RSV F Nanoparticle Vaccine: Update Gregory M. Glenn M.D., SVP R&D

Transcription

1 RSV F Nanoparticle Vaccine: Update Gregory M. Glenn M.D., SVP R&D Summary of Findings in Recent Clinical Trials International Society of Vaccines October 26,

2 2 The Problem with RSV The RSV F Nanoparticle Vaccine Summary of Immunogenicity to date Supportive Preclinical Studies Summary of Clinical Results in Women of Childbearing Age M202: Women of Childbearing Age Results and dose selection M203: Safety and immunogenicity in 3 rd trimester women and their infants Decreased Infection Rates in RSV F Vaccinees in M201 Summary

3 Target Populations for an RSV Vaccine Young Infants via Maternal Immunization Pediatric Elderly Provide protection for infants younger than six months and most at risk of serious RSV disease, prevent hospitalization, medical care, wheezing Decrease respiratory disease burden in children, prevent medical care, wheezing Mitigate RSV disease burden that results from waning immunity and immunosenescence, prevent hospitalization and death 3

4 Naturally Derived Immunity is Robust but Relatively Ineffective: A Persistent Puzzle The Very Young 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 Antibody Transfer Age of Hospitalization Peak Hospitalization Rates when Maternal Antibodies are Near Peak Suara et al., CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY, July 1996, p

5 RSV F Nanoparticle Antigen Vaccine Technology RSV F Recombinant Protein Nanoparticles Near Full Length, Recombinant RSV F RSV virus Fusion (F) McLellan JS Purified, recombinant near-full-length RSV F fusion glycoprotein trimers Trimers spontaneously assemble into nm nanoparticle structures Present neutralizing sites such as Site II, palivizumab binding site, in a multimeric format RSV F trimer RSV F Nanoparticle 5

6 RSV F: Genetic Stability of Surface Glycoproteins is Critical in Selection of the Vaccine Target RSV Surface Glycoproteins Attachment Protein (G) Fusion Protein (F) Frequency of Amino Acid Changes In Glycoproteins G and F Strain changes due to the G protein variability The Fusion F protein changes less Site II on the F protein does not change in nature & is the target of Palivizumab 6

7 F Protein Nanoparticle Vaccine Displays Site II: Palivizumab Binding Palivzimab binds avidly to the F protein nanoparticle vaccine 120 Competitive Inhibition (%) % Inhibition = 2.1 µg/ml 25 µg 2.5 µg 0.25 µg µg Palivizumab (µg/ml) binding RSV F Antigenic site II: Amino acids NSELLSLINDMPITNDQKKLMSNNV * McLellan, et al. JV Aug. 2011, p

8 Palivizumab-Competitive ELISA (PCA) Labeled Palivizumab Human Immune Sera Vaccine-induced antibodies compete with palivizumab for binding to Site II on the F Protein Protective levels elucidated by the cotton rat studies: 30ug/ml 8

9 Vaccine Immunity: Amplifying the Near Absence of Palivizumab Competing Antibodies PCA levels up to 400μg/ml, potential for placental concentration effect Palivizumab protective at 30μg/ml in CR PCA Near absence suggests that the site is immunologically cryptic, important to reinfection 500 Two-dose, 60μg One-dose, 120μg Palivizumab-Competitive ELISA Responses ~400μg/ml Day 0 Day 14 Day 28 Near-Absence of PCA 0 Placebo Group B Group C Group D Group E Group F Group G Group A N=77 N=75 N=76 N=79 N=76 N=81 N=85 N=80 *European Summary Basis for Approval 9

10 Outcomes of the RSV F Nanoparticle Vaccine Development Program to Date In preclinical models,the vaccine is protective both with active and passive studies, as well as maternal immunization Concordance Between Increased Anti-F and PCA After Vaccination The vaccine is well tolerated and immunogenic in adults, women of childbearing age and the elderly The general population has little or no palivizumab competing antibodies (PCA) potentially explaining why reinfections are common The vaccine induces ~10x the protective level of palivizumab (PCA) The vaccine induces neutralizing antibodies at levels known to be protective 10

11 Summary of Clinical Studies to Date Study 101: Safety and immunogenicity in healthy adults (n=120) Stimulated robust immune responses Induced production of palivizumab-competing antibodies Study E101: Safety and Imunogenicity and dose finding in Elderly Adults Safety, dose selection Study E201: Safety, epidemiology and efficacy in Elderly Adults Define attack rate, Vaccine effect Enrolling Study M201: Safety and immunogenicity in women of childbearing age (n=330) Confirmation of safety and immunogenicity in target population Study M202: Safety dose finding in women of childbearing age (n=720) Selection of dose and schedule for pregnant women Study M203: Safety and immunogenicity in 3 rd trimester women and their infants Safety, transplacental antibody transfer and half life Enrolling 11

12 Maternal Antibody Transfer Mother s Blood Baby s Blood Antibody Active transport of mother s antibodies into baby s blood Mother s antibodies from past infections and vaccines At full term baby has >100% of mother s antibody levels. Antibodies from natural RSV infection of mothers over decades are actively transported to infants blood Vaccine delivered this way are efficacious: tetanus for neonatal tetanus, pertussis, influenza for infants and their mothers 12

13 Modeling Maternal Antibody Transport in the Guinea Pig Guinea Pigs Transfer of Vaccine Antibodies in Humans Guinea pig transfer rates of anti-f IgG and two other functional measures appear similar to licensed protein vaccines 13

14 Maternal Immunization Prevents Tachypnea in Infant Baboons Challenged with RSV Fold Rise in Respiratory Rate Above Baseline In Placebo and Transplacentally Immunized Infant Baboons Fold Rise, Respiratory Rate p= Maternal immunization study* Pregnant Baboons immunized in 3 rd trimester Develop PCA, neuts and anti-f Placental transfer of antibody 30day old infants challenged with RSV develop tachypnea Infants of RSV F nanoparticle immunized mothers are protected 1 month after birth *Presented at ICAAC, 2014 Challenge p- values were calculated using t-test. Error bars represent standard errors of the mean (SEM) 14

15 M202 Clinical Trial Safety and Immunogenicity in Women of Child-Bearing Age Trial Design 720 healthy women, years Placebo-controlled, dose-ranging trial to assess safety and the kinetics and magnitude of the anti-rsv immune response 60 or 120µg RSV F vaccines adsorbed with descending dosages of aluminum adjuvant (0.8 to 0.2mg), given as two-dose (60µg) or single-dose (120µg) regimen Results Vaccine was immunogenic and well tolerated Single dose regimen selected 15

16 Women of Childbearing Age Immunogenicity: One Dose (120ug) vs Two Dose (60ug) Regimens, and Alum Titration (M202) Primary endpoint-anti F IgG response Single dose, 120µg F with 0.4mg Al, provides the best immune response to D56 Single dose improves compliance in maternal immunization Palivizumab Competing Antibodies Track Anti-F IgG Closely Anti-F IgG Fold Rises in Response to 2-dose Regimens Anti-F IgG Fold Rises in Response to 1-dose Regimens Two Dose, Day 0 and 28 One dose 16

17 Microneutralization: Responses to 1-dose Regimens (M202) Groups E, F, and G = 120µg F + 0.8, 0.4, or 02 mg Al x 1 dose, respectively Major RSV/A MN response at Day 28 in 1-dose groups Little impact of formulation Minimal decrement through Day 56 17

18 M202 Women of Childbearing Age:Palivizumab Competing Antibodies PCA levels up to 400μg/ml, potential for placental concentration effect Palivizumab protective at 30μg/ml in CR Palivizumab-Competitive ELISA Responses Two-dose, 60μg One-dose, 120μg Selected regimen Day 0 Day 14 Day 28 Near-Absence of PCA 0 Placebo Group B Group C Group D Group E Group F Group G Group A N=77 N=75 N=76 N=79 N=76 N=81 N=85 N=80 *European Summary Basis for Approval 18

19 PCA Responses in Women of Childbearing Age: Implications for Coverage of Infants Born at Different Gestational Ages 1,600 CDC Birth Frequencies by Gestational Week Data 1,400 U.S. Births (in thousands) 1,200 1, > 90% of Births Weeks All Births * PCA = Palivizumab-Competing Antibodies 19

20 PCA Responses in Women of Childbearing Age: Implications for Coverage of Infants Born at Different Gestational Ages 1,600 CDC Birth Frequencies by Gestational Week Data 1,400 U.S. Births (in thousands) 1,200 1, Peak Transplacental Antibody Transfer > 90% of Births Weeks All Births * PCA = Palivizumab-Competing Antibodies 20

21 PCA Responses in Women of Childbearing Age: Implications for Coverage of Infants Born at Different Gestational Ages 1,600 PCA* Kinetic Curve for Single Dose (120µg RSV-F mg Al) Aligned Over CDC Birth Frequencies by Gestational Week Data 450 1, U.S. Births (in thousands) 1,200 1, Peak Transplacental Antibody Transfer > 90% of Births Palivizumab Protective at = µg/ml PCA* µg/ml Weeks Immunization All Births PCA µg/ml 0 * PCA = Palivizumab-Competing Antibodies 21

22 Modeling Effect of PCA via Maternal Immunization: Potential for Clinical Benefit for infants up to 5-6 months Protection * * Protective level for palivizumab at 30 µg/ml 22

23 M203: RSV F Protein Nanoparticle Vaccine Candidate, First Study in Pregnant Women Trial synopsis Randomized, observer-blinded, placebo-controlled 25 active, 25 placebo third trimester women Active will receive 120ug RSV F/ 0.4 mg Aluminum Phosphate Immunization at gestational age Maternal subjects followed for 6 months postpartum Infant subjects followed for one year Consultation with Investigators includes global RSV KOLs and thought leaders in maternal immunization Study Objectives (FSI: 16 Sept, 2014) Safety of mothers and their infants through an RSV season Maternal transplacental antibody transfer to infants Antibody half-life in infants up to 6 months 23

24 Rate of RSV Infections Decreased by 50% in RSV F Vaccinees Western Blot Analysis Immunized at the beginning of RSV season Immunization complete by day 56 Assessed for new onset infections between day 56 and 112 by Western Blot Evidence of recent past infection balanced between placebo and vaccinees Rate of new infections in placebo, 20% Rate of new infections in vaccine, 10% Reduction of new infections of 50% Table 1. Rate of RSV Infections by Western Blot All Vacc Vacc/No Al Vac/Al Placebo n=269 n=119 n=150 n=61 Western Blot Results n(%) n(%) n(%) n(%) Acute RSV infection DAY 0 0 (0) 0 (0) 0 (0) 0 (0) DAY (4) 6 (5) 5 (3) 2 (3) DAY (10) 9 (8) 17 (11) 12 (20) * Recent Past infection DAY 0 40 (15) 26 (22) 14 (9) 9 (15) DAY 56 0 (0) 0 (0) 0 (0) 0 (0) DAY (0) 0 (0) 0 (0) 0 (0) 24 *p<0.004

25 Implications of Decreased Rate of RSV Infections Healthy adults have clinically significant RSV disease (O Shea et al, JID) Pregnant women who contract influenza have more adverse outcomes and increased fetal loss Vaccine Efficacy is generally better the more severe the case definition RSV epidemiology in pregnant woman needed RSV F vaccine likely to protect pregnant women as well as infants, similar to influenza Efficacy data in pregnant women will be collected in M301 25

26 Conclusions RSV causes severe and recurrent infections in the face of robust natural immunity Natural immunity induces little Site II immunity Immunological cryptic and critical to protection? The RSV F nanoparticle vaccine induces Site II immunity and neutralizing antibodies These antibodies are protective and transplacentally transferred Clinical data in 1,182 subjects has shown the vaccine to be safe and immunogenic There is a 50% decrease infection rates in vaccinees vs placebo over an RSV season Evidence that the vaccine will show efficacy against disease 26

27 Acknowledgements Discovery Gale Smith, Mike Massare, Ye Liu, David Flyer, Yingyung Wu, Hanxin Liu Clinical/Regulatory/PM Louis Fries, D. Nigel Thomas, Eloi Kpamegan, Judy Wen, Dewal Jani, Somia Hickman, Matt Lawlor, Amy Fix, Kathleen Callahan, and Gregory Glenn. Baylor College of Medicine Pedro Piedra M.D. 27