Antigen discovery to accelerate Acinetobacter baumannii vaccine development

Summary

Untreatable infections caused by antimicrobial resistant bacteria are one of the major healthcare threats facing mankind. Most of these fatal infections occur in low- and middle-income countries (LMICs), where drug resistant bacteria are more prevalent. We are aiming to prevent infections caused by the bacterium Acinetobacter baumannii, a common cause of infections within hospitalised individuals; the disease has a very high mortality rate in Southeast Asia. One approach to tackle the problem of drug resistant Acinetobacter baumannii is to develop vaccines to prevent infection. In order to develop vaccines we need to understand how our immune systems see the bacteria, and to specifically identify which parts of the bacteria can be targeted by antibodies to prevent infection.

Our project is a collaboration between two leading academic institutions, Imperial College and the University of Cambridge, researchers in Vietnam and the biotechnology company Kymab. We will screen bacterial isolates collected from hospitals in Vietnam to find novel antigens. In particular we will be using infection models to determine whether these new vaccines can protect against infection. This work will provide a platform for future work to control this pathogen.

Project outcomes

Lower respiratory tract infections (LRTIs) are the leading cause of infectious death globally. Affecting low to middle income countries most severely, major risk factors include HIV, low vaccination rates, overcrowding, and malnutrition. Pneumonia is a leading cause of death in children under 5 years old. Ventilator associated pneumonia (VAP) is defined as pneumonia that occurs over 48 hours after a patient has been mechanically ventilated. VAP is the most frequently occurring infection in intensive care units of hospitals and has the highest associated costs and mortality rates out of any infections acquired through hospitalisation. 

The bacteria Acinetobacter baumannii is frequently responsible for causing hospital acquired pneumonia. A. baumannii is a Gram negative bacterium, which means it has an external protective membrane around it. This outer membrane provides protection against many antibiotics. A. baumannii have also acquired many genetic elements that give the bacterium additional mechanisms to both evade antibiotics and reduce their effectiveness. Infections with A. baumannii can be very problematic. Many different strains of A. baumannii  are now able to survive treatment with many modern day antibiotics. A. baumannii are constantly evolving and developing new mechanisms to protect themselves against the already severely limited options.With the efficacy of antibiotic treatment quickly declining and the slow development of new antibiotics we must develop new methods to treat antibiotic resistant infections. 

We have been using A. baumannii bacterial isolates that have been collected from hospitals in Vietnam to develop lower respiratory tract infection models using clinical strains of A. baumannii and develop protocols that can be used to assess the efficacy of the immune response. We were able to intranasally infect mice with a laboratory reference strain of A. baumannii, which resulted in low levels of colonisation and mild disease. 

When we intranasally infected mice with clinical strains we saw increased levels of colonisation and more severe disease when compared to the laboratory reference strain. We then vaccinated mice using outer membrane vesicles (OMVs), which are spherical vesicles that are produced naturally by Gram negative bacteria and are made up of an inner cell membrane and a bacterial outer membrane. OMVs produced by the laboratory reference strain and clinical strains of A. baumannii were used to immunise mice in a prime boost approach before intranasal infection with the same strain of A. baumannii that each mouse was vaccinated against. We found that OMVs provide protection against infection in mice, increasing levels of OMV specific antibodies and reducing bacterial loads. 

In conclusion we developed effective A. baumannii infection models with both clinical strains and a laboratory reference strain. We also showed that A. baumannii OMVs can be used to vaccinate mice to reduce bacterial burden and induce A. baumannii cross-reactive antibody responses. The development of this model provides a platform that can be used to test novel vaccines and therapeutics against multi drug resistant A. baumannii  respiratory tract infection. We have also shown that OMVs have good potential to be used in the development of an A. baumannii vaccine.


John TregoningDr John Tregoning
Senior Lecturer
Imperial College London (UK)

Collaborators:
Prof Paul Kellam, Kymab Ltd (UK)

Prof Stephen Baker, Medicine, Cambridge and OUCRU Vietnam (UK & Vietnam)

Miss Sophie Higham, Imperial College London (UK)

Dr Stephen Reece, Kymab Ltd (UK)

Dr Aisha Krishna, Kymab Ltd (UK)