1486 - Phylogenetic and alpha toxin variant analyses of Staphylococcus aureus strains isolated from patients during the SAATELLITE study

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Presenting Author(s)

David E. Tabor

Associate Principle Scientist
AstraZeneca
South San Francisco, California
Disclosure: AstraZeneca (Employee, Shareholder)

Co-Author(s)

CT

Christine Tkaczyk

Principal scientist
AstraZeneca BioPharmaceuticals R&D
Gaithersburg, Maryland
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
AT

Andrey Tovchigrechko

Principal Scientist
AstraZeneca
Gaithersburg, Maryland
Disclosure: AstraZeneca (Employee, Shareholder)KitePharma, a Gilead company (Employee, Shareholder)
BS

Bret R. Sellman

Director
AstraZeneca
Gaithersburg, Maryland
Disclosure: AstraZeneca (Employee, Shareholder)
MM

Michael McCarthy

Global Medicines Leader
AstraZeneca
Washington, District of Columbia
Disclosure: AstraZeneca (Employee)
PR

Pin Ren

Statistician
AstraZeneca
Gaithersburg, Maryland
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
KS

Kathryn Shoemaker

Senior Principal Statistician
Biometrics, Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA
Gaithersburg, Maryland
Disclosure: AstraZeneca (Employee)
HJ

Hasan S. Jafri

Senior Director, Clinical Development
AstraZeneca
Gaithersburg, Maryland
Disclosure: AstraZeneca (Employee)
BF

Bruno François

MD
CHU Limoges
Limoges, Limousin, France
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
Mark T. Esser

Phylogenetic and alpha toxin variant analyses of Staphylococcus aureus strains isolated from patient
AstraZeneca
Gaithersburg, Maryland
Disclosure: AstraZeneca (Employee)
JC

Jasmine Coppens

Dr
University of Antwerp
Wilrijk, Antwerpen, Belgium
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
LT

Leen Timbermont

Senior Researcher
University of Antwerp
Wilrijk, Antwerpen, Belgium
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
BX

Basil Xavier

Post doctoral researcher
University of Antwerp
Wilrijk, Antwerpen, Belgium
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
CL

Christine Lammens

Bcs
University Antwerp, Department of Medical Microbiology
Antwerp, Antwerpen, Belgium
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
HG

Herman Goossens

Professor
Vaccine & Infectious Disease Institute, University of Antwerp
Antwerp, Antwerpen, Belgium
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
SM

Surbhi Malhotra-Kumar

Prof
Universiteit Antwerpen
Wilrijk, Antwerpen, Belgium
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
AR

Alexey Ruzin

Principal Scientist
AstraZeneca
Gaithersburg, Maryland
Disclosure: AstraZeneca (Employee, Shareholder)

Background: Suvratoxumab is a human monoclonal antibody that neutralizes S. aureus (SA) alpha toxin (AT). SAATELLITE, a phase 2 study of the safety and efficacy of suvratoxumab for reducing the incidence of SA pneumonia (NCT02296320), was conducted within the consortium for Combatting Bacterial Resistance in Europe.

Methods: A total of 304 SA isolates (baseline, onset and last available isolates from suspected serious bacterial infections, SSBIs) collected from the lower respiratory tract samples from 165 subjects during SAATELLITE were subjected to whole genome sequencing.
AT gene (hla) sequences were translated and amino acid variation was identified in comparison to the reference SA USA300 FPR3757. Phylogenetic analysis, genomic annotation and ST analysis were performed.
AT expression in SA culture supernatants was performed by ELISA. Representative isolates with novel AT subtypes that had not been identified in previous studies were tested for hemolytic activity and suvratoxumab neutralizing activity.
Wilcoxon rank sum test and Fisher’s exact test were performed, respectively: a) to compare difference in baseline AT expression in relation to SA pneumonia incidence; b) to evaluate the association between occurrence of AT stop codons and incidence of SA pneumonia at baseline, as well as the association between occurrence of AT stop codons and treatment arms at post baseline.

Results: We identified a total of 44 sequence types (STs) and 21 unique AT subtypes, 7 of which have not been described previously. No substitutions were located in the suvratoxumab binding region and all novel AT subtypes displaying lytic activity were neutralized by suvratoxumab.
We detected stop codons Q113B and W205B in AT sequences in 53 and 2 SA isolates, respectively. We uncovered no significant associations of: 1) baseline AT expression with SA pneumonia incidence [p=0.967]; 2) occurrence of AT gene stop codon with either SA pneumonia incidence [p >0.999] or suvratoxumab treatment [p=0.103; lower frequency of stop codons in suvratoxumab arm versus placebo].

Conclusion: Our data indicated that: 1) suvratoxumab target region in (AT) remains conserved; 2) suvratoxumab is active against all AT variants identified to date; 3) suvratoxumab did not exert pressure on SA clinical isolates for selection of escape mutants.