RSV F Vaccine: Phase 2 Clinical Trial to Protect Infants via Maternal Immunization Allison August, MD

Transcription

1 RSV F Vaccine: Phase 2 Clinical Trial to Protect Infants via Maternal Immunization Allison August, MD

2 Agenda 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 2

3 Novavax: An Overview 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 3

4 RSV Vaccine Target Populations Infants via Maternal Immunization Infants <6 months Older Adults Healthy individuals 60+ years and high risk adults Pediatrics Children >6 months - 5 years 4

5 Global Burden of Infant and Pediatric RSV Infections 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 ,000 deaths due to RSV, 99% in developing countries Estimated 3-9% of all deaths from acute lower respiratory diseases 5

6 Antibody Responses after RSV Exposure: Robust in the Mother, Fails to Protect Infants 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 Suara et al., CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY, July 1996, p CDC, National Hospital Discharge Survey,

7 RSV the Virus 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 7

8 RSV F-Protein Presents Multiple Conserved Sites RSV Surface Proteins G protein: Variable F protein: Conserved 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 Site IV Site II Site I Antigenic site I, Antigenic site IV Known broadly neutralizing antibodies Likely to contribute to protection 1 Also poorly elicited by natural infection 1 Beeler et al, Neutralization Epitopes of the F Glycoprotein of Respiratory Syncytial Virus: Effect of Mutation upon Fusion Function. J Virol,

9 Novel RSV F Vaccine 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 9

10 Women of Childbearing Age: Summary of Prior Clinical Trial Data The vaccine was well-tolerated in non-pregnant women, 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 10

11 RSV F Vaccine Phase 2 Clinical Trial to Evaluate the Safety and Immunogenicity of RSV F Vaccine for Third Trimester Maternal Immunization 11

12 P2 Maternal Immunization: Study Objectives Primary Secondary 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 Mothers: Evaluate amplitude and duration of anti-f IgG, PCA and RSV A/B microneutralizing antibody responses in through delivery and 6 months postdelivery 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 12

13 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. 13

14 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. 14

15 P2 Maternal Immunization: Exclusion Criteria -2- Exclusion Known HIV, HBV, or HCV infection, as assessed by serologic tests, or pimary genital 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. 15

16 P2 Maternal Immunization: Design and Protocol Treatments 120µg RSV F + 0.4mg aluminum phosphate Randomization was stratified by age: 18 to < 29 years and 29 to 40 years Design: Treatment Group Label RSV F Antigen Content Aluminum Adjuvant Content Dosing Volume Maternal Subjects per Group, N A 0µg mL 28* B 120µg 0.4mg 0.5mL 22* *Small difference in randomization is due to block randomization and low numbers per site 16

17 P2 Maternal Immunization: Safety Follow-up Infant participants were assigned to one of two postpartum phlebotomy cohorts: Mothers: Infant cohort 1*: Infant cohort 2**: Day 14 * Delivery +14 days +35 days +60 days +180 days *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. 17

18 P2 Maternal Immunization: Maternal Population and Demographics Active Placebo Safety ITT Per-protocol Mean Age +/- SD (yrs) / / to <29 yrs 59% 57% 29 to 40 yrs 41% 43% White 82% 79% Black 14% 14% Asian 5% 7% BMI (kg/m 2 )

19 Maternal: P2 Maternal Immunization, Top Line Safety Placebo Active Total N 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%). *Predominantly mild-moderate and transient injection site pain, consistent with prior trial in women of child-bearing age 19

20 Infant: P2 Maternal Immunization, Top Line Safety Placebo Active Total N 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%) 20

21 P2 Maternal Immunization: Labor & Delivery Events Placebo Active Total N 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 1 Overall rate of U.S. C-sections is 32.2%, 21

22 P2 Maternal Immunization: Safety Summary 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 22

23 P2 Maternal Participants: Anti-F IgG Placebo Active Anti-F IgG GMEU (95% CI) N=28 N=22 Day (667-1,140) 690 ( ) Day (648-1,144) 9,906 (7,075-13,870) GM Rise Sero-response 2 4% 100% Delivery 942 (724-1,226) 7,244 (4,645-11,296) GM Rise Sero-response 4% 96% Delivery +35 days 1,281 (995-1,650) 9,907 (7,595-12,922) GM Rise Sero-response 2 4% 91% 1 geometric mean rise relative to Day 0 2 % of group with EU >95 th percentile of the placebo group on that day 23

24 P2 Maternal Participants: PCA Palivizumab competitive antibody GMC (µg/ml) Placebo Active N=28 N=22 Day 0 <14 (< ) <14 (<14-14) Day 14 <14 (<14-21) 270 ( )* GM Rise Sero-response 2 4% 100% Delivery <14 (<14-16) 182 ( ) GM Rise Sero-response 2 1% 96% Delivery +35 days 17.2 (<14-28) 254 ( ) GM Rise Sero-response 2 4% 100% 1 geometric mean rise relative to Day 0 2 % of group with EU >95 th 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) 24

25 P2 Maternal Participants: RSV A Microneutralization Placebo Active RSV/A GMT (95% CI) N=28 N=22 Day ( ) 309 ( ) Day ( ) 868 (563-1,340) GM Rise Delivery 431 ( ) 759 (477-1,209) GM Rise Delivery +35 days 493 ( ) 977 (615-1,552) GM Rise geometric mean rise relative to Day 0 25

26 P2 Maternal Participants: RSV B Microneutralization Placebo Active RSV/B GMT (95% CI) N=28 N=22 Day ( ) 256 ( ) Day ( ) 521 ( ) GM Rise Delivery 425 ( ) 481 ( ) GM Rise Delivery +35 days 439 ( ) 599 ( ) GM Rise geometric mean rise relative to Day 0 26

27 P2 Maternal participants: RSV A and B Microneutralizing Antibodies Geometric Mean Rise in Neutralizing Titers (baseline adjusted) Active Placebo Active Placebo Active Placebo Active Placebo Active Placebo Active Placebo Day 14 postvaccine Delivery Day 35 postdelivery Day 14 postvaccine Delivery Day 35 postdelivery RSV/A RSV A RSV/B RSV B 27

28 P2 Infants: Time from Vaccination to Delivery (Days) Impacts Placental Antibody Transfer Cord Blood Titer/ Maternal Serum Titer Infant/Maternal Anti-F Antibody Ratio Delivery < 30 days Post Vaccination Delivery > 30 days Post Vaccination Time from Vaccination to Delivery Ad hoc analysis Excludes 1 mother/infant pair with delivery 5 days post-immunization, late pre-term delivery 28

29 P2 Infants: Time from Vaccination to Delivery (Days) Impacts Placental Antibody Transfer Assay Source Del. < 30d post vacc., n=7* Del. > 30d post vacc., n=14 All n=21* Anti F IgG Cord 7,227 8,659 8,153 Mothers 12,979 6,993 8,594 Ratio PCA Cord Mothers Ratio RSV/A Cord Mothers 1, Ratio RSV/B Cord Mothers Ratio *Excludes 1 mother/infant pair with delivery 5 day after immunization, late GA preterm = gestational delivery. age Ad 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 29

30 P2 Infants: Estimated RSV Antibody Half-life Vaccine (N=22) Anti-F IgG Cord Blood, GMEU (95% CI) 7307 ( ) Half Life 30 days PCA Cord Blood, GMC (95% CI) 163 ( )* Half Life 41 days RSV/A MN Cord Blood, GMT (95% CI) 691 ( ) Half Life 36 days RSV/B MN Cord Blood, GMT (95% CI) 496 ( ) Half Life 34 days *PCA = 189 with N=21 subjects, see also slide 29 30

31 Antibody Persistence in Infants of Immunized Mothers 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 ug/ml in cotton rats 1 1 Johnson, S. et al. JID, 176:

32 P2 Maternal Immunization: RSV F Vaccine Elicits Additional Known Neutralizing Antibodies Delivery GMT (95% CI) Placebo Vaccine Site IV Site I Site I Site IV Mother <20 (< ) 161 ( ) Cord Blood 25 (<20-35) 135 (99-184) Mother <20 (<20-<20) 96 (71-129) Cord Blood 20 (<20-<20) 86 (64-116) Site II 1 maternal baseline GMTs were < 20 for all assays Beeler et al, Neutralization Epitopes of the F Glycoprotein of Respiratory Syncytial Virus: Effect of Mutation upon Fusion Function. J Virol,

33 P2 Maternal Immunization: Primary Objective Outcomes 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 33

34 P2 Maternal Immunization: Secondary Objective Outcomes 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 days PCA half-life ~41 days (interim analysis) T 1/2 predicts potential for protection beyond 3 months (P3 primary endpoint) 34

35 Potential Benefits of a Maternal Vaccination Strategy 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 35

36 P2 Maternal Immunization: Next Steps Next Steps Manufacture and release product End of Phase 2 meeting Initiate Phase 3 trial 1Q16 Proposed endpoints* Primary: Prevention of RSV bronchiolitis with hypoxia** Secondary: Prevention of severe RSV bronchiolitis with hypoxia Exploratory: Examine immune 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 *Pending FDA approval **Primary will be assessed at 3 months; if positive, then assessed at 4 months, 5 months and 6 months 36

37 Breaking News 37