Abstract
We measured the ability of nine DNA vaccine plasmids encoding candidate malaria vaccine antigens to induce antibodies and interferon-γ responses when delivered alone or in a mixture containing all nine plasmids. We further examined the possible immunosuppressive effect of individual plasmids, by assessing a series of mixtures in which each of the nine vaccine plasmids was replaced with a control plasmid. Given alone, each of the vaccine plasmids induced significant antibody titers and, in the four cases for which appropriate assays were available, IFN-γ responses. Significant suppression or complete abrogation of responses were seen when the plasmids were pooled in a nine-plasmid cocktail and injected in a single site. Removal of single genes from the mixture frequently reduced the observed suppression. Boosting with recombinant poxvirus increased the antibody response in animals primed with either a single gene or the mixture, but, even after boosting, responses were higher in animals primed with single plasmids than in those primed with the nine-plasmid mixture. Boosting did not overcome the suppressive effect of mixing for IFN-γ responses. Interactions between components in a multiplasmid DNA vaccine may limit the ability to use plasmid pools alone to induce responses against multiple targets simultaneously.
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Acknowledgements
This work was supported by the Naval Medical Research Center (Military Infectious Diseases Research Program) work units 61102A.S13.F.A0009 and 62787A.870.F.A0010, and by the Office of Naval Research Grant N00014-89-J-1856 to The University of Maryland at Baltimore (MS). The assertions herein are the private ones of the authors and are not to be construed as official or as reflecting the views of the US Navy or the Naval service at large. In conducting the research described in this report, all aspects involving animal use were conducted in an AAALAC accredited facility, and in accordance with the Animal Welfare Act implementing the instructions (9 CFR, Subchapter A, Parts 1–3), Department of Defense regulations, and recognized standards relating to the care and use of laboratory animals. We thank David Lanar (Walter Reed Army Institute for Research) for recombinant PfCSP, PfSSP2, and PfLSA1; Jennifer Meeks and Autumn Ramirez (Vical, Inc.) for assistance in preparing plasmid mixtures; R Ridley (Hoffman-La-Roche) for anti-Exp1 mAb N1, Tony Holder (NIMR, Mill Hill) for anti-MSP1 mAb 5.2, and Alan Thomas for anti-AMA-1 mAb 4G2; and HM1 Robert Arcilla, HM1 Arnel Belmonte, HM2 Thomas Smalls, and Patricia de la Vega for excellent technical assistance and providing P. falciparum parasites.
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Sedegah, M., Charoenvit, Y., Minh, L. et al. Reduced immunogenicity of DNA vaccine plasmids in mixtures. Gene Ther 11, 448–456 (2004). https://doi.org/10.1038/sj.gt.3302139
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DOI: https://doi.org/10.1038/sj.gt.3302139
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