Artificial induction of immunity

Immunity against some infections that can cause serious illness is generally beneficial. Since Pasteur provided support for a germ theory of infectious disease, we have increasingly induced immunity against a widening number of diseases to prevent the associated risks from the wild infections. With further understanding of the underlying molecular basis of immunity, it is hoped this will transfer to improved clinical practice in the future.

This is a historical overview and introductory article to a collection of detailed articles on the main topics.

Variolation and smallpox

See main articles variolation and smallpox.

Typical site of inoculation in Europe and the British colonies

The earliest recorded artificial induction of immunity in humans was by variolation or inoculation, which is the controlled infection of a less lethal form of smallpox (known as Variola Minor) into a subject to reder him or her subsequenly immune to re-infection. This was practiced in ancient times in China and India, and later imported into Europe, via Turkey, around 1720 by Lady Montagu and perhaps others. From England the technique spread rapidly to the Colonies, and was also spread by African slaves arriving into Boston.

Variolation had the disadvantage that the inoculating agent used, Variola Minor, was still an active form of smallpox and, while less potent than the more lethal form, could still kill the inoculee or spread in its full form to others nearby. However, since the risk of death from inoculation with Variola Minor was just 1% to 2%, as compared to the 20% risk of death from the natural form of smallpox, the risks of inoculation were generally considered acceptable.

Vaccination

See main articles vaccination and Edward Jenner.

In 1796, Edward Jenner, a doctor and scientist who had practiced variolation, performed an experiment based on the folk-knowledge that infection with cowpox, a disease which had minor symptoms and which was never fatal, also conferred immunity to smallpox. Jenner induced cowpox infection by transfering material from a lesion on one patient to another patient, thus infecting the second patient with cowpox. He then demonstrated that the latter was immune to smallpox by exposing him. This principle had been demonstrated some years earlier by Benjamin Jesty, who had not publicized his discovery. As it was Jenner who followed up by describing and generalising the process and then making arrangements to propagate cowpox for therapeutic use, he is credited with the discovery.

Jenner, as were all members of the Royal Society in those days, was an empiricist. The theory to support further advances in vaccination arrived in later years.

Germ theory

See main articles Pasteur and germ theory.

Pasteur perfected experiments which disproved the then-popular theory of spontaneous generation and from which he derived the modern germ theory of (infectious) disease. Using experiments based on this theory, which posited that specific microorganisms cause specific diseases, Pasteur isolated the infectious agent from anthrax. He then derived a vaccine for the disease by altering the infectious agent so as to make it harmless and then introducing this inactivated form of the infectious agents into farm animals, which then proved to be immune to the disease.

Pasteur had also isolated a crude preparation of the infectious agent for rabies. In a brave piece of rapid medicine development, he likely saved the life of a person who had been bitten by a clearly rabid dog by performing the same inactivating process upon his rabies preparation and then inoculating the patient with it. The patient, who had been expected to die, subsequenly lived, and thus was the first person successfully vaccinated.

Anthrax is now known to be caused by a bacterium, and rabies is known to be caused by a virus. The microscopes around the time could reasonably be expected to show bacteria, but imaging of viruses had to wait until the development of electron microscopes with their greater resolving power in the 20th century.

Toxoids

Some diseases, such as Tetanus, cause disease not by bacterial growth but by bacterial production of a toxin. Tetanus toxin is so lethal that humans are incapable of developing immunity to a natural infection, since the amount of toxin required to kill a person is much less than is required by the immune system to recognize the toxin and produce antibodies against it. It has been found, however, that heating the Tetanus toxin sufficiently to denature it causes it to lose its ability to produce disease, but still be capable of inducing immunity to Tetanus when injected into subjects. The heated, denatured toxin is called a toxoid.

See also Botulism

Adjuvants

Simple molecules such as toxoids tended to produce a low response, and poor immune memory. Adding certain substances - eg adsorbing tetanus toxoid onto Alum greatly enhanced the immune response. Various adjuvants have been used, and are also used for other purposes to do with studying the immune system.

A much later - contemporary - approach is to conjugate the antigen eg. a polysacharide from the capsule of the bacteria responsible for most lobar pneumonia with another molecule such as a toxoid, the combination triggering immune memory rather than just a humoural antibody response.

Temporarily induced immunity

See also immunoglobulin.

Once the fraction of the blood which contained the immune molecules - the antibodies - was known, it could be isolated and given to people. The portion of immunity which is humoural - carried in the humours or body fluids, rather than cell-mediated, could be transferred thus. Within reason it need not be from a human, and horse Tetanus anti-serum has saved many lives, although since anaphylactic shock is a possibility with a cross-species transfer of such (heterologous) proteins, it has also cost a few.

File:Ornithorhynchidae-00.jpg

Platypus: monotremes lack placental transfer of immunity

Every placental mammal has experienced temporarily induced immunity by transfer of (homologous) antibodies. This is the transfer of maternal antibodies across the placenta which gives babies passive immunity to those things the mother retains immunity to, for around a year.

Synthetic (recombinant or cell-clone) human immunoglobulins are now possible to produce and for several reasons including the risk of prion contamination of biological products are likely to become more used. They are not in industrial scale production in 2006. In the future it may be possible to design antibodies to fit an antigen, then produce them, and thus induce temporary immunity in people in advance of human exposure to a pathogen. At present the science to understand that is available, but not the technology to do so. Among other possible applications would be the the neutralisation of prions.

References

Further references given in the main articles indicated above.

• Essential Immunology. Roitt, I Blackwell Scientific Publications 3rt edition, subsequent revisions. ISBN 063200276X
• Pier GB, Lyczak JB, and Wetzler LM. (2004). Immunology, Infection, and Immunity. ASM Press. ISBN 1555812465