TY  - JOUR
AU  - D'Onofrio, Valentino
AU  - Santana, Ana Carolina
AU  - Pauwels, Marthe
AU  - Waerlop, Gwenn
AU  - Willems, Anthony
AU  - De Boever, Fien
AU  - Müller, Martin
AU  - Sehr, Peter
AU  - Waterboer, Tim
AU  - Leroux-Roels, Isabel
AU  - Sharma, Ashish A
AU  - Sékaly, Rafick Pierre
AU  - Leroux-Roels, Geert
TI  - AS04 drives superior cross-protective antibody response by increased NOTCH signaling of dendritic cells and proliferation of memory B cells.
JO  - Frontiers in immunology
VL  - 16
SN  - 1664-3224
CY  - Lausanne
PB  - Frontiers Media
M1  - DKFZ-2025-01680
SP  - 1623405
PY  - 2025
AB  - The Gardasil-4® vaccine targets HPV types 6, 11, 16 and 18 and is formulated with amorphous alum. Cervarix® targets HPV types 16 and 18 using AS04 (Al(OH)3 + TLR4 agonist MPL) to enhance immune response. Cervarix elicits higher cross-protection against other high-risk HPV types, likely mediated by AS04.To investigate mechanisms of cross-neutralizing potential, six monozygotic twins (12 females aged 9-13 years) were vaccinated with either Cervarix or Gardasil-4 (2 doses, 6 months apart). Serum neutralizing antibody titers against HPV 6,16,18,31,33,45,52, and 58 were assessed pre-vaccination and 7 days post-second dose. Multi-omic single cell RNA and ATAC sequencing of PBMCs was performed at the latter timepoint.Cervarix generated higher cross-neutralizing antibody titers than Gardasil-4. Higher frequencies of dendritic cells and memory B cells were observed. Gene Set Enrichment Analysis (GSEA) indicated enhanced pathways related to NOTCH2 signaling in DCs and cell cycling/RNA translation in B cells, correlating positively with cross-neutralizing antibody titers. Increased chromatin accessability in genes related to NOTCH signaling in cDC1 was also observed. Cervarix-vaccinated subjects showed increased DC-to-memory B signaling, through upregulation of NOTCH ligands. Engagement of NOTCH was associated to BCL2 expression in memory B cells, supporting an anti-apoptotic state.Increased DC signaling, including NOTCH, through AS04 in Cervarix supports cell survival and sustained RNA translation in memory B cells, 7 days post-vaccination. This may enhance adaptive immune cell maturation, providing a mechanism that can lead to improved cross-reactivity.
KW  - HPV vaccine (Other)
KW  - adjuvant (Other)
KW  - dendritic cells (Other)
KW  - immune response (Other)
KW  - memory B cell (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40808939
C2  - pmc:PMC12344523
DO  - DOI:10.3389/fimmu.2025.1623405
UR  - https://inrepo02.dkfz.de/record/303489
ER  -