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@ARTICLE{DOnofrio:303489,
      author       = {V. D'Onofrio and A. C. Santana and M. Pauwels and G.
                      Waerlop and A. Willems and F. De Boever and M. Müller$^*$
                      and P. Sehr and T. Waterboer$^*$ and I. Leroux-Roels and A.
                      A. Sharma and R. P. Sékaly and G. Leroux-Roels},
      title        = {{AS}04 drives superior cross-protective antibody response
                      by increased {NOTCH} signaling of dendritic cells and
                      proliferation of memory {B} cells.},
      journal      = {Frontiers in immunology},
      volume       = {16},
      issn         = {1664-3224},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {DKFZ-2025-01680},
      pages        = {1623405},
      year         = {2025},
      abstract     = {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.},
      keywords     = {HPV vaccine (Other) / adjuvant (Other) / dendritic cells
                      (Other) / immune response (Other) / memory B cell (Other)},
      cin          = {D320},
      ddc          = {610},
      cid          = {I:(DE-He78)D320-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40808939},
      pmc          = {pmc:PMC12344523},
      doi          = {10.3389/fimmu.2025.1623405},
      url          = {https://inrepo02.dkfz.de/record/303489},
}