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Streptococcus Pyogenes : A global pathogen that needs a global vaccine
Academic Children’s Hospital Queen Fabiola, Brussels, Belgium Molecular Bacteriology Laboratory,
Free University of Brussels, Belgium
Anne Botteaux and Pierre Smeesters Belgium
500,000 deaths/year
Streptoccocus pyogenes Clinical outcomes
Pharyngitis
Invasive infections (Necrotising fasciitis) ‘flesh eating bacteria’
Impetigo
Wide spectrum of disease
Rheumatic Fever burden
No vaccine available
Wal
ker,
CMR,
201
4
Streptoccocus pyogenes The M protein
223 M proteins (emm-types) described worldwide
emm gene
M protein
Streptoccocus pyogenes The M protein : structure
Smee
ster
s, T
rend
s Mic
ro, 2
010
Smee
ster
s, E
xper
t Rev
iew
Vac
cine
, 200
9
Hypervariable region
aa c
onse
rvat
ion
A Repeats
B Repeats
C Repeats
D Repeats
Streptoccocus pyogenes The M protein : a key virulence factor
Smee
ster
s, T
rend
s Mic
ro, 2
010
Complement inhibitor (alternative pathway)
•Convertase inhibition?
•Steric hindrance to antibody binding?
Complement inhibitor (classic pathway)
Smee
ster
s, E
xper
t Rev
iew
Vac
cine
, 200
9
Streptoccocus pyogenes The M protein : a typing tool
Standard typing => 223 emm-types described so far
Beal
l, JC
M, 1
996
Fack
lam
, CID
, 200
2
Hypervariable region 50 aa
emm gene
Nucleotide Sequencing
emm-pattern
75 % emm-types Poorly characterized
Streptoccocus pyogenes The M protein
McM
illan
, CM
I, 20
13
Streptoccocus pyogenes The M protein : a vaccine candidate
Dale
, Vac
cine
, 201
1 Pa
ndey
, J. I
mm
, 201
3
Rebecca Lancefield
Wannamaker, Arch Dis Child, 1953
“immune protection against GAS is due to acquisition of type-specific antibodies”
Streptoccocus pyogenes M protein : a vaccine candidate
McN
eil e
t al.,
Clin
Infe
ct d
is. 2
005
Streptoccocus pyogenes M protein : a vaccine candidate
McN
eil e
t al.,
Clin
Infe
ct d
is. 2
005
26 emm types chosen from >223 known emm types: -Most common emm types assoc. with ARF -Most common emm types causing invasive GAS -Most common emm types causing pharyngitis
In high income settings
Streptoccocus pyogenes M protein : a vaccine candidate
What about the predicted coverage in low income settings where the burden of disease is greatest?
High diversity of emm-types in low incomes settings
Brussels, Belgium Brasília, Brazil
Smee
ster
s et a
l., P
los O
ne. 2
006
St
eer,
LID,
200
9 Sm
eest
ers,
ERV
, 200
9 Streptoccocus pyogenes
Diversity of emm-types
26-valent vaccine theoretical coverage in low incomes settings?
Streptoccocus pyogenes Diversity of emm-types
Smee
ster
s, E
RV, 2
009
Streptoccocus pyogenes Diversity of emm-types
Brazil Belgium
Two different emm-types do not always represent the same genetic differences...
Smee
ster
s, V
acci
ne, 2
008
Smee
ster
s, V
acci
ne, 2
010
• 31 countries • 1278 isolates • 175 emm-types
⇒ 78% of all emm-types
Systematic review of global emm distribution: 50,914 typable isolates included: 99.8% of them belong to these 175 emm-types
Streptoccocus pyogenes M protein multicentric survey
McM
illan
, CM
I, 20
13 –
Sm
eest
ers e
t al.,
in p
rep
Sand
erso
n-Sm
ithl,
JID, 2
014
HYPER-VARIABLE REGION
Basis of M/emm typing : > 220 M-types
Sequencing of the region encoding the 50 first aa
Sequencing of the entire emm genes
SOME DEGREE OF CONSERVATION
Basis of cluster typing : 48 M-clusters
2 clades (X and Y)
Streptoccocus pyogenes M protein multicentric survey
schu
lman
, CID
, 201
4 Sa
nder
son-
Smith
l, JID
, 201
4
A functional classification for Streptococcus pyogenes
Streptoccocus pyogenes The emm-clusters
Sand
erso
n-Sm
ithl,
JID, 2
014
?
emm-type
emm-cluster ?
Streptoccocus pyogenes The emm-clusters
Sand
erso
n-Sm
ithl,
JID, 2
014
Dale
et a
l, Va
ccin
e, 2
013
Unexplained cross-protection of the 30-valent vaccine
• New typing tool • Help to predict virulence • Framework for vaccine development
Streptoccocus pyogenes emm-clusters : a new tool
Group A Streptococcus classification 1950 1990 2014
M serotyping
emm Typing (PCR)
emm-cluster
(functional classification)
≈ 50 serotypes 223 emm-types 48 emm-clusters
Sanderson-Smith, JID, 2014 Baroux, CID, 2014 Shulman, CID, 2014 Smeesters, CID 2017
Beal, JCM, 1996 Facklam, CID 2002
Denny, JCI, 1957 Lancefield, JEM, 1959
Streptoccocus pyogenes emm-clusters : a new typing tool
• Prospective passive surveillance in New Caledonia • 1 January to 31 December 2012 • All GAS infections • 2 hospitals
Streptoccocus pyogenes emm-clusters : a new typing tool
Added value of the emm-cluster system in molecular epidemiological surveys
• emm-cluster typing identifies similarities across pacific countries
Streptoccocus pyogenes emm-clusters : a new typing tool
Baro
ux e
t al.,
201
4
• emm-cluster typing highlights the vaccine target priorities
Streptoccocus pyogenes emm-clusters : framework for vaccine development ?
Role of M-like protein?
In human biobank In controlled human challenge
In epidemiological surveys across the Asia-Pacific region
emm-cluster base for virulence and immunity against Streptococcus pyogenes ?
Streptoccocus pyogenes emm-clusters : future challenge
Anne Botteaux
Valerie Delforge Dalila Lakhloufi Kobenan Guy Wilfried
Molecular Bacteriology Lab
Mahendar Kadari
Hannah Frost
Pierre Smeesters
University of Melbourne Melbourne, Australia
University of Queensland Brisbane, Australia
Mark Walker
Andrew Steer Mark Davies
Jim Dale
University of Tennessee Memphis, USA University of Wollongong
Sydney, Australia Martina Sanderson-Smith
Pierre.Smeesters@huderf.be Anne.botteaux@ulb.ac.be
Chris Van Beneden Bernard Beall
Center for Disease Control Atlanta, USA
Molecular Bacteriology Laboratory, Free University of Brussels, Belgium
Anne Botteaux Mahendar Kadari Hannah Frost Dalila Lakhloufi Valerie Delforge Kobenan Guy Wilfried
Academic Children’s Hospital Queen Fabiola, Brussels, Belgium
Marine Rodesh Christina Karasthati Isabel Castroviejo Gabrielle de Crombrughe Bernard Wenderickx Julie N’Guyen
Laurence Van Melderen
Free University of Brussels, Brussels, Belgium
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