A Ready Reckoner for Vaccinations Swati Y Bhave, A Parthasarathy, Sangeeta Yadav
INDEX
×
Chapter Notes

Save Clear

Basic Immunology-related to VaccinationsCHAPTER 1

Naveen Thacker,
Swati Y Bhave
Immunity is the ability of the human body to tolerate the presence of material indigenous to the body “self”, and to eliminate foreign “nonself” material. Immunity is generally very specific to a single organism or group of closely related organisms.1
 
ACTIVE AND PASSIVE IMMUNITY
There are two basic mechanisms for acquiring immunity, active and passive.
Immunity
Active
Passive
Host's immune system
Produced by the person's own immune system.
Not produced by persons own immune system.
Mechanism
It is the stimulation of the immune system to produce antigen-specific humoral (antibody) and cellular immunity.
Provided by products that are produced by an animal or human and transferred to another human, usually by injection.
Degree of protection
Very good.
Often provides effective protection.
Duration of protection
Lasts for many years, often for a lifetime.
Protection is short lasting and wanes (disappears) with time, usually within a few weeks or months.
Common Example
Vaccinations.
Transplacental maternal antibodies.1
2
Immunity that lasts for a long-time preferably for life is preferable. Natural disease will give such immunity but will have associated complications. Vaccines interact with the immune system and often produce an immune response similar to that produced by the natural infection, but they 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.1
 
INNATE AND ADAPTIVE IMMUNITY
Immunity
Innate
Adaptive
Induction
Basic immunity of the body and comes into play within hours of the entry of an infective agent.
Triggered by antigen presentation by the cells of the innate immune system. It takes time to develop.
Components
Epithelial and mucosal barriers, the antibacterial chemicals in these barriers, phagocytes (neutrophils, macrophages and NK cells) as well as complement.
Humoral and cell mediated immunity.
Properties
It is not very specific as it is triggered by structures shared by different microbes instead of specific microbial antigens.
It is specific and has two arms: humoral immunity (B lymphocyte mediated) and cell mediated immunity CMI (T lymphocyte mediated).
Immune memory
There is no immune memory.
Possesses immune memory.
Role
Important role as the first line of defense. It also is the effector pathway of adaptive immunity.
Main defence against microbes. It has intense diversity and is capable of responding to millions of antigens.
3
 
HUMORAL AND CELL MEDIATED IMMUNITY
The immune system launches a defense against a foreign antigen which is called the immune response and usually involves the production of protein molecules, called antibodies (or immunoglobulins), and of specific cells (also known as cell-mediated immunity, CMI) whose purpose is to facilitate the elimination of foreign substances.
Humoral immunity
Cellular immunity
Role
Principal defense mechanism against extracellular microbes and their toxins.
Principal defense mechanism against intracellular microbes (bacteria/viruses).
Mechanism of action
Neutralization, complement activation or by promoting opsonophagocytosis.
The helper T cells secrete proteins called cytokines that stimulate the proliferation and differentiation of T cells as well as other cells including B lymphocytes, macrophages and other leukocytes such as the Natural killer (NK) cells.
Types
Antibodies are of several different types (IgG, IgM, IgA, IgD and IgE) and they differ in their structure, half life, site of action and mechanism of action.
The effectors of CMI, the T cells are of two types the helper T cells and the killer T cells.
 
HOW VACCINES PROVIDE PROTECTION?
  1. Most of the currently available vaccines provide protection through induction of B cells and production of antigen-specific antibodies. Antibodies either neutralize the antigen or promote opsonophagocytosis which results in early reduction of pathogen load and clearance of extracellular pathogens.
    4
  2. Another way vaccine provides protection is by induction of T cells by the cell mediated immunity. (a) The role of CMI in currently used vaccines is mainly by supporting antibody protection in T–dependent antigens. (b) Other less common mechanisms by which cell mediated immunity works are by cytotoxic CD8 + T lymphocytes that may limit the spread of infectious agents by recognizing and killing infected cells or secreting specific antiviral cytokines. Cellular immunity is essential for clearance of intracellular pathogens.
 
Specific Examples of Various Vaccines
BCG is the only currently used human vaccine for which there is conclusive evidence that T cells are the main effectors.2
There is indirect evidence that vaccine-induced T cells contribute to the protection conferred by other vaccines. CD4+ T cells seem to support the persistence of protection against clinical pertussis in children primed in infancy, after vaccine-induced antibodies have waned.2
Another example is that of measles immunization in 6-month-old infants. These infants fail to raise antibody responses because of immune immaturity and/or the residual presence of inhibitory maternal antibodies, but generate significant IFN-γ (Interferon Gamma) producing CD4 + T cells. These children remain susceptible to measles infection, but are protected against severe disease and death, presumably because of the viral clearance capacity of their vaccine-induced T cell effectors. Thus, prevention of infection may only be achieved by vaccine-induced antibodies, whereas disease attenuation and protection against complications may be supported by T cells even in the absence of specific antibodies.2
 
Sequence of Events after Vaccination
  • Following a vaccination by injection the vaccine antigens attract local and systemic dendritic cells, monocytes and neutrophils.
  • These activated monocytes and dendritic cells change their surface receptors and migrate along lymphatic vessels, to5 the draining lymph nodes where the activation of T and B lymphocytes takes place. So in case of a deltoid injection, the draining lymph nodes will be the axillary group and in the case of quadriceps injection, it will be the inguinal group of lymph nodes.
Vaccine
Live
Non-live
Action
These antigen replicate, disseminate and activate dendritic cells at multiple sites, which migrate towards the corresponding draining lymph nodes and launch multiple foci of T and B cell activation.
There is no microbial replication at the site of injection hence the vaccine-induced activation of dendritic cells (DCs) remains more limited, both in time and space.
Immunogenicity
High.
Limited as compared to live vaccines.
Site and route of adminis-tration
Minor importance, IM (intramuscular) has same effect as SC (Subcutaneous) injection.
Limited activation has implications related to route and site of administration. DCs numerous in the well-vascularized muscles, thus IM route is the best.
DCs are fewer in adipose tissues, therefore, SC injections may be less effective than IM injections under conditions of limited immunogenicity, e.g. adult immunization against hepatitis B.
Dendritic cells are in highest number in the skin – this allows a marked reduction (e.g. 10 fold) of the antigen dose in ID (Intradermal) route which can be advantageous in immunization, e.g. Rabies.2
Immune interference
Yes, unless given on same day or with different routes of administration, e.g. OPV with injectable polio vaccine.
Simultaneous administration of several distinct vaccines may take place without immune interference if vaccines are administered at sites draining into distinct lymph node areas.
6
 
IMPORTANT POINTS TO REMEMBER FOR VACCINE RESPONSES TO POLYSACCHARIDE ANTIGENS
  1. Polysaccharide antigen released from the injection site essentially reach the marginal zone of the spleen/lymph nodes.
  2. B cells use their specific Ig surface receptors to bind to the repetitive structures of polysaccharides.
  3. In the absence of antigen-specific T cell help, B cells are activated, they proliferate and differentiate in plasma cells without undergoing affinity maturation in germinal centers.
  4. These plasma cells migrate towards the red pulp of the spleen where they survive for a few weeks/months, secreting low levels of low affinity IgM, IgG or IgA antibodies.
  5. So polysaccharide (PS) antigens induce only extra-follicular phase resulting in induction of moderate titers of low-affinity antibodies. There is production of only short lived plasma cells and no long lived plasma cells are formed.
  6. As polysaccharide antigens do not induce germinal centers, bonafide memory B cells are not elicited so there is absence of immune memory.
  7. Consequently, subsequent re-exposure to the same polysaccharide results into a repeat primary response that follows the same kinetics as in previously vaccinated and in naïve individuals.2
  8. Revaccination with certain bacterial PS - of which group C Meningococcus is a prototype—may even induce lower antibody responses than the first immunization, a phenomenon referred to as hyporesponsiveness and whose molecular and cellular basis is not yet fully understood.2
  9. Due to the phenomena of immunologic hypo-responsiveness only a single booster of either pneumococcal or meningococcal polysaccharide vaccine is recommended even in patients who require life-long protection.
 
IMPORTANT POINTS TO REMEMBER FOR VACCINE RESPONSES TO PROTEIN ANTIGENS
  1. In response to a protein antigen reaching lymph nodes or spleen, extrafollicular reaction is same as in PS antigen B cells rapidly differentiate in plasma cells that produce7 low affinity antibodies (of the IgM +/- IgG/IgA isotypes) that appear at low levels in the serum within a few days after immunization.
  2. Antigen-specific helper T cells that have been activated by antigen-bearing dendritic cells trigger some antigen-specific B cells to migrate towards follicular dendritic cells (FDCs), initiating the germinal center (GC) reaction.
  3. In GCs, B cells receive additional signals from follicular T cells (Tfh) and undergo massive clonal proliferation, switch from IgM towards IgG, IgA or IgE, and undergo affinity maturation and differentiate into plasma cells secreting large amounts of antigen-specific antibodies.2
  4. Most of the plasma cells die at the end of germinal center reaction and thus a decline in antibody production and thus resultant decline in antibody levels is noted 4–8 weeks after vaccination. However, a few plasma cells exit nodes/spleen and migrate to survival niches mostly located in the bone marrow, where they survive through signals provided by supporting stromal cells. This results in prolonged production of antibodies and persistence of antibodies in the serum.2
All protein containing vaccines (T cell dependent vaccines) whether live or non-live induce immunologic memory, e.g. DPT, Pneumococcal Conjugate Vaccine, MMR. Non-protein containing vaccines (T cell independent vaccines) do not induce memory as explained earlier, e.g. 23 Pneumococcal vaccine, Typhoid polysaccharide vaccine.
 
IMPORTANT POINTS TO REMEMBER FOR NEED OF MORE THAN ONE DOSE FOR PRIMARY IMMUNIZATION AND THE REQUIREMENT OF BOOSTER DOSES IN SOME VACCINATIONS
  1. Memory B cells do not produce antibodies unless re-exposed to antigen which drives their differentiation into antibody producing plasma cells. When the second exposure with the similar antigen occurs at a short interval from the first dose, it triggers off a second wave of primary response rather8 than a true boosting response. Due to this the antibody levels attained are not very high. Most of the childhood vaccines like DPT, Hib, Injectable polio require booster doses.
  2. When the second antigenic exposure occurs after a long interval between two doses (4 months) then an exuberant booster response is elicited. This is due to affinity maturation of B cells that results in high levels of antibodies of high affinity. This is why ideal schedule for hepatitis B vaccine is considered to be 0-1-6 though other schedules are acceptable.
  3. Factors that derive the differentiation of B cells in germinal center towards either plasma cells or memory B cells differentiation are poorly understood. As a rule factors enhancing plasma cells and primary antibody responses therefore, also support induction of memory B cells. Higher post primary antibody titres reflect stronger GC reactions and generally predict higher secondary responses.2
  4. Dose of antigen is important determinant of memory B cell responses. At priming—higher antigen dose favors induction of plasma cells, whereas lower dose may favor induction of memory B cells. Thus, a lower antigen dose is preferred when rapid induction of protection is not required. At the time of boosting a higher antigen content raises strong booster response by engaging more B memory cells.2
 
SUMMARY
Vaccinations are safe and effective methods of inducing long-term immunity in the host when given in the appropriate dosage, at the correct age and in the correct interval and at the appropriate site by the best indicated route. It is important for a clinician to understand the basic immunological response of the vaccine he is administering so as to yield the best results. Understanding the basic immunology will also help us to understand the nuances of the newer vaccines that will be coming into practice in the coming years.
REFERENCES
  1. Principles of Immunization. In “Epidemiology of vaccine preventable diseases: CDC 2007, Chapter 1, 1–3.
  1. Siegrist CA. Vaccine Immunology. In: Vaccines. 5th edition. Elsevier.  2007,2,20–34.