{
  "abstract": "Seasonal influenza vaccination only elicits a strong and durable antibody response in a subset of recipients, and prior homologous booster trials have failed to improve on single-dose vaccination. Here, we conducted a phase 4 clinical trial to test if a heterologous prime-boost increases antibody magnitude or breadth as well as reduces the rate of non-responders (ClinicalTrials.gov ID# NCT06567860). Participants received a late-season 2023 inactivated influenza vaccine followed by the 2024 booster four months later containing an updated H3N2 strain alongside unchanged H1N1 and B/Victoria strains, allowing within-subject comparison of heterologous and homologous boosting. The booster vaccination halted or reversed antibody titer waning for all vaccine strains, most notably restoring seroprotective and seroconverting titers for B/Victoria at the cohort-level. Critically, the heterologous booster decreased the rate of non-responders (exhibiting HAI[≤]10 at all time points), with 0% H3N2 non-responders among subjects receiving the prime and boost compared to 29% H1N1 non-responders. A similar pattern held in a larger cohort administering consecutive fall vaccinations, where non-response rate was 20% of H3N2 compared to 37% for H1N1. Across all non-responders that had consistently low titers against the vaccine strains, up to half elicited an antibody response against historical variants, suggesting that immune imprinting partially underlies the non-responder phenotype. Despite differing vaccination timing, late-season priming and standard fall vaccination produced comparable antibody breadth 30 days post-vaccination when cohorts were matched on pre-vaccination titers. These findings suggest that heterologous vaccinations or other multi-strain exposures can reduce the fraction of the population that does not mount an antibody response during an influenza season.",
  "abstract_shown": true,
  "affiliations": [
    "La Jolla Institute for Immunology"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 3,
  "authors": [
    {
      "name": "S. Orsinelli-Rivers"
    },
    {
      "name": "T. M. Ross"
    },
    {
      "affs": [
        0
      ],
      "name": "T. Einav"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6e62v2y4nyc26.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.28.26366744",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.10.28.26366744v1.full",
  "id": "6e62v2y4nyc26",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.10.28.26366744v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "infectious diseases"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.10.28.26366744v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-28",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/6e62v2y4nyc26.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T00:20:43Z",
      "native_id": "10.64898/2026.10.28.26366744",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.10.28.26366744v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:infectious diseases",
      "subfield": "infectious-disease"
    }
  ],
  "title": "More Shots on Goal: Heterologous Influenza Prime-Boost Vaccination Decreases the Likelihood of a Negligible Antibody Response to Current or Historical Variants",
  "title_text": "More Shots on Goal: Heterologous Influenza Prime-Boost Vaccination Decreases the Likelihood of a Negligible Antibody Response to Current or Historical Variants",
  "type": "preprint",
  "updated_at": "2026-11-01T00:20:31Z",
  "url": "https://research.draconitic.com/paper/6e62v2y4nyc26",
  "venue": "medRxiv",
  "versions": []
}