Antiserum

Antiserum is human or nonhuman blood serum containing monoclonal or polyclonal antibodies that is used to spread passive immunity to many diseases via blood donation (plasmaphoresis). For example, convalescent serum, passive antibody transfusion from a previous human survivor, used to be the only known effective treatment for ebola infection with a high success rate of 7 out of 8 patients surviving.[1]

This article is about the applications of antiserum. For an explanation of its production, see polyclonal antibodies.

Antisera are widely used in diagnostic virology laboratories. The most common use of antiserum in humans is as antitoxin or antivenom to treat envenomation.

Serum therapy, also known as serotherapy, describes the treatment of infectious disease using the serum of animals that have been immunized against the specific organisms or their product, to which the disease is supposedly referable.

History

The first therapies for the treatment of diphtheria and tetanus came into use in the mid-1890s and had a major impact on the development of the history of medicine.

Emil Behring (1854–1917) had pioneered the technique, using guinea pigs to produce serum.[2] Based on his observation that people who survived infection with the diphtheria bacterium never became infected again, he discovered that the body continually produces an antitoxin, which prevents survivors of infections from being infected again with the same agent.

It was necessary for Behring to immunize larger animals in order to produce enough serum to protect humans, because the amount of antiserum produced by guinea pigs was too little to be practical. Horses proved to be the best serum producer, as the serum of other large animals is not concentrated enough, and horses were not believed to carry any diseases that could be transferred to humans.

Due to the First World War, a large number of horses were needed for military purposes. It was difficult for Behring to find enough German horses for his serum facility. He chose to obtain horses from Eastern European countries, mostly Hungary and Poland. Because of Behring's limited financial resources, most horses he selected had been intended for slaughter; however, the usefulness of the animal to others had no influence on the production of serum. Serum horses were calm, well-mannered, and in good health. Age, breed, height, and color were irrelevant.[3]

Horses were transported from Poland or Hungary to the Behring facilities in Marburg, in the west-central part of Germany. Most of the horses were transported by rail and treated like any other freight load. During the interminable border crossing, horses were left at the mercy of the weather.[4] Once the horses arrived in Marburg, they had three to four weeks to recover in a quarantine facility, where data on them was recorded. They had to be in perfect medical condition for the immunization, and the quarantine facility ensured that they were free of microbes which could infect the other horses. In the Behring facilities, the horses were viewed as life savers; therefore, they were well treated. A few of the individual horses used for serum production were named, and celebrated for their service to medicine, both human and non-human.

At the end of the 19th century, every second child in Germany was infected with diphtheria, the most frequent cause of death in children up to 15 years. In 1891 Emil Behring saved the life of a young girl with diphtheria by injecting antiserum for the first time in history. Serum horses proved to be saviors of diphtheria-infected people. Subsequently, treatment of tetanus, rabies, and snake venom developed, and proactive protective vaccination against diphtheria and other microbial diseases began.

In 1901, Behring won the first Nobel Prize in Medicine for his work in the study of diphtheria.

Modern use

During the early stages of the Coronavirus disease 2019 pandemic, reliable treatment options had not been found. In reaction, convalescent blood plasma was considered as a possible and is used as a treatment option at least for severe cases[5] [6][7].

How it works

Antibodies in the antiserum bind the infectious agent or antigen.[8] The immune system then recognizes foreign agents bound to antibodies and triggers a more robust immune response. The use of antiserum is particularly effective against pathogens which are capable of evading the immune system in their unstimulated state but are not robust enough to evade the stimulated immune system. The existence of antibodies to the agent depends on an initial survivor whose immune system, by chance, discovered a counteragent to the pathogen or a host species which carries the pathogen but does not suffer from its effects.[9] Further stocks of antiserum can then be produced from the initial donor or from a donor organism that is inoculated with the pathogen and cured by some stock of preexisting antiserum. Diluted snake venom is often used as an antiserum to give passive immunity to snake venom itself.[10][11]

Horses that were infected by a pathogen were vaccinated thrice in increasing sizes of the dose. The time between each vaccination varied from each horse and its health condition. Normally the horses needed a few weeks to produce the serum in the blood after the last vaccination. Even though they tried to empower the immune system of the horses during this immunization with painstaking care, most of the horses suffered appetite loss, fever, and in worse cases shock and dyspnea.

The highest immunization risk for horses was the production of antiserum for snake venom.

The horse was immunized with all types of snake poison at the same time because it was not always possible to know by which snake species a person had been bitten. Therefore, the serum had to immunize the subject against the venom of every snake species.

In order to find the moment when most antitoxins in the blood cells of the horses is produced, frequent blood samples were taken from the horses. At the point when the highest amount of antibodies were produced, five liters of blood, a tenth of the blood volume of a horse, were taken through a cannula.

The blood was collected in a glass cylinder and brought to the laboratory in the Behring facilities. Above the rouleaux formation which contained the red blood cells, the serum was visible. The color of the serum varied from milky to brown.

Concentration and sterility of the serum were checked carefully, and the serum was filtered many times. Protein content was decreased in order to use the serum for humans.

After the blood sampling, the horses could rest for three to four weeks and received extra food to recover the blood loss. In this period the horses were especially weak and prone to disease and infection.

Within a few years, with experience and observation of the horses, a rouleaux formation of the blood sample was placed back into the animal's body. This procedure is called plasmapheresis.

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References
  1. Mupapa, K; Massamba, M; Kibadi, K; Kuvula, K; Bwaka, A; Kipasa, M; Colebunders, R; Muyembe-Tamfum, JJ (1999). "Treatment of Ebola Hemorrhagic Fever with Blood Transfusions from Convalescent Patients". The Journal of Infectious Diseases. 179 Suppl 1 (179): S18–S23. doi:10.1086/514298. PMID 9988160. Retrieved 6 August 2014.
  2. "Emil von Behring".
  3. "Serum therapy, especially in its application against diphtheria".
  4. Kautz, Gisela (2004). Die Stute Namenlos. Stuttgart: Thienemann-Esslinger. ISBN 978-3522176446.
  5. https://ec.europa.eu/health/blood_tissues_organs/covid-19_en
  6. https://www.pei.de/EN/newsroom/press-releases/year/2020/07-pei-approves-first-covid-19-therapy-study-with-convalescent-plasma.html
  7. https://www.uscovidplasma.org/
  8. de Andrade, Fábio Goulart, et al. "The Production And Characterization Of Anti-Bothropic And Anti-Crotalic Igy Antibodies In Laying Hens: A Long Term Experiment." Toxicon 66.(2013): 18–24.
  9. Mortimer, Nathan T., et al. "Parasitoid Wasp Venom SERCA Regulates Drosophila Calcium Levels And Inhibits Cellular Immunity." Proceedings Of The National Academy Of Sciences Of The United States Of America 110.23 (n.d.): 9427–32. Biological Abstracts 1969–Present.
  10. O'Leary, M.A., K. Maduwage, and G.K. Isbister. "Use Of Immunoturbidimetry To Detect Venom–Antivenom Binding Using Snake Venoms." Journal of Pharmacological & Toxicological Methods 67.3 (2013): 177–81.
  11. Vogel, Carl-Wilhelm, Paul W. Finnegan, and David C. Fritzinger. "Humanized Cobra Venom Factor: Structure, Activity, And Therapeutic Efficacy In Preclinical Disease Models." Molecular Immunology 61.2 (2014): 191–203.
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