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Acta biomaterialia2025; 203; 578-590; doi: 10.1016/j.actbio.2025.07.042

Equine influenza antigen-based particle vaccine protects mice against homologous and heterosubtypic viral challenges.

Abstract: Influenza virus is a common source of respiratory illness and poses a major public health burden globally. Significant efforts have been dedicated towards developing and deploying effective vaccines. However, since being licensed in 1945, influenza vaccines have made limited progress and still suffer from several limitations, including suboptimal efficacy against variants. In this work, we report on two influenza A polyanhydride particle- and pentablock copolymer-based vaccine formulations intended for intranasal or subcutaneous administration. These nanovaccines are based on a newly discovered equine influenza A H3N8 hemagglutinin antigen (A/equine/1/KY/91), A/HK/1/68 nucleoprotein antigen, and a small molecule adjuvant. When these nanovaccines were administered to naïve mice, both formulations induced robust humoral and cellular immune responses that were protective against lethal challenges with influenza A/HK/1/68 (H3N2) or A/PR/8/34 (H1N1). This protection was characterized by reduced viral load, reduced airway disruption, and preservation of weight post-infection. Further studies with immunization and challenge of CD8T cell depleted mice and passive serum transfer into recipient mice reinforced that the observed protection was due to a combination of both vaccine-induced antibody responses and CD8T cell immunity. These findings demonstrate that intranasal and subcutaneous polymeric particle-based vaccines based on potentially universal influenza antigens are effective and promising platforms for supra-seasonal influenza vaccines. STATEMENT OF SIGNIFICANCE: We designed two influenza virus vaccine formulations based on polyanhydride microparticles and pentablock copolymer micelles for intranasal and subcutaneous administration. The intranasal vaccine is based on polyanhydride microparticles while the subcutaneous vaccine contains both polyanhydride microparticles and pentablock copolymer micelles. Both vaccines contain a newly discovered equine influenza H3N8 hemagglutinin antigen, a nucleoprotein antigen, and an adjuvant. Both vaccines induced robust antibodies and cellular immune responses and protected mice upon lethal challenge. The use of CD8T cell depleted mice and passive transfer of sera from vaccinated mice to recipient mice reinforced that the protection was driven by vaccine-induced antibody and CD8T cell responses. These findings demonstrate that polymeric particle- and micelle-based vaccines are promising supra-seasonal influenza vaccines.
Copyright © 2025 Acta Materialia Inc. Published by Elsevier Inc. All rights reserved.
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Publication Date: 2025-07-22 PubMed ID: 40706783PubMed Central: PMC12798653DOI: 10.1016/j.actbio.2025.07.042Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Equine influenza antigen-based nanovaccines were developed and shown to provide effective protection against different strains of influenza virus in mice by inducing strong antibody and cellular immune responses.

Background and Rationale

  • Influenza virus causes widespread respiratory illness and poses a significant public health challenge worldwide.
  • Current influenza vaccines, licensed since 1945, have limited effectiveness, especially against emerging viral variants.
  • There is a need for improved influenza vaccines that provide broader and more durable immunity against multiple virus subtypes.

Vaccine Design and Formulations

  • Two vaccine formulations were created using nanotechnology platforms: polyanhydride microparticles and pentablock copolymer-based micelles.
  • The vaccines were designed for two administration routes: intranasal and subcutaneous.
  • Antigen components included:
    • A newly identified hemagglutinin (HA) antigen from equine influenza A H3N8 strain (A/equine/1/KY/91), representing a novel source potentially providing broader cross-reactivity.
    • Nucleoprotein (NP) antigen from influenza A/HK/1/68 (H3N2), a conserved viral protein important for cellular immunity.
    • A small molecule adjuvant to enhance immune response.
  • The intranasal vaccine utilized only polyanhydride microparticles, while the subcutaneous vaccine combined polyanhydride microparticles and pentablock copolymer micelles.

Immune Responses Elicited

  • Both vaccine formulations elicited strong humoral (antibody) responses in naïve mice.
  • Robust cellular immune responses were also induced, including activation of CD8+ T cells critical for viral clearance.

Protection Against Influenza Virus Challenges

  • Mice vaccinated with these formulations were challenged with lethal doses of influenza virus strains:
    • Influenza A/HK/1/68 (H3N2) – homologous strain.
    • Influenza A/PR/8/34 (H1N1) – heterosubtypic strain (different subtype).
  • Vaccinated mice exhibited:
    • Reduced viral loads in the respiratory tract.
    • Less damage and disruption in airway tissues.
    • Preserved body weight, indicating reduced illness severity.

Mechanisms of Protection

  • Protection was determined to rely on both antibody and cellular immunity:
    • Experiments depleting CD8+ T cells in vaccinated mice reduced protection, indicating the importance of T cell immunity.
    • Passive transfer of serum from vaccinated mice to naïve mice provided partial protection, highlighting the role of antibodies.
  • The combination of humoral and cellular immune responses contributed to broad protection against both matched and mismatched influenza virus strains.

Implications and Significance

  • This study demonstrates that polymeric particle-based vaccines, incorporating conserved and novel influenza antigens, are promising platforms for developing supra-seasonal (broadly protective and lasting) influenza vaccines.
  • Nanoparticle and micelle delivery platforms effectively enhance immune responses and allow for different routes of administration (intranasal and subcutaneous).
  • The use of the equine H3N8 hemagglutinin antigen may contribute to cross-protection and offers a new antigen source for vaccine design.
  • Overall, these vaccines could improve protection against evolving influenza virus variants and reduce the limitations of existing seasonal vaccines.

Cite This Article

APA
Siddoway AC, Van Zanten A, Verhoeven D, Wannemuehler MJ, Mallapragada SK, Narasimhan B. (2025). Equine influenza antigen-based particle vaccine protects mice against homologous and heterosubtypic viral challenges. Acta Biomater, 203, 578-590. https://doi.org/10.1016/j.actbio.2025.07.042

Publication

Acta biomaterialia
ISSN: 1878-7568
NlmUniqueID: 101233144
Country: England
Language: English
Volume: 203
Pages: 578-590
PII: S1742-7061(25)00539-2

Researcher Affiliations

Siddoway, A C
  • Department of Chemical & Biological Engineering, Iowa State University, Ames, IA 50011, USA; Nanovaccine Institute, Iowa State University, Ames, IA 50011, USA.
Van Zanten, A
  • Department of Chemical & Biological Engineering, Iowa State University, Ames, IA 50011, USA.
Verhoeven, D
  • Department of Veterinary Microbiology & Preventive Medicine, Iowa State University, Ames, IA 50011, USA; Nanovaccine Institute, Iowa State University, Ames, IA 50011, USA.
Wannemuehler, M J
  • Department of Veterinary Microbiology & Preventive Medicine, Iowa State University, Ames, IA 50011, USA; Nanovaccine Institute, Iowa State University, Ames, IA 50011, USA.
Mallapragada, S K
  • Department of Chemical & Biological Engineering, Iowa State University, Ames, IA 50011, USA; Nanovaccine Institute, Iowa State University, Ames, IA 50011, USA.
Narasimhan, B
  • Department of Chemical & Biological Engineering, Iowa State University, Ames, IA 50011, USA; Nanovaccine Institute, Iowa State University, Ames, IA 50011, USA. Electronic address: nbalaji@iastate.edu.

MeSH Terms

  • Animals
  • Influenza Vaccines / immunology
  • Influenza Vaccines / pharmacology
  • Orthomyxoviridae Infections / prevention & control
  • Orthomyxoviridae Infections / immunology
  • Horses
  • Mice
  • Female
  • Antigens, Viral / immunology
  • Mice, Inbred BALB C
  • Influenza A Virus, H3N8 Subtype / immunology
  • Influenza A Virus, H1N1 Subtype / immunology
  • Influenza A Virus, H3N2 Subtype / immunology

Grant Funding

  • R01 AI141196 / NIAID NIH HHS
  • R01 AI154458 / NIAID NIH HHS

Conflict of Interest Statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Balaji Narasimhan and Michael Wannemuehler are co-founders of ImmunoNanoMed Inc., a start-up with business interests in the development of particle-based vaccines against infectious diseases. Surya Mallapragada also has a financial interest in ImmunoNanoMed Inc. David Verhoeven is a co-founder of Syntherna.

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