Antibacterial Vaccines and Diagnostics Development (ACTIVATE)
The DZIF working group "Antibacterial Vaccines and Diagnostics Development" (ACTIVATE) led by Alexander Klimka develops active and passive vaccines against bacterial pathogens and antibody-based rapid tests to detect antibiotic-resistant bacteria. In 2017, the World Health Organization (WHO) published a list of bacterial pathogens against which active agents must be found as a matter of priority. Without suitable new agents, the increasing prevalence of antibiotic-resistant bacteria will lead to untreatable infections in the near future. Against this background, the development of alternative antimicrobial agent candidates is urgently needed.
Infections with multi-resistant germs are occurring more and more frequently in hospitals. Pathogens that cause such nosocomial infections are summarised under the acronym "ESKAPE": Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species. Another problem is a decline in the number of approvals for new classes of antibiotics.
Possible alternatives are vaccines, which can be used therapeutically as passive immunisation in the form of monoclonal antibodies or prophylactically as active immunisation in the form of a vaccination with a bacterial target molecule. Passive immunisation is useful when a person has already been infected with a pathogen. Active immunisation is intended to protect against infection with a pathogen. The aforementioned procedures could significantly reduce the consumption of reserve antibiotics in particular and thus prevent the spread of resistance. An occurrence of resistance with the antibacterial vaccines developed so far has not been observed. Moreover, these vaccines have a pathogen-specific effect and thus spare the intestinal flora.
Alexander Klimka's working group has expertise in the development of antibacterial vaccines, which includes both the identification and purification of suitable target proteins and the generation and selection of monoclonal antibodies using appropriate infection models. The identification and recombinant production of resistance biomarkers and the subsequent generation of monoclonal antibodies by hybridoma technology is also used to develop simple and inexpensive antibody-based rapid tests that detect antibiotic resistance-mediating proteins in patient isolates. The rapid and reliable detection of antibiotic-resistant bacteria at the patient's bedside ("point-of-care") is another important key to the effective therapy of bacterial infections and the targeted containment of local endemics (outbreak management).
Antibodies are purified using Fast Protein Liquid Chromatography (FPLC) (left). In the middle, antibody-producing hybridoma cells are shown in 10-fold magnification. On the right, a target protein is under purification.
The working group is currently, in cooperation with Prof. Dr Martin Krönke, developing a vaccine against the methicillin-resistant hospital germ Staphylococcus aureus (MRSA). Furthermore, antibody-based rapid tests for the detection of antibiotic-resistant bacteria—such as carbapenem-resistant Klebsiella pneumoniae, vancomycin-resistant enterococci and carbapenem-resistant Acinetobacter baumannii—are to be developed for clinical application.
In cooperation with the Belgian company Coris BioConcept, a rapid test (OXA-23 K-SeT®; external link to a technical article on the evaluation of the rapid test) has already been launched on the market with which carbapenem-resistant A. baumannii pathogens can be detected. The second-generation rapid test called "RESIST ACINETO" detects three other resistance factors to the antibiotic in addition to OXA-23. The multi-carbapenemase assay is able to identify over 95 per cent of carbapenem resistance in A. baumannii infections within 15 minutes.
In addition, a DZIF platform shall make the expertise for the generation, selection and storage of monoclonal antibodies against novel antigens of the ESKAPE pathogens or other medically relevant target proteins available to other research groups in the future.
