Whooping cough is a vaccine preventable disease presenting with epidemic cycles linked to natural and/or vaccine-driven evolution of the etiologic agent of the disease, Bordetella pertussis. Adenylate-cyclase hemolysin (AC-Hly) is a major toxin produced by this pathogen that mediates macrophage apoptosis in-vitro and in-vivo. While current acellular pertussis vaccine (APV) formulations do not include AC-Hly, they all containpertussis toxin (PT) and can comprise filamentous haemagglutinin (FHA), that interacts with AC-Hly, and pertactin (PRN), which has been hypothesized to interact with that toxin as well. We aimed to study the capacity of specific antibodies to inhibit the in-vitro B. pertussis AC-Hly mediated cytotoxicity of J774A.1 murine macrophages in a background of changing bacterial population. We demonstrate that (i) clinical isolates of different type or PRN phenotype are all cytotoxic and lethal in the mouse model of respiratory infection and that lack of PRN production does not impact AC-Hly related phenotypes. (ii) Anti-AC-Hly antibodies inhibit cell lysis whatever the phenotype of the isolate while (iii) Anti-PRN antibodies significantly inhibit cell lysis provided the isolate produces this antigen, which might be relevant in-vivo for APV induced immunity, and (iv) anti-FHA antibodies only inhibit lysis induced by isolates collected in 2012, maybe indicating specific characteristics of epidemic lineages of B. pertussis.