This page contains a list, with brief overviews, of topics that are addressed in more detail on the pages that follow. If you click on any red header, below, it will take you to a page with more info on that topic.
1. BRIEF INTRODUCTION TO MUCOSAL MEMBRANES, AND MUCOSAL PATHOGENS
This page describes how mucous membranes are very different from "dry skin", why they are major targets for pathogenic microbes, and why "mucosal pathogens" are – by far – the most important pathogens on this planet.
2. MALT PATCHES, AND HOW "M CELLS" SAMPLE AND PULL IN APPARENT PATHOGENS
MALT ("mucosal associated lymphoid tissue") patches are surface-mounted lymph nodes, and they are a crucial part of the "first line of defense" against pathogens that try to infect mucous membrane cells.
M cells are "sampling cells" on the surfaces of MALT patches. If they detect a particle carrying a "pathogen pattern", they will grab it and pull it in; however, rather than processing it, they will push it through the cell, as rapidly as possible, and eject it into a "docking site" where a different type of immune cell – a dendritic cell – is waiting for that type of "pathogen delivery".
Therefore, "MALT-targeting" peptides are "pathogen pattern" peptides that can be attached to the surfaces of vaccine particles, so that they will “trick” the M cells into pulling them in, and passing them on to dendritic cells.
Dendritic cells play the absolutely crucial role, in determining: (i) which foreign particles are not really important and dangerous, and should be gobbled up and digested on the spot, without further ado; versus (ii) which foreign particles appear to be dangerous and important pathogens, which need to be taken to a lymph node (while being broken apart and semi-digested along the way), so that T and B cells in a lymph node can make antibodies that will bind to those alien/invading particles. With the help of “chemo-attractant” signals, newly-formed dendritic cells find and settle into the "docking sites" on the undersides of M cells, to await a pathogen delivery that will cause them to transform from an “immature” dendritic cell, into an “antigen-presenting” cell. Therefore, "MALT-targeting peptides" – when attached to the surfaces of mucosal vaccine particles – offer an ideal way to get those vaccine particles rapidly delivered to dendritic cells, and to get the dendritic cells which receive those particles to do exactly what is needed, to launch an antibody-forming response to any antigens on the surfaces of those vaccine particles..
The Y-shaped internal IgG antibodies are not large or powerful enough to hinder a virus, let alone a bacterial cell, so they fight pathogens by using a shape-changing “tag and flag” process. When either “sticky arm” latches on to a particle, the antibody “stem” changes from a “Leave me alone, I’m an antibody” shape, into a different shape that signals, “I’ve latched onto something important, so somebody go find an immune cell, and tell it to come here and help me.” Guided to that location by “complement proteins” which “amplify” that signal, the immune cells do the actual work of fighting and killing pathogens.
However, in secreted mucosal fluids that are outside of any cells or tissues, there are not enough immune cells (or complement proteins) to respond to any such signals. So, "secreted mucosal antibodies" needed a totally different structure, and function, to be able to function effectively, and the mucosal immune system developed a remarkably clever way to strap two antibodies to each other, via their stem components, in a way that creates an "antibody dimer", with FOUR different "sticky arms" (with two, at each end of an elongated molecular complex). These IgA antibody dimers perform a "grab-and-drag" function, which prevents pathogens from penetrating into any mucous membrane cells. If a pathogen is grabbed in the mouth or nasal cavity, it will be dragged down into the stomach acids, which will kill nearly all pathogens; if grabbed in the intestines, it will be kept suspended in the food that is being digested, until it is "pooped out" and eliminated.
“Adjuvants” are compounds added to injected vaccines, to make them more effective and potent. However, in practical terms, they are harsh, irritating, inflammatory, distress-causing agents, and they are added to injectable vaccines, to cause the muscle cells, at the injection site, to send out distress signals, to recruit any nearby immune cells to come to the injection site, before the vaccine particles can be diluted, diffused, or degraded. Because of how they work, MALT-targeting vaccines have the potential to completely eliminate any need for harsh and irritating adjuvants, and if that turns out to be the case, they will offer a major benefit, for all vaccines.
Most people have never even heard of "secreted antibody dimers", but there are more than twice as many of those – in just the few pounds of saliva, nasal mucus, lung fluids, and digestive juices, in a healthy human – as all of the internal antibodies in the entire remaining weight and bulk of that person's body. Our bodies would not devote so many resources to creating huge numbers of mucosal antibodies, unless they were truly important, and immunologists know, full well, that if vaccines could be created which could safely and reliably create mucosal AND internal antibodies, those “balanced, bi-functional vaccines” would be better and more effective (especially against "upper respiratory tract" infections) than vaccines which can only create internal antibodies. However, scientists and vaccine companies have never previously been able to make vaccines which can trigger BOTH internal AND mucosal antibodies, without using truly nasty chemicals which are not acceptable for livestock or pets, let alone humans. MALT-targeting mucosal vaccines have the potential to change that, dramatically.
"Phages" (originally called "bacteriophages") are the smallest viruses ever discovered. Each type can infect only a small set of bacteria, and none can infect plants or animals, so they are treated as harmless and non-pathogenic.
Phage “libraries" (aka phage display libraries) contain billions of different phage particles, and each particle carries a different, randomly-created "foreign peptide insert" on an exposed "coat protein." They took decades to develop, but now, a top-quality library with a trillion different phage particles can be purchased for less than $800.
"Screening tests" are clever ways, thought up by scientists, to subject millions of phage particles to a fair competition, usually involving something like, "Uptake and processing, by a specific and unusual type of cell", so that they can isolate and then analyze those few phages which happened to be carrying an inserted peptide sequence which caused those cells to perform that activity.
So, we thought up and used a new type of screening test which isolated about 100 phage particles (out of a billion candidates/contestants) which happened to be carrying peptide inserts which made those particles appear to be so dangerous, and important, to the M cells and dendritic cells in mice, that those specific particles needed to be taken in and processed – as quickly as possible – in a way that would have led to antibody formation, if we had allowed the cells to continue. Instead, we extracted a mixed batch of mucosal surface cells, and used a clever screening method, to isolate only those dendritic cells which had become transformed and activated, by their contact with the specific phages they had taken in. We then broke those activated dendritic cells open, and analyzed the foreign inserts in the phages they had taken in.
Once we knew the DNA and amino acid sequences for the phage inserts that functioned as “MALT-targeting” peptides, we hired a phage assembly lab to create “the first testable constructs", carrying 15 copies of the best-performing MALT-targeting sequences; and hundreds of copies of a well-known antigen that is easy to test for. In both mice and pigs, a single nasal infusion of those particles (with no adjuvants) caused "robust" formation of BOTH: (i) internal IgG antibodies, in blood, AND, (ii) secreted IgA antibody dimers, in saliva, as shown by both ELISA and SDS-PAGE/Western assays. Those results were so good that we shifted over to a different type of phage that is better suited for pathogen challenge tests.
As described on the home page, we do not want to compete against any vaccine companies; we do not want to become a manufacturing company; and, we do not want to build, or learn how to use, biosafety equipment, to be able to do pathogen testing on animals. Other people are already experts in all those things, and we truly and genuinely respect their expertise, and hope to work with them, in ways that will let them use their talents and skills to make the best vaccines that can possibly be made, both for humans (some day), and for non-human animals (as soon as possible).
Therefore, our goal is: (i) to become a licensing company, and (ii) to find good and effective ways to encourage, motivate, and incentivize experts in animal testing, to begin doing the work that needs to be done, in order to create the best possible government-approved and publicly-available vaccines.
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