Evolution of Immunology

Events

Earliest Account of Vaccination

1549

Ming Dynasty pediatrician, Wan Quan, administered the earliest known vaccine. He developed and used Douzhen Xinfa to fight against the smallpox.

African Use of Variolation

1706

Cotton Mather, a Boston minister, noticed scars on the bodies of African slaves and after further investigation came to understand that they were due to variolation of smallpox, making the slaves "immune" to the smallpox disease.

Variolation in Turkey

1717

Lady Mary Wortley Montagu had her son variolated in Constantinople by Dr. Charles Maitland. Lady Montagu, whose husband was ambassador to Turkey, had been disfigured by smallpox around 1715. She had heard about variolation upon her arrival in Turkey, and was anxious that her six-year-old son, Edward, have the procedure. In 1717, she wrote to a friend:

"The old woman comes with a nut-shell full of the matter of the best sort of smallpox, and asks what veins you please to have opened…. She immediately rips open that you offer her with a large needle … and puts into the vein as much venom as can lie upon the head of her needle…. Every year thousands undergo this operation."

Vaccinations in the Ottoman Empire

1718

The smallpox vaccine makes its way to the Ottoman Empire where positive effects are observed in people of different races and nationalities.

Throat Distemper

1735

A diphtheria epidemic swept through New England. In one New Hampshire town, 32% of children under 10 died of diphtheria. A Boston newspaper reported on the method of vaccination for this outbreak:

METHOD OF CURE OF THROAT DISTEMPER.

What is used is as follows. First be sure that a vein be opened under the tongue, and if that can't be done, open a vein in the arm, which must be first done, as all other means will be ineffectual. Then take borax or honey to bathe or annoint the mouth and throat, and lay on the Throat a plaister Vngiuntum Dialthae. To drink a decoction of Devil's bitt or Robbin's Plantain, with some Sal Prunelle dissolved therein, as often as the patient will drink. If the body be costive use a clyster agreeable to the nature of the Distemper. I have known many other things used, especially a root called Physick Root, filarie or five-leaved physick; also a root that I know no name for, only Canker Root. But be sure and let blood, and that under the tongue. We havemany times made Blisters under the arms, but that has proved sometimes dangerous.

—Boston Gazette, March 18, 1735

Laws and Regulation

1792

Stricter laws are passed in some nations regarding inoculations. Most refer to the ability to deliberately infect a person with smallpox (or any form of pox).

Official Smallpox Vaccine

1796

Edward Jenner creates the smallpox vaccine using the cowpox strain.

Cowpox Remodel

1836

English physician, Edward Ballard, observed that cowpox transmitted from human to human seemed to decline in potency over time. He recommended choosing new strains of cowpox and reintroducing the pustule matter (lymph) back into cows to boost its potency. This method came to be used to supply sufficient material for vaccination.

"Germ Theory of Disease"

1840

Jakob Henle proposed the "Germ Theory of Disease".

Definition: Many diseases are caused by microorganisms. These small organisms, too small to see without magnification, invade humans, animals, and other living hosts. Their growth and reproduction within their host can cause a disease.

Animal Vaccines

1864

Awareness of the danger of the spread of diseases such as syphilis via arm-to-arm transmission of vaccine virus began to grow in France. Several doctors, having read of the Neopolitan practice of serial vaccination of calves with vaccinia, had a vaccinated calf shipped to Paris, where it was used as a source of vaccine. The use of calves for vaccine material came to be widespread, not only in France, but in other parts of Europe and the United States. Great Britain, however, did not adopt the practice in until 1881 and finally banned arm-to-arm transmission in 1898.

Microbes Can Cause Disease

1876

Robert Koch became the first person to link a specific microorganism with a specific disease -- anthrax in his case -- rejecting the idea of spontaneous generation and supporting The Germ Theory of Disease.

Phagocytosis

1876

Canadian physician, William Olser, first recorded phagocytosis.

Mast Cells

1877

Paul Elrich, German physician and scientist, discovered Mast Cells.

Hematological Staining

1878

Paul Elrich and his supervisor, Julius Friedrich Cohnheim, published " Contributions to the Theory and Practice of Histological Staining", which discussed their discoveries using Staining.

Examples: Differentiation between nongranular lymphocytes, mono- and poly-nuclear leukocyte, eosinophil granulocytes, and mast Cells.

Attenuated Vaccines

1880 - 1881

Louis Pasteur; French biologist, microbiologist, and chemist; created the theory that bacterial virulence could be attenuated by culture in vitro and used as vaccines. He proposed that live attenuated microbes produced immunity by depleting host of vital trace nutrients. He used this discovery to make chicken cholera and anthrax "live vaccines".

Further Classifying the Immune System

1882

Russian zoologist, Élie Metchnikoff, discovered the major defense mechanism of innate immunity, phagocytes(macrophages). He also established the concept of cell-mediated immunity.

Bacterium Identified

1883

Edwin Klebs, a Swiss-German pathologist, identified and described the bacterium that causes diphtheria. It was known at first as the Klebs-Loeffler bacterium. The bacterium’s club-shaped appearance helped Klebs differentiate it from other microbes.

Therapeutic Vaccines

1885

Louis Pasteur introduced the concept of "therapeutic vaccination" and the use of attenuated Vaccines in replacement for dead Vaccines.

Definition: A vaccine which prevents or eases the severity of the problems from a infection that has already occurred.

Parasites

1888

American-British bacteriologist, George Nuttal, contributed much to the knowledge of parasites and insect carriers of diseases. He also studied about diseases transmitted by anthropoids, especially ticks. Finally, he also did work on Malaria in mosquitos in England.

Hummoral Immunity

1890

Demonstration of antibody activity against diphtheria and tetanus toxins by Emil von Behring and Kitasaton Shibasaburō. The beginning of hummoral theory of immunity.

Antitoxin and Serum Therapy

1890

Shibasaburo Kitasato and Emil von Behring immunized guinea pigs with heat-treated diphtheria toxin.

Kitasato and von Behring showed that the blood products (sera, or, singular, serum) of the guinea pigs contained a substance that prevented the harmful effects of C. diphtheriae and its toxin when the guinea pigs were re-exposed to lethal doses of the bacteria and toxin. Next, they showed that they could cure diphtheria in an animal by injecting it with the serum of an immunized animal. They called the substance antitoxin and their treatment serum therapy. They realized that they needed to immunize large animals, such as horses and sheep, to produce enough antitoxin to protect humans.

Air-Dryed Vaccine

1909

At the Vaccine Institute in Paris, Lucien Camus dried smallpox vaccine pulp in an evacuated chamber, removing all of the moisture from the sample. Such air-dried vaccines were used in tropical areas, where the temperature would destroy non-dried vaccine material. However, this method was not well-suited for large-scale production, and bacterial contamination was often a problem.

Development of Adjuvant

1926

Alexander Thomas Glenny (1882-1965) increased the effectiveness of diphtheria toxoid by treating it with aluminum salts.

Efforts to improve diphtheria toxoid were necessary because toxoid alone produced a lower level of antibody response than desired. Moreover, the immunity it produced was shorter than desired.

Observing that animals achieved better immunity to diphtheria when the injected toxoid created a local inflammatory reaction, Glenny began to add substances to the toxoid to trigger such a response. Today we call these substances adjuvants, and they are used in several types of vaccines.

Antigen - Antibody Binding

1938

Antibodies bind antigens through weak chemical interactions, and bonding is essentially non-covalent. Electrostatic interactions, hydrogen bonds, van der Waals forces, and hydrophobic interactions are all known to be involved depending on the interaction sites.

Whooping Cough Vaccine

1939

American bacteriologist Pearl Kendrick, PhD (1890-1980), and her colleague Grace Elderding, PhD (1900-1988), at the Michigan Department of Public Health published the results of a landmark pertussis (whooping cough) vaccine study. The two scientists demonstrated the effectiveness of a vaccine when compared with a control group that did not receive the vaccine: the annual attack-rates per 100 children were 2.3 in the vaccinated group and 15.1 in the control group, respectively, with no deaths in either group. In addition, the disease was milder in the group that had been vaccinated.

Influenza Vaccine Approved

1945

The first influenza vaccine was approved for military use in the United States in 1945 and civilian use in 1946. This whole-virus, inactivated influenza A and B vaccine had been tested in military recruits and college students before approval. Thomas Francis Jr., MD, and Jonas Salk, MD, who would become closely associated with the poliovirus vaccine, were key investigators on much of the influenza vaccine research. Influenza vaccine development was a high priority for the U.S. military after the deaths of approximately 1 in every 67 soldiers from influenza during the 1918-1919 pandemic.

Mice in Research

1946

Snell's work in mice led to the discovery of HLA, the major histocompatibility complex, in humans (and all vertebrates) that is analogous to the H-2 complex in mice. Recognition of these key genes was prerequisite to successful tissue and organ transplantation.

Combined Vaccines

1948

The first combined DTP (diphtheria, tetanus, and pertussis) vaccines became available in the United States. This type of combined shot used a whole-cell pertussis vaccine; decades later, in the mid-1990s, the whole-cell vaccine would be replaced with an acellular version that resulted in fewer adverse reactions.

Antibody Structure

1959 - 1962

Discovery of human leukocyte antigens (Jean Dausset and others).

Vaccine for Animals

1968

The first combined DTP (diphtheria, tetanus, and pertussis) vaccines became available in the United States. This type of combined shot used a whole-cell pertussis vaccine; decades later, in the mid-1990s, the whole-cell vaccine would be replaced with an acellular version that resulted in fewer adverse reactions.

Rubella Vaccine Lisencec

1969

The first combined DTP (diphtheria, tetanus, and pertussis) vaccines became available in the United States. This type of combined shot used a whole-cell pertussis vaccine; decades later, in the mid-1990s, the whole-cell vaccine would be replaced with an acellular version that resulted in fewer adverse reactions.

Measles, Mumps, Rubella Vaccine Licensed

1971

The U.S. government licensed Merck’s combined trivalent measles, mumps, and rubella vaccine (MMR).

Combination vaccines have several advantages over single vaccines. They reduce the need for several separate injections, and they reduce costs of stocking and shipping multiple containers. Combination vaccines can help improve overall vaccination rates by simplifying the vaccination process.

Rabies: New Inactivated Vaccine

1971

Koprowski’s team of scientists, at the Wistar Institute in Philadelphia, wanted to improve on the antibody response created by the experimental HEP live-virus vaccines. They looked to a cell line created from human embryonic cells as a medium for cultivating the rabies virus. Their initial tests successfully used live vaccine virus, as had the previous HEP tests. But medical resistance was strong to using a live virus rabies vaccine. The risk for inadvertent infection with a fatal illness was seen to be too high.

Accordingly, Koprowski’s team used a chemical disinfectant to inactivate their rabies vaccine virus.

In 1971, Koprowski, veterinarian Tadeusz Wiktor, and American physician Stanley Plotkin inoculated themselves with their experimental rabies vaccine. Plotkin went on to successfully test the vaccine in trials with human subjects.

Swine Flu Vaccine

1976

Maurice Hilleman and other scientists met with U.S. President Gerald Ford to discuss a vaccine response to an outbreak of swine influenza at Fort Dix, New Jersey. Congress committed funds to a nationwide vaccination program.

Merck intended to produce 50 million swine-flu vaccine doses by January 1977 and delivered about 11 million doses in late September 1976. The nationwide vaccination program, however, ended after vaccination was associated with an increased risk of a condition called Guillain-Barré syndrome (GBS). GBS has several causes, the most common of which is infection with bacteria called Campylobacter. But GBS occurred in recipients of the 1976 swine-flu vaccine at a rate higher than usual: beyond the normal "expected" rate for the general population, about one additional case occurred for every 100,000 vaccine recipients. And, despite what first promised to be a widespread outbreak, few cases of swine flu actually developed among the American people.

Hepatitis B: First Subunit Viral Vaccine in U.S.

1981

The FDA licensed Hilleman’s human-blood-derived hepatitis B vaccine, Heptavax-B. It was the first subunit viral vaccine developed in the United States.

Hilleman transformed the hepatitis B surface protein, discovered by Baruch Blumberg and known as the Australia antigen, into an effective vaccine. Hilleman harvested serum from several IV drug users and homosexual men, in whom the disease was sometimes present, to obtain the antigen. He used three methods to purify the blood so that the infectious particles were assuredly killed, but the antigen remained.

The vaccine proved effective at preventing hepatitis B. But, because of concerns about HIV infection, it was superseded in 1986 by a product that did not use human serum. This new effort produced the first vaccine based on recombinant technology--in this case, changing yeast cells so that they produced the protein that is the active ingredient in the current hepatitis B vaccine.

Gene Therapy

1990

The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990

West African Ebola Epidemic

2014

Ebola virus disease (EVD) emerged at unprecedented epidemic levels in 2014. Whereas previous outbreaks had occurred in remote areas and were contained fairly quickly, this epidemic spread to crowded urban areas where long transmission chains occurred.

The center of the epidemic occurred in Sierra Leone, Guinea, and Liberia. Nigeria and Senegal saw small outbreaks related to importations from more heavily affected countries, but they were able to contain spread of the disease. Several cases and deaths were reported from Mali in October and November 2014. In total, 15,261 confirmed, probable, and suspected deaths occurred, including two in the United States. More than 28,000 cases of EVD were reported.

Several healthcare workers acquired Ebola virus disease outside West Africa from contact with imported cases. Two U.S. nurses and one Spanish nurse became ill. All three recovered.

Ebola virus disease has no cure, but supportive care in a hospital setting can increase a patient's chance for survival. Additionally, plasma transfusions from convalescent patients and an experimental antibody preparation have been used to treat certain patients.

Several vaccines were advanced rapidly into clinical trials in both African and non-African countries.