INFECTIOUS DISEASE

BACTERIOLOGY IMMUNOLOGY MYCOLOGY PARASITOLOGY VIROLOGY

VIDEO LECTURE

 
IMMUNOLOGY - CHAPTER   FOURTEEN 

IMMUNIZATION 

Dr Abdul Ghaffar and Dr Tariq Haqqi
 

 

ALBANIAN

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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 the means of providing specific protection against most common and damaging pathogens. The mechanism of immunity depends on the site of the pathogen and also the mechanism of its pathogenesis. Thus, if the mechanism of pathogenesis involves exotoxins, the only immune mechanism effective against it would be neutralizing antibodies that would prevent its binding to the appropriate receptor and promoting its clearance and degradation by phagocytes. Alternatively, if the pathogen produces disease by other means, the antibody will have to react with the organism and eliminate by complement-mediated lysis or phagocytosis and intracellular killing. However, if the organism is localized intracellularly, it will not be accessible to antibodies while it remains inside and the cell harboring it will have to be destroyed and, only then antibody can have any effect. Most viral infections and 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 can expose the organism to elements of humoral immunity. Alternatively, cells harboring intracellular pathogen themselves can be activated to kill the organism. Such is 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 1).

 

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 practiced in numerous acute situations of infections (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 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 different 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). 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 animal or thermal mutation, they can revert to their pathogenic form and cause serious illness. It is for this reason, polio live (Sabin) vaccine, which was used for many years, has been replaced in many countries by the inactivated (Salk) vaccine.
 

Killed vaccines
While live vaccines normally produce only self-limiting non-clinical infections and subsequent immunity, they carry a serious risk of causing overt disease in immunocompromised individuals. 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). Other bacterial vaccines utilize their cell wall components (haemophilus, pertussis, meningococcus, pneumococcus, etc.) (figure 5). Some viral vaccines (hepatitis-B, rabies, etc.) consist of antigenic proteins 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) 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).

 

Sub-unit vaccines
Some vaccines consist of subcomponents of the pathogenic organisms, usually 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.). Hepatitis-B, rabies vaccines consist of antigenic proteins cloned into a suitable vector (e.g., yeast). These subunit vaccines are designed to reduce the problems of toxicity and risk of infection. When the pathogenic mechanism of an agent involves a toxin, a modified form of the toxin (toxoid) is used as vaccine (e.g., diphtheria, tetanus, etc.). Toxoids, although lose their toxicity, they remains immunogenic.


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 antibody produce long lasting immune responses with immunologic memory. Viral peptide genes cloned into vectors, when injected transfect host cells and consequently produce a response similar to that produced against live-attenuated viruses (both cell-mediated and humoral). 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 certain bacteria (Freundís incomplete adjuvant). Bacteria most often used in an adjuvant are Mycobacteria (BCG) and Nocardia. In some instance 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 2-3 months (diphtheria, pertussis, tetanus, polio), or 13-15 months (mumps, measles, rubella).  The currently recommended schedule of routine immunization in the USA (recommended by CDC and AIP) is summarized in Table 2.  This schedule is revised on 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 prophylactic ally, 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 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 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, sometimes fatal (pertussis), or neurological disorders (influenza). Allergies to egg may develop as a consequence of viral vaccines produced in egg (measles, mumps, influenza, yellow fever). Booster shots result in more pronounced inflammatory effects than the primary immunization. The noticeable and serious side effects documented have been those following the DTP vaccine (Table 3). Most of these were attributable to the whole pertussis component of the vaccine and have been eliminated since the use of the 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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