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Antiserum is a blood serum containing monoclonal or polyclonal antibodies that is used to spread passive immunity to many diseases via
blood donation A blood donation occurs when a person voluntarily has blood drawn and used for transfusions and/or made into biopharmaceutical medications by a process called fractionation (separation of whole blood components). Donation may be of whole blo ...
( plasmapheresis). For example, convalescent serum, passive antibody transfusion from a previous human survivor, used to be the only known effective treatment for
ebola Ebola, also known as Ebola virus disease (EVD) and Ebola hemorrhagic fever (EHF), is a viral hemorrhagic fever in humans and other primates, caused by ebolaviruses. Symptoms typically start anywhere between two days and three weeks after bec ...
infection with a high success rate of 7 out of 8 patients surviving. Antisera are widely used in diagnostic
virology Virology is the scientific study of biological viruses. It is a subfield of microbiology that focuses on their detection, structure, classification and evolution, their methods of infection and exploitation of host cells for reproduction, th ...
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

In 1890, Emil Behring and Kitasato Shibasaburō published their first paper on serum therapy. Behring had pioneered the technique, using guinea pigs to produce serum. 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 World War I (28 July 1914 11 November 1918), often abbreviated as WWI, was one of the deadliest global conflicts in history. Belligerents included much of Europe, the Russian Empire, the United States, and the Ottoman Empire, with fig ...
, 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 Europe Eastern Europe is a subregion of the European continent. As a largely ambiguous term, it has a wide range of geopolitical, geographical, ethnic, cultural, and socio-economic connotations. The vast majority of the region is covered by Russia, wh ...
an 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. 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. Once the horses arrived in
Marburg Marburg ( or ) is a university town in the German federal state (''Bundesland'') of Hesse, capital of the Marburg-Biedenkopf district (''Landkreis''). The town area spreads along the valley of the river Lahn and has a population of approx ...
, 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 Tetanus, also known as lockjaw, is a bacterial infection caused by '' Clostridium tetani'', and is characterized by muscle spasms. In the most common type, the spasms begin in the jaw and then progress to the rest of the body. Each spasm usuall ...
, 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 Diphtheria is an infection caused by the bacterium '' Corynebacterium diphtheriae''. Most infections are asymptomatic or have a mild clinical course, but in some outbreaks more than 10% of those diagnosed with the disease may die. Signs and s ...
. Serum therapy became increasingly prevalent for infectious diseases, and was even used to treat patients during the influenza pandemic in 1918. Its uses were then quickly expanded to also treat diseases such as
polio Poliomyelitis, commonly shortened to polio, is an infectious disease caused by the poliovirus. Approximately 70% of cases are asymptomatic; mild symptoms which can occur include sore throat and fever; in a proportion of cases more severe sym ...
, measles, pneumococcus, Haemophilus influenza B, and meningococcus. In the 1920s, Michael Heidelberger and Oswald Avery proved that antibodies were proteins that targeted the capsule of the
virus A virus is a wikt:submicroscopic, submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and ...
or
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
. The discovery of
antibiotics An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...
in the 1940s diminished interest in treating bacterial infections with antiserum, but its use for viral infections continued with the development of ethanol fractionation of blood plasma (which allowed for purified antibodies), discovered by Edwin Cohn. Antisera were developed to prevent and/or treat
diphtheria Diphtheria is an infection caused by the bacterium '' Corynebacterium diphtheriae''. Most infections are asymptomatic or have a mild clinical course, but in some outbreaks more than 10% of those diagnosed with the disease may die. Signs and s ...
,
tetanus Tetanus, also known as lockjaw, is a bacterial infection caused by '' Clostridium tetani'', and is characterized by muscle spasms. In the most common type, the spasms begin in the jaw and then progress to the rest of the body. Each spasm usuall ...
,
Hepatitis B Hepatitis B is an infectious disease caused by the '' Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. F ...
, rabies, varicella zoster virus,
cytomegalovirus ''Cytomegalovirus'' (''CMV'') (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order '' Herpesvirales'', in the family '' Herpesviridae'', in the subfamily '' Betahe ...
, and botulinum. However, these were not widely used. In 1984,
Milstein Milstein may refer to: *The Milstein method in mathematics People * Adam Milstein, Israeli-American real estate investor and philanthropist *Beth Milstein, producer/writer *César Milstein (1927-2002), scientist, recipient of the Nobel Prize in Phy ...
and Köhler won a Nobel Prize for their paper that described their method for making murine monoclonal antibodies by immortalizing B cells as
hybridomas Hybridoma technology is a method for producing large numbers of identical antibodies (also called monoclonal antibodies). This process starts by injecting a mouse (or other mammal) with an antigen that provokes an immune response. A type of white ...
. Another breakthrough occurred in 2003. A new technology allowed for heavy and light chain immunoglobulin genes to be amplified from human B cells and cloned into expression vectors. In 2008, this method was refined with a greater ability to sort cells and clone, which led to the discovery of more human monoclonal antibodies. In 1996, the FDA approved the use of RSV-IGIV (Respigam), a polyclonal antibody drug to inhibit respiratory syncytial virus (RSV) for high-risk newborns. This was considered a breakthrough, as the clinical trial was proven to reduce infant hospitalizations by 41% and length of hospital stays by 53%. After two years the product demand began to exceed the supply of plasma and
Synagis Palivizumab, sold under the brand name Synagis, is a monoclonal antibody produced by recombinant DNA technology used to prevent severe disease caused by respiratory syncytial virus (RSV) infections. It is recommended for infants at high-risk for RS ...
, the first humanized monoclonal antibody was approved in its place. Monoclonal antibodies became advantageous due to their decreased variability in quality, a decreased risk of bloodborne diseases, and increased potency. This enabled a large expansion of the usages of antiserum and opened the door for the treatment of autoimmune diseases. The past 30 years have seen the transformation of how chronic and autoimmune diseases (e. g.
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
, ulcerative colitis) are treated, with 30 drugs—28 of which for chronic conditions—with monoclonal antibodies being approved. Monoclonal antibodies are currently being researched to treat viral diseases without vaccines, such as
HIV The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immu ...
,
SARS Severe acute respiratory syndrome (SARS) is a viral respiratory disease of zoonotic origin caused by the severe acute respiratory syndrome coronavirus (SARS-CoV or SARS-CoV-1), the first identified strain of the SARS coronavirus species, '' s ...
, and MERS.


Modern use

For a more complete list of monoclonal antibodies visit list of therapeutic monoclonal antibodies. Monoclonal antibodies are used to treat both acute and chronic conditions. Acute conditions may include, but are not limited to Ebola virus, envenomation (e. g. snake bites), and
anthrax Anthrax is an infection caused by the bacterium '' Bacillus anthracis''. It can occur in four forms: skin, lungs, intestinal, and injection. Symptom onset occurs between one day and more than two months after the infection is contracted. The s ...
infection. Chronic conditions may include, but are not limited to
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and ...
, ulcerative colitis, and lupus. There are four main types of monoclonal antibodies. They are murine, chimeric, humanized, and human. Murine monoclonal antibodies are identified with the suffix "-omab". They originate from a
murine The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families ex ...
animal and can trigger allergic reactions in humans. An example of a murine monoclonal antibody is
Blinatumomab Blinatumomab, sold under the brand name Blincyto, is a biopharmaceutical medication used as a second-line treatment for Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia. It belongs to a class of constructed mo ...
, which is used to treat acute lymphoblastic leukemia. Chimeric monoclonal antibodies are identified with the suffix "-ximab". They originate partially from a murine animal and partially from a human. An example of a chimeric monoclonal antibody is Infliximab, which is used to treat Crohn disease. Humanized monoclonal antibodies are identified with the suffix "-zumab". They mostly originate from a human but differ in the component that attaches to its target. An example of a humanized monoclonal antibody is
Crizanlizumab Crizanlizumab, sold under the brand name Adakveo & Ryverna both by Novartis, is a monoclonal antibody medication that binds to P-selectin. It is a drug used to reduce the frequency of vaso-occlusive crisis in people aged 16 years and older who ha ...
, which treats sickle cell disease. Human monoclonal antibodies are identified with the suffix "-umab". They originate from a human. An example of a human monoclonal antibody is Ustekinumab, which treats psoriasis. During the early stages of the
COVID-19 pandemic The COVID-19 pandemic, also known as the coronavirus pandemic, is an ongoing global pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel virus was first identified ...
, reliable treatment options had not yet been found or approved. In reaction, convalescent blood plasma was considered as a possibility and is used as a treatment option at least for severe cases. In May 2021, India was one of the first major country to remove plasma from its national COVID-19 guideline. This was after public criticism on the lack of its effectiveness and health systems burdening from leading Indian scientists including Shahid Jameel, Soumyadeep Bhaumik, Gagandeep Kang, Soumitra Pathare, and others. The World Health Organization recommended against use of plasma in COVID-19 in December 2021. Monoclonal antibodies ( Casirivimab/imdevimab) were developed for the treatment of COVID-19. On June 7, 2021, the FDA approved Aducanumab, the first Alzheimer's drug in 20 years.


How it works

Antibodies in the antiserum bind the infectious agent or
antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
. The
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as Tumor immunology, cancer cells and objects such ...
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 experience its effects. 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 pre-existing antiserum. Diluted snake venom is often used as an antiserum to give passive immunity to snake venom itself. 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 experienced appetite loss,
fever Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...
, 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.


References


External links

* {{Authority control Blood Immune system