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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