Monday, November 22, 2010

Essay on Development of Vaccines

Essay on The Historical Development of Vaccines

Preventative measures to limit the spread of communicable, infectious diseases have been practiced since ancient times. A simple, but often cruel, safeguard was to separate diseased from healthy individuals by isolation or quarantine. These infectious diseases have had significant impacts on life expectancy, infant mortality and population growth. With the exception of safe and clean water no other modality not even antibiotics has had such a major effect on mortality reduction and population growth (Poltkin and Plotkin 1988;1). Thus the impact that vaccine development has had in the scientific, medical and social context is enormous. Through the development of vaccines to combat these infectious diseases the quality of life has increased considerably.

Vaccination is the deliberate attempt to protect humans and confer immunity against these diseases. Thus the purpose of immunisation through vaccination is to stimulate a specific immunological response to a microbial agent or antigen, with the expectation that this will result in humoral factors (i.e. protective antibodies) in the blood or the development of cell-mediated immunity (Friedman and Voller, 1978;1). Although vaccination has a long history the practice has really only flowered into routine in the 20th century. Since Edward Jenner, more than 200 years ago, vaccination has controlled diseases such as smallpox, anthrax, rabies, diphtheria, measles, mumps, rubella, yellow fever and poliomyelitis that were once dreaded by the human race.

It is usually assumed that modern vaccination began with the English country physician Edward Jenner (1749-1823), in the midst of the Age of Reason during the 18th century, when he prevented smallpox by vaccinating an individual with cowpox. But there is ample historic evidence to suggest that ancient civilisations have understood the concepts of immunity in relation to smallpox. Furthermore, the prevention of infection through exposure to an attenuated infectious agent was also known centuries before Jenner. The Chinese Sung Dynasty (550BC) allegedly treated against smallpox with an exposure to a mild case of the disease. The first written record ‘The Correct Treatment of Smallpox’ was attributed to a Buddhist nun practicing during the rein of Jen Tsung (1022 –1063AD). She recommended selecting scabs from infected cases that had but a few pustules and that were one month old. These scabs were dried and ground with a specific type of shrub and then blown up the nostril (Plotkin and Plotkin 1988;2). Another early Chinese medical text ‘The Golden Mirror of Medicene’ lists the forms of inoculation against smallpox as follows: (1) nose plugged with powdered scabs laid on cotton wool, (2) powdered scabs blown into the nose, (3) undergarments of an infected child put on a healthy child for several days and (4) a piece of cotton smeared with the contents of a vesicle and stuffed into the nose (Hume 1940;32).


In the 16th century, variolation was practiced at regular intervals by the Brahman caste of Hindus in India. Some claim that a description of variolation can be found in the ‘Atharva Veda’ (a pre-Hindu Indian religious text circa 1000BC) (Major 1953;17). What's more is that a century before Jenner, the Chinese used white cow fleas for prevention against smallpox. These fleas were ground into powder and made into pills, which presumably was the first attempt at an oral vaccine.

Smallpox was specifically a human disease, which was virtually pandemic in the 18th century. Without a doubt, Edward Jenner’s work with the cowpox vaccination against smallpox holds the title to the first scientific attempt to control an infectious disease. However, it must be appreciated that Jenner had precedents to draw from with earlier attempts for protection against smallpox. In 1721, Lady Mary Worthy Montague (1689-1762) the wife of the British Ambassador to the Turkish court, accurately described the technique of inoculation whilst returning from Constantinople. This practice of inoculation divulged in the West introduced dried pus from smallpox pustules into an open wound on the patient being inoculated. She also described the clinical manifestations of a mild form of the disease that followed preventive inoculation. During smallpox outbreaks in the 18th century inoculations became common only to the rich. However, inoculation was not the complete answer to smallpox as the risks were great and many people died. But it did lead many people to think that maybe diseases could be defeated.

In the United States many different personalities entered the public debate on the controversial smallpox inoculation. These personalities included the stern puritan minister Reverend Cotton Mather (1663-1728) and Benjamin Franklin (1706-1790) a witty American statesman, patriot and scientist. Both became strong adherents of variolation and smallpox inoculation. Yet inoculation wasn’t a complete cure for smallpox as some people still contracted the deadly disease. It was the Boston physician Zabdiel Boylston (1680-1766) who introduced the practice of inoculation to America. On June 26, 1721 with the support from Rev. Mather, Dr. Boylston became the first man in America to inoculate New Englanders against smallpox, despite strong social opposition.

In 1774 in Yetminster, England, the cattle breeder Benjamin Jesty, himself immune to smallpox after contracting cowpox from his cattle directly inoculated his wife and two sons with cowpox to avoid the smallpox epidemic and succeeded.

Between 1780 and 1800 in one city, London, England, smallpox killed over 36 000 people; the disease was responsible overall for nearly one out of every ten deaths and nine out of ten deaths in children under the age of 5 (Mackett and Williamson 1995;5). Jenner’s discovery and his contribution were possible because as it often happens in medical history, he made a valid and fateful observation. He noticed that diary workers afflicted with cowpox from cattle only had chills and malaise for a few days and recovered without sequlae. These cowpox sores (vaccina) were very similar to the smallpox sores (varriola). He also observed that when smallpox broke out in the area, those who had already contracted a mild case of cowpox didn’t contract smallpox, therefore conveying immunity. On the 14th May 1796, Jenner inoculated an eight-year-old boy James Phillips, with a mild form of cowpox without contracting any serious infection. Again on the 1st July 1796 Jenner inoculated the boy this time with smallpox and didn’t contract the serious disease. Through the scientific method of observation and experimentation Jenner conducted another 23 different cases, concluding those who had suffered cowpox were indeed immune to smallpox. The word ‘vaccine’ was derived from the latin word vacca meaning cow and the word ‘vaccination’ was and still is used to describe the process of immunisation against disease.

In 1798, Jenner submitted his findings to the Royal Society. Since doctors were accustomed to inoculation they opposed the new idea of vaccination and subsequently the Royal Society refused to publish Jenner’s findings. The Royal family did however show support for Jenner and his work and were vaccinated, thus leading to the acceptance of vaccination abroad. In 1801, Jenner published a treatise on ‘The Origin of the Vaccine Inoculation’ which expressed his hope that the annihilation of the Smallpox, the most dreadful scourage of the human species, must be the final result of this practice (Mackett and Williamson 1995;5). The government granted Jenner 10000 pounds in 1802 and a further 20000 pounds in 1806. Vaccination became free for all infants in1840 and complusory in Britain in 1853 and in 1980 the World Health Assembly declared that smallpox had been eradicated throughout the world (Faria 1993;3). As Sir William Osler said ‘in science the credit goes not to the one who first thinks of the idea but the one who convince the world’ (Faria 1993;4). This development paved the way for the advances of Pasteur and general immunisation through vaccination.

During the 87 years that elapsed between Jenner’s vaccination treatise and Pasteur’s first human vaccination against rabies, the field wasn’t dormant. The ideas of attenuation and virulence were developing and the necessity of revaccination were being discussed (Plotkin and Plotkin 1978;2). Jenner realised by 1810 that immunity wasn’t lifelong but he didn’t know why (Parish 1965;22). It was Ballard who then discussed the problems of choosing new strains of cowpox for vaccination in 1836 because the old strains were too weak from so many passages.

Louis Pasteur (1822-1895), a French chemist, was well read and draw on the numerous concepts that had been developing for at least forty years – attenuation; modification through passage; renewed virulence and a need to replace person to person vaccinations to avoid the transmission of other diseases. Through his process of pasteurisation (boiling liquids to kill germs in the wine industry), he discovered that germs were present in the blood of infected persons. This was a critical discovery and with the developing germ theory an explanation on how vaccination worked was possible.

As in most epochal discoveries, serendipity played a role. Pasteur discovered by chance that a weakened fowl of cholera provided immunity against the virulent organism. His work on this attenuation of the chicken cholera was the first major advance since Jenner. He observed that this vaccine would be more pure since it consisted of a weakened form of the same organism that caused the disease. In this sense, Pasteur’s chicken cholera vaccine harkened back to the variolation techniques of Lady Montague and even back to the ancient Chinese practice (Plotkin and Plotkin 1978;2).

Robert Koch (1843-1910), a German Scientist began research into the microbes affecting diseased animals and people. In combination with Pastuer a clear relationship between microorganisms and disease was established and subsequently, the completion of the germ theory in 1885. With this development came the demolition of the old theory of spontaneous generation that had held medicine back for centuries. Also the development of techniques for growth in vitro of the causal agents of infectious diseases was a legacy of Koch. He identified 21 germs causing diseases such as the microbes that caused tuberculosis and cholera. He also demonstrated that there was a causal relationship between the anthrax bacillus and the disease anthrax. His discoveries were the results of careful research and observation using the microscope, photography and dyes. In 1891, the German government set up an ‘Institute of Infectious Diseases’ in Berlin as a result of his work.

In 1881 Pastuer was successful in developing a vaccine against anthrax. The first controlled experiment of the anthrax vaccine took place at the farm Pouilly-le-Fort. ‘Pasteur took three flocks of sheep. The first group of ten sheep, was to act as the control animals. The second flock of 25 sheep, had previously been inoculated with an attenuated culture of live anthrax germs. The third flock also of 25 sheep had not. Then before an audience of scientists, doctors and other interested parties, some of whom believed in the importance of what he was doing and some whom did not, Pasteur injected all the animals save those in his control group with a virulent culture of anthrax germs. To the great satisfaction of his friends and sympathisers and to the equally great chagrin of his critics, all the uninoculated animals died, as he said they would and all the inoculated ones remained alive’ (Williams 1987;77). After the successful experiment in Pouilly-le-Fort he wrote that he had shown man could now have vaccines, cultivated at will by a method that could be generalised (Plotkin and Plotkin 1978;2). Just as the demonstration of the pathogenic role of the anthrax bacillus had been the touchstone of the germ theory of disease, it was the vaccination against anthrax that revealed to the medical community the endless practical possibilities of the new science of vaccinology and immunology.

In Pasteur’s early work on rabies, he showed that the spinal cords of rabbits dead of the disease could be rendered almost nonvirulent by keeping them sterile in dried air for two weeks. By inoculating dogs with emulsions of progressively less attenuated cord, it was possible to protect the animal against inoculation with the most virulent form of the virus. Since exposure to rabies developed slowly in humans, he concluded that there was a possibility of establishing resistance by vaccination even after the bite had been inflicted. Experiments made on dogs bitten by rabid animals, and then treated with the vaccine, gave promising results (Dubos 1988; 118). On July 6th 1885 a young boy, Joseph Meister was brought from Alsace for treatment after suffering bites from a rabid dog. On July 7th, sixty hours after the accident, Meister was injected with rabbit spinal cord that had been attenuated by 14 days drying. On July16, after receiving 12 successive inoculations each of a stronger virus, he was injected with a fully virulent spinal cord. He exhibited no symptoms and returned to Alsace in good health. The second case treated by Pasteur was that of Jean Baptiste Jupille. Again he made a full recovery after being bitten six days earlier by a rabid dog. The thought of introducing a deadly virus into a person was met with outrage at the time evoking a murderous status among the doctors. And as had happened with Jenner’s smallpox vaccination, the rabies treatment was immediately attacked as valueless and capable of causing the very disease it was designed to control.

At the age of 65, the sick Pasteur began to think about new approaches to the still controversial vaccination technique and the problem of immunity. His vaccines against fowl cholera, anthrax and rabies consisted of living microbes, attenuated, but still capable of multiplying in the body. Pasteur’s belief that the immunity elicited by these vaccines depended precisely upon the fact that they did multiply in the body was correct. However, he again stumbled upon findings in his work that led him to think that it might be possible to cause immunity by injecting not living, attenuated microbes, but instead lifeless material made up of some of their constituents or products. For example, the bacteria of fowl cholera released in the culture medium a soluble substance toxic for animals – would it not be possible to immunise by injecting this toxic material into the animal? (Dubos 1988;123). Due to his ill health, Pastuer could not continue his dream of ‘chemical vaccines’, however this notion was the next major step in the development of vaccines.

This step took place in the United States in 1886. Edmund Salmon and Theobald Smith published their work on the heat killed hog cholera ‘virus’ vaccine. This virus would immune pigeons against the disease (Plotkin and Plotkin 1988;3). This vaccine was actually a bacterial vaccine against cholera like salmonellosis (Chase 1982;22). Not surprisingly, their discovery was overshadowed by the aura of Pasteur’s and his colleagues work at the Institute Pasteur when Emile Roux and Chamberland published a paper in 1887 on the same topic. These new vaccination techniques really expanded when three human bacterial vaccines (all killed) were developed for typhoid, cholera and plague.

The majority of concepts involved in the development of vaccines were introduced in the 19th century. Inevitably, the early work in the 20th century would bring refinements to these theoretical underpinnings. It was Paul Ehrlich’s receptor theory of immunity in 1897 that soon became one of the cornerstones in 20th century immunology. Earlier, Emile Roux and Alexander Yersin in 1888 demonstrated that diphtheria produced powerful toxins. But it was Ehrlichs’s theory that sought out to explain these toxin-antitoxin interactions. The chemical inactivation of these toxins and other bacterial toxins lead to the development of the first toxoids for diphtheria and tetanus by von Behring and Kitasato.

In 1923, the vaccine against tuberculosis, bacille Calmette-Guerin (BCG), was the first live, attenuated vaccine since Pasteur’s rabies vaccination in 1885. Another live vaccine, this time for treatment against yellow fever was developed by Max Theiler in 1935 and was derived from mouse bran passage.

In 1944, the discovery of virus propagation in cell culture marked the golden age in vaccine development. Previously in the early 1930’s E. W. Goodpasture introduced a medium for growing viruses through the use of the chorioallantoic membrane of a fertile hen’s egg. This technique was a major advance since the growth of human viruses was only possible in ferrets and mice. John Enders, Thomas Weller and Frederick Robbins began research into cell cultures in the Boston Childrens Hospital. They decided to grow viruses in human cells (a legacy of the Goodpasture type). This breakthrough saw the first licensed product to be developed as a result of the new tissue culture technique. This was the trivalent, formalin-inactivated poliovirus vaccine of Jonas Salk, in 1955. In 1957, the oral poliovirus vaccine, was developed by Albert Sabin who attenuated poliovirus by repeated passage through cell culture to obtain the live vaccine given by mouth. A hive of activity that still continues today in vaccinolgy can be attributed to this ability to grow human viruses outside a living host.

During the mid 1950’s, the successful propagation of the measles virus in the chick embryo tissue culture by Enders and Peeble provided a means for the development of the mealses vaccine. Two kinds were licensed in the US - a live attenuated measles virus vaccine (Edmonston B strain) that was developed by Enders, Katz and colleagues and a formalin-inactivated aluminium-precipitated vaccine. An attenutation by M. Hilleman of the Jeryl Lynn strain of the mumps virus lead to the mumps vaccine. The rubella virus was also attenuated in a cell culture following an extensive epidemic of German measles in the United States in 1964 that resulted in the birth of 20000 children with congenital disabilities (Mackett and William 1995;8).

Three bacterial vaccines were developed in the 1970’s and 1980’s containing purified capsular polysaccharides through the advances in biochemical analyse of their polysaccharide structure. These were the meningococcal vaccine, the pneumococcal vaccine and the H. influenza type B vaccine developed by Artrnstein and associates, Austrian and associates and Anderson and associates respectively.

It is now widely recognised that after most infectious diseases immunity is generally acquired and that similar forms of immunity can be induced by administration of appropriately prepared vaccines derived from inactivated or live microorganisms of modified (i.e. attenuated) disease producing potential (Voller and Friedman 1978;22). One century after Jenner, Pasteur’s guess that the vaccination against smallpox with cowpox was in reality the specialised application of a general law of nature – namely, that one can vaccinate against many types of diseases by using related microorganisms of attenuated virulence (Dubos 1988;126). This generalisation led to the development of general techniques for the production of vaccines. Subsequently, it gave birth to new fields in science – vaccinology and immunology and encouraged both scientists and chemists to study the nature of substances in microorganisms that are capable of inducing a resistance to infection and disease. It has taken close to 200 years to develop a refined knowledge and understanding in the development of vaccines. As science encounters a wealth of opportunity in the 21st century, a new wave of vaccine development will explode as a result of the increasing advances in the biotechnology domain to defeat today’s killer diseases.

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