Active Immunization – Definition, Mechanism, Advantages, Disadvantages, Examples

Active immunization is the process by which body own immune system is stimulated by giving antigen or vaccine. It produce antibodies and memory cells. The immunity is slow but long lasting.

Active immunization is the process by which a harmless antigen is introduced into the body to produce immune response. It is commonly done by using vaccines. It helps the body to form protection against a particular disease.

In this process, the vaccine acts like a natural infection but does not cause the serious disease. It stimulates the immune system safely. Then the body produces antibodies and special memory cells like memory B-cells and memory T-cells.

The protection in active immunization is not formed immediately. It usually takes about 10 to 14 days to develop properly. But after formation, it gives long lasting immunity and sometimes life-long immunity.

Due to this immunological memory, the immune system can recognise the same pathogen in future. Then it gives quick response and destroys the pathogen before it causes severe illness.

Active immunization may be artificial or natural. Artificial active immunization occurs by vaccination. Natural active immunity occurs when a person gets infection and then recovers from the disease.

Historical Background of Active Immunization

• In 430 BC, the early idea of variolation was seen. At that time, the persons who survived from smallpox were called to nurse the patients suffering from same disease.
• In 17th century, some early practices of immunization were recorded in China. Buddhist monks intentionally drank snake venom to develop protection against snake bite.
• In 18th century, Edward Jenner developed the first safe vaccine against smallpox. He is commonly known as the founder of modern vaccinology.
• During early 1900s, scientists studying animal diseases observed one important thing. When most of the animals in a group survived from infection, the whole group become more safe. This idea later helped in forming the concept of herd immunity.
• In 1920s, Topley and Wilson tested the concept of herd immunity in laboratory mice. They showed that infectious disease could not spread easily when enough number of mice were already immune.
• In 1980, smallpox was completely eradicated from the world by active immunization programme. It became the only human disease eliminated fully through vaccination.

Principles of Active Immunization

Principles of Active Immunization is based on safe stimulation of the body immune system by using harmless antigenic substance. This antigen is commonly given in the form of vaccine. It gives the body a safe contact with disease causing agent without producing severe natural infection.

It is based on the ability of vaccine antigen to mimic the real or wild type pathogen. The immune system recognises this antigen as foreign material. Then it starts immune response against the specific antigen.

During this process, both innate immunity and adaptive immunity are involved. The antigen is first detected and processed by immune cells. Then the adaptive immune system produces specific antibodies and activated lymphocytes.

The main principle is the formation of immunological memory. Memory B-cells and memory T-cells are produced after vaccination. These cells remain in the body for long period and may give life long protection in some diseases.

The protection is not immediate because the body has to produce its own immune response. Usually it takes about 10 to 14 days for proper development of immunity. This period is called the lag phase of immune response.

After this, if the same pathogen enters the body in future, the immune system recognises it quickly. A rapid and strong immune response is formed. Thus the pathogen is destroyed before it causes serious disease.

Characteristics of Active Immunization

• Active immunization is produced by giving inducing agents like antigen, toxoid or genetic material. These substances stimulate the body own immune system.
• In this process, ready-made antibody is not given from outside. The host body itself produces protective immunoglobulins by the activity of plasma cells.
• The protection is not immediate. It needs some time for primary immune response. Usually 10 to 14 days are required for proper development of immunity.
• The immunity produced is long lasting. It may remain for many years, decades or sometimes for whole life.
• It produces immunological memory. Special memory B-cells and memory T-cells are formed, which remember the same pathogen for future response.
• It can produce both humoral immunity and cell-mediated immunity. Humoral immunity is mainly antibody mediated and cell-mediated immunity involves CD4+ T-cells and CD8+ T-cells.
• Active immunization is mainly used for prevention of disease. It is useful for long term control of infectious and transmissible pathogens in population.

Types of Active Immunization

1. Live vaccine– These are live but weakened organism. It may be virus or bacteria. It multiply little in body and produce strong immunity. Examples are MMR, chickenpox and rotavirus vaccine.
2. Killed vaccine– These vaccine contain killed organism. It is killed by heat, chemical or radiation. It cannot produce disease. But it can act as antigen. Examples are injectable polio, hepatitis A and rabies vaccine.
3. Toxoid vaccine– These are prepared from toxin of bacteria. The toxin is inactivated. It does not cause toxic effect. It produce antibody against toxin. Examples are tetanus and diphtheria vaccine.
4. Subunit vaccine– It contain only part of organism. The antigenic part may be protein or sugar. Whole organism is not used. So it is safer vaccine. The important subunit vaccines are recombinant protein vaccine, polysaccharide vaccine and conjugate vaccine.
   • Recombinant vaccine– This vaccine contain antigen made by recombinant method. The antigen is purified and then used. Examples are Hepatitis B and HPV vaccine.
   • Polysaccharide vaccine– It contain purified sugar coating of bacteria. This sugar coating work as antigen. Example is pneumococcal vaccine.
   • Conjugate vaccine– It contain polysaccharide joined with carrier protein. It gives better immune response. Mainly useful in children. Examples are Hib and meningococcal vaccine.
5. mRNA vaccine– It contain synthetic mRNA. It enters body cell and make viral protein. Then immune response is produced. Examples are Pfizer-BioNTech and Moderna COVID-19 vaccine.
6. Vector vaccine– It uses harmless virus as carrier. It carry antigen gene into host cell. Then antigen is formed in body. Examples are AstraZeneca COVID-19 and Ebola vaccine.

Mechanism of Active Immunization

1. Step 1– After vaccine is given, local immune cells first detect the vaccine. Mainly macrophages and neutrophils. A small inflammatory reaction starts at injection site.
2. Step 2– Due to inflammation, dendritic cells come to that site. These cells are antigen presenting cells. They take up the vaccine antigen.
3. Step 3– The vaccine antigen is digested inside dendritic cells. It is broken into small peptide fragments. Then these fragments are placed with MHC-II molecule.
4. Step 4– The dendritic cells move to nearby lymph node. There it show antigen to naive CD4+ helper T-cells. The T-cell receptor (TCR) bind with antigen-MHC-II complex.
5. Step 5– For full activation, second co-stimulatory signal is also needed. After this, helper T-cell become activated. It starts dividing many times.
6. Step 6– Many same type helper T-cells are formed. This is called clonal expansion. These cells secrete cytokines which help other immune cells.
7. Step 7– B-cells recognise vaccine antigen by their own receptor. Then they interact with activated helper T-cells. This gives proper activation to B-cells.
8. Step 8– Activated B-cells multiply in germinal centre. Their receptor becomes more fitting to antigen. This is called affinity maturation.
9. Step 9– B-cells also change the class of antibody. At first IgM is formed. Later IgG, IgA or other antibody may be produced.
10. Step 10– Selected B-cells become plasma cells. These cells produce high affinity protective antibody. The antibody circulates in blood and body fluid.
11. Step 11– At same time, CD8+ T-cells may recognise antigen with MHC-I molecule. Under cytokine effect, it multiply and become cytotoxic T lymphocytes (CTLs).
12. Step 12– Cytotoxic T lymphocytes destroy infected cells. This is cell mediated immunity. It works along with antibody mediated response.
13. Step 13– When vaccine antigen is cleared, immune response becomes less. About 90% to 95% active effector cells die. This is contraction phase.
14. Step 14– Few cells remain as memory B-cells and memory T-cells. These cells remain in body for long time. In future infection, they give rapid and strong immune response.

Antibody Production During Active Immunization

• Naive B-lymphocytes first recognise the vaccine antigen. It is done by B-cell receptor (BCR) present on its surface. The antigen bind directly with its specific receptor.
• In protein antigen, the B-cell take antigen inside the cell. Then it breaks the antigen into small pieces. These pieces are shown on the surface with MHC-II molecule.
• After this, Follicular helper T-cell (T FH cell) recognise the antigen shown by B-cell. It gives necessary signal to B-cell. CD40-CD40L binding and cytokine like IL-21 are important in this step.
• In some non-protein antigen, mainly sugar or polysaccharide antigen, T-cell help is not needed. These antigen cross-link many B-cell receptors together. Then antibody production starts directly.
• In T-cell independent response, mainly IgM antibody is produced. It is low affinity antibody. Long term memory is not formed properly in this type response.
• In T-cell dependent response, activated B-cells divide repeatedly. Many same type B-cells are produced from one B-cell. These cells form special area called germinal centre.
• Inside germinal centre, the B-cells undergo small random change in their receptor. This process is called somatic hypermutation. The B-cells which bind antigen more strongly are selected.
• After selection, class switching takes place. At first IgM and IgD are produced. Then under the effect of T-cell cytokines, B-cells change to produce IgG, IgA or IgE.
• The selected B-cells then change into plasma cells. These cells are antibody forming cells. They produce large amount of specific protective antibody inside the body.
• Some activated B-cells do not become plasma cell. They become memory B-cells. These cells remain in body for long time, sometimes 10 years or more.
• When the same pathogen enter in future, these memory B-cells quickly become antibody secreting plasma cells. So the second response is fast and strong.
• The formed antibodies circulate in blood and body fluids. They bind with antigen, toxin or pathogen. Then they neutralize it or help in destruction of disease producing organism.

Antibody Production During Active Immunization

• Naive B-cell first recognise the vaccine antigen. It recognise by B-cell receptor (BCR). The antigen bind with the specific receptor.
• In protein antigen, B-cell take the antigen inside. It breaks the antigen into small parts. Then antigen is shown on the surface with MHC-II.
• Follicular helper T-cell (T FH cell) recognise this antigen. It gives signal to the B-cell. CD40-CD40L binding and IL-21 help in this activation.
• Some antigen are non-protein type. Mainly sugar or polysaccharide antigen. These antigen cross-link many BCRs and start antibody production without T-cell help.
• In this T-cell independent response, mainly IgM is produced. It is low affinity antibody. Long term memory is not formed properly.
• Activated B-cell divide many times. Many similar B-cells are formed. In T-cell dependent response, these cells form germinal centre.
• Inside germinal centre, B-cells undergo small changes in receptor. This is called somatic hypermutation. The cells which bind antigen strongly are selected.
• After this, class switching takes place. First IgM and IgD are formed. Then B-cells change to IgG, IgA or IgE according to T-cell cytokine signal.
• Selected B-cells become plasma cells. These cells produce large amount of specific antibody. The antibody is formed by body own immune cells.
• Some activated B-cells become memory B-cells. These cells remain for long time in body. They give quick antibody response in future infection.
• The antibodies circulate in blood and tissue fluid. They bind with antigen, toxin or pathogen. Then they neutralize it or help in its destruction.

Immunological Memory in Active Immunization

• After vaccine antigen is removed from body, primary immune response starts decreasing. This is called contraction phase. About 90% to 95% active effector cells die in this phase.
• Few cells do not die. These cells remain as antigen specific memory cells. They are mainly memory B-cells and memory T-cells.
• Memory B-cells are formed in germinal centre. These cells carry high affinity and class switched antibody on surface. They are already selected against the same antigen.
• Memory B-cells can remain in body for long time. Sometimes up to 10 years or more. They move through blood and lymphoid tissues.
• When same pathogen enter again, memory B-cells become active very fast. They change into antibody secreting plasma cells. Then large amount of antibody is produced.
• Memory T-cells also remain for long period. They may persist for many years, sometimes up to 25 years. They do not need continuous presence of vaccine antigen for survival.
• Survival of memory T-cells is maintained by cytokines. Mainly Interleukin-7 (IL-7) and Interleukin-15 (IL-15) are important for their maintenance.
• Central memory T-cells (T CM) are present mainly in secondary lymphoid organs. When same antigen stimulate them, they divide rapidly. Then many new effector T-cells are formed.
• Effector memory T-cells (T EM) move in blood and peripheral tissues. They act more quickly at the site of infection. They can destroy infected cells and give immediate protection.
• In early infection, some inflammatory cytokines may activate memory CD8+ T-cells also. This may occur before direct antigen recognition. So early protective response is formed.
• The response produced by memory cells is called secondary immune response. It is faster than primary response. It need less amount of pathogen for activation.
• In secondary response, antibodies are produced in higher amount. These antibodies are high affinity type. So the pathogen is removed quickly before severe disease occurs.

Types of Vaccines Used for Active Immunization

1. Live vaccine– It contain live but weakened virus or bacteria. It behave like natural infection. But severe disease is not produced. Examples are MMR, varicella, rotavirus, yellow fever and BCG vaccine.
2. Killed vaccine– It contain whole killed organism. The organism is killed by heat, chemical or radiation. It cannot multiply in body. So more dose may be required. Examples are injectable polio, hepatitis A, rabies and injectable influenza vaccine.
3. Toxoid vaccine– It contain inactivated toxin of bacteria. The toxin does not cause toxic effect. It produce antibody against active toxin. Examples are tetanus and diphtheria vaccine.
4. Subunit vaccine– It contain only antigenic part of pathogen. Whole organism is not used. The antigen may be protein or outer sugar coating. It gives specific immune response.
   • Recombinant vaccine– It contain purified protein antigen. The antigen gene is inserted into cell culture. Then target protein is produced. Examples are Hepatitis B, HPV and shingles vaccine.
   • Polysaccharide vaccine– It is made from purified sugar coating of bacteria. It gives protection for few years. Long term memory is not formed properly. Example is pneumococcal polysaccharide vaccine.
   • Conjugate vaccine– It contain bacterial sugar joined with carrier protein. It gives stronger and longer immunity. It is very useful in infants also. Examples are Hib, pneumococcal conjugate and meningococcal vaccine.
5. mRNA vaccine– It contain synthetic mRNA. It is protected by lipid nanoparticle. It enter host cell and form viral protein. Then immune response is produced. Examples are Pfizer-BioNTech and Moderna COVID-19 vaccine.
6. Vector vaccine– It use harmless modified virus as carrier. Mostly adenovirus may be used. It carry antigen gene into host cell. Examples are AstraZeneca, Johnson & Johnson COVID-19 and Ebola vaccine.
7. DNA vaccine– It contain DNA having gene for antigen. It is developing type vaccine. It is cheap to produce and designed for long term immunity.

Factors Affecting Active Immunization

• Age– Infants have immature immune system. So vaccine response may be weak. Mainly plain polysaccharide vaccine do not work well below two years. In old age also immunity becomes less due to immunosenescence.
• Immune health– The immune system must be normal for good vaccine response. In B-cell or T-cell defect, response becomes poor. In diseases like HIV/AIDS, leukemia or organ failure, protection may not develop properly.
• Immunosuppression– Some treatment suppress immune system. These are chemotherapy, radiation therapy, high dose corticosteroids and some biologic drugs. So antibody formation may be low or absent.
• Maternal antibody– Some antibodies pass from mother to baby through placenta. These antibodies give passive protection. But they may also block infant active response to some vaccines.
• Pathogen nature– Some pathogen change their antigen by mutation. This is called antigenic drift. Some have many strains or serotypes. So old vaccine immunity may not protect fully.
• Vaccine type– Type of vaccine affect the immune response. Live attenuated vaccine usually gives strong and long lasting immunity. Killed vaccine and plain polysaccharide vaccine may give weaker and short time protection.
• Dose schedule– Correct dose and proper time is important. Many non-live vaccines need more than one dose. Booster dose is also needed to maintain antibody level.
• Storage– Vaccine must be stored in proper temperature. If cold chain is broken, vaccine potency is lost. Expired vaccine, manufacturing fault or wrong handling can cause primary vaccine failure.

Booster Doses and Their Importance

• Booster dose is given after primary vaccination. It helps to increase the antibody level again. Because antibody level may decrease slowly with time.
• When antibody level becomes low, person may become susceptible again. This is called secondary vaccine failure. Booster dose prevent this condition.
• Booster dose is important for non-live vaccines. Such as killed vaccine, subunit vaccine and toxoid vaccine. These vaccines do not multiply in body.
• Non-live vaccines usually produce weaker immune response than live vaccine. Mainly humoral immunity is produced. So booster dose is needed to maintain protective antibody level.
• Some pathogens change their antigen again and again. This is called antigenic drift. In such condition, booster or new vaccine formulation is needed.
• Influenza vaccine is given every year because the virus changes frequently. It helps the immune system to recognise the newly circulating strains.
• Booster dose produces rapid secondary immune response. This is called anamnestic response. It occurs because memory B-cells and memory T-cells are already present.
• In previously vaccinated person exposed to rabies, only booster doses may be needed. Memory cells rapidly produce antibody. So passive immunoglobulin may not be required in such condition.
• Booster dose is also useful in immunocompromised persons. Their immune response is weak after normal vaccine schedule. Extra dose or high dose vaccine may help to produce protective immunity.
• After hematopoietic stem cell transplant (HSCT), old immune memory is lost. Because bone marrow cells are destroyed before transplant. So complete re-immunization and booster doses are needed again.
• Thus booster dose maintain long term protection. It strengthen old immunity. It also helps in protection against changed pathogen and weak immune persons.

Advantages of Active Immunization

• It gives long lasting protection. The immunity may remain for many years. Sometimes it remain for whole life.
• It produce immunological memory. Memory B-cells and memory T-cells are formed. These cells act fast during future infection.
• It gives immunity without severe natural infection. So disease, complication and death risk becomes less.
• It produces specific protection against selected antigen. The antigen may be protein, toxin or other protective part.
• When many persons are immunized, disease spreading becomes less. The chain of transmission is broken. This is called herd immunity.
• It also protect weak and vulnerable persons indirectly. Newborn, old person and immunocompromised patient get protection from immunized population.

Limitations of Active Immunization

• It does not give protection immediately. The body need time to form immune response. Usually 10 to 14 days are needed and sometimes few weeks also.
• During this early period, person may still get infection. Because protective antibody and memory cells are not formed properly yet.
• Booster dose may be required. Antibody level may decrease slowly with time. So immunity may not remain sufficient without booster.
• Some viruses change their antigen by mutation. This is called antigenic drift. Due to this, old vaccine may not give complete protection.
• Vaccine failure may occur in some persons. It may be due to old age, weak immune response or presence of many strains of pathogen.
• In immunocompromised person, vaccine response is often weak. The body cannot produce good protective immunity. So vaccine may become less effective.
• Live attenuated vaccine cannot be given to some persons. In severely immunocompromised person, it may cause severe infection. It is also generally avoided during pregnancy.
• Some side effects may occur after vaccination. Common effects are pain, swelling at injection site and fever. These are usually mild and temporary.
• Rare severe reactions may occur. These include anaphylaxis, myocarditis or Guillain-Barré syndrome (GBS). These are very uncommon but important limitation.

Clinical Applications of Active Immunization

• It is mainly used for prevention of infectious disease. It gives long term protection. The person does not suffer from severe natural infection.
• It is used as routine prophylaxis in children and adults. Many diseases are prevented by vaccination. Such as measles, polio, diphtheria, tetanus, hepatitis B and others.
• It gives safe immunity without producing actual disease. So tissue damage, severe illness and death risk becomes reduced.
• It is also used after exposure in some dangerous infections. Mainly in rabies and tetanus. Vaccine is given after suspected exposure.
• In post exposure condition, active vaccine alone may not give immediate protection. Because active immunity takes about 10 to 14 days. So immunoglobulin may be given with vaccine.
• It is used to produce herd immunity in population. When many persons are vaccinated, disease transmission becomes less. The chain of spread is broken.
• It protect weak persons indirectly. Newborn baby, old person and severely immunocompromised patient may get protection from vaccinated people around them.
• It also reduce severity of disease. Sometimes vaccinated person may still get infection. But disease usually becomes mild than non-vaccinated person.
• In diseases like chickenpox and pertussis, vaccination can make the disease less severe. Serious complication becomes less.
• It is used for special risk group also. Vaccine timing may be adjusted before giving immunosuppressive therapy. Sometimes more dose are given to increase response.
• Cocooning method is also used. In this method, family members, close contacts and healthcare workers are vaccinated. It prevents entry of pathogen near weak patient.

Examples of Active Immunization

• Live vaccine– MMR vaccine, varicella vaccine, rotavirus vaccine, yellow fever vaccine, smallpox vaccine and BCG vaccine are examples.
• Killed vaccine– Inactivated polio vaccine (IPV), hepatitis A vaccine, injectable influenza vaccine, Q fever vaccine and rabies vaccine are examples.
• Toxoid vaccine– Tetanus toxoid and diphtheria toxoid are examples. These are prepared from inactivated toxin.
• Polysaccharide vaccine– Pneumococcal polysaccharide vaccine (PPSV23) is example. It is made from bacterial sugar coating.
• Conjugate vaccine– Haemophilus influenzae type b (Hib), pneumococcal conjugate vaccine (PCV13) and meningococcal vaccine (MenACWY) are examples.
• Recombinant vaccine– Hepatitis B vaccine, Human papillomavirus (HPV) vaccine and recombinant shingles vaccine (RZV) are examples.
• mRNA vaccine– Pfizer-BioNTech COVID-19 vaccine and Moderna COVID-19 vaccine are examples. These contain synthetic mRNA.
• Vector vaccine– AstraZeneca COVID-19 vaccine and Ebola vaccine are examples. These use harmless virus as carrier.

Comparison of Active and Passive Immunization

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