Pathology and Pathophysiology of Inhalational Anthrax in a Guinea Pig Model

Savransky, Vladimir; Sanford, Daniel; Syar, Emily S; Austin, Jamie L.; Tordoff, Kevin P.; Anderson, Mary B.; Stark, Gregory V.; Barnewall, Roy E.; Briscoe, Crystal M.; Lemiale-Biérinx, Laurence; Park, Sukjoon; Ионин, Б. И.; Skiadopoulos, Mario H.

doi:10.1128/iai.01289-12

Cited by 25 publications

(33 citation statements)

References 57 publications

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“…The course of disease in guinea pigs and NHPs is similar to that of humans. Histopathological findings in guinea pigs and NHP are also similar to those found in humans and include necrotizing lymphadenitis, splenitis, pneumonia, vasculitis, hemorrhage, congestion, and edema in multiple tissues and meninges (21–23). …”

Section: Discussionsupporting

confidence: 60%

“…Aqueous suspensions of B. anthracis spores were aerosolized by a 3-jet Collison nebulizer and delivered to the animals via a nose-only (guinea pigs) or head-only (NHPs) inhalational exposure system. The anthrax target challenge dose was 200 LD 50 of B. anthracis Ames spores, using the LD 50 values of 5.01 × 10 4 spores/animal for guinea pigs (21) and 6.18 × 10 4 spores/animal for cynomolgus macaques (23). Actual challenge doses achieved in the studies are shown in Table 1.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, a guinea pig model was developed as the small animal model for evaluation of AV7909 vaccine immunogenicity and efficacy. The guinea pig and cynomolgus macaque models of inhalational anthrax have been characterized extensively to support their use for licensure of AV7909, and the clinical signs of disease observed in these models are similar to those of inhalational anthrax in humans (21–23). Furthermore, studies in these animal models have demonstrated that serum TNA and anti-PA IgG titres are reliable predictors of survival following lethal B. anthracis challenge (24– 27).…”

Section: Introductionmentioning

confidence: 99%

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Correlation between anthrax lethal toxin neutralizing antibody levels and survival in guinea pigs and nonhuman primates vaccinated with the AV7909 anthrax vaccine candidate

Savransky

Shearer

Gainey

et al. 2017

Vaccine

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The anthrax vaccine candidate AV7909 is being developed as a next generation vaccine for a post-exposure prophylaxis (PEP) indication against anthrax. AV7909 consists of the Anthrax Vaccine Adsorbed (AVA, BioThrax®) bulk drug substance adjuvanted with the immunostimulatory oligodeoxynucleotide (ODN) compound, CPG 7909. The addition of CPG 7909 to AVA enhances both the magnitude and the kinetics of antibody responses in animals and human subjects, making AV7909 a suitable next-generation vaccine for use in a PEP setting. The studies described here provide initial information on AV7909-induced toxin-neutralizing antibody (TNA) levels associated with the protection of animals from lethal Bacillus anthracis challenge. Guinea pigs or nonhuman primates (NHPs) were immunized on Days 0 and 28 with various dilutions of AV7909, AVA or a saline or Alhydrogel + CPG 7909 control. Animals were challenged via the inhalational route with a lethal dose of aerosolized B. anthracis (Ames strain) spores and observed for clinical signs of disease and mortality. The relationship between pre-challenge serum TNA levels and survival following challenge was determined in order to calculate a threshold TNA level associated with protection. Immunisation with AV7909 induced a rapid, highly protective TNA response in guinea pigs and NHPs. Surprisingly, the TNA threshold associated with a 70% probability of survival for AV7909 immunized animals was substantially lower than the threshold which has been established for the licensed AVA vaccine. The results of this study suggest that the TNA threshold of protection against anthrax could be modified by the addition of an immune stimulant such as CPG 7909 and that the TNA levels associated with protection may be vaccine-specific.

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Section: Discussionsupporting

confidence: 60%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Correlation between anthrax lethal toxin neutralizing antibody levels and survival in guinea pigs and nonhuman primates vaccinated with the AV7909 anthrax vaccine candidate

Savransky

Shearer

Gainey

et al. 2017

Vaccine

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“…The exposure conditions for guinea pigs appeared to be identical to those described for NHP and the guinea pig minute volume was reported at 150 mL/min. The second guinea pig data set came from a recent study that examined dose response and disease in Hartley guinea pigs exposed to aerosols of Ames strain B. anthracis …”

Section: Data Utilizedmentioning

confidence: 99%

Evaluation of Inhaled Versus Deposited Dose Using the Exponential Dose‐Response Model for Inhalational Anthrax in Nonhuman Primate, Rabbit, and Guinea Pig

et al. 2014

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The application of the exponential model is extended by the inclusion of new nonhuman primate (NHP), rabbit, and guinea pig dose-lethality data for inhalation anthrax. Because deposition is a critical step in the initiation of inhalation anthrax, inhaled doses may not provide the most accurate cross-species comparison. For this reason, species-specific deposition factors were derived to translate inhaled dose to deposited dose. Four NHP, three rabbit, and two guinea pig data sets were utilized. Results from species-specific pooling analysis suggested all four NHP data sets could be pooled into a single NHP data set, which was also true for the rabbit and guinea pig data sets. The three species-specific pooled data sets could not be combined into a single generic mammalian data set. For inhaled dose, NHPs were the most sensitive (relative lowest LD50) species and rabbits the least. Improved inhaled LD50 s proposed for use in risk assessment are 50,600, 102,600, and 70,800 inhaled spores for NHP, rabbit, and guinea pig, respectively. Lung deposition factors were estimated for each species using published deposition data from Bacillus spore exposures, particle deposition studies, and computer modeling. Deposition was estimated at 22%, 9%, and 30% of the inhaled dose for NHP, rabbit, and guinea pig, respectively. When the inhaled dose was adjusted to reflect deposited dose, the rabbit animal model appears the most sensitive with the guinea pig the least sensitive species.

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“…After pathogen challenge, all guinea pigs in the control groups that received either saline or empty DNA vector succumbed within 3–4 days, a time to death interval c . 1 day more than that determined for guinea pigs aerosol challenged with an equivalent dose of B. anthracis Ames spores (Savransky et al ., ). Protein and DNA–protein vaccinated animals conversely showed either partial (i.e.…”

Section: Tna Serum Fractions Compared With Total Antigen‐specific Iggmentioning

confidence: 97%

Protein- and DNA-based anthrax toxin vaccines confer protection in guinea pigs against inhalational challenge withBacillus cereusG9241

Palmer¹,

Bell²,

Darko³

et al. 2014

Pathogens Disease

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In the past decade, several Bacillus cereus strains have been isolated from otherwise healthy individuals who succumbed to bacterial pneumonia presenting symptoms resembling inhalational anthrax. One strain was indistinguishable from B. cereus G9241, previously cultured from an individual who survived a similar pneumonia-like illness and which was shown to possess a complete set of plasmid-borne anthrax toxin-encoding homologs. The finding that B. cereus G9241 pathogenesis in mice is dependent on pagA1-derived protective antigen (PA) synthesis suggests that an anthrax toxin-based vaccine may be effective against this toxin-encoding B. cereus strain. Dunkin Hartley guinea pigs were immunized with protein- and DNA-based anthrax toxin-based vaccines, immune responses were evaluated and survival rates were calculated after lethal aerosol exposure with B. cereus G9241 spores. Each vaccine induced seroconversion with the protein immunization regimen eliciting significantly higher serum levels of antigen-specific antibodies at the prechallenge time-point compared with the DNA-protein prime-boost immunization schedule. Complete protection against lethal challenge was observed in all groups with a detectable prechallenge serum titer of toxin neutralizing antibodies. For the first time, we demonstrated that the efficacy of fully defined anthrax toxin-based vaccines was protective against lethal B. cereus G9241 aerosol challenge in the guinea pig animal model.

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Pathology and Pathophysiology of Inhalational Anthrax in a Guinea Pig Model

Cited by 25 publications

References 57 publications

Correlation between anthrax lethal toxin neutralizing antibody levels and survival in guinea pigs and nonhuman primates vaccinated with the AV7909 anthrax vaccine candidate

Correlation between anthrax lethal toxin neutralizing antibody levels and survival in guinea pigs and nonhuman primates vaccinated with the AV7909 anthrax vaccine candidate

Evaluation of Inhaled Versus Deposited Dose Using the Exponential Dose‐Response Model for Inhalational Anthrax in Nonhuman Primate, Rabbit, and Guinea Pig

Protein- and DNA-based anthrax toxin vaccines confer protection in guinea pigs against inhalational challenge withBacillus cereusG9241

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