Staphylococcus aureus Alpha-Toxin Is Conserved among Diverse Hospital Respiratory Isolates Collected from a Global Surveillance Study and Is Neutralized by Monoclonal Antibody MEDI4893.
Staphylococcus aureus infections lead to an array of illnesses ranging from mild skin infections to serious diseases, such endocarditis, osteomyelitis, and pneumonia. Alpha-toxin (Hla) is a pore-forming toxin, encoded by the hla gene, that is thought to play a key role in S. aureus pathogenesis. A monoclonal antibody targeting Hla, MEDI4893, is in clinical development for the prevention of S. aureus ventilator-associated pneumonia (VAP). The presence of the hla gene and Hla protein in 994 respiratory isolates collected from patients in 34 countries in Asia, Europe, the United States, Latin America, the Middle East, Africa, and Australia was determined. Hla levels were correlated with the geographic location, age of the subject, and length of stay in the hospital. hla gene sequence analysis was performed, and mutations were mapped to the Hla crystal structure. S. aureus supernatants containing Hla variants were tested for susceptibility or resistance to MEDI4893. The hla gene was present and Hla was expressed in 99.0% and 83.2% of the isolates, respectively, regardless of geographic region, hospital locale, or age of the subject. More methicillin-susceptible than methicillin-resistant isolates expressed Hla (86.9% versus 78.8%; P = 0.0007), and S. aureus isolates from pediatric patients expressed the largest amounts of Hla. Fifty-seven different Hla subtypes were identified, and 91% of the isolates encoded an Hla subtype that was neutralized by MED4893. This study demonstrates that Hla is conserved in diverse S. aureus isolates from around the world and is an attractive target for prophylactic monoclonal antibody (MAb) or vaccine development.
Applied Immunology and Microbiology, MedImmune LLC, Mountain View, California, USA tabord@medimmune.com.
David E
DE
Tabor
Statistical Sciences, MedImmune LLC, Gaithersburg, Maryland, USA.
Li
L
Yu
Applied Immunology and Microbiology, MedImmune LLC, Mountain View, California, USA.
Hoyin
H
Mok
Infectious Disease-Vaccine Research, MedImmune LLC, Gaithersburg, Maryland, USA.
Christine
C
Tkaczyk
Infectious Disease-Vaccine Research, MedImmune LLC, Gaithersburg, Maryland, USA.
Bret R
BR
Sellman
Clinical Pharmacology and DMPK, MedImmune LLC, Gaithersburg, Maryland, USA.
Yuling
Y
Wu
Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland, USA.
Vaheh
V
Oganesyan
Research Bioinformatics, MedImmune LLC, Cambridge, United Kingdom.
Tim
T
Slidel
Infectious Disease Clinical Research, MedImmune LLC, Gaithersburg, Maryland, USA.
Hasan
H
Jafri
Infectious Disease Innovative Medicines, MedImmune LLC, Gaithersburg, Maryland, USA.
Michael
M
McCarthy
Global Medicines Development, AstraZeneca, Waltham, Massachusetts, USA.
Patricia
P
Bradford
Infectious Disease Innovative Medicines, MedImmune LLC, Gaithersburg, Maryland, USA.
Mark T
MT
Esser
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D000080908:Broadly Neutralizing Antibodies; D002648:Child; D002675:Child, Preschool; D017124:Conserved Sequence; D062665:Epidemiological Monitoring; D005260:Female; D014943:Global Health; D006460:Hemolysin Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007902:Length of Stay / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D053717:Pneumonia, Ventilator-Associated / Q000453:epidemiology / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D011487:Protein Conformation; D017422:Sequence Analysis, DNA; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology / Q000473:pathology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D001427:Bacterial Toxins; D000080908:Broadly Neutralizing Antibodies; D006460:Hemolysin Proteins; C021091:staphylococcal alpha-toxin; C000600718:suvratoxumab