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Molecular adjuvant HMGB1 enhances anti-influenza immunity during DNA vaccination

Gene Therapy volume 18, pages 1070–1077 (2011)Cite this article

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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.

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Acknowledgements

We thank the University of Pennsylvania, Department of Pathology Histology Core and Daniel Martinez for their help with immunohistochemical analyses. We also acknowledge Dr Niranjan Y Sardesai and Dr J Joseph Kim from Inovio Pharmaceuticals, PA, for their research expertize. This research was supported by the Inovio Pharmaceuticals, PA, under a collaborative research and development agreement with University of Pennsylvania (KM and DBW).

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Author notes

  1. P Fagone and D J Shedlock: These authors contributed equally to this work.

Authors and Affiliations

  1. Deptartment of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    P Fagone, D J Shedlock, H Bao, O U Kawalekar, J Yan, D Gupta, M P Morrow, K Muthumani & D B Weiner

  2. Special Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada

    A Patel & G P Kobinger

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  1. P Fagone
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Correspondence to K Muthumani.

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Competing interests

The DBW laboratory notes possible commercial conflicts associated with this work, which may include the following: Inovio, BMS, Virxsys, Ichor, Merck, Althea and Aldevron, and possibly others. The funders had no role in the study design, data collection, analysis, decision to publish or preparation of the manuscript.

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Fagone, P., Shedlock, D., Bao, H. et al. Molecular adjuvant HMGB1 enhances anti-influenza immunity during DNA vaccination. Gene Ther 18, 1070–1077 (2011). https://doi.org/10.1038/gt.2011.59

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