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MICROBIOLOGY AND IMMUNOLOGY MOBILE  -  IMMUNOLOGY CHAPTER FOURTEEN

IMMUNIZATION

Immunization is a means of providing specific protection against many common and damaging pathogens by stimulating an organism's immune system to either produce humoral antibodies against the pathogen (or toxins produced by the pathogen) or T cells that can provide cell-mediated immunity.
The type of immunity that is needed to neutralize a specific pathogen depends on the site of the pathogen and the mechanism of its pathogenesis. For example, some pathogens produce disease by secreting exotoxins. If this is the case, the only immune mechanism effective against the organism would be neutralizing antibodies that prevent exotoxin binding to the appropriate receptor on its target cell and promoting its clearance and degradation by phagocytes.
If the pathogen produces disease by other means, an antibody will have to react with the pathogen itself and eliminate it either by complement-mediated lysis or phagocytosis and intracellular killing. However, if the pathogenic organism is localized intracellularly, it will not be accessible to antibodies and the cell harboring it will have to be destroyed instead; only then could antibody have any effect on the pathogen. Most viruses, together with intracellular bacteria and protozoa, are examples of such pathogens. In this case, the harboring cells can be destroyed by elements of cell-mediated immunity or, if they cause the infected cell to express unique antigens recognizable by antibody, antibody-dependent and complement-mediated killing of the infected cell can expose the pathogen to elements of humoral immunity. It is also possible for cells harboring intracellular pathogen to be activated to kill the pathogen. Such is clearly not the case with pathogens that have the capability of surviving within phagocytic cells.
Specific immunity can result from either passive or active immunization and both modes of immunization can occur by natural or artificial processes (Figure 1C).

Passive Immunity
Immunity can be acquired, without the immune system being challenged with an antigen. This is done by transfer of serum or gamma-globulins from an immune donor to a non-immune individual. Alternatively, immune cells from an immunized individual may be used to transfer immunity. Passive immunity may be acquired naturally or artificially.

Naturally acquired passive immunity
Immunity is transferred from mother to fetus through placental transfer of IgG or colostral transfer of IgA.

Artificially acquired passive immunity
Immunity is often artificially transferred by injection with gamma-globulins from other individuals or gamma-globulin from an immune animal. Passive transfer of immunity with immune globulins or gamma-globulins is used in numerous acute situations of infection (diphtheria, tetanus, measles, rabies, etc.), poisoning (insects, reptiles, botulism), and as a prophylactic measure (hypogammaglobulinemia). In these situations, gamma-globulins of human origin are preferable, although specific antibodies raised in other species are effective and used in some cases (poisoning, diphtheria, tetanus, gas gangrene, botulism). While this form of immunization has the advantage of providing immediate protection, heterologous gamma-globulins are effective for only a short duration and often result in pathological complications (serum sickness) and anaphylaxis. Homologous immunoglobulins also carry the risk of transmitting hepatitis and HIV.

Passive transfer of cell-mediated immunity can also be accomplished in certain diseases (cancer, immunodeficiency). However, it is difficult to find histocompatible (matched) donors and there is severe risk of graft versus host disease.
 

Active Immunity

This refers to immunity produced by the body following exposure to antigens.

Naturally acquired active immunity
Exposure to various pathogens leads to sub-clinical or clinical infections which result in a protective immune response against these pathogens.

Artificially acquired active immunity
Immunization may be achieved by administering live or dead pathogens or their components. Vaccines used for active immunization consist of live (attenuated) organisms, killed whole organisms, microbial components or secreted toxins (which have been detoxified). 

Live vaccines

The first live vaccine was cowpox virus introduced by Edward Jenner as a vaccine for smallpox (see vaccine section); however, variolation (innoculation using pus from a patient with a mild case of smallpox) has been in use for over a thousand years (figure 2)

Live vaccines are used against a number of viral infections (polio (Sabin vaccine), measles, mumps, rubella, chicken pox, hepatitis A, yellow fever, etc.) (figure 3). The only example of live bacterial vaccine is one against tuberculosis (Mycobacterium bovis: Bacille Calmette-Guerin vaccine: BCG). This is is used in many African, European and Asian countries but not in the United States. Whereas many studies have shown the efficacy of BCG vaccine, a number of studies also cast doubt on its benefits.

Live vaccines normally produce self-limiting non-clinical infections and lead to subsequent immunity, both humoral and cell-mediated, the latter being essential for intracellular pathogens. However, they carry a serious risk of causing overt disease in immunocompromised individuals. Furthermore, since live vaccines are often attenuated (made less pathogenic) by passage in animals or thermal mutation, they can revert to their pathogenic form and cause serious illness. It is for this reason that live polio (Sabin) vaccine, which was used for many years, has been replaced in many countries by the inactivated (Salk) vaccine.

Killed vaccines
Killed (heat, chemical or UV irradiation) viral vaccines include those for polio (Salk vaccine), influenza, rabies, influenza, rabies, etc. Most bacterial vaccines are killed organisms ( typhoid, cholera, plague, pertussis, etc.) (figure 4).

Sub-unit vaccines
Some anti-bacterial vaccines utilize purified cell wall components (haemophilus, pertussis, meningococcus, pneumococcus, etc.) (figure 5). Some viral vaccines (hepatitis-B, etc.) consist of purified antigenic proteins manufactured after expression from a gene cloned into a suitable vector (e.g., yeast). When the pathogenic mechanism of an agent involves a toxin, a modified form of the toxin (toxoid, which has lost its toxicity while remaining immunogenic) is used as a vaccine (e.g., diphtheria, tetanus, cholera) (figure 6). These subunit vaccines are designed to reduce the toxicity problems. Each type of vaccine has its own advantages and disadvantages (figure 7).

Subunit vaccines may consist of proteins or polysaccharides. Since polysaccharides are relatively weak T-independent antigens, and produce only IgM responses without immunologic memory, they are made more immunogenic and T-dependent by conjugation with proteins (e.g., haemophilus, meningococcus, pneumococcus, etc.).

Other novel vaccines
A number of novel approaches to active immunization are in the investigative stage and are used only experimentally. These include anti-idiotype antibodies, DNA vaccines and immunodominant peptides (recognized by the MHC molecules) and may be available in the future.

• Anti-idiotype antibodies against polysaccharide antibodies produce long lasting immune responses with immunologic memory.
• DNA vaccines (viral peptide genes cloned into vectors) must be injected. They transfect host cells and consequently produce a response similar to that produced against live-attenuated viruses (both cell-mediated and humoral). Several anti-HIV DNA vaccines have been developed.
• Immunodominant peptides are simple and easy to prepare and, when incorporated into MHC polymers, can provoke both humoral and cell mediated responses.

Adjuvants
Weaker antigens may be rendered more immunogenic by the addition of other chemicals. Such chemicals are known as adjuvants. There are many biological and chemical substances that have been used in experimental conditions (Table 1). However, only aluminum salts (alum) are approved for human use and it is incorporated in DTP vaccine. Furthermore, pertussis itself has adjuvant effects. Adjuvants used experimentally include mixtures of oil and detergents, with (Freund’s complete adjuvant) or without (Freund’s incomplete adjuvant) certain bacteria. Bacteria most often used in an adjuvant are Mycobacteria (BCG) and Nocardia. In some instances, sub-cellular fractions of these bacteria can also be used effectively as adjuvants. Newer adjuvant formulations include synthetic polymers and oligonucleotides. Most adjuvants recognize TOLL-like receptors, thus activating mononuclear phagocytes and inducing selective cytokines that can enhance Th1 or Th2 responses, depending on the nature of the adjuvant.
 

The protective immunity conferred by a vaccine may be life-long (measles, mumps, rubella, small pox, tuberculosis, yellow fever, etc.) or may last as little as a few months (cholera). The primary immunization may be given at the age of 2 to 3 months (diphtheria, pertussis, tetanus, polio), or 13 to 15 months (mumps, measles, rubella). The currently recommended schedule for routine immunization in the United States (recommended by CDC and AIP) is summarized in Table 2. This schedule is revised on a yearly basis or as need by the CDC Advisory Committee on Immunization Practice (AICP).

Prophylactic versus therapeutic immunization
Most vaccines are given prophylactically, i.e. prior to exposure to the pathogen. However, some vaccines can be administered therapeutically, i.e. post exposure (e.g., rabies virus). The effectiveness of this mode of immunization depends on the rate of replication of the pathogen, incubation period and the pathogenic mechanism. For this reason, only a booster shot with tetanus is sufficient if the exposure to the pathogen is within less than 10 years and if the exposure is minimal (wounds are relative superficial). In a situation where pathogen has a short incubation period, the pathogenic mechanism is such that only a small amount of pathogenic molecules could be fatal (e.g., tetanus and diphtheria) and/or a bolus of infection is relatively large, both passive and active post exposure immunization are essential. Passive prophylactic immunization is also normal in cases of defects in the immune system, such as hypogammaglobulinemias.

Adverse effects of immunization
Active immunization may cause fever, malaise and discomfort. Some vaccine may also cause joint pains or arthritis (rubella), convulsions, that may sometimes be fatal (pertussis), or neurological disorders (influenza). Allergies to eggs may develop as a consequence of viral vaccines produced in eggs (measles, mumps, influenza, yellow fever). Booster shots result in more pronounced inflammatory effects than the primary immunization. The serious side effects have been documented after use of the DTP vaccine (Table 3). Most of these were attributable to the whole pertussis component of the vaccine and have been eliminated by the use of an acellular pertussis preparation.
 

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