Maternal GBS vaccine

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Immaculada Margarit PD-VAC Meeting Geneve, September 7th 2015

The Group B Streptococcus (GBS)

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Streptococcus agalactiae (Group B Streptococcus,

GBS) is a Gram-positive beta-hemolytic microorganism

that colonizes the human lower Gastro Intestinal and

Genital tracts

GBS can cause life-threatening infections in neonates

and in immuno-compromised adults

Mother to Infant Transmission:

• 20-25% women are colonized (global)

.......................................200/1000

• 50% of babies born to these mothers are colonized

..................100/1000

• 2% become

infected.......................................................................2/1000

Edwards MS & Nizet V 2011, in Infectious diseases of the fetus and newborn infant. Elsevier Saunders, :419-469

Stages of GBS maternal and neonatal infection

3 Adapted from: Doran & Nizet Molecular Microbiology 2004 54 (1), 23–31

2.9 Million neonatal deaths occuring world-wide annually1, 98

% of which in developing countries2-3

32% of neonatal deaths are due to infections2,4

GBS is a leading cause of neonatal sepsis and meningitis5

GBS as major cause of neonatal invasive disease

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1) Lozano R et al. The Lancet 2011; 378: 1139; 2) Vergnano Arch Dis Child Fetal Neon 2005; 90: F220-F224 3) Report WHO/FRH/MSM/967,

1996.; 4) Costello et al. The state of the world’s newborns. Washington: Save the Children Fund, 2001; 5) Thigpen MC, et al. NEJM 364:2016, 2011.

GBS

meningitis

86.1%

GBS neonatal infections cause significant

mortality and sequelae

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Early Onset Disease

(EOD)

Late Onset Disease

(LOD)

Age ≤ 6 days 7-89 days

Acquisition1 Mother Mother or community

Manifestations1-2

Bacteremia

Pneumonia

Meningitis

Meningitis

Bacteremia

Osteoarthritis

CFR1,4 5-10% in developed world

up to 38% in developing world

3-11% in developed world

up to 29% in developing world

Sequelae rates3,4 26% 34-46% (post-meningitis)

Typical

Sequelae5 Deafness, Blindness, Seizures, long-term Neurodevelopmental defects

1) Edwards M, Baker C, Chapter 202 in Infectious Diseases (Mandell et al), 2010 ; 2) Melin, P CMI 2011; 17, 1294-1303; 3) Colbourn T et al, Health Tech. Assess. 2007 Vol ll: No. 29; 4) Libster R et al. Pediatrics 2012; 130:e8-e15.; 5) Edwards MS, et al. J Pediatr. 1985;106:717–722;

Maternal infection:

• Invasive GBS disease has declined with IAP, but still occurs in 0.04 pregnant and 0.49 post-partum women /1000 live births (US)1

• Chorioamnionitis occurs in 2.9% of pregnant women vaginally colonized at the time of delivery

Stillbirth:

• 2009 global estimates: ~2.6 milion, corresponding to ~1.9% live births2

• ~20% stillbirths are due to infection, ~4-10% to GBS3

Preterm birth:

• Accounts for 75% of perinatal mortality worldwide4

• 2010 estimates: ~15 mn/year (~11%, up to 18% in some African countries)5-6

• 25-40% may be due to infections, including GBS

1) Deutscher M et al. CID 2011 53 114; 2) Cousens S et al. Lancet 2011; 377: 1319–30; 3) Gibbs R & Roberts DJ. NEJM 2007 , 357:918-925; 4)

Goldenberg et al 2000; 5)Liu L, et al. Lancet 2012; 379:2151–2161 6) Blencowe H et al. Lancet 2012; 379: 2162–72

GBS causes peripartum morbidity

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GBS toxins cause placental damage

Preterm birth and fetal infection can be caused by GBS b-

hemolysin induced damage of maternal-fetal barriers and

inflammation1-3

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b-hemolytic GBS Uterine Tissue

GBS

infected

Uninfected

control

Inflammatory cells,

necrotic tissue

1) Whidbey et al. J Exp Med. 2013;210(6):1265-81; Vanderhoeven et al. PLoS Pathog.

2014;10(3):e1003920; Randis et al. J Infect Dis. 2014 15;210(2):265-73

Global incidence of GBS neonatal infection

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Estimated number of cases per 1000 live births in infants <90

days1

Edmond et al. The Lancet 2012 Vol 379: 547; Black et al. Sci Transl Med. 2013 Jul 24;5(195):195ps11

GBS neonatal infections may be under reported

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In LMIC there are a high percentage of home deliveries and

deaths not reported due to limited health care access, lack of

awareness, logistical hurdles

GBS can be difficult to detect due to:

• Poor blood collection: 1.0 mL neonatal blood volume for 90%

sensitivity

• Lack of pediatric blood culture bottles

• Lack of proper media/supplies for GBS isolation and identification

Dagnew et al. Clin Infect Dis. 2012 Jul;55(1):91-102

GBS preventive and treatment measures

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Difficult treatment: very early, quick onset (most EOD within

48 h)

Intrapartum antibiotic prophylaxis (IAP) for women at risk is

the only available prevention measure.

Two approaches:

• GBS screening by vagino/rectal swabs at

~35-37 gestation weeks → all colonized

women receive IAP (e.g. US, CA, FR, BE, AU,

supported by key obs/gyn organizations)

• Clinical factors: previous infant with GBS

disease, chorioamnionitis, prematurity,

PROM, fever (e.g. UK, DK)

Verani et al. Clin Perinatol 37 (2010) 375–392

Decline in the incidence of invasive GBS disease among infants in US

prior and after IAP recommendations in 19931:

IAP limitations: no effect on LOD, failures due to precipitous labor or

false negative screening, allergies, concern for induction of antibiotic

resistance

Even in US, with 85% compliance for IAP, ~2500 GBS cases occur each

year

IAP has reduced but not eradicated the disease

11 1) Jordan et al. Pediatr Infect Dis J. 2008 Dec;27(12):1057-64

Increasing GBS antibiotic resistance

Erythromycin resistance in invasive group B streptococcal (GBS)

isolates according to patient age, England and Wales, 1991 – 20101:

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1) Lamagni TL et al. Clin Infect Dis. 2013 Sep;57(5):682-8

GBS infection occurs too soon for any infant vaccine

Maternal immunization at 26-35 gestation weeks could reduce

the risk of neonatal infection

Placental IgG transfer increases >32 wks and persists for 3 mo

after birth

Maternal vaccination to prevent tetanus and influenza is

recommended in international guidelines1-3

1) The CVI and WHOs GVP, SAGE Part I Wkly Epidemiol. Rec 1998; 73:281-288; 2) CDC. MMWR Morb Mortal Wkly Rep. 2011

Oct 21;60(41):1424-6; 3) http://www.cdc.gov/vaccines/pubs/preg-guide.htm#11

A GBS Maternal Vaccine to protect neonates

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Antibodies confer protection A vaccine is possible

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Cases non cases

• *Baker CJ et al. J Clin Invest

1977;59:810.

Antibody to GBS III CPS in Sera from Mothers Whose Infants Had III GBS

Colonization or Disease*

High maternal IgG levels specific to the GBS capsular

polysaccharide (CPS) correlate with reduced risk of newborn

infection in humans1-4

Anti-CPS antibodies protect humans against neonatal infection

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1) Baker & Kasper NEJM 1976; 294:753-756 ; 2) Lin et al. JID 2001 184:1022-1028; 3) Lin et al. JID 2004;190:928-934; 4) Baker et al.

JID 2014;209:781–8

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Percentage of mothers of infected (cases) or non infected babies (controls) with

CPS–specific IgG serum concentrations ≥ to the value shown on the horizontal

axis4

A vaccine for GBS is possible

Tools to evaluate immunogenicity of GBS vaccine

candidates

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CPS conjugates confer protection in

neonatal mice mice

Female mice were immunized with each conjugate individually and the pups

were challenged with a strain of the corresponding serotype

Challenge to GBS Vaccine Design

A substantial challenge to GBS vaccine design is the

natural diversity of GBS capsular polysaccharides

(CPS):

• 10 serotypes of GBS have been characterized

(Ia, Ib, II, III, IV, V, VI, VII, VIII, IX) and found to be

antigenically unique

GBS Vaccine Design: Conquering Diversity

Approaches to overcoming GBS diversity:

1. Prepare combination of CPS-glycoconjugates

–Combination of Ia, Ib, III, II and V may represent

>90% of isolates

2. Inclusion of GBS proteins to increase protection and

breadth of responses

–Surface-associated proteins identified mainly by

genome analysis1-5

1) Brodeur et al. I&I 2000; 2).Cheng et al. I&I 2001. 69, 2302; 3) Madoff et al. I&I 60, 4989 (1992); 4) Stalhammar-Carlemalm et al.

1993 J. Exp. Med. 177:1593; 4) Maione et al. Science. 2005 309: 148-50 ; 5) Margarit et al. JID 2009 199:108-15

Clinical studies on CPS conjugates supporting

vaccine development

Phase I/II using monovalent /bivalent CPS conjugated to TT or CRM

on healthy adults and pregnant women (III-TT)1-4

Phase I/II using trivalent CPS Ia, Ib, III-CRM conjugates (GSK):

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1) Kasper et al. JCI 1996; 98: 2308; 2) Baker et al. JID. 1999;179:142-50; 3) Baker et al. JID, 2003;188:66-73; 4) Baker, et al. J Infect

Dis. 2004;189:1103-12

Maternal results: • The vaccine was well-tolerated in pregnant women

• >75% of women had >4-fold rise in specific IgG

Infant results: • For all serotypes, mother to infant IgG transfer rates ranged from 50-81%

• Ab concentrations in infants remained above placebo recipients through 90

days post-partum

• No evidence of a detrimental effect on infant Ab response to diphtheria (or

pneumococcal) immunization

Possible paths to licensure

Efficacy PhIII study:

• Case-driven, including EOD and LOD

• Possibly conducted in LMICs with high burden of disease and high

uptake of TT maternal vaccine1

• Participants (≥50000) randomized to receive GBS vaccine or

placebo in addition to locally available standard of care2

• Possible need of bridging studies for licensure in HIC

Maternal IgG concentrations as serological correlates of protection:

• Rational: a) High maternal anti-CPS IgG correlate with reduced

neonatal disease risk3; b) Anti-CPS IgG correlate with OPKA functional

titers4

• Approach: Develop specific IgG thresholds based on estimation of

disease risk reduction using serum samples from case-control studies5-7

• Lower number of participants required

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1) Madhi et al. Vaccine. 2013 31 Suppl 4:D52-7; 2) White & Madhi Vaccine. 2015 Aug 10. pii: S0264-10X(15)01117-2; 3) Baker & Kasper

NEJM 1976 294:753-756; 4) Kasper DL et al. J Clin Invest 1996;98:2308; 5) Lin et al. JID 2001 184:1022-1028; 6) Lin et al. JID

2004;190:928-934 5) Baker et al. JID 2014;209:781–8

GBS vaccine cost effectiveness

GBS is a global disease both in developing and developed world

• High awareness in HIC countries (e.g., universal IAP, active surveillance),

Ob/Gyn as responsible for GBS prevention

• Less awareness in LMIC

Two recent studies confirmed GBS vaccine cost effectiveness:

• US cost-effectiveness estimates based on expected reduction in GBS

cases & prevention of GBS-related deaths, Quality-Adjusted Life-Years.

Results: US cost/QALY ($91,321) for GBS trivalent vaccine comparable to

ACIP-recommended vaccines1

• CDC-cost effectiveness model in S Africa. Results: maternal GBS

vaccination very cost effective per WHO guidelines at prices up to

$30/dose2

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Oster, G. et al Vaccine 2014, 32:4778-4785 ; Kim, S.-Y. et al Vaccine 2014, 32:1954-1963

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GBS vaccine development hurdles

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Maternal vaccination acceptance, increased rate of adverse

events during pregnancy

Difficulty in conducting efficacy trials due to low incidence

and to IAP treatment.

• To detect a 75% reduction in EOD and LOD requires >50.000

women if incidence ~3/1000 and >150000 women if lower

incidence

• Lower microbiological, clinical and analytical data quality

standards in LMIC countries

Regulatory acceptance of protection serocorrelates based

on case-control studies for vaccine licencing and

recommendation

Low public awareness of GBS as a cause of vaccine-

preventable illness

Need for more reliable epidemiological data

Co-administrations of other recommended vaccines

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WHO support needed

Raise education/awareness regarding GBS and its impact

Initiatives to obtain more reliable epidemiological data

Create consensus on indication for vaccine use in

pregnant women

Definition of serocorrelates of protection for vaccine

licencing and recommendation

Definition of preferred product characteristics

Roadmap for vaccine introduction in LMIC

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