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Recombinant rabies virus particles presenting botulinum neurotoxin antigens elicit a protective humoral response in vivo.

Hudacek AW, Al-Saleem FH, Willet M, Eisemann T, Mattis JA, Simpson LL, Schnell MJ - Mol Ther Methods Clin Dev (2014)

Bottom Line: Our previous research has shown that recombinant rabies virus-based particles can effectively present heterologous antigens.Administration of a combination of these vectors also demonstrated antibody responses against all three serotypes based on enzyme-linked immunosorbent assay (ELISA) measurements, with minimal decay within the study timeline.Complete protection was achieved against toxin challenge from the serotypes /A and /B and partial protection for /E, indicating that a multivalent approach is feasible.

View Article: PubMed Central - PubMed

Affiliation: Molecular Targeting Technologies, Inc. , West Chester, Pennsylvania, USA ; Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University , Philadelphia, Pennsylvania, USA.

ABSTRACT
Botulinum neurotoxins are one of the most potent toxins found in nature, with broad medical applications from cosmetics to the treatment of various neuropathies. Additionally, these toxins are classified as Category A-Tier 1 agents, with human lethal doses calculated at as little as 90 ng depending upon the route of administration. Of the eight distinct botulinum neurotoxin serotypes, the most common causes of human illness are from serotypes /A, /B, and /E. Protection can be achieved by eliciting antibody responses against the receptor-binding domain of the neurotoxin. Our previous research has shown that recombinant rabies virus-based particles can effectively present heterologous antigens. Here, we describe a novel strategy using recombinant rabies virus particles that elicits a durable humoral immune response against the botulinum neurotoxin receptor binding domains from serotypes /A, /B, and /E. Following intramuscular administration of β-propiolactone-inactivated rabies virus particles, mice elicited specific immune responses against the cognate antigen. Administration of a combination of these vectors also demonstrated antibody responses against all three serotypes based on enzyme-linked immunosorbent assay (ELISA) measurements, with minimal decay within the study timeline. Complete protection was achieved against toxin challenge from the serotypes /A and /B and partial protection for /E, indicating that a multivalent approach is feasible.

No MeSH data available.


Related in: MedlinePlus

IgG isotype analysis of antibody responses indicates a Th1-biased response. Sera from immunized mice at weeks 4 and 6 were pooled and tested for their IgG1 and IgG2a responses to (a) RABV-G, (b) HC50/A, (c) HC50/B, and (d) HC50/E, and presented as the ratio of the optical densities corresponding to the IgG2a to IgG1-specific enzyme-linked immunosorbent assay signals for the specific antigen (each panel represents one antigen). Only the groups with immune responses to the specific antigens, as grouped by panel, were assayed.
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fig7: IgG isotype analysis of antibody responses indicates a Th1-biased response. Sera from immunized mice at weeks 4 and 6 were pooled and tested for their IgG1 and IgG2a responses to (a) RABV-G, (b) HC50/A, (c) HC50/B, and (d) HC50/E, and presented as the ratio of the optical densities corresponding to the IgG2a to IgG1-specific enzyme-linked immunosorbent assay signals for the specific antigen (each panel represents one antigen). Only the groups with immune responses to the specific antigens, as grouped by panel, were assayed.

Mentions: To further characterize the immune responses against the different antigens, we analyzed the IgG2a to IgG1 isotype ratio. When the isotype-specific antibody responses from weeks 4 and 6 were analyzed for each of the four different antigens, we found that all groups developed a strong IgG2a (Th-1)-biased response to the HC50 antigens by week 4 (Figure 7, left panels). This response, while staying predominantly biased toward a Th-1 like response, had a further increase in IgG1 (Th-2)-specific antibody–antigen responses at week 6 for /A and /B. However, we did not observe a similar increase in the IgG1 response against HC50/E in mice immunized with BNSP-333-HC50/E particles (Figure 7, right panels, and Supplementary Figure S1).


Recombinant rabies virus particles presenting botulinum neurotoxin antigens elicit a protective humoral response in vivo.

Hudacek AW, Al-Saleem FH, Willet M, Eisemann T, Mattis JA, Simpson LL, Schnell MJ - Mol Ther Methods Clin Dev (2014)

IgG isotype analysis of antibody responses indicates a Th1-biased response. Sera from immunized mice at weeks 4 and 6 were pooled and tested for their IgG1 and IgG2a responses to (a) RABV-G, (b) HC50/A, (c) HC50/B, and (d) HC50/E, and presented as the ratio of the optical densities corresponding to the IgG2a to IgG1-specific enzyme-linked immunosorbent assay signals for the specific antigen (each panel represents one antigen). Only the groups with immune responses to the specific antigens, as grouped by panel, were assayed.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362357&req=5

fig7: IgG isotype analysis of antibody responses indicates a Th1-biased response. Sera from immunized mice at weeks 4 and 6 were pooled and tested for their IgG1 and IgG2a responses to (a) RABV-G, (b) HC50/A, (c) HC50/B, and (d) HC50/E, and presented as the ratio of the optical densities corresponding to the IgG2a to IgG1-specific enzyme-linked immunosorbent assay signals for the specific antigen (each panel represents one antigen). Only the groups with immune responses to the specific antigens, as grouped by panel, were assayed.
Mentions: To further characterize the immune responses against the different antigens, we analyzed the IgG2a to IgG1 isotype ratio. When the isotype-specific antibody responses from weeks 4 and 6 were analyzed for each of the four different antigens, we found that all groups developed a strong IgG2a (Th-1)-biased response to the HC50 antigens by week 4 (Figure 7, left panels). This response, while staying predominantly biased toward a Th-1 like response, had a further increase in IgG1 (Th-2)-specific antibody–antigen responses at week 6 for /A and /B. However, we did not observe a similar increase in the IgG1 response against HC50/E in mice immunized with BNSP-333-HC50/E particles (Figure 7, right panels, and Supplementary Figure S1).

Bottom Line: Our previous research has shown that recombinant rabies virus-based particles can effectively present heterologous antigens.Administration of a combination of these vectors also demonstrated antibody responses against all three serotypes based on enzyme-linked immunosorbent assay (ELISA) measurements, with minimal decay within the study timeline.Complete protection was achieved against toxin challenge from the serotypes /A and /B and partial protection for /E, indicating that a multivalent approach is feasible.

View Article: PubMed Central - PubMed

Affiliation: Molecular Targeting Technologies, Inc. , West Chester, Pennsylvania, USA ; Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University , Philadelphia, Pennsylvania, USA.

ABSTRACT
Botulinum neurotoxins are one of the most potent toxins found in nature, with broad medical applications from cosmetics to the treatment of various neuropathies. Additionally, these toxins are classified as Category A-Tier 1 agents, with human lethal doses calculated at as little as 90 ng depending upon the route of administration. Of the eight distinct botulinum neurotoxin serotypes, the most common causes of human illness are from serotypes /A, /B, and /E. Protection can be achieved by eliciting antibody responses against the receptor-binding domain of the neurotoxin. Our previous research has shown that recombinant rabies virus-based particles can effectively present heterologous antigens. Here, we describe a novel strategy using recombinant rabies virus particles that elicits a durable humoral immune response against the botulinum neurotoxin receptor binding domains from serotypes /A, /B, and /E. Following intramuscular administration of β-propiolactone-inactivated rabies virus particles, mice elicited specific immune responses against the cognate antigen. Administration of a combination of these vectors also demonstrated antibody responses against all three serotypes based on enzyme-linked immunosorbent assay (ELISA) measurements, with minimal decay within the study timeline. Complete protection was achieved against toxin challenge from the serotypes /A and /B and partial protection for /E, indicating that a multivalent approach is feasible.

No MeSH data available.


Related in: MedlinePlus