New oral delivery system for vaccines could help to combat infectious diseases.

Infectious Bursal Disease occurs in chicken flocks

Scientists from the University of Greenwich develop a new oral vaccine delivery system that could have a potential use in combating Infectious Bursal Disease which is widespread in commercial chicken flocks. Credit:Dreamstime
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Infectious Bursal Disease (IBD) or Gumboro’s disease is caused by the highly contagious Infectious Bursal Disease Virus (IBDV) and is widespread in commercial chicken flocks. The virus causes increased susceptibility to infections and is a big problem for farmers who suffer a huge loss of productivity due to the disease. Current vaccinations against the disease are labour intensive, sub-optimally effective, costly and time consuming. In a recent study scientists from the University of Greenwich and ISIS have used neutrons to help them develop a new oral vaccine delivery system that could have a potential use in combating this disease in the future leading to increased productivity.

This research has recently been published in the International Journal of Pharmaceutics.

An effective oral vaccine delivery system could have enormous humanitarian value for both clinical and veterinary usage.

With the average Britain throwing out about a fifth of their food –enough to fill 9 Wembley stadiums, it’s clear that the idea of food security doesn’t resonate very highly with many of us. However, with the global population predicted to hit 10 billion by 2050, generating enough food to feed ourselves is becoming a fundamental issue, and one which me might start to feel the pinch of in years to come.

Part of the problem in ensuring a secure food supply is the spread of diseases in livestock. Infectious Bursal disease poses a major setback to productivity and profitability in the poultry industries of both developing and industrialised countries. In fact, a recent study of three recurrent outbreaks of IBD experienced by a Nigerian farmer between 2009-2011, found that even with vaccination against IBD at two and four weeks of age, losses amounted to over 53,000 birds and over three billion in Nigerian currency.

So what’s the problem with current vaccines?

Most current vaccines show a poor efficacy in the presence of certain levels of maternally derived antibodies. Some other vaccines have a better efficacy and may even break through higher levels of maternally derived antibodies; however, these vaccines can also reduce activation of the immune system. Therefore they may not fully protect chickens against infection by the virus. Furthermore on-farm administration of the vaccines via injection of a large number of animals is technically demanding, and costly.

Dr Simon Richardson, University of Greenwich explains, ‘IBD is prevalent among chicken populations both in the developed world and third world. The nature of the disease is that it’s a bit like chicken HIV, it does terrible things to the chickens immune system which leaves them susceptible to other infections. The problem is however that maternal antibodies, present in the chicks, interfere with vaccine efficacy and you can imagine, if you have a bunch of chickens all born on different days this immunity drops off at different times. Also when you have thousands and thousands of hens, vaccinating them all is very difficult and time consuming. So the idea behind the project was really to develop something that we could put in the chickens feed in a form that could be used to inoculate chickens over multiple rounds, so you don’t have to have a synchronised regime and therefore hopefully there’s a better chance of successful vaccination.’

Dr Richardson and his team have come up with a new complex that could be used in this way to deliver vaccines orally, with some development this system has the potential to be of huge benefit economically. Some of the barriers to successful oral vaccination are the acidic and proteolytic environment of the stomach and the ability to present antigens successfully to cells of the immune system and so the group are working on systems that can overcome these barriers.

The complex they are working on consists of a silica bead in the middle surrounded by the protein which is the antigen. The protein is buffered so it has a positive charge which will then interact with the negatively charged silica. The entire system is then coated in a very thin layer of fatty acid called myristic acid which is a food additive derived from nutmeg..

What’s special about silica?

‘The reason why we started working with silica’ explains Dr Richardson, ‘is that it has a lot of properties that we look for in a good carrier; it’s used by chickens in their diet to help digest things and its considered a safe material to take orally and generally regarded as safe by the FDA. One of the first things we discovered is that we could get a synthetic protein to stick to the silica core but it wasn’t protected against proteases in the gut. However we then found that coating it in a variety of fatty acids created a steric barrier stopping the proteases from getting to the protein.’

The idea behind the coating is that the complex is stable as it goes through the stomach but releases the protein, as it goes into the intestine, which is surveyed by the immune defence system. The complex is stable in an acid pH, but as soon as the pH starts to neutralise, the myristic acid ionises and this drives release from the silica core.

The vaccine delivery system

The vaccine delivery system is stable as it goes through the stomach but releases the protein as it enters the smal intestine. Creative Commons, graphical abstract, Journal of Pharmaceutics, licensed under CC BY-NC-ND 3.0
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The team used the LOQ and SANS2D Instrument at ISIS in order to characterise the system and measure the different layers. Dr Richardson explains, ‘In any pharmaceutical endeavour one of the first things you need to know is what you’ve got in the pot. To figure out how a material is going to behave it’s important to know what it is and that’s one of the things we have been using neutrons for.’

‘These are materials that are very small; they’re on the nanoscale, and in contrast to other analytical techniques neutrons are particularly good because of the resolution they offer.  One of the things that we discovered in this system is that we have managed to get a very thin coating of fat around our protein which is immobilised on silica. We wouldn’t be able to see that coating of fat with enough accuracy using other analytical methodologies, which is one of the reasons why neutrons are so particularly brilliant for this application.’

‘There were three things we found out in this study. Firstly that we could see protection of the protein being mediated by the myristic acid coat. Secondly that when we released proteins they retained secondary structure which is very important if we are going to mediate transport over the epithelial lining of the cell. The third and unexpected discovery we have made was that our proteins are stable at 42 degrees over weeks which in itself is quite interesting because it cuts down on cold chain storage so therefore has the capability to not only turn vaccines into things that can be given orally, but also make the transport and storage of those vaccines considerably cheaper. And because this technology isn’t limited to the veterinary arena as we develop it this could be real benefit for clinical use.’

The team now have an initial proof of concept of their vaccine delivery system, with the silica protein and myristic acid structure.  The next step will be to incorporate more complex proteins and to see if it is possible to raise an immune response in specific cells.

‘In this study we have used proteins which are well characterised so they are easy to handle and analyse. However we are now working on the antigens from the Bursal disease virus (IBDV) to take the research a step further. We’re still at the early stages of the research but this system certainly has potential.’

Felice Laake

Research date: May 2014

Further Information

This research has recently been published in the International Journal of Pharmaceutics.

For further information please contact Dr Simon Richardson

References

[1] J.E. Cohen Human population: the next half century Science, 302 (2003), pp. 1172–1175

[2] Economic Impact of Recurrent Outbreaks of Gumboro Disease in a Commercial Poultry FARM IN Kano, Migeria. Asian Jornal of Poioultry Science. 2012.

[3] Current status of vaccines against infectious bursal disease. 2012. Avian Pathology.

[4] Graphical representation of delivery system. Creative Commons, graphical abstract, Journal of Pharmaceutics, licensed under CC BY-NC-ND 3.0

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