Radiation-Inactivated Acinetobacter baumannii Vaccine Candidates

Abstract

Acinetobacter baumannii is a bacterial pathogen that is often multidrug-resistant (MDR) and causes a range of life-threatening illnesses, including pneumonia, septicemia, and wound infections. Some antibiotic treatments can reduce mortality if dosed early enough before an infection progresses, but there are few other treatment options when it comes to MDR-infection. Although several prophylactic strategies have been assessed, no vaccine candidates have advanced to clinical trials or have been approved. Herein, we rapidly produced protective whole-cell immunogens from planktonic and biofilm-like cultures of A. baumannii, strain AB5075 grown using a variety of methods. After selecting a panel of five cultures based on distinct protein profiles, replicative activity was extinguished by exposure to 10 kGy gamma radiation in the presence of a Deinococcus antioxidant complex composed of manganous (Mn2+) ions, a decapeptide, and orthophosphate. Mn2+ antioxidants prevent hydroxylation and carbonylation of irradiated proteins, but do not protect nucleic acids, yielding replication-deficient immunogenic A. baumannii vaccine candidates. Mice were immunized and boosted twice with 1.0 × 107 irradiated bacterial cells and then challenged intranasally with AB5075 using two mouse models. Planktonic cultures grown for 16 h in rich media and biofilm cultures grown in static cultures underneath minimal (M9) media stimulated immunity that led to 80–100% protection.

Select Whole-Cell Biofilm-Based Immunogens Protect against a Virulent Staphylococcus Isolate in a Stringent Implant Model of Infection

“…In each instance, the CFU per mL of MRSA-M2 was over 1 × 10 9 initially and declined to zero after a 100 s exposure, indicating rapid and complete inactivation. For each of the preparations, the inactivation kinetics was equivalent in the presence or absence of MDP, indicating that MDP did not enhance survival, consistent with previous observations that MDP does not protect against direct nucleotide damage [25,26,32]. A five-minute UVC exposure was selected for subsequent in vitro and in vivo experiments to give a large safety margin.…”

“…To overcome epitope damage, we have developed a method: irradiation in the presence of the powerful antioxidant manganese-decapeptide-phosphate (MDP), derived from the extreme radioresistant bacterium Deinococcus radiodurans. When bacteria are mixed with MDP and exposed to supralethal doses of γ-rays or UVC irradiation, their genomes are destroyed, but antigenic epitopes remain intact [25,26]. In the presence of MDP, the epitopes are protected and can still stimulate immune protection.…”

Gamma-Irradiated Fowl Cholera Mucosal Vaccine: Potential Vaccine Candidate for Safe and Effective Immunization of Chicken Against Fowl Cholera

“…For example, gamma-irradiated S. pneumoniae vaccine produced after inactivation with 10 kGy gamma irradiation elicits strong mucosal and systemic immune responses in mice model, which is indicative of the affectivity of gamma irradiation as a method for the development of a killed whole-cell pneumococcal vaccine ( 21 ). Furthermore, sterilization doses for radiation-sensitive organisms could be significantly reduced, which would be expected to reduce damage to epitopes required to develop a protective immune response while maintaining an adequate margin of safety to ensure complete inactivation ( 22 ).…”

Vaccine development to control the rising scourge of antibiotic-resistant Acinetobacter baumannii: a systematic review

“…). An inactivated whole-cell vaccine derived from antibiotic-exposed MDR A. baumannii (I-M28-47-114) (Shu et al 2016) and radiation inactivated cells were found to be protective (Dollery et al 2021).…”