Molecular adjuvant HMGB1 enhances anti-influenza immunity during DNA vaccination

P. Fagone, D. J. Shedlock, H. Bao, O. U. Kawalekar, J. Yan, D. Gupta, M. P. Morrow, A. Patel, G. P. Kobinger, K. Muthumani, D. B. Weiner

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

DNA-based vaccines, while highly immunogenic in mice, generate significantly weaker responses in primates. Therefore, current efforts are aimed at increasing their immunogenicity, which include optimizing the plasmid/gene, the vaccine formulation and method of delivery. For example, co-immunization with molecular adjuvants encoding an immunomodulatory protein has been shown to improve the antigen (Ag)-specific immune response. Thus, the incorporation of enhancing elements, such as these, may be particularly important in the influenza model in which high titered antibody (Ab) responses are critical for protection. In this regard, we compared the ability of plasmid-encoded high-mobility group box 1 protein (HMGB1), a novel cytokine in which we have previously mutated in order to increase DNA vaccine immunogenicity, with boost Ag-specific immune responses during DNA vaccination with influenza A/PR/8/34 nucleoprotein or the hemagglutinin of A novel H1N1/09. We show that the HMGB1 adjuvant is capable of enhancing adaptive effector and memory immune responses. Although Ag-specific antibodies were detected in all vaccinated animals, a greater neutralizing Ab response was associated with the HMGB1 adjuvant. Furthermore, these responses improved CD8 T-cell effector and memory responses and provided protection against a lethal mucosal influenza A/PR/8/34 challenge. Thus, co-immunization with HMGB1 has strong in vivo adjuvant activity during the development of immunity against plasmid-encoded Ag.

Original languageEnglish (US)
Pages (from-to)1070-1077
Number of pages8
JournalGene Therapy
Volume18
Issue number11
DOIs
StatePublished - Nov 2011
Externally publishedYes

Keywords

  • A/PR/8/34 viral challenge
  • Ag presentation
  • DNA vaccine
  • H1N1/09 (swine flu)
  • HMGB1
  • adaptive immunity

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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