Enhanced Staphylococcus aureus protection by uncoupling of the α-toxin-ADAM10 interaction during murine neonatal vaccination

Kelly L. Tomaszewski, Meagan Blanchard, Reuben Olaniyi, Hannah R. Brenton, Samantha Hayes, Farheen Fatma, Gaya K. Amarasinghe, Byoung-Kyu Cho, Young Ah Goo, Andrea C. DeDent, Stephanie A. Fritz and Juliane Bubeck Wardenburg ()
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Kelly L. Tomaszewski: Washington University School of Medicine
Meagan Blanchard: Washington University School of Medicine
Reuben Olaniyi: Washington University School of Medicine
Hannah R. Brenton: Washington University School of Medicine
Samantha Hayes: Washington University School of Medicine
Farheen Fatma: Washington University School of Medicine
Gaya K. Amarasinghe: Washington University School of Medicine
Byoung-Kyu Cho: Mass Spectrometry Technology Access Center at the McDonnell Genome Institute - Washington University School of Medicine
Young Ah Goo: Mass Spectrometry Technology Access Center at the McDonnell Genome Institute - Washington University School of Medicine
Andrea C. DeDent: The University of Chicago
Stephanie A. Fritz: Washington University School of Medicine
Juliane Bubeck Wardenburg: Washington University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Staphylococcus aureus remains a leading global cause of bacterial infection-associated mortality and has eluded prior vaccine development efforts. S. aureus α-toxin (Hla) is an essential virulence factor in disease, impairing the T cell response to infection. The anti-Hla antibody response is a correlate of human protective immunity. Here we observe that this response is limited early in human life and design a vaccine strategy to elicit immune protection against Hla in a neonatal mice. By targeted disruption of the interaction of Hla with its receptor ADAM10, we identify a vaccine antigen (HlaH35L/R66C/E70C, HlaHRE) that elicits an ~100-fold increase in the neutralizing anti-Hla response. Immunization with HlaHRE enhances the T follicular helper (TFH) cell response to S. aureus infection, correlating with the magnitude of the neutralizing anti-toxin response and disease protection. Furthermore, maternal HlaHRE immunization confers protection to offspring. Together, these findings illuminate a path for S. aureus vaccine development at the maternal-infant interface.

Date: 2024
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DOI: 10.1038/s41467-024-52714-7

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