Tetanus Shot: How Do We Know That It Works?


Tetanus Shot: How Do We Know That It Works?

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Do we know how tetanus shots work? The medical establishment holds a view that a tetanus shot prevents tetanus, but how do we know this view is correct?

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.

Antitoxin molecules are thought to inactivate the corresponding toxin molecules by virtue of their toxin-binding capacity.  This implies that to accomplish its protective effect, antitoxin must come into close physical proximity with the toxin and combine with it in a way that would prevent or preempt the toxin from binding to nerve endings.  Early research on the properties of a newly discovered antitoxin was done in small-sized research animals, such as guinea pigs.  The tetanus toxin was pre-incubated in a test tube with the animal's serum containing antitoxin before being injected into another (antitoxin-free) animal, susceptible to tetanus.  Such pre-incubation made the toxin lose its ability to cause tetanus in otherwise susceptible animals — i.e. the toxin was neutralized.

Nevertheless, researchers in the late 19th and early 20th centuries were baffled by a peculiar observation.  Research animals, whose serum contained enough antitoxin to inactivate a certain amount of the toxin in a test tube, would succumb to tetanus when they were injected with the same amount of the toxin.  Furthermore, it was noted that the mode of the toxin injection had a different effect on the ability of serum antitoxin to protect the animal.  The presence of antitoxin in the serum of animals afforded some degree of protection against the toxin injected directly into the bloodstream (intravenously).  However, when the toxin was injected into the skin it would be as lethal to animals containing substantial levels of serum antitoxin as to animals virtually free of serum antitoxin.[1]

The observed difference in serum antitoxin's protective "behavior" was attributed to the toxin's propensity to bind faster to nerve cells than to serum antitoxin.  The pre-incubation of the toxin with antitoxin in a test tube, or the injection of the toxin directly into the bloodstream, where serum antitoxin is found, gives antitoxin a head start in combining with and neutralizing the toxin.  However, a skin or muscle injection of the toxin does not give serum antitoxin such a head start.

Researchers in the 21st century have developed an advanced fluorescent labeling technique to track the uptake of the injected tetanus toxin into neurons.  Using this technique, researchers examined the effect of serum antitoxin, which was induced by vaccinating mice with the tetanus toxoid vaccine ahead of time (the same one currently used in humans), on blocking the neuronal uptake and transport of the tetanus toxin fragment C (TTC) to the brain from the site of intramuscular injection.  Vaccinated and non-vaccinated animals showed similar levels of TTC uptake into the brain.  The authors of the study concluded that the "uptake of TTC by nerve terminals from an intramuscular depot is an avid and rapid process and is not blocked by vaccination."[2] They have further commented that their results appear to be surprising in view of protective effects of immunization with the tetanus toxoid.  Indeed, the medical establishment holds a view that a tetanus shot prevents tetanus, but how do we know this view is correct?

Neonatal Tetanus

Neonatal tetanus is common in tropical under-developed countries but is extremely rare in developed countries.  This form of tetanus results from unhygienic obstetric practices, when cutting the umbilical cord is performed with unsterilized devices, potentially contaminating it with tetanus spores.  Adhering to proper obstetric practices removes the risk of neonatal tetanus, but this has not been the standard of birth practices for some indigenous and rural people in the past or even present.

The authors of a neonatal tetanus study performed in the 1960s in New Guinea describe the typical conditions of childbirth among the locals:

"The mother cuts the cord 1 inch (2.5 cm) or less from the abdominal wall; it is never tied.  In the past she would always use a sliver of sago bark, but now she uses a steel trade-knife or an old razor blade.  These are not cleaned or sterilized in any way and no dressing is put of the cord.  The child lies after birth on a dirty piece of soft bark, and the cut cord can easily become contaminated by dust from the floor of the hut or my mother's feces expressed during childbirth, as well as by the knife and her finger."[3]

Not surprisingly, New Guinea had a high rate of neonatal tetanus.  Because improving birth practices seemed to be unachievable in places like New Guinea, subjecting pregnant women to tetanus vaccination was contemplated by public health authorities as a possible solution to neonatal tetanus.

A randomized controlled trial (RCT) assessing the effectiveness of the tetanus vaccine in preventing neonatal tetanus via maternal vaccination was conducted in the 1960s in rural Colombia in a community with high rates of neonatal tetanus.[4] The design of this trial has been recently reviewed by the Cochrane Collaboration for potential biases and limitations and, with minor comments, has been considered of good quality for the purposes of vaccine effectiveness (but not safety) determination.[5] The trial established that a single dose of the tetanus vaccine given before or during pregnancy had a partial effect on preventing neonatal tetanus in the offspring: 43% reduction was observed in the tetanus vaccine group compared to the control group, which instead of the tetanus shot received a flu shot.  A series of two or three tetanus booster shots, given six or more weeks apart before or during pregnancy, reduced neonatal tetanus by 98% in the tetanus vaccine group compared to the flu shot control group.  The duration of the follow up in this trial was less than five years.

In addition to testing the effects of vaccination, this study has also documented a clear relationship between the incidence of neonatal tetanus and the manner in which childbirth was conducted.  No babies delivered in a hospital, by a doctor or a nurse, contracted neonatal tetanus regardless of the mother's vaccination status.  On the other hand, babies delivered at home by amateur midwives had the highest rate of neonatal tetanus.

Hygienic childbirth appears to be highly effective in preventing neonatal tetanus and makes tetanus vaccination regimen during pregnancy unnecessary for women who give birth under hygienic conditions.  Furthermore, it was estimated in 1989 in Tanzania that 40% of neonatal tetanus cases still occurred in infants born to mothers who were vaccinated during pregnancy,[6] stressing the importance of hygienic birth practices regardless of maternal vaccination status.

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Tetanus In Adults

Based on the protective effect of maternal vaccination in neonatal tetanus, demonstrated by an RCT and discussed above, we might be tempted to infer that the same vaccine also protects from tetanus acquired by stepping on rusty nails or incurring other tetanus-prone injuries, when administered to children or adults, either routinely or as an emergency measure.  However, due to potential biologic differences in how tetanus is acquired by newborns versus by older children or adults, we should be cautious about reaching such conclusions without first having direct evidence for the vaccine effectiveness in preventing non-neonatal tetanus.

It is generally assumed that the tetanus toxin must first leach into the blood (where it would be intercepted by antitoxin, if it is already there due to timely vaccination) before it reaches nerve endings.  This scenario is plausible in neonatal tetanus, as it appears that the umbilical cord does not have its own nerves.[7] On the other hand, the secretion of the toxin by C. tetani germinating in untended skin cuts or in muscle injuries is more relevant to how children or adults might succumb to tetanus.  In such cases, there could be nerve endings near germinating C. tetani, and the toxin could potentially reach such nerve endings without first going through the blood to be intercepted by vaccine-induced serum antitoxin.  This scenario is consistent with the outcomes of the early experiments in mice, discussed in the beginning.

Although a major disease in tropical under-developed countries, tetanus in the USA has been very rare.  In the past, tetanus occurred primarily in poor segments of the population in southern states and in Mexican migrants in California.  It was swiftly diminishing with each decade prior to the 1950s (in the pre-vaccination era), as inferred from tetanus mortality records and similar case-fatality ratios (about 67-70%) in the early 20th century[8] versus the mid-20th century).[9] The tetanus vaccine was introduced in the USA in 1947 without performing any placebo-controlled clinical trials in the segment of the population (children or adults), where it is now routinely used.

The rationale for introducing the tetanus vaccine into the U.S. population, at low overall risk for tetanus anyway, was simply based on its use in the U.S. military personnel during World War II.  According to a post-war report:[10]

  1. the U.S. military personnel received a series of three injections of the tetanus toxoid, routine stimulating injection was administered one year after the initial series, and an emergency stimulating dose was given on the incurrence of wounds, severe burns, or other injuries that might result in tetanus;
  2. throughout the entire WWII period, 12 cases of tetanus have been documented in the U.S. Army;
  3. in World War I there were 70 cases of tetanus among approximately half a million admissions for wounds and injuries, an incidence of 13.4 per 100,000 wounds.  In World War II there were almost three million admissions for wounds and injuries, with a tetanus case rate of 0.44 per 100,000 wounds.

The report leads us to conclude that vaccination has played a role in tetanus reduction in wounded U.S. soldiers during WWII compared to WWI, and that this reduction vouches for the tetanus vaccine effectiveness.  However, there are other factors (e.g. differences in wound care protocols, including the use of antibiotics, higher likelihood of wound contamination with horse manure rich in already active C. tetani in earlier wars, when horses were used by the cavalry, etc.), which should preclude us from uncritically assigning tetanus reduction during WWII to the effects of vaccination.

Severe and even deadly tetanus is known to occur in recently vaccinated people with high levels of serum antitoxin.[11] Although the skeptic might say that no vaccine is effective 100% of the time, the situation with the tetanus vaccine is quite different.  In these cases of vaccine-unpreventable tetanus, vaccination was actually very effective in inducing serum antitoxin, but serum antitoxin did not appear to have helped preventing tetanus in these unfortunate individuals.

The occurrence of tetanus despite the presence of antitoxin in the serum should have raised a red flag regarding the rationale of the tetanus vaccination program.  But such reports were invariably interpreted as an indication that higher than previously thought levels of serum antitoxin must be maintained to protect from tetanus, hence the need for more frequent, if not incessant, boosters.  Then how much higher "than previously thought" do serum levels of antitoxin need to be to ensure protection from tetanus?

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