New thinking on meningitis vaccines
The Daily Mail has hailed the possibility of a “universal vaccine” that could be “the key to beating all forms of meningitis”.
The news is based on scientific research in mice, which investigated the potential for a protein-based vaccine against Streptococcus pneumoniae. This bacterium causes pneumococcal meningitis, the second most common and life-threatening form of bacterial meningitis in the UK. The current pneumococcal vaccine used as part of the childhood immunisation schedule works by targeting the fragments of sugars on the surface of bacteria. However, patterns of sugar vary widely across bacterial strains, while related strains of bacteria tend to possess similar surface proteins. In theory, a protein-based vaccine could offer wider protection.
While this research found that a protein-based vaccine gave mice protection against pneumococcal bacteria, there is still a long way to go before it could be used in humans. A vaccine based on this technology would first need to be developed for testing in humans and then be proven effective and safe through various clinical trials The most common life-threatening form of bacterial meningitis in the UK is meningococcal meningitis. This is caused by the Neisseria meningitidis bacterium, which was not examined in this research.
Where did the story come from?
The study was carried out by researchers from Harvard Medical School, Boston, and was funded by the US National Institutes of Health, the PATH research foundation and other fellowship awards. The study was published in the peer-reviewed scientific journal Cell Host & Microbe.
The Daily Mail generally represented this research well, though the newspaper is incorrect in talking about a “universal meningitis vaccine”. This trial vaccine could potentially offer protection against a wide range of Streptococcus pneumoniae strains, but there are other bacterial causes of meningitis, including meningococcal meningitis, the most common and life-threatening form of bacterial meningitis.
What kind of research was this?
Current meningitis vaccines target the sugar coat found on the surface of bacteria. This laboratory research in mice investigated the possibility of developing a vaccine that targets the proteins on the surface of the bacteria. This is because the proteins found on their surface are consistent between strains of bacteria. It is hoped that vaccines acting on these common proteins would offer protection against a wider range of strains of a particular bacterium.
Meningitis involves inflammation of the lining of the brain and spinal cord. It can be caused by infection from viral, bacterial and sometimes fungal organisms, but bacterial meningitis is the most serious and most widely known form. It can sometimes progress to bacteria invading the blood stream and causing blood poisoning (septicaemia).
There are several bacterial causes of meningitis, but meningococcal meningitis is the most common form in the UK. It is caused by the Neisseria meningitidis bacterium, of which there are several strains, referred to as A, B, C etc. The second most common cause of life-threatening bacterial meningitis in the UK is pneumococcal meningitis, caused by Streptococcus pneumoniae.
Currently, there are three routuine vaccinations that give some protection against different forms of bacterial meningitis, with one protecting against meningococcal meningitis, one against streptococcal meningitis and another protecting against meningitis caused by Haemophilus influenzae type b bacteria:
- The current meningococcal vaccine in the UK acts against the ‘C’ strain of the Neisseria meningitidis bacterium and has been widely offered to adolescents and young adults since that late 1990s. However, it only protects against strain C, and offers no protection against other bacterial causes or against other meningococcal strains, including the more common B strain.
- Protection against Streptococcus pneumoniae is provided by the pneumococcal vaccine, given as part of routine childhood immunisations. This vaccine protects against most of the common strains of this streptococcal bacteria.
- Babies are routinely vaccinated using the Hib vaccine, which offers protection against meningitis caused by Haemophilus influenzae type b bacteria. This is one of the vaccines included in the 5-in-1 vaccinations given to babies from 8 weeks onwards.
All three types of meningitis vaccine contain a fragment of the bacteria’s sugar coat linked to a protein (so-called conjugate vaccines). When exposed to the vaccine, the body mounts an immune response against these sugar coat fragments and produces antibodies against them. This allows the body to swiftly mount an immune response if it encounters the relevant bacteria in the future.
This research specifically investigated the development of a new pneumococcal vaccine that targets surface proteins rather than sugars. The researchers say that a consistent range proteins is found across more than 90 known pneumococcal strains.
What did the research involve?
This animal research focused on the background knowledge that when mice have been infected with live pneumococcal bacteria (or a vaccine to mimic this), a type of cell called a CD4 T lymphocyte (T helper cell) is activated. These cells do not destroy foreign organisms or infected cells themselves, but instead send chemical signals that recruit other immune cells which produce antibodies and destroy the organisms. The researchers wanted to see which pneumococcal bacterial proteins would activate CD4 T cells. For their tests, they created a protein “expression library”, which was believed to contain over 95% of all possible pneumococcal proteins.
To start with, the researchers used the group of mice that already had immunity against pneumococcal bacteria (either through previous infection or through being given a protein-based vaccine). They isolated CD4 T helper cells from the spleen of these mice, and then placed these cells in culture with the different proteins in their expression library. The aim was to measure the amount of a molecule called IL-17A that the CD4 T helper cells released when exposed to the different proteins. Release of IL-17A indicates the activation of the CD4 T helper cells. In this way, the researchers could see which pneumococcal proteins had been “recognised” by the CD4 T helper cells from the immune mice (i.e. which proteins were the "best match" and would be the most suitable candidates for use in a vaccine).
The researchers also did another screen of CD4 T cells taken from normal, non-immune mice. They found that these cells did not release IL-17A, thereby demonstrating that the earlier responses were specific to T cells from mice that had already been exposed to pneumococcal bacterial proteins.
They then presented mouse cells and human white blood cells with Streptococcus pneumoniae in the laboratory. This was done to confirm that there was a response from IL-17A-secreting T cells against the proteins that had been identified through the screen.
They also carried out further tests to confirm that immunisation of mice with the identified pneumococcal proteins later protected mice against colonisation of the lining of the nose and throat by pneumococcal bacteria.
What were the basic results?
From their protein screen, the researchers prioritised five proteins out of 17 tested proteins that gave the best response when incubated with the CD4 T helper cells.
They also demonstrated that when human white blood cells and mouse cells were exposed to pneumococcal bacteria, IL-17A-secreting CD4 T helper cells mounted a response against two of the proteins they had identified in their screen.
When mice were immunised with the identified pneumococcal proteins, this prevented the membranes lining their noses and throats from being colonised by the bacteria. Further tests also treated the mice with anti-CD4 or anti-IL-17A antibodies, which “blocked” the response of CD4 T helper cells. This reduced their immune response so that they were no longer protected against pneumococcal bacteria. This confirmed that the cells most likely to be initiating this immune response to the bacterial proteins were IL-17A-producing CD4 T helper cells.
How did the researchers interpret the results?
The researchers say that their work demonstrates how protein screening can identify specific proteins that could protect against colonisation by Streptococcus pneumoniae when included as part of a vaccine that triggers T helper cells to act against common bacterial proteins.
Conclusion
This scientific research used protein screening to identify which pneumococcal bacteria proteins elicit an immune response from mice that have already been exposed to Streptococcus pneumoniae, and hence which pneumococcal proteins would be the most appropriate to trial in a vaccine. Traditional conjugate vaccines use fragments of sugar from the bacterial surface, but as different strains of bacteria tend to possess certain common proteins, it is hoped that such a vaccine would lead to wider immunity.
After this research identified key proteins, the findings were then explored through animal testing. These identified pneumococcal bacterial proteins, which were then put into a vaccine that was given to a set of mice. It prevented the membranes in their nose and throat from being colonised when they were exposed to live Streptococcus pneumoniae bacteria.
While this research demonstrated that such a protein-based vaccine could give mice protection against pneumococcal bacteria, there is still a long way to go before a vaccine for humans can be developed. Such a vaccine would need to be tested in humans and undergo various clinical trial stages to establish safety and efficacy. As the researchers say, at the current time, it is unknown whether giving a human a vaccine against proteins would provide as much immunity as the currently available conjugate vaccines that target bacterial sugars.
Also, though the newspapers talked about a “universal meningitis vaccine”, this research only considered a pneumococcal vaccine that would give protection against wider strains of Streptococcus pneumoniae. Streptococcus pneumoniae is only one cause of bacterial meningitis, the most common form of which, meningococcal meningitis, is caused by Neisseria meningitidis. There are also several strains of this bacteria, and we currently only have a conjugated vaccine against the single ‘C’ strain. Other, direct research would be needed to investigate whether it is possible to produce a protein-based vaccine against wider strains of Neisseria meningitidis, which cannot be judged at the current time.
