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Infection and Immunity, February 2009, p. 739-748, Vol. 77, No. 2
0019-9567/09/$08.00+0     doi:10.1128/IAI.00974-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Enhanced Immunogenicity of Plasmodium falciparum Peptide Vaccines Using a Topical Adjuvant Containing a Potent Synthetic Toll-Like Receptor 7 Agonist, Imiquimod {triangledown}

Caroline Othoro,1,{dagger} Dean Johnston,2,{dagger} Rebecca Lee,1 Jonathan Soverow,1 Jean-Claude Bystryn,3 and Elizabeth Nardin1*

Department of Medical Parasitology,1 Department of Dermatology and New York University Cancer Institute, School of Medicine, New York University, New York, New York 10010,3 Hunter College School of Health Sciences, New York, New York 100102

Received 4 August 2008/ Returned for modification 4 October 2008/ Accepted 20 November 2008

Plasmodium sporozoites injected into the skin by malaria-infected mosquitoes can be effectively targeted by antibodies that block parasite invasion of host hepatocytes and thus prevent the subsequent development of blood stage infections responsible for clinical disease. Malaria subunit vaccines require potent adjuvants, as they lack known pathogen-associated molecular patterns found in attenuated viral or bacterial vaccines that function as Toll-like receptor (TLR) agonists to stimulate dendritic cells and initiate strong adaptive immune responses. A synthetic TLR7 agonist, imiquimod, which is FDA approved for topical treatment of various skin conditions, can function as a potent adjuvant for eliciting T-cell responses to intracellular pathogens and model protein antigens. In the current studies, the topical application of imiquimod at the site of subcutaneously injected Plasmodium falciparum circumsporozoite (CS) peptides elicited strong parasite-specific humoral immunity that protected against challenge with transgenic rodent parasites that express P. falciparum CS repeats. In addition, injection of a simple linear peptide followed by topical imiquimod elicited strong Th1 CD4+ T-cell responses, as well as high antibody titers. The correlation of high anti-repeat antibody titers with resistance to sporozoite challenge in vivo and in vitro supports use of this topical TLR7 agonist adjuvant to elicit protective humoral immunity. The safety, simplicity, and economic advantages of a topical synthetic TLR7 agonist adjuvant also apply to other vaccines requiring high antibody titers, such as malaria asexual or sexual blood stage antigens to prevent red blood cell invasion and block transmission to the mosquito vector, and to vaccines to other extracellular pathogens.

* Corresponding author. Mailing address: Department of Medical Parasitology, New York University School of Medicine, 341 East 25th Street, New York, NY 10010. Phone: (212) 263-6819. Fax: (212) 263-8116. E-mail: Elizabeth.Nardin{at}nyumc.org

{triangledown} Published ahead of print on 1 December 2008.

Editor: W. A. Petri, Jr.

{dagger} C.O. and D.J. contributed equally as first authors.

Infection and Immunity, February 2009, p. 739-748, Vol. 77, No. 2
0019-9567/09/$08.00+0     doi:10.1128/IAI.00974-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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