The original idea of creating a vaccine was based on the principle of attenuation for developing tolerance to poisons. Nowadays, vaccines are routinely used in healthcare to generate an immunological memory against common but deadly pathogens.

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Edward Jenner carried out some of the earliest experiments in vaccination more than 200 years ago. Previously, the practice of variolation, or inoculation with a small amount of foreign antigen, had been developed as a protective measure against smallpox. Jenner improved the safety of variolation when he began immunizing against smallpox using the cowpox virus.

Louis Pasteur advanced on the idea of attenuation in his work with Pasteurella multocida, a diarrheal disease of chickens, then anthrax in sheep and rabies virus in animals and humans.

Attenuation

In the 1940’s, further advancements in vaccines were made by scientists using passage in abnormal hosts to attenuate the virus. Hilary Koprowki and her colleagues developed rabies and oral polio vaccines by passage through chicken embryo or mouse. A later advancement made use of cell cultures as substrates for viral growth.

The oral polio vaccine developed by Albert Sabin and the measles, mumps, rubella, and varicella vaccines were all developed through the use of cell-culture passage. Passage through cell culture resulted in adaptation of the virus to that medium. Those mutants lost the genes that allowed them to infect or spread in a human host.

The polio vaccine was created through cell-culture passage and then selection of clones with low neurovirulence in monkeys. In the case of polio vaccine, that attenuation was sometimes lost and the virulent genes regained, leading to very rare cases of paralysis following vaccination. Low temperature growth is another method of attenuation that was developed for vaccine production, and has been notably used for rubella vaccine.

Reassortment

RNA viruses with segmented genomes can be reassorted in cell culture by cocultivation of two viruses, yielding a selection of clones with gene segments from both. Reassortment is used in the manufacture of live and inactivated influenza vaccine, as well as a rotavirus vaccine.

For the inactivated influenza vaccine, segments coding for hemagglutinin and neuraminidase are combined with other segments coding for the internal genes of healthy viruses. The resulting virus is safe to handle, but generates antibodies against a virulent strain. For live influenza virus, hemagglutinin and neuraminidase RNA segments are reassorted with previously attenuated cold-adapted virus.

Inactivation

For bacterial infections, immunogenicity can be achieved by heat treatment or chemical inactivation.  These methods were used to make early vaccines for typhoid, plague, and cholera. More recently, inactivation has been used for influenza vaccine and polio vaccine. A Hepatitis A vaccine has also been made using chemical inactivation.

Capsular polysaccharides

Immune response to many bacterial pathogens is triggered by the polysaccharide capsule of the bacteria. The first use of polysaccharides for vaccination purposes was the meningococcal polysaccharide vaccine.

Pneumococcal vaccines and Hemophilus influenzae type b vaccines are also based on polysaccharides. These vaccines generate immune responses in adults, but do not trigger immune responses in infants who are too young to mount a B-cell response to polysaccharide alone. Coupling proteins to polysaccharides allows T cells to assist B cells in activating an immune response, thus increasing the applicability of the vaccine.

Protein vaccines

Most inactivated influenza vaccines are protein vaccines. The viruses are passaged through eggs and broken up using detergents. Following this, the viral hemagglutinin protein is purified and used as a vaccine antigen, usually with other components of the virus in the final product. Acellular pertussis vaccines represent another example of a protein based vaccine.