Streptococcus Pyogenes

CAMPUS INNENSTADT

KINDERKLINIK UND KINDERPOLIKLINIK IM DR. V. HAUNERSCHEN KINDERSPITAL

STREPTOCOCCI AND ENTEROCOCCI: THE ENEMY WITHIN

Prof. Dr. med. Johannes Huebner Abteilung für Pädiatrische Infektiologie v. Hauner´sche Kinderklinik, Ludwigs-Maximilian Universität München

• Streptococcus pneumoniae

• Streptococcus pyogenes

• Streptococcus agalactiae © by author • Enterococcus faecalis and Enterococcus faecium ESCMID Online Lecture Library • oral streptococci "Poster Child" Pneumococcus

• A successful vaccine will likely be based on polysaccharide- conjugates • Large numbers of serotypes are not a problem due to technological advances with multiple polysaccharide-protein conjugates • clinically extremely useful • economically very successful© by author • "enemy within" –ESCMIDpneumococci are Online part of the normalLecture upper respiratory Library tract flora – complete elimination from mucosal surfaces difficult – prevention of "invasion" and systemic spread Streptococcus pyogenes

• Not really a problem with regards to antibiotic resistance – Penicillin G works still fine • GAS pharyngitis is the most common disease • Serious sequalae are quite uncommon in Europe, but much more common elsewhere© -by about author 500,000 death per year world-wide • Vaccine target antigen should not be crESCMIDoss-reactive with Online host antigens Lecture – Library development of rheumatic fever !!

Carapetis JR, Steer AC, Mulholland EK, Weber M. 2005. Lancet Infect Dis 5:685–694. Streptococcus pyogenes

• Antibodies against N-terminal region of M protein are opsonic, bactericidal and protective • sProtection type i -specific (M-typing or emm-genotyping) • M-type-specific IgG persist for up to 30 years • A 26-valent M-protein vaccine© by has author been tested in Phase I and II trials and would protect against 80-90% of US isolates • > ESCMID150 emm types, emergenceOnline of Lecturenew Library types is probably a frequent event

Lancefield RC. J Immunol 1962; 89:307–313. Problems with GAS Vaccine

• M protein extremely variable • 26-valent M-protein vaccine good in the US but not in the developing world • Safety concerns because M protein seems to ©be bycross author- reactive with host tissue • SeveralESCMID promising Online non- MLecture Library protein targets are currently studied Streptococcus agalactiae

• About 20-30% pregnant women colonized with GBS • Perinatal transmission can lead to early- or late-onset infection in neonates • Lethality of neonatal GBS infection has dropped from 20- 50% in the '70 to about 5% in recent years • Nowadays about 2/3 of systemic GBS infections occur in adults • 10 different serotypes© of by GBS author exist and sero-distribution is geographical • ESCMIDPenicillin or ampicillin Online during Lecture birth (IPA) successfully Library prevents early-onset infection in neonates • Implementation of guidelines for intra-partum antibiotics resulted in a significant decline in incidence Streptococcus agalactiae

• Group B streptococcal sepsis in neonates is associated with low maternal antibodies to type-specific capsular polysaccharides • Immunogenicity of unconjugated type Ia, II, and III polysaccharides was variable in non- immune adults • Type Ia, Ib, II, III© a ndby V author polysaccharide covalently linked to tetanus toxoid is save and ESCMIDimmunogenic Online, and the Lecture antibodies Libraryelicited are functional and protective in vitro and in vivo. Streptococcus agalactiae

• A type III polysaccharide–tetanus toxoid conjugate vaccine has been administered to healthy women in the third trimester • Capsular polysaccharide–specific IgG was transferred transplacentally and functional in vitro through the first 2 months of life in infants • This would prevent© notby only author early-onset sepsis, but also late-onset sepsis •ESCMIDA type V polysaccharide Online Lecture–tetanus toxoid Library conjugate vaccine was safe and immunogenic in healthy adults > 65 years Problems with GBS Vaccine

• IPA strategies very successful • Serotypes are geographically diverse • Early preemptive antibiotic therapy in neonates • "Unease" regarding© by vaccination author of pregnant women • ESCMIDTarget population Online for vaccine Lecture Library unclear Enterococcus faecalis and Enterococcus faecium: the Good, the Bad, and The Ugly

physiologic opportunistic world-wide spread of commensal pathogen VRE

Lipoteichoic Acid as Vaccine Target

• antibodies against purified LTA from E. faecalis HO R O 12030 O P O OH R OCH O n 2 O P O OH HO • mouse- sepsis model with bacterial colony O OH O O HO HO O counts from liver, spleen, and kidney O O O R1 O OH O R2 • statistically significant reduction:  active immunization with purified LTA  passive immunization  therapeutic application© of serumby upauthor to 4 days after bacterial challenge ESCMID protection against Online some E. faecium Lecture Library • serum against enterococcal LTA also active against other gram-positive bacteria

Huebner et al. (Infect Immun 2000), Theilacker et al. (Infect Immun 2006) E. faecalis Capsular Polysaccharide - DHG

Theilacker et al., PLoS ONE 2011 © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library New Paradigm for Vaccine Development

CLASSICAL

??? Basic LTA Structure of Gram-positive Pathogens

Gro GLc Glc P Gro E. faecalis, E. faecium, E. hirae Kojibiose Glc

Glc

Gro Glc Glc P Gro S. aureus,

Gentiobiose NAc- coag. neg. Staphylococci Glc

ESCMID OnlineP Gro Lecture Library Antibodies against E. faecalis LTA are cross- protective against several gram-positive pathogens

mouse sepsis model passive immunotherapy bacteria in blood

S. epidermidis M187 E. faecalis 12030 © by author Mouse peritonitis model passive immunotherapy ESCMID Online Lecture lethalityLibrary

S. aureus S. aureus MRSA ATCC SA113 Newman 4330 Theilacker et al., J Infect Dis 2012 205, 1076 LTA as conserved epitope for cross-reactive antibodies streptococci enterococci staphylococci Listeria

Hogendorf et al., Bioorganic & Medicinal Chemistry 18 (2010) 3668–3678 Opsonophagocytic Inhibition by WH6 and WH7

BSA

• Lipoteichoic acid – Effective against a subset of E. faecalis, E. faecium, streptococci, listeria and staphylococci – Synthetic LTA mimetic identified with activity comparable to native LTA • Type IV Secretion System Protein – Broadly cross-protective against several gram- positive species © by author • poly-N-acetyl glucosamine (PNAG, PIA) – S. aureus, S. epidermidis, streptococci, Listeria, ESCMIDmenigococci Online, N. gonorrhoae Lecture, Plasmodia, Library Trichomonas, Candida – Cywes-Bentely et al. PNAS (in press) What are the challenges ?

• Increasing antibiotic resistances • "The enemy within" – pathogen is normal commensal: consequence of "elimination" ? – (sometimes) low virulence • (Relatively) low incidence of disease − economically viable© ? by author − clinical studies possible ? • TargetESCMID patient pOnlineopulation Lecture Library – can immunocompromized patients be protected ? • Optimal vaccine targets