Maximising mucosal responses to mRNA vaccines for Acinetobacter baumannii

Summary

Bacterial lung infection leading to pneumonia is a common consequence of long-term hospitalisation, especially when patients are intubated. One of the main causes of hospital acquired pneumonia in low and middle income countries is Acinetobacter baumannii. This bacterium is extremely drug resistant, leading to high mortality rates following infection. Previously we have developed a model of A. baumannii lung infection and used this to identify novel antigens using a reverse-vaccinology approach. 

The identification of novel antigens enables us to explore different vaccine platforms. Of particular interest, following their success in the control of the COVID-19 pandemic, are RNA vaccines. In the proposed project we wish to explore how we can use the new RNA vaccine technology to generate immune protection directly in the lungs. We hypothesize that, because A. baumannii mostly infects the lungs, targeting immune responses to them will give much better protection. 

We will investigate how best to deliver RNA vaccines against A. baumannii into the lungs and dissect which aspects of induced immunity provide protection. By combining RNA vaccines with other vaccine approaches (for example outer membrane vesicle vaccines) we may synergise the best aspects of each vaccine.

The project will generate proof of concept data about a novel vaccine approach for an important AMR bacteria; delivering the vaccine to the site of infection for maximum protection. We anticipate taking this research forwards into early clinical trials with a view of developing a vaccine as part of a broader strategy to control infections with A. baumannii.

Project Outcomes

Vaccines are a core part the strategy to prevent AMR bacteria. One particularly challenge bacteria with extremely high rates of antimicrobial resistance is Acinetobacter baumannii. This can cause a very severe lung infection, especially in people who are in intensive care, with very high rates of mortality (up to 50%).  We have previously developed a novel vaccine that we have shown can reduce infection with this bacteria. In follow up work we dissected the response induced by our successful vaccine and identified 2 bacterial proteins that are recognised by the immune system. We hypothesised that these proteins might be able to provide protection against infection by themselves.

To understand more about the immune response, we used the RNA vaccine platform that has been so successful during the COVID-19 pandemic. One of the advantages of the RNA platform is the speed with which new proteins can be tested for vaccines. In the current project, we cloned the proteins from A. baumannii into an RNA vaccine. We then tested this in pre-clinical models for whether it would lead to an immune response and if this could protect against infection. One of the two proteins we identified was able to protect against subsequent infection. This is a very promising result because RNA vaccines have not been tested as much for bacterial infections.

The other aim of this project was to look at whether immunising via the nose as part of an RNA vaccine regime would be protective. To do this, we made use of a heterologous prime-pull approach; what this means is that the first immunisation was performed intramuscularly, the second intranasally. For the intranasal vaccination, we used the same bacterial protein, but using a novel delivery platform derived from bacteria called recombinant OMV (rOMV). The rOMV technology utilises a natural feature of bacteria – that they spit out little bubbles of their cell walls containing proteins. We and other groups have shown these make great vaccines especially if delivered up the nose. The advantage of immunising the nose is that this is where the bacterial infections happen, so protection there may be able to prevent the bacteria entering the body and also stop spread to other people. We generated a novel rOMV that contained our protein of interest and immunised mice with RNA into the muscle followed by the rOMV intranasally. However, in this instance we did not see increased protection. Further work is needed to optimise the approach and look for ways to improve mucosal immunity to RNA vaccines.

Overall the project demonstrated that the RNA vaccine approach can be used for this clinically important bacteria, and we hope with some further improvements that we can use it as a way to prevent disease and death from this deadly bacteria.