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