in the 1990s  Other preventive measures have not been shown to work on a public health scale 26

27. Slide 27: Anti-OspA Protective Response

    Anti-OspA Protective Response Step 1 Step 2 Step 3 Step 4 Vaccine, Tick attaches Anti-OspA Antibodies when to vaccinated antibodies kill B. injected, human and from burgdorferi in elicits high begins vaccinee midgut, levels of anti- blood meal enter tick preventing OspA (24- to 48-hour transmission

28. Slide 28: Lymerix Efficacy in the Phase III Trial

    Lymerix Efficacy in the Phase III Trial Data from Steere et al, NEJM, 1998 OspA antibodies neutralize Borrelia in the tick Clinical Infectious Diseases , Vol 52(2):Supplement 3, 2011 28

29. Slide 29: Pediatric Response to Lymerix

    Pediatric Response to Lymerix Titer > 1400 Age GMT E.U./ml 4-16 y 29,650 100% 15-18 20,722 100% Sikand et al, Pediatrics, 2001 29

30. Slide 30: Overview of Lyme Vaccine History

    Overview of Lyme Vaccine History  LYMErix was released in December 1998 Permissive recommendation for use of vaccine in persons 15-70 years of age who lived or worked in B. burgdorferi- infected woody and grassy areas.  It was voluntarily withdrawn by GSK in February 2002.  First time in the mode

31. Slide 31: Mistakes That Were Made with Lymerix

    Mistakes That Were Made with Lymerix By GSK: • Advertising directly to public, not physicians • Launching pediatric study too late • Not engaging patient groups By CDC: • Assigning vaccine recommendations to Fort Collins people • Making weak recommendations: “should be considered” By Others: • Weak

32. Slide 32: Safety of OspA Vaccines

    Safety of OspA Vaccines  In a hamster model, vaccination followed by infection led to arthritis; however, in human trials, this did not occur.  Infection in vaccinated dogs or humans does not lead to arthritis.  FDA Panel concluded no evidence for association between vaccine and arthritis.  Late

33. Slide 33: Veterinary Vaccines

    Veterinary Vaccines Company/ Vaccine Species Antigen Adjuvant Abbreviation country Merilym Merial, B. burgdorferri Lysate Yes V1-Bbss-lys-adj Germany s.s. LymeVax Fort Dodge, B. burgdorferri Lysate Yes V2-Bbss-lys-adj USA s.s. ProLyme Intervet,USA B. burgdorferri rOspA Yes V3-Bbss-rOspA- s.s. adj Re

34. Slide 34: Protein persists after antibiotic treatment

    A protein from Lyme disease persists in infected patients even after antibiotic treatment, inducing cytokines that could induce chronic arthritis. THIS MEANS THAT ANTIBIOTICS DO NOT NECESSARILY PREVENT CHRONIC ARTHRITIS, AND A VACCINE IS THE ONLY WAY TO PREVENT CHRONIC LYME ARTHRITIS! 34

35. Slide 35: LA-2 Borrelia Antigens Needed in a Vaccine

    LA-2 Borrelia Antigens Needed in a Vaccine ST Strain 1 burgdorferii 2 afzelii 3 garinii 4 bavariensis 5 garinii 6 garinii 35

36. Slide 36: The Way Forward for a New Vaccine

    The Way Forward for a New Vaccine  Definition of Correlate of Protection  Tests of adjuvants to prolong antibody  Early studies in children  Incorporation of Lyme vaccine in VFC 36

37. Slide 37: VLA15

    VLA15 Valneva - R&D Investor Day July 9, 2019 37

38. Slide 38: Lyme disease increasingly common in the US and Europe

    Lyme disease increasingly common in the US and Europe There is a prospect for a new (or old) vaccine against it

39. Slide 39: Lyme disease (Lyme borreliosis)

    Lyme disease (Lyme borreliosis) LYME  Tickborne disease (Vector-Ixodes ticks) DISEASE  Caused by Borrelia burgdorferi s.l. spirochete (resides A severe tick-transmitted infection that is increasingly common in gut of tick – migrates to salivary gland – enters host in the US and Europe during feedi

40. Slide 40: Lyme disease – Epidemiology

    Lyme disease – Epidemiology Prevalent Strains in the US & Europe Valneva - R&D Investor Day July 9, 2019 40

41. Slide 41: Justification for a Lyme vaccine

    Vaccination against Lyme disease Justification for a Lyme vaccine  Vaccination with OspA has been proven to work in the past (Lymerix®, ImuLyme®)  Disproven postulate1, restrictive recommendations and corporate decisions resulted in there being no Lyme vaccine available for humans since 2002  Del

42. Slide 42: History of Lyme disease vaccines

    History of Lyme disease vaccines Vaccination with OspA has been proven effective in the past Efficacy of two OspA (ST-1) based vaccines in the 1990s: › LYMErix (licensed in 1998, withdrawn from market in 2002): Vaccine efficacy (symptomatic LD) 1: 49% in 1st year, 76% in 2nd year › ImuLyme: Vaccine

43. Slide 43: Anti-OspA protective response with Lyme disease vaccines

    Anti-OspA protective response with Lyme disease vaccines Mode of Action Step 1 Step 2 Step 3 Step 4 Vaccine, when Tick attaches Anti-OspA Antibodies kill B. injected, elicits high to vaccinated antibodies from burgdorferi in levels of anti-OspA human and begins vaccinee enter tick midgut, antibodies

44. Slide 44: The Lyme Disease Vaccine Project (VLA15)

    The Lyme Disease Vaccine Project (VLA15)

45. Slide 45: VLA15 – Design

    VLA15 – Design Product based on three engineered proteins Full-length OspA Truncated stabilized Stabilized OspA monomers representing 6 OspA monomer serotypes joined with a linker to 3 fusion proteins N ST1 N Linker* ST1-ST2 C ST4-ST3 C C ST2 ST5-ST6 * linked with a 21 amino acid linker derived from

46. Slide 46: VLA15 Target Product Profile

    Valneva’s Lyme disease vaccine candidate (VLA15) Target Product Profile  Prophylactic active immunization against Lyme disease in individuals ≥ 2 Indications years of age in US and Europe  Route of administration: Intramuscular injection  Recommended dose: Best dose of 3 fusion proteins (ST 1/2,

47. Slide 47: VLA15 Clinical Development Roadmap

    VLA15 Clinical Development Route To Potential US & EU license Roadmap TODAY 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 Phase 1, 18-40 yrs 3 Dose levels +/- Alum Month 0-1-2-(13) Phase 2, 18-65 yrs 2 Dose levels, with Alum Two studies: M0-1-2 and M0-2-6 Booster follow-up studies planned Licens

48. Slide 48: VLA15 – Key Regulatory Agency Feed-back

    VLA 15 – Key Regulatory Agency Feed-back Some take-aways… “The company´s concept to use OspA fusion proteins for a vaccine against Lyme borreliosis is in principle supported since all six described OspA serotypes are incorporated and provisions to ensure the drug substance´s stability, epitope acces

49. Slide 49: Phase 1 and 2 Data & Outline

    Phase 1 and 2 Data & Outline

50. Slide 50: VLA15 Clinical Development Phase 1/2 Roadmap

    VLA15 Clinical Development Phase 1/2 Roadmap 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 PHASE 1 incl booster Addendum M12 safety data release Dec 20 Interim CSR both FSI 12/2018 studies VLA15-201 + VLA15-202 N=820 VLA15-201 + VLA15-202 Booster FUs 2018 2019 2020 2021 FSI Main Phase Data Relea

51. Slide 51: VLA15-101 Phase 1 Study

    VLA15-101 Phase 1 Study Observer-blind, partially randomized, dose escalation study + Study Population: ~180 healthy volunteers aged 18 to <40 years + 1 site in Belgium (145 subjects), 2 sites in the US (34 subjects) + Immunization route: I.M. in non-dominant arm + Booster administered at Month 12-1

52. Slide 52: Phase 1 study (VLA15-101) – Safety

    Phase 1 study (VLA15-101) – Safety Favorable safety profile and no associated safety concerns No associated safety concerns:  No serious adverse event considered related to VLA15 immunization  No cases of arthritis or rheumatoid arthritis Very few severe, related AEs:  Total of 8 subjects with se

53. Slide 53: Phase 1 study (VLA15-101) – Immunogenicity (SCR)

    Phase 1 study (VLA15-101) – Immunogenicity SCR for Highest Adjuvanted Dose Group between 71.4% (ST1) and 96.4% (ST2), Substantial Booster Effect Seroconversion Rates (SCR) After Primary Series and Booster Dose Average* Seroconversion Rate by Treatment Group, Day 84 and Month 14 100 Post Primary Post

54. Slide 54: Phase 1 study (VLA15-101) – Immunogenicity (GMT)

    Phase 1 study (VLA15-101) – Immunogenicity GMT for Highest Adjuvanted Dose Group between 61 (ST1) and 269 (ST2), Substantial Booster Effect IgG GMT of Highest Adjuvanted Group (90µg + Alum) Before and After Primary Series and Booster Dose IgG GMT by Serotype over Time 1000 Post Primary Post Booster

55. Slide 55: Phase 1 Study (VLA15-101) – Key Study Conclusions

    Phase 1 Study (VLA15-101) – Key Study Conclusions Encouraging results fully supporting further development  VLA15 generally safe and well tolerated, no associated safety concerns  VLA15 was substantially more immunogenic in adjuvanted dose groups as compared to respective non-adjuvanted groups in

56. Slide 56: Design Phase 2 Clinical Study VLA15-201

    Design Phase 2 Clinical Study VLA15-201 Dose Increase and Dose Confirmation Run-in Phase › Study population: Subjects aged 18-65 years, B.B. s.l. VLA15 90 µg w/ alum 30 subjects seronegative & seropositive (VlsE ELISA) VLA15 135 µg w/ alum 30 subjects › Ratio 18-49 yrs to 50-65 years, 2:1 › Study co

57. Slide 57: Design Phase 2 Clinical Study VLA15-202

    Design Phase 2 Clinical Study VLA15-202 Impact of Alternative Schedule › Study population: Subjects aged 18-65 years, B.B. s.l. seronegative & seropositive (VlsE ELISA) › Ratio 18-49 yrs to 50-65 years, 2:1 › Study conduct & sites: endemic regions in US › Serological testing for EoP2 Package: - ELIS

58. Slide 58: Phase 3 Outline & First Market Access considerations

    Phase 3 Outline & First Market Access considerations

59. Slide 59: First Outline for Phase 3 Clinical Development Plan

    Lyme vaccine candidate (VLA15) First Outline for Phase 3 Clinical Development Plan* Phase 2 expected to provide first data by mid-2020 › Initial Data: Day 85 after short schedule: dose determination › Alternative schedule data expected mid 2020 › Booster studies with additional 12 months follow-up E

60. Slide 60: Seasonality of Lyme Disease Cases

    Seasonality of Lyme Disease Cases Valneva - R&D Investor Day July 9, 2019 60

61. Slide 61: Phase 3 Clinical Study VLA15-301 / 302 Execution considerations

    Phase 3 Clinical Study VLA15-301 / VLA15-302 Execution considerations  Full protection by mid April at Tick season the latest (Start of tick season – Vacc. Follow-up avoidance to see breakthrough Best dose VLA15 4000 - 5000 subjects cases due to incomplete schedule) Placebo 4000 - 5000 subjects  3

62. Slide 62: Market access considerations: handling scientific misconceptions

    Market access considerations Focus on handling scientific misconceptions Engagement with and education of the Lyme disease community crucial to gaining their acceptance of VLA15  Emphasize the ability of VLA15 to prevent (chronic manifestations of) Lyme disease  Generate and communicate robust saf

63. Slide 63: Market access: recommended for at risk populations

    Market access considerations VLA15 is expected to be recommended for at risk populations in the majority of markets VLA15 recommendations are expected to cover at risk areas and populations  Experts expect VLA15 to be recommended for high risk individuals in endemic areas  Expected vaccination rat

64. Slide 64: Disease burden for Lyme disease in the US

    Market access considerations The disease burden for Lyme disease in the US is estimated at $0.7bn-$1.3bn annually  A 2015 study based on large insurance patient databases estimated the total direct medical costs attributable to LD and Post-Treatment Lyme Disease Syndrome (PTLDS) at $0.7bn-$1.3bn an

65. Slide 65: Chikungunya

    CHIKUNGUNYA STANLEY A. PLOTKIN, MD Professor Emeritus Wistar Institute University of Pennsylvania Valneva - R&D Investor Day July 9, 2019 65

66. Slide 66: Should We Vaccinate Against Chikungunya?

    Should We Vaccinate Against Chikungunya? 66

67. Slide 67: Chikungunya

    Chikungunya An RNA arbovirus ORF codes for 4 NS proteins, 5 structural C, E1, E2, E3, 6K E1 mutation at 226 valine to alanine. Increased infection of Aedes Albopictus Replicates in mosquito midgut, goes to salivary glands Replicates in fibroblasts of humans and animals 67

68. Slide 68: Chikungunya

    Chikungunya 271K reported cases in 2016 Can be transmitted via mosquito bite, blood transfusion, vertically in near-term deliveries (cesarean doesn’t help) Causes fever, maculopapular or petechial rash due to cytokines, IL1, IL6 TNF alpha May involve eyes, heart, brain IgG works as prophylaxis and t

69. Slide 69: Distribution of chikungunya virus

    Figure 1. Distribution of chikungunya virus The figure shows the spread and divergence of the East Central South African (ECSA) lineage to the Indian Ocean islands (IOLs) and Asia,9; 69 ; 70 the spread of the Asian lineage to the Americas in 2013,82 and the sp... Burt et al, Lancet Infect Dis 2017 6

70. Slide 70: Global Spread of Chikungunya

    Global Spread of Chikungunya Powers, A., Clinical Microbiology Review 2017 70

71. Slide 71: Sequelae of Chikungunya

    Sequelae of Chikungunya Persistent Arthralgia Réunion 83% at 32 months Mexico 42% 46% at 10 months Curacao 64% at 100 days Phillipines 32-95% at 3 years High viral load predicts poor prognosis 71

72. Slide 72: Duration of Chikungunya Symptoms

    Duration of Chikungunya Symptoms Elsinga et al, JID 2017 72

73. Slide 73: Evasion of Antibody in Chronic Cases

    Evasion of Antibody in Chronic Cases 73

74. Slide 74: Expected and observed monthly deaths in Puerto Rico

    Expected and observed monthly deaths in Puerto Rico, 2014–2015. Excess number of monthly deaths and number of chikungunya, dengue, and influenza A and B cases diagnosed Freitas, et al Emerging Infectious Diseases Dec 2018 74

75. Slide 75: Persistent arthralgia and impaired physical functionality

    Prevalence of persistent arthralgia and impaired physical functionality among residents in a study of persistent arthralgia after a Chikungunya virus outbreak, US Virgin Islands, December 2014 - February 2016* * Adjusted for age group, sex, and self-reported history of arthritis Curacao = 64% disabi

76. Slide 76: Correlates of Protection Against Chikungunya

    Correlates of Protection Against Chikungunya Passive antibodies have been shown to protect in animal models Induction of neutralizing antibodies has been protective and even therapeutic lg G3 antibodies associated with neutralization T cell responses may be responsible for symptoms 76

77. Slide 77: Types of Chikungunya Vaccines in Development

    Types of Chikungunya Vaccines in Development Live Attenuated Subunit Vectored: Inactivated, whole Measles Alphavirus DNA VSV MVA RNA Adenovirus Vaccinia RNA Replicon VLPs 77

78. Slide 78: Response to Chikungunya VLP Vaccine

    Response to Chikungunya VLP Vaccine Neutralization IC titre50 (strain OPY1) 0* 50 51 52 4* 188 236 346 8 2688 1775 7246 20* 650 510 1485 22 NA NA NA 24 8745 4525 5390 44 940 717 1385 *Boosts Chang et al, LANCET 2014 78

79. Slide 79: VLA1553

    VLA1553 Dr. WOLFGANG BENDER, MD, PhD, MPH, MHA, DTMP, CHIEF MEDICAL OFFICER Valneva - R&D Investor Day July 9, 2019 79

80. Slide 80: Arbovirus outbreaks difficult to predict

    Arbovirus outbreaks difficult to predict Preparedness strategy options needed

81. Slide 81: Ecological Effects on Arbovirus-Mosquito Cycles of Transmission

    Ecological Effects on Arbovirus-Mosquito Cycles of Transmission Will AI and quantum-tech bring break-through in forecasting? Factors e.g. Bayesian networks - R0 Tabachnik 2016 Valneva - R&D Investor Day July 9, 2019 81

82. Slide 82: Chikungunya Virus

    Chikungunya Virus  Single stranded RNA virus  Family Togaviridae - Genus Alphavirus  Antigenically related to other polyarthritis causing alphaviruses e.g. Mayaro-, Semliki Forest-, O’nyong-nyong- and Ross River viruses Picture: Weaver and Lecuit 2015 Valneva - R&D Investor Day July 9, 2019 82

83. Slide 83: Chikungunya Virus Vectors

    Chikungunya Virus Vectors Aedes aegypti Aedes albopictus Valneva - R&D Investor Day July 9, 2019 83

84. Slide 84: Virus – Vector Interplay: Pathogen Mutation with Impact

    Virus – Vector Interplay: Pathogen Mutation with Impact Examples: Viral Envelope E1 Mutation  Ae. albopictus Transmission ↑↑↑ of IOL CHIKV; Ae. aegypti E1:K211E and E2:V264A 100 Percent Infected 80 LR-GFP-226V (I) E1-A226V mutation LR-GFP-226V (II) 60 LR-GFP-226A (I)  Viral fusion to 40 LR-GFP-226

85. Slide 85: Chikungunya: Vector Prevalence and Disease Outbreaks

    Chikungunya: Vector Prevalence and Disease Outbreaks Global warming  increased vector prevalence, longer transmission season Rezza & Weaver 2019 Valneva - R&D Investor Day July 9, 2019 85

86. Slide 86: Human Migration and VFR Add Risk

    Human Migration and Visiting Friends & Relatives (VFR) Add Risk …on top of other travellers (business, tourists), military Murphy et al 2014 Valneva - R&D Investor Day July 9, 2019 86

87. Slide 87: Speed of Outbreaks: 1 Year of Chikungunya 2014

    December 2013 Often Overwhelming Speed of Outbreaks: Example: 1 Year of Chickungunya 2014 (1 slide = 1 month) Simon 2016 87

88. Slide 88: January 2014

    January 2014 British Virgin Islands @ e: Martin (Ff) Sint Maarten ( : Legend Number of autochthonous cases ® v Mattniq 11001 - 10,000 e @ 100,001 539,188 Country boundaries

89. Slide 89: January 2014

    Legend Number of autochthonous cases 0 11001 - 10,000 e ® 100,001 539,188 Country boundaries Bish Vigin Jalands Martin (Ff) ‘Sint Maarten ( int Barthélemy: Guadelo att Martin French Guyana January 2014

90. Slide 90: February 2014

    Legend Number of autochthonous cases 0 11001 - 10,000 e @ 100,001 539,188 Country boundaries Bish Virgin Islands, ‘Sint Maarten (AN) French Guyana February 2014

91. Slide 91: March 2014

    Legend Number of autochthonous cases 0 11001 - 10,000 e @ 100,001 539,188 Country boundaries Bish Virgin Islands, laerten (AN) Barthélemy iste French Guyana March 2014

92. Slide 92: April 2014

    Legend Number of autochthonous cases 0 11001 - 10,000 e @ 100,001 539,188 Country boundaries ‘Sint Maarten (AN) unican Rep, and Barbuda int Kitts and Barthélemy British Virgin Islands Guadeb Me \Vincont and the Grenadines iste French Guyana April 2014

93. Slide 93: May 2014

    Legend Number of autochthonous cases 0 11001 - 10,000 e @ 100,001 539,188 Country boundaries Bal Saint Marin (FSi Maarton (AN) rican Rep, ila lis and Nevis otenion and Barbuda yy \Vincont and the Grenadines French Guyana May 2014

94. Slide 94: June 2014

    June 2014 rks and Caicos Islands int Martin (Fe) Sint Maarten (AN) ican Rep ila Unt Islands, British Virgin Islands EISah eo” \Vincont and the Grenadines °@ Legend Number of autochthonous cases 0 11001 - 10,000 e @ 100,001 539,188 Country boundaries

95. Slide 95: July 2014

    e July 2014 United States of America int Man (St Naron (8) i Caymastends Unt f British Virgin Islands EI Sat eo” rados Saint Vinoent and the Grenadines @riviaas and Torago Pena ‘ee oy rench Guyana Sur Legend Number of autochthonous cases 0 11001 - 10,000 e @ 100,001 539,188 Country boundaries

96. Slide 96: August 2014

    United States of America int Man (St Naron () i Cayma stands r Jamai ; British Virgin Islands Elsah “eg e Panama oe oy rench Guyana Sur Legend Number of autochthonous cases 0 Saint Vinoent and the Grenadines @riviaas ant Torago 11001 - 10,000 e @ 100,001 539,188 Country boundaries August 2014

97. Slide 97: September 2014

    ° September 2014 Urited States of America oe rks and Caicos Islands rt Narin St Maton (8) il tis and News ——@ oN Guatemala Jama oy cia as: cao Gren 8 Saint Vinoent and the Grenadines inidad and To e @: ago Costa Rica t Panama oy rench Guyana si Legend Number of autochthonous cases 0 11001 - 10,000 e

98. Slide 98: October 2014

    e October 2014 Urited States of America covers rks and Caicos Islands (Fe Sint Maarten (AN) ilaSaint Barthélemy a. is and Nevis CaymeAMlands, ate Guatemala, damal ya cia als. e icant adit cenres ida and To e eel Costa Rica , Panama oy rench Guyana si Legend Number of autochthonous cases 0 11001 - 10

99. Slide 99: November 2014

    ° November 2014 United States of America in (Fr Sint Marton (AN) jilaSaint Barthélemy is and Nevis oyna nies Guatemala i ah Baitish Vigin islands 2 a Nicaragua incent and the Grenadines o inidad and Tobago Costa Rica Panama oy ich Guyana si Legend Number of autochthonous cases 0 11001 - 10,000 e Bra

100. Slide 100: December 2014

     Legend Number of autochthonous cases 0 11001 - 10,000 e @ 100,001 539,188 Country boundaries United States of America covers rks and Caicos Islands Balze co. Guater J Bash Virgin Islands al icaraqua ° Costa Rica Panama ow Brazil in (Fx) Sint Maarton (AN) jilaSaint Barthélemy oy ee Guyana Paraguay e

101. Slide 101: January 2015

     United Statos of America r Belize _ cor cy icaragua Costa Rica Panama ; ich Guyana Legend Number of autochthonous cases SS 0 : U 2-100 or 11001 - 10,000 e Brazil { 10.001 - 100,000 100,001 539,188 Country boundaries \ Simon 2016 S| January 2015 oa am “DOL Km

102. Slide 102: The Chikungunya Virus Vaccine Project

     The Chikungunya Virus Vaccine Project

103. Slide 103: Valneva's Chikungunya Vaccine Candidate VLA1553

     Valneva’s Chikungunya Vaccine Candidate VLA1553 Attenuation Principle Vaccine construct CHIKV Δ5nsP3 (VLA1553) vaccine is based on ECS African strain of Indian Ocean lineage with ∆5nsP3 cross-protective immunity against Asian isolate which is now rapidly spreading across the Americas.  60 amino aci

104. Slide 104: VLA1553 Target Product Profile

     VLA1553 Target Product Profile Chikungunya Vaccine Candidate Target Product Profile Key Value Proposition Single-dose, live-attenuated Chikungunya virus vaccine Indication Prophylactic active immunization against Chikungunya virus in individuals ≥ 1 year of age, including › Travelers to endemic or o

105. Slide 105: Non-Clinical Studies in Non Human Primates – Safety

     VLA1553 - Chikungunya Vaccine Candidate Non-Clinical Studies in Non Human Primates – Safety  Viremia 3-4 logs lower than compared to wild type LR-CHIKV infection  Delayed onset of viremia by 1-2 days compared to wild type LR-CHIKV infection  No significant fever (rectal) after vaccination  No fe

106. Slide 106: Non-Clinical Studies in NHPs – Immunogenicity/Efficacy

     VLA1553 - Chikungunya Vaccine Candidate Non-Clinical Studies in Non Human Primates – Immunogenicity/Efficacy Neutralizing antibodies* against CHIKV in sera of cynomolgus macaques Single immunization of 1 x 105 pfu VLA1553 s.c. Challenge with app. 1 x 104 pfu (100 AID50) wild type LR-CHIKV i.v. Persi

107. Slide 107: VLA1553 Summary pre-clinic: Safety and immunogenicity

     VLA1553 – Chikungunya Vaccine Candidate Summary pre-clinic: Safety and immunogenicity  VLA1553 has a 60 aa deletion in nsP3 causing the attenuation which is stable and does not revert back when passaged 20 times on Vero cells  A single shot of VLA1553 was highly immunogenic and induced a strong an

108. Slide 108: Safety Phase 1

     Safety Phase 1

109. Slide 109: Single Shot Chikungunya Vaccine Candidate Phase 1 Study

     Valneva‘s Single Shot Chikungunya Vaccine Candidate Phase 1 Study: VLA1553-101  Observer-blinded, randomized, multicenter, dose escalation study  Study Population: 120 healthy volunteers aged 18 to 45 years  Dosage: 3.2x103 TCID50 (0.1ml), 3.2x104 TCID50 (1ml), 3.2x105 TCID50 (1ml)  Immunization

110. Slide 110: VLA1553-101: Summary Safety Outcomes

     VLA1553-101: Summary Safety Outcomes No AE of Special Interest (AESI), one unrelated SAE in all dose groups Solicited Local AEs:  Few solicited local AEs were reported by 3.2%, 6.7% and 6.8% of subjects in Groups L, M and H, respectively; all mild.  The most common solicited local AE was tendernes

111. Slide 111: VLA1553-101: Higher Reactogenicity in High Dose Group

     VLA1553-101: Higher Reactogenicity in High Dose Group Subjects with solicited AEs after Single Vaccination by Maximum Severity Low Dose Medium Dose High Dose Low dose: 3.2*103 TCID50 Medium Dose: 3.2*104 TCID50 High Dose: 3.2*105 TCID50 The low and medium dose of VLA1553 have a superior safety profi

112. Slide 112: High Dose After Single- or Re-Vaccination

     VLA1553-101: High Dose After Single- or Re-Vaccination High Dose Vaccination Protects against Challenge-Induced AEs Reactogenicity of High Dose After Single Vaccination Reactogenicity of High Dose After Re-Vaccination (M6): Protection from AEs High Dose: 3.2*105 TCID50 Valneva - R&D Investor Day Jul

113. Slide 113: VLA1553-101 Plasma Viremia

     VLA1553-101 Plasma Viremia at Days 0, 3, 7, 14 after Single Dose 300000 229.224 226.870 200000 Plasma Genomes/ml 40.647 27.028 100000 89.354 15.725 8.814 73.601 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Study days after single vaccination Treatment arm Arm L Arm M Arm H Arm H2 Numbers indicate mean genom

114. Slide 114: VLA1553-101 Phase 1 Conclusions - Safety

     VLA1553-101 Phase 1 Conclusions - Safety  VLA1553 was generally safe and well-tolerated in the low and medium dose group.  The low and medium dose of VLA1553 have a superior safety profile (including viremia) compared to the high dose group.  No Adverse Events of Special Interest (AESIs) and one

115. Slide 115: Immunogenicity Phase 1

     Immunogenicity Phase 1

116. Slide 116: VLA1553-101: High GMTs in All Dose Groups

     VLA1553-101: High GMTs in All Dose Groups Day 14 CHIKV-specific neutralizing antibodies (GMT) after Single Vaccination and Re-Vaccination ** ** ANOVA p=0.0007 Valneva - R&D Investor Day July 9, 2019 116

117. Slide 117: VLA1553-101: 100% SCR Day 14

     VLA1553-101: 100% SCR Day 14 CHIKV-specific Seroconversion Rates after Single and Re-Vaccination * SCR defined as proportion of subjects achieving a CHIKV-specific neutralizing antibody titer of at least 20 (NT50 ≥20) * Pairwise test p=0.0092 Valneva - R&D Investor Day July 9, 2019 117

118. Slide 118: Phase 1 Summary and Conclusions - Immunogenicity

     VLA1553-101 Phase 1 Summary and Conclusions - Immunogenicity VLA1553 showed an excellent immunogenicity profile after a single vaccination in all dose groups.  100% seroconversion* was already achieved at Day 14 after a single vaccination in all dose groups and sustained at 100% until Month 6.  >

119. Slide 119: Overall Conclusions Phase 1

     Overall Conclusions Phase 1

120. Slide 120: VLA1553-101 Phase 1 Overall Conclusions

     VLA1553-101 Phase 1 Overall Conclusions  VLA1553 was well-tolerated in the low and medium dose groups and generally safe in all dose groups after a single vaccination. The low and medium dose of VLA1553 have a superior safety profile (including viremia) compared to the high dose group.  VLA1553 sh

121. Slide 121: Next steps

     Next steps

122. Slide 122: VLA1553: Regulatory Pathway to Licensure

     VLA1553: Regulatory Pathway to Licensure Approval of Chikungunya vaccine based on immunological correlate Immune Correlate of Protection (ICOP)  Good evidence from animals and humans that neutralizing antibodies provide protection against CHIKV1.  Robust IgM/IgG antibody responses following CHIKV

123. Slide 123: VLA1553: Further Development Considerations and Plans

     VLA1553: Further Development Considerations and Plans Outline Accelerated Clinical Development * FDA Fast track granted to VLA1553 development program Phase 1 generated data for dose-selection  Day 28 safety and immunogenicity after single dose  Viremia data at Days 3, 7 and 14 post-vaccination 

124. Slide 124: VLA1553: Pivotal Study Considerations

     VLA1553: Further Development Considerations and Plans Outline Accelerated Clinical Development * Pivotal Study Considerations  Large double-blinded, controlled, multicenter safety and immunogenicity study in adults ≥18 yrs.  N = ca. 4,000 subjects of either gender  Including antibody persistence

125. Slide 125: Questions & Answers

     QUESTIONS & ANSWERS Valneva - R&D Investor Day July 9, 2019 125

126. Slide 126: Closing Remarks

     CLOSING REMARKS Valneva - R&D Investor Day July 9, 2019 126

127. Slide 127: Thank you

     Thank you Merci Danke Tack ‘WAvalneva

Valneva — Investor Day (July 2019) on 6ix