Machine Maintenance and Proofing

October 18, 2010 - 2:57 pm
Irradiated by LabRat
Comments Off on Machine Maintenance and Proofing

After doing a Morbo imitation at a commenter elsewhere making a series of false assumptions about vaccinations, it occurred to me that maybe the exact details of how vaccines do work is maybe not such general knowledge as I thought. Sure, my high school biology teacher thought it was the perfect structure to frame the chapter about the immune system around, but probably that’s not standard curriculum nationwide. So, How Stuff Works: Vaccines and You.

The most important thing to realize, and the one which most people seem to have, is that vaccines don’t contain any immunity-inducing properties of their own; their entire function is based on spurring the body’s immune system to develop specific recognition capabilities for pathogens before encountering the pathogen in question. Normally immune adaptation is acquired partly from one’s mother during nursing (this fades in 6-12 months), and partly from a learn-as-you go approach to finding and destroying hostile invaders as they come. The learn-as-you-go portion isn’t particularly pleasant, and sometimes has unfortunate side effects such as permanent injury or death, so finding ways around this has been historically viewed as a social good.

The way the immune system actually recognizes anything is by its “appearance”; anything that can provoke an immune response is called an antigen, and while some toxins fill this role, most antigens are proteins and most of the immune system’s recognition task is in making friend-or-foe identifications by protein coat. When innocuous substances are slotted into the “foe” category, these reactions are defined as allergic; when the body’s own cells are accidentally thrown into the “foe” category, this is an autoimmune reaction. Both friendly and neutral microorganisms as well as a handful of particularly well-adapted pathogens also have the capacity to get themselves flagged “friend” and ignored by the immune system. As any adaptive system theoretically capable of learning and responding in a massive number of ways is, the immune system includes these kinds of potentials for error as a consequence of its own flexibility, but it also provides a way for the humans to directly game the system.

Most of the body’s resistance to invasion is surface-based; skin basically exists in the first place to be a physical barrier composed of material indigestible to bacteria. The mucous membranes where tough skin can’t be are either covered in saliva or tears, which are full of enzymes designed to terminate proteins with extreme prejudice, or mucus, which is designed to simply trap invaders in place. Internally, the body is patrolled by macrophages, which devour everything in their path; dead cellular debris, foreign bodies, and foreign bodies that are pathogens. Macrophages display portions of the pathogens that they devour on their own coating; these antigens are then recognized by helper T cells, whose basic role in the immune system is “cellular terror alert level”.

At this point a truly accurate explanation of helper T cells, macrophages, and immune response and regulation would involve a great deal of biochemistry and an intimate and delicate dance involving the exchange of signals and careful up and down regulation of both the white cells themselves and every other aspect of immune response, but this would not only take a great deal of time, it wouldn’t actually add much to a basic explanation of how vaccines work except to help some student pass his MCAT somewhere. So for purposes of serving the task and accomplishing the explanation while also making it clear that I AM grossly simplifying, I will say that the role of helper T cells is first to recognize that the macrophage is going around with the heads of the enemy dangling off its metaphorical fender and then to run through the body screaming “THE BRITISH ARE COMING!”.

Somewhat less metaphorically, they multiply themselves, stimulate the production of killer T cells that destroy the body’s own cells that are infected by the invader*, and importantly for the purposes of vaccination, it interacts with B cells. B cells are produced by the bone marrow in ways that vary by the millions; each one has a slightly different receptor protein on its surface. When the B cell encounters an antigen that matches its own receptor, and is stimulated by the helper T cells shrieking about the redcoats, it immediately begins rapid and prolific division and production of new B cells. A few of them become memory B cells that will exist from then on out to hasten immune response to that antigen again, but most of them become plasma B cells whose job is to pump out antibodies to the antigen. Antibodies attach to the antigen and make it easier for macrophages to destroy it; a crude but useful-for-our-purposes analogy would be that of attaching handles to an awkwardly-shaped object to make it easier to pick up. For obvious reasons pathogens do not wish to be consumed, and a great many of them are very resistant to the process; antibodies make them less resistant.

Over the course of the infection, helper T cells gradually subdivide themselves into effector T cells, whose job is essentially to maintain the alarm effect and general up-regulation of the immune system, memory T cells that are antigen-specific and will hang around long after as the memory B cells will, and regulatory T cells whose job is to call the whole thing off**. When the memory T cells encounter their antigen again, they will rapidly divide and produce effector T cells to ramp up the alarm system again, much as their B counterparts will start producing antibodies again.

The original discovery of the principle of vaccination was made by Edward Jenner, who observed that milkmaids rarely got smallpox. At the time, the basic idea of inoculation- which vaccination is a safe variant of- was known; if you wanted to protect someone against smallpox, you got some material from a victim and gave the intended beneficiary a bit of it, hoping for a light and nonfatal infection that conferred later immunity. Cowpox, on the other hand, was something that milkmaids tended to pick up from infected cows that did nothing in particular that harmful to humans other than a few blisters; Jenner’s idea was that the milkmaids were being inoculated with a less risky disease, a theory he proved by using the pus from a local milkmaid’s cowpox infection to inoculate his gardener’s son, then later inoculating him with material from a smallpox blister in the usual fashion and producing a total lack of reaction***. 23 subjects later, he had demonstrated that cowpox inoculation produced smallpox immunity sufficiently to get the attention of the Royal Society.

Jenner’s time lacked a germ theory of disease, but now we know that the cowpox worked because cowpox and smallpox are closely related viruses; their antigens are close enough that an immune response to cowpox will produce an effective immune response to smallpox. Later smallpox vaccines were derived from neither, but rather from the again closely related Vaccinia, which is even more innocuous to humans and whose etymological implications are obvious.

The basic principle of vaccination is this: introduce an antigen in a way that will elicit a full-blown immune response, specific to the disease of interest, and sufficient to create a healthy crop of memory B and T cells that will respond appropriately if they ever encounter that pathogen. This can be a live microbe that is sufficiently related to the pathogen to provide a specific response to that pathogen (but represents a major risk to the immunocompromised for whom the experience is not so innocuous), as in the case of Vaccinia, a live microbe that has been deliberately bred or engineered to remove its virulence (referred to as live attenuated- the measles-mumps-rubella contains three live attenuated bugs), just bits and pieces of the bug to provide a selection of antigens, or a toxoid vaccine in which the antigen is actually an altered-for-safety version of whatever toxins the bug produces that cause the real problem for the host. Tetanus and diphtheria are toxoid vaccines, and the hepatitis A and B shots are component vaccines; all of them are different means to the same end, which is finding a way to safely introduce an antigen that will be reliably associated with a particular harmful pathogen and get a complete immune response.

Where the process of producing vaccines becomes complicated is that pathogens have a number of tricks to evade detection and capture by the immune system, which can make acquired immunity to the pathogen acquired the straightforward way difficult, let alone induced immunity from a vaccine. The easiest way for viruses to evade the immune system is simply to mutate very rapidly; their antigens simply don’t remain stable enough for the memory cells to be able to produce effective recognition and effective antibodies. This is one of several reasons that a childhood vaccines may last but a flu vaccine must be applied once a year and may not even be effective- there are multiple different strains and all of them mutate very rapidly, so any given year’s vaccine is a best-guess as to which strain is going to be dominant that year. HIV has been a bear to produce a vaccine for for the same basic reason; it doesn’t share influenza’s strength in infecting multiple host species and having that be a driver of variation, but it still mutates fast enough for there to be multiple strains and for those strains to mutate fast enough that an HIV victim taking no precautions can become infected with multiple different strains, some of them more or less resistant to treatment than others.

Protist pathogens, or single-celled eukaryotic organisms that have become specialized as parasites, have some more sophisticated tricks at their disposal. Malaria has been resistant to both vaccination and effective treatment because the bugs in question simply change their entire protein coat repeatedly, so that it can take up to five years before the immune system is even exposed to all the different versions of antigens that the single infecting Plasmodium strain can present. This may not even matter much, because it also partially disables the immune response, so that the helper T cells are sluggish and don’t properly signal B cells. Giardia protists share the same coat-swapping trick, which can make them tricky to even diagnose, since the symptoms of infection are so general and blood tests for the presence of most diseases relies on being able to find either the antigen or the antibodies produced in response- and fecal floats rely on a certain amount of luck of the draw in even getting a protist to show up in an opportune way.

Other pathogens subvert various components of the immune system (animal parasites are particularly good at this), bunker up in specialized structures within tissues and evade the strongest part of the immune response and re-emerge and begin breeding again when this has passed or the immune system is weaker in general, or somehow display a false-flag “friend” signal to the immune system. Like the number of human ailments easily defeatable with simple antibiotics, the number of pathogens easy to create and deploy a vaccine against is actually a minority of pathogens overall, and we are fortunate in that so many of our most lethal ones were among them.

Finally, the important thing to remember about vaccines is that they rely entirely on the memory T and B cells in order to produce immunity. The body isn’t truly immunized in the sense of being invulnerable to that disease, it merely has a much faster antibody response against pathogens- which in most cases is more than sufficient to overwhelm the invaders before they establish the numbers to out-breed the immune system. “Booster” vaccinations are given to up the population of memory cells so that it remains artificially high; someone who had childhood vaccinations but no boosters will still have some memory cells, but still be more vulnerable to infection than someone whose repeated artificial exposure means a well-reinforced garrison.

The principle of “community immunty” or “herd immunity” rests, essentially, on math; the more individuals a pathogen can’t get an effective foothold to breed in, the fewer chances an individual who can’t be or wasn’t vaccinated (and the most common cause of “can’t be” is a compromised immune system that isn’t strong enough to function in the ways the vaccine normally provokes) has to be exposed and successfully infected. If enough of the community is vaccinated, outbreaks simply have no chance to get rolling and produce dominating numbers of pathogen.

The reverse case- a few vaccinated individuals in a vulnerable community- is, of course, also true. It does not matter if you’ve constructed a truly great wall and fortified it with a well-armed garrison; if sixty million armed Mongolians show up on the other side rather than six thousand, there’s a pretty good chance you’re going down.

*Or cancerous, or otherwise “ain’t right”. This is flagged by the compromised cell displaying the wrong protein coat, resulting from having to process foreign substances. More or less. Please do not try to pass biochemistry with this. Either way, it’s sort of like flying an upside-down flag.

**I actually can’t get all that more specific here, because the current state of immunology regarding them is “yes, they exist, and yes this is what they do”. How exactly they do it and what mechanism prompts a regulatory T cell response to dominate over THE BRITISH ARE COMING is still rather foggy.

***The practice of just trying stuff on random victims and seeing what came out well was rather common for Enlightenment era medicine, thus demonstrating that House, M.D. would be praised for its gritty realism had they merely set the series in the eighteenth century.

No Responses to “Machine Maintenance and Proofing”

  1. Mousie762 Says:

    The practice of just trying shit on random victims and seeing what came out well was rather common for Enlightenment era medicine

    This is pretty tangential to the vaccination subject at hand, but I think we’ve gone too far the other way in recent decades. Not that I want my doctors trying random shit on me Enlightenment-style, but I want medical tort law to recognize the fact that doctors are human, are occasionally going to make mistakes, and if you financially ruin every doctor who saves 99 and loses 1 to human dumbness, you won’t have any human doctors.

    It’s crazy. We expect ASTRONAUTS to be safe these days.

  2. TJIC Says:

    > House, M.D. would be praised for its gritty realism had they merely set the series in the eighteenth century

    Makes a lot of sense, when you realize that House is based on Sherlock Holmes, who in turn was based on Dr. Joseph Bell ( ) who was a doctor two centuries back!

  3. Jason Says:

    That’s how I learned about vaccination in high school too. What medium is used to convey the weakened/dead pathogen into the body though.

    I’d have thought it was saline, as that seems the most sensible thing, but am I mistaken?

  4. LabRat Says:

    Depends on the vaccine. Especially if you’re using a live attenuated strain, you need to include food and housing for the bug in there, which usually translates into some sort of animal tissue. Also depending on the exact nature of the vaccine, there can be some sort of preservative, and some sort of antimicrobial agent to prevent it from being colonized by a bug not of interest or one that could be harmful. (Classic case being protecting a viral vaccine from invasion by bacteria.) Sometimes there’s also some hydrocortisone to minimize inflammation and discomfort at the site- inflammation is part of the immune response but it’s also what makes your arm hurt like a bitch after getting some vaccines.

    Some of the “other” contents of vaccines are toxins, but the dose you actually get is negligibly small, especially in comparison to environmental exposures- kind of like how flying in an airplane gives you a dose of radiation exposure, but so does living in New England anywhere there’s granite bedrock.