The immune system and vaccination

Overview of the immune system

Our environment contains a great variety of infectious microbes – viruses, bacteria, fungi, protozoa and multi cellular parasites which can cause disease, and if they multiply unchecked, eventually kill their host. Most infections in normal individuals are short-lived leaving little damage. This is due to the immune system, which combats infectious agents.

Immunology is a complicated subject, and a detailed discussion of it is beyond the scope of these web pages. However, an understanding of the basic function of the immune system is useful in order to understand both how vaccines work and the basis of recommendations for their use.

The immune system is a complex system of interacting cells whose primary purpose is to identify foreign (“non-self”) substances referred to as antigens. The immune system provides protection from infectious disease by identify most of these microbes as foreign. Immunity is generally very specific to a single organism or group of closely related organisms. Because microorganisms come in many different forms, a wide variety of immune responses are required to deal with each type of infection.

The immune system could be described as a sensory organ much like vision, hearing and touch.  Instead of recognising light, sound waves or large objects, the immune system recognises molecular shapes - only a few amino acids in length.  Those shapes lacking a self identification tag may be recognised as foreign, triggering a series of events that eventuate in an immune response.
This module discusses the various ways in which the body protects itself against infection and how vaccination works with these processes. The description that follows is simplified; however there are many excellent immunology textbooks and websites are available to provide additional detail and are recommended at the end of this module. Keep in mind that the immune system is like an octopus – therefore difficult to cover in a linear page-by-page fashion.

Antigen

An antigen is a substance that stimulates an immune response, especially the production of antibodies.  Antigens are usually proteins or polysaccharides (long chains of sugar molecules that make up the cell wall of certain bacteria), but can be any type of molecule, including small molecules (haptens) coupled to a protein (carrier).

Antigens induce immunity. The immune system develops a defence against foreign antigens. This defence is known as the immune response and usually involves the production of protein molecules, called antibodies (or immunoglobulins or Ig), and of specific cells (also known as cell-mediated immunity) whose purpose is to facilitate the elimination of foreign substances. The most effective immune responses are generally produced in response to a live organism. However, an antigen does not necessarily have to be a live natural infection with a virus or bacteria, to produce an excellent immune response. Some proteins, such as hepatitis B surface antigen, are easily recognised by the immune system. Other material, such as polysaccharides, are less effective antigens and the immune response may not provide as good protection.

The part of the antigen that antibody binds to is called the antigenic determinant, antigenic site or epitope.  A given organism contains many different antigens.  Viruses can contain as few as three (polyoma virus) to more than 100 (herpes and pox), whereas protozoa, fungi and bacteria contain hundreds to thousands.

Non s​pecific defences

In the first instance the exterior defences of the body present an effective barrier to most organisms and very few infectious agents can penetrate the intact skin. There are also a variety of biochemical and physical barriers. The body also tolerates a number of commensal organisms, which compete effectively with many potential pathogens.
Examples of non-specific immunity:

  • Skin - a great physical barrier, like a waterproof wall.
  • Mucus – sticky, germs get stuck in it, it also has antibody in it.
  • Cilia – hairs that pass debris up throat and out to the nostrils.
  • Lysosyme - an enzyme present in tears that breaks down bacteria.
  • Phagocytes – various cells that scavenge up and engulf cell debris.
  • Commensal bacteria- Non-harmful bacteria on skin and gut that leave little or no room for harmful bacteria to attach, and limited nutrients for them to grow.
  • Acid - in stomach and urine, make it hard for any germs to survive.
  • Fever – elevates the temperature making it difficult for infectious agents to survive.

Non-specific defences are present in all normal individuals. The non-specific system alerts the specific arm of the immune system to infection.  In contrast to the non specific arm, some of the specific defence systems require time to develop following exposure to infection. Specific immunity may be acquired naturally by infection or artificially by immunisation. The body prevents infection by a number of non-specific and specific mechanisms working on their own or together.
When we discuss the immune system in terms of vaccination we usually refer to the Specific arm of the immune system, also known as adaptive immunity.

Specific immunity

Active and passive immunity

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

Active immunity is protection that is produced by the person’s own immune system. This type of immunity is usually permanent.

Passive immunity is protection by products produced by an animal or human, and transferred to another human, usually by injection. Passive immunity often provides effective protection, but this protection wanes (disappears) with time, usually a few weeks or months.

Passive immunity is the transfer of antibody produced by one human or other animal to another. Passive immunity provides protection against some infections, but this 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 its mother. Antibodies are transported across the placenta during the last 1-2 months of pregnancy. These antibodies will protect the infant from certain diseases for up to a year. Protection is better against some diseases (e.g., measles, rubella, tetanus) than others (e.g., polio, pertussis).
Active immunity is stimulation of the immune system to produce antigen-specific humoral (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 have the natural disease. In general, once persons recover from an infectious disease, they will be immune to those diseases for the rest of their lives. Pertussis is an exception.

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 cells (memory B-cells) continue to circulate in the blood (and also reside in the bone marrow) for many years. Upon re-exposure to the antigen, these memory cells begin to replicate and produce antibody very rapidly to re-establish protection.
Another way to produce active immunity is by vaccination. Vaccines interact with the immune system and often produce an immune response similar to that produced by the natural infection, but do not subject the recipient to the disease and its potential complications. Vaccines produce immunologic memory similar to that acquired by having the natural disease.

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

Specific (adaptive) immunity

Any immune response involves, firstly, recognition of the pathogen or other foreign material, and secondly, a reaction to eliminate it.
Broadly, the different types of immune response fall into two categories; innate (non adaptive) and adaptive immune responses. The important difference between these is that the adaptive immune response is highly specific for a particular pathogen. Moreover, although innate response does not alter on repeated exposure to a given infectious agent, the adaptive response improves with each successive encounter. In effect the adaptive immune system ‘remembers’ the infection agent and can prevent it from causing disease later. For example diseases such as measles and diphtheria induce adaptive immunity which generates lifelong immunity following infection. The two key features of the adaptive immune response are thus specificity and memory.

In order to understand the mechanics of immunity it is useful to meet some of the important tissues and cells of the immune system:

The lymphatic system

The lymphatic vessels (or lymphatics) are a network of thin tubes that branch, like blood vessels, into tissues throughout the body. Lymphatic vessels carry lymph, a colorless, watery fluid originating from interstitial fluid (fluid in the tissues). Along this network of vessels are small organs called lymph nodes. Clusters of lymph nodes are found in the underarms, groin, neck, chest, and abdomen. The lymphatic system, which transports infection-fighting cells called lymphocytes, is involved in the removal of foreign matter and cell debris by phagocytes (cells that engulf) and is part of the body's immune system. When the body is fighting an infection, these lymphocytes multiply rapidly and produce a characteristic swelling of the lymph nodes. Lymphatic tissue is also found in other parts of the body, including the stomach, intestines, and skin. Other parts of the lymphatic system are the spleen, thymus, tonsils, and bone marrow.

The thymus and bone marrow are the primary lymphatic organs. Lymphocytes are produced by stem cells in the bone marrow and then migrate to either the thymus or bone marrow where they mature. T-lymphocytes undergo maturation in the thymus (hence their name), and B-lymphocytes undergo maturation in the bone marrow. After maturation, both B- and T-lymphocytes circulate in the lymph and accumulate in secondary lymphoid organs, where they await recognition of antigens.

The spleen, lymph nodes, and accessory lymphoid tissue (including the tonsils and appendix) are the secondary lymphoid organs. These organs contain scaffolding that support circulating B and T-lymphocytes and other immune cells like macrophages and dendritic cells. When microorganisms invade the body or the body encounters other antigens (such as pollen), the antigens are transported from the tissue to the lymph. The lymph is carried in the lymph vessels to regional lymph nodes. In the lymph nodes, the macrophages and dendritic cells which have phagocytosed (engulfed) the antigens, process them, and present the antigens to lymphocytes, which can then start producing antibodies or serve as memory cells to recognize the antigens again in the future.

The spleen contains lymphocytes that filter the blood stream rather than the lymphatics. Thus, the spleen has importance in fighting infections that have invaded the blood.

Accessory lymphoid tissues act as barriers along points of entry for infections, such as the lung, the reproductive system, and the gut.

Cells and molecules of the immune system

Immune responses are mediated by a variety of cells, and by the soluble molecules that they secrete. Although the leucocytes are central to all immune responses, other cells also participate, by signalling to the lymphocytes and responding to the cytokines (chemical messengers) released by T lymphocytes and macrophages.

Selected cells and their functions

Leukocytes (White Blood Cells)

B-cells: Lymphocytes normally involved in the production of antibodies to combat infection. They are precursors to plasma cells. During infections, individual B-cell clones multiply and are transformed into plasma cells, which produce large amounts of antibodies against a particular antigen on a foreign microbe. This transformation occurs through interaction with the appropriate CD4 T-helper cells.

T-cells: A class of lymphocytes, so called because they are derived from the thymus and have been through thymic processing. Involved primarily in controlling cell-mediated immune reactions and in the control of B-cell development. The T-cells coordinate the immune system by secreting lymphokine hormones (these are cytokines released by lymphocytes). There are 3 fundamentally different types of T-cells : helper, killer, and suppressor. Each has many subdivisions. T-cells are also called T lymphocytes.

Phagocytes - Mononuclear phagocytes, Neutrophils, Eosinophils. These cells engulf foreign organisms or particles. They form a link between the specific and the non specific arms of the immune system by presenting foreign fragments on their surface to T-cells and B-cells.

Auxiliary cells control inflammation and soluble mediators to the site of infection.  – Basophils and Mast-cells have granules in them that produce inflammation in surrounding tissues. They also release a number of mediators that control the development of immune reactions. Platelets also release inflammatory mediators.

Dendritic cells (DC) are immune cells and present at a low frequency in those tissues which are in contact with the environment: in the skin (where they are often called Langerhans cells) and the lining of nose, lungs, stomach and intestines. Especially in immature state, they can also be found in blood. Once activated, they migrate to the lymphoid tissues where they interact with T-cells and B-cells to initiate and shape the immune response. In certain stages they have long spiky arms, called dendrites, hence the name.

Soluble mediators: A wide variety of molecules are involved in the development of immune responses. These include antibodies, cytokines and compliment (normally present in serum). Although there is a vast array of these molecules, with many functions it is important to be aware of a few as these are important in vaccination.

Antibody

An antibody is a protein used by the immune system to identify and neutralise foreign objects like bacteria and viruses. Each antibody recognises a specific antigen unique to its target. Production of antibodies is referred to as the humoral immune system. The terms antibody and immunoglobulin are often used interchangeably. They are found in the blood and tissue fluids, as well as many secretions. They are synthesised and secreted by plasma cells which are derived from the B-cells of the immune system. B-cells are activated upon binding to their specific antigen and differentiate into plasma cells.

There are five classes of antibody – IgG, IgA, IgM, IgD and IgE. These are all structurally slightly different have a range of functions. Each B-cell can produce only one specific antibody to an antigen, each antibody is highly specific and will bind to only one antigen.

 

  • IgG- This class of antibody is the most important class of immunoglobulin in secondary immune responses. IgG crosses the placenta, conferring protection to the new born and is able to activate the complement system through the classical pathway.
  • IgM is the predominant antibody in the primary immune responses. It can also activate the classical pathway complement.
  • IgA is found primarily in secretions such as breast milk, tears, saliva and mucosal membranes.
  • IgE – evolved to provide protection against certain parasitic infections however in developed countries it is more commonly associated with allergic diseases such as asthma and hayfever.
  • IgD – there is little known about this antibody.

Cytokines

Cytokines are small protein molecules that regulate communication among immune system cells and between immune cells and those of other tissue types. Immune cells, as well as other cell types in response to external stimuli actively secrete these chemicals. Cytokines that are produced by immune cells form a subset known as lymphokines.

The actions of cytokines are complex - the same cytokine can have different effects on a cell depending on the state of the cell. For instance, there are several known cytokines that have both stimulating and suppressing action on lymphocyte cells and immune response.
There are three classes of cytokines. Hundreds of cytokines have been discovered, and the rate of discovery shows no sign of slowing.

Complement

The complement system is derived from many small plasma proteins that form the complex biochemical cascade of the immune system, leading to cell destruction, attraction of immune cells, opsonisation and inflammation; it can mark pathogens for phagocytosis. It consists of more than 35 proteins, 12 which are directly, involved in the complement pathways, while the rest have regulatory functions. There are three biochemical pathways, which activate the complement system: the classical complement pathway, the alternate complement pathway and the mannan-binding lectin pathway.

Opsonisation – antibody and complement

An opsonin is any molecule that acts as a binding enhancer for the process of phagocytosis. During the process of opsonisation, antigens are bound by antibody and/or complement molecules. Phagocytic cells express receptors that bind opsonin molecules. With the antigen coated in these molecules, binding of the antigen to the phagocyte is greatly enhanced. Most phagocytic binding cannot occur without opsonisation of the antigen. Furthermore, opsonisation of the antigen and subsequent binding to an activated phagocyte will cause increased expression of complement receptors on neighboring phagocytes. Examples of opsonin molecules include the IgG antibody and the C3b, C4b, and iC3b components of the complement system. Antibody opsonisation is when antibodies opsonise a pathogen. This opsonisation then makes the pathogen vulnerable for phagocytosis because the antibody interacts with a receptor on the phagocyte. Since antibodies also trigger the complement system, and the complement molecules also bind to the pathogen to opsonise it, the pathogen is then doubly vulnerable since the complement can bind to complement receptors on the phagocyte's surface, and is thus more recognizable as a pathogen.

T-cells

T-cells are a subset of lymphocytes that play a large role in the immune response. The abbreviation "T" stands for thymus, the organ in which their final stage of development occurs.

  • Cytotoxic T-cells (CD8+) destroy infected cells. These cells function as "killer" or cytotoxic cells because they are able to destroy target T-cells which express specific antigens that they recognize. These cells are important in fighting viral infections and tumours.
  • Helper T-cells (CD4+) are "middlemen" in the immune response. When they get activated, they proliferate and secrete cytokines that regulate or "help" effector lymphocyte function. They are known as one of the targets of HIV infection, and the decrease of CD4+ T-cells results in AIDS. Some helper T-cells secrete cytokines that turn off the immune response once an antigen has been eliminated from the body.
  • Regulatory T-cells (also known as suppressor T-cells) suppress activation of the immune system and maintain immune system homeostasis. Failure of regulatory T-cells to function properly may result in autoimmune diseases in which the immunocytes attack healthy cells in the body.

Every effective immune response involves T-cell activation; however, T-cells are especially important in cell-mediated immunity, which is the defense against tumor cells and pathogenic organisms inside body cells. They are also involved in rejection reactions.

CD4 and CD8 refer to the characteristic antigens on the surface of the different sub-types of T-lymphocytes.

Phagocytes

A phagocyte is a cell that ingests (and destroys) foreign matter, such as microorganisms or debris via a process known as phagocytosis, in which these cells ingest and kill offending cells by cellular digestion. These phagocytes are extremely useful as an initial immune system response to tissue damage. There are two types of phagocytes, polymorphonuclear leukocytes and macrophages, and each have an important role in the immune system. While polymorphonuclear leukocytes typically respond swiftly and efficiently to invading pathogens; they are mainly adapted for short term response. Macrophages, on the other hand, are initially slow to react, but are capable of engulfing and digesting almost any foreign agent, and last for a longer period of time.

Polymorphonuclear leukocytes

The polymorphonuclear leukocytes, also known as granulocytes, include neutrophils, eosinophils and basophils. Neutrophils are the most abundant kind of phagocytes. They reduce bacterial cells to their constituent amino acids by ingesting, killing, and digesting them. Eosinophils secrete special enzymes intended to create holes in parasitic worms. Finally, basophils secrete substances such as histamine, in order to extend the period of inflammation.

Macrophages

Macrophages are adapted especially for sustained battles against foreign agents. In addition, they help to clean up and remove damaged tissues. Immature macrophages, which are circulating in the bloodstream, are called monocytes. These macrophages cannot react immediately, but once they have developed, they are often referred to as 'killing machines' they act by phagocytising and destroying anything that isn't recognized as belonging to the body. Macrophages are an important part of the immune response to TB and other mycobacterial diseases (i.e. leprosy).

Phagocytes serve as an important link between the innate and the adaptive arms of the immune systems

Antigen presenting cells

There are a number of cells that are able to take up foreign antigen and “present” it on their surface for the rest of the immune system to see – in particular, T-cells and B-cells.

Cells that are particularly good at presenting antigen are: Dentritic cells, Macrophages and B-cells.

Humoral and​ cellular immune responses – making memory

Immune memory is retained by B-cells and T-cells. Responses by B-cells are humoral, responses by T-cells are called cellular.

Humoral immunity is mediated by secreted antibodies, produced in the cells of the B lymphocyte lineage (B-cell). Secreted antibodies bind to antigens on the surfaces of invading microbes, which flags them for destruction. Humoral immunity refers to antibody production, and all the accessory processes that accompany it.

Cell-mediated immunity is an immune response that does not involve antibodies but rather involves the activation of macrophages and natural killer cells, the production of antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen. Cellular immunity protects the body by:

  • activating antigen-specific cytotoxic T-lymphocytes that are able to destroy body cells displaying epitopes (fragments) of foreign antigen on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumor antigens;
  • activating macrophages and natural killer cells, enabling them to destroy intracellular pathogens; and
  • stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses.

Cell-mediated immunity is directed primarily at microbes that survive in phagocytes and microbes that infect non-phagocytic cells. It is most effective in removing virus-infected cells, but also participates in defending against fungi, protozoans, cancers, and intracellular bacteria.

Primary and secondary responses

When the body is first exposed to an antigen, several days pass before the adaptive immune response becomes active. Immune activity then rises, levels off, and falls. During following exposures to the same antigen, the immune system responds much more quickly and reaches higher levels. Because the first, or primary, immune response is slow, it cannot prevent disease, although it may help in recovery. In contrast, subsequent, or secondary, immune responses usually can prevent disease because the pathogen is detected, attacked, and destroyed before symptoms appear.

What is different about the infant immune system?

The infants’ immune system is intact but immature at birth.  Some vaccines such as BCG and Hepatitis B work well when they are administered at birth whereas others do not generate as strong a response.

The main problem with babies’ immunity is that it is very naïve.  At the time of birth babies have not been exposed to any pathogens.  This means that babies have to generate a full immune response to every pathogen they encounter. Each immune response takes about 10 days to generate.  This is where maternal antibody can be important when present: It will help to protect an infant if they are exposed to a pathogen in those first 10 days.  Unlike other animals (such as ruminants) which rely mainly on passive transfer of maternal antibodies in breast milk, humans receive most of their maternal antibodies through placental transfer of IgG.  However, there will still be some antibodies transferred in breast milk, but the levels are much lower.  In addition human babies don’t have a porous stomach (like calves do) in order to absorb the antibody.  Therefore most of the antibody in breast milk will work in protecting pathogens crossing the oral cavity.

The developing immune system before and after birth

Maternal

The immune system is designed to recognise ‘self’ versus ‘non self’. This means our own immune system can recognise our own cells as being safe and anything else as being a threat. Obviously this has implications in pregnancy, where a developing fetus will be expressing antigens from the father. Therefore during pregnancy modifications occur in the maternal immune system at many levels. These changes are necessary to ensure a successful pregnancy. In the absence of such changes the mother’s immune system would recognise the fetus as foreign (like a pathogen) and reject it.  Potentially dangerous T-cell responses are down regulated (reduced) and some aspects of the non-specific immune system are activated. As previously mentioned, at this time specific IgG antibody passes from the mother through the placenta to the developing fetus providing it with temporary protection against some of the infections that the mother has been exposed to or vaccinated against.  This gives opportunities to provide newborns with transient protection against some diseases.

Infant

The infant’s immune system is relatively complete at birth. It is clear that the IgG antibodies received from mother are important for the protection of the infant during the first few months of life while the infant is starting to develop its own repertoire. Passive transient protection by IgA against many common illnesses is also provided to the infant in breastmilk. Mother's milk provides IgA against a wide range of microbes that the mother has had in her gut. Breast milk has also been shown to assist in the development of the infant’s own immune system. There is some, although weak, evidence to show that breastfed infants respond better to some vaccines. The major impetus however for the expansion of lymphocytes (B and T cells) is the exposure to microbes which colonise the gut during birth.

Premature and low birth weight infants are at increased risk of experiencing complications of vaccine preventable diseases and although the immunogenicity of some vaccines may be decreased in the smallest preterm infants, the antibody concentrations achieved are usually protective.

Figure 3. The protective effect of maternal antibodies in serum and milk.

Panel A – if maternal antibodies are present they afford protection to the infant. They can also attenuate (weaken) infections should they occur allowing the infant to develop their own immunity.

Panel B – There is no protection offered to the infant in the absence of maternal antibody.

Rolf M. Zinkernagel.  Maternal Antibodies, Childhood Infections, and Autoimmune Diseases (2001) NEJM 345;18:1331-1335

The relative immaturity of the infant immune system leaves them unable to respond well to certain infectious agents, as well as some types of vaccine.

For the reasons discussed above, young infants are at particular risk of some diseases. Each disease comes with its own set of peculiarities listed below.

Table: Risks and immunity to diseases vary widely.

Disease Risk to young infants
Pertussis (whooping cough) Young infants are at highest risk from complications from this disease and morbidity and mortality are inversely associated with age – the younger the more dangerous. 90% of deaths occur in infants <4 weeks of age. 75% of cases in first year of life are hospitalized. Most deaths occur in infants under 1 year of age. Breastfeeding offers no protection from pertussis regardless of the mothers’ immune status.
Measles Young infants are at lower risk from contracting measles as they receive protective antibody from their mother. This maternal protection wanes from about 6-9 months. Vaccination is not offered until 15 months of age as giving it early creates the possibility that the maternally derived antibody inactivates the vaccine. Vaccination occurs later to ensure the infant develops its own lifelong immunity. In situations of high risk from measles babies can be immunised against measles at a younger age however the vaccine may be less effective.
Mumps same as measles
Rubella Rubella is not usually a serious disease of childhood however if contracted during pregnancy can have disastrous consequences for the fetus. Immunisation against rubella occurs at 15 months with measles and mumps vaccination.
Meningoccoccal disease Babies are vulnerable to meningococcal disease due to their inability to produce high levels of IgG2. The most vulnerable period is when any maternal protection conferred has waned (6 – 12 months). Group B vaccine can be given from 6 weeks of age and 4 doses are required. Group C vaccines can also be given from 6 weeks and only one dose is required. (Not funded in NZ)
Pneumococcal disease Babies are more vulnerable to pneumococcal disease due to their inability to produce high levels of IgG2. Vaccination is recommended and available from 6 weeks of age. (Not funded in NZ)
Tetanus Any unimmunised person is at risk from tetanus including infants.
Hepatitis B Consequences of hepatitis are inversely associated with age and if acquired early in life is very likely to result in chronic infection and associated morbidity and mortality. Infants of carrier mothers should be immunised starting from birth.
Haemophilus influenzae As with Meningococcal and pneumococcal, infants are at particular risk from this disease due to their inability to produce IgG2
Diphtheria, Polio No longer endemic in New Zealand however until global eradication occurs it is important to continue to immunise.