Novartis Group B Streptococcus vaccine programme

Development of a Maternal Vaccine forGroup B Streptococcus (GBS)

Karen Slobod MD5 Nov 2013

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 effect1 Zuccotti GV, et al. JAMA 304:2360-612 JCVI Notes

Maternal Immunization: rationalePrevention of the earliest infections


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


GBS Neonatal DiseaseUnmet medical need

1 Lamagni TL, et al. CID 57:682; 2013.2 Edmond K, et al. Lancet 20113 Weisner 2004; Clin Infect Dis 2004; 38: 1203-08

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


GBS: Important cause of bacterial meningitisUnmet medical need

1 Phares CR, et al. JAMA 2008..2 Colbourn 2007 Health Technologies Assess (11) No 29; 20073 Libster R, et al. Pediatrics, 2012.

4 NEJM 357:918-25, 2007

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


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)

Prevention: No vaccine yet licensedIntrapartum antibiotic prophylaxis (IAP) only prevention


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sGBS: Universal screening and IAP (US) Reduced but not eradicated disease

Incidence of invasive GBS disease among infants (recommendations issued 1993)


GBS: Risk-based IAP (UK)Little change with risk-based IAP

Source: Lamagni, T et al. CID, 2013

RCOG guidelines for GBS implemented

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


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.


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

GBS: Maternal vaccine can be protectiveLong-standing data supports protection of maternal anti-CPS Ab

1Vaccine 2001;19:2118-21262JID 1992;166:635-6393NEJM 1976; 294:753-7564JID 2001;184:1022-10285JID 2004;190:928-934


Females immunized(0 and 21 days)

+

Mating

(day 21)

GBS challenge of pups at 24-48 hrs age

(intraperitoneal, 90% LD)

Measure2 day survival

Key data: GBS CPS-specific Ab protectsPups born to vaccinated dams survive lethal challenge

Anti-CPS Ab protects - NVD glycoconjugates protect.

% Survival (Alive/Treated) Vaccineserotype Challenge strain (type) CRM-conjugate PBS

Ia 090 (Ia) Ib 7357B (Ib) III COH1 (III)

86% (54/63) 73% (71/97) 93% (95/102)

0% (0/59) 0% (0/38) 2% (1/48)


Trivalent glycoconjugate vaccineNovartis GBS vaccine

Vaccine: CRM197 conjugated capsular polysaccharide representing three serotypes (at 1:1:1 ratio):

» Ia» Ib» III

Trivalent coverage ≈ 79% globally

Bacterial capsular polysaccharide

Glycoproteinconjugate

CRM protein


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GBS: Maternal vaccination allows infant protectionPlacental transfer increases markedly >32 wks

3-6 mo

Decay of passively

transferred AbPassive Ab transfer occurs largely in third trimester


Novartis: GBS vaccine development

Phase I

Formulation

Serotype Ib & III)

Monovalent: Serotype Ia

Trivalent PG US

Phase II Trivalent HIV+/- PG

Phase Ib/II Trivalent PG

Trivalent (Ia, Ib & III), NPG

Trivalent PG (functional Ab)

Trivalent: Phase I

Non-pregnantPregnantTrial completeRecruiting completeFSFV in next 9 mo

NPG:PG:


No added benefit from aluminum hydroxide, 2 injections or 20 vs 5 ugStudy 1: GBS Trivalent Vaccine in Non-pregnant women

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GBS ELISA Concentrations (mg/mL)

16 | ESPID | Karen Slobod | 30 May 2013 | GBS Vaccine | Confidential

Adjuvant No Alum AlumPlacebo (saline)

Injection # 1 2 1 2 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

Reverse Cumulative Ab Distribution: Serotype Ia at day 61

GBS Vx dosage1

(Ia/Ib/III GC)Study subjects (n)

0.5/0.5/0.5 µg 80

2.5/2.5/2.5 µg 80

5/5/5 µg 80

Placebo (saline) 80

Subjects: Healthy, pregnant women between 28-35 wks gestation (18-40 yrs) Study site: South Africa

1 Formulated without adjuvant; administered as a single injection

Delivery

Objective: Select dosage in pregnant womenStudy 2: Phase Ib/II study in pregnant women


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GBS Ia ELISA Delivery


5 mg ▲ - _____ (N = 75)

2.5 mg * - --------- (N = 77)

0.5 mg ● - ______ (N = 77)Placebo ■ - _ _ _ _ (N = 76)

All subjectsStudy 2: Ph II Dose-ranging in pregnant women

Reverse Cumulative Distribution at delivery: Serotype Ia


Ph II Dose-ranging in PG: Serotype IaSubjects < limit of detection at baseline

5 mg ▲ - _____ (N = 43)

2.5 mg * - --------- (N = 42)

0.5 mg ● - ______ (N = 31)Placebo ■ - _ _ _ _ (N = 39)

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GBS Ia ELISADelivery


5 ug dosage superior


Reverse Cumulative Distribution at delivery: Serotype Ia

Novartis GBS VaccineImmunogenic and well-tolerated in NPG and PG women

5/5/5 µg

Single injection administered between 28-35 weeks gestation

No adjuvant (no preservatives)


GBS Maternal Vaccine: Phase III StudyEnroll and vaccinate mothers; follow mothers and infants

Phase III study:• Size: >10,000 mothers → >10,000 infants

• Eligibility: women between 28-35 wks gestation

• End-points: Mother/infant safety; vaccine immunogenictiy (efficacy); infant response to CRM-containing vaccines

EnrollMothers

Immunize Delivery

Infant(>10,000)

Mother(>10,000)


GBS Maternal Vaccine DevelopmentNext 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


Contributors

ResearchJohn TelfordPaolo CostantinoDomenico MaioneFrancesco BertiEmanuela PallaElena MoriBarbara BaudnerMikkel NissumMaria Rosaria RomanoMarzia Giuliani

TechOps/TDStefano RicciStefania BertiStefania FerrariStefania PezzottiAntonella Damarini

Fabiana BaldoniFriedhelm HellingGabriella RolliMario ContorniLorenzo TarliConcetta CicalaMassimo PaciniHans Joachim MaiManfred BoeseMelanie MucheFrancesca TittaFrancesco NorelliFrederica SpongaValeria Carinci

Development• Pietro Forte• Irving Boudville• Richard de Rooij• Geert Prins• Anke Hilbert• Annette Karsten• Rachid Marhaba

Silvia BenocciSue FeketeLisa BedellAllen IzuKatherine LanierWayne WooAlessandra SchiavoneJonathan GoNarcisa Cuceanu Ana Vila RealAldo SchepersRenate Enzinga

GBS Global Program Team

Stephen ChoBrian CooperMarianne CunningtonLaura DeschenesPeter Dull Guido GrandiDominika KovacsMartha LeibbrandtImma Margarit Y RosMariska Mulder


Novartis Group B Streptococcus vaccine programme

Health & Medicine

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