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 INFECTIOUS DISEASE

BACTERIOLOGY IMMUNOLOGY MYCOLOGY PARASITOLOGY VIROLOGY

VIDEO LECTURE

 
IMMUNOLOGY - CHAPTER   FOURTEEN 

IMMUNIZATION 

Dr Abdul Ghaffar and Dr Tariq Haqqi
 

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READING:
Male et al. Immunology
7th edition, chapter 18

 

TEACHING OBJECTIVES
Know the distinction between passive and active immunization and their examples
Distinguish between artificial and natural means of immunization
Know the applications and problems of artificial passive immunization
Know the applications and problems of artificial active immunization
Know the modern approaches to 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.

 

 

See also Virology Chapter "Vaccines" in this On-line Textbook

jenner-cart.jpg (107838 bytes)  
Figure 1A. Edward Jenner carries out a vaccination

imm-2.jpg (45416 bytes)  B. Pre and post vaccine incidence of common infectious diseases

imm-f1-2000.jpg (15994 bytes)  C. Modes of immunization

vac022.jpg (72629 bytes) D. Milestones of immunization

vac023.jpg (88745 bytes)
Figure 2  Introduction of variolation

vac025.jpg (68018 bytes) Figure 3 
Live attenuated vaccines

vac026.jpg (62369 bytes) Figure 4 Killed whole organism vaccines

vac027.jpg (72315 bytes) 
vac028.jpg (66140 bytes)  Figure 5
Microbial fragment vaccines

vac029.jpg (58942 bytes)  Figure 6 Modification of toxin to toxoid

vac024.jpg (67958 bytes)
Figure 7  Advantages and disadvantages of passive immunization

 

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 but none has so far shown much efficacy. 

  • 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 (Freundís complete adjuvant) or without (Freundís 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.
 

Table 1.  Selected adjuvants in clinical or experimental use

Adjuvant type human use Experimental only

Salts:

aluminum hydroxide, aluminum phosphate-calcium phosphate

Yes
Yes

Slow release of antigen, TLR interaction and cytokine induction

Beryllium hydroxide
 

No
 

Synthetic particles:

Liposomes, ISCOMs, polylactates

 

 

No
No

 

Slow release of antigen

Polynucleotides:

CpG and others
 

No* TLR interaction and cytokine induction

Bacterial products:

B.pertussis

Yes

TLR interaction and cytokine induction

M. bovis (BCG and others)

No

Mineral oils

No Antigen depot

Cytokines:

IL-1, IL-2, IL12, IFN-γ, etc.
 

No*

Activation and differentiation of T- and B cells and APC

*Experimental use in human malignancies

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). 

Table 2   Schedule for Active Immunization of Normal Children*

Age

Vaccine

Birth

Months 

Years

1

2

4

6

12

15

18

19 -23

2-3

4-6

Hepatitis-B  1

HeB

HeB

1

HeB 

   

HeB

Rotavirus

    Rota Rota Rota          

Diphtheria, Tetanus, Pertussis  3

 

 

DTaP

DTaP

DTaP

 3

DTaP

 

 

DTaP

Hemophilus influenzae-b (CV) 4

 

 

Hib

Hib

Hib4

Hib

 

Pneumococcal 5

    PCV PCV PCV

PCV

 

PPV

Inactivated Poliovirus

 

 

IPV

IPV

IPV

 

 

 IPV

Influenza 6

       

Influenza (yearly)

 

Measles, Mumps, Rubella 7

 

 

MMR

 

 

MMR

MMR

Varicella  8

 

 

Var

 

 

 

 

Hepatitis A  9

         

Hep A (2 doses)

 HepA series

Meningococcal 10

           

MCV4

*Recommended by Advisory Committee on Immunization , American academy of Pediatrics (2008).

NOTES

 

Range of recommended ages Certain high risk groups

CDC Immunization schedules

 

vac021.jpg (83387 bytes) 
Adverse events occurring with 48 hours of DPT vaccination

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 relatively superficial). In a situation where the pathogen has a short incubation period, only a small amount of pathogenic molecules could be fatal (e.g., tetanus and diphtheria); therefore both passive and active post exposure immunization are essential. This is also the case when a bolus of infection is relatively large

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.

 

Table 3. Approximate rates of adverse event occurring within 48 hours DTP vaccination

Event

Frequency

Local

redness, swelling, pain 1 in 2-3 doses

Mild/moderate systemic

fever, drowsiness, fretfulness 1 in 2-3 doses
vomiting, anorexia 1 in 5-15 doses

More serious systemic

persistent crying, fever 1 in 100-300 doses
collapse, convulsions 1 in 1750 doses
acute encephalopathy 1 in 100,000 doses
permanent neurological deficit 1 in 300,000 doses
 

You have learned: 

Different modes of acquiring immunity

Which mode is used or applicable in what situation

Advantages and disadvantages of different modes of immunization

Rationale for vaccine design

Risk and benefits of vaccination

  

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