Adenylate cyclase toxin-hemolysin relevance for pertussis vaccines

Abstract

The adenylate cyclase toxin-hemolysin (ACT, AC-Hly or CyaA) is a key virulence factor of Bordetella pertussis. It targets bactericidal activities of phagocytes, such as oxidative burst and complement- or antibody-mediated opsonophagocytic killing of bacteria. Through cAMP signaling, CyaA also skews TLR-triggered maturation of dendritic cells, inhibiting proinflammatory IL-12 and TNF-α secretion and enhancing IL-10 production and Treg expansion, likely hampering induction of adaptive immune responses to Bordetella infections. Non-enzymatic CyaA toxoid is a potent protective antigen and adjuvant that boosts immunogenicity of co-administered B. pertussis antigens and improves potency of acellular pertussis (aP) vaccines in mice. This makes CyaA a prime antigen candidate for inclusion into a next generation of aP vaccines. Moreover, recombinant CyaA toxoids were recently shown to be safe in humans in frame of Phase I clinical evaluation of a CyaA-based immunotherapeutic vaccine that induces Th1-polarized CD8⁺ cytotoxic T-lymphocyte responses targeting cervical tumors.

Keywords::

• adenylate cyclase toxin
• antigen delivery
• Bordetella pertussis
• cancer immunotherapy
• complement receptor 3
• dendritic cell
• pertussis
• pertussis vaccine
• T-cell epitope
• T-cell vaccine
• whooping cough

Financial & competing interests disclosure

This work was supported by grants No. GA13-14547S (P Sebo), GAP302/11/0580 (R Osicka) and P302/12/0460 (J Masin) from the Czech Science Foundation and by the Institutional Research Project RVO 61388971 of the Institute of Microbiology. All three co-authors are co-inventors on several patents protecting CyaA as antigen for pertussis vaccines and as a delivery tool and have participated on development of the technology licensed by Genticel S.A. as consultants (P Sebo) or by working on a contract research projects sponsored by Genticel and Crucell Holland BVP Sebo is co-owner of the start-up company Revabiotech SE that aims at development of a next generation of detoxified whole-cell pertussis vaccine. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Adenylate cyclase toxin-hemolysin (CyaA) is a key immunosubversive toxin of pathogenic Bordetellae and neutralizes host phagocytes by inhibiting their bactericidal capacities, thereby suppressing host innate immunity in the early phases of bacterial colonization.

• Adenylate cyclase toxin (ACT) subverts also adaptive immune responses through modulatory action on host dendritic cells.

• At the time of current acellular pertussis (aP) vaccine development efforts, ACT was unavailable as antigen that could be produced at an economic scale, little was known of its nature, mechanism of action, structure, protective antigenicity and possible use in aP vaccines.

• Over the past 25 years, much was learned on ACT, its immunogenicity in human infections was demonstrated, its protective vaccine antigen potency was shown in mice respiratory challenge models and mechanism of action was largely deciphered.

• Large-scale production of recombinant adenylate cyclase toxoids has been optimized and clinical cGMP batches have been produced and tested to be safe in Phase I clinical trials of T-cell vaccines developed for cancer immunotherapy.

• CyaA toxoid carrying HPV-16 and 18 oncoantigen E7 is currently under Phase II clinical trial evaluation as immunotherapeutic for papilloma virus-induced cervical cancer in women.

• Genetically fully detoxified CyaA-AC^–Hly^– toxoid has been developed, protected by an US patent and awaits evaluation as novel aP vaccine component in baboon weanling immunization and B. pertussis challenge studies.

• Current aP vaccines induce short-lasting immune memory and predominantly Th2-polarized immune response against only few B. pertussis antigens among which ACT, a key virulence factor is missing. It is expected that addition of CyaA and perhaps of some additional B. pertussis antigens into a next generation of aP vaccines, will significantly improve the Th1/Th2 polarity, efficacy and duration of immune memory induced upon vaccination of infants.

Notes