An anti-invasiveness pneumococcal vaccine design: cost-effective pan-serotype protection

Summary

Streptococcus pneumoniae is the leading bacterial cause of vaccine-preventable pneumonia. It is a major cause of death in young children and the elderly. The bacteria live harmlessly in our noses but can cause severe infections when they spread to other sites, such as the lungs. Existing vaccines offer protection against a subset of the most common strains of these bacteria, but replacement disease is seen in vaccinated populations, whereby there is an increase in infections caused by non-vaccine strains. This happens when those serotypes not targeted by immunisation fill the niches vacated by vaccine-induced immune responses clearing the original bacteria from our noses. Replacement disease is a particular problem in parts of the world where S. pneumoniae spreads most readily between people. These tend to be low- and middle-income countries, particularly in sub-Saharan Africa and south/south-east Asia.

One solution to the problem of replacement disease is to design a vaccine that specifically targets our immune defences against S. pneumoniae that are able to cause severe infection, leaving the non-virulent (‘harmless’) bacteria untouched. With this approach, vaccination would not create an opportunity for other disease-causing bacteria to colonise the nose.

We have identified proteins that are present in all disease-causing S. pneumoniae, but absent from non-virulent strains. Use of these proteins in a vaccine may help us achieve immunity that is specifically directed against the most dangerous bacterial strains. The first step towards generating the vaccine would be to purify the proteins and determine whether they can stimulate immune responses in animal models.

Project Outcomes

Streptococcus pneumoniae is the leading bacterial cause of vaccine-preventable pneumonia. It is a major cause of death in young children and the elderly. The bacteria live harmlessly in our noses but can cause severe infections when they spread to other sites, such as the lungs. Existing vaccines offer protection against a subset of the most common strains of this bacterium, but replacement disease is seen in vaccinated populations, whereby there is an increase in infections caused by non-vaccine strains. This happens when those strains not targeted by immunisation fill the niches vacated by vaccine-induced immune responses clearing the original bacteria from our noses. Replacement disease is a particular problem in parts of the world where S. pneumoniae spreads most readily between people. These tend to be low- and middle-income countries, particularly in sub-Saharan Africa and south/south-east Asia.

One solution to the problem of replacement disease is to design a vaccine that specifically targets our immune defences against S. pneumoniae that are able to cause severe infection, leaving the non-virulent (‘harmless’) bacteria untouched. With this approach, vaccination would not create an opportunity for other disease-causing bacteria to colonise the nose.

We identified proteins that are present in all disease-causing S. pneumoniae, but absent from non-virulent strains. Use of these proteins in a vaccine may help us achieve immunity that is specifically directed against the most dangerous bacterial strains. The first step towards generating a vaccine is to purify the proteins and determine whether they can stimulate immune responses in animal models. That is what we have achieved in this project. We purified two proteins and tested them separately in infection models. After three immunisations with one of our two proteins, given together with an adjuvant to boost immune responses, mice were completely protected against pneumonia and bloodstream infection caused by S. pneumoniae. The second protein did not provide complete protection against infection, but immunised mice were still much more resistant to disease than those given a control (non-bacterial) protein. 

Using laboratory assays, we demonstrated that mice immunised with either of our two proteins produce strong antibody responses against the protein and also produce cytokines (chemical messengers) that help direct immune responses against the bacteria. The next steps for our project will be to repeat these experiments at scale and to investigate whether giving the two proteins in combination might boost their effectiveness further.