Last week, I talked about strategies to improve vaccine efficacy and safety. Most of those strategies were in the context of standard, inject-into-your-arm vaccines, but what about totally new delivery methods? This week, there was a review in PLoS Pathogens of strategies for generating vaccines that you can swallow:
The immune system in the gastrointestinal tract plays a crucial role in the control of infection, as it constitutes the first line of defense against mucosal pathogens. The attractive features of oral immunization have led to the exploration of a variety of oral delivery systems. However, none of these oral delivery systems have been applied to existing commercial vaccines. To overcome this, a new generation of oral vaccine delivery systems that target antigens to gut-associated lymphoid tissue is required.
Using oral vaccines makes a lot of intuitive sense – lots of people are afraid of needles, and using an oral route opens up the intriguing possibility of growing vaccines in plants. In addition, many of the infections that we care about vaccinating against infect us through mucosal tissues (airways, gastrointestinal tract, urogenital tract etc), and we presume that an immune response generated at a mucosal site is more likely to protect against a mucosal infection. But there are many pitfalls that have prevented effective oral vaccines from being developed.
The gut is our largest immune organ. It’s lined by structures called Peyer’s patches or gut-associated lymphoid tissue (GALT), that contain all the cells necessary for generating a robust immune response. But its regulation is also incredibly complex – the gut immune system needs to be able to respond quickly to potential pathogens, but it also needs to learn to ignore food, and the trillions upon trillions of non-pathogenic microorganisms that live there. This is no small feat, and errors in this regulation can lead to food allergies or various hyperinfammatory disorders like Crohn’s disease and inflammatory bowel syndrome. Most things that enter our guts cause immune tolerance, not activation, so oral vaccines must be designed to look like a pathogen.
One strategy to do this is to put vaccine antigens into live attenuated pathogens – this is roughly how the
Salk Sabin polio vaccine works. We can use either bacteria or viruses for this purpose, but the large numbers of commensal microbes tend to crowd out exogenous vaccine strains from being introduced (that’s kinda their job), and previous immunity to many of the recombinant viral vectors can prevent new immunity from forming to the antigen of choice.
Plant-based delivery systems are also mentioned (references removed):
Plant-based oral vaccines are another delivery system that has been tested in recent years. Seed crops such as rice, maize, and soybean appear to be suitable expression and delivery systems that offer several advantages, such as resistance to intestinal enzymes, rapid scale-up of exogenous antigens, low-cost production, and a decreased risk of contamination by human pathogens.
Not mentioned here is the fact that the model antigen used in this study is cholera toxin, which is able to inject itself into intestinal cells and invoke an immune response (the normal toxin has 2 subunits, the vaccine uses only the part that gets into cells, not the part that causes problems). Don’t get me wrong, this could be a huge development (made even more poignent by the epidemic that’s spreading in Haiti right now), but it’s not necessarily applicable to other diseases.
The strategy advocated most by this review is targeting microfold cells (M cells), that make up a small percentage of the cells lining the gut and other mucosal surfaces. These cells are generally associated with GALT, and are able to pick up antigens and shuttle them across the epithelial barrier. Several studies in mice have shown that targeting these cells can generate robust immune responses, both in T-cells and B-cells, but it’s really hard to study these cells in humans (it’s hard in mice too, but there are more options in mice). They make up a very small percentage of total gut epithelium, and are more or less impossible to culture. Still, there are a few receptors that are expressed on M cells and not other intestinal cells that we could use for targeting. The hope is that targeting entry into these cells might induce immunity instead of tolerance, but the jury is still out.
Again, I’ll let the authors take us out.
We think that the absence of a potent oral vaccine might be due to other challenges, including antigen degradation by proteolytic enzymes, the low dose of antigen absorbed, a lack of potent mucosal adjuvants, and not actively directing antigens to M cells. To overcome these issues, further work regarding oral vehicle delivery systems that protect antigens and specifically target M cells is required.
Azizi, A., Kumar, A., Diaz-Mitoma, F., & Mestecky, J. (2010). Enhancing Oral Vaccine Potency by Targeting Intestinal M Cells PLoS Pathogens, 6 (11) DOI: 10.1371/journal.ppat.1001147