BT 13: history, types and functions of immunity and vaccines

History of immunology

Written records from over 2,500 years ago reveal an awareness that persons who recover from certain diseases cannot contract them again. For example, one of the earliest accounts of immunity comes from China, where they not only noticed that people who recovered from smallpox were resistant to reinfection, but also that the various epidemics varied in their severity - one year being usually fatal and other years being much milder. Chinese physicians therefore deliberately infected healthy people with material (crusts or fluid) taken from cases of mild smallpox, thus rendering them resistant during the serious epidemics. Although this practice was introduced to Europe in the early 1700's it was at best a risky procedure, since people occasionally died from these "mild" infections! It was not until 1796 that Edward Jenner, an English country physician, put into practice a well known countryside observation that the beauty of milk maids was often due to the fact that they rarely contracted smallpox since they almost invariably caught cowpox which made them immune to smallpox. This procedure was the first example of vaccination (from Vacca which is the latin for cow), a term later coined by Louis Pasteur in honor of Jenners contribution to include any procedure which induces immunity. Nowadays vaccination is synonymous with immunization.

The next major step towards an understanding of immunology was not possible until the late 1800's when Pasteur in France, and Koch in Germany demonstrated how microbes cause disease. The initial studies on vaccination using a defined microbe were made in Pasteur's laboratory where they were working on Chicken Cholera (Pasteurella aviseptica). Pasteur, on returning from holiday, tried to use an old culture of the bacilli, only to discover that it was apparently ineffective in producing the disease. Being a careful person (or maybe mean!!) he tried to reuse the animals with a fresh isolate of the microbe, and discovered that the old "attenuated" culture had induced immunity in the chickens to challenge with the virulent organisms. This finding may have prompted Pasteur to make his famous epigram that "chance favors only the prepared mind". Pasteur later extended these findings to Anthrax and finally to Rabies, which after experiments in animals was given to a small boy who survived and became the gate keeper of the Pasteur Institute!

In 1883 a Russian, Eli Metchnikoff first demonstrated the role of phagocytic cells in the immune process. Again like the discovery of Pasteur, it occurred while he was on holiday (actually he was unemployed, since he had resigned from his job!) Metchnikoff was a Zoologist, and since he was on holiday near the sea he decided to examine some starfish larvae that he found. He pushed a splinter of wood into one of the animals and was surprised to see that many phagocytic cells surrounded the "foreign object". His subsequent investigations elucidated much of the basic role of phagocytic cells in dealing with infections. Much of Metchnikoff`s work was carried out at the Pasteur Institute where Roux and Yersin had isolated a toxin from diphtheria bacilli which was responsible for many of the symptoms of this disease.

The next major step forward was in the discovery (initially by Von Behring in Robert Kochs laboratory in Berlin) that immunity could be passively transferred using serum taken from a previously immunized animal. This serum component became known as antibodies. The next step was the discovery that antibodies could not only protect an individual from infection, but could directly lyse (in vitro) bacteria cultures such as cholera . Soon afterwards two other phenomena of antibacterial serum were demonstrated, precipitation and agglutination. These discoveries soon lead to the development of serotherapy where serum from horses immunized with organism such as diphtheria and tetanus would cure people if administered soon after the infection developed. In 1899 Bordet discovered that immune serum contained two components, a heat stable one that had the activity of agglutination and precipitation (the antibody activity), and a heat labile one that was responsible for bacterial lysis (later known as complement). At the beginning of the 1900's Landsteiner demonstrated that antibodies could not only be produced against complex organism and proteins but also against simple organic chemical such as diamino benzene sulphonate.

The development of these two different approaches to immunity, the cells of Metchnikoff, and the antibodies of the German investigators lead to considerable controversy as to which was the most important in immunity. This question was largely settled in the early 1900's when it became clear that both cellular and humoral factors were involved in immune protection, and that immune serum could also act together with phagocytic cells to increase phagocytosis (opsonization).

Between 1903 and 1910 the role of histamine in the phenomena of anaphylaxis was elucidated, initially by Riche and Portier, and later by Dale and his colleagues. Up until the late 1940's the actual substance responsible for antibody activity was not known until the development of electrophoretic protein separation techniques by Tiselius in 1939. He demonstrated that the gamma globulin fraction of serum increased in concentration following immunization and that antibody activity was confined to this fraction.

The next 50 years saw the development and expansion of immunology into the major discipline it is today

Timeline of immunology:

• 1549 - The earliest account of inoculation of smallpox (variolation) occurs in Wan Quan's (1499–1582) Douzhen Xinfa

• 1718 – Lady Mary Wortley Montagu, the wife of the British ambassador to Constantinople, observed the positive effects of variolation on the native population and had the technique performed on her own children.

• 1796 – First demonstration of vaccination smallpox vaccination (Edward Jenner)• 1837 – Description of the role of microbes in putrefaction and fermentation (Theodore

Schwann)• 1838 – Confirmation of the role of yeast in fermentation of sugar to alcohol (Charles

Cagniard-Latour)

• 1840 – Proposal of the germ theory of disease (Jakob Henle)• 1850 – Demonstration of the contagious nature of puerperal fever (childbed fever)

(Ignaz Semmelweis)• 1857-1870 – Confirmation of the role of microbes in fermentation (Louis Pasteur)• 1862 – phagocytosis (Ernst Haeckel)• 1867 – Aseptic practice in surgery using carbolic acid (Joseph Lister)• 1876 – Demonstration that microbes can cause disease-anthrax (Robert Koch)• 1877 – Mast cells (Paul Ehrlich)• 1878 – Confirmation and popularization of the germ theory of disease (Louis Pasteur)• 1880 – 1881 -Theory that bacterial virulence could be attenuated by culture in vitro and

used as vaccines. Proposed that live attenuated microbes produced immunity by depleting host of vital trace nutrients. Used to make chicken cholera and anthrax "vaccines" (Louis Pasteur)

• 1883 – 1905 – Cellular theory of immunity via phagocytosis by macrophages and microphages (polymorhonuclear leukocytes) (Elie Metchnikoff)

• 1885 – Introduction of concept of a "therapeutic vaccination". Report of a live "attenuated" vaccine for rabies (Louis Pasteur).

• 1888 – Identification of bacterial toxins (diphtheria bacillus) (Pierre Roux and Alexandre Yersin)

• 1888 – Bactericidal action of blood (George Nuttall)• 1890 – Demonstration of antibody activity against diphtheria and tetanus toxins.

Beginning of humoral theory of immunity. (Emil von Behring) and (Kitasato Shibasaburō)

• 1891 – Demonstration of cutaneous (delayed type) hypersensitivity (Robert Koch)• 1893 – Use of live bacteria and bacterial lysates to treat tumors-"Coley's Toxins"

(William B. Coley)• 1894 – Bacteriolysis (Richard Pfeiffer)• 1896 – An antibacterial, heat-labile serum component (complement) is described (Jules

Bordet)• 1900 – Antibody formation theory (Paul Ehrlich)• 1901 – blood groups (Karl Landsteiner)• 1902 – Immediate hypersensitivity anaphylaxis (Paul Portier) and (Charles Richet)• 1903 – Intermediate hypersensitivity, the "Arthus reaction" (Maurice Arthus)• 1903 – Opsonization• 1905 – "Serum sickness" allergy (Clemens von Pirquet and (Bela Schick)• 1909 – Paul Ehrlich proposes "immune surveillance" hypothesis of tumor recognition

and eradication• 1911 – 2nd demonstration of filterable agent that caused tumors (Peyton Rous)• 1917 – hapten (Karl Landsteiner)• 1921 – Cutaneous allergic reactions (Otto Prausnitz and Heinz Küstner)• 1924 – Reticuloendothelial system• 1938 – Antigen-Antibody binding hypothesis (John Marrack)• 1940 – Identification of the Rh antigens (Karl Landsteiner and Alexander Weiner)• 1942 – Anaphylaxis (Karl Landsteiner and Merill Chase)

• 1942 – Adjuvants (Jules Freund and Katherine McDermott)• 1944 – hypothesis of allograft rejection• 1945 – Coombs Test aka antiglobulin test (AGT)• 1946 – identification of mouse MHC (H2) by George Snell and Peter A. Gorer• 1948 – antibody production in plasma B cells• 1949 – growth of polio virus in tissue culture, neutralization with immune sera, and

demonstration of attenuation of neurovirulence with repetitive passage (John Enders) and (Thomas Weller) and (Frederick Robbins)

• 1951 – vaccine against yellow fever• 1953 – Graft-versus-host disease• 1953 – Validation of immunological tolerance hypothesis• 1957 – Clonal selection theory (Frank Macfarlane Burnet)• 1957 – Discovery of interferon by Alick Isaacs and Jean Lindenmann[2]• 1958–1962 – Discovery of human leukocyte antigens (Jean Dausset and others)• 1959–1962 – Discovery of antibody structure (independently elucidated by Gerald

Edelman and Rodney Porter)• 1959 – Discovery of lymphocyte circulation (James Gowans)• 1960 – Discovery of lymphocyte "blastogenic transformation" and proliferation in

response to mitogenic lectins-phytohemagglutinin (PHA) (Peter Nowell)• 1961-1962 Discovery of thymus involvement in cellular immunity (Jacques Miller)• 1961- Demonstration that glucocorticoids inhibit PHA-induced lymphocyte

proliferation (Peter Nowell)• 1963 – Development of the plaque assay for the enumeration of antibody-forming cells

in vitro by Niels Jerne and Albert Nordin• 1963 Gell and Coombs classification of hypersensitivity• 1964-1968 T and B cell cooperation in immune response• 1965 – Discovery of lymphocyte mitogenic activity, "blastogenic factor" (Shinpei

Kamakura) and (Louis Lowenstein) (J. Gordon) and (L.D. MacLean)• 1965 – Discovery of "immune interferon" (gamma interferon) (E.F. Wheelock)• 1965 – Secretory immunoglobulins• 1967 – Identification of IgE as the reaginic antibody (Kimishige Ishizaka)• 1968 – Passenger leukocytes identified as significant immunogens in allograft rejection

(William L. Elkins and Ronald D. Guttmann)• 1969 – The lymphocyte cytolysis Cr51 release assay (Theodore Brunner) and (Jean-

Charles Cerottini)• 1971 – Peter Perlmann and Eva Engvall at Stockholm University invented ELISA• 1972 – Structure of the antibody molecule• 1973 – Dendritic Cells described by Ralph M. Steinman• 1974 - Immune Network Hypothesis (Niels Jerne)• 1974 – T-cell restriction to MHC (Rolf Zinkernagel and (Peter C. Doherty)• 1975 – Generation of monoclonal antibodies (Georges Köhler) and (César Milstein)[3]• 1975 - Discovery of Natural Killer cells (Rolf Kiessling, Eva Klein, Hans Wigzell)• 1976 – Identification of somatic recombination of immunoglobulin genes (Susumu

Tonegawa)

• 1980-1983 – Discovery and characterization of interleukins, 1 and 2 IL-1 IL-2 (Robert Gallo, Kendall A. Smith, Tadatsugu Taniguchi)

• 1983 – Discovery of the T cell antigen receptor TCR (Ellis Reinherz) (Philippa Marrack) and (John Kappler)[4] (James Allison)

• 1983 – Discovery of HIV (Luc Montagnier)• 1985-1987 – Identification of genes for the T cell receptor• 1986 – Hepatitis B vaccine produced by genetic engineering• 1986 – Th1 vs Th2 model of T helper cell function (Timothy Mosmann)• 1988 – Discovery of biochemical initiators of T-cell activation: CD4- and CD8-p56lck

complexes (Christopher E. Rudd)• 1990 – Gene therapy for SCID• 1991 – Role of peptide for MHC Class II structure (Scheherazade Sadegh-Nasseri &

Ronald N. Germain)• 1992- Discovery of transitional B cells (David Allman & Michael Cancro) [5][6]• 1994 – 'Danger' model of immunological tolerance (Polly Matzinger)• 1995 – Regulatory T cells (Shimon Sakaguchi)• 1995 – Dendritic cell vaccine trial reported by Mukherji et al.• 1996-1998 – Identification of Toll-like receptors• 2000-Discovery of M1 and M2 macrophage subsets (Charles Mills)[7]• 2001 – Discovery of FOXP3 – the gene directing regulatory T cell development• 2005 – Development of human papillomavirus vaccine (Ian Frazer)• 2010 – An immune checkpoint inhibitor, ipilimumab (anti-CTLA-4) is approved by the

FDA for treatment of stage IV melanoma• 2011 – Carl June reports a successful use of CAR T-cells for the treatment of CD19+

malignancies• 2014 – The second immune checkpoint inhibitor, pembrolizumab (anti-PD-1) is

approved by the FDA for the treatment of melanoma

Types of immunity

All of us are exposed to a number of infections in our day to day life, but some agents affect our body whereas others do not. To find out why, read this article about the defense mechanism of human body.

Immunity is the ability of human body to fight against the disease causing organisms. The human immune system has two types of immunity:

Innate immunityAcquired immunity

Innate ImmunityThe innate immune system is the type of immunity that is present naturally in the child at the time of birth. These natural protectors are already present in human body.The first and the foremost important barrier which prevents entry of the harmful micro-organisms in human body is skin. Skin acts as a barrier to the entry of harmful micro-organism in many vital organs of the body. Natural secretions of our body also help to prevent microbial growth in our body.

Vital systems such as respiratory, gastrointestinal, and urogenital are prevented by the mucus coating of the epithelium lining these systems. fluids which are protective in our body are acid in the stomach, saliva in the mouth and tears from the eyes.White blood cells present in human blood also protect the body from many infections. Macrophages in tissues help in the destruction of harmful microbes entering into the body.Every one of us suffers from one or other type of viral infection in our life. These viral infected cells produce special proteins called interferon to protect healthy cells from further viral infection.

Acquired ImmunityAcquired immunity, also called the adaptive immune system, involves two processes. The primary response is produced when our body encounters a pathogen for the first time. This is a mild response produced by our body. The secondary response is produced when our body encounters the same pathogen for the second time. This secondary response is highly intensified.These responses are produced in our body by two types of lymphocytes in our blood. These two special lymphocytes are B-lymphocytes and T-lymphocytes. Whenever a foreign substance enters our body, B-lymphocytes produce proteins to fight them. These proteins are called immunoglobulin or antibodies. T-cells do not produce such proteins, but they help B-lymphocytes to produce them. There are many different kind of antibodies produced in our body. Some of the important antibodies present in human body are IgA, IgM, IgE and IgG.

Functions of immune systemThe Immune System Fights Infections caused by various pathogens:BacteriaOur bodies are covered with bacteria and our environment contains bacteria on most surfaces. Our skin and internal mucous membranes act as physical barriers to help prevent infection. When the skin or mucous membranes are broken due to disease, inflammation or injury, bacteria can enter the body. Infecting bacteria are usually coated with complement and antibodies once they enter the tissues, and this allows neutrophils to easily recognize the bacteria as something foreign. Neutrophils then engulf the bacteria and destroy them (Figure 4).

When the antibodies, complement, and neutrophils are all functioning normally, this process effectively kills the bacteria. However, when the number of bacteria is overwhelming or there are defects in antibody production, complement, and/or neutrophils, recurrent bacterial infections can occur.

VirusesMost of us are exposed to viruses frequently. The way our bodies defend against viruses is different than how we fight bacteria. Viruses can only survive and multiply inside our cells. This allows them to “hide” from our immune system. When a virus infects a cell, the cell releases cytokines to alert other cells to the infection. This “alert” generally prevents other cells from becoming infected. Unfortunately, many viruses can outsmart this protective strategy, and they continue to spread the infection.

Circulating T-cells and NK cells become alerted to a viral invasion and migrate to the site where they kill the particular cells that are harboring the virus. This is a very destructive mechanism to kill the virus because many of our own cells can be sacrificed in the process. Nevertheless, it is an efficient process to eradicate the virus.

At the same time the T-lymphocytes are killing the virus, they are also instructing the B-lymphocytes to make antibodies. When we are exposed to the same virus a second time, the antibodies help prevent the infection. Memory T-cells are also produced and rapidly respond to a second infection, which also leads to a milder course of the infection.

A. Neutrophil (Phagocytic Cell) Engages Bacteria (Microbe): The microbe is coated with specific antibody and complement. The phagocytic cell then begins its attack on the microbe by attaching to the antibody and complement molecules.

B. Phagocytosis of the Microbe: After attaching to the microbe, the phagocytic cell begins to ingest the microbe by extending itself around the microbe and engulfing it.

C. Destruction of the Microbe: Once the microbe is ingested, bags of enzymes or chemicals are discharged into the vacuole where they kill the microbe.

The Immune System and Primary Immunodeficiency DiseasesImmune deficiencies are categorized as primary immune deficiencies or secondary immune deficiencies. Primary immune deficiencies are “primary” because the immune system is the primary cause and most are genetic defects that may be inherited. Secondary immune deficiencies are so called because they have been caused by other conditions.

Secondary immune deficiencies are common and can occur as part of another disease or as a consequence of certain medications. The most common secondary immune deficiencies are caused by aging, malnutrition, certain medications and some infections, such as HIV.

The most common medications associated with secondary immune deficiencies are

chemotherapy agents and immune suppressive medications, cancer, transplanted organ rejection or autoimmune diseases. Other secondary immune deficiencies include protein losses in the intestines or the kidneys. When proteins are lost, antibodies are also lost, leading to low immune globulins or low antibody levels. These conditions are important to recognize because, if the underlying cause can be corrected, the function of the immune system can be improved and/or restored.

Regardless of the root cause, recognition of the secondary immune deficiency and provision of immunologic support can be helpful. The types of support offered are comparable to what is used for primary immune deficiencies.

The primary immunodeficiency diseases are a group of disorders caused by basic defects in immune function that are intrinsic to, or inherent in, the cells and proteins of the immune system. There are more than 200 primary immunodeficiency diseases. Some are relatively common, while others are quite rare. Some affect a single cell or protein of the immune system and others may affect two or more components of the immune system.

Although primary immunodeficiency diseases may differ from one another in many ways, they share one important feature. They all result from a defect in one or more of the elements or functions of the normal immune system such as T-cells, B-cells, NK cells, neutrophils, monocytes, antibodies, cytokines or the complement system. Most of them are inherited diseases and may run in families, such as X-Linked Agammaglobulinemia (XLA) or Severe Combined Immune Deficiency (SCID). Other primary immunodeficiencies, such as Common Variable Immune Deficiency (CVID) and Selective IgA Deficiency are not always inherited in a clear-cut or predictable fashion. In these disorders, the cause is unknown, but it is believed that the interaction of genetic and environmental factors may play a role in their causation.

Because the most important function of the immune system is to protect against infection, people with primary immunodeficiency diseases have an increased susceptibility to infection. This may include too many infections, infections that are difficult to cure, unusually severe infections, or infections with unusual organisms. The infections may be located anywhere in the body. Common sites are the sinuses (sinusitis), the bronchi (bronchitis), the lung (pneumonia) or the intestinal tract (infectious diarrhea).

Another function of the immune system is to discriminate between the healthy tissue (“self”) and foreign material (“non-self”). Examples of foreign material can be microorganisms, pollen or even a transplanted kidney from another individual. In some immunodeficiency diseases, the immune system is unable to discriminate between self and non-self. In these cases, in addition to an increased susceptibility to infection, people with primary immunodeficiencies may also have autoimmune diseases in which the immune system attacks their own cells or tissues as if these cells were foreign, or non-self.

There are also a few types of primary immunodeficiencies in which the ability to respond to an infection is largely intact, but the ability to regulate that response is abnormal.

Examples of this are autoimmune lymphoproliferative syndrome (ALPS) and IPEX (an X-linked syndrome of immunodeficiency, polyendocrinopathy and enteropathy).

Primary immunodeficiency diseases can occur in individuals of any age. The original descriptions of these diseases were in children. However, as medical experience has grown, many adolescents and adults have been diagnosed with primary immunodeficiency diseases. This is partly due to the fact that some of the disorders, such as CVID and Selective IgA Deficiency, may have their initial clinical presentation in adult life. Effective therapy exists for several of the primary immunodeficiencies, and many people with these disorders can live relatively normal lives.

Primary immunodeficiency diseases were initially felt to be very rare. However, recent research has indicated that as a group they are more common than originally thought. It is estimated that as many as 1 in every 1,200–2,000 people may have some form of primary immunodeficiency.

Vaccines:A vaccine is a biological preparation that provides active acquired immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing micro-organism and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and keep a record of it, so that the immune system can more easily recognize and destroy any of these micro-organisms that it later encounters.

Vaccines are dead or inactivated organisms or purified products derived from them.

There are several types of vaccines in use. These represent different strategies used to try to reduce risk of illness, while retaining the ability to induce a beneficial immune response.

InactivatedSome vaccines contain inactivated, but previously virulent, micro-organisms that have been destroyed with chemicals, heat, radiation, or antibiotics. Examples are influenza, cholera, bubonic plague, polio, hepatitis A, and rabies.

AttenuatedSome vaccines contain live, attenuated microorganisms. Many of these are active viruses that have been cultivated under conditions that disable their virulent properties, or that use closely related but less dangerous organisms to produce a broad immune response. Although most attenuated vaccines are viral, some are bacterial in nature. Examples include the viral diseases yellow fever, measles, rubella, and mumps, and the bacterial disease typhoid. The live Mycobacterium tuberculosis vaccine developed by Calmette and Guérin is not made of a contagious strain, but contains a virulently modified strain called "BCG" used to elicit an immune response to the vaccine. The live attenuated vaccine-containing strain Yersinia pestis EV is used for plague immunization. Attenuated vaccines have some advantages and disadvantages. They typically provoke more durable immunological responses and are the preferred type for healthy adults. But they may not

be safe for use in immunocompromised individuals, and may rarely mutate to a virulent form and cause disease.

ToxoidToxoid vaccines are made from inactivated toxic compounds that cause illness rather than the micro-organism. Examples of toxoid-based vaccines include tetanus and diphtheria. Toxoid vaccines are known for their efficacy. Not all toxoids are for micro-organisms; for example, Crotalus atrox toxoid is used to vaccinate dogs against rattlesnake bites.

SubunitProtein subunit – rather than introducing an inactivated or attenuated micro-organism to an immune system (which would constitute a "whole-agent" vaccine), a fragment of it can create an immune response. Examples include the subunit vaccine against Hepatitis B virus that is composed of only the surface proteins of the virus (previously extracted from the blood serum of chronically infected patients, but now produced by recombination of the viral genes into yeast), the virus-like particle (VLP) vaccine against human papillomavirus (HPV) that is composed of the viral major capsid protein, and the hemagglutinin and neuraminidase subunits of the influenza virus. Subunit vaccine is being used for plague immunization.

ConjugaConjugate – certain bacteria have polysaccharide outer coats that are poorly immunogenic. By linking these outer coats to proteins (e.g., toxins), the immune system can be led to recognize the polysaccharide as if it were a protein antigen. This approach is used in the Haemophilus influenzae type B vaccine.

Experimental

Electroporation System for experimental "DNA vaccine" deliveryA number of innovative vaccines are also in development and in use:

• Dendritic cell vaccines combine dendritic cells with antigens in order to present the antigens to the body's white blood cells, thus stimulating an immune reaction. These vaccines have shown some positive preliminary results for treating brain tumors and are also tested in malignant melanoma.

• Recombinant Vector – by combining the physiology of one micro-organism and the DNA of the other, immunity can be created against diseases that have complex infection processes

• DNA vaccination – an alternative, experimental approach to vaccination called DNA vaccination, created from an infectious agent's DNA, is under development. The proposed mechanism is the insertion (and expression, enhanced by the use of electroporation, triggering immune system recognition) of viral or bacterial DNA into human or animal cells. Some cells of the immune system that recognize the proteins expressed will mount an attack against these proteins and cells expressing them. Because these cells live for a very long time, if the pathogen that normally expresses these proteins is encountered at a later time, they will be attacked instantly by the immune system. One potential advantage of DNA vaccines is that they are very easy to produce and store. As of 2015, DNA vaccination is still experimental and is not approved for human use.

• T-cell receptor peptide vaccines are under development for several diseases using models of Valley Fever, stomatitis, and atopic dermatitis. These peptides have been shown to modulate cytokine production and improve cell mediated immunity.

• Targeting of identified bacterial proteins that are involved in complement inhibition would neutralize the key bacterial virulence mechanism.

While most vaccines are created using inactivated or attenuated compounds from micro-organisms, synthetic vaccines are composed mainly or wholly of synthetic peptides, carbohydrates, or antigens.

ValenceVaccines may be monovalent (also called univalent) or multivalent (also called polyvalent). A monovalent vaccine is designed to immunize against a single antigen or single microorganism. A multivalent or polyvalent vaccine is designed to immunize against two or more strai ns of the same microorganism, or against two or more microorganisms. The valency of a multivalent vaccine may be denoted with a Greek or Latin prefix (e.g., tetravalent or quadrivalent). In certain cases a monovalent vaccine may be preferable for rapidly developing a strong immune response.

HeterotypicAlso known as Heterologous or "Jennerian" vaccines these are vaccines that are pathogens of other animals that either do not cause disease or cause mild disease in the organism being treated. The classic example is Jenner's use of cowpox to protect against smallpox. A current example is the use of BCG vaccine made from Mycobacterium bovis to protect against human tuberculosis.