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The Concept of Immunity. History and Applications. 


Roots of the term and concept of immunity

Immunology is the study of immunity. The term derives from the latin immunitas, meaning exemption from military service, tax payments or other public services. In later Roman literature the term acquired a broader meaning (ie the ability to survive poison, contagion) and has been used both in the earlier and later meanings throughout medieval and modern history. In contemporary scientific language immunity defines resistance to disease, typically, to infectious diseases.

Man must have been fascinated by the ability of some to resist disease well before he acquired a written language. In historic times, however, the first European believed to have addressed the concept of immunity was the Athenian Thucydides. In 430 BC, the second year of the Peoponnesian War, the plague hit Athens and killed more than 30,000 people bringing the population from 172,000 to less than 140,000. Athens was the only Greek city hit by the epidemics but several Egyptian cities and Rome were affected and it is conceivable that the plague travelled along the trade routes from Carthage. Thucydides provides us with a terrifying account of the epidemic, he describes the dead laying unburied, the temples full of corpses and the violation of the funeral customs. He himself was struck by the disease but fortunately survived to leave us one of the greatest works of mankind, the Peloponnesian War. In a short passage in his book, Thucydides states that: 'the sick and the dying were tended by the pitying care of those who had recovered, because they knew the course of the disease and were themselves free from apprehensions. For no one was ever attacked a second time, or not with a fatal result'. These Athenians had become immune to the plague.


Natural and artificial immunity

There are several different types of immunity. The immunity outlined above is a natural immunity, as the contact with the agent causing the disease was not deliberate. It is also acquired, in the sense that it only occurs after contact with the pathogen, and specific because it only protected against the plague from which they had survived but not from other disease. We now know that acquired immunity is a property of vertebrate organisms. Invertebrate organisms do possess a form immunity that is known as innate which lacks the features of specificity and memory typical of acquired immunity but does confer nevertheless a certain degree of protection against infection. This type of immunity also exists in vertebrtate organisms alongside the acquired one. The rest of this lecture will deal, however, with a type of immunity that is defined artificial because it occurs in response to the deliberate action of man (Fig 1).

The deliberate transfer of a disease from affected to non-affected humans may lead to resistance in the same way in which natural transfer can. The result is artificial immunity as in contrast to natural immunity. In Europe man-induced immunity emerged in the attempt to contain smallpox. Smallpox had been for centuries the gravest disease throughout Europe. It was probably introduced into Europe by the Saracens who invaded Spain or the Crusaders who returned from Palestine. In seventeenth century England one person out of four would die throughout life of smallpox. Further, blindness due to smallpox was a common occurrence and the majority of people had pockmarks. It is known that Chinese and Indians practiced for many centuries a form of deliberate contact (ingrafting) of healthy individuals with material derived from individuals affected by smallpox. The Chinese used several procedures in order to induce immunity to smallpox but the commonest procedure apparently involved selecting and drying scabs from cases with mild disease (a few pustules), grinding them with a particular type of shrub and introducing this material into the nostrils.

There is also evidence that a different procedure, namely variolation was used in India in the 16th century. Variolation also utilized dried material from the scabs of affected individuals but this material was introduced through scarification (ie several skin incisions) rather into the nostrils. Both the Chinese and Indian procedures often led to protection from disease although there is evidence that a number of subjects undergoing ingrafting developed serious or fatal disease.

This practice of ingrafting was introduced in the Western world at the beginning of the 18th century by several Europeans living in the East, among whom E Timoni, a man with degrees from Padua and Oxford, a member of the Royal Society of London and the family physician to the British ambassador in Costantinople. In December 1713, Timoni wrote an extensive note to the Royal Society (extracts of which were communicated to the members in May 1714) detailing the 'practice of procuring the small pox by incision or inoculation as it has been practised for some time in Costantinople'. This letter had been preceded in 1700 by a letter to M Lister from an East India trader stationed in China describing 'a method of communicating the smallpox involving opening the pustules of one who has the smallpox ripe upon them and drying the matter with a little cotton and afterwards put it up the nostrils of those they would infect'. Although M Lister, a distinguished physician and member of the Royal Society, did not report the content of this letter to the Society, the Chinese procedure was described by another member of the Society in the same year but nothing followed. In contrast, the Timoni report raised considerable discussion and induced the Society to commission a full investigation to J Pylarini, Venetian ambassador in Smyrna, published in 1716.

The following year (1717) Lady Mary Montagu, the wife of the British ambassador in Turkey (Fig. 2 below) wrote to her friend S Chiswell in enthusiastic terms about the local practice of inoculation and the following year she had her little daughter inoculated. Following her return to England in 1919, Lady Montagu continued to campaign for inoculation and in 1721, the year of a severe epidemic, she had another daughter, who was just three year old, safely inoculated.

Fig 2. Lady Montagu (left), an early advocate of vaccination in the western world; E Jenner (centre), the discoverer of a new smallpox vaccination and L Pasteur (right) who discovered attenuation and widened the scope of vaccination to other diseases.

There followed in the same year an experiment sponsored by the Royal family and Sir H Sloane (President of the Royal College of Physisician and later President of the Royal Society) in which six prisoners sentenced to death were inoculated. Five developed a brief illness from which they recovered, the sixth did not develop any disease and was found to have had smallpox the year before. On the same year the Chinese technique was tried on another prisoner. The following year (1722) the Prince and Princess of Wales had their children inoculated.

In spite of these positive results and Royal patronage, the practice of inoculation did not spread in England. Only a few hundred people were inoculated between 1722 and 1730 and a number of doctors and churchmen opposed the practice. Only when another epidemic emerged in 1746, inoculation resumed on a larger scale but in subsequent decades the practice was carried out on a negligible number of people.Towards the end of century however, a general practitioner named E Jenner (Fig. 2 above) heard from a milklady that she would never contract smallpox because she had cowpox, a disease that showed similarities with smallpox and commonly affected European cattles (see footnote 1 at the end of the page). This suggestion prompted Jenner to inoculate unaffected humans with material derived from skin lesions induced by cowpox. The procedure produced encouraging results which Jenner submitted to the Royal Society for publication in 1797. The Society, however, declined publication and the following year Jenner resorted to publishing his findings privately. The Jenner procedure rapidly came into general use in England and in 1802 and 1806 the Parliament voted Jenner £ 10,000 and £ 20,000 respectively for his achievement. In 1838 the British Parliament passed a law that made inoculation available to everyone free of charge and twenty years later (1858) inoculation with cow pox became compulsory in Britain.

The success and general acceptance of Jenner's procedure became the starting point of the general practice of vaccination developed by L Pasteur (Fig. 3 below) and others towards the end of the 19th century. The role of L Pasteur in establishing the general nature of vaccination was critical. His experiments in which old (attenuated) germs causing chicken cholera induced protection from infection with young, virulent germs brought for the first time the phenomenon of immunity within the realm of microbiology (1879). From this realisation it took Pasteur only four years to demonstrate the possibility of inducing immunity against anthrax, swine erysipela and rabies. 'Modern vaccination' was born on the strength of the young science of microbiology and Pasteur's committment to the idea that Jenner'sprocedure could be generalized.


Further Development of vaccination in the Western world

The Table below summarizes, in a simplified form, the key steps in the development of vaccination in the Western world. The table starts with Jenner's cowpox vaccine, which behaved for all practical purposes as an attenuated one, and moves to L Pasteur's vaccines bona fide attenuated vaccines. It is interesting that in the short period of two years (1896-1897) several killed vaccines were developed for thyphoid, cholera and plague although the effectiveness of such vaccines has proved limited throughout the years. Effective vaccines for diphteria and tetanus were developed only in the first half of this century when Alexander Glenny reported a treatment of the diphteria toxin with formaldheyde leading to full inactivation but good residual antigenicity. The resulting toxin is called a toxoid. This approach was subsequently extended to the tetanus toxin where it proved equally successful. Finally, it is clear from Table 1 that a number of modern anti-viral and anti-bacterial vaccines are the so-called subunit vaccines in which the immunizing agent is a purified component (or a mixture of a few components) of the infectious agent. Such approach has proved particularly successful with hepatitis B, pneumonia and meningitis and is presntly being pursued with a number of other vaccines.

Table 1. The Development of vaccination in the Western world

 

Attenuated

Killed

Toxoid

 Subunit

 18th Century  Smallpox (1798)
-
-
-
19th Century  Rabies (1895)
Thyphoid (1896)
Cholera (1896)
Plague (1897)
Diphteria (1888)
-
Early 20th Century
Tubercolosis (1919)
Yellow fever (1935)
Pertussis (1926)
Influenza (1936)
Diphteria (1923), Tetanus (1927)
-
Late 20th Century
Polio
Measles
Mumps
Rubella
Polio
Rabies
-
Hepatitis B
Pneumonia, Meningitis

Impact of vaccination on population and health

To what extent has the practice of vaccination improved the health of modern population ? Scientists and practicising physicians clearly hold the belief that vaccination has had a major impact on human health but it obviously important to establish if the belief is supported by adequate evidence. T McKeown, a British epidemiologist, addressed this problem in considerable depth and an outline of his research is presented here. We are not in the position to evaluate the impact of medicine on human health before the second half of the eighteen century (as we lack the primary data) but we can address the problem over the last two centuries. During this period, population data were collected in certain European states (for example England and Wales, Sweden and France) and the analysis of the data is of great interest.

According to the Domesday Book the population in England and Wales was approximately 1.5 million in the eleventh century. Around 1700 it was approximately 5.5 million. From 1800 to 1971 the populaiton increased from less than 10 millions to 49 millions (see Fig. 3 below). The data available indicate that during the last century and a half both the birth and death rates declined but that the mortality rate showed a greater decrease, hence the population increased considerably. When death rates attributable to the major disease classes were analysed, it emerged that the major change concerned the number of deaths from infectious diseases (Fig. 4 below).

The dramatic changes in the population just described occurred roughly at the time when vaccination and chemotherapy were developed. It seemed natural, therefore, to conclude that the new preventive medicine and the new treatments caused the decline in death rate due to infectious diseases.The data available indicate that this is not true for a number of diseases but it is true for others. In the case of tubercolosis, scarlet fever, whooping cough and measles (Figs. 5-8 below) either chemotherapy or vaccination has had a rather modest contribution to the decline in death rate. For example in the case of tubercolosis, the death rate in England and Wales had already declined from 4,000 per million in 1838 to less than 2,000 per million in the 1880s (ie at the time when R Koch isolated the tubercle bacillum) and continued to decline to ~ 500 per million until the late 1940s when effective chemotherapy first became available (see Fig. 5 below). The results with scarlet fever, measles and whooping cough are even more striking (Figs. 5-8).

Fig. 3. Population of England and Wales from 1066 until 1960 (re-drawn from T Mc Keown, 1976) Fig. 4. Mortality England and Wales from 1840 circa until 1970 (re-drawn from T Mc Keown, 1976)


Fig. 5. Mortality caused by tubercolosis in England and Wales (re-drawn from T Mc Keown, 1976) Fig. 6. Mortality caused by scarlet fever in England and Wales (re-drawn from T Mc Keown, 1976)


Fig 7. Mortality caused by whooping cough in England and Wales (re-drawn from T Mc Keown, 1976) Fig 8. Mortality caused by measles in England and Wales (re-drawn from T Mc Keown, 1976)

The data just summarised, therefore, point to a major role for "external" factors (ee below) in the control of a number of infectious diseases such tubercolosis, scarlet fever, whooping cough and measles. In other cases, however, such as smallpox, diphteria and tetanus, the contribution of vaccination has been considerable. For example in the case of tetanus, immunization decreased the death rate by approximately 50 fold between 1910 and 1970. In the case of smallpox the results have been even more striking and vaccination has been the single most important factor that has led to the eradication of this disease (see Fig. 9 below). In the case of diphteria the disease has not been eradicated yet but the contributions of passive immunotherapy (the antitoxin) and, subsequently of vaccination to disease control have been very considerable (Fig. 10 below)

Fig 9. Mortality caused by smallpox in England and Wales (re-drawn from T Mc Keown, 1976) Fig 10. Mortality caused by diphteria in England and Wales (re-drawn from T Mc Keown, 1976)

From the anlaysis of T. McKeown and from other data analysis it is fair to conclude that the major changes in population and disease control that have occurred in England and Wales (and most probably in other parts of Europe) during the last century and half are due to factors external to the medical practice. Among these food supply, housing and water sanitation are probably the most significant. However, the role played by medicine is undeniable in the case of other diseases (exemplified above by smallpox and diphteria). In the latter group, however, the major impact is attributable to vaccination rather than chemotherapy. Thus the single most important achievement of Western medicine, namely the control of infectious diseases, has occurred largely, albeit not solely, through vaccination. The practice itself was imported from non-European cultures but, when it met with the developing science of microbiology, it became a general and effective procedure. Hence, the study of immunity, a topic of considerable biological interest in itself should also be viewed as the study of the major contribution of Western medicine to human health.


Current state of disease control through immunization.

Over the last 200 years that separate us from the publication of Edward Jenner's seminal work, vaccination has had a major impact on the control of nine diseases, namely: smallpox, diphteria, tetanus, yellow fever, pertussis, poliomyelitis, measles, mumps and rubella. As a result of improvement of diet, housing and water quality as well as medical progress, infectious diseases have thus been controlled to a large extent in developed countries. In contrast, these diseases still represent the major cause of death in thirld world countries (Fig. 11 below). A further and considerable effort is thus required in order to contain the impact of infectious diseases on the population of thirld world countries.

The work of T. McKeown and other researchers clearly indicates that this will require first and above dramatic improvements in diet, housing and water sanitation, ie in the social and economic fabric of such countries. It will also require, however, effective immunization. This translates, on the one hand, in access to vaccines of proved efficacy which have been available for considerable time to the populations of developed countries. The "World Health Organization Expanded Programme of immunization" is the major initiative of this kind and aimed in 1974 in vaccinating all children in all countries of the world against four bacterial diseases (diphteria, tetanus, tubercolosis and pertussis) and two viral diseases (polio and measles). The programme aimed to achieve 90% coverage of the world population by year 2,000, a figure which the Programme failed to reach. This initiative was, nevertheless, the major step taken so far in order to ensure control of infectious disease through immunization on a worldwide basis.

Containment of infectious diseases in thirld world countries will also require, however, new and effective vaccines diseases such as malaria, lepra and schistosomiasis for which there is no effective or large scale immunization yet and after a number of years of serious underfunding, there has been a recent increase in the resources made available for specific tasks, such as the development of a malaria vaccine and, interestingly, much of this funding has been made available by private Foundations, such as the Bill and Melinda Gates Foundation. Immunological research may thus continue to play a major role in the control of infectious disease although the focus of this work should now be directed to diseases that affect primarily the less developed countries.

Fig 11.

The major causes of death in developed and thirld world countries in 1993

(from The World Health Report 1995: Bridging the Gaps, WHO 1995)


Topics for Exam

 

Further readings

Parish HJ
A history of immunization. Edinburgh, Livingstone, 1965
 
McKeown T
The modern rise of population. Edward Arnolds Publishers Ltd, 1976
 

Footnotes

(1) E Jenner later acknowledged that, unknown to him, the English farmer Benjamin Jesty had become aware of being immune from smallpox because he had contracted smallpox from his herd. In 1774 he also incoculated wife and children with cowpox in order to protect them from smallpox . There is no question, threfore, that Benjamin Jesty had fully understood the potential of using inoculation with cowpox in order to achieve protection from smallpox although this in no way diminishes the contribution of E Jenner in the development of vaccination in the Western world.

"Part 1 Lectures"