Nailing tetanus

In the second of a series of articles about lifesaving vaccines for children, our Chief Scientific Officer traces the research path towards prevention of a terrible disease that can be caught from a rusty nail or a pair of dirty scissors.

Tetanus vaccine is included in Crucell’s Quinvaxem® vaccine, which protects millions of children worldwide from five major health threats. Tetanus is a huge problem in regions with a hot, damp climate, soil rich in organic matter and a high population density. The World Health Organization (WHO) estimates that in 2008, about 60,000 babies died as a result of neonatal tetanus.

Tetanus is a very deadly disease, with reported case mortality rates of over 50% in some parts of the world. Disease symptoms appear between three days and a few weeks after infection with Clostridium tetani, a Gram-positive, spore-forming, anaerobic bacillus. The severity of tetanus is inversely related to the length of the incubation period: the later disease symptoms occur, the milder the course.

Most tetanus cases in humans are generalized, with symptoms affecting all parts of the body, because C. tetani spreads rapidly through the bloodstream. The first sign of the disease is usually spasm of the jaw muscles, which is why tetanus used to be called ‘lockjaw’. Next, the facial muscles spasm and the patient’s face contorts, with raised eyebrows, tightly closed eyelids, wrinkling of the forehead and lateral extension of the corners of the mouth. The final and characteristic symptom is sustained spasm of the back muscles and then the glottis, leading to death. Tetanus victims die in terrible agony. Most cases of serious tetanus occur among the elderly, while neonatal tetanus has most impact on a community.

Step by step towards a vaccine
Arthur Nicolaier was the first to show, in 1884, that the C. tetani bacillus lived in soil, and that tetanus-like symptoms developed in rodents if soil from streets or fields was introduced beneath their skin. Antonie Carl and Giorgio Rattone proved that human tetanus is caused by the same bacillus in 1890, when they induced tetanus in rabbits by exposing them to pus from a fatal human tetanus case. A year earlier, the Japanese scientist Kitasato Shibasaburo had isolated and produced pure cultures of C. tetani from a human victim.

Most cases of tetanus in adults are associated with puncture wounds, particularly those caused by rusty nails. Oxydation of iron resulting in rust is not in itself the cause of tetanus, of course. Iron objects that rust are generally exposed to oxygen in the open air and have a rough surface that provides a habitat for the C. tetani spores. A nail can easily puncture the skin, after which the spore finds the right anaerobic (oxygen-free) environment to propagate. In newborns, the cause of tetanus is generally contamination of the unhealed umbilical cord stump with soil or manure, or with spores transmitted from rusty or dirty scissors used to cut the cord.

After the spores have entered the damaged tissue or skin, they transform into bacteria producing the deadly neurotoxin tetanospasmin, or tetanus toxin.

In 1897, Nocard demonstrated the protective effect of passively transferred antitoxin immunoglobulin, a treatment used in the trenches of Verdun during World War I. The first people to receive tetanus antiserum were German soldiers, after the German doctor Emil Adolf von Behring showed in 1914 that hyperimmune antitetanus serum prevented disease. (Von Behring had already been awarded the first Nobel Prize in Physiology or Medicine in 1901 for his work on serum therapy.) Shortly after the end of World War I, in 1924, Pierre Descombey developed detoxified tetanus toxin, called tetanus toxoid, which was successfully used for vaccination during World War II.

Optimizing protection
The best way to prevent neonatal tetanus is to give the vaccine to pregnant women. This ensures that anti-tetanus antibodies pass from mother to unborn child through the placenta and protect the baby from becoming infected with tetanus bacilli shortly after delivery. The next-best option is to vaccinate newborn babies at 6, 10 and 14 weeks of age with a combination vaccine like Quinvaxem®, as is current practice under the Expanded Program of Immunization (EPI).

Ideally, both strategies are used. Unfortunately, there are still many mothers and newborns who are not vaccinated and are therefore at risk. To minimize the risk of tetanus, WHO recommends a three-dose course of vaccine for newborns, followed by two booster vaccinations: one at 4–7 years of age and a second at 12–15 years. To protect older people against tetanus, a final vaccination for women at the time of first pregnancy and for men at the start of military service is recommended.

Intriguing facts
Two characteristics of tetanus and vaccination against tetanus stand out. Firstly, tetanus is the only vaccine-preventable disease that is not contagious. All infections result from exposure to spores in soil, either in nature or in a dirty indoor environment. No bacteria are transmitted from animals or among humans. Secondly, tetanus toxoid vaccines can only prevent disease, not the spread of infection, which is self-limiting in humans. The reservoir in soil will always remain and people will continue to get infected if C. tetani spores get into a wound.

In 1942, two German researchers called Wolters and Dehmel conducted a now-famous experiment that established the correlates of protection from tetanus and the amount of antitoxin antibody required for protection. The researchers vaccinated each other three times with tetanus toxoid and then exposed themselves to a deadly dose of tetanus toxin. Fortunately, this dangerous experiment ended well, as the vaccine provided complete protection. Wolters and Dehmel recorded this research and its happy outcome on the occasion of their professor’s birthday, in an article published in the German-language journal Zeitschrift für Hygiene und Infektionskrankheiten.

The introduction to Wolters and Dehmel’s account of their ground-breaking study reveals how far advanced the vaccine know-how was in the Germany of Koch and von Behring before World War II:

“Wenn wir das Auftreten von nachweisbaren Antitoxinmengen in Blut als Aufdruck einer erworbenen Immunität werten, so ist durch diese Untersuchungen eindeutig festgestellt, dass ohne Ausnahme durch ein-bzw. zweimalige Impfung mit hochantigenen Aluminium-Depotimpfstoffen ein ausreichender Impfschutz erzielt wird. Die Höhe des Antitoxintiters ist abhängig von der Art des Impfstoffen, von Konstitutionell bedingten Faktoren des Impflings, von der Anzahl der Impfungen und dem Impfintervall.”

In view of the Germans’ sophisticated understanding of tetanus immunization, it is ironical that the British and American armed forces were vaccinated against tetanus from 1941 on, whereas the German army was given antitoxin serum only. As a result, there were only a few tetanus fatalities among the Anglo-American troops during World War II, but high rates of disease and death from tetanus among the German soldiers.<<

December 2010