Paced immune activation by AS04 drives superior cross-protective antibody response in Cervarix 2918

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Abstract Description The Gardasil®-4 vaccine targets HPV type 6,11,16 and 18 and is formulated with AlHO9PS-3. Cervarix® targets HPV type 16 and 18 using AS04 (Al(OH)3 + TLR4 agonist MPL) to enhance immunogenicity and cross-protection against non-vaccine HPV types. To investigate mechanisms of cross-neutralizing potential, 6 monozygotic twins (F, 9-13 years) were vaccinated with either vaccine (2 doses, 6 months apart). Neutralizing antibody titers against HPV 6,16,18,31,33,45,52, and 58, and single cell RNA sequencing of PBMCs were performed 7 days post-second dose. Cross-neutralizing antibody titers and frequencies of plasmacytoid (pDC) and conventional dendritic cells (cDC1, cDC2), CD4+ T effector memory (Tem) and B memory cells were higher after Cervarix compared to Gardasil. Gene Set Enrichment Analysis showed enhanced cell migration in DCs and cell cycling in CD4+ T and B cells, correlating with cross-neutralizing antibody titers. Cervarix showed increased pDC-to-CD4+ Tem antigen presentation and NOTCH signaling. This induced FOS in CD4+ Tem cells and BCL2 in B memory cells, supporting proliferative and anti-apoptotic states leading to T cell memory development. AS04 appears to facilitate pDC migration and better antigen presentation. This results in delayed activation and sustained proliferation of adaptive immune cells at day 7, relying more on memory T and B cells. A paced immune activation may enhance adaptive immune cell maturation, providing a mechanism for improved cross-reactivity. Funding Sources Valentino D’Onofrio has received a travel grant (V476023N) from FWO (Flanders Research Foundation) for his stay at Emory University in 2024 to conduct the resaerch presented in this work. Topic Categories Vaccines and Immunotherapy (VAC)

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