Human Monoclonal Antibody AVP-21D9 to Protective Antigen Reduces Dissemination of the Bacillus anthracis Ames Strain from the Lungs in a Rabbit Model

Abstract

Dutch-belted and New Zealand White rabbits were passively immunized with AVP-21D9, a human monoclonal antibody to protective antigen (PA), at the time of Bacillus anthracis spore challenge using either nasal instillation or aerosol challenge techniques. AVP-21D9 (10 mg/kg) completely protected both rabbit strains against lethal infection with Bacillus anthracis Ames spores, regardless of the inoculation method. Further, all but one of the passively immunized animals (23/24) were completely resistant to rechallenge with spores by either respiratory challenge method at 5 weeks after primary challenge. Analysis of the sera at 5 weeks after primary challenge showed that residual human anti-PA levels decreased by 85 to 95%, but low titers of rabbit-specific anti-PA titers were also measured. Both sources of anti-PA could have contributed to protection from rechallenge. In a subsequent study, bacteriological and histopathology analyses revealed that B. anthracis

Protective-antigen (PA) based anthrax vaccines confer protection against inhalation anthrax by precluding the establishment of a systemic infection

“…More importantly, in few studies where post-challenge bacteremia has been evaluated in vaccinated NHP or rabbits, the detection of vegetative bacteria in the blood has been infrequent and rare. 9,21,22 The very limited initial vegetative growth we observed with bioluminescence in the NALT of mice vaccinated with the three vaccines is consistent with the trace levels of LF we detected in rabbits vaccinated with Wyeth/IL-15/PA or AVA/Biothrax (see Table 1). It is likely that in these vaccinated rabbits, just as in vaccinated mice, some minimal initial vegetative growth of B. anthracis would have occurred with the release of some trace amounts of exotoxins that we were able to capture with our ultra sensitive LF detection assay, although the bacillary biomass of this limited growth was not only insufficient to trigger a pyrogenic response, but was also rapidly cleared without any evidence of detectable bacteremia in these rabbits.…”

Expression of either Lethal Toxin or Edema Toxin by Bacillus anthracis Is Sufficient for Virulence in a Rabbit Model of Inhalational Anthrax

“…Thus, we hypothesize that the production of both toxins enabled the WT organisms to effectively overcome host defenses, first in the LALN and then systemically, while host defenses were able to slow the proliferation and subsequent spread of organisms producing only one toxin, and effectively prevent systemic spread of organisms that lacked both toxins or a capsule. Such a function of toxin(s) may also help explain the protective effect of passive treatment with anti-PA MAbs in preventing widespread dissemination in infected animals (51,57). Interestingly, the postmortem organ histopathology following an i.v.…”

Killed but Metabolically Active Bacillus anthracis Vaccines Induce Broad and Protective Immunity against Anthrax

“…The titers of individual aliquots were determined by serial dilution and plating on BHI agar. Ames spores for challenge experiments were produced as described previously (41).…”