A single-dose combination therapy that both prevents and treats anthrax infection

Abstract

Exposure to anthrax leaves susceptible hosts at prolonged risk of infection since spores can persist in vivo for months before germinating to cause life-threatening disease. Anthrax vaccine adsorbed (AVA, the licensed US vaccine) induces immunity too slowly to protect susceptible individuals post-exposure. Antibiotics prevent the proliferation of vegetative bacilli but do not block latent spores from germinating. Thus, anthrax-exposed individuals must remain on antibiotic therapy for months to eliminate the threat posed by delayed spore germination. Unfortunately, long-term antibiotic treatment is poorly tolerated and frequently discontinued. This work explores whether administering a single dose of a long-acting antibiotic (Dalbavancin) combined with a rapidly immunogenic vaccine/adjuvant combination can provide seamless protection from anthrax with minimal patient compliance. Results show that significant protection is achieved by delivering a single dose of this therapeutic combination any time before through 3 days after anthrax exposure.

Fig. 1.

Protection against anthrax infection is optimized by adding Dalbavancin to CpG-adjuvanted AVA. A/J mice were challenged with 30 LD₅₀ of Sterne strain anthrax spores on day 0. Animals were treated once i.p. with 150 μg of Dalbavancin (□), 10 μl of AVA + 20 μg of CpG ODN (▲), or both (●) in the period from 30 days before to 3 days after challenge. Survival was monitored for 3 weeks. Data represent the combined results from three independent experiments involving a total of 10–18 mice/group. *p < .02 comparing combination therapy with either single therapy.

Fig. 2.

Vaccination, but not Dalbavancin treatment, induces long-term protection against infection. A/J mice were treated and challenged as described in Fig. 1. Surviving mice were re-challenged 6 weeks later with 30 LD₅₀ of Sterne strain anthrax spores. Data represent the combined results from three independent experiments involving a total of 16–18 mice/group.*p < .01.

Fig. 3.

Dalbavancin and CpG-adjuvanted AVA can be co-administered in a single syringe. A/J mice were challenged with 30 LD₅₀ of Sterne strain anthrax spores on day 0. Animals were treated i.p. with 10 μl of AVA + 20 μg of CpG ODN anytime from 15 days before through 2 days after challenge. 150 μg of Dalbavancin was co-administered with vaccine in the same syringe (■) or delivered 30 min later in a separate syringe (□). Survival was monitored for 3 weeks post-challenge. Results show the combined survival of all mice in each treatment group (N = 25/treatment from two independent experiments).

Fig. 4.

Anti-PA Abs do not improve the protection conferred by Dalbavancin plus CpG-adjuvanted AVA. (A) A/J mice were challenged with 30 LD₅₀ of Sterne strain anthrax spores. 3 days later, they were treated with 150 μg of Dalbavancin plus CpG-adjuvanted AVA and/or 100 μl of high-titered anti-PA antiserum. This quantity of antiserum was protective if administered within 24 h of challenge. (B) A/J mice were immunized with CpG-adjuvanted AVA plus Dalbavancin alone or combined with 100 μl of high-titered anti-PA antiserum. These mice were challenged 1 month later with 30 LD₅₀ of Sterne strain anthrax spores. The percent improvement in survival vs. controls is shown (N = 8–10 mice/group). *p < .01 vs. animals treated with Dalbavancin.