TY - JOUR
T1 - Enhanced Staphylococcus aureus protection by uncoupling of the α-toxin-ADAM10 interaction during murine neonatal vaccination
AU - Tomaszewski, Kelly L.
AU - Blanchard, Meagan
AU - Olaniyi, Reuben
AU - Brenton, Hannah R.
AU - Hayes, Samantha
AU - Fatma, Farheen
AU - Amarasinghe, Gaya
AU - Cho, Byoungkyu
AU - Goo, Young Ah
AU - DeDent, Andrea C.
AU - Fritz, Stephanie
AU - Wardenburg, Juliane Bubeck
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85205973648&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-52714-7
DO - 10.1038/s41467-024-52714-7
M3 - Article
C2 - 39379345
AN - SCOPUS:85205973648
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 8702
ER -