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Mucosal Vaccine Targeting Improves Onset of Mucosal and Systemic Immunity to Botulinum Neurotoxin A¹

Massimo Maddaloni^*, Herman F. Staats, Dagmara Mierzejewska, Teri Hoyt^*, Amy Robinson^*, Gayle Callis^*, Shunji Kozaki, Hiroshi Kiyono^¶, Jerry R. McGhee^||, Kohtaro Fujihashi^|| and David W. Pascual^2,*

^* Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717; Department of Pathology, Duke University Medical Center, Durham, NC 27710; Department of Food Chemistry, Institute of Food Research, Polish Academy of Science, Olsztyn, Poland; Laboratory of Veterinary Epidemiology, Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Sakai-shi, Osaka, Japan; ^¶ Department of Microbiology and Immunology, Division of Mucosal Immunology, Institute for Medical Sciences, University of Tokyo, Tokyo, Japan; and ^|| Department of Microbiology and Department of Pediatric Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294

Absence of suitable mucosal adjuvants for humans prompted us to consider alternative vaccine designs for mucosal immunization. Because adenovirus is adept in binding to the respiratory epithelium, we tested the adenovirus 2 fiber protein (Ad2F) as a potential vaccine-targeting molecule to mediate vaccine uptake. The vaccine component (the host cell-binding domain to botulinum toxin (BoNT) serotype A) was genetically fused to Ad2F to enable epithelial binding. The binding domain for BoNT was selected because it lies within the immunodominant H chain as a -trefoil (Hctre) structure; we hypothesize that induced neutralizing Abs should be protective. Mice were nasally immunized with the Hctre or Hctre-Ad2F, with or without cholera toxin (CT). Without CT, mice immunized with Hctre produced weak secretory IgA (sIgA) and plasma IgG Ab response. Hctre-Ad2F-immunized mice produced a sIgA response equivalent to mice coimmunized with CT. With CT, Hctre-Ad2F-immunized mice showed a more rapid onset of sIgA and plasma IgG Ab responses that were supported by a mixed Th1/Th2 cells, as opposed to mostly Th2 cells by Hctre-dosed mice. Mice immunized with adjuvanted Hctre-Ad2F or Hctre were protected against lethal BoNT serotype A challenge. Using a mouse neutralization assay, fecal Abs from Hctre-Ad2F or Hctre plus CT-dosed mice could confer protection. Parenteral immunization showed that the inclusion of Ad2F enhances anti-Hctre Ab titers even in the absence of adjuvant. This study shows that the Hctre structure can confer protective immunity and that use of Hctre-Ad2F gives more rapid and sustained mucosal and plasma Ab responses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Public Health Service Grants DE-13812, AI-56286, AI-18958, DE-12242, AI-43197, and DC-04976, and in part by Montana Agricultural Station and the U.S. Department of Agriculture Formula Funds. The Veterinary Molecular Biology flow cytometry facility was supported in part by the Center of Biomedical Research Excellence P20 RR-020185 from the National Institutes of Health/National Center for Research Resources.

² Address correspondence and reprint requests to Dr. David W. Pascual, Veterinary Molecular Biology, P.O. Box 173610, Montana State University, Bozeman, MT 59717-3610. E-mail address: dpascual{at}montana.edu

³ Abbreviations used in this paper: BoNT, botulinum neurotoxin; Hctre, -trefoil stucture of Hc for BoNT; Ad2F, adenovirus 2 fiber protein; AFC, Ab-forming cell; CFC, cytokine-forming cell; CM, complete medium; DAPI, 4',6-diamidino-2-phenylindole; CT, cholera toxin; LN, lymph node. sIgA, secretory IgA.

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