Adenovirus F protein as a delivery vehicle for botulinum B.

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2010-07-07

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Abstract

BACKGROUND: Immunization with recombinant carboxyl-terminal domain of the heavy chain (Hc domain) of botulinum neurotoxin (BoNT) stimulates protective immunity against native BoNT challenge. Most studies developing a botulism vaccine have focused on the whole Hc; however, since the principal protective epitopes are located within beta-trefoil domain (Hcbetatre), we hypothesize that immunization with the Hcbetatre domain is sufficient to confer protective immunity. In addition, enhancing its uptake subsequent to nasal delivery prompted development of an alternative vaccine strategy, and we hypothesize that the addition of targeting moiety adenovirus 2 fiber protein (Ad2F) may enhance such uptake during vaccination. RESULTS: The Hcbetatre serotype B immunogen was genetically fused to Ad2F (Hcbetatre/B-Ad2F), and its immunogenicity was tested in mice. In combination with the mucosal adjuvant, cholera toxin (CT), enhanced mucosal IgA and serum IgG Ab titers were induced by nasal Hcbetatre-Ad2F relative to Hcbetatre alone; however, similar Ab titers were obtained upon intramuscular immunization. These BoNT/B-specific Abs induced by nasal immunization were generally supported in large part by Th2 cells, as opposed to Hcbetatre-immunized mice that showed more mixed Th1 and Th2 cells. Using a mouse neutralization assay, sera from animals immunized with Hcbetatre and Hcbetatre-Ad2F protected mice against 2.0 LD50. CONCLUSION: These results demonstrate that Hcbetatre-based immunogens are highly immunogenic, especially when genetically fused to Ad2F, and Ad2F can be exploited as a vaccine delivery platform to the mucosa.

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10.1186/1471-2172-11-36

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Clapp, Beata, Sarah Golden, Massimo Maddaloni, Herman F Staats and David W Pascual (2010). Adenovirus F protein as a delivery vehicle for botulinum B. BMC Immunol, 11. p. 36. 10.1186/1471-2172-11-36 Retrieved from https://hdl.handle.net/10161/4351.

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Staats

Herman Ford Staats

Professor of Pathology

Areas of Research Interest:

Our laboratory studies methods to induce and regulate antigen-specific immune responses at the mucosal surfaces of the host. The mucosal tissues and surfaces are often the first site of contact with infectious agents, a common location of life-threatening cancers and in constant contact with environmental antigens. A better understanding of factors that control the induction and regulation of mucosal immune responses may aid the development of vaccines and treatments for infectious agents such as HIV and agents of bioterrorism, cancers and environmental allergies.

Research interests in the Staats’ lab currently focus on:

1. DISCOVERING AND DEVELOPING NOVEL MUCOSAL ADJUVANTS AND THEIR MECHANISM OF ACTION

Adjuvants are substances commonly added to vaccines that enhance the induction of protective immune responses to the vaccine antigen. We have been successful at identifying substances with mucosal adjuvant activity such as the pro-inflammatory cytokine interleukin 1α/β (IL-1α/β). IL-1α/β provides effective nasal adjuvant activity in mice, rabbits and non-human primates. Recent studies performed in collaboration with Dr. Soman Abraham have determined that the chemical mast cell activator compound 48/80 provides effective nasal adjuvant activity in mice and rabbits. Recent funding in the laboratory supported the discovery of small molecule mast cell activators with vaccine adjuvant activity.   Current funding in the laboratory supports the discovery of IL-1 receptor agonists (small molecules, peptides, aptamers)  that exhibit vaccine adjuvant activity.

2. OPTIMIZING NASAL IMMUNIZATION TO MAXIMIZE VACCINE IMMUNOGENICITY

Nasal immunization studies in mice have demonstrated the ability of nasal immunization to induce protective immune responses equal to those induced by a vaccine delivered with a needle. However, when nasal immunization is performed in rabbits or non-human primates, animals with a nasal cavity structure/anatomy that closely resembles the human nasal cavity, nasal immunization is often not as effective as immunization delivered with a needle. Studies in our lab have demonstrated that an increased nasal residence time in rabbits correlates with increased vaccine immunogenicity. Studies are being performed to develop vaccine delivery techniques and vaccine formulations that maximize nasal residence time and therefore, the immunogenicity of the vaccine.  Nasal immunization studies performed in rabbits and non-human primates are performed to optimize nasal vaccine methods that may be tested in humans in the future.

3. EVALUATING FACTORS THAT INFLUENCE THE INDUCTION OF FOOD ALLERGY AND DEVELOPING NOVEL MUCOSAL TREATMENTS FOR FOOD ALLERGY

The number of individuals with food allergy in steadily increasing in developed countries. The administration of food allergens via mucosal routes, a procedure known as “mucosal immunotherapy”, has provided encouraging results suggesting that mucosal immunotherapy is able to modify the host anti-food allergen response to reduce the severity of allergic responses. A recent avenue of research in the laboratory is to 1) develop novel mucosal immunotherapy formulations to treat existing food allergy and 2) evaluate the influence of environmental factors on the induction and severity of food allergies.


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