Overview presentation: The Burden of Group B Streptococcus Worldwide for Pregnant Women, Stillbirths and Children: 1st International Symposium on ‘Streptococcus agalactiae’ Disease (Clinical Infectious Diseases, revised April 2018)

Clinical Infectious Diseases
The Burden of Group B
Streptococcus Worldwide for
Pregnant Women, Stillbirths,
and Children
Overview presentation
On behalf of the Clinical Infectious Diseases GBS Burden
estimation expert group
https://academic.oup.com/cid/issue/65/suppl_2 #GBSburden #momandbaby

Adapting this presentation
• You are welcome to use slides and adapt
• Please respect all sources and references
• Clinical Infectious Diseases GBS Series supplement
and executive summary
• Please maintain formatting where possible
• Consider adding country or regional-level
data, examples of programmes or stories of
personal loss

This work was supported by a grant to the London School of Hygiene
& Tropical Medicine from the Bill & Melinda Gates Foundation.
Editors: Joy E Lawn, Anna C Seale.
Lead authors: Joy E Lawn, Neal Russell, Jennifer Hall, Anna C Seale,
Fiorella Bianchi-Jassir, Kirsty Le Doare, Lola Madrid, Maya Kohli-Lynch,
and Cally J Tann.
Expert Advisory Group: Ajoke Sobanjo-ter Meulen, Carol Baker,
Linda Bartlett, Claire Cutland, Michael Gravett. Paul Heath, Margaret
Ip, Shabir A Madhi, Craig Rubens, Samir Saha, Stephanie Schrag and
Johan Vekemans.
We thank all authors and those that contributed data.
PPT slides, executive summary and infographics coordinated by Joy
Lawn, Anna Seale, Fiorella Bianchi-Jassir, and Victoria Ponce Hardy

All authors: Ajoke Sobanjo-ter Meulen, Anna C Seale, Beate
Kampmann, Cally J Tann, Carmen Briner, Carol Baker, Caroline Trotter,
Catherine O’Sullivan, Claire Cutland, Clara Menendez, Craig Rubens,
Farah Seedat, Firdose Nakwa, Fiorella Bianchi-Jassir, Habib Soua, Hannah
Blencowe, Hechmi Ben Hamouda, Hilary Rattue, James A Berkley, Jaume
Ordi, Jennifer Hall, Johan Vekemans, Joy E Lawn, Juan Gonzalez-Guarin,
Karen M Edmond, Kim Turner, Kirsty Le Doare, Kyriaki Giorgakoudi, Linda
Bartlett, Lola Madrid, Maira Vega-Pobleete, Margaret Ip, Maya Kohli-
Lynch, Megan O’Driscoll, Michael G Gravett, Nadine Hack Adams, Neal
Russell, Nicholas Embleton, Paul Heath, Samantha Sadoo, Samir K Saha,
Shabir A Madhi, Shamex Ladhani, Simon Cousens, Stephanie Schrag,
Theresa Lamagni, Quique Bassat, and Ziyaad Dangor.
Acknowledgements: Alegria Perez, Anne Lee, Claudia Da Silva, Debora
Pedrazzoli, Francesca Cavvalaro, Ipek Gurol, Jana Zitha, Jane Falconer,
Kazuyo Machiyama, Ketevan Glonti, Laura Ferreras, Ludovico Ghilardi,
Monika Ogerek, Quique Bassat, Sadie Sareen, S. Nanduri, Tapan
Bhattacharyya, Victoria Ponce Hardy, and Vladimir Gordeev.

Media coveragehttp://bit.ly/GBS_Map
http://bit.ly/GBS_Infographic
Over 250 articles in at least 45 countries
>140 in English from at least 19 countries
>45 in French from at least 7 countries
>45 in Spanish from at least 16 countries
>20 in Portuguese from at least 3 countries

Photocredit:©Bill&MelindaGatesFoundation/SarahElliott
Group B Streptococcus worldwide burden
for pregnant women, stillbirths and children
Published in the journal of Clinical Infectious Diseases, Nov 2017
#GBSburden #momandbaby
On behalf of the GBS Burden estimation expert group

Series in journal of Clinical Infectious Diseases, Nov 2017
#GBSburden #everynewborn @joylawn
Burden of Group B Streptococcus worldwide for
pregnant women, stillbirths and children: Why?
What outcomes? How to estimate?
Professor Joy Lawn
London School of Hygiene & Tropical Medicine

8
Intervening Early in Life Course is Key to Achieving SDG U5
Mortality Targets
1 Golding N et al. Mapping under-5 and neonatal mortality in Africa, 2000–15: a baseline analysis for the Sustainable Development Goals. The Lancet. 2017.
2 Liu L et al. Global, regional and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the SDGs. The Lancet. 2016.
We need to make faster progress… …against more complex burden…
Composition of U5 deaths, 2000 vs. 2015 2
2000-2015 2015-2030
Annualized rate of U5MR reduction
observed, 2000-2015
Annualized rate of reduction needed to
reach SDG targets, 2015-2030
Historical and target annualized rates of reduction in U5MR (ARR) 1
From 2000-15, proportionate neonatal mortality increased from 26% to 35% in
SSA and from 49% to 57% in S/SE Asia. In both regions, post-neonatal deaths
due to diarrhea, pneumonia, measles and malaria decreased; whereas, deaths
due to prematurity are a higher proportion of the mortality pie.
Sub-Saharan Africa South/SE Asia
Compared to the average 2-4% annual U5MR reduction observed in sub-
Saharan Africa during the MDG era, substantial acceleration will be needed to
attain the 6-9% reduction per year required to attain the SDG targets by 2030.

Why this organism ?
• Commonly found in gut or
lower vaginal tract
• Leading cause of neonatal
infections Early Onset and
Late Onset (sepsis,
meningitis) in high income
countries with high case
fatality rate
• No previous systematic
estimates

Why estimate the worldwide burden of
group B Streptococcus (GBS) disease?
Clinical Infectious Diseases #GBSburden #momandbaby
WHO/UNICEF 2017
• Global “black box” for aetiological data
regarding 600,000 deaths due to neonatal
infections. What proportion is due to GBS?
• Geographic distribution of GBS – is this
real epidemiological variation in
incidence, virulence or data gaps?
• Global public health policy - candidate
for maternal vaccine development
Neonatal infections:
~600,000 deaths per year
>10% of child deaths <5 years
About 6x that for deaths from AIDS
and 2x that from malaria
46%
neonatal
Causes of death for children under 5 years in 2016
Lawn JE, et al Clinical Infectious Diseases. 2017;65(S2):S89-99

What outcomes of GBS should be included?
NOW
Maternal,
perinatal
and child
outcomes
including
cases,
deaths and
disability
Major
focus in
the past
Maternal GBS
colonization
Infection
Impairment
Healthy mother
Healthy child
development
Maternal death
Neonatal death
Premature death
Stillbirth
Impairment
Maternal sepsis
Third trimester
stillbirths
Preterm
births
Neonatal
encephalopathy
Sepsis
Pneumonia
Meningitis
Neonatal and infant
invasive
GBS disease
GBS isolated from a sterile site
Death
Healthy development
GBS attributable preterm birth (estimated
based on risk from maternal colonization)
GBS attributable cases of NE by sensitisation through
maternal infection (not estimated)
Later impairment

Modelling approach
Estimate national, regional, worldwide burden
• Pregnant women colonised, infants with GBS disease,
deaths and disability
• Maternal GBS disease
• Stillbirths with GBS disease
• Preterm birth attributed to maternal GBS colonisation
Four step
compartmental
model
1 2 3
4
To estimate GBS infant cases and sequelae we
applied a compartmental model:
1. Exposed (maternal colonisation)
2. Cases (early and late onset)
3. Deaths (neonatal and infant)
4. Disability amongst survivors
“All models are wrong but some are useful” - Lord Box

Data inputs
• Systematic searches, multiple databases, all
languages (more than 20,000 abstracts
screened)
• Investigator groups to access unpublished
data for the outcomes (colonisation,
stillbirths, infant disease and GBS associated
Neonatal Encephalopathy)
• Meta-analyses by country or regional if
enough data
• Relevant population at risk per country for all
195 UN member states
• Relevant GBS risk estimate applied for
• Pregnant women
• Stillbirths
• Preterm births

What are the challenges with the available data?
- Data from as many countries as possible
- Biases (e.g. swab type, lab culture)
assessed and adjusted for if predictable
- Sensitivity analyses undertaken to show
effect of adjustments or assumptions
- Conservative model estimates compared
with reported results from countries with
good data
At every stage we followed the Guidelines
for Accurate and Transparent Health
Estimates Reporting (GATHER) (Lancet 2016)
What we did to minimise
biases
Cascade affecting case ascertainment for GBS
True
cases
of GBS
disease
(mother,
stillbirth,
newborn)
Cases
accessing
care
and have
clinical
assessment
Cases
with
micro-
biological
sample
taken
correctly
Samples
where
lab
correctly
detects
GBS
Cases
seeking
care
100%
1
2
3
4
Care and measurement GAP
0%

Paper 1: Group B Streptococcal disease worldwide for pregnant women, stillbirths and children:
why, what and how to undertake estimates?
Paper 11: Estimates of the burden of Group B Streptococcal disease worldwide
for pregnant women, stillbirths and children
2. Maternal colonisation with Group B Streptococcus and serotype distribution worldwide
3. Maternal disease with Group B Streptococcus and serotype distribution worldwide
4. Stillbirth with Group B Streptococcus disease worldwide
5. Preterm birth associated with Group B Streptococcus maternal colonisation worldwide
6. Intrapartum antibiotic chemoprophylaxis policies for prevention of Group B Streptococcal
Disease worldwide
7. Risk of early-onset neonatal Group B Streptococcus disease with maternal colonisation worldwide
8. Infant Group B Streptococcal disease incidence and serotypes worldwide
9. Neonatal encephalopathy with Group B Streptococcus disease worldwide
10. Neurodevelopmental impairment in children after Group B Streptococcus disease worldwide
Overview of papers in CID – open access and launched today

What is new to inform interventions?
• Input data worldwide
• Worldwide reach from almost 100 countries and all regions (translated from ~20 languages)
• Volume of inputs at least doubled compared with previous databases
• Investigator groups bringing important unpublished datasets – notably for stillbirths and
regarding hypoxic ischaemic encephalopathy in neonates with GBS infection
• All outcomes of relevance
• All relevant outcomes: cases, deaths and disability for pregnant women, stillbirths, and children
• More data needed, particularly for stillbirths, preterm and disability, maternal cases
• ‘Inverse care law’, where the most vulnerable have highest burden and least available data
• Informing vaccine impact
• Inform vaccine design & potential
• Better understand possible variation in virulence by region or by cases (e.g. maternal, fetal, child)
11 papers, collaboration of 103 authors from over 30 institutions
coordinated by the London School of Hygiene & Tropical Medicine

Maternal Group B Streptococcus colonisation
prevalence, and risk of infant disease worldwide
Dr Neal Russell
On Behalf of the GBS Burden estimation expert group

What is the prevalence of maternal GBS colonisation?
Serotypes?
• Case definition
• Pregnant women
• Culture isolation from vagina/rectum/peri-anal region
• Published and unpublished material (investigators)
• Including Chinese and Russian searches
• Inclusion & exclusion criteria
• Culture method described
• Not if bias in population selection
• Not if molecular methods alone (for prevalence)
• Data quality assessment
• Time of GBS screening (during pregnancy or at delivery)
• Sampling site (rectal samples performed?)
• Laboratory culture techniques (selective enrichment broth?)
369 studies included
Russel N, et al Clinical Infectious Diseases. 2017;65(S2):S100-11
Additional studies comparing
culture methods/sites and without
contributing to prevalence/serotype
(n=21)
Full-text articles excluded (n=402)
Methods papers (n=167)
Review (n=51)
Unrep pop (n=24)
Culture method poorly described
(n=27)
Serotypes not reported (n=9)
GBS Bacteriuria only (n=13)
Non pregnant women (n=31)
Developed region pre2000 (n=74)
Records excluded
(n=5367)
Duplicates
excluded
(n=2030)
Records screened
(n=6159)
Total
(n=8189)
Records from databases
MEDLINE/ EMBASE/
WHOLIS/SCOPUS/LILAC
S
(n=8134)
Chinese database search (n=20)
Unpublished data (n=7)
Handsearching refs/investigators
(n=28)
Studies included in
meta-analysis of
colonisation and
serotype
prevalence
(n=369)
Full-text articles
assessed for
eligibility
(n=792)
IdentificationScreeningIncludedEligibility

NOTE: Weights are from random effects analysis
.
.
.
Overall (I-squared = 73.1%, p = 0.000)
India
USA
Ireland
Poland
Iran
Subtotal (I-squared = 81.6%, p = 0.000)
Australia
Greece
Developed Regions
Iran
Saudi Arabia
India
Malawi
USA
India
Austria
Asia
South Africa
Africa
Zimbabwe
France
Thailand
USA
Belgium
Australia
India
Belgium
Country
USA
USA
Czech Republic
USA
Netherlands
2011
2000
1998
2012
2015
2013
2003
2010
2011
2013
2005
1982
2001
1998
2014
2000
2003
2007
1995
2009
2002
2016
2010
Year
1977
2004
2004
1995
1982
Sharmila
Quinlan
Kieran
Brzychczy-wloch
Goudarzi
Law
Tsolia
Moghaddam
Zamzami
Patil
Dzowela
Dillon
Kulkarni
Hafner
Kwatra
Moyo
Jaureguy
Kovavisarach
Philipson
El Aila
Gilbert
Chaudhary
El Aila
Author
Badri
Jamie
Motlova
Platt
Hoogkamp-Korstanje
300
222
501
1176
100
278
1014
201
326
905
97
2540
317
Total
3569
521
206
370
320
94
150
1096
300
100
samples
789
200
586
870
762
2
44
100
313
14
52
60
22
95
68
14
434
3
Vaginal
326
99
52
41
43
17
28
238
32
9
samples
81
55
127
105
60
Positive
7
54
126
353
17
64
67
25
103
110
16
895
8
Vagino-rectal
520
148
65
90
58
29
36
296
45
17
samples
162
67
172
146
102
Positive
1.42 (1.29, 1.57)
3.50 (0.73, 16.71)
1.23 (0.86, 1.74)
1.26 (1.00, 1.59)
1.13 (0.99, 1.28)
1.21 (0.63, 2.33)
1.46 (1.28, 1.66)
1.23 (0.89, 1.71)
1.12 (0.80, 1.56)
1.14 (0.66, 1.95)
1.08 (0.86, 1.37)
1.62 (1.21, 2.16)
1.14 (0.59, 2.21)
2.06 (1.86, 2.28)
2.67 (0.71, 9.96)
1.60 (1.40, 1.82)
1.49 (1.20, 1.87)
1.25 (0.92, 1.70)
1.32 (1.13, 1.54)
2.20 (1.56, 3.08)
1.35 (0.94, 1.94)
1.71 (1.01, 2.89)
1.29 (0.83, 1.99)
1.24 (1.07, 1.44)
1.41 (0.92, 2.15)
1.89 (0.88, 4.03)
RR (95% CI)
2.00 (1.56, 2.56)
1.22 (0.90, 1.64)
1.35 (1.11, 1.65)
1.39 (1.10, 1.75)
1.39 (1.16, 1.65)
1.70 (1.26, 2.30)
100.00
0.39
3.50
4.63
5.58
1.71
69.85
3.73
3.63
2.22
4.62
4.08
1.68
5.78
0.53
%
5.56
4.71
3.88
19.88
3.60
3.41
2.29
2.82
5.41
2.93
1.36
Weight
4.47
3.98
4.95
4.62
10.27
3.94
1.42 (1.29, 1.57)
3.50 (0.73, 16.71)
1.23 (0.86, 1.74)
1.26 (1.00, 1.59)
1.13 (0.99, 1.28)
1.21 (0.63, 2.33)
1.46 (1.28, 1.66)
1.23 (0.89, 1.71)
1.12 (0.80, 1.56)
1.14 (0.66, 1.95)
1.08 (0.86, 1.37)
1.62 (1.21, 2.16)
1.14 (0.59, 2.21)
2.06 (1.86, 2.28)
2.67 (0.71, 9.96)
1.60 (1.40, 1.82)
1.49 (1.20, 1.87)
1.25 (0.92, 1.70)
1.32 (1.13, 1.54)
2.20 (1.56, 3.08)
1.35 (0.94, 1.94)
1.71 (1.01, 2.89)
1.29 (0.83, 1.99)
1.24 (1.07, 1.44)
1.41 (0.92, 2.15)
1.89 (0.88, 4.03)
RR (95% CI)
2.00 (1.56, 2.56)
1.22 (0.90, 1.64)
1.35 (1.11, 1.65)
1.39 (1.10, 1.75)
1.39 (1.16, 1.65)
1.70 (1.26, 2.30)
100.00
0.39
3.50
4.63
5.58
1.71
69.85
3.73
3.63
2.22
4.62
4.08
1.68
5.78
0.53
%
5.56
4.71
3.88
19.88
3.60
3.41
2.29
2.82
5.41
2.93
1.36
Weight
4.47
3.98
4.95
4.62
10.27
3.94
Adjustment factor: Increased sensitivity with Rectal sampling included
• Adjustment for lower
sensitivity methods
• Meta-analysis of 40 studies with
methods comparisons
• Vaginal vs. recto-vaginal
• With/without selective enrichment
• Major increase in usable data
• 299,924 pregnant women
• 85 countries
• More than doubled previous data
set – (37 countries & 73,791 women)
What is the prevalence of maternal GBS colonisation?
Meta-analysis of increased sensitivity with addition of rectal site
Adjustment factors to address biases
Addition of rectal swabs
(Recto-vaginal vs vaginal)
1.4
(1.3-1.6)
Inclusion of selective enrichment broth
to unselective agar
1.9
(1.6-2.1)
Inclusion of selective enrichment broth
to an agar with antibiotics
1.5
(1.3-1.7)

Prevalence of GBS colonisation in pregnant women by country
adjusting for sampling site & laboratory culture method
• Worldwide: 18% (17%-19%)
• Highest: Caribbean 35% (35%-40%)
• Lowest: Southern and Eastern Asia (11%, 13%)
Maternal GBS colonisation

Serotypes? Global distribution of Maternal Colonisation Serotype data
GBS Serotypes Worldwide
First systematic review
51 countries
16,181 typed isolates
Any serotype method
Serotypes Ia/Ib,II, III, V = 98% globally

• Serotype III:
- Globally 25%
- Central America: 11%
- South-Eastern Asia: 12%
- India: 11%
- Bangladesh: 11%
Serotypes
Serotypes? Global distribution of Maternal Colonisation Serotype data
Serotype I (Ia/Ib) (%)
Serotype II (%)
Serotype III (%)
Serotype IV (%)
Serotype V (%)
Other Serotypes*
(VI/VII/VIII/IX) (%)
Southern Asia Western Asia
South Eastern Asia Eastern Asia

Risk of Early Onset GBS from maternal GBS colonisation and
variation with Intrapartum Antibiotics
30 studies
included
• Case definitions
• Culture isolation from vagina/rectum/peri-anal
• Culture positive blood or CSF
• Systematic searches and unpublished material
through an investigator group
• Inclusion
• Cohort of >200 GBS colonised mothers + infant
outcomes
• Description of IAP use/coverage
• Risk of bias assessment
• Meta-analyses
• Sensitivity analyses
Russel N, et al Clinical Infectious Diseases. 2017;65(S2):S152-72 IdentificationScreeningIncludedEligibility
Unpublished data (n=3)
Identified by handsearching Cochrane and
other reviews of interventions (n=36)
Alternative sources (n=55)
Records screened after duplicates
removed
(n=6198)
Records excluded
(n=5367)
Full-text articles
assessed for eligibility
(n=831)
Full-text articles
excluded (n=396)
No data on risk (n=372)
High risk of bias (n=9)
Less than 200 pregnant
women (n=24)
Studies included in
meta-analyses
(n=30)
Total
(n=8228)
Duplicate Records
excluded
(n=2030)
Records
identified from
databases
(n=8134)

• Baseline risk of Early Onset GBS with maternal
GBS colonisation
• no IAP policy  1.1% risk (95% CI, 0.7%–
1.6%)
• Risk of Early Onset GBS by estimated coverage
of IAP for GBS colonised mothers
• 40% coverage  0.9 % risk (0.4-1.5)
• 80% coverage  0.3 % risk (0-0.9)
• Baseline risk is likely underestimated
• low case ascertainment/exposure misclassification/etc
• Other factors affecting risk of Early Onset GBS
less well understood
Risk of Early Onset GBS from maternal GBS colonisation
and variation with Intrapartum Antibiotic Prophylaxis (IAP)
80%
0.3

What is new?
• Input data
• At least doubled volume and geographic spread of inputs
• Addresses identifiable, predictable biases e.g. swab type, culture enhancement
• Results on colonisation
• Prevalence fairly consistent globally 18%, but slightly lower in Asia (11%)
• Prevalence of Early-onset disease decreases as coverage of IAP increases, but not
possible to reduce to zero
• Serotypes
• Globally 98% serotypes Ia/Ib, II, III, V  informing vaccine design
• Asia  higher prevalence of other serotypes VI-X, lower III
More research needed especially on the “Asian” conundrum

#GBSburden #momandbaby @A_Seale
Group B Streptococcus worldwide burden for
pregnant women, stillbirths and children
Dr Anna Seale

Aims and approach
1. Estimate national, regional, worldwide burden
• Pregnant women colonised, infants with GBS disease,
deaths and disability
• Maternal GBS disease
• Stillbirths with GBS disease
• Preterm birth attributed to maternal GBS colonisation
2. Describe GBS serotypes
• Colonizing pregnant women
• Causing stillbirths
• Causing neonatal/infant invasive disease
3. Estimate cases preventable by
• Intrapartum Antibiotics (IAP)
• Maternal GBS vaccination
Four step
compartmental
model
1 2 3
4

Seale AC et al Clinical Infectious Diseases. 2017;65(S2):S200-19
Step 1. Newborns exposed to maternal GBS colonisation
• 140 million live births in
2015
• Prevalence of GBS
maternal colonisation
• adjusted for sensitivity of
detection
• applied by country where
data were sufficient, or
sub-regions (11.1%-34.7%)
21.3 million newborns exposed to GBS

Step 2. Infant cases of GBS
• 21.3 million newborns
exposed at birth
• Risk of early onset GBS
disease for IAP context (0.3-
1.1% depending on policy and
implementation)
• Ratio of early to late onset
GBS disease applied by
region (highest in Asia, 5.99,
lowest in Africa, 1.02)
205,000 (101,00-327,000) early infant GBS cases
114,000 (44,000-326,000) late infant GBS cases

• Cases of GBS higher in
compartmental model
compared to cases reported
• Discrepancies most notable in
Asia
• May in part be low case
ascertainment
• Wide uncertainty in all
regions, but uncertainty for
incidence data may be under-
represented
Comparing infant cases from model to incidence data
Geographic and Outcome data gaps

Step 3. Infant deaths of GBS
• 319,000 cases of infant
GBS disease
• Case fatality risks for
regions applied
according to whether
• early onset GBS disease
born without skilled birth
attendance (90%)
• early onset GBS disease
born with skilled birth
attendance (5%-27%)
• late onset GBS disease
(4%-12%)
90,000 (36,000-169,000) deaths in infants <3 months of age in 2015

‘Iceberg’ of data on
neurodevelopmental outcomes
Kohli-Lynch, et al Clinical Infectious Diseases. 2017;65(S2):S190-99
Moderate/severe
Neurodevelopmental
impairment after infant
GBS meningitis
and GBS sepsis
Survivors of infant
GBS meningitis and GBS sepsis
Cases of infant
GBS disease
Lack of cohorts and lack of
consistent case
definitions, tools & timing
• 229,000 survivors of infant
GBS disease with
• Sepsis: 171,000
• Meningitis: 58,000
• Risk of neurodevelopmental
impairment after
• Sepsis: not able to quantify
• Meningitis: 18% moderate/severe
NDI at 18 months
10,000 infants (3000-27,000) minimum moderate-severe neurodevelopment impairment after
GBS meningitis, and unknown after GBS sepsis
Step 4. Neurodevelopmental impairment after GBS

[1,2]
[0,1]
No data
Maternal GBS disease
• Input data on GBS
• Data limited, mostly developed countries
• GBS incidence low in developed region (0.38 per 1,000 pregnancies)
• Case estimation
• Applied developed incidence worldwide
Hall J, et al Clinical Infectious Diseases. 2017;65(S2):S112-24
Geographic distribution of data on maternal GBS disease
• Case fatality risk with GBS
• 0.2% for pregnant and postpartum
women
• 2.2% for newborns born to women
with maternal GBS sepsis
• Mortality for women not estimated here
but sepsis is third leading cause of
maternal deaths worldwide
CASES: 33,000 (13,000-52,000) pregnant and post-partum women – very conservative

4% of stillbirths may be associated with GBS
1% of stillbirths may be associated with GBS
Stillbirths with GBS disease
• Data limited, none from Asia
• GBS associated stillbirth
• Developed ~1%
• Africa ~4%
• Case estimation
• Percentage of GBS-associated
stillbirth applied to national
number of stillbirths
• Where no data, applied
developed countries ~1% (very
conservative)
Seale AC, et al Clinical Infectious Diseases. 2017;65(S2):S125-32
Proportion of GBS–associated stillbirth for regions
DEATHS: 57,000 stillbirths – very conservative

Geographic distribution of data on maternal GBS colonisation and preterm birth
Preterm Birth associated with maternal GBS colonisation
Bianchi-Jassir F, et al Clinical Infectious Diseases. 2017;65(S2):S133-42
• Data from 23 countries
• Cohort/cross-sectional studies
21% increased risk
• Case-control studies 85%
increased risk
• Case estimation
• Preterm births attributable to
GBS based on population
attributable fraction, given
prevalence of maternal GBS
colonization
Up to 3.5 million preterm births may be attributable to GBS,
but insufficient evidence to quantify

Neonatal Encephalopathy with GBS worldwide
• Data from 4 published & 25
unpublished datasets, total of
10,436 infants with NE
• 0.58% NE cases with GBS (0.18-
0.98%)
• Incidence = 0.019/1000 live births
(0.019-0.02) in UK
• Higher risk of mortality:
Mortality for GBS-associated
NE 20% vs.13.4% for NE alone
RR: 2.07 (1.47-2.91)
WHAT’S NEXT?
• Published data are lacking
• Infants with NE >10 times more likely to be affected by invasive
GBS than term infants without NE
• GBS infection contributes to global burden of NE
Geographic distribution of data on neonatal encephalopathy & GBS

Cases of GBS in pregnant women, fetus, and infants
worldwide
Developed countries
Caribbean
Central America
South America
Western Africa
Northern Africa
Middle Africa
Eastern Africa
Southern Africa
Western Asia
Central Asia
Southern Asia
Eastern Asia
South-eastern Asia
Oceania
Latin America
N=24,000
(6,000-37,000)
Africa
N=220,000
(63,000-265,000)
Asia
N=143,000
(70,000-230,000)
Developed
N=20,000
(5,000-37,000)
Oceania
N=500
(300-800)
CASES: 319,000 infants; 33,000 pregnant and postpartum women; 57,000 fetus

Developed countries
Caribbean
Central America
South America
Western Africa
Northern Africa
Middle Africa
Eastern Africa
Southern Africa
Western Asia
Central Asia
Southern Asia
Eastern Asia
South-eastern Asia
Oceania
Deaths from GBS: stillbirths and infants worldwide
Latin America
N=5,000
(1,000-12,000)
Asia
N=45,000
(14,000-90,000)
Developed
N=1,000
(0-3,000)
Oceania
N=200
(0-2,800)Africa
N=96,000
(33,000-169,400)
DEATHS: 90,000 infants (mostly neonatal); 57,000 stillbirths

• Data and methods
• Double previous data but waterfall: most for colonisation, least for disability
• Includes outcomes for pregnant and post-partum women, stillbirth, infants, and later disability
• Compartmental model is appropriate given available data, but all models have limitations
• Burden
• Cases: 319,000 infants, 57,000 fetus, 33,000 pregnant or post-partum women
• Deaths: 57,000 stillbirths and 90,000 infants
• Disability: >10,000 new cases of neurodevelopmental impairment each year
• Highest burden is in sub-Saharan Africa
• Priority data gaps
• Geographic: particularly Asia
• Outcomes: stillbirth, disability, preterm birth, neonatal encephalopathy and maternal disease
What is new?

Maternal Group B Streptococcus vaccination:
progress and priorities
Dr Ajoke Sobanjo-ter Meulen
Bill & Melinda Gates Foundation

Deaths from GBS compared to other maternal infections or non-immunity
DISEASE
OUTCOMES PER YEAR
Stillbirths
Number of neonatal or other deaths related
to maternal infection or non-immunity
Number of neonatal/
infant cases
Group B Streptococcus 57,000
(12,000- 103,000)
90,000a
(36,000- 169,000)
319,000
(119,000- 417,000)
Pertussis NA 2,700c NA
Syphilis 200,000 62,000c 102,000
Tetanus NA 34,000
(18,000- 84,000) c
NA
HIV/AIDS 9,000 86,000
(76,000- 101,000) d
NA
Malaria 213,000 NA NA
a Young infants (0-89 days) b Infants 0-6 months c Neonates (0-27 days) d Children <5 years of age but due to mother-to-child transmission. NA relevant estimate available
GBS accounts for 57,000 stillbirths and 90,000 infant deaths,
more than the total number of deaths from mother-to child transmission of HIV,
or more than the combined neonatal deaths from tetanus, and pertussis

Why pursue a maternal GBS vaccine?
Executive summary for GBS Burden
Could be prevented
by IAP
Could be prevented by
maternal GBS vaccine
1. Higher impact than IAP as affects more outcomes
2. Higher coverage especially in challenging settings  more equitable than IAP
3. Leverage existing programmatic platforms (e.g. antenatal care)
4. Reduce antibiotic exposure (21.7 million women)
Could be prevented
by IAP
Could be prevented by
maternal GBS vaccine

© Bill & Melinda Gates Foundation | 43
GBS membrane vesicles discovered which cause
preterm birth and infant death in mice
Surve et al. PLoS Pathog, 2016, 12(9): e1005816 PBS=phosphate buffered saline, MVs=membrane vesicles, IUFD=intrauterine fetal death

Intrapartum Antibiotic Prophylaxis (IAP) Reduces Early-Onset Disease (EOD), but
Does Not Prevent Late-Onset-Disease (LOD)
Rate of Early- and Late-Onset GBS, US 1990-2008*
Early-onset GBS
Late-onset GBS
IAP effectiveness
continues to plateau
in 2016*
Before national prevention policy Transition Universal screening
*CDC Active Bacterial Core surveillance / Emerging Infections Program
~80% reduction of
early-onset disease
~30% of pregnant women
receive antibiotics

How many GBS deaths could be prevented?
Not estimated
Current approach (IAP) prevents 29 000 (UR, 0–51 ]000) early onset GBS cases
A maternal vaccination could prevent 231 000 (UR, 114 000–507 000) infant and maternal GBS cases,
41 000 (UR, 8000–75 000) stillbirths, 66 000 (UR, 12 000–123 000) infant deaths

Do GBS serotypes differ between colonisation and disease?
Maternal colonisation 28%
Maternal GBS disease 29%
Early Onset GBS 48%
Late Onset GBS 74%
Seale AC et al Clinical Infectious Diseases. 2017;65(S2): S200-19
Serotypes I-V = 98% globally
Serotypes III = dominant

Vaccines targeting disease-associated bacterial antigens can reduce severe
disease and clones associated with antimicrobial resistance
Acquisition of Tetracycline resistance (TcR) led to expansion of hypervirulent CC17 clones followed by the
emergence of neonatal GBS disease in the 1960s1
1Da Cunha V, Nat comm 2017; 2Almeida A, msystems ASM 2017
- In HIC ~32% of pregnant
women receive intrapartum antibiotics
(Penicillin) to protect their newborn infants
against GBS disease
- Emerging resistance to second-line antibiotics
Presence of CC17 correlates with cases of LOD
and meningitis2
GBS glyco-conjugate vaccine targeting CC17 isolates (Type III and IV)
Decreased use of antibiotics and less severe disease
Severe GBS diseasePotential resistance

Baker et al. (USA) J Infect Dis 2014 Dangor Z et al. (South Africa) Vaccine 2015
Need for Standardized Immunology Assays to Establish Correlate of
Protection Against Invasive GBS disease

GBS vaccine development pipeline
http://www.who.int/immunization/research/development/ppc_groupb_strepvaccines/en/
Seale AC et al Clinical Infectious Diseases. 2017;65(S2): S200-19

MI COMPLEMENTS EXISTING VACCINES AND INTERVENTIONS1 IN
THE CONTINUUM OF MOTHER-INFANT CARE
MI could be a key
component of the
continuum of care
Vulnerability zone
(up to 3 months)
Too early for childhood vaccines
Continuum of care
Obstetric, childbirth, and essential newborn care
Clean birth
In-facility and community ANC
Neonatal sepsis prevention and treatment
Pregnancy home visit
Pregnancy Infant
Childhood vaccines / EPI
6 wksBirth 10 wks 14 wks
Protection from maternal immunization
MI may provide
protection until
childhood vaccines
Early and late postnatal care for mother and newborn
Care of newborn, infant and child
GBS
RSV
Tetanus
1. Maternal Newborn Child Health; Source: Every Newborn: An action plan to end preventable deaths (2013).

Where do we go from here?
Focus area Activity
Vaccine development - Assay standardization
- Validate path to licensure
Evidence Generation - CHAMPS network
- Neonatal Cause-of-Death studies
- Disease burden modeling
- Whole genome sequencing
Economic analysis - WHO global value proposition, with LSHTM
- Cost-effectiveness modeling
Policy, guidance and
norms
- WHO Preferred Product Characteristics and technical R&D
roadmap
- Support for WHO activities to facilitate GBS vaccine development,
licensure, and prequalification with a focus on LMIC
Delivery/Integration
in antenatal care
- Standardization of pregnancy vigilance
- MNCH stakeholder engagement
Focus area Activity
Improved data on the
burden
- Neonatal and stillbirth cause-of-death studies
eg CHAMPS network
- Cohort studies for impairment outcomes
- Whole genome sequencing
Value proposition - Global value proposition, WHO
- Additional burden and Cost-effectiveness modeling with LSHTM
Vaccine development - Assay standardization
- Validate path to licensure
Policy, guidance and
norms
- WHO Preferred Product Characteristics, technical R&D roadmap
- Support for WHO activities to facilitate GBS vaccine development,
licensure, and prequalification with a focus on LMIC
Delivery/Integration
in antenatal care
- Improved pregnancy vigilance
- MNCH stakeholder engagement

Overview presentation: The Burden of Group B Streptococcus Worldwide for Pregnant Women, Stillbirths and Children: 1st International Symposium on ‘Streptococcus agalactiae’ Disease (Clinical Infectious Diseases, revised April 2018)

Overview presentation: The Burden of Group B Streptococcus Worldwide for Pregnant Women, Stillbirths and Children: 1st International Symposium on ‘Streptococcus agalactiae’ Disease (Clinical Infectious Diseases, revised April 2018)

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Overview presentation: The Burden of Group B Streptococcus Worldwide for Pregnant Women, Stillbirths and Children: 1st International Symposium on ‘Streptococcus agalactiae’ Disease (Clinical Infectious Diseases, revised April 2018)

Similar to Overview presentation: The Burden of Group B Streptococcus Worldwide for Pregnant Women, Stillbirths and Children: 1st International Symposium on ‘Streptococcus agalactiae’ Disease (Clinical Infectious Diseases, revised April 2018) (20)

Recently uploaded

Recently uploaded (20)

Overview presentation: The Burden of Group B Streptococcus Worldwide for Pregnant Women, Stillbirths and Children: 1st International Symposium on ‘Streptococcus agalactiae’ Disease (Clinical Infectious Diseases, revised April 2018)

Editor's Notes