Historical background to vaccination and vaccinal strategy
SIMFEROPOL
History of Diphtheria
Diphtheria was named in 1826 by French physician Pierre Bretonneau. The name alludes to the leathery, sheath-like membrane that grows on the tonsils, throat, and in the nose. The pronunciation was originally considered incorrect, but has become the most common way of saying the word, and is accepted as a correct form. While many writers today use the spelling "diptheria" which fits the modern pronunciation, this spelling is rarely found in dictionaries.
A bottle of diphtheria antitoxin, produced by the United States Hygienic Laboratory (now the National Institutes of Health and dated May 8, 1895.
Diphtheria was once a dreaded disease, with frequent large-scale outbreaks. A diphtheria epidemic in the New England colonies between 1735 and 1740 was said to have killed as many as 80% of the children under 10 years of age in some towns. In the 1920s there were an estimated 100,000 to 200,000 cases of diphtheria per year in the United States, causing 13,000 to 15,000 deaths. Children represented a large majority of these cases and fatalities. One of the most famous outbreaks of diphtheria was in Nome, Alaska; the trip made to get the antitoxin is now celebrated by the Iditarod Trail Sled Dog Race.
Diphtheria was also prevalent in the British royal family during the late 19th century. Famous cases included a daughter and granddaughter of Britain's Queen Victoria. Princess Alice of Hesse (second daughter of Queen Victoria) died of diphtheria after she contracted it from her children in December of 1878 while nursing them. One of Princess Alice's own daughters, Princess Marie, also died of diphtheria in November of 1878.
One of the first effective treatments for diphtheria was discovered in the 1880s by U.S. physician Joseph O'Dwyer (1841-1898). O'Dwyer developed tubes that were inserted into the throat, and prevented victims from suffocating due to the membrane sheath that grows over and obstructs airways. In the 1890s, the German physician Emil von Behring developed an antitoxin that did not kill the bacteria, but neutralized the toxic poisons that the bacteria releases into the body. von Behring was awarded the first Nobel Prize in Medicine for his role in the discovery, and development of a serum therapy for diphtheria. (Americans William H. Park and Anna Wessels Williams; and Pasteur Institute scientists Emile Roux and Martin Chaillou also independently developed diphtheria antitoxin in the 1890s.) The first successful vaccine for diphtheria was developed in 1923. However, antibiotics against diphtheria were not available until the discovery and development of sulfa drugs following World War II.
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 Gram stained Corynebacterium diphtheriae culture | ||||||||||||
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Corynebacterium diphtheriae is a pathogenic bacterium that causes diphtheria. It is also known as the Klebs-Löffler bacillus, because it was discovered in 1884 by German bacteriologists Edwin Klebs (1834 – 1912) and Friedrich Löffler (1852 – 1915).
C. diphtheriae is a facultatively anaerobic [1] Gram positive organism, characterized by non-encapsulated, non-sporulated, immobile, straight or curved rods with a length of 1 to 8 µm and width of 0.3 to 0.8 µm, which form ramified aggregations in culture (looking like "Chinese characters"). It is not pathogenic only in humans.
Many strains of C. diphtheriae produce a proteic exotoxin with a molecular weight of 62 kilodaltons which ADP-ribosylates host EF-2, which is responsible for the signs of diphtheria. The inactivation of this toxin with an antitoxic serum (antitoxin) is the basis of the antidiphtheric vaccination. However, not all strains are toxigenic; toxin production is associated with infection of the bacterium by a bacteriophage.
Three subspecies are recognized: C. diphtheriae mitis, C. diphtheriae intermedius, and C. diphtheriae gravis. The three subspecies differ slightly in their ability to metabolize certain nutrients, but all may be toxigenic (and therefore cause diphtheria) or non-toxigenic.
The bacterium is sensitive to the majority of antibiotics, such as the penicillins, ampicillin, cephalosporins, quinolones, chloramphenicol, tetracyclines, cefuroxime and trimethoprim.
Epidemiology
Diphtheria is a serious disease, with fatality rates between 5 and 10 percent in adults. In children under 5 years and adults over 40 years, the fatality rate may be as much as 20%. Outbreaks, though very rare, still occur worldwide, even in developed nations. After the breakup of the former Soviet Union in the late 1980s, vaccination rates in its constituent countries fell so low that there was an explosion of diphtheria cases. In 1991 there were 2,000 cases of diphtheria in the USSR. By 1998, according to Red Cross estimates, there were as many as 200,000 cases in the Commonwealth of Independent States, with 5,000 deaths. This was so great an increase that diphtheria was cited in the Guinness Book of World Records as "most resurgent disease".
Such statistics show that constant vigilance must be maintained even on largely eradicated diseases, especially since many of these diseases show growing resistance to drugs that have been used to fight them for decades.
Before vaccination became widespread, diphtheria was one of the main causes of infantile mortality and morbidity.
In the United States in the 1920s, between 100,000 and 200,000 cases of diphtheria were reported yearly, resulting the death of 13 to 15,000 people. In England and Wales in 1937-38, diphtheria was the second leading cause of mortality in children aged under 15 years, just behind pneumonia. In France, diphtheria was one of the most serious childhood diseases until the middle of the 20th century, and still accounted for 3,000 deaths as late as 1945 [Ref 2 p 3]. Before the institution of the Extended Vaccination Programme (EVP) by the World Health Organisation (WHO), it was stimated that almost one million cases of diphtheria occurred yearly in the Third World, resulting in the death of 50 to 60,000 subjects In the industrialised countries, routine vaccination of infants against diphtheria was introduced into the child vaccination schedule between 1938 and 1950. By 1990, the disease had been stamped out in most countries.The major epidemic cycles were replaced by the onset of sporadic cases and minor low-grade epidemics In the tropical and sub-tropical countries, immunity is acquired very early by means of 3 EVP injections for infants, and is maintained by repeated contact with C. diphtheriae due to the high prevalence of subclinical and cutaneous infections
Between 1980 and 2002, the number of reported cases of diphtheria throughout the world fell from 97,427 to 9,235 cases, with 80% of remaining cases occurring in Africa and Southeast Asia. In 2001, the WHO estimated the number of annual deaths related to diphtheria at 5,000 throughout the world, 4,000 of which were seen in children aged under 5 years
However, diphtheria persists in many countries throughout the world despite the development of the EVP, and a number of epidemics have occurred over the last ten years. These epidemics chiefly affected adults
The most important recent epidemic occurred in the 1990s in the Russian Federation, then in the Commonwealth of Independent States (CIS) as a result of inadequate vaccinal cover, disorganisation of the healthcare system and migration to urban areas with a high population
The epidemic culminated in 1995 with 50,000 cases and 1,500 reported deaths in the CIS, i.e. 88% of reported cases throughout the world for that particular year. A number of imported cases were seen in neighbouring countries. Thanks to the institution of a more effective strategy of prevention and control by the public health authorities resulted in control of the diphtheria epidemic in the majority of Baltic countries and in the CIS member states. In 2002, 1189 cases of diphtheria were reported for the entire European region, with 359 cases in the CIS
Historical background to vaccination and vaccinal strategy
In 1888, Emile Roux discovered a diphtheria toxin secreted by Corynebacterium diphtheriae, the causative agent of diphtheria [Ref 6 p 211].
In 1890, studies by Emil Von Behring on diphtherial antitoxin antibodies paved the way for the use of therapy against the disease. In 1894, Roux and Martin immunised horses to produce antidiphtheria serum on a large scale. In 1897, Ehrlich succeeded in normalising diphtheria toxin. These studies of passive immunisation by serum therapy were followed by active immunisation programmes involving vaccination.
In 1923, Alexander Glenny and Barbara Hopkins demonstrated that formol can be used to eradicate the virulence of diphtheria toxin. In the same year, Gaston Ramon discovered that the product of degradation of diphtheria toxin by formaldehyde is devoid of toxicity but conserves its specific immunogenic power [Ref 6 p 212]. The vaccines obtained by this type of chemical treatment are known as anatoxins, “toxoids” or “formalin-toxoids” in the English-speaking countries.
Diphtheria vaccines used throughout the world today are manufactured entirely from diphtheria anatoxin. They were rapidly combined with other valences. The paediatric forms containing diphtheria anatoxin may be bivalent (combined with tetanus valence), trivalent (combined with acellular or whole-organism whooping cough and tetanus valences), tetravalent, pentavalent or hexavalent, depending on whether the trivalent diphtheria-tetanus-pertussis vaccine is combined with Hæmophilus Influenzae b, hepatitis B or inactivated poliovirus.
A vaccine is also available containing a low concentration of diphtheria anatoxin (1/10 of the normal dose) and is recommended for booster doses in children aged over 7 years and for adult vaccinations [Ref 1 p 1]. The low dose of diphtheria anatoxin reduces reactivity but is sufficient to trigger an anamnestic immune response in patients already vaccinated or partially naturally immunised. These vaccines are generally combined with tetanus vaccine, but also with whooping cough vaccine and poliomyelitis vaccine.
The trivalent diphtheria-tetanus-pertussis vaccine is the lynchpin of the EVP programme instituted by the WHO. Each infant normally receives 3 doses of this vaccine in the first year of life, with the aim being to obtain global vaccinal cover above 90%. Where the resources of individual countries allow, a booster dose is recommended during the second or third year of life [Ref 1 p 1].
In the developed countries, a second booster is often recommended before starting school, and the vaccination schedules also provide for subsequent boosters.
Vaccination booster policies vary from one country to another: in the United States, boosters are advised every 10 years with the low-dose vaccinal combination of tetanus and diphtheria. In Europe, Italy, Finland, Germany, Spain and Austria recommend a low-dose tetanus-diphtheria booster every ten years for all adults. In France, the vaccination calendar recommends boosters up to the age of 18 years. Subsequently, vaccination is recommended for travellers visiting endemic areas.