by Daniel Keays

 

Beating ‘em To the Punch

Eschewing toxins,

Employing natural methods.

Elegant vaccine.

 

            The threat of infectious diseases isn’t what it used to be. Certainly, we have enormous problems with microorganisms, and we always will. The pandemic of the novel coronavirus that began in late 2019 was a stark reminder of the unremitting ferocity of infectious diseases. But anyone born after the 1960s in the developed world can never appreciate the fearful impact of many diseases we now see as historical relics. Smallpox, diphtheria, typhoid, polio, tetanus, whooping cough. These are things you read about in history books. But to have held a child or other loved one in your arms as they lay suffering and dying of such a disease, with nothing on this earth to save them, is the most heart-wrenching experience of the human spirit. Infectious diseases know no boundaries. Anyone and everyone are susceptible. There is no escape from the illness or the anguish it brings.

            To our great good fortune, we have curtailed these and other diseases. Smallpox is now extinct. Polio types 2 and 3 are nearly gone as well. Diphtheria, the strangler, is not seen in the developed world. When we get a cut on our body, we don’t immediately fear the onset of one of the most horrible things a human can experience: tetanus. When a stray dog bites us, we don’t feel the panic of the possible onset of rabies and the horror that goes with it. These and other infectious diseases have been removed from our experience and consciousness by a medical marvel that started at the dawn of the 19^th century: vaccination.

            The concept of vaccination is simple. Our bodies are equipped with a vast and exquisite array of cells and chemicals designed by nature to help keep us free from invading organisms. But these defense mechanisms take time. Before our immune system can effectively respond to organisms that have acquired the means to circumvent the complex scheme organized against them, it may be too late, and the microbe has its way with us. With vaccination, we introduce the microbe (or a piece of it) into our body, but under our terms. We don’t give it a chance to develop a foothold. If it does enter, our immune system is primed and ready to answer the challenge.

            Our acquired immunity is the most effective deterrence against an invading microbe. The innate system works well but is designed to rebuff the initial challenge and hold it at bay. The actual removal and protection from infectious diseases come from our antibodies and cells that have acquired specific chemical receptors for specific chemical components of the invading organism. We don’t even know we were challenged when it all works well.

            Acquired immunity occurs as the result of a process. We have millions of lymphocytes circulating, both B and T types. Each B cell, and many T cells, have a unique chemical receptor on their surface. Their job is to wander around, bumping into things until they encounter a peptide or carbohydrate that fits into their receptor. They then get a signal to proliferate. The B cells start to crank out antibodies, and the T cells produce an antibody-like substance that sticks to their surface. That, crudely put, is the foundation of humoral and cellular immunity.

            These B and T cells don’t work on their own, however. They don’t just bump into a complete organism and get turned on. The antibody-generating substance, or antigen, must be presented to them in a very orderly fashion. The presenting chemical is called the major histocompatibility complex, or MHC.

            After infection, the offending organism is internalized into a cell, either a phagocyte such as a macrophage or dendritic cell or into a “non-professional” cell such as an epi- or endothelial cell. The host cell’s digestive enzymes then digest the bug. Little pieces of the organism are then mounted upon a ridge emanating from the MHC molecule. (There are two types of MHCs, class I and class II. The MHC I receives peptides from organisms generated in the cell’s cytoplasm, primarily viruses. MHC I is found in just about every cell in the body. The MHC II receives antigens from organisms that end up in intracellular vesicles, primarily bacteria, parasites, and fungi. MHC II is found only in macrophages and some T-lymphocytes). 

              After being loaded with a microbial peptide, the MHC complex, whether I or II, makes its way to the cell’s surface, there displaying the offending little piece of microbe or toxin.  Eventually, a lymphocyte, either B or T, will come along, recognize the displayed antigen, and get activated.

                        

            The B cells begin to manufacture antibodies directed explicitly to a specific piece of the offending microbe’s antigen and begin to proliferate prodigiously, thus creating many antibodies. The T cells don’t produce antibodies. Depending on their type, their job is to destroy or help destroy the cell displaying the microbial antigen. They also proliferate extensively. If the T lymphocyte is of the CD8 type, it can directly kill the cell containing the microbe and displaying the antigen. Thus, the nickname is killer lymphocyte. If it is of the CD4 type, it works in harmony with other cells to facilitate the cell’s destruction. That has earned them the nickname T-helper cell.

            The first type of acquired immunity is called humoral immunity since the antibodies circulate throughout the body. The second type is called cellular immunity since it is centered in cells. The most effective vaccines induce both humoral and cellular immunity.

 

            Several different types of vaccines are used. The first one developed, that used against variola (smallpox), employed a strain of virus similar to the dangerous virus but not nearly as virulent.

 

            Another type of vaccine is prepared by killing the organism, be it a virus or bacteria, and injecting the entire dead microbe into a person. Influenza and injectable polio vaccines work this way. 

 

            Some organisms hurt us not by their direct invasion but by making a toxin that damages our tissues. A vaccine can be made not against the organism itself, but against the toxin.  The toxin is altered, leaving the antigenic portion intact but negating its ability to attach to its active site on our cells and cause illness. Diphtheria and tetanus anti-toxins are this type of vaccine.

 

            A very good vaccine preparation can be made by taking a strain of a virulent organism and altering (attenuating) it. The live microbe loses its ability to cause damage during infection but still can stimulate the immune system to build an acquired defense against it. Oral polio, measles, mumps, and rubella vaccines are of this type.

 

            Some organisms, the encapsulated bacteria, are resistant to the innate immune system by the nature of a carbohydrate capsule surrounding the cell. The capsule rebuffs complement and neutrophils, the main initial resistance force against such bacteria. Purifying and injecting the capsule material into a person triggers an acquired immune response, but it is only of the B-lymphocyte type and, therefore, short-lived. If the capsular material is conjugated onto a carrier protein such as the altered diphtheria toxin, a T-cell response is mounted in addition to the B-cell one, giving much longer protection. Vaccines against a cause of pneumonia, Streptococcus pneumoniae, use this principle.

 

            A new vaccine modality was introduced shortly after the beginning of the Covid pandemic in late 2019 and early 2020. With highly technical and sophisticated techniques, the entire genome of the novel coronavirus was determined within weeks of its bursting upon the scene. The human cell receptor for the virus was determined to be angiotensin-converting enzyme 2, ACE2, which is found in multiple human tissues. The chemical structure of the virus’s protein that attaches to ACE2 was determined; it is referred to as the “spike antigen.” Like something out of a science fiction novel, researchers constructed a messenger RNA strand that would enter the ribosomes of human cells and code for the viral spike protein. Humans were made to make a viral protein, which as a foreign protein, is antigenic. This introduced a revolutionary form of vaccine production, messenger RNA, or mRNA. The Covid pandemic lent a sense of urgency to the program, and a new vaccine was made in less than a year. How this novel approach to vaccine production proceeds is of great interest.

            

            Sometimes injecting a killed organism can make us ill. Not as sick as the viable wild-type organism attacking us, but some component of their structure is illness provoking. This is especially true of Gram-negative bacteria, which all have the endotoxin lipid-A in their cell wall. Injection of toxic lipid-A is illness provoking, as agents such as TNFa and IL-1b are released from the cells encountering it. In turn, these cytokines stimulate the release of other chemical agents. They all serve to give us fever and muscle aches. A solution to this is not to inject whole, dead Gram-negative bacteria but only antigenic pieces of the organism that result in a good level of protective acquired immunity.

            Pertussis (whooping cough) vaccine is a good example of this. Initially, whole, dead Bordetella pertussis organisms were injected. Even though relatively few in number, the vaccine still commonly induced a mild fever and some muscle aches because of the lipid-A in the bacterial cell wall. Children often became febrile and more than a little fussy after their pertussis vaccination. But modern preparations use only parts of the pertussis organism, such as their attachment fimbriae or a modified toxin. This is known as the acellular preparation. Since it doesn’t contain the entire bacterium and its endotoxin, acute toxic reactions are avoided. Unfortunately, there is some evidence that the immunity induced by this method doesn’t last as long as the whole cell preparation. (Pertussis vaccine is usually administered to children in combination with diphtheria and tetanus vaccines, abbreviated DPT.  When the acellular pertussis preparation is used the abbreviation is DTaP, the lowercase “a” standing for acellular).

 

            The most effective and long-lasting vaccines are those in which an attenuated organism is administered alive.  The microorganism can enter cells and engage in many metabolic activities that arouse immunity, but it cannot make us sick because it lacks a critical component.  Unfortunately, attenuated organisms that can be guaranteed safe and effective are very few and far between.  Sometimes hundreds of passes through cells or animals are needed, often taking years, with no guarantee of success. One recent scientific breakthrough that enables researchers to exploit the principle of a live attenuated organism while avoiding the risk is genetic engineering. Some viruses are well known to invade human cells but are incapable of inducing human disease. They enter a cell and go about their metabolic activities, but the body’s innate immune system shuts them down very soon, before the full release of defense chemicals that make us sick and before the organism can proliferate beyond its initial stages. Such viruses are often pathogens of non-human animals or even of plants. When a critical gene from a pathogen is spliced onto such a virus's genome and injected into or consumed by a human, the individual gene product is immunogenic but not pathogenic. The result can be the development of acquired immunity against the target pathogenic strain from which the supplanted gene was taken. The vaccine against the Ebola virus uses this principle.  The vaccine for malaria uses a piece of the circumsporozoite, the parasitic form which enters the liver.  It is attached to an attenuated liver virus, hepatitis B.

 

            For a vaccine to work most effectively, various adaptive immune system cells must be engaged. To help the process along, an unrelated substance known to enhance immune response can be administered along with the vaccine. These substances are called adjuvants, from the Latin word juvare, meaning “helper.” Adjuvants are non-toxic, but they have the ability to attract the correct immune cells to the site of vaccine injection. The greater the number of engaged immune cells picking up vaccine material and transporting it to the nearest lymph tissue, the greater the chance for a high immune response to the vaccine and hence the pathogen.

            

            Vaccines have remarkably reduced human and animal suffering and loss of life, but, alas, nothing is perfect. That’s especially true when it comes to the practice of medicine. We never say “never” or “always.” By the nature of their profession, epidemiologists and physicians think in terms of “very often” or “most likely.” When we are injected with an organism, alive or dead, or a piece of one, there is no guarantee that the various components of our immune system will recognize it and form a perfectly orchestrated defense against it. Some vaccines may be only 80-90% effective. The older we get, the less the likelihood of vaccine effectiveness. For instance, most people in their 20s and 30s will develop a strong antibody response to the yearly influenza vaccine, about 90-95% (but not 100%). For people in their 50s, the antibody response is only seen in around 80% of vaccinees.  For those over 70, the antibody response is only detected in about 70% of them. Better than nothing, but certainly no guarantee of immunity to that year’s influenza strain. (A big reason why younger people who interact with older people should get their flu shot is to protect against infecting the more vulnerable older person whose vaccination may not have been effective).

            This lack of universal immunity after vaccination is a big reason to vaccinate as many people as possible against a specific pathogen. Herd immunity is a somewhat abrasive term (none of us like to think of ourselves as part of the “herd”), but it says a lot. For an organism to spread by a communicable means, having most of the population already immune to it is the end of it. Without vulnerable individuals readily available for new transmission, the organism, and the disease it brings, will soon die out. The rate of immune individuals needed to thwart an infectious disease completely varies with the disease but, usually, around 85-90% will do the trick. It sounds simple, but since not all vaccination attempts are successful, that level of immunity requires a very high level of community compliance.  

 

            Smallpox was the first (and let’s hope not the last) infectious disease to be eradicated mainly by vaccination. In retrospect, smallpox would be the obvious one. The disease was so horrific that any means available to do away with it would be acceptable, even a procedure like variolation in the 18^th century, wherein some of those vaccinated died of the inoculation. There is no animal carrier, so there was no need to vaccinate or cull large numbers of animals. Also, the disease has no carrier state, so if you have smallpox it shows up without any mystery. The ultimate end of the disease came from an epidemiologic tool known as “ring vaccination.” When the disease had become rare, any report of its recurrence usually reached public health authorities, who would travel to the affected area as quickly as possible. The workers were already immune to the disease so they could work with impunity. Starting with those in immediate contact with the victim, they would vaccinate. Next, they would vaccinate those a little further away and work their way out. A relevant fact about variola is that even after exposure to the virus, you can still be successfully vaccinated with the vaccinia virus up to about 4-5 days post-exposure. By applying ring vaccination, those most likely to have been exposed are made immune, and the spread of the disease is much lessened. The last person to have acquired smallpox in the wild was a cook who lived in Somalia, Ali Maow Maalin, in 1977. He had the variola minor strain.  The last known case of variola major was reported in India two years earlier. (It is the policy of the World Health Organization to wait three full years before declaring a disease eradicated. The WHO did so for smallpox in 1980).

 

            The eradication of smallpox, in the final years by the incredible work of Dr. D.A. Henderson and his international team, was one of humankind's great achievements. The knowledge gained in the last two centuries about our immune system and how it works has been astounding. The scientists of early times, such as Edward Jenner, knew nothing of microbes, antibodies, killer lymphocytes, or anything else about the immune system. We now know the structure and function of many molecules involved in the defense of our bodies, and we learn much more every day. It’s been, and will continue to be, an amazing journey.

 

 

Summary of some common vaccines

Vaccine Type	Example
Live, related, less pathogenic microbe	Vaccinia virus for smallpox
Altered toxins	Diphtheria, tetanus
Killed entire microbe	Polio, influenza, pertussis
Multiple bacterial capsule types; toxoid carrier	Pneumococcus, Haemophilus
Live, attenuated virus	Measles, mumps, rubella, polio, rotavirus
Live, attenuated bacteria	BCG (Tuberculosis)
Messenger RNA coding for microbe antigen (mRNA)	Coronavirus
Individual bacterial antigens	Pertussis
Microbial antigen attached to unrelated carrier virus	Ebola, coronavirus, malaria

Eggs being inoculated with influenza virus to produce a vaccine (PHIL)

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