Passive Immunization

The Historical Medical Library of The College of Physicians of Philadelphia
Administering diphtheria antitoxin derived from horse serum, 1895
 
The Historical Medical Library of The College of Physicians of Philadelphia
Serum being drawn from a horse injected with diphtheria toxin, 1895
 
March of Dimes Foundation
William M. Hammon preparting for IGG polio trials
000219,000225,000359

This article assumes familiarity with the terms antibody, antigen, immunity, and pathogen. See the Glossary for definitions.

A person may become immune to a specific disease in several ways. For some illnesses, such as measles and chickenpox, having the disease usually leads to lifelong immunity to it. Vaccination is another way to become immune to a disease. Both ways of gaining immunity, either from having an illness or from vaccination, are examples of active immunity. Active immunity results when a person’s immune system works to produce antibodies and activate other immune cells to certain pathogens. If the person encounters that pathogen again, long-lasting immune cells specific to it will already be primed to fight it.

A different type of immunity, called passive immunity, results when a person is given someone else’s antibodies. When these antibodies are introduced into the person’s body, the “loaned” antibodies help prevent or fight certain infectious diseases. The protection offered by passive immunization is short-lived, usually lasting only a few weeks or months. But it helps protect right away.

Passive Immunity: Natural vs. Artificial

Natural      Infants benefit from passive immunity acquired when their mothers’ antibodies and pathogen-fighting white cells cross the placenta to reach the developing children, especially in the third trimester. A substance called colostrum, which an infant receives during nursing sessions in the first days after birth and before the mother begins producing “true” breast milk, is rich in antibodies and provides protection for the infant. Breast milk, though not as rich in protective components as colostrum, also contains antibodies that pass to the nursing infant. This protection provided by the mother, however, is short-lived. During the first few months of life, maternal antibody levels in the infant fall, and protection fades by about six months of age.

Artificial       Passive immunity can be induced artificially when antibodies are given as a medication to a nonimmune individual. These antibodies may come from the pooled and purified blood products of immune people or from non-human immune animals, such as horses. In fact, the earliest antibody-containing preparations used against infectious diseases came from horses, sheep, and rabbits.

The History of Passive Immunization

Antibodies were first used to treat disease in the late 19th century as the field of bacteriology was emerging. The first success story involved diphtheria, a dangerous disease that obstructs the throat and airway of those who contract it. 

In 1890, Shibasaburo Kitasato (1852-1931) and Emil von Behring (1854-1917) immunized guinea pigs against diphtheria with heat-treated blood products from animals that had recovered from the disease. The preparations contained antibodies to the diphtheria toxin that protected the guinea pigs if they were exposed soon thereafter to lethal doses of diphtheria bacteria and its toxin. Next, the scientists showed that they could cure diphtheria in an animal by injecting it with the blood products of an immunized animal. They soon moved to testing the approach on humans and were able to show that blood products from immunized animals could treat diphtheria in humans. The antibody-containing blood-derived substance was called diphtheria antitoxin, and public boards of health and commercial enterprises began producing and distributing it from 1895 onward. Kitasato, von Behring, and other scientists then devoted their attention to treatment of tetanus, smallpox, and bubonic plague with antibody-containing blood products.

The use of antibodies to treat specific diseases led to attempts to develop immunizations against the diseases. Joseph Stokes Jr, MD, and John Neefe, MD, conducted trials at the University of Pennsylvania under contract to the US Navy during World War II to investigate the use of antibody preparations to prevent infectious hepatitis (what we now call hepatitis A).  Their pioneering work, along with advances in the separation of the antibody-containing blood component, led to many studies on the effectiveness of antibody preparations for immunization against measles and infectious hepatitis.

Before the polio vaccine was licensed, health officials had hopes for the use of gamma globulin (an antibody-containing blood product) to prevent the disease. William M. Hammon, MD, of the University of Pittsburgh Graduate School of Public Health, building on Stokes’s and Neefe’s work, conducted important trials to test this idea in 1951-52. He showed that administration of gamma globulin containing known poliovirus antibodies could prevent cases of paralytic polio. However, the limited availability of gamma globulin, and the short-term protection it offered, meant that the treatment could not be used on a wide scale. The licensure of the inactivated Salk polio vaccine in 1955 made reliance on gamma globulin for poliovirus immunization unnecessary.

Passive Immunization Today

Today, patients may be treated with antibodies when they are ill with diphtheria or cytomegalovirus. Or, antibody treatment may be used as a preventive measure after exposure to a pathogen to try to stop illness from developing (such as with respiratory syncytial virus [RSV], measles, tetanus, hepatitis A, hepatitis B, rabies, or chickenpox).  Antibody treatment may not be used for routine cases of these diseases, but it may be beneficial to high-risk individuals, such as people with immune system deficiencies.

Advantages and Disadvantages of Passive Immunization

Vaccines typically need time (weeks or months) to produce protective immunity in an individual and may require several doses over a certain period of time to achieve optimum protection. Passive immunization, however, has an advantage in that it is quick acting, producing an immune response within hours or days, faster than a vaccine. Additionally, passive immunization can override a deficient immune system, which is especially helpful in someone who does not respond to immunization.

Antibodies, however, have certain disadvantages. First, antibodies can be difficult and costly to produce. Although new techniques can help produce antibodies in the laboratory, in most cases antibodies to infectious diseases must be harvested from the blood of hundreds or thousands of human donors. Or, they must be obtained from the blood of immune animals (as with antibodies that neutralize snake venoms). In the case of antibodies harvested from animals, serious allergic reactions can develop in the recipient. Another disadvantage is that many antibody treatments must be given via intravenous injection, which is a more time-consuming and potentially complicated procedure than the injection of a vaccine. Finally, the immunity conferred by passive immunization is short lived: it does not lead to the formation of long-lasting memory immune cells.

In certain cases, passive and active immunity may be used together. For example, a person bitten by a rabid animal might receive rabies antibodies (passive immunization to create an immediate response) and rabies vaccine (active immunity to elicit a long-lasting response to this slowly reproducing virus).

Future Trends

Monoclonal Antibodies Increasingly, technology is being used to generate monoclonal antibodies (MAbs)– “mono” meaning that they are a pure, single type of antibody targeted at a single site on a pathogen, and “clonal” because they are produced from a single parent cell. These antibodies have wide-ranging potential applications to infectious disease and other types of diseases.

Monoclonal antibodies were first created by researchers Cesar Milstein, PhD (1927-2002), and Georges Kohler, PhD (1946-1995), who combined short-lived antibody-producing mouse spleen cells (which had been exposed to a certain antigen) with long-lived mouse tumor cells. The combined cells produced antibodies to the targeted antigen. Milstein and Kohler won the Nobel Prize in Physiology or Medicine for their discovery in 1984.

To date, only one MAb treatment is commercially available for the prevention of an infectious disease. This is a MAb preparation for the prevention of severe disease caused by RSV in high-risk infants. Physicians are also increasingly using MAbs to combat noninfectious diseases, such as certain types of cancer, multiple sclerosis, rheumatoid arthritis, Crohn’s disease, and cardiovascular disease.

Scientists are researching other new technologies for producing antibodies in the laboratory, such as recombinant systems using yeast cells or viruses and systems combining human cells and mouse cells, or human DNA and mouse DNA.

Bioterror threats In the event of the deliberate release of an infectious biological agent, biosecurity experts have suggested that passive immunization could play a role in emergency response. The advantage of using antibodies rather than vaccines to respond to a bioterror event is that antibodies provide immediate protection, whereas a protective response generated by a vaccine is not immediate and in some cases may depend on a booster dose given at a later date. 

Candidates for this potential application of passive immunization include botulinum toxin, tularemia, anthrax, and plague. For most of these targets, only animal studies have been conducted, and so the use of passive immunization in potential bioterror events is still in experimental stages.

Summary

Antibodies were one of the first tools used against specific infectious diseases. As antibiotics came to be widely used, and as vaccines were developed, the use of passive immunization became less common. Even today, however, antibodies play a role against infectious disease when physicians use antibodies to achieve passive immunity and to treat certain diseases in patients. Scientists are investigating new applications for passive immunization and antibody treatment as well as new and more efficient methods of creating antibodies.

Sources

Casadevall A. Passive antibody administration (immediate immunity) as a specific defense against biological weapons. Emerg Infect Dis [serial online] 2002 Aug;8. http://www.cdc.gov/ncidod/EID/vol8no8/01-0516.htm Accessed July 31, 2014.

Centers for Disease Control and Prevention. Immunity Types. http://www.cdc.gov/vaccines/vac-gen/immunity-types.htm Accessed July 31, 2014.

Keller MA, Stiehm ER. Passive immunity in prevention and treatment of infectious diseases. Clinical Microbiology Reviews. October 2000, pp. 602-614, vol. 13, no. 4.

Feign RD, Cherry JD, Demmler GJ, Kaplan SL. Textbook of Pediatric Infectious Diseases. 5th ed, vol. 2. Philadelphia:  Saunders, 2004.

Kaempffert W. Cause of Army jaundice is now discovered and the means of control indicated. New York Times, January 21, 1945. http://query.nytimes.com/mem/archive/pdf?res=F60F1FF8385E1B7A93C3AB178AD85F418485F9  Accessed July 31, 2014.

Kaempffert W. Preventing measles: Gamma globulin, separated from the blood, destroys the germ. New York Times, May 14, 1944. http://query.nytimes.com/mem/archive/pdf?res=F50E12FB385C167B93C6A8178ED85F408485F9 Accessed July 31, 2014.

Rinaldo CR, Jr. Passive immunization against poliomyelitis. The Hammon gamma globulin field trials, 1951-1953. Am J Pub Health. 2005 May;95(5):790-799. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1449257/  Accessed July 31, 2014.

Synagis (Palivizumab) Information Page. Medimmune. http://medimmune.com/about_us_products.aspx  Accessed July 31, 2014.

Last update 31 July 2014

Timeline Entry: 1890 Antitoxin and Serum Therapy

National Library of Medicine
Emil von Behring
 
National Library of Medicine
Shibasaburo Kitasato, about 1911
000236,000237

Shibasaburo Kitasato (1852-1931) and Emil von Behring (1854-1917) 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.

Von Behring would win the first Nobel Prize in medicine in 1901 for his work on diphtheria.

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Timeline Entry: 10/22/1952 IgG Used for Polio Protection

March of Dimes Foundation
William M. Hammon preparting for IGG polio trials
 
The Historical Medical Library of The College of Physicians of Philadelphia
1953 Polio Brochure 2
000359,000363

Several researchers had been investigating whether use of human immunoglobulin (IgG, or gamma globulin) could protect individuals from polio. Immunoglobulin is an antibody preparation made from blood pooled from many people who most likely have antibodies to common infections. Their disease-specific antibodies in the IgG, when injected into a person who had recently or would soon be exposed to the disease, had been shown to provide protection. This type of protection is known as passive immunization.

William M. Hammon, MD (1904-1989), a University of Pittsburgh researcher, tested gamma globulin in a set of three clinical trials in 1951-52. The trials were carefully constructed and used a double-blind, placebo-controlled design, one of the first of this kind. The trials showed some likely protective effects of gamma globulin use against polio.

Use of the preparation presented several problems, though. Gamma globulin was expensive to produce and it gave only temporary protection. It would need to be used again in each subsequent epidemic. Moreover, physicians relied on gamma globulin for protection against measles, hepatitis, and other diseases for which there were no vaccines. The supply was limited, and the need was great. As Time magazine wrote at the time, “It takes almost a pint of blood to make an average shot of G.G. (7 cc). To give protection for a single polio season to all the 41 million U.S. children under 15 might take 100 million shots or more, and there simply is not that much gamma globulin available, nor the blood or plasma to extract it from” (Time, November 3, 1952).

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Assessment Questions

What is the difference between active immunity and passive immunity?
A) Both are short lived, but active immunity helps protects right away.
B) Passive immunity results when a person is given someone else’s antibodies, whereas active immunity results when a person’s immune system works to produce antibodies and activate other immune cells to certain pathogens.
C) Active immunity results when a person is given someone else’s antibodies, whereas passive immunity results when a person’s immune system works to produce antibodies and activate other immune cells to certain pathogens.
D) None of the above
Which of the following is not a disadvantage of passive immunization?
A) The antibodies confer long-term immunity only.
B) The antibodies are expensive to produce.
C) The antibodies confer short-term immunity only.
D) Passive immunization can lead to serious allergic reaction.
True or false? In certain cases, passive and active immunization can be used together.
A) True
B) False
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