%0 Journal Article
%A D'Onofrio, Valentino
%A Santana, Ana Carolina
%A Pauwels, Marthe
%A Waerlop, Gwenn
%A Willems, Anthony
%A De Boever, Fien
%A Müller, Martin
%A Sehr, Peter
%A Waterboer, Tim
%A Leroux-Roels, Isabel
%A Sharma, Ashish A
%A Sékaly, Rafick Pierre
%A Leroux-Roels, Geert
%T AS04 drives superior cross-protective antibody response by increased NOTCH signaling of dendritic cells and proliferation of memory B cells.
%J Frontiers in immunology
%V 16
%@ 1664-3224
%C Lausanne
%I Frontiers Media
%M DKFZ-2025-01680
%P 1623405
%D 2025
%X 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.
%K HPV vaccine (Other)
%K adjuvant (Other)
%K dendritic cells (Other)
%K immune response (Other)
%K memory B cell (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40808939
%2 pmc:PMC12344523
%R 10.3389/fimmu.2025.1623405
%U https://inrepo02.dkfz.de/record/303489