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<p>Immune imprinting, in which prior antigenic exposures biases recall toward dominant epitopes, constrains the breadth and durability of influenza vaccine protection. Here we show that targeted variation across multiple hemagglutinin (HA) head sites (A, B, and D) between sequential A(H3N2) vaccines reprograms epitope hierarchy—redirecting recall toward conserved, subdominant head and stem epitopes. In a controlled ferret model mimicking imprinting-like recall in humans, antigenically distant priming accelerates neutralizing antibody induction, broadens reactivity, enhances cross-protection, and reduces viral shedding after drifted virus challenge. Epitope mapping and structural analysis confirms redirection toward conserved epitopes; single-cell transcriptomics and ELISpot assays reveal amplified germinal center B cell and Th1 responses. This “epitope hierarchy reshaping” links targeted antigenic variation to enhanced B cell competition, amplified T cell help, and improved viral control. This principle is likely applicable to vaccines against other rapidly evolving viruses where strong imprinting effects similarly limit immune breadth.</p>

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Epitope-spanning antigenic variation reprograms immunodominance and broadens immunity in sequential influenza vaccination

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月2日

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  • Xiu-Feng Wan,
  • Minhui Guan,
  • Pradeep Balamalaliyage,
  • Hanqiao Chen,
  • Kritika Prasai,
  • Ana Alcala,
  • John Driver,
  • Alicia K. Olivier,
  • Weihong Gu,
  • Christina Frymire,
  • De Darling Melany Carvalho Madrid,
  • Cheng Gao,
  • Chengcheng Wang,
  • Tao Li,
  • Wikanda Tunterak,
  • Qiongying Yang,
  • Ashwin Ramesh,
  • Muzaffar Ali,
  • David Smith,
  • Lei Li,
  • Andrea J. Sant,
  • Jun Hang,
  • Hang Xie,
  • Mingyi Zhou,
  • Yizhi Jane Tao

摘要

Immune imprinting, in which prior antigenic exposures biases recall toward dominant epitopes, constrains the breadth and durability of influenza vaccine protection. Here we show that targeted variation across multiple hemagglutinin (HA) head sites (A, B, and D) between sequential A(H3N2) vaccines reprograms epitope hierarchy—redirecting recall toward conserved, subdominant head and stem epitopes. In a controlled ferret model mimicking imprinting-like recall in humans, antigenically distant priming accelerates neutralizing antibody induction, broadens reactivity, enhances cross-protection, and reduces viral shedding after drifted virus challenge. Epitope mapping and structural analysis confirms redirection toward conserved epitopes; single-cell transcriptomics and ELISpot assays reveal amplified germinal center B cell and Th1 responses. This “epitope hierarchy reshaping” links targeted antigenic variation to enhanced B cell competition, amplified T cell help, and improved viral control. This principle is likely applicable to vaccines against other rapidly evolving viruses where strong imprinting effects similarly limit immune breadth.