F*cking vaccines, How do they work! -Part Three

He folks, you know what? The next installment in our series of post is actually about vaccines! I mean, it only took me two days to get to that point! And, if you are curious of what was said previously, the first and second posts are but a click away!

Recap, the story thus far:

So, we mentioned previously how both of the two main populations of lymphocytes underwent somatic recombination leading to each individual lymphocyte to produce a very unique version of a cell receptor. Then, upon introduction of an antigen, the ones whose receptor matched the antigen would replicate to face the threat… Out of the cloned lymphocytes, a few would become what is called memory cell. Their lifespan would be greatly expanded and they would move to the bone marrow where they will supply the blood with a continuous supply of clones. That was, if the antigen is encountered a second time, the immune system would react faster and more strongly… This specific immune response is the truly remarkable achievement of 450 million years of evolution. It makes one proud to be jawed vertebrate, let me tell you!

And, as we also mentioned, vaccines simply take advantage of this mechanism. In the simplest term, vaccination simply consists in supply the immunitary machinery with antigens to grind. There are, however, a few different ways of doing that…

Use of closely related agents:

As we mentioned, by providing antigens from one disease agent to the immune system, one can select the immune cells that will react against this antigen.

But, it is important to note that such antigens are not necessarily unique to one species. Closely related species can express antigens that are similar, or at least similar enough that the corresponding T and B cell receptors will work equally for both.

Therefore, by vaccinating with an agent, one can confer protection against another, similar, agent. The trick, of course, being to use a less virulent agent to vaccinate against a more lethal one.

This is how vaccines were first discovered, when Edward Jenner, after noticing that milkmaid, often infected with cowpox, were resistant to smallpox, was the first to report the protective effect of exposure to Vaccinia virus against smallpox infection. It is now known that the vaccinia virus, the cowpox virus and Variola virus (the causative agent of smallpox) all belong to the same Orthopoxvirus family. This viruses are simply close enough that the cells raised by one would still recognize the others… (as a side note, it is often said that Jenner used cowpox virus, in fact, when we looked at it more closely, decades later, it was discovered that Vaccinia was a distinct species. It is however very possible that the strain was initially indeed a cowpox virus and that it just mutated since Jenner’s 1796 report…).

From a practical point of view, the use of such method of vaccination is, however, very limited. First of all, nature needs to provide you with a non-virulent but conveniently closely related organism. Moreover, the organism in question is still a pathogen in its own right, if not a proper human pathogen, as such it can cause some side-effect, especially in immunocompromised patients. Vaccinia for example, can cause some rashes or fever and even, in rare case, mostly in patient whose immune system is otherwise compromised, can even develop in a full-blown infection…

Despite these concern, this still constitute the vaccine of choice for the protection against smallpox, presumably because efforts toward the development of an alternate method were stopped by the disease eradication in 1979. However concern about the use of smallpox as an agent of bioterrorism has lead to a renewal in the use of this vaccine for troops stationed overseas.

Use of inactivated agents and toxoid vaccines:

These constitute the bulk of vaccines. Essentially, you are taking your agent and kill it (either by formalin or heat treatment) and then inject it into the body and let the non-specific immune system pick it up and present it to the specific one. It is a common, comparatively easy to develop (grow your agent and then nuke it) and cheap method for the production of a vaccine. Jonas Salk success in developing a vaccine against polio relied on the use of a killed virus when previous, unsuccessful efforts, had attempted to develop an attenuated strain of the virus.

It is not perfect, however, because the agent is inactivated, it will not colonize the mucosa. You have to inject it directly into the body, not only can this be a problem for the most needle-phobic among us, but it also mean you are by-passing the whole mucosal compartment of the immune response (remember the various compartment do not really communicate with each others), so the cells in your first line of defense will be caught unaware… Moreover, because the pathogen is inactivated, it will not multiply within the body, which means, it won’t stimulate the immune system as well or for as long as an actual infection. For this reason, boosters shot can be required. Another method, to make sure that the immune system will notice the introduction of the antigen, is to inject it alongside an adjuvant, an immunogenic molecule that will help recruiting cells of the innate immune system. The drawback of this method is that such molecules are going to cause inflammation at the site of injection, that is in fact, the point, as this inflammation corresponds to the recruitment at the site of the antigen (some of these signs, swelling, redness, as a sign of the tissue increasing its permeabeability to facilitate the arrival of the immune cells, other, heat, pain, are an effect of the cells action once arriving on site). In some case, this non-specific reaction can induce fever and other non-specific immune response. Indeed, more often than not, the adverse effects that one experience from an inactivated vaccine are due to the adjuvant rather than the antigenic component of the vaccine and, when people think of the side effects of the vaccine, they are often thinking of these…

Toxoid vaccines are pretty similar, except, in that particular case, rather than targeting the actual infectious agent, it is one of its toxins that is being denatured and injected. Tetanus and diphtheria toxins, for example, are the main toxins targeted by such vaccines.

Use of sub-unit, recombinant and conjugate vaccine:

As we mentioned a few times, the specific immune system is not presented with the whole pathogen, but only with its antigenic components.

Therefore, it is possible to only use the antigenic parts of the pathogen and still induce an immune response. These parts can be obtained either directly by purification lysates from the pathogen, or, more sneakily, in the case of recombinant vaccines, by looking in the pathogen genome for the genes that codes for the antigens. Then, you can copy these genes and stick them on some innocent by-stander so that it will express the proteins in question. You then isolate the proteins from the culture, and inject that instead.

In some case, the protein itself will not be recognized by the immune system, generally, because it is too small. In such a case, this protein, called a hapten, will be ligated to a larger molecule, called a carrier and it is the hapten-carrier complex that will be recognized by the immune system in order to create a conjugate vaccine.

The use of a sub-unit or conjugate vaccine is a bit more involved than that of a inactivated vaccine but it often allows the use of antigens from multiple strains of a pathogen. Also, it allows to avoid certain element of the pathogen. For example, the caustative agent of whooping cough, Bordetella pertusis’s outer membrane harbor harbors endotoxins that can cause adverse reaction by stimulating the immune-system too much and produce a inflammatory response. Recently, a sub-unit preparation was developed that did not include the endotoxins, allowing for a safer vaccine that is now part of the DTaP (alongside diphtheria and tetanus). Because of the new availability of this safer alternative, the vaccination against pertussis is now recommended to adults and teenagers, especially considering their potential role as carrier and the recrudence of whooping cough numbers, that are reaching their highest levels of incidence in 50 years…

Use of live attenuated vaccines:

The last major type of vaccines is termed life-attenuated. There is a couple of method to obtain them… Firstly, many virulence factors are only useful for the pathogen once it is in its host. After all, what use is the clot dissolving streptokinase when there are no platelets around? In fact, the metabolic expenses of expressing such virulence factor often become a drawback when the pathogen is cultivated in vitro. So, it is often observed, that after a few generations of being cultivated in vitro, many pathogen will some of their virulence, in a simple illustration of selection whose sight would warm Charles Darwin’s cockles (he actually did work on barnacles quite a bit). The main area of concern in this context, is reversal to virulence. If the lack of selective pressure on the pathogen lead to the down-regulation of the virulence genes, one would expect that reestablishment of this pressure once the pathogen is introduced in the body might restore it. This is a logical concern, but also something that vaccine makers are aware of and keep an eye to and the attenuated vaccines that make their way to the general public have been repased so many time that they have accumulated a number of mutations in their virulence genes, making in unlikely (albeit not impossible) that the vaccine will revert to virulence.

An alternative method is to target the virulence genes directly and proceed to genetically engineer them away, for example, through genetic recombination. In this case, the risk of reversion to virulence is nil as the genes responsible are no longer present within the pathogen genomes.

In addition to this reversion to virulence, attenuated genes have a few drawbacks. They are more costly to produce. They are also more fragile than inactivated organisms making their distribution, especially within the developed countries, more difficult and complicated, for example, they often require to be maintain under refrigerated temperatures. Furthermore, even when they remained attenuated, they sometime can over-come the immune system of particularly immunodeficient patients. Nonetheless, they have a number of great advantages… contrary to the inactivated vaccines, attenuated vaccines can colonize a mucosal epithelium, it is therefore possible to administer them, for example orally or nasally as is done for the attenuated version of the polio vaccine. Not only does it simplify administration, it allows to stimulate the mucosal compartment of the immune system. They also tend to remain longer in the organism and are less likely to require a booster. Finally, in the case of the intra-cellular pathogen, they will remain their ability to invade host cells and stimulate the cellular component of the immune response…

DNA vaccine, the way of the future?

There is a last interesting vaccine method. This method is still experimental and, I suspect, will remain so for a long time. Essentially, it starts in a way pretty similar to a recombinant vaccine by making copy of the genes responsible for the expression of the antigens. Then, instead of expressing them in a third organism, these genes are conjugated to an expression vector (generally based on viral promoter such as a Herpesviridae such as cytomegalovirus) and injected directly into the patient. Some of these DNA fragment will then be picked up by the patient’s own cells that will produce the proteins.

The advantages of this type of vaccines are numerous: there is no risk of infection, it will allows to stimulate both arms of the immune system. It last for a very long time and there is no need for adjuvant and no molecules such as endotoxin, so the risks for inflammation are very low. These vaccines are also more stable than the attenuated ones and easier and cheaper to store and move around. There are also a few difficulties, but the main problem I suspect for its adoption will be people’s resistance to get themselves injected with viral DNA that will travel to their nucleus and get mixed with their own…

Why no words about autism?

So, I just spend the last 17 hundred or so words talking about the various types of vaccines and their various drawbacks… and yet, I have yet to acknowledge the elephant in the room: the often publicized relationship between vaccines and autism.

Why? Well, to put it bluntly, because there is no reason to think that such a link exists. The association between the two is pretty much entirely based on a faulty correlation: the first vaccinations occur at about the same time that the symptoms of autism become evident…

But, apart from this ‘Post Hoc Ergo Propter Hoc’; there is little reason to believe the two are linked. Indeed, there are no theorical mechanisms through which vaccination would cause autism, as illustrated by the forever shifting rationales explained by the vaccine opponents from mercury toxicity to Wakefield’s discredited ‘leaky gut’ hypothesis, to the idea of an immune system overload. And when investigated, these claims were systematically proven to be inaccurate. In fact, there is good evidence that the often taunted autism epidemic is but an artifact of a subjective diagnostic and moving definition, after all, if the real incidence of autism was rising, one would expect that the rate of autism would be higher among younger children. But it is not the case, and the rates appear uniform among all age groups…

Yet, the connection persists in the collective mind. This is not difficult to see why. Raising a special child is taxing and difficult. It leads to anxiety and, too often, to an irrational feeling of guilt. What’s more, autism is a complex condition, without a clearly defined mechanism and cause and this incertitude, this lack of answers, only adds to the distress of the parents…

In these circumstances, it is not surprising to see the appeal of the vaccine connection when it offers not only answer but also a party to point the blame at and, in many occasion, the promise, however elusive, of a cure.

There is something tragically human, eminently understandable, to this behavior, and, while trying not to sound patronizing, I can do nothing but feel the deepest sympathy for the parents in this situation.

And yet, and yet it does not change the facts. On the contrary, because this issue is so charged emotionally, one has to cling to the cold objectivity of science harder than ever… And the facts are that vaccines are, on the whole, very safe and very efficacious. That, while they do carry some risks of side effects, not autism, mind you, but other, real, risks, these risks are dwarfed a thousandfolds by that of the actual diseases that vaccines protect against and that the world before the multiplication of vaccines, was a much grimmer place, full of cemeteries with tiny headstones a world where too many diseases were endemic especially among younger children: In 1952, for example, the year Jonas Salk first tested his polio vaccine, 38,000 cases of infection by the virus were reported in the U.S alone, killing thousands and leaving more than 20,000 disabled. Today, vaccinations has allowed this number to drop to about a thousand case annually reported world-wide, mainly from developing countries in Africa and Asia were the vaccination efforts is impaired by war and extreme poverty.

Measles were similarly fought back: In the decade before the measles vaccination program began, an estimated 3–4 million cases were reported each year in the United States resulting in 400 to 500 fatalities and thousands of people left disabled from the encephalitis. Nowadays, these numbers have been driven down to the mere hundreds of new cases annually and it is considered that the virus is no longer endemic in the U.S. And diphtheria which once claimed 13,000 to 15,000 life annually (out of 100,000 to 200,000 cases) has only been reported about twice annually in the 2000.

Yes, we must listen to the vaccine opponents and understand where they are coming from. But we also need to battle their misconceptions at every opportunity, because we are talking about lives, potentially thousands of them, being lost due to their well-meaning, misguided crusade and that is simply a tragedy…