Developing a vaccine to protect against multidrug resistant Acinetobacter baumannii infections

Summary

Acinetobacter baumannii causes serious infections in patients admitted to hospital with other medical problems. A. baumannii infections are particularly common in Asian low- and middle-income countries (LMICs) such as Thailand, where it also causes infections caught by people outside of hospital. A. baumannii has very high levels of resistance to multiple antibiotics which makes it particularly difficult to treat and as a result, A. baumannii infections have a >30% mortality and are responsible for about 15,000 deaths per year in Thailand alone. Hence, there is a dire need for a vaccine to prevent serious A. baumannii infections, yet there are no existing A. baumannii vaccines and no vaccine candidates have reached clinical trials to date. In a study developing an antibody therapy to treat patients with A. baumannii infections, we have identified multiple A. baumannii proteins that cause immune responses in mice and humans. Antibody to these proteins binds to the bacteria and improves the ability of the body to kill A. baumannii. As well as being good targets for an antibody therapy, these proteins could be effective vaccine candidates. The work planned in this proposal would test this by investigating how effective these proteins are as vaccines in mouse models of A. baumannii infection. The results would allow us to select the best proteins to take forward in future studies to develop a vaccine that can reduce the significant amount of illness and deaths caused by A. baumannii.

Project Outcomes

Acinetobacter baumannii causes serious infections, such as pneumonia, in hospitalised patients with other underlying conditions. These infections are commonly found in Asian low- and middle-income countries (LMICs) where antibiotic use is not well-regulated. A. baumannii is very resistant to multiple antibiotics, making these infections extremely difficult to treat, which often leads to death. For example, mortality rates can be as high as 70%^1-6, with around 80% of strains being multi-drug resistant, and some strains that are resistant to last-resort antibiotics^1,5,8. Therefore, we are in dire need of a new antimicrobial therapy or vaccine to treat and prevent these multidrug resistant infections. Currently, there are no vaccines in development for A. baumannii.

 To approach this, we identified multiple A. baumannii proteins which stimulate an immune response both in mice and in humans during an infection. We have previously shown that antibody to these proteins can bind multiple strains of A. baumannii and can help to inhibit this pathogen. Therefore, our aim was to test the proteins themselves as vaccine candidates in a mouse model of infection.

To test how protective these proteins are as vaccines, mice were vaccinated three times with single proteins. We collected sera from the mice which showed that antibodies from the mice can recognise their respective A. baumannii proteins. We also infected these vaccinated mice with a clinical A. baumannii strain, which showed that some of these vaccines can partially protect against an A. baumannii infection.

Next, we vaccinated mice three times with a combination of the proteins, in an attempt to improve protection. However, the vaccination with combinations of these antigens did not fully protect mice from a clinical A. baumannii infection. We concluded from this study that although our potential vaccine antigens can result in significant antibody responses in mice, further work is needed to ensure these immune responses are strong enough to prevent future A. baumannii infections.