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000303489 1001_ $$aD'Onofrio, Valentino$$b0
000303489 245__ $$aAS04 drives superior cross-protective antibody response by increased NOTCH signaling of dendritic cells and proliferation of memory B cells.
000303489 260__ $$aLausanne$$bFrontiers Media$$c2025
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000303489 520__ $$aThe Gardasil-4® vaccine targets HPV types 6, 11, 16 and 18 and is formulated with amorphous alum. Cervarix® targets HPV types 16 and 18 using AS04 (Al(OH)3 + TLR4 agonist MPL) to enhance immune response. Cervarix elicits higher cross-protection against other high-risk HPV types, likely mediated by AS04.To investigate mechanisms of cross-neutralizing potential, six monozygotic twins (12 females aged 9-13 years) were vaccinated with either Cervarix or Gardasil-4 (2 doses, 6 months apart). Serum neutralizing antibody titers against HPV 6,16,18,31,33,45,52, and 58 were assessed pre-vaccination and 7 days post-second dose. Multi-omic single cell RNA and ATAC sequencing of PBMCs was performed at the latter timepoint.Cervarix generated higher cross-neutralizing antibody titers than Gardasil-4. Higher frequencies of dendritic cells and memory B cells were observed. Gene Set Enrichment Analysis (GSEA) indicated enhanced pathways related to NOTCH2 signaling in DCs and cell cycling/RNA translation in B cells, correlating positively with cross-neutralizing antibody titers. Increased chromatin accessability in genes related to NOTCH signaling in cDC1 was also observed. Cervarix-vaccinated subjects showed increased DC-to-memory B signaling, through upregulation of NOTCH ligands. Engagement of NOTCH was associated to BCL2 expression in memory B cells, supporting an anti-apoptotic state.Increased DC signaling, including NOTCH, through AS04 in Cervarix supports cell survival and sustained RNA translation in memory B cells, 7 days post-vaccination. This may enhance adaptive immune cell maturation, providing a mechanism that can lead to improved cross-reactivity.
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000303489 650_7 $$2Other$$aHPV vaccine
000303489 650_7 $$2Other$$aadjuvant
000303489 650_7 $$2Other$$adendritic cells
000303489 650_7 $$2Other$$aimmune response
000303489 650_7 $$2Other$$amemory B cell
000303489 7001_ $$aSantana, Ana Carolina$$b1
000303489 7001_ $$aPauwels, Marthe$$b2
000303489 7001_ $$aWaerlop, Gwenn$$b3
000303489 7001_ $$aWillems, Anthony$$b4
000303489 7001_ $$aDe Boever, Fien$$b5
000303489 7001_ $$0P:(DE-He78)47d2c5b8ee00ab8a0c16e14137427579$$aMüller, Martin$$b6$$udkfz
000303489 7001_ $$aSehr, Peter$$b7
000303489 7001_ $$0P:(DE-He78)6b4ebb9791b983b5620c0caaf3468e30$$aWaterboer, Tim$$b8$$udkfz
000303489 7001_ $$aLeroux-Roels, Isabel$$b9
000303489 7001_ $$aSharma, Ashish A$$b10
000303489 7001_ $$aSékaly, Rafick Pierre$$b11
000303489 7001_ $$aLeroux-Roels, Geert$$b12
000303489 773__ $$0PERI:(DE-600)2606827-8$$a10.3389/fimmu.2025.1623405$$gVol. 16, p. 1623405$$p1623405$$tFrontiers in immunology$$v16$$x1664-3224$$y2025
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