Passive immunity

Passive immunity is the transfer of active humoral immunity of ready-made antibodies. Passive immunity can occur naturally, when maternal antibodies are transferred to the fetus through the placenta, and it can also be induced artificially, when high levels of antibodies specific to a pathogen or toxin (obtained from humans, horses, or other animals) are transferred to non-immune persons through blood products that contain antibodies, such as in immunoglobulin therapy or antiserum therapy.[1] Passive immunization is used when there is a high risk of infection and insufficient time for the body to develop its own immune response, or to reduce the symptoms of ongoing or immunosuppressive diseases.[2] Passive immunization can be provided when people cannot synthesize antibodies, and when they have been exposed to a disease that they do not have immunity against.[3]

Naturally acquired

Maternal passive immunity is a type of naturally acquired passive immunity, and refers to antibody-mediated immunity conveyed to a fetus or infant by its mother. Naturally acquired passive immunity can be provided during pregnancy, and through breastfeeding.[4] In humans, maternal antibodies (MatAb) are passed through the placenta to the fetus by an FcRn receptor on placental cells. This occurs predominately during the third trimester of pregnancy, and thus is often reduced in babies born prematurely. Immunoglobulin G (IgG) is the only antibody isotype that can pass through the human placenta, and is the most common antibody of the five types of antibodies found in the body. IgG antibodies protects against bacterial and viral infections in fetuses. Immunization is often required shortly following birth to prevent diseases in newborns such as tuberculosis, hepatitis B, polio, and pertussis, however, maternal IgG can inhibit the induction of protective vaccine responses throughout the first year of life. This effect is usually overcome by secondary responses to booster immunization.[5] Maternal antibodies protect against some diseases, such as measles, rubella, and tetanus, more effectively than against others, such as polio and pertussis.[6] Maternal passive immunity offers immediate protection, though protection mediated by maternal IgG typically only lasts up to a year.[7]

Passive immunity is also provided through colostrum and breast milk, which contain IgA antibodies that are transferred to the gut of the infant, providing local protection against disease causing bacteria and viruses until the newborn can synthesize its own antibodies.[8] Protection mediated by IgA is dependent on the length of time that an infant is breastfed, which is one of the reasons the World Health Organization recommends breastfeeding for at least the first two years of life.[9]

Other species besides humans transfer maternal antibodies before birth, including primates and lagomorphs (which includes rabbits and hares).[10] In some of these species IgM can be transferred across the placenta as well as IgG. All other mammalian species predominantly or solely transfer maternal antibodies after birth through milk. In these species, the neonatal gut is able to absorb IgG for hours to days after birth. However, after a period of time the neonate can no longer absorb maternal IgG through their gut, an event that is referred to as "gut closure". If a neonatal animal does not receive adequate amounts of colostrum prior to gut closure, it does not have a sufficient amount of maternal IgG in its blood to fight off common diseases. This condition is referred to as failure of passive transfer. It can be diagnosed by measuring the amount of IgG in a newborn's blood, and is treated with intravenous administration of immunoglobulins. If not treated, it can be fatal.

Artificially acquired
See also: Temporarily induced immunity

Artificially acquired passive immunity is a short-term immunization achieved by the transfer of antibodies, which can be administered in several forms; as human or animal blood plasma or serum, as pooled human immunoglobulin for intravenous (IVIG) or intramuscular (IG) use, as high-titer human IVIG or IG from immunized donors or from donors recovering from the disease, and as monoclonal antibodies (MAb). Passive transfer is used to prevent disease or used prophylactically in the case of immunodeficiency diseases, such as hypogammaglobulinemia.[11][12] It is also used in the treatment of several types of acute infection, and to treat poisoning.[2] Immunity derived from passive immunization lasts for a few weeks to three to four months.[13][14] There is also a potential risk for hypersensitivity reactions, and serum sickness, especially from gamma globulin of non-human origin.[8] Passive immunity provides immediate protection, but the body does not develop memory, therefore the patient is at risk of being infected by the same pathogen later unless they acquire active immunity or vaccination.[8]

History and applications of artificial passive immunity
A vial of diphtheria antitoxin, dated 1895

In 1888 Emile Roux and Alexandre Yersin showed that the clinical effects of diphtheria were caused by diphtheria toxin and, following the 1890 discovery of an antitoxin-based immunity to diphtheria and tetanus by Emil Adolf von Behring and Kitasato Shibasaburō, antitoxin became the first major success of modern therapeutic immunology.[15][16] Shibasaburo and von Behring immunized guinea pigs with the blood products from animals that had recovered from diphtheria and realized that the same process of heat treating blood products of other animals could treat humans with diphtheria.[17] By 1896, the introduction of diphtheria antitoxin was hailed as "the most important advance of the [19th] Century in the medical treatment of acute infective disease".[18]

Prior to the advent of vaccines and antibiotics, specific antitoxin was often the only treatment available for infections such as diphtheria and tetanus. Immunoglobulin therapy continued to be a first line therapy in the treatment of severe respiratory diseases until the 1930s, even after sulfonamides were introduced.[12]

This image is from the Historical Medical Library of The College of Physicians of Philadelphia. This displays the administration of diphtheria antitoxin from horse serum to young child, dated 1895.

In 1890 antibody therapy was used to treat tetanus, when serum from immunized horses was injected into patients with severe tetanus in an attempt to neutralize the tetanus toxin, and prevent the dissemination of the disease. Since the 1960s, human tetanus immune globulin (TIG) has been used in the United States in unimmunized, vaccine-naive or incompletely immunized patients who have sustained wounds consistent with the development of tetanus.[12] The administration of horse antitoxin remains the only specific pharmacologic treatment available for botulism.[19] Antitoxin also known as heterologous hyperimmune serum is often also given prophylactically to individuals known to have ingested contaminated food.[20] IVIG treatment was also used successfully to treat several victims of toxic shock syndrome, during the 1970s tampon scare.

Antibody therapy is also used to treat viral infections. In 1945, hepatitis A infections, epidemic in summer camps, were successfully prevented by immunoglobulin treatment. Similarly, hepatitis B immune globulin (HBIG) effectively prevents hepatitis B infection. Antibody prophylaxis of both hepatitis A and B has largely been supplanted by the introduction of vaccines; however, it is still indicated following exposure and prior to travel to areas of endemic infection.[21]

In 1953, human vaccinia immunoglobulin (VIG) was used to prevent the spread of smallpox during an outbreak in Madras, India, and continues to be used to treat complications arising from smallpox vaccination. Although the prevention of measles is typically induced through vaccination, it is often treated immuno-prophylactically upon exposure. Prevention of rabies infection still requires the use of both vaccine and immunoglobulin treatments.[12]

During a 1995 Ebola virus outbreak in the Democratic Republic of Congo, whole blood from recovering patients, and containing anti-Ebola antibodies, was used to treat eight patients, as there was no effective means of prevention, though a treatment was discovered recently in the 2013 Ebola epidemic in Africa. Only one of the eight infected patients died, compared to a typical 80% Ebola mortality, which suggested that antibody treatment may contribute to survival.[22] Immune globulin or immunoglobulin has been used to both prevent and treat reactivation of the herpes simplex virus (HSV), varicella zoster virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV).[12]

FDA licensed immunoglobulins

The following immunoglobulins are the immunoglubulins currently approved for use for infectious disease prophylaxis and immunotherapy, in the United States.[23]

FDA approved products for passive immunization and immunotherapy
DiseaseProduct[lower-alpha 1]SourceUse
BotulismSpecific equine IgGhorseTreatment of wound and food borne forms of botulism, infant
botulism is treated with human botulism immune globulin (BabyBIG).
Cytomegalovirus (CMV)hyper-immune IVIGhumanProphylaxis, used most often in kidney transplant patients.
DiphtheriaSpecific equine IgGhorseTreatment of diphtheria infection.
Hepatitis A, measlesPooled human Ighuman serumPrevention of Hepatitis A and measles infection,
treatment of congenital or acquired immunodeficiency.
Hepatitis BHepatitis B IghumanPost-exposure prophylaxis, prevention in high-risk infants
(administered with Hepatitis B vaccine).
ITP, Kawasaki disease,
IgG deficiency		Pooled human IgGhuman serumTreatment of ITP and Kawasaki disease,
prevention/treatment of opportunistic infection with IgG deficiency.
RabiesRabies IghumanPost-exposure prophylaxis (administered with rabies vaccine).
TetanusTetanus IghumanTreatment of tetanus infection.
VacciniaVaccinia IghumanTreatment of progressive vaccinia infection
including eczema and ocular forms (usually resulting from
smallpox vaccination in immunocompromised individuals).
Varicella (chicken-pox)Varicella-zoster IghumanPost-exposure prophylaxis in high risk individuals.
  1. Specific or not noted: hyperimmune globulin or antitoxin. Pooled: mixed Ig from ordinary sources, also known as normal human immunoglobulin.

Passive transfer of cell-mediated immunity

The one exception to passive humoral immunity is the passive transfer of cell-mediated immunity, also called adoptive immunization which involves the transfer of mature circulating lymphocytes. It is rarely used in humans, and requires histocompatible (matched) donors, which are often difficult to find, and carries severe risks of graft-versus-host disease.[2] This technique has been used in humans to treat certain diseases including some types of cancer and immunodeficiency. However, this specialized form of passive immunity is most often used in a laboratory setting in the field of immunology, to transfer immunity between "congenic", or deliberately inbred mouse strains which are histocompatible.

Advantages and disadvantages

An individual's immune response of passive immunity is "faster than a vaccine" and can instill immunity in an individual that does not "respond to immunization", often within hours or a few days. In addition to conferring passive immunities, breastfeeding has other lasting beneficial effects on the baby's health, such as decreased risk of allergies and obesity.[17][24]

A disadvantage to passive immunity is that producing antibodies in a laboratory is expensive and difficult to do. In order to produce antibodies for infectious diseases, there is a need for possibly thousands of human donors to donate blood or immune animals' blood would be obtained for the antibodies. Patients who are immunized with the antibodies from animals may develop serum sickness due to the proteins from the immune animal and develop serious allergic reactions.[25] Antibody treatments can be time consuming and are given through an intravenous injection or IV, while a vaccine shot or jab is less time consuming and has less risk of complication than an antibody treatment. Passive immunity is effective, but only lasts a short amount of time.[17]

See also

References
  1. "Vaccines: Vac-Gen/Immunity Types". www.cdc.gov. Retrieved 2015-11-20.
  2. Microbiology and Immunology On-Line Textbook Archived 2020-04-08 at the Wayback Machine: USC School of Medicine
  3. "Passive Immunization - Infectious Diseases". Merck Manuals Professional Edition. Retrieved 2015-11-12.
  4. Kalenik, Barbara; Sawicka, Róża; Góra-Sochacka, Anna; Sirko, Agnieszka (2014-01-01). "Influenza prevention and treatment by passive immunization". Acta Biochimica Polonica. 61 (3): 573–587. doi:10.18388/abp.2014_1879. ISSN 1734-154X. PMID 25210721.
  5. Lambert, Paul-Henri, Margaret Liu and Claire-Anne Siegrist Can successful vaccines teach us how to induce efficient protective immune responses? (Full text-html) Nature Medicine 11, S54 - S62 (2005).
  6. "Centers for Disease Control and Prevention" (PDF).
  7. "Centers for Disease Control and Prevention" (PDF).
  8. Janeway, Charles; Paul Travers; Mark Walport; Mark Shlomchik (2001). Immunobiology; Fifth Edition. New York and London: Garland Science. ISBN 0-8153-4101-6..
  9. "WHO | Exclusive breastfeeding". www.who.int. Retrieved 2016-06-06.
  10. Mucosal Immunology. ISBN 9780124158474.
  11. "prophylactically". Cite journal requires |journal= (help)
  12. Keller, Margaret A. and E. Richard Stiehm Passive Immunity in Prevention and Treatment of Infectious Diseases Clinical Microbiology Reviews, October 2000, p. 602-614, Vol. 13, No. 4
  13. Immunity Types from Centers for Disease Control and Prevention. Page last updated: May 19, 2014
  14. Baxter, David (2007-12-01). "Active and passive immunity, vaccine types, excipients and licensing". Occupational Medicine. 57 (8): 552–556. doi:10.1093/occmed/kqm110. ISSN 0962-7480. PMID 18045976.
  15. Dolman, C.E. (1973). "Landmarks and pioneers in the control of diphtheria". Can. J. Public Health. 64 (4): 317–36. PMID 4581249.
  16. Silverstein, Arthur M. (1989) History of Immunology (Hardcover) Academic Press. Note: The first six pages of this text are available online at: (Amazon.com easy reader)
  17. "Passive Immunization — History of Vaccines". www.historyofvaccines.org. Retrieved 2015-11-20.
  18. (Report) (1896). "Report of the Lancet Special Commission on the relative strengths of diphtheria antitoxic serums". Lancet. 148 (3803): 182–95. doi:10.1016/s0140-6736(01)72399-9. PMC 5050965.
  19. Shapiro, Roger L. MD; Charles Hatheway, PhD; and David L. Swerdlow, MD Botulism in the United States: A Clinical and Epidemiologic Review Annals of Internal Medicine. 1 August 1998 Volume 129 Issue 3 Pages 221-228
  20. "Centers of Disease Control and Prevention" (PDF).
  21. Casadevall, A., and M. D. Scharff. 1995. Return to the past: the case for antibody-based therapies in infectious diseases. Clin. Infect. Dis. 21:150-161
  22. Mupapa, K., M. Massamba, K. Kibadi, K. Kivula, A. Bwaka, M. Kipasa, R. Colebunders, and J. J. Muyembe-Tamfum on behalf of the International Scientific and Technical Committee. 1999. Treatment of Ebola hemorrhagic fever with blood transfusions from convalescent patients. J. Infect. Dis. 179(Suppl.):S18-S23
  23. Samuel Baron MD (1996) Table 8-2. U.S. Licensed Immunoglobulin For Passive Immunization Medical Microbiology Fourth Edition The University of Texas Medical Branch at Galveston
  24. "Breastfeeding Overview". WebMD. Retrieved 2015-11-20.
  25. "Centers for Disease Control and Prevention" (PDF).

Could Intravenous Immunoglobulin Collected from Recovered Coronavirus Patients Protect against COVID-19 and Strengthen the Immune System of New Patients

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