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. 2019 Apr 25;63(5):e02049-18.
doi: 10.1128/AAC.02049-18. Print 2019 May.

Effective Treatment of Staphylococcal Enterotoxin B Aerosol Intoxication in Rhesus Macaques by Using Two Parenterally Administered High-Affinity Monoclonal Antibodies

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Free PMC article

Effective Treatment of Staphylococcal Enterotoxin B Aerosol Intoxication in Rhesus Macaques by Using Two Parenterally Administered High-Affinity Monoclonal Antibodies

Daniel Verreault et al. Antimicrob Agents Chemother. .
Free PMC article

Abstract

Staphylococcal enterotoxin B (SEB) is a protein exotoxin found on the cell surface of Staphylococcus aureus that is the source for multiple pathologies in humans. When purified and concentrated in aerosol form, SEB can cause an acute and often fatal intoxication and thus is considered a biological threat agent. There are currently no vaccines or treatments approved for human use. Studies with rodent models of SEB intoxication show that antibody therapy may be a promising treatment strategy; however, many have used antibodies only prophylactically or well before any clinical signs of intoxication are apparent. We assessed and compared the protective efficacies of two monoclonal antibodies, Ig121 and c19F1, when administered after aerosol exposure in a uniformly lethal nonhuman primate model of SEB intoxication. Rhesus macaques were challenged using small-particle aerosols of SEB and then were infused intravenously with a single dose of either Ig121 or c19F1 (10 mg/kg of body weight) at either 0.5, 2, or 4 h postexposure. Onset of clinical signs and hematological and cytokine response in untreated controls confirmed the acute onset and potency of the toxin used in the challenge. All animals administered either Ig121 or c19F1 survived SEB challenge, whereas the untreated controls succumbed to SEB intoxication 30 to 48 h postexposure. These results represent the successful therapeutic in vivo protection by two investigational drugs against SEB in a severe nonhuman primate disease model and punctuate the therapeutic value of monoclonal antibodies when faced with treatment options for SEB-induced toxicity in a postexposure setting.

Keywords: Macaca mulatta; aerosol; antibody therapy; staphylococcal enterotoxin.

Figures

FIG 1
FIG 1
Binding of 121 and 19F1 to SEB or STEBVax. (A) Binding of 121 to SEB and STEBVax. (B) Binding of 19F1 to SEB and STEBVax. N.D., not determined.
FIG 2
FIG 2
Individual inhaled challenge doses of rhesus macaques with aerosolized SEB toxin expressed as total micrograms inhaled and by a per-weight basis. The line and error bars represent the means and SDs for either antibody-treated or sham groups across all experiments for both measures (n = 23). There was no statistically significant difference between challenge doses in group comparison of total micrograms (P = 0.2392) or microgram-per-kilogram values (P = 0.8942).
FIG 3
FIG 3
(A) Diagram of antibody treatment schedule, representing single dosage time point/group, and sampling time after SEB challenge in macaques. Orange arrow, c19F1 0.5-h treatment; olive arrow, c19F1 4-h treatment; green arrow, IgG121 2-h treatment; blue arrow, IgG121 4-h treatment. The asterisk represents the hour of SEB challenge. (B) Kaplan-Meier survival curve for the sham group (n = 9) and groups treated with c19F1 at 0.5 h (n = 8), c19F1 at 4 h (n = 4), IgG121 at 2 h (n = 4), and IgG121 at 4 h (n = 4).
FIG 4
FIG 4
Cellularity from peripheral blood from all animals (n = 23) prior to SEB challenge (Pre) and 24 h postchallenge and/or treatment with either antibody. Each graph represents neutrophil (A), lymphocyte (B), or monocyte (C) count. All postchallenge values for either sham- or antibody-treated animals were significantly different (*, P < 0.05) from preexposure values. There was no statistical difference between sham control and treatment animals postexposure for any of the values presented.
FIG 5
FIG 5
Aspartate aminotransferase (AST) and alanine transaminase (ALT) measured from peripheral blood from all animals (n = 23) prior to SEB challenge and 24 h postchallenge and/or treatment with either antibody. Significant differences (P < 0.05) for either sham control or treated animals compared to preexposure values are indicated with an asterisk.
FIG 6
FIG 6
Relevant clinical chemistries derived from peripheral blood from all animals (n = 23) prior to SEB challenge and 24 h postchallenge and/or treatment with either antibody. Each graph shows blood urea nitrogen (A), creatinine (B), serum protein (C), or serum albumin (D). Significant differences (P < 0.05) for either sham control or treated animals from preexposure values is indicated with an asterisk.
FIG 7
FIG 7
Hierarchical cluster analysis of cytokine data between c19F1-treated animals and controls. Each column represents blood collection time point prior to SEB exposure or postexposure (either 24 or 48 h) for c19F1 or sham-treated animal groups. Each horizontal category refers to time of treatment (either 0.5 or 4 h p.i.) and corresponding timed sham treatments. Orange indicates cytokines with a greater concentration relative to the geometrical mean of the naive values, and blue indicates cytokines with a concentration lower than the naive geometrical mean.
FIG 8
FIG 8
Wet lung weights of animals at necropsy. Lines and error bars represent means and SDs of each group. Weights of sham-treated animals were significantly different than all treated groups. *, significance at a P value of <0.05. There was no significant difference in lung weight between treatment groups.
FIG 9
FIG 9
Representative tissues from MAb-treated (IgG121 and 19F1 at 10 mg/kg each) and sham controls. Lungs from treated animals showed minimal inflammation; bronchial lymph nodes of treated animals showed mild lymphoid, diffuse hyperplasia. Lungs from sham-treated animals showed severe inflammation and acute fibrinous accumulation; bronchial lymph nodes showed inflammation and edema. The bar represents 100 μm.
FIG 10
FIG 10
Categorical scoring of lesion severity in lungs and bronchial lymph nodes for major representative histological changes in each tissue type examined. Categories are represented as follows: 0, normal; 1, minimal; 2, mild; 3, moderate; and 4, severe.

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