Development of a Maternal Vaccine for
Group B Streptococcus (GBS)
Karen Slobod MD
5 Nov 2013
Agenda
 Epidemiologyand epidemiology
 NVD trivalent maternal vaccine
 Clinical Development Approach

2 | MRF | K Slobod...
Maternal Immunization: rationale
Prevention of the earliest infections
 H1N11
•

Pregnant women = 13% of all H1N1 deaths
...
Group B streptococcus (GBS)
Leading cause of neonatal sepsis and meningitis globally

 Transmission:
• Mother to infant:
...
GBS Neonatal Disease
Unmet medical need

 Leading cause of neonatal sepsis and meningitis
in the first 3 months of life

...
GBS: Important cause of bacterial meningitis
Unmet medical need

 Meningitis occurs among 7% of EOD and 27%
LOD1

 Case ...
Prevention: No vaccine yet licensed
Intrapartum antibiotic prophylaxis (IAP) only prevention

 IAP = Intravenous ampicill...
GBS: Universal screening and IAP (US)
Reduced but not eradicated disease
Incidence of invasive GBS disease among infants (...
GBS: Risk-based IAP (UK)
Little change with risk-based IAP
In the UK, IAP-eligible women are identified via risk factors; ...
GBS: Lead cause pediatric bacterial meningitis (US)
Causes >85% meningitis in infants <2mo (US)

1.

Thigpen MC, et al. Ba...
GBS: Maternal vaccine can be protective
Long-standing data supports protection of maternal anti-CPS Ab

Ab against CPS pro...
Key data: GBS CPS-specific Ab protects
Pups born to vaccinated dams survive lethal challenge
Measure
2 day survival

+

Fe...
Novartis GBS vaccine
Trivalent glycoconjugate vaccine

 Vaccine: CRM197 conjugated capsular polysaccharide representing
t...
GBS: Maternal vaccination allows infant protection
Placental transfer increases markedly >32 wks

Decay of passively

Pass...
Novartis: GBS vaccine development

Monovalent:
Phase I

Trivalent: Phase I

Serotype Ia
Serotype Ib & III)

Trivalent (Ia,...
Study 1: GBS Trivalent Vaccine in Non-pregnant women
No added benefit from aluminum hydroxide, 2 injections or 20 vs 5 ug
...
Study 2: Phase Ib/II study in pregnant women
Objective: Select dosage in pregnant women
 Subjects: Healthy, pregnant wome...
Study 2: Ph II Dose-ranging in pregnant women
All subjects
Reverse Cumulative Distribution at delivery: Serotype Ia
GBS Ia...
Ph II Dose-ranging in PG: Serotype Ia
Subjects < limit of detection at baseline
GBS Ia ELISA
Reverse Cumulative Distributi...
Novartis GBS Vaccine
Immunogenic and well-tolerated in NPG and PG women

 5/5/5 µg
 Single injection administered betwee...
GBS Maternal Vaccine: Phase III Study
Enroll and vaccinate mothers; follow mothers and infants

 Phase III study:
• Size:...
GBS Maternal Vaccine Development
Next Steps

 Complete Ph II dose-ranging studies
- placental transfer
- functional Ab

...
Contributors
GBS Global Program
Team
Stephen Cho
Brian Cooper
Marianne Cunnington
Laura Deschenes
Peter Dull
Guido Grandi
...
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Novartis Group B Streptococcus vaccine programme

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Dr Karen Slobod's presentation at Meningitis Research Foundation's 2013 conference, Meningitis & Septicaemia in Children & Adults

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  • Latest incidence data comes from sentinel surveillance network of neonatal units, but data are only published ad hoc.Same neonatal network reported GBS to be responsible for 50% neonatal sepsis cases within first 48hrs life...From CDC Pinkbook (May 2012), CFR of meningococcal meningitis is 9-12%.
  • Latest incidence data comes from sentinel surveillance network of neonatal units, but data are only published ad hoc.Same neonatal network reported GBS to be responsible for 50% neonatal sepsis cases within first 48hrs life...From CDC Pinkbook (May 2012), CFR of meningococcal meningitis is 9-12%.
  • GBS causes 86.1% of bact meningitis among infants &lt; 2 mo of age (US).
  • Novartis Group B Streptococcus vaccine programme

    1. 1. Development of a Maternal Vaccine for Group B Streptococcus (GBS) Karen Slobod MD 5 Nov 2013
    2. 2. Agenda  Epidemiologyand epidemiology  NVD trivalent maternal vaccine  Clinical Development Approach 2 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
    3. 3. Maternal Immunization: rationale Prevention of the earliest infections  H1N11 • Pregnant women = 13% of all H1N1 deaths • Most childhood deaths < 6 mo of age  Influenza and Tdap routinely recommended in pregnancy2:  Seasonal influenza vaccination recommended for all pregnant women  UK uptake = 40.3%  Tdap: “Immunisation could be offered at one of the routine antenatal visits following the routine week 20 anomaly scan”  UK uptake ≈ 50%  GBS: Prime candidate for prevention by maternal vaccination • 95% of all „early‟ infection occurs within 48 hrs, before infant vaccine can take effect 1 Zuccotti GV, et al. JAMA 304:2360-61 2 JCVI Notes 3 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
    4. 4. Group B streptococcus (GBS) Leading cause of neonatal sepsis and meningitis globally  Transmission: • Mother to infant: 20-25% women are colonized (global) ..................................................200/1000 ↓ ↓ 50% of babies born to these mothers are colonized .............................100/1000 ↓ ↓ 2% become infected...............................................................................2/1000 • • 95% of „early‟ onset disease (EOD: 0-6 days) occurs within 48 hrs Median age of „late‟ onset disease (LOD: 7-89 days) is 37 days (3rd quartile is 53 days) • Maternal vaccination needed to prevent such early infection 4 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
    5. 5. GBS Neonatal Disease Unmet medical need  Leading cause of neonatal sepsis and meningitis in the first 3 months of life  UK incidence: EOD + LOD = 0.7 cases/1000 live births (~500 cases/yr)1  Case fatality rate (UK): 8-9%2-3 1 Lamagni TL, et al. CID 57:682; 2013. K, et al. Lancet 2011 3 Weisner 2004; Clin Infect Dis 2004; 38: 1203-08 2 Edmond 5 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
    6. 6. GBS: Important cause of bacterial meningitis Unmet medical need  Meningitis occurs among 7% of EOD and 27% LOD1  Case fatality rate among meningitis cases: up to 23% in preterm infants and 12% in term infants2.  Long-term neurologic sequelae/disability in almost half of GBS meningitis cases3,4 1 Phares CR, et al. JAMA 2008.. 2007 Health Technologies Assess (11) No 29; 2007 3 Libster R, et al. Pediatrics, 2012. 4 NEJM 357:918-25, 2007 2 Colbourn 6 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
    7. 7. Prevention: No vaccine yet licensed Intrapartum antibiotic prophylaxis (IAP) only prevention  IAP = Intravenous ampicillin q4h during labor for women at risk. Risk determined: • Universal screening: All pregnant women are screened at ~35-37 wks gestation → all colonized women receive IAP (e.g. USA) • Clinical factors: previous infant with GBS disease, prematurity, PROM, fever (e.g. UK) 7 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
    8. 8. GBS: Universal screening and IAP (US) Reduced but not eradicated disease Incidence of invasive GBS disease among infants (recommendations issued 1993) Cases / 1,000 live births 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 8 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
    9. 9. GBS: Risk-based IAP (UK) Little change with risk-based IAP In the UK, IAP-eligible women are identified via risk factors; no evident decrease in cases since the recommendations were issued in 2003 Incidence of EOD and LOD in the England and Wales and N. Ireland between 2003-2011 RCOG guidelines for GBS implemented Source: Lamagni, T et al. CID, 2013 9 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
    10. 10. GBS: Lead cause pediatric bacterial meningitis (US) Causes >85% meningitis in infants <2mo (US) 1. Thigpen MC, et al. Bacterial meningitis in the United States 1998-2007. NEJM 364:2016, 2011. 10 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
    11. 11. GBS: Maternal vaccine can be protective Long-standing data supports protection of maternal anti-CPS Ab Ab against CPS protects against neonatal infection: 1. GBS capsular polysaccharide conjugate (CPS-CRM197) vaccines protect in GBS neonatal pup challenge model1 2. Passive transfer of anti-CPS Ab protects newborn mice2 3. Low levels of maternal anti-CPS Ab correlate with neonatal disease susceptibility3 4. Higher levels of maternal anti-CPS Ab correlate with reduced risk of neonatal disease4,5 1Vaccine 2001;19:2118-2126 1992;166:635-639 3NEJM 1976; 294:753-756 4JID 2001;184:1022-1028 5JID11 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only 2004;190:928-934 2JID
    12. 12. Key data: GBS CPS-specific Ab protects Pups born to vaccinated dams survive lethal challenge Measure 2 day survival + Females immunized Mating (0 and 21 days) (day 21) GBS challenge of pups at 24-48 hrs age (intraperitoneal, 90% LD) Vaccine serotype Challenge strain (type) Ia 090 (Ia) Ib 7357B (Ib) III COH1 (III) % Survival (Alive/Treated) CRM-conjugate PBS 86% (54/63) 0% (0/59) 73% (71/97) 0% (0/38) 93% (95/102) 2% (1/48) Anti-CPS Ab protects - NVD glycoconjugates protect. 12 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
    13. 13. Novartis GBS vaccine Trivalent glycoconjugate vaccine  Vaccine: CRM197 conjugated capsular polysaccharide representing three serotypes (at 1:1:1 ratio): »Ia »Ib »III Bacterial capsular polysaccharide CRM protein  Trivalent coverage ≈ 79% globally 13 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only Glycoprotein conjugate
    14. 14. GBS: Maternal vaccination allows infant protection Placental transfer increases markedly >32 wks Decay of passively Passive Ab transfer occurs largely in third trimester % maternal Ab in cord blood transferred Ab 120 100 80 60 40 20 3-6 mo 0 0 20 Gestational Age 14 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only 28 32 40
    15. 15. Novartis: GBS vaccine development Monovalent: Phase I Trivalent: Phase I Serotype Ia Serotype Ib & III) Trivalent (Ia, Ib & III), NPG Phase Ib/II Trivalent PG Phase II Trivalent HIV+/- PG Trivalent PG (functional Ab) Trivalent PG US Formulation 15 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only NPG: Non-pregnant PG: Pregnant Trial complete Recruiting complete FSFV in next 9 mo
    16. 16. Study 1: GBS Trivalent Vaccine in Non-pregnant women No added benefit from aluminum hydroxide, 2 injections or 20 vs 5 ug Adjuvant No Alum Injection # 1 Placebo (saline) 2 Alum 2 1 2 Dose (each GC) 5 µg 20 µg 5 µg 20 µg 5 µg 20 µg 5 µg 20 µg 0 µg n 40 38 40 40 40 39 40 38 18 Cumulative Percentage Reverse Cumulative Ab Distribution: Serotype Ia at day 61 GBS ELISA Concentrations ( g/mL) 16 | ESPID | Karen Slobod | 30 May 2013 | GBS Vaccine | Confidential
    17. 17. Study 2: Phase Ib/II study in pregnant women Objective: Select dosage in pregnant women  Subjects: Healthy, pregnant women between 28-35 wks gestation (18-40 yrs)  Study site: South Africa GBS Vx dosage1 (Ia/Ib/III GC) Study subjects (n) Delivery 0.5/0.5/0.5 µg 80 2.5/2.5/2.5 µg 80 5/5/5 µg 80 Placebo (saline) 80 1 Formulated without adjuvant; administered as a single injection 17 | ESPID | Karen Slobod | 30 May 2013 | GBS Vaccine | Confidential
    18. 18. Study 2: Ph II Dose-ranging in pregnant women All subjects Reverse Cumulative Distribution at delivery: Serotype Ia GBS Ia ELISA Delivery 5 g Cumulative Percentage 2.5 g 0.5 g Placebo GBS ELISA Concentrations ( g/mL) 18 | ESPID | Karen Slobod | 30 May 2013 | GBS Vaccine | Confidential - _____ (N = 75) *- --------- (N = 77) - ______ (N = 77) - _ _ _ _ (N = 76)
    19. 19. Ph II Dose-ranging in PG: Serotype Ia Subjects < limit of detection at baseline GBS Ia ELISA Reverse Cumulative Distribution at delivery: Serotype Ia Delivery 5 g Cumulative Percentage 2.5 g 0.5 g Placebo  5 ug dosage superior GBS ELISA Concentrations ( g/mL) 19 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only - _____ (N = 43) *- --------- (N = 42) - ______ (N = 31) - _ _ _ _ (N = 39)
    20. 20. Novartis GBS Vaccine Immunogenic and well-tolerated in NPG and PG women  5/5/5 µg  Single injection administered between 28-35 weeks gestation  No adjuvant (no preservatives) 20 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
    21. 21. GBS Maternal Vaccine: Phase III Study Enroll and vaccinate mothers; follow mothers and infants  Phase III study: • Size: >10,000 mothers → >10,000 infants Infant Enroll Mothers (>10,000) Immunize Delivery Mother (>10,000) • Eligibility: women between 28-35 wks gestation • End-points: Mother/infant safety; vaccine immunogenictiy (efficacy); infant response to CRM-containing vaccines 21 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
    22. 22. GBS Maternal Vaccine Development Next Steps  Complete Ph II dose-ranging studies - placental transfer - functional Ab  Ph III maternal/infant study start • Planned start Q1 2015 • Global study enrolling >10k pregnant women in EU/US/global  Ongoing advocacy for role of maternal vaccination in prevention of neonatal disease 22 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
    23. 23. Contributors GBS Global Program Team Stephen Cho Brian Cooper Marianne Cunnington Laura Deschenes Peter Dull Guido Grandi Dominika Kovacs Martha Leibbrandt Imma Margarit Y Ros Mariska Mulder Research Fabiana Baldoni Friedhelm Helling Gabriella Rolli Mario Contorni Lorenzo Tarli Concetta Cicala Massimo Pacini Hans Joachim Mai Manfred Boese Melanie Muche Francesca Titta Francesco Norelli Frederica Sponga Valeria Carinci John Telford Paolo Costantino Domenico Maione Francesco Berti Emanuela Palla Elena Mori Barbara Baudner Mikkel Nissum Maria Rosaria Romano Marzia Giuliani TechOps/TD Stefano Ricci Stefania Berti Stefania Ferrari Stefania Pezzotti Antonella Damarini 23 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only Development • • • • • • • Pietro Forte Irving Boudville Richard de Rooij Geert Prins Anke Hilbert Annette Karsten Rachid Marhaba Silvia Benocci Sue Fekete Lisa Bedell Allen Izu Katherine Lanier Wayne Woo Alessandra Schiavone Jonathan Go Narcisa Cuceanu Ana Vila Real Aldo Schepers Renate Enzinga
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