The cure for tetanus, a life-threatening and often deadly disease, has been sought from the very inception of the modern field of Immunology. The original horse anti-serum treatment of tetanus was developed in the late 19th century and introduced into clinical practice at the time when a bio-statistical concept of a randomized placebo-controlled trial (RCT) did not yet exist. The therapy was infamous for generating a serious adverse reaction called serum sickness attributed to the intolerance of humans to horse-derived serum. To make this tetanus therapy usable, it was imperative to substitute the animal origin of anti-serum with the human origin. But injecting a lethal toxin into human volunteers as substitutes for horses would have been unthinkable.

A practical solution was found in 1924: pre-treating the tetanus toxin with formaldehyde (a fixative chemical) made the toxin lose its ability to cause clinical tetanus symptoms. The formaldehyde-treated tetanus toxin is called the toxoid. The tetanus toxoid can be injected into human volunteers to produce a commercial human therapeutic product from their sera called tetanus immunoglobulin (TIG), a modern substitute of the original horse anti-serum. The tetanus toxoid has also become the vaccine against clinical tetanus.

The tetanus toxin, called tetanospasmin, is produced by numerous C. tetani bacterial strains. C. tetani normally live in animal intestines, notably in horses, without causing tetanus to their intestinal carriers. These bacteria require anaerobic (no oxygen) conditions to be active, whereas in the presence of oxygen they turn into resilient but inactive spores, which do not produce the toxin. It has been recognized that inactive tetanus spores are ubiquitous in the soil. Tetanus can result from the exposure to C. tetani via poorly managed tetanus-prone wounds or cuts, but not from oral ingestion of tetanus spores. Quite to the contrary, oral exposure to C. tetani has been found to build resistance to tetanus without carrying the risk of disease, as described in the section on Natural Resistance to Tetanus.

Once secreted by C. tetani germinating in a contaminated wound, tetanospasmin diffuses through the tissue’s interstitial fluids or bloodstream. Upon reaching nerve endings, it is adsorbed by the cell membrane of neurons and transported through nerve trunks into the central nervous system, where it inhibits the release of a neurotransmitter gamma-aminobutyric acid (GABA). This inhibition can result in various degrees of clinical tetanus symptoms: rigid muscular spasms, such as lockjaw, sardonic smile, and severe convulsions that frequently lead to bone fractures and death due to respiratory compromise.

Curative effects of the anti-serum therapy as well as the preventative effects of the tetanus vaccination are deemed to rely upon an antibody molecule called antitoxin. But the assumption that such antitoxin was the sole “active” ingredient in the original horse anti-serum has not been borne out experimentally. Since horses are natural carriers of tetanus spores, their bloodstream could have contained other unrecognized components, which got harnessed in the therapeutic anti-serum. Natural Resistance to Tetanus discusses other serum entities detected in research animals carrying C. tetani, which better correlated with their protection from clinical tetanus than did serum antitoxin levels. Nevertheless, the main research effort in the tetanus field remained narrowly focused on antitoxin.

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