Nature Medicine publishes BPRC findings
Rijswijk, 21 january - A different approach to vaccination could stop hypersensitive rhesus monkeys from developing tuberculosis (TB). Researchers from the Biomedical Primate Research Centre (BPRC) have demonstrated that administration of the existing BCG vaccine via the airways instead of the skin can protect against TB. As far as is known, this is the first time that the protection of rhesus monkeys against infection with TB - by means of a preventive vaccine - has been documented. Nature Medicine, a prominent scientific magazine, published the BPRC article about this study this week.
The research findings show that possibly not so much a new vaccine, but a different approach to the administration of BCG, could herald a breakthrough in the preventive treating of tuberculosis at some point. ‘Prospects for the future are promising’, says Frank Verreck, head of the tuberculosis research team at the BPRC. ‘The alternative administration of BCG via a different route could quickly progress to the clinical test phase. In this respect, it is interesting to note the description, earlier this year, of how people could benefit from being revaccinated with BCG later in life.’
Further research and translation to application in clinics
According to Verreck, it seems obvious to consider the mucosal route (via the lung mucus) for a BCG revaccination strategy of this nature. However, additional research will be necessary, particularly given the need to safeguard the safety of individuals. ‘We discovered the potential for protection after administering a mucosal vaccination to animals that had not previously been exposed to mycobacteria, as far as we had been able to determine. It is very rare to encounter humans who have not had any previous exposure to mycobacteria.’
Verreck explains that 80% of children worldwide are vaccinated with the living, attenuated Mycobacterium bovis Bacille Calmette-Guérin (BCG) at birth. Added to this, many people in areas where TB is prevalent are latently infected: they carry the bacteria without becoming ill themselves. ‘It still needs to be established whether it is possible to safely administer a living BCG vaccination via the lungs following a previous exposure to the disease and also provide the same level of protection as that currently found.’ However, Verreck is optimistic. ‘If nothing else, the results we have just published do show us what a successful, improved TB vaccine response could look like!’
Tuberculosis: a world-class challenge
Tuberculosis is developed following infection with the Mycobacterium tuberculosis bacteria and is still the most deadly infectious disease in the world. Antibiotics are relatively ineffective and have a large number of unpleasant side effects. Also, despite the widespread use of BCG as a preventive vaccine, approximately 4,500 thousand people a day are still dying from TB.
To be in a position to combat TB better, scientists are doing research to establish why one individual will develop protective immunity - whether or not after a BCG vaccination - while another will become ill, with the ultimate object of improving the current BCG vaccination regime and, by doing this, reducing the spread of TB.
Just a very limited number of research centres are able to conduct TB research of this nature on primates. Given this situation, the BPRC frequently works with foreign researchers as part of bigger networks. The current research was co-funded by the European Commission, via the so-called TBVAC.2020 project, in which tens of groups from Europe and beyond are working together to develop a better TB Vaccine. This project is being led by the TuBerculose Vaccine Initiative (TBVI) in Lelystad and there is also a special working group that focuses on developing new models for TB vaccine analysis and research.
A new study design: simulating natural exposure
The most important discoveries made by BPRC tuberculosis researchers may contribute to the development of an improved vaccination strategy. Building on specialist literature and their earlier findings, the recent research done by these researchers shows that the administration of BCG via the lung mucus (the mucosa) results in a unique immune pattern of immune responses and protects a very sensitive host species population against TB infection and illness.
Experimental infection usually involves the administration of a one-off dose of Mycobacterium tuberculosis, resulting in demonstrable bacteria growth and pathology (illness) within a period of three months. It is hoped that this experimental treatment will help limit this growth and illness. However, in the current experiment, Mycobacterium tuberculosis was administered not just once, but a number of times, in an extremely low dose, in simulation of a natural exposure situation.
At the end of the experiment, it was found that all non-vaccinated controls were infected. However, it was also found that infection with TB was delayed significantly in subjects that had been immunised in advance via the lung mucus - and not via the skin, as is customary when administering the BCG vaccination. Even better, after the experiment, the researchers encountered no symptoms of the disease at all in two out of eight of rhesus monkeys and no TB bacteria in the tissues either; they were found to have full protection. The disease was significantly less severe in the animals that had become infected and a significant reduction in the number of bacteria was evident. So-called open TB, where the pathogen is present in saliva or lung lavage fluid in a transmittable form, was not encountered at all following vaccination via the lung.
A better understanding of protective immunity
To gain a better understanding of how mucosal vaccination via the lung mucus works - in comparison with standard BCG administration via the skin - scientists from the BPRC also conducted research on immunological responses. When doing this, they focused initially on the response pattern of the so-called T-helper lymphocytes. T-helper cells play a key role in complex immune responses. They were studied both after vaccination and after the repeated infection, in the blood and in the lung. ‘What was striking was the unique immune pattern responses in the lung following mucosal BCG vaccination’, says Karin Dijkman, the PhD student who conducted this research. ‘Of all of the responses, multifunctional, interleukin-17-producing T-helper cells and the production of the signal substance interleukin-10 following test infection were found to be very prominent in animals in which BCG has previously been administered via the lungs.’
These results shed new light on what has been misunderstood for years now: both BCG vaccination and the Mycobacterium tuberculosis infection prompt immune-activating responses. The best known of these responses is the production of the signal substance interferon-gamma (also often an indication leading to the diagnosis of TB). Although the interferon-gamma response is important, it is not sufficient to explain why BCG provides protection in some situations and not in others, for example. The interleukin-17 that is found in this study is an activator of antibacterial responses too, but switches differently. By contrast, interleukin-10 has an attenuating effect on inflammatory responses. ‘Perhaps it is the combination of these two substances in the lung that helps to get the mycobacteria under control without the infection causing any damage’, Karin emphasises.
The importance of animal testing for TB
Experimental tuberculosis research on humans has its limitations. Given the severity of the disease and the relatively poor efficacy of antibiotics, the experimental infection of humans with Mycobacterium tuberculosis is out of the question. The testing of new vaccination strategies in areas where TB is a serious problem is time-consuming, expensive and fundamental research opportunities are just limited. Animal testing is important to ensure the early selection of promising new vaccines for research on humans and, above all else, to gain a better understanding of how protective immunity to TB works. Rhesus monkeys are very susceptible to TB and are, perhaps, the best animal model with strong predictive value for humans.
‘The data just published has enabled us to establish the possibility, in principle, to use vaccination to protect super-susceptible individuals against TB’, Frank Verreck emphasises. ‘We have also learned what a successful improved resistance response could look like following vaccination. This is something that we can focus on in future TB vaccine research. So, we are definitely on the right track. If we are able to gain the support and resources we need for our research, we can be very confident in the successful completion of our mission to rid the world of TB one day.’