@article{01K1Z65V8PHD1S1PK0WTVC58WD,
  abstract     = {{Introduction: 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.

Methods: 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.

Results: 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.

Conclusion: 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.}},
  articleno    = {{1623405}},
  author       = {{D'Onofrio, Valentino and Santana, Ana Carolina and Pauwels, Marthe and Waerlop, Gwenn and Willems, Anthony and De Boever, Fien and Müller, Martin and Sehr, Peter and Waterboer, Tim and Leroux-Roels, Isabel and Sharma, Ashish A. and Sékaly, Rafick Pierre and Leroux-Roels, Geert}},
  issn         = {{1664-3224}},
  journal      = {{FRONTIERS IN IMMUNOLOGY}},
  keywords     = {{HPV vaccine,adjuvant,immune response,dendritic cells,memory B cell,CERVICAL-CANCER,HPV TYPES,VACCINE,IMMUNOGENICITY,CERVARIX(R),PREVENTION,EFFICACY,LESIONS,SAFETY}},
  language     = {{eng}},
  pages        = {{18}},
  title        = {{AS04 drives superior cross-protective antibody response by increased NOTCH signaling of dendritic cells and proliferation of memory B cells}},
  url          = {{http://doi.org/10.3389/fimmu.2025.1623405}},
  volume       = {{16}},
  year         = {{2025}},
}

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