Development of Protective Immunity in New Zealand White Rabbits Challenged with Bacillus anthracis Spores and Treated with Antibiotics and Obiltoxaximab, a Monoclonal Antibody against Protective Antigen

Abstract

The recommended management of inhalational anthrax, a high-priority bioterrorist threat, includes antibiotics and antitoxins. Obiltoxaximab, a chimeric monoclonal antibody against anthrax protective antigen (PA), is licensed under the U.S. Food and Drug Administration's (FDA's) Animal Rule for the treatment of inhalational anthrax. Because of spore latency, disease reemergence after treatment cessation is a concern, and there is a need to understand the development of endogenous protective immune responses following antitoxin-containing anthrax treatment regimens. Here, acquired protective immunity was examined in New Zealand White (NZW) rabbits challenged with a targeted lethal dose of Bacillus anthracis spores and treated with antibiotics, obiltoxaximab, or a combination of both. Survivors of the primary challenge were rechallenged 9 months later and monitored for survival. Survival rates after primary and rechallenge for controls and animals treated with obiltoxaximab, levofloxacin, or a combination of both were 0, 65, 100, and 95%, and 0, 100, 95, and 89%, respectively. All surviving immune animals had circulating antibodies to PA and serum toxin-neutralizing titers prior to rechallenge. Following rechallenge, systemic bacteremia and toxemia were not detected in most animals, and the levels of circulating anti-PA IgG titers increased starting at 5 days postrechallenge. We conclude that treatment with obiltoxaximab, alone or combined with antibiotics, significantly improves the survival of rabbits that received a lethal inhalation B. anthracis spore challenge dose and does not interfere with the development of immunity. Survivors of primary challenge are protected against reexposure, have rare incidents of systemic bacteremia and toxemia, and have evidence of an anamnestic response.

Physiological Responses to Multiple Low-Doses of Bacillus anthracis Spores in the Rabbit Model of Inhalation Anthrax

“…Only one rabbit (Rabbit 2) in the 1.22 × 10 3 CFU mean daily dose group died of anthrax on Study Day 17.9. Rabbits surviving after an anthrax challenge usually seroconvert by Day 7 with titers increasing to Day 14 post-challenge [20,21]. Rabbit 2 never seroconverted, suggesting an infection was not established until completion of the first 2 weeks of challenges.…”

“…Bacteremia was detected, but below the countable range, in Rabbit 38 that survived inhalation anthrax. One potential explanation for the lack of positive bacteremic measurements may be the presence of measurable bacteremia occurred only during the gap days in the blood collection days (i.e., Study Days 3,[5][6][7][8]10,[12][13][14][15][17][18][19][20][21][22]. Furthermore, most rabbits that succumb to inhalation anthrax from single high-dose exposures have detectable PA levels in the late stage blood samples [14,[22][23][24].…”

Monoclonal Antibodies as an Antibacterial Approach Against Bacterial Pathogens

“…Using the Animal Rule, efficacy of Anthim ® was evaluated using New Zealand white rabbits [39]. Inhalation of Bacillus anthracis spores cause anthrax infection and, because of the ability of the spores to withstand harsh environments, spores can serve as a source for subsequent infection [40]. Another interesting study, performed after approval, showed that Anthim ® could also prevent these types of infections, which further bolstered the product's utility [40].…”

“…Inhalation of Bacillus anthracis spores cause anthrax infection and, because of the ability of the spores to withstand harsh environments, spores can serve as a source for subsequent infection [40]. Another interesting study, performed after approval, showed that Anthim ® could also prevent these types of infections, which further bolstered the product's utility [40]. Later Antibiotics 2020, 9, 155 4 of 12 that year, in October of 2016, the FDA approved the second antibody for bacterial infection, Zinplava™ (bezlotoxumab), for Clostridum difficile infections in adults [41].…”

Bacillus anthracis as a biological warfare agent: infection, diagnosis and countermeasures

“…The authors dis-cussed the effects of the antibody-based therapy and problems with evaluation of the therapy effi cacy using an animal model. Testing of a new drug called Obiltoxaximab, which is a chimeric monoclonal antibody against protective antigen of anthrax toxin proved some effect and improved the chance to survive the infection (59)(60)(61)(62). The drug is under clinical trials.…”