Preclinical Safety

The genetic attenuation achieved in the BPZE1 strain has been demonstrated to be stable and without reversion to virulence. Since no natural horizontal gene transfer mechanism exists between B. pertussis cells, reversion of large deletions, such as those for the dermonecrotic and ampG genes, is thus unfeasible. Pertussis toxin was inactivated in BPZE1 by two independent mutations affecting two amino acid residues that are both critical for its ADP-ribosyltransferase activity, one being essential for substrate binding and the other for catalysis. Reversion of both to active amino acid residues is required to regain enzyme activity, which is virtually impossible.

The genetic stability of BPZE1 has been demonstrated upon continuous serial passages both in vitro and in vivo in mice for up to one year (Feunou et al., 2008). Further preclinical safety data also indicates that BPZE1 does not exacerbate airway pathology associated with allergen sensitization, although virulent B. pertussis infection exacerbates inflammation in such model (Kavanagh et al., 2010). Instead, BPZE1 administration actually protects against experimentally induced allergic pulmonary pathology, and reduces allergen-driven IL-4, IL-5 and IL-13 production. Finally, whereas the virulent parent strain kills MyD88-deficient mice within one to two weeks after nasal infection with 104 colony-forming units, all mice survive for at least one month after infection with even a 100-fold higher dose of BPZE1, and no significant weight loss is observed upon infection with BPZE1.

The genetic stability and excellent pre-clinical safety profile of BPZE1 has allowed this strain to be downgraded from safety level 2 to safety level 1 in several European countries and was a predecessor to testing in Phase I studies.

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