RSV F Vaccine: Phase 2 Clinical Trial to Protect Infants via Maternal Immunization

Allison August, MD

Agenda

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• Novavax: Brief Overview

• RSV Disease Burden in Target Population

• Novavax’ RSV F Recombinant Nanoparticle Vaccine Technology

• Summary of Prior Clinical Data

• Phase 2 Results in Third-trimester Pregnant women Immunized with RSV F Vaccine and Their Infants

Novavax: An Overview

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Novavax Vaccine Platform

• Recombinant nanoparticle technology induces robust immunity• Matrix-M™ adjuvant increases magnitude and quality of immune

response

Clinical Development Programs

• RSV: Older adults, infants via maternal immunization, pediatrics• Seasonal & Pandemic Influenza: Funded by BARDA contract• Ebola, H7N9: Validate platform technology

Unique Clinical Data

• Only RSV vaccine to demonstrate protection in any population• Proof-of-principle in RSV maternal immunization• Immunogenic vaccines against emerging viruses: Ebola, H7N9

Strong Vaccine Development Infrastructure

• Proven clinical development capabilities• Commercial GMP manufacturing capacity

RSV Vaccine Target Populations

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Infants via Maternal

Immunization

Infants <6 months

Older Adults

Healthy individuals 60+ years and high

risk adults

Pediatrics

Children

>6 months - 5 years

Global Burden of Infant and Pediatric RSV Infections

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• Globally RSV accounts for ~34 Million Acute Lower Respiratory Infections (LRTI) annually in children <5 years of age vs…• 14 Million pneumococcal pneumonia

• 8 Million cases of haemophilus influenza type b

• Annual rate of morbidity in the first year of life is 2-3 times greater than reported for children <5 years

• 3.4 million develop severe LRTI necessitating hospitalization

• 66-199,000 deaths due to RSV, 99% in developing countries• Estimated 3-9% of all deaths from acute lower respiratory diseases

Antibody Responses after RSV Exposure:Robust in the Mother, Fails to Protect Infants

6Suara et al., CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY, July 1996, p. 477–479CDC, National Hospital Discharge Survey, 2005-2009

• Infants receive the mother’s RSV antibodies transplacentally, but the decades of mother’s RSV exposure does not evoke an immune response that is highly protective.

• A change in the quality of the immune response, induced by vaccination, may confer protection during the period of highest vulnerability.

Antibody Transfer Age at Hospitalization

Peak Hospitalization Rates when Maternal Antibodies are Near Peak

RSV the Virus

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• Member of the Paramyxovirus family• Same family as other respiratory agents such as measles.

mumps, and parainfluenza viruses

• Enveloped

• Single strand, negative sense RNA genome

• 10 genes encoding a total of 11 proteins

• Surface proteins include:• G – responsible for attachment to host cells

• F – responsible for membrane fusion

1Beeler et al, Neutralization Epitopes of the F Glycoprotein of Respiratory Syncytial Virus: Effect of Mutation upon Fusion Function. J Virol, 1989

RSV F-Protein Presents Multiple Conserved Sites

Site II

Site IV

Site IRSV Surface Proteins

• G protein: Variable

• F protein: Conserved

Antigenic site I, Antigenic site IV• Known broadly neutralizing antibodies• Likely to contribute to protection1

• Also poorly elicited by natural infection

Antigenic site II• Targeted by palivizumab (Synagis®) and motavizumab• Antibodies shown to prevent RSV disease in infants in 5

randomized clinical trials• Cryptic sites displayed on the F protein antigen in our

RSV F Vaccine • RSV F Vaccine induces antibodies with similar activity• De-risks our program

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Novel RSV F Vaccine

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Novel RSV Fusion-protein vaccine (RSV F Vaccine) developed using recombinant nanoparticle technology

Elicits palivizumab competing antibodies (PCA)

Palivizumab levels correlate to protection

Six clinical trials completed or initiated, demonstrating safety and immunogenicity in over 2,000 participants

Positive data in all 3 target populations

First RSV vaccine to demonstrate efficacy in any population

Proof-of-principle in maternal immunization

Women of Childbearing Age: Summary of Prior Clinical Trial Data

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The vaccine was well-tolerated in non-pregnant women, 18-35 years of age

The vaccine was highly immunogenic

• Data supported antigen and adjuvant dose selection

• Immune response amplitude and kinetics supported single-dose immunization of pregnant women

Data support advancement to Phase 2 in target population of pregnant women

RSV F Vaccine Phase 2 Clinical Trial to Evaluate the Safety and Immunogenicity of RSV F Vaccine for Third Trimester

Maternal Immunization

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Primary

• Mothers: Describe safety of the RSV F vaccine through delivery and 6 months post-delivery

• Infants: Describe safety through their first year of life, including at least one RSV season

Secondary

• Mothers: Evaluate amplitude and duration of anti-F IgG, PCA and RSV A/B microneutralizing antibody responses in through delivery and 6 months post-delivery

• Mothers and Infants: Describe transplacental transfer of maternal anti-F IgG, PCA and RSV A/B microneutralizing antibodies based on the ratio of antibody levels in maternal and cord blood at delivery

• Infants: Estimate the half-life of anti-F IgG, PCA and RSV A/B microneutralizing antibodies over the first 6 months of life, in the presence and absence of maternal immunization

P2 Maternal Immunization: Study Objectives

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P2 Maternal Immunization: Inclusion Criteria

Inclusion• Pregnant women ≥18 and ≤40 years of age with a

• Singleton pregnancy of 33 to 35 weeks gestation on the day of planned vaccination.

• Good general health as assessed by:• Medical history.

• Physical examination including documentation of fetal heart tones.

Clinical laboratory parameters, based on adjusted norms for the third trimester of pregnancy.

• Detailed Ultrasound that confirms no significant anatomic or growth abnormalities, or ultrasound plus maternal serum analyses that confirm no significant anatomic or growth abnormalities.

• Willing and able to give informed consent for themselves and their infant; able to comply with study requirements; adequate transportation.

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P2 Maternal Immunization: Exclusion Criteria -1-

Exclusion

• Symptomatic cardiac or pulmonary disease requiring chronic drug therapy.

• Pregnancy complications (in the current pregnancy) such as preterm labor, hypertension, pre-eclampsia or evidence of intrauterine growth restriction.

• Grade 2 or higher clinical laboratory or vital sign abnormality.

• Planned receipt of >1 dose of any licensed vaccine.

• Received any RSV vaccine at any time.

• Body mass index (BMI) of ≥40, at the time of the screening visit.

• Hemoglobinopathy, blood dyscrasias, hepatic or renal dysfunction, established diagnosis of seizure disorder, auto-immune disease or immunodeficiency syndrome, endocrine disorders.

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P2 Maternal Immunization: Exclusion Criteria -2-

Exclusion

• Known HIV, HBV, or HCV infection, as assessed by serologic tests, or pimarygenital Herpes simplex (HSV) infection during the current pregnancy.

• Prior stillbirth or neonatal death, or multiple (≥3) spontaneous abortions.

• Prior preterm delivery ≤34 weeks gestation or having ongoing intervention (medical/surgical) in current pregnancy to prevent preterm birth.

• Greater than five (5) prior deliveries.

• Previous infant with a known genetic disorder or major congenital anomaly.

• Neuro-psychiatric illness deemed likely to interfere with protocol compliance, safety reporting, or receipt of pre-natal care; or other physical, psychiatric or social condition which may increase the risks of study participation to the maternal subject.

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P2 Maternal Immunization: Design and Protocol Treatments

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• 120µg RSV F + 0.4mg aluminum phosphate

• Randomization was stratified by age:• 18 to < 29 years and 29 to ≤40 years

*Small difference in randomization is due to block randomization and low numbers per site

TreatmentGroup Label

RSV F Antigen Content

Aluminum Adjuvant Content

Dosing Volume

Maternal Subjects per

Group, N

A 0µg -- 0.5mL 28*

B 120µg 0.4mg 0.5mL 22*

Design:

P2 Maternal Immunization: Safety Follow-up

17*Passive and active follow-up for RSV disease began day 14**An infant blood draw may have been obtained within 24 hours of birth if cord blood was not collected at delivery or the integrity of the sample was compromised.

Infant participants were assigned to one of two postpartum phlebotomy cohorts:

+180 daysDay 14* Delivery +35 days+14 days +60 days

Infant cohort 1*: Infant cohort 2**:Mothers:

P2 Maternal Immunization: Maternal Population and Demographics

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Active Placebo

Safety 22 28

ITT 22 28

Per-protocol 22 28

Mean Age +/- SD (yrs) 27.8 +/- 4.53 27.7 +/-4.91

18 to <29 yrs 59% 57%

29 to ≤40 yrs 41% 43%

White 82% 79%

Black 14% 14%

Asian 5% 7%

BMI (kg/m2) 30 30

Maternal: P2 Maternal Immunization, Top Line Safety

19*Predominantly mild-moderate and transient injection site pain, consistent with prior trial in women of child-bearing age

Placebo Active

Total N 28 22

Any TEAE 27 (96%) 22 (100%)

Any solicited AE (w/i 7 d) 10 (36%) 15 (68%)

Any severe solicited AE 0 (0%) 0 (0%)

Any local solicited AE 1 (4%) 13 (59%)*

Any systemic solicited AE 10 (36%) 6 (27%)

Fever 1 (4%) 0 (0%)

Any unsolicited AE 27 (96%) 22 (100%)

Any severe unsolicited AE 4 (14%) 3 (14%)

Any related unsolicited AE 3 (11%) 2 (9%)

Any severe and related AE 0 (0%) 0 (0%)

Medically-attended AE 24 (86%) 18 (82%)

Any serious AE (SAE) 1 (4%) 2 (9%)

.

Infant: P2 Maternal Immunization, Top Line Safety

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Placebo Active

Total N 28 22

Any unsolicited AE 20 (71%) 14 (64%)

Any severe unsolicited AE 3 (11%) 0 (0%)

Any related unsolicited AE 0 (0%) 0 (0%)

Any severe and related AE 0 (0%) 0 (0%)

Medically-attended AE 18 (64%) 13 (59%)

Any serious AE (SAE) 6 (21%) 3 (14%)

P2 Maternal Immunization: Labor & Delivery Events

211Overall rate of U.S. C-sections is 32.2%, http://www.cdc.gov/nchs/data/nvsr/nvsr64/nvsr64_06.pdf

Placebo Active

Total N 28 22

Obstructed Labor 14 (50%) 8 (36%)

Postpartum Hemorrhage 8 (29%) 5 (22%)

Pre-eclampsia 1 (4%) 0 (0%)

Gestational Diabetes 0 (0%) 1 (5%)

Placental Abruption 0 (0%) 1 (5%)

Gestational Thrombocytopenia

1 (4%) 0 (0%)

Oligohydramnios 1 (4%) 0 (0%)

Premature Delivery 1 (4%) 1 (5%)

Chorioamnionitis 1 (4%) 1 (5%)

Fetal Heart Rate Abnormalities

1 (4%) 1 (5%)

Caesarean Delivery 4 (14%) 7 (32%)1

P2 Maternal Immunization: Safety Summary

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The vaccine was safe for both mothers and infants

• Increase in local AEs (placebo, 4%; vaccine, 59%)

• Predominantly mild-moderate, transient injection site pain

• Pattern similar to that seen in non-pregnant women

• Pattern similar to that observed in non-pregnant women

No Severe Respiratory Events

• No hospitalizations

• No enhanced disease

RSV Infections

• Two RSV positive episodes in the placebo group

• None in the vaccinees

P2 Maternal Participants: Anti-F IgG

231 geometric mean rise relative to Day 02 % of group with EU >95th percentile of the placebo group on that day

Placebo Active

Anti-F IgG GMEU (95% CI) N=28 N=22

Day 0 872 (667-1,140) 690 (547-870)

Day 14 861 (648-1,144) 9,906 (7,075-13,870)

GM Rise1 1.0 14.1

Sero-response2 4% 100%

Delivery 942 (724-1,226) 7,244 (4,645-11,296)

GM Rise 1.1 10.0

Sero-response 4% 96%

Delivery +35 days 1,281 (995-1,650) 9,907 (7,595-12,922)

GM Rise1 1.5 13.6

Sero-response2 4% 91%

P2 Maternal Participants: PCA

241 geometric mean rise relative to Day 02% of group with EU >95th percentile of the placebo group on that day*Excludes 1 mother with delivery 5 days post-immunization, thus no Day 14 blood draw (see slide 29)

Placebo Active

Palivizumab competitiveantibody GMC (µg/mL)

N=28 N=22

Day 0 <14 (<14- 18.5) <14 (<14-14)

Day 14 <14 (<14-21) 270 (219-331)*

GM Rise1 1.1 29.4

Sero-response2 4% 100%

Delivery <14 (<14-16) 182 (123-270)

GM Rise1 0.9 20.2

Sero-response2 1% 96%

Delivery +35 days 17.2 (<14-28) 254 (203-317)

GM Rise1 1.6 28

Sero-response2 4% 100%

P2 Maternal Participants: RSV A Microneutralization

251 geometric mean rise relative to Day 0

Placebo Active

RSV/A GMT (95% CI) N=28 N=22

Day 0 441 (303-644) 309 (181-528)

Day 14 466 (342-636) 868 (563-1,340)

GM Rise1 1.1 2.7

Delivery 431 (316-587) 759 (477-1,209)

GM Rise1 1.0 2.3

Delivery +35 days 493 (363-668) 977 (615-1,552)

GM Rise1 1.2 2.9

P2 Maternal Participants: RSV B Microneutralization

261 geometric mean rise relative to Day 0

Placebo Active

RSV/B GMT (95% CI) N=28 N=22

Day 0 400 (249-643) 256 (125-406)

Day 14 408 (274-608) 521 (346-784)

GM Rise1 1.1 2.1

Delivery 425 (284-637) 481 (304-761)

GM Rise1 1.2 1.9

Delivery +35 days 439 (302-638) 599 (371-969)

GM Rise1 1.3 2.4

P2 Maternal participants:RSV A and B Microneutralizing Antibodies

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1

2

4

Active Placebo Active Placebo Active Placebo Active Placebo Active Placebo Active Placebo

Day 14 post-vaccine

Delivery Day 35 post-delivery

Day 14 post-vaccine

Delivery Day 35 post-delivery

RSV/A RSV/B

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RSV A RSV B

P2 Infants: Time from Vaccination to Delivery (Days) Impacts Placental Antibody Transfer

28Ad hoc analysis Excludes 1 mother/infant pair with delivery 5 days post-immunization, late pre-term delivery

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Delivery < 30 days Post Vaccination Delivery > 30 days Post Vaccination

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Time from Vaccination to Delivery

P2 Infants: Time from Vaccination to Delivery (Days) Impacts Placental Antibody Transfer

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GA = gestational ageAd hoc analysis*Excludes 1 mother/infant pair with delivery 5 days post-immunization, late pre-term delivery

Important Findings:• Maternal antibody peaks

14d after vaccination • Period of placental transfer

>30 days maximizes antibody titer in infants

• P3 recruitment window opened to 31 weeks to maximize antibody transfer

AntiFIgG Cord 7,227 8,659 8,153

Mothers 12,979 6,993 8,594

Ratio 0.6 1.2 0.9

PCA Cord 177 195 189

Mothers 303 178 213

Ratio 0.6 1.1 0.9

RSV/A Cord 928 672 748

Mothers 1,448 580 786

Ratio 0.6 1.2 1.0

RSV/B Cord 565 512 529

Mothers 724 410 495

Ratio 0.8 1.2 1.1

Assay Source

Del.<30d

postvacc.,

n=7

Del.>30d

postvacc.,

n=14

All

n=21*

*Excludes1mother/infantpairwithdelivery5dayafterimmunization,late

pretermdelivery.

*

P2 Infants: Estimated RSV Antibody Half-life

30*PCA = 189 with N=21 subjects, see also slide 29

Vaccine (N=22)

Anti-F IgG

Cord Blood, GMEU (95% CI) 7307 (5113-10443)

Half Life 30 days

PCA

Cord Blood, GMC (95% CI) 163 (112-237)*

Half Life 41 days

RSV/A MN

Cord Blood, GMT (95% CI) 691 (452-1056)

Half Life 36 days

RSV/B MN

Cord Blood, GMT (95% CI) 496 (310-793)

Half Life 34 days

Antibody Persistence in Infants of Immunized Mothers

311Johnson, S. et al. JID, 176:1215-1223

Predicted PCA persistence

• ≥30µg/mL ~ 16 weeks

• ≥25µg/mL ~ 18 weeks

• 14 µg/mL (assay lower limit of quantitation) ~ 22 weeks

• >99% reduction of lung RSV titers was observed at serum concentration of 25-30 ug/ml in cotton rats1

P2 Maternal Immunization: RSV F Vaccine Elicits Additional Known Neutralizing Antibodies

321 maternal baseline GMTs were < 20 for all assaysBeeler et al, Neutralization Epitopes of the F Glycoprotein of Respiratory Syncytial Virus: Effect of Mutation upon Fusion Function. J Virol, 1989

Delivery GMT (95% CI) Placebo Vaccine

Site I

Mother <20 (<20-25.2) 161 (119-217)

Cord Blood 25 (<20-35) 135 (99-184)

Site IV

Mother <20 (<20-<20) 96 (71-129)

Cord Blood 20 (<20-<20) 86 (64-116)

Site II

Site IV

Site I

P2 Maternal Immunization: Primary Objective Outcomes

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No observed prenatal, labor, delivery or immediate postpartum safety issues

• Short-term local reactogenicity is low

• No meaningful imbalance in unsolicited AEs

• No vaccine related SAEs

No observed safety issues related to fetal well-being and infant outcomes through 60 days

• No evidence of enhanced vulnerability to RSV

• Infants will be followed for first year of life

P2 Maternal Immunization: Secondary Objective Outcomes

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Robust immune response to vaccine in mothers

• Anti-F IgG, PCA, and microneutralizing antibody responses are similar to prior trials in women of child-bearing age

All antibody measures show transient dilution at delivery, rebound at day 35 post-delivery

•Likely reflects expansion of maternal blood volume through use of IV fluids prior to delivery, followed by equilibrium

•Maternal immunity remains post-delivery, potential “cocooning” benefits

Efficient transplacental transfer of anti-RSV antibodies

• Anti-F IgG, PCA, microneutralizing antibodies

• Induction and transfer of Site I, Site II and Site IV neutralizing antibodies

Antibody half-life in infants

• Current analysis suggests range of all antibodies between 30 - 41 days

• PCA half-life ~41 days (interim analysis)

• T1/2 predicts potential for protection beyond 3 months (P3 primary endpoint)

Potential Benefits of a Maternal Vaccination Strategy

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Passive Antibody Prophylaxis

• Serum antibody, single specificity with monoclonal

Active Maternal Immunization

• Serum antibody, polyclonal with multiple specificities

• Higher affinity than palivizumab

• Antibodies to sites I, II, IV

• Possible vaccine-induced breast milk antibody

• Cocooning due to heightened maternal immunity

• Decreased infection rate by Western blot analysis in young women

• Efficacy in older adults

P2 Maternal Immunization: Next Steps

36*Pending FDA approval**Primary will be assessed at 3 months; if positive, then assessed at 4 months, 5 months and 6 months

Next Steps

Manufacture and release product

End of Phase 2 meeting

Initiate Phase 3 trial

1Q16

Proposed endpoints*

Primary: Prevention ofRSV bronchiolitis with hypoxia**

Secondary: Prevention of severe RSV bronchiolitis with hypoxia

Exploratory: Examineimmune correlates and other medical interventions

Adaptive trial design

Anticipated subjects: 4,500 to 9,000

Expect to initiate Phase 3 trial in U.S.

Followed by South Africa, Argentina, Chile, Australia, NZ in 2016

Expand to other countries including EU in 2nd year of trial

Breaking News

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