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12.1A: Passive Immunization - Biology

12.1A: Passive Immunization - Biology



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Learning Objectives

  • Describe how artificial and natural passive immunity function to provide antibody protection against microorganisms

There are two types of passive immunity: artificial and natural. Artificial passive immunity is achieved by infusion of serum or plasma containing high concentrations of antibody. This form of passive immunity provides immediate antibody protection against microorganisms such as hepatitis A by administering preformed antibodies. These antibodies have been produced by another person or animal that has been actively immunized, but the ultimate recipient has not produced them. The recipient will only temporarily benefit from passive immunity for as long as the antibodies persist in their circulation.This type of immunity is short acting, and is typically seen in cases where a patient needs immediate protection from a foreign body and cannot form antibodies quickly enough independently.

Passive immunity can also be acquired naturally by the fetus due to the transfer of antibodies by the maternal circulation in utero through the placenta around the third month of gestation. Immunity in newborn babies is only temporary and starts to decrease after the first few weeks, or months. Breast milk also contains antibodies, which means that babies who are breastfed have passive immunity for longer periods of time. The thick, yellowish milk (colostrum) that is produced during the first few days after birth is particularly rich in antibodies. For the newborn to have lasting protection, active immunity must be received. The first immunisation, given when a baby is two months old, includes whooping cough and Hib (haemophilus influenza type b) because immunity to these diseases decreases the fastest. Passive immunity to measles, mumps and rubella (MMR) usually lasts for about a year, which is why the MMR is given just after the baby’s first birthday.

Key Points

  • Passive immunization provides humoral immunity.
  • Artificial passive immunization is the injection of preformed antibody solution when a patient is incapable of producing antibodies fast enough to combat a disease.
  • Natural passive immunization is the transfer of antibodies through the placenta of a pregnant woman to the fetus. Immunity lasts for a couple of months after the baby is born, after which active immunization is required.

Key Terms

  • in utero: Occurring or residing within the uterus or womb; unborn.

Principles of Vaccination

To understand how vaccines work and the basis of recommendations for their use, it is useful to have an understanding of the basic function of the human immune system. The following description is simplified. Many excellent immunology textbooks are available to provide additional detail.

Immunity is the ability of the human body to tolerate the presence of material indigenous to the body and to eliminate foreign substances. Immunity is generally specific to a single organism or group of closely related organisms. The discriminatory ability to eliminate foreign substances is performed by a complex system of interacting cells called the immune system. Since most organisms (such as bacteria, viruses, and fungi) are identified as foreign, the ability to identify and eliminate these substances provides protection from infectious disease.

The immune system develops a defense against antigens, which are substances that can stimulate the immune system. This defense is known as the immune response and usually involves the production of:

  • Protein molecules (immunoglobulins or antibodies, the major component of humoral immunity) by B-lymphocytes (B-cells)
  • Specific cells, including T-lymphocytes (also known as cell-mediated immunity).

The most effective immune responses are generally produced in response to antigens present in a live organism. However, an antigen does not necessarily have to be present in a live organism (as occurs with infection with a virus or bacterium) to produce an immune response. Some antigens, such as hepatitis B surface antigen, are easily recognized by the immune system and produce adequate protection even if they are not carried on the live hepatitis B virus. Other materials are less effective antigens, and the immune response they produce may not provide good protection.

There are two basic mechanisms for acquiring immunity: passive and active.

Passive Immunity

Passive immunity is protection by antibody or antitoxin produced by one animal or human and transferred to another. Passive immunity provides immediate protection against infection, but that protection is temporary. The antibodies will degrade during a period of weeks to months, and the recipient will no longer be protected.

The most common form of passive immunity is that which an infant receives from the mother. Antibodies, specifically the class of antibody referred to as IgG, are transported across the placenta primarily during the last 1&ndash2 months of pregnancy. As a result, a full-term infant will have the same type of antibodies as the mother. These antibodies can protect the infant from certain diseases within the first few months after birth. Maternal antibodies provide better protection from some diseases (e.g., measles, rubella, tetanus) than from others (e.g., polio, pertussis).

Passive immunity can also be acquired through the transfusion of blood products. Some blood products (e.g., washed or reconstituted red blood cells) contain a relatively small amount of antibody, while some (e.g., intravenous immune globulin and plasma products) contain a large amount.

In addition to blood products used for transfusion, there are three other major sources of antibody used in human medicine. These are homologous pooled human antibody, homologous human hyperimmune globulin, and heterologous hyperimmune serum.

Homologous pooled human antibody, also known as immune globulin, is produced by combining the antibody fraction, specifically the class of antibody referred to as IgG from the blood of thousands of adult donors in the United States. Because it comes from many different donors, it contains antibody to many different antigens. It is used primarily for prophylaxis for hepatitis A and measles and treatment of certain congenital immunoglobulin deficiencies.

Homologous human hyperimmune globulins are antibody products that contain high titers of antibody targeting more specific antigens. These products are made from donated human plasma with high levels of the antibody of interest. Since hyperimmune globulins are from humans, they are primarily polyclonal, containing many types of antibodies in lesser quantities. Hyperimmune globulins are used for postexposure prophylaxis for several diseases, including hepatitis B, rabies, tetanus, and varicella.

Heterologous hyperimmune serum, also known as antitoxin, is produced in animals, usually horses, and contains antibodies against only one antigen. In the United States, antitoxins are available for the treatment of botulism and diphtheria. These products can cause serum sickness, an immune reaction to the horse protein.

Immune globulin products from human sources are primarily polyclonal they contain many kinds of antibodies. Monoclonal antibody products have many applications, including the diagnosis of certain types of cancer (colorectal, prostate, ovarian, breast), treatment of cancer (B-cell chronic lymphocytic leukemia, non-Hodgkin lymphoma), prevention of transplant rejection, and treatment of autoimmune diseases (Crohn&rsquos disease, rheumatoid arthritis) and infectious diseases.

While certain antibody products, like immune globulins, interfere with the immune response to live-virus vaccines, monoclonal antibody products do not because they are directed against one antigen or closely related group of antigens. A monoclonal antibody product, palivizumab (Synagis), is available for the prevention of respiratory syncytial virus (RSV) infection. Since Synagis only contains RSV antibody, it will not interfere with the response to a live vaccine.

Active Immunity

Active immunity is protection produced by a person&rsquos own immune system. The immune system is stimulated by an antigen to produce antibody and cellular immunity. Unlike passive immunity, which is temporary, active immunity usually lasts for many years, often for a lifetime.

One way to acquire active immunity is to survive infection with the disease-causing form of the organism. In general, once persons recover from infectious diseases, they will have lifelong immunity to that disease (there are exceptions, such as malaria). The persistence of protection for many years after the infection is known as immunologic memory. Following exposure of the immune system to an antigen, certain memory B-cells continue to circulate in the blood and reside in the bone marrow for many years. Upon reexposure to the antigen, these memory cells begin to replicate and produce antibody rapidly to reestablish protection.

Another way to produce active immunity is by vaccination. Vaccines contain antigens that stimulate the immune system to produce an immune response that is often similar to that produced by the natural infection. With vaccination, however, the recipient is not subjected to the disease and its potential complications.

Many factors may influence the immune response to vaccination. These include the presence of maternal antibody, the nature and dose of antigen, the route of administration, and the presence of an adjuvant (e.g., aluminum-containing material added to improve the immunogenicity of the vaccine). Host factors, such as age, nutrition, genetics, and coexisting disease, may also affect the response.


Prevention and treatment of COVID-19 disease by controlled modulation of innate immunity

The recent outbreak of coronavirus disease 2019 (COVID-19), triggered by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses an enormous threat to global public health and economies. Human coronaviruses normally cause no or mild respiratory disease but in the past two decades, potentially fatal coronavirus infections have emerged, causing respiratory tract illnesses such as pneumonia and bronchitis. These include severe acute respiratory syndrome coronavirus (SARS-CoV), followed by the Middle East respiratory syndrome coronavirus (MERS-CoV), and recently the SARS-CoV-2 coronavirus outbreak that emerged in Wuhan, China, in December 2019. Currently, most COVID-19 patients receive traditional supportive care including breathing assistance. To halt the ongoing spread of the pandemic SARS-CoV-2 coronavirus and rescue individual patients, established drugs and new therapies are under evaluation. Since it will be some time until a safe and effective vaccine will be available, the immediate priority is to harness innate immunity to accelerate early antiviral immune responses. Second, since excessive inflammation is a major cause of pathology, targeted anti-inflammatory responses are being evaluated to reduce inflammation-induced damage to the respiratory tract and cytokine storms. Here, we highlight prominent immunotherapies at various stages of development that aim for augmented anti-coronavirus immunity and reduction of pathological inflammation.

Keywords: COVID-19 SARS-CoV-2 cytokine innate immunity lung.

© 2020 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Contents

The immune system has two components: innate and adaptive immunity. The innate immunity is present in all metazoans, [2] while the adaptive immunity only occurs in vertebrates.

The innate system relies on the recognition of certain foreign molecules to stimulate two types of innate immune responses: inflammatory responses and phagocytosis. [3] The adaptive system, on the other hand, is composed of more advanced lymphatic cells that are programmed to distinguish between specific "non-self" substances in the presence of "self". The reaction to foreign substances is etymologically described as inflammation, meaning to set on fire. The non-reaction to self substances is described as immunity - meaning to exempt. These two components of the immune system create a dynamic biological environment where "health" can be seen as a physical state where the self is immunologically spared, and what is foreign is inflammatorily and immunologically eliminated. "Disease" can arise when what is foreign cannot be eliminated or what is self is not spared. [4]

Innate immunity, also known as native immunity, is a semi-specific and widely distributed form of immunity. It is defined as the first line of defense against pathogens, representing a critical systemic response to prevent infection and maintain homeostasis, contributing to the activation of an adaptive immune response. [5] It does not adapt to specific external stimulus or a prior infection, but relies on genetically encoded recognition of particular patterns. [6]

Adaptive or acquired immunity is the active component of the host immune response, mediated by antigen-specific lymphocytes. Unlike the innate immunity, the acquired immunity is highly specific to a particular pathogen, including the development of immunological memory. [7] Like the innate system, the acquired system includes both humoral immunity components and cell-mediated immunity components.

Adaptive immunity can be acquired either 'naturally' (by infection) or 'artificially' (through deliberate actions such as vaccination). Adaptive immunity can also be classified as 'active' or 'passive'. Active immunity is acquired through the exposure to a pathogen, which triggers the production of antibodies by the immune system. [8] Passive immunity is acquired through the transfer of antibodies or activated T-cells derived from an immune host either artificially or through the placenta it is short-lived, requiring booster doses for continued immunity.

The diagram below summarizes these divisions of immunity. Adaptive immunity recognizes more diverse patterns. Unlike innate immunity it is associated with memory of the pathogen. [6]

The concept of immunity has intrigued mankind for thousands of years. The prehistoric view of disease was that supernatural forces caused it, and that illness was a form of theurgic punishment for "bad deeds" or "evil thoughts" visited upon the soul by the gods or by one's enemies. [9] Between the time of Hippocrates and the 19th century, when the foundations of the scientific methods were laid, diseases were attributed to an alteration or imbalance in one of the four humors (blood, phlegm, yellow bile or black bile). [10] Also popular during this time before learning that communicable diseases came from germs/microbes was the miasma theory, which held that diseases such as cholera or the Black Plague were caused by a miasma, a noxious form of "bad air". [9] If someone were exposed to the miasma in a swamp, in evening air, or breathing air in a sickroom or hospital ward, they could get a disease.

The modern word "immunity" derives from the Latin immunis, meaning exemption from military service, tax payments or other public services. [11] The first written descriptions of the concept of immunity may have been made by the Athenian Thucydides who, in 430 BC, described that when the plague hit Athens: "the sick and the dying were tended by the pitying care of those who had recovered, because they knew the course of the disease and were themselves free from apprehensions. For no one was ever attacked a second time, or not with a fatal result". [11] The term "immunes", is also found in the epic poem "Pharsalia" written around 60 B.C. by the poet Marcus Annaeus Lucanus to describe a North African tribe's resistance to snake venom. [10]

The first clinical description of immunity which arose from a specific disease-causing organism is probably A Treatise on Smallpox and Measles ("Kitab fi al-jadari wa-al-hasbah'', translated 1848 [12] [13] ) written by the Islamic physician Al-Razi in the 9th century. In the treatise, Al Razi describes the clinical presentation of smallpox and measles and goes on to indicate that exposure to these specific agents confers lasting immunity (although he does not use this term). [10] The first scientist who developed a full theory of immunity was Ilya Mechnikov after he revealed phagocytosis in 1882. With Louis Pasteur's germ theory of disease, the fledgling science of immunology began to explain how bacteria caused disease, and how, following infection, the human body gained the ability to resist further infections. [11]

The birth of active immunotherapy may have begun with Mithridates VI of Pontus (120-63 B.C.). [14] To induce active immunity for snake venom, he recommended using a method similar to modern toxoid serum therapy, by drinking the blood of animals which fed on venomous snakes. [14] He is thought to have assumed that those animals acquired some detoxifying property, so that their blood would contain transformed components of the snake venom that could induce resistance to it instead of exerting a toxic effect. Mithridates reasoned that, by drinking the blood of these animals, he could acquire a similar resistance. [14] Fearing assassination by poison, he took daily sub-lethal doses of venom to build tolerance. He is also said to have sought to create a 'universal antidote' to protect him from all poisons. [10] [15] For nearly 2000 years, poisons were thought to be the proximate cause of disease, and a complicated mixture of ingredients, called Mithridate, was used to cure poisoning during the Renaissance. [16] [10] An updated version of this cure, Theriacum Andromachi, was used well into the 19th century.

In 1888 Emile Roux and Alexandre Yersin isolated diphtheria toxin, and following the 1890 discovery by Behring and Kitasato of antitoxin based immunity to diphtheria and tetanus, the antitoxin became the first major success of modern therapeutic Immunology. [10]

In Europe, the induction of active immunity emerged in an attempt to contain smallpox. Immunization, however, had existed in various forms for at least a thousand years. [11] The earliest use of immunization is unknown, however, around 1000 A.D. the Chinese began practicing a form of immunization by drying and inhaling powders derived from the crusts of smallpox lesions. [11] Around the fifteenth century in India, the Ottoman Empire, and east Africa, the practice of inoculation (poking the skin with powdered material derived from smallpox crusts) became quite common. [11] This practice was first introduced into the west in 1721 by Lady Mary Wortley Montagu. [11] In 1798, Edward Jenner introduced the far safer method of deliberate infection with cowpox virus, (smallpox vaccine), which caused a mild infection that also induced immunity to smallpox. By 1800 the procedure was referred to as vaccination. To avoid confusion, smallpox inoculation was increasingly referred to as variolation, and it became common practice to use this term without regard for chronology. The success and general acceptance of Jenner's procedure would later drive the general nature of vaccination developed by Pasteur and others towards the end of the 19th century. [10] In 1891, Pasteur widened the definition of vaccine in honour of Jenner and it then became essential to qualify the term, by referring to polio vaccine, measles vaccine etc.

Passive immunity is the transfer of immunity, in the form of ready-made antibodies, from one individual to another. Passive immunity can occur naturally, when maternal antibodies are transferred to the foetus through the placenta, and can also be induced artificially, when high levels of human (or horse) antibodies specific for a pathogen or toxin are transferred to non-immune individuals. 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. [17] 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. [18]

Naturally acquired Edit

Maternal passive immunity is a type of naturally acquired passive immunity, and refers to antibody-mediated immunity conveyed to a fetus by its mother during pregnancy. Maternal antibodies (MatAb) are passed through the placenta to the fetus by an FcRn receptor on placental cells. This occurs around the third month of gestation. IgG is the only antibody isotype that can pass through the placenta. Passive immunity is also provided through the transfer of IgA antibodies found in breast milk that are transferred to the gut of the infant, protecting against bacterial infections, until the newborn can synthesize its antibodies. Colostrum present in mothers milk is an example of passive immunity. [18]

Artificially acquired Edit

Artificially acquired passive immunity is a short-term immunization induced by the transfer of antibodies, which can be administered in several forms as human or animal blood plasma, as pooled human immunoglobulin for intravenous (IVIG) or intramuscular (IG) use, and in the form of monoclonal antibodies (MAb). Passive transfer is used prophylactically in the case of immunodeficiency diseases, such as hypogammaglobulinemia. [19] It is also used in the treatment of several types of acute infection, and to treat poisoning. [17] Immunity derived from passive immunization lasts for only a short period of time, and there is also a potential risk for hypersensitivity reactions, and serum sickness, especially from gamma globulin of non-human origin. [18]

The artificial induction of passive immunity has been used for over a century to treat infectious disease, and before the advent of antibiotics, was often the only specific treatment for certain infections. Immunoglobulin therapy continued to be a first line therapy in the treatment of severe respiratory diseases until the 1930s, even after sulfonamide lot antibiotics were introduced. [19]

Transfer of activated T-cells Edit

Passive or "adoptive transfer" of cell-mediated immunity, is conferred by the transfer of "sensitized" or activated T-cells from one individual into another. It is rarely used in humans because it requires histocompatible (matched) donors, which are often difficult to find. In unmatched donors this type of transfer carries severe risks of graft versus host disease. [17] It has, however, been used to treat certain diseases including some types of cancer and immunodeficiency. This type of transfer differs from a bone marrow transplant, in which (undifferentiated) hematopoietic stem cells are transferred.

When B cells and T cells are activated by a pathogen, memory B-cells and T- cells develop, and the primary immune response results. Throughout the lifetime of an animal, these memory cells will "remember" each specific pathogen encountered, and can mount a strong secondary response if the pathogen is detected again. The primary and secondary responses were first described in 1921 by English immunologist Alexander Glenny [20] although the mechanism involved was not discovered until later. This type of immunity is both active and adaptive because the body's immune system prepares itself for future challenges. Active immunity often involves both the cell-mediated and humoral aspects of immunity as well as input from the innate immune system.

Naturally acquired Edit

Naturally acquired active immunity occurs when a person is exposed to a live pathogen and develops a primary immune response, which leads to immunological memory. [17] This type of immunity is "natural" because deliberate exposure does not induce it. Many disorders of immune system function can affect the formation of active immunity such as immunodeficiency (both acquired and congenital forms) and immunosuppression.

Artificially acquired Edit

Artificially acquired active immunity can be induced by a vaccine, a substance that contains antigen. A vaccine stimulates a primary response against the antigen without causing symptoms of the disease. [17] Richard Dunning coined the term vaccination, a colleague of Edward Jenner, and adapted by Louis Pasteur for his pioneering work in vaccination. The method Pasteur used entailed treating the infectious agents for those diseases, so they lost the ability to cause serious disease. Pasteur adopted the name vaccine as a generic term in honor of Jenner's discovery, which Pasteur's work built upon.

In 1807, Bavaria became the first group to require that their military recruits be vaccinated against smallpox, as the spread of smallpox was linked to combat. [21] Subsequently, the practice of vaccination would increase with the spread of war.

There are four types of traditional vaccines: [22]

  • Inactivated vaccines are composed of micro-organisms that have been killed with chemicals and/or heat and are no longer infectious. Examples are vaccines against flu, cholera, plague, and hepatitis A. Most vaccines of this type are likely to require booster shots.
  • Live, attenuated vaccines are composed of micro-organisms that have been cultivated under conditions which disable their ability to induce disease. These responses are more durable, however, they may require booster shots. Examples include yellow fever, measles, rubella, and mumps. are inactivated toxic compounds from micro-organisms in cases where these (rather than the micro-organism itself) cause illness, used prior to an encounter with the toxin of the micro-organism. Examples of toxoid-based vaccines include tetanus and diphtheria. , recombinant, polysaccharide, and conjugate vaccines are composed of small fragments or pieces from a pathogenic (disease-causing) organism. [23] A characteristic example is the subunit vaccine against Hepatitis B virus.
  • DNA vaccines: DNA vaccines are composed of DNA encoding protein antigens from the pathogen. These vaccines are inexpensive, relatively easy to make and generate a strong, long-term immunity. [23]
  • Recombinant vector vaccines (platform-based vaccines): These vaccines are harmless live viruses that encode a one/or a few antigens from a pathogenic organism. They are used widely in veterinary medicine. [23][24][25]

Most vaccines are given by hypodermic or intramuscular injection as they are not absorbed reliably through the gut. Live attenuated polio and some typhoid and cholera vaccines are given orally in order to produce immunity based in the bowel.


Active & passive immunity & vaccinations (CIE A-level Biology)

A Science teacher by trade, I've also been known to be found teaching Maths and PE! However, strange as it may seem, my real love is designing resources that can be used by other teachers to maximise the experience of the students. I am constantly thinking of new ways to engage a student with a topic and try to implement that in the design of the lessons.

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This fully-resourced lesson distinguishes between active and passive, natural and artificial immunity and explains how vaccinations can be used to control disease. The engaging and detailed PowerPoint and accompanying resources have been designed to cover point 11.2 (d) of the CIE A-level Biology specification and there is also a description and discussion on the concept of herd immunity.

In topic 11.1, students were introduced to the primary and secondary immune responses so the start of this lesson uses an imaginary game of TOP TRUMPS to challenge them on the depth of their understanding. This will act to remind them that a larger concentration of antibodies is produced in a quicker time in the secondary response. The importance of antibodies and the production of memory cells for the development of immunity is emphasised and this will be continually referenced as the lesson progresses. The students will learn that this response of the body to a pathogen that has entered the body through natural processes is natural active immunity. Moving forwards, time is taken to look at vaccinations as an example of artificial active immunity. Another series of questions focusing on the MMR vaccine will challenge the students to explain how the deliberate exposure to antigenic material activates the immune response and leads to the retention of memory cells. A quick quiz competition is used to introduce the variety of forms that the antigenic material can take along with examples of diseases that are vaccinated against using these methods. The eradication of smallpox is used to describe the concept of herd immunity and the students are given time to consider the scientific questions and concerns that arise when the use of this pathway is a possible option for a government. The remainder of the lesson looks at the different forms of passive immunity and describes the drawbacks in terms of the need for a full response if a pathogen is re-encountered

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Topics 10 & 11: Infectious disease & Immunity (CIE A-level Biology)

This lesson bundle contains 9 detailed and engaging lessons which have been designed to cover the following content in topics 10 & 11 of the CIE A-level Biology specification: 10.1: Infectious diseases * The meaning of the term disease and the difference between infectious and non-infectious diseases * The name and type of pathogen that causes cholera, malaria, TB, HIV/AIDS, smallpox and measles * Explain how cholera, malaria, TB, HIV and measles are transmitted 10.2: Antibiotics * Outline how penicillin acts on bacteria and why antibiotics do not affect viruses * Outline how bacteria become resistant to antibiotics with reference to mutation and selection * Discuss the consequences of antibiotic resistance and the steps that can be taken to reduce its impact 11.1: The immune system * State that phagocytes have their origin in bone marrow and describe their mode of action * Describe the modes of action of B and T lymphocytes * The meaning of the term immune response, with reference to antigens, self and non-self * Explain the role of memory cells in long term immunity * Autoimmune diseases as exemplified by myasthenia gravis 11.2: Antibodies and vaccination * Relate the molecular structure of antibodies to their functions * Distinguish between active and passive, natural and artificial immunity and explain how vaccination can control disease Each of the lesson PowerPoints is accompanied by worksheets which together contain a wide range of tasks that will engage and motivate the students whilst challenging them on their understanding of the current topic as well as previously-covered topics. If you would like to get an understanding of the quality of the lessons in this bundle, then download the transmission of infectious diseases and phagocytes and phagocytosis lessons as these have been shared for free.

Topic 11: Immunity (CIE A-level Biology)

The 5 lessons included in this bundle are all fully-resourced and contain a wide range of activities that will motivate and engage the students whilst covering the content as detailed in topic 11 of the CIE A-level Biology specification (Immunity). Exam-style questions which check on current and prior understanding, differentiated tasks, discussion points and quick quiz competitions cover the following specification points: * Phagocytes have their origin in bone marrow * Phagocytosis * The modes of action of B and T lymphocytes * The meaning of term immune response, with reference to the terms antigen, self and non-self * The role of memory cells in long term immunity * Autoimmune diseases * The relationship between the structure and function of antibodies * Distinguish between active and passive immunity * The use of vaccinations to control disease If you would like to sample the quality of these lessons, download the phagocytes and phagocytosis lesson as this has been uploaded for free


Immunity

Assorted References

Immunity from disease is actually conferred by two cooperative defense systems, called nonspecific, innate immunity and specific, acquired immunity. Nonspecific protective mechanisms repel all microorganisms equally, while the specific immune responses are tailored to particular types of invaders. Both systems work together to thwart organisms…

Patients with impaired immunological defenses against bacteria can be placed in complete biological isolation using gnotobiotic techniques. Babies suspected of lacking the ability to synthesize immunoglobulins (blood proteins that include antibodies) have been delivered into germfree isolators and maintained there until laboratory tests have shown that they could…

Disease

…host, the barrier known as immunity must be overcome. Defense against infection is provided by a number of chemical and mechanical barriers, such as the skin, mucous membranes and secretions, and components of the blood and other body fluids. Antibodies, which are proteins formed in response to a specific substance…

…induce a firm and enduring immunity. On first exposure to a virus, children may or may not contract the disease, depending on their resistance, the size of the infective dose of virus, and many other variables. Those who contract the disease, as well as those who resist the infection, develop…

The immunologic system of the body is responsible for the defense against disease. This highly complex system involves the production of antibodies (proteins that can recognize and attack specific infectious agents) the action of granulocytes and macrophages, cells that destroy infecting organisms by ingesting them (a…

…interaction may result in cellular immunity, which plays an important role in certain autoimmune disorders that involve solid organs, as well as in transplant rejection and cancer immunity.

…disease, a phenomenon termed herd immunity.

…off because it encounters only immune individuals among the host population. The rise and fall in epidemic prevalence of a disease is a probability phenomenon, the probability being that of transfer of an effective dose of the infectious agent from the infected individual to a susceptible one. After an epidemic…

As the patient develops immunity to the prevailing type and recovers from the attack, a new (mutant) type of the spirochete develops and produces the relapse. Because neither the bite nor the excreta of the louse is infectious, human infections usually result from crushing the louse on the skin…

Although infected individuals develop lasting immunity to a particular strain following an attack of influenza, the immunity is highly specific as to type, and no protection is afforded against even closely related strains. Artificial immunization with high- potency vaccines is of value in protecting against previous strains, and the vaccines…

…with one type confers no immunity against the others, and individuals who have experienced one attack of rheumatic fever are especially prone to subsequent attacks. Both the initial and recurrent attacks can be effectively prevented with penicillin. Symptomatic treatment of the condition includes the use of salicylates such as aspirin…

In order to understand why rejection occurs and how it may be prevented, it is necessary to know something of the operations of the immune system. The key cells of the immune system are the white blood cells known as lymphocytes. These are…

Mechanisms

The body is continuously exposed to damage by viruses, bacteria, and parasites ingested toxins and chemicals, including drugs and food additives and foreign protein of plant origin. These insults are received by the skin, the respiratory system, and the digestive system, which constitute the…

Immunity is the ability of an individual to recognize the “self” molecules that make up one’s own body and to distinguish them from such “nonself” molecules as those found in infectious microorganisms and toxins. This process has a prominent genetic component. Knowledge of the genetic…

Every animal species possesses some natural resistance to disease. Humans have a high degree of resistance to foot-and-mouth disease, for example, while the cattle and sheep with which they may be in close contact suffer in the thousands from it. Rats are highly resistant…

Humans and all other vertebrates react to the presence of parasites within their tissues by means of immune mechanisms of which there are two types: nonspecific, innate immunity and specific, acquired immunity. Innate immunity, with which an organism is born, involves protective factors, such…

The immune reaction is one of the most important defense mechanisms against biotic invasion and is therefore vital to the preservation of health. The devastating effects of acquired immune deficiency syndrome (AIDS) and other conditions that suppress or destroy the immune system are…

…are particularly important in stimulating immune responses, such as inflammation.

…contains the proteins that convey immunity to some infections from mother to young, although not in such quantity as among domestic animals. The human infant gains this type of immunity largely within the uterus by the transfer of these antibody proteins through the placenta the young baby seldom falls victim…

In addition to serving as a drainage network, the lymphatic system helps protect the body against infection by producing white blood cells called lymphocytes, which help rid the body of disease-causing microorganisms. The organs and tissues of the lymphatic system are the major sites…

…or participate in the acquired immunity to foreign cells and antigens. They are responsible for immunologic reactions to invading organisms, foreign cells such as those of a transplanted organ, and foreign proteins and other antigens not necessarily derived from living cells. The two classes of lymphocytes are not distinguished by…

Research

…understanding of the chemistry of immunological processes.

…provide an animal with passive immunity against tetanus by injecting it with the blood serum of another animal infected with the disease. Behring applied this antitoxin (a term he and Kitasato originated) technique to achieve immunity against diphtheria. Administration of diphtheria antitoxin, developed with Paul Ehrlich and first successfully marketed

…Brussels), Belgian physician, bacteriologist, and immunologist who received the Nobel Prize for Physiology or Medicine in 1919 for his discovery of factors in blood serum that destroy bacteria this work was vital to the diagnosis and treatment of many dangerous contagious diseases.

…discovery of how the body’s immune system distinguishes virus-infected cells from normal cells.

A bout with tuberculosis forced Ehrlich to interrupt his work and seek a cure in Egypt. When he returned to Berlin in 1889, the disease had been permanently arrested. After working for some time in a tiny and primitive private…

…made possible the production of vaccines for such diseases as smallpox, influenza, yellow fever, typhus, Rocky Mountain spotted fever, and other illnesses caused by agents that can be propagated only in living tissue.

…their discovery of how the immune system distinguishes virus-infected cells from normal cells.


New COVID-19 Vaccine: Nanoparticle Immunization Technology Could Protect Against Many Strains of Coronaviruses

The SARS-CoV-2 virus that is causing the COVID-19 pandemic is just one of many different viruses in the coronavirus family. Many of these are circulating in populations of animals like bats and have the potential to “jump” into the human population, just as SARS-CoV-2 did. Researchers in the laboratory of Pamela Björkman, the David Baltimore Professor of Biology and Bioengineering, are working on developing vaccines for a wide range of related coronaviruses, with the aim of preventing future pandemics.

Now, led by graduate student Alex Cohen, a Caltech team has designed a protein-based 60-subunit nanoparticle onto which pieces of up to eight different types of coronavirus have been attached. When injected into mice, this vaccine induces the production of antibodies that react to a variety of different coronaviruses—including similar viruses that were not presented on the nanoparticle.

The research is described in a paper in the journal Science.

This new vaccine prototype works by attaching many protein fragments (specifically, receptor-binding domains or RBDs) to an engineered protein-based nanoparticle. The study, in mice, showed that the vaccine induced the production of antibodies that are broadly reactive to a wide range of coronaviruses. RBDs are particularly important for a virus to be able to infect a cell, so antibodies that recognize RBDs are likely more effective at preventing bad infections. Credit: Courtesy of A. Cohen via BioRender

This vaccine platform, called a mosaic nanoparticle, was developed initially by collaborators at the University of Oxford. The nanoparticle is shaped like a cage made up of 60 identical proteins, each of which has a small protein tag that functions like a piece of Velcro. Cohen and his team took fragments of the spike proteins of different coronaviruses (spike proteins play the biggest role in infection) and engineered each to have a protein tag that would bind to those on the cage—the other half of the piece of Velcro. When these viral pieces were mixed together with the nanoparticle cage structure, each virus tag stuck to a tag on the cage, resulting in a nanoparticle presenting spikes representing different coronavirus strains on its surface.

Displaying eight different coronavirus spike fragments (known as receptor-binding domains or RBDs) with this particle platform generated a diverse antibody response, which is an advantage over traditional vaccine methods that present pieces from only a single type of virus. After inoculation, the antibodies subsequently produced by mice were able to react to many different strains of coronavirus. Importantly, the antibodies were reactive to related strains of coronavirus that were not present on the nanoparticle. This suggests that, by presenting the immune system with multiple different coronavirus variants, the immune system learns to recognize common features of coronaviruses and thus could potentially react to a newly emerging coronavirus—not just a SARS-CoV-2 variant—that might cause another pandemic.

Although the team is still studying the mechanism underlying this phenomenon, the results are promising. The next step is to examine whether immunization prevents viral infection and/or infection symptoms in animals making these antibodies.

“If we can show that the immune response induced by our nanoparticle technology indeed protects against illness resulting from infection, then we hope that we could move this technology forward into human clinical trials, though there are a lot of steps that need to happen between now and then,” says Cohen. “We don’t envision that this methodology would replace any existing vaccines, but it’s good to have many tools on hand when facing future emerging viral threats.”

“Unfortunately SARS-CoV-2 is unlikely to be the last coronavirus to cause a pandemic,” says Björkman. “Alex’s results show that it is possible to raise diverse neutralizing antibody responses, even against coronavirus strains that were not represented on the injected nanoparticle. So we are hopeful that this technology could be used to protect against future animal coronaviruses that cross into humans. In addition, the nanoparticles elicit neutralizing responses against SARS-CoV-2, so it could be possible to use them now to protect against COVID-19 as well as other coronaviruses with pandemic potential.”

The paper is titled “Mosaic nanoparticles elicit cross-reactive immune responses to zoonotic coronaviruses in mice.” Additional Caltech co-authors are research technicians Priyanthi Gnanapragasam, Yu Lee, Pauline Hoffman, and Leesa Kakutani Susan Ou research scientist Jennifer Keeffe (PhD 󈧍) senior research specialist Anthony West (PhD 󈨦) and senior postdoctoral scholar Christopher Barnes. Other co-authors include Hung-Jen Wu and Mark Howarth at the University of Oxford, and Michel Nussenzweig of The Rockefeller University. Funding was provided by the Caltech Merkin Institute for Translational Research, the National Institutes of Health, a George Mason University Fast Grant, and the Medical Research Council of the European & Developing Countries Clinical Trials Partnership program.


Discussion

Our ABM successfully generated 30 years of longitudinal data to evaluate the effects of supplemental ORI in a controlled study. For this purpose, we expanded mechanisms widely adopted from a previously published pertussis compartmental model by developing a spatially-localized 500,000-person contact network representing a typical small-to-moderate size Canadian public health district, and also supplemented such elements with novel mechanisms to dynamically recognize outbreaks suitable for ORI, and trigger resulting immunization campaigns.

Modeling is used to enhance fundamental understanding of pertussis characteristics and transmission and to more pragmatically evaluate impacts of interventions (e.g., adolescent or adult routine vaccination or cocooning strategy). While the latter is often a subject of recent enquiries, our model, to our knowledge, is the first to represent and evaluate the effects of pertussis ORI. Such an ORI-specific evaluation is an important contribution to our understanding of outbreaks dynamics, as the force of infection of the sort of focused, large scale outbreak needed to motivate ORI may generate different transmission patterns which cannot be seen in the non-outbreak settings, and because ORI can re-shape both short- and long-term transmission dynamics either for the benefit or possibly to a detriment. The large scale outbreak itself may exhaust the pool of susceptibles and consequently yield a decrease in the number of cases in post-outbreak years, and lower incidence can lead to diminished natural boosting. For example, annual pertussis incidence rates were at historically low levels in 2 years following a large scale outbreak in New Brunswick in 2012 (187, 0.5 and 1.2 per 100,000 in 2012, 2013 and 2014, respectively) with a smaller outbreak reported in the third year (Office of the Chief Medical Officer of Health, 2013 Office of the Chief Medical Officer of Health, 2014b). While this observation could be due to the effect of the outbreak itself, the contribution of the ORI (which was implemented in New Brunswick 2012 outbreak) is an important consideration.

We conclude that the effect of ORI is beneficial independently of the effect of the outbreak itself and leads to a net number of cases averted in all age groups, particularly in the short and medium term. While the objective of this model project focused on evaluation of the effects of ORI, the model also supported a set of interesting secondary observations. We found that reducing the exogenous infection rate resulted in a lower background incidence rate punctuated by more pronounced outbreaks. This may suggest that jurisdictions with lower migration may be more prone to larger scale but less frequent outbreaks, while jurisdiction with higher migration may exhibit more frequent outbreaks with lower peak incidence. No significant changes to our conclusions were observed from positing prolonged duration of natural disease-derived immunity, increasing adult vaccine-coverage or restricting vaccination eligibility during ORI. We observed no effect of altering the assumptions concerning waning immunity for those who received whole-cell vaccine, which may be due to the fact that our model ran prospectively into the future, with the number of individuals who had whole-cell vaccines progressively decreasing over time. However, our findings in a sensitivity analysis that positing a stronger boosting effect of vaccination implies a notably reduced burden of pertussis supports current thinking that insufficient duration of immunity contributes to the recent resurgence of pertussis outbreaks.

One of the considerations in modeling/reproducing outbreaks is that, while historical surveillance data plays an important role in defining whether an outbreak exist or not, the identification of an outbreak is often judgement-based, with similar magnitude of pertussis incidence determined to be an outbreak in a one jurisdiction, but not in others. We set outbreak and ORI thresholds in our model high, effectively excluding instances of “borderline” outbreaks where ORI is unlikely to ever be a consideration. As a result, ORI in our simulations was triggered once every 26 years on average. This reflects the reality that ORI is not a commonplace intervention, particularly if disease is endemic. In our model, we implemented ORIs only to adolescents 10–14 years of age, reflecting recent outbreaks affecting this age group, who are largely fully immunized (and for whom immunization schedule adherence was not protective) and their accessibility to school-mediated campaigns however, our model has the capability to test outbreak response in any age group. To ascertain whether ORI administered to young adolescents confer an indirect protection to other age groups via interruption of transmission, we specifically examined the effects of ORI administered to the adolescent age group on the number of cases averted among individuals of all ages and among infants, as protecting infants is one the main priorities for public health interventions. While we observed protective effect among adolescents and individuals of all ages, our study revealed that a protective effect to infants is modest, as suggested by high NNV generated by our model. These results are in the agreement with recent recommendations concluding that a booster dose in adolescence or adulthood had minimal impact on infant disease (World Health Organization , 2014) however, the latter recommendation was not specifically in the ORI context.

The main strength of our study is that we analysed longitudinal data generated by the model in a manner of a controlled study, thus allowing us to independently evaluate and quantify the effects of the ORI. As propagation of outbreaks depends on both intrinsic characteristics of individuals as well as transmission-permitting connections, which exist between these agents, including both characteristics in a single agent-based model allowed us to examine their interplay in outbreak occurrence. Our model included age-structure to model pertussis vaccination and incorporated vaccination attitudes into determination of vaccine coverage. Our model quantified both vaccine-induced and natural disease-derived waning immunity. Furthermore, we calibrated and validated the model by statistical comparison of the model-generated data and observed surveillance data as well as by utilizing pattern-oriented modeling. Our model could be adapted, with varying levels of ease, for different contexts and to investigate different types of research questions. Adaptation to investigate similar ORI phenomena in other jurisdictions would involve a circumscribed set of changes, including primarily changes to the vaccination statechart and associated probabilities (to represent local vaccination regimes), probabilities associated with vaccine attitude (reflecting differences in local attitudes towards vaccination), population sizes and population density, and potentially age-specific mixing assumptions. With a greater degree of modifications, and contingent on retaining current disease transmission logic, our model would also permit to investigate effects of other public health interventions ranging from altering vaccination schedules, evaluating effects of passive messaging to adhere to immunization schedules and adding vaccine doses in adults.

Our study has several limitations. We used disease mechanism parameters initially outlined in the Hethcote model. While conducting several sensitivity analyses involving key parameters, our experiments with different disease transmission logic were limited to enhancing boosting effect a broader set of altered assumptions in this area may or may not yield different results for our research question. Recent study suggests that non-human primates vaccinated with acellular pertussis vaccine were protected from severe symptoms, but not infection, and readily transmitted Bordetella pertussis to contacts (Warfel, Zimmerman & Merkel, 2014). In recent review of pertussis models, Campbell, McCaw & McVernon (2015) identified incomplete understanding relating infection and disease and lack of supporting data to derive parameters as common limitations of proposed pertussis models. While our calibration process helped ensure that our model output is realistic, we did not test variations in every single parameter given the multi-faceted nature of our model. Furthermore until further knowledge emerges to narrow down or alter parameters value, using the classic model structures on which our model is based would appear appropriate. We did not aim to examine and compare public health strategies other than ORI, and the need to pursue such research is strong. Economic evaluations can offer valuable additions to conclusions generated by our work.


Contents

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 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 Edit

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]

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 Edit

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

FDA approved products for passive immunization and immunotherapy
Disease Product [a] Source Use
Botulism Specific equine IgG horse Treatment of wound and food borne forms of botulism, infant
botulism is treated with human botulism immune globulin (BabyBIG).
Cytomegalovirus (CMV) hyper-immune IVIG human Prophylaxis, used most often in kidney transplant patients.
Diphtheria Specific equine IgG horse Treatment of diphtheria infection.
Hepatitis A, measles Pooled human Ig human serum Prevention of Hepatitis A and measles infection,
treatment of congenital or acquired immunodeficiency.
Hepatitis B Hepatitis B Ig human Post-exposure prophylaxis, prevention in high-risk infants
(administered with Hepatitis B vaccine).
ITP, Kawasaki disease,
IgG deficiency
Pooled human IgG human serum Treatment of ITP and Kawasaki disease,
prevention/treatment of opportunistic infection with IgG deficiency.
Rabies Rabies Ig human Post-exposure prophylaxis (administered with rabies vaccine).
Tetanus Tetanus Ig human Treatment of tetanus infection.
Vaccinia Vaccinia Ig human Treatment of progressive vaccinia infection
including eczema and ocular forms (usually resulting from
smallpox vaccination in immunocompromised individuals).
Varicella (chicken-pox) Varicella-zoster Ig human Post-exposure prophylaxis in high risk individuals.

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.

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]


Contents

Protection of those without immunity Edit

Some individuals either cannot develop immunity after vaccination or for medical reasons cannot be vaccinated. [16] [6] [17] Newborn infants are too young to receive many vaccines, either for safety reasons or because passive immunity renders the vaccine ineffective. [18] Individuals who are immunodeficient due to HIV/AIDS, lymphoma, leukemia, bone marrow cancer, an impaired spleen, chemotherapy, or radiotherapy may have lost any immunity that they previously had and vaccines may not be of any use for them because of their immunodeficiency. [6] [17] [18] [19]

A portion of those vaccinated may not develop long-term immunity. [2] [20] [21] Vaccine contraindications may prevent certain individuals from being vaccinated. [17] In addition to not being immune, individuals in one of these groups may be at a greater risk of developing complications from infection because of their medical status, but they may still be protected if a large enough percentage of the population is immune. [6] [17] [21] [22]

High levels of immunity in one age group can create herd immunity for other age groups. [9] Vaccinating adults against pertussis reduces pertussis incidence in infants too young to be vaccinated, who are at the greatest risk of complications from the disease. [23] [24] This is especially important for close family members, who account for most of the transmissions to young infants. [9] [21] In the same manner, children receiving vaccines against pneumococcus reduces pneumococcal disease incidence among younger, unvaccinated siblings. [25] Vaccinating children against pneumococcus and rotavirus has had the effect of reducing pneumococcus- and rotavirus-attributable hospitalizations for older children and adults, who do not normally receive these vaccines. [25] [26] [27] Influenza (flu) is more severe in the elderly than in younger age groups, but influenza vaccines lack effectiveness in this demographic due to a waning of the immune system with age. [9] [28] The prioritization of school-age children for seasonal flu immunization, which is more effective than vaccinating the elderly, however, has been shown to create a certain degree of protection for the elderly. [9] [28]

For sexually transmitted infections (STIs), high levels of immunity in heterosexuals of one sex induces herd immunity for heterosexuals of both sexes. [11] [29] [30] Vaccines against STIs that are targeted at heterosexuals of one sex result in significant declines in STIs in heterosexuals of both sexes if vaccine uptake in the target sex is high. [29] [30] [31] Herd immunity from vaccination of one sex does not, however, extend to homosexuals of the other sex. [30] High-risk behaviors make eliminating STIs difficult because, even though most infections occur among individuals with moderate risk, the majority of transmissions occur because of individuals who engage in high-risk behaviors. [11] For these reasons, in certain populations it may be necessary to immunize high-risk individuals regardless of gender. [11] [30]

Evolutionary pressure and serotype replacement Edit

Herd immunity itself acts as an evolutionary pressure on pathogens, influencing viral evolution by encouraging the production of novel strains, referred to as escape mutants, that are able to evade herd immunity and infect previously immune individuals. [32] [33] The evolution of new strains is known as serotype replacement, or serotype shifting, as the prevalence of a specific serotype declines due to high levels of immunity, allowing other serotypes to replace it. [34] [35]

At the molecular level, viruses escape from herd immunity through antigenic drift, which is when mutations accumulate in the portion of the viral genome that encodes for the virus's surface antigen, typically a protein of the virus capsid, producing a change in the viral epitope. [36] [37] Alternatively, the reassortment of separate viral genome segments, or antigenic shift, which is more common when there are more strains in circulation, can also produce new serotypes. [32] [38] When either of these occur, memory T cells no longer recognize the virus, so people are not immune to the dominant circulating strain. [37] [38] For both influenza and norovirus, epidemics temporarily induce herd immunity until a new dominant strain emerges, causing successive waves of epidemics. [36] [38] As this evolution poses a challenge to herd immunity, broadly neutralizing antibodies and "universal" vaccines that can provide protection beyond a specific serotype are in development. [33] [39] [40]

Initial vaccines against Streptococcus pneumoniae significantly reduced nasopharyngeal carriage of vaccine serotypes (VTs), including antibiotic-resistant types, [25] [41] only to be entirely offset by increased carriage of non-vaccine serotypes (NVTs). [25] [34] [35] This did not result in a proportionate increase in disease incidence though, since NVTs were less invasive than VTs. [34] Since then, pneumococcal vaccines that provide protection from the emerging serotypes have been introduced and have successfully countered their emergence. [25] The possibility of future shifting remains, so further strategies to deal with this include expansion of VT coverage and the development of vaccines that use either killed whole-cells, which have more surface antigens, or proteins present in multiple serotypes. [25] [42]

Eradication of diseases Edit

If herd immunity has been established and maintained in a population for a sufficient time, the disease is inevitably eliminated – no more endemic transmissions occur. [7] If elimination is achieved worldwide and the number of cases is permanently reduced to zero, then a disease can be declared eradicated. [8] Eradication can thus be considered the final effect or end-result of public health initiatives to control the spread of infectious disease. [8] [9]

The benefits of eradication include ending all morbidity and mortality caused by the disease, financial savings for individuals, health care providers, and governments, and enabling resources used to control the disease to be used elsewhere. [8] To date, two diseases have been eradicated using herd immunity and vaccination: rinderpest and smallpox. [2] [9] [43] Eradication efforts that rely on herd immunity are currently underway for poliomyelitis, though civil unrest and distrust of modern medicine have made this difficult. [2] [44] Mandatory vaccination may be beneficial to eradication efforts if not enough people choose to get vaccinated. [45] [46] [47] [48]

Herd immunity is vulnerable to the free rider problem. [49] Individuals who lack immunity, particularly those who choose not to vaccinate, free ride off the herd immunity created by those who are immune. [49] As the number of free riders in a population increases, outbreaks of preventable diseases become more common and more severe due to loss of herd immunity. [12] [13] [14] [46] [48] Individuals may choose to free ride for a variety of reasons, including the belief that vaccines are ineffective, [50] or that the risks associated with vaccines are greater than those associated with infection, [2] [13] [14] [50] mistrust of vaccines or public health officials, [51] bandwagoning or groupthinking, [46] [52] social norms or peer pressure, [50] and religious beliefs. [13] Certain individuals are more likely to choose not to receive vaccines if vaccination rates are high enough to convince a person that he or she may not need to be vaccinated, since a sufficient percentage of others are already immune. [2] [48]

Individuals who are immune to a disease act as a barrier in the spread of disease, slowing or preventing the transmission of disease to others. [5] An individual's immunity can be acquired via a natural infection or through artificial means, such as vaccination. [5] When a critical proportion of the population becomes immune, called the herd immunity threshold (HIT) or herd immunity level (HIL), the disease may no longer persist in the population, ceasing to be endemic. [7] [32]

The theoretical basis for herd immunity generally assumes that vaccines induce solid immunity, that populations mix at random, that the pathogen does not evolve to evade the immune response, and that there is no non-human vector for the disease. [2]

Values of R0 and herd immunity thresholds (HITs) of well-known infectious diseases prior to intervention
Disease Transmission R0 HIT [a]
Measles Aerosol 12–18 [53] [54] 92–94%
Chickenpox (varicella) Aerosol 10–12 [55] 90–92%
Mumps Respiratory droplets 10–12 [56] 90–92%
Rubella Respiratory droplets 6–7 [b] 83–86%
Polio Fecal–oral route 5–7 [b] 80–86%
COVID-19
(Variants)
[[Respiratory droplets
and aerosol]]
3,4-8,5 [61] +80%
Pertussis Respiratory droplets 5.5 [62] 82%
Smallpox Respiratory droplets 3.5–6.0 [63] 71–83%
COVID-19
(wild type)
Respiratory droplets
and aerosol [64]
2.87 ( 2.39 – 3.44 ) [65] 65% ( 58 – 70% )
HIV/AIDS Body fluids 2–5 [66] 50–80%
SARS Respiratory droplets 2–4 [67] 50–75%
Common cold Respiratory droplets 2–3 [68] 50–67%
Diphtheria Saliva 2.6 ( 1.7 – 4.3 ) [69] 62% ( 41 – 77% )
Ebola
(2014 Ebola outbreak)
Body fluids 1.78 ( 1.44 – 1.80 ) [70] 44% ( 31 – 44% )
Influenza
(2009 pandemic strain)
Respiratory droplets 1.58 ( 1.34 – 2.04 ) [71] 37% ( 25 – 51% )
Influenza
(seasonal strains)
Respiratory droplets 1.3 ( 1.2 – 1.4 ) [72] 23% ( 17 – 29% )
Nipah virus Body fluids 0.48 [73] 0% [c]
MERS Respiratory droplets 0.47 ( 0.29 – 0.80 ) [74] 0% [c]

The critical value, or threshold, in a given population, is the point where the disease reaches an endemic steady state, which means that the infection level is neither growing nor declining exponentially. This threshold can be calculated from the effective reproduction number Re, which is obtained by taking the product of the basic reproduction number R0, the average number of new infections caused by each case in an entirely susceptible population that is homogeneous, or well-mixed, meaning each individual is equally likely to come into contact with any other susceptible individual in the population, [11] [32] [45] and S, the proportion of the population who are susceptible to infection, and setting this product to be equal to 1:

S can be rewritten as (1 − p), where p is the proportion of the population that is immune so that p + S equals one. Then, the equation can be rearranged to place p by itself as follows:

With p being by itself on the left side of the equation, it can be renamed as pc, representing the critical proportion of the population needed to be immune to stop the transmission of disease, which is the same as the "herd immunity threshold" HIT. [11] R0 functions as a measure of contagiousness, so low R0 values are associated with lower HITs, whereas higher R0s result in higher HITs. [32] [45] For example, the HIT for a disease with an R0 of 2 is theoretically only 50%, whereas a disease with an R0 of 10 the theoretical HIT is 90%. [32]

When the effective reproduction number Re of a contagious disease is reduced to and sustained below 1 new individual per infection, the number of cases occurring in the population gradually decreases until the disease has been eliminated. [11] [32] [75] If a population is immune to a disease in excess of that disease's HIT, the number of cases reduces at a faster rate, outbreaks are even less likely to happen, and outbreaks that occur are smaller than they would be otherwise. [2] [11] If the effective reproduction number increases to above 1, then the disease is neither in a steady state nor decreasing in incidence, but is actively spreading through the population and infecting a larger number of people than usual. [46] [75]

An assumption in these calculations is that populations are homogeneous, or well-mixed, meaning that every individual is equally likely to come into contact with any other individual, when in reality populations are better described as social networks as individuals tend to cluster together, remaining in relatively close contact with a limited number of other individuals. In these networks, transmission only occurs between those who are geographically or physically close to one another. [2] [45] [46] The shape and size of a network is likely to alter a disease's HIT, making incidence either more or less common. [32] [45]

In heterogeneous populations, R0 is considered to be a measure of the number of cases generated by a "typical" infectious person, which depends on how individuals within a network interact with each other. [2] Interactions within networks are more common than between networks, in which case the most highly connected networks transmit disease more easily, resulting in a higher R0 and a higher HIT than would be required in a less connected network. [2] [46] In networks that either opt not to become immune or are not immunized sufficiently, diseases may persist despite not existing in better-immunized networks. [46]

Overshoot Edit

The cumulative proportion of individuals who get infected during the course of a disease outbreak can exceed the HIT. This is because the HIT does not represent the point at which the disease stops spreading, but rather the point at which each infected person infects fewer than one additional person on average. When the HIT is reached, the number of additional infections does not immediately drop to zero. The excess of the cumulative proportion of infected individuals over the theoretical HIT is known as the overshoot. [76] [77] [78]

Vaccination Edit

The primary way to boost levels of immunity in a population is through vaccination. [2] [79] Vaccination is originally based on the observation that milkmaids exposed to cowpox were immune to smallpox, so the practice of inoculating people with the cowpox virus began as a way to prevent smallpox. [44] Well-developed vaccines provide protection in a far safer way than natural infections, as vaccines generally do not cause the diseases they protect against and severe adverse effects are significantly less common than complications from natural infections. [80] [81]

The immune system does not distinguish between natural infections and vaccines, forming an active response to both, so immunity induced via vaccination is similar to what would have occurred from contracting and recovering from the disease. [82] To achieve herd immunity through vaccination, vaccine manufacturers aim to produce vaccines with low failure rates, and policy makers aim to encourage their use. [79] After the successful introduction and widespread use of a vaccine, sharp declines in the incidence of diseases it protects against can be observed, which decreases the number of hospitalizations and deaths caused by such diseases. [83] [84] [85]

Assuming a vaccine is 100% effective, then the equation used for calculating the herd immunity threshold can be used for calculating the vaccination level needed to eliminate a disease, written as Vc. [2] Vaccines are usually imperfect however, so the effectiveness, E, of a vaccine must be accounted for:

From this equation, it can be observed that if E is less than (1 − 1/R0), then it is impossible to eliminate a disease, even if the entire population is vaccinated. [2] Similarly, waning vaccine-induced immunity, as occurs with acellular pertussis vaccines, requires higher levels of booster vaccination to sustain herd immunity. [2] [23] If a disease has ceased to be endemic to a population, then natural infections no longer contribute to a reduction in the fraction of the population that is susceptible. Only vaccination contributes to this reduction. [11] The relation between vaccine coverage and effectiveness and disease incidence can be shown by subtracting the product of the effectiveness of a vaccine and the proportion of the population that is vaccinated, pv, from the herd immunity threshold equation as follows:

It can be observed from this equation that, all other things being equal ("ceteris paribus"), any increase in either vaccine coverage or vaccine effectiveness, including any increase in excess of a disease's HIT, further reduces the number of cases of a disease. [11] The rate of decline in cases depends on a disease's R0, with diseases with lower R0 values experiencing sharper declines. [11]

Vaccines usually have at least one contraindication for a specific population for medical reasons, but if both effectiveness and coverage are high enough then herd immunity can protect these individuals. [16] [19] [22] Vaccine effectiveness is often, but not always, adversely affected by passive immunity, [86] [87] so additional doses are recommended for some vaccines while others are not administered until after an individual has lost his or her passive immunity. [18] [22]

Passive immunity Edit

Individual immunity can also be gained passively, when antibodies to a pathogen are transferred from one individual to another. This can occur naturally, whereby maternal antibodies, primarily immunoglobulin G antibodies, are transferred across the placenta and in colostrum to fetuses and newborns. [88] [89] Passive immunity can also be gained artificially, when a susceptible person is injected with antibodies from the serum or plasma of an immune person. [82] [90]

Protection generated from passive immunity is immediate, but wanes over the course of weeks to months, so any contribution to herd immunity is temporary. [7] [82] [91] For diseases that are especially severe among fetuses and newborns, such as influenza and tetanus, pregnant women may be immunized in order to transfer antibodies to the child. [16] [92] [93] In the same way, high-risk groups that are either more likely to experience infection, or are more likely to develop complications from infection, may receive antibody preparations to prevent these infections or to reduce the severity of symptoms. [90]

Herd immunity is often accounted for when conducting cost–benefit analyses of vaccination programs. It is regarded as a positive externality of high levels of immunity, producing an additional benefit of disease reduction that would not occur had no herd immunity been generated in the population. [94] [95] Therefore, herd immunity's inclusion in cost–benefit analyses results both in more favorable cost-effectiveness or cost–benefit ratios, and an increase in the number of disease cases averted by vaccination. [95] Study designs done to estimate herd immunity's benefit include recording disease incidence in households with a vaccinated member, randomizing a population in a single geographic area to be vaccinated or not, and observing the incidence of disease before and after beginning a vaccination program. [96] From these, it can be observed that disease incidence may decrease to a level beyond what can be predicted from direct protection alone, indicating that herd immunity contributed to the reduction. [96] When serotype replacement is accounted for, it reduces the predicted benefits of vaccination. [95]

The term "herd immunity" was coined in 1923. [97] Herd immunity was first recognized as a naturally occurring phenomenon in the 1930s when A. W. Hedrich published research on the epidemiology of measles in Baltimore, and took notice that after many children had become immune to measles, the number of new infections temporarily decreased, including among susceptible children. [98] [10] In spite of this knowledge, efforts to control and eliminate measles were unsuccessful until mass vaccination using the measles vaccine began in the 1960s. [10] Mass vaccination, discussions of disease eradication, and cost–benefit analyses of vaccination subsequently prompted more widespread use of the term herd immunity. [2] In the 1970s, the theorem used to calculate a disease's herd immunity threshold was developed. [2] During the smallpox eradication campaign in the 1960s and 1970s, the practice of ring vaccination, to which herd immunity is integral, began as a way to immunize every person in a "ring" around an infected individual to prevent outbreaks from spreading. [99]

Since the adoption of mass and ring vaccination, complexities and challenges to herd immunity have arisen. [2] [79] Modeling of the spread of infectious disease originally made a number of assumptions, namely that entire populations are susceptible and well-mixed, which is not the case in reality, so more precise equations have been developed. [2] In recent decades, it has been recognized that the dominant strain of a microorganism in circulation may change due to herd immunity, either because of herd immunity acting as an evolutionary pressure or because herd immunity against one strain allowed another already-existing strain to spread. [36] [35] Emerging or ongoing fears and controversies about vaccination have reduced or eliminated herd immunity in certain communities, allowing preventable diseases to persist in or return to these communities. [12] [13] [14]