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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

Survival of mice following intraperitoneal challenge with BoNT. Groups of five mice were immunized as outlined in Figure 6a, then challenged via intraperitoneal administration of 1000 mouse LD50 (a) BoNT/A, (b) BoNT/B, or (c) BoNT/E. Combined vaccine groups (ABE) were challenged sequentially with BoNT/A, /B, then /E.
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fig8: Survival of mice following intraperitoneal challenge with BoNT. Groups of five mice were immunized as outlined in Figure 6a, then challenged via intraperitoneal administration of 1000 mouse LD50 (a) BoNT/A, (b) BoNT/B, or (c) BoNT/E. Combined vaccine groups (ABE) were challenged sequentially with BoNT/A, /B, then /E.

Mentions: In order to assess the protective efficacy of the immunization schedule, we repeated the immunizations and verified seroconversion (data not shown). These mice were then challenged with 1000 mouse LD50 of the respective BoNTs, a dose sufficient to produce respiratory paralysis within ~120 minutes. A complete (100%) protective response in this model system is survival postchallenge for 4 days. We found that groups of mice (n = 5) that were challenged with BoNT/A or /B were completely protected (Figure 8a,b, A and B groups) whereas only a prolongation of survival from 132 minutes for control mice to 480 minutes was seen for mice immunized against serotype /E (Figure 8c; compare black and blue survival curves, P = 0.0027). This is noteworthy as it indicates that there is a reduction in toxin potency of between one and two orders of magnitude. All of the mice receiving the trivalent (ABE) immunization were challenged sequentially with BoNT/A, /B, and then /E. The trivalent group survived the first two challenges (Figure 8a,b; ABE group survival curves). When challenged with BoNT/E, three of five mice survived the intoxication (Figure 8c; ABE group survival, P = 0.0027 between ABE and control). While immunization with only BNSP-333-HC50/E was not able to protect mice from lethal challenge with the cognate toxin, we observed a partially protective response against BoNT/E when incorporated into the trivalent vaccine, indicating some sort of “cross-immunity” or enhanced affect when applied in combination. These data indicate that the multivalent vaccine strategy is effective.


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)

Survival of mice following intraperitoneal challenge with BoNT. Groups of five mice were immunized as outlined in Figure 6a, then challenged via intraperitoneal administration of 1000 mouse LD50 (a) BoNT/A, (b) BoNT/B, or (c) BoNT/E. Combined vaccine groups (ABE) were challenged sequentially with BoNT/A, /B, then /E.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig8: Survival of mice following intraperitoneal challenge with BoNT. Groups of five mice were immunized as outlined in Figure 6a, then challenged via intraperitoneal administration of 1000 mouse LD50 (a) BoNT/A, (b) BoNT/B, or (c) BoNT/E. Combined vaccine groups (ABE) were challenged sequentially with BoNT/A, /B, then /E.
Mentions: In order to assess the protective efficacy of the immunization schedule, we repeated the immunizations and verified seroconversion (data not shown). These mice were then challenged with 1000 mouse LD50 of the respective BoNTs, a dose sufficient to produce respiratory paralysis within ~120 minutes. A complete (100%) protective response in this model system is survival postchallenge for 4 days. We found that groups of mice (n = 5) that were challenged with BoNT/A or /B were completely protected (Figure 8a,b, A and B groups) whereas only a prolongation of survival from 132 minutes for control mice to 480 minutes was seen for mice immunized against serotype /E (Figure 8c; compare black and blue survival curves, P = 0.0027). This is noteworthy as it indicates that there is a reduction in toxin potency of between one and two orders of magnitude. All of the mice receiving the trivalent (ABE) immunization were challenged sequentially with BoNT/A, /B, and then /E. The trivalent group survived the first two challenges (Figure 8a,b; ABE group survival curves). When challenged with BoNT/E, three of five mice survived the intoxication (Figure 8c; ABE group survival, P = 0.0027 between ABE and control). While immunization with only BNSP-333-HC50/E was not able to protect mice from lethal challenge with the cognate toxin, we observed a partially protective response against BoNT/E when incorporated into the trivalent vaccine, indicating some sort of “cross-immunity” or enhanced affect when applied in combination. These data indicate that the multivalent vaccine strategy is effective.

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