Antibodies binding diverse pertactin epitopes protect mice from Bordetella pertussis infection

Blockade of the Adenylate Cyclase Toxin Synergizes with Opsonizing Antibodies to Protect Mice against Bordetella pertussis

“…(B) Mice ( n = 4) were administered different amounts of the antipertactin antibody 2E9 via intranasal or intraperitoneal administration to determine a partially protective dose. Data shown are from the same experiment; isotype and intranasal data were previously reported ( 39 ). (C) To evaluate potential synergies between the antipertactin 2E9 and neutralizing anti-ACT M2B10 responses, mice were intranasally administered a partially protective 2E9 dose (0.5 μg), an M2B10 dose (10 μg), and/or an isotype control antibody for a total antibody dose of 10.5 μg.…”

“…To determine whether anti-ACT antibodies reduce B. pertussis lung bacterial colonization levels during the early stages of infection, we infected mice with a lower bacterial dose (5 × 10 6 CFU) and measured lung B. pertussis levels on day 3 after infection. Individual anti-ACT antibodies, a cocktail of four antipertactin antibodies ( 39 ), or controls were administered to mice intranasally before B. pertussis infection. Mice treated with only the isotype control antibody, M2B10, or M1F5 had similar bacterial colonization levels of ~10 7 CFU per mouse lung, whereas treatment with an antipertactin cocktail reduced lung levels ~100-fold ( P < 0.0001) ( Fig.…”

“…Accordingly, we hypothesized that neutralizing anti-ACT antibodies may synergize with antipertactin antibodies in vivo by protecting phagocytes, which can then more effectively target opsonized bacteria. To evaluate this possibility, we determined a dose and a route of administration of the bactericidal antipertactin antibody 2E9 ( 39 ) that provided a low but significant reduction in lung colonization. The intranasal administration of 10, 2, or 0.5 μg 2E9 correlated with lung colonization levels (Pearson correlation coefficient of −0.93), with even 0.5 μg significantly reducing B. pertussis colonization compared to isotype control-treated mice (~10-fold [ P < 0.001]) ( Fig.…”

“…This pathway can be triggered by pertussis lipooligosaccharides to deposit C3b on the bacterial surface, which, after conversion to iC3b, binds the α M β 2 receptor to trigger phagocytosis ( 54 , 55 ). In vitro , large amounts of naive serum efficiently kill wild-type B. pertussis ( 39 , 56 , 57 ), with different isolates exhibiting various sensitivities based on the recruitment of complement inhibitors ( 42 , 55 ). Since B. pertussis employs strategies to evade complement, and B. pertussis phagocytosis via α M β 2 is generally less efficient than Fc-mediated phagocytosis ( 52 ), the overall impact may be modest but sufficient to allow mouse survival after a high-dose bacterial infection, which is less impacted by complement evasion ( 58 ).…”

“…Hypothesizing that the preservation of phagocyte activities may be most useful in the presence of opsonizing antibodies, we evaluated the potential for ACT neutralization to synergize with a bactericidal antipertactin monoclonal antibody ( 39 ). Previous in vitro assays with human neutrophils showed that monoclonal antibodies neutralizing ACT contribute to B. pertussis killing only in the presence of opsonizing human immune sera ( 40 ).…”