Epitope-spanning antigenic variation reprograms immunodominance and broadens immunity in sequential influenza vaccination
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.
Authors
- John P. Driver (ORCID: https://orcid.org/0000-0002-6714-3335)
- Kritika Prasai
- Ashwin Ramesh (ORCID: https://orcid.org/0000-0002-4009-6823)
- Yizhi Jane Tao (ORCID: https://orcid.org/0000-0002-0149-2241)
- Cheng Gao (ORCID: https://orcid.org/0000-0002-2182-0804)
- David R. Smith (ORCID: https://orcid.org/0000-0002-4832-6208)
- Wikanda Tunterak
- Jun Hang (ORCID: https://orcid.org/0000-0002-6597-7045)
- Alicia K. Olivier (ORCID: https://orcid.org/0000-0002-6987-0720)
- Mingyi Zhou (ORCID: https://orcid.org/0000-0003-3514-0372)
- Minhui Guan (ORCID: https://orcid.org/0000-0003-3442-1068)
- Hanqiao Chen (ORCID: https://orcid.org/0000-0003-1764-303X)
- Chengcheng Wang
- Lei Li (ORCID: https://orcid.org/0000-0001-8723-3461)
- Hang Xie (ORCID: https://orcid.org/0000-0002-0642-204X)
- Muzaffar Ali (ORCID: https://orcid.org/0000-0002-7582-4800)
- Andrea Sant
- Pradeep Balamalaliyage
- Xiu-Feng Wan
- De Darling Melany Carvalho Madrid
- Weihong Gu
- Ana Alcala
- Tao Li
- Christina Frymire
- Qiongying Yang
Institutions
- Center for Biologics Evaluation and Research (US)
- United States Food and Drug Administration (US)
- Georgia State University (US)
- Missouri College (US)
- University of Rochester (US)
- Rice University (US)
- University of Missouri (US)
- Walter Reed Army Institute of Research (US)
- Mississippi State University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-03-02
- DOI
- https://doi.org/10.1038/s41467-026-70202-y
- Primary Topic
- Immune responses and vaccinations
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- National Institutes of Health