Page 14: Canadian Immunization Guide: Part 1 - Key Immunization Information

Basic Immunology and Vaccinology

Introduction

Immunology is the study of the structure and function of the immune system. Vaccinology is the science of vaccine development and how the immune system responds to vaccines, as well as the ongoing evaluation of immunization programs, vaccine safety and effectiveness, and surveillance of the epidemiology of vaccine preventable diseases. This chapter provides a brief overview of some of the main concepts of immunology and vaccinology as they relate to immunization. A detailed review of immunology and vaccinology is beyond the scope of the Canadian Immunization Guide.

Human Immune System

Components of the immune system

An antigen is a substance that the body may recognize as foreign and that may trigger immune responses. The terms immunogen and antigen are often used interchangeably.

Antibodies are proteins that are produced in response to antigens introduced into the body. Antibodies protect the body from disease by:

  • binding to the surface of the antigen to block its biological activity (neutralization)
  • binding to the antigen that coats the surface of the infectious agent to make it more susceptible to clearance (phagocytosis) by phagocytes (opsonization)
  • binding to specialized cells of the immune system, allowing them to recognize and respond to the antigen
  • activation of the complement system to directly cause disintegration (lysis) of the infectious agent (pathogen) to enhance its phagocytosis, and to attract other immune cells towards the pathogen.

Immune responses

Immunity is the ability of the human body to protect itself from infectious diseases. The human immune system is able to react to an enormous number and variety of foreign antigens and provides immunity through two complementary types of responses:

  • Innate immunity is the body’s initial defense mechanism that comes into play immediately or within hours of a pathogen’s entry into the body. Innate immunity is made up of physical barriers (skin and mucous membranes); physiologic defenses (temperature, low pH and chemical mediators); evolutionarily-conserved pattern recognition receptors that react to protein signatures on microbes (i.e. pathogen associated molecular patterns), as well as phagocytic and humoral inflammatory responses. Innate immunity:
    • does not depend upon previous exposure to the pathogen
    • does not produce immunologic memory
    • does not improve with repeated exposure to the pathogen.
  • Adaptive immunity is the body’s second level of defense, which develops as a result of infection with a pathogen or following immunization. Adaptive immunity defends against a specific pathogen and takes several days to weeks to become protective. Adaptive immunity:
    • has the capacity for immunologic memory
    • provides long term immunity which may persist for a lifetime 
    • increases in strength and precision each time it encounters a specific antigen.

The cells of the adaptive immune system include specialized white blood cells (B and T lymphocytes) which can contribute to either cell-mediated immunity or antibody-mediated (humoral) immunity:

  • Cell-mediated immunity provides protection through the activation of T cells which can destroy infected host cells or stimulate other immune cells to directly destroy pathogens.
  • Antibody-mediated (humoral) immunity provides protection through the activation of B cells which produce antibodies. The terms antibody and immunoglobulin or immune globulin (Ig) are often used interchangeably. There are five types (classes) of antibodies: IgA, IgD, IgE, IgG and IgM (IgA and IgG also have several subclasses).  Each class of antibody has a different way of contributing to immunity.

Immunologic memory is the immune system’s ability to remember its experience with an infectious agent, leading to effective and rapid immune response upon subsequent exposure to the same or similar infectious agents. Development of a complete immunologic memory requires participation of both B and T cells; memory B cell development is dependent on the presentation of antigens by T cells.

Immunizing Agents

Immunization refers to the process by which a person becomes protected against a disease through exposure to immunizing agents. Immunizing agents are classified as active or passive, depending on the process by which they confer immunity; prevention of disease through the use of immunizing agents is called immunoprophylaxis. 

Active immunization is the inherent production of antibodies against a specific agent after exposure to the antigen through vaccination. Active immunizing agents are typically referred to as vaccines. Refer to vaccine-specific chapters in Part 4 for information about active vaccines. 

Passive immunization involves the transfer of pre-formed antibodies, from one person to another or from an animal product, to provide immediate, temporary protection from infection or to reduce the severity of illness caused by the infectious agent. Protection provided by passive immunization is temporary because the transferred antibodies degrade over time. Passive immunization can occur by transplacental transfer of maternal antibodies to the developing fetus, or it can be provided by systemic administration of a passive immunizing agent.

Vaccines

Vaccines are complex biologic products designed to induce a protective immune response effectively and safely. An ideal vaccine is: safe with minimal adverse effects; effective in providing lifelong protection against disease after a single dose that can be administered at birth; inexpensive; stable during shipment and storage; and easy to administer. Some vaccines come closer to fulfilling these criteria than others. Although each vaccine has its own benefits and risks, and indications and contraindications, all vaccines offer protection against the disease for which they were created.

Vaccines are classified according to the type of active component (antigen) they contain and are most often categorized in two groups - live attenuated vaccines and inactivated vaccines:

  • Live attenuated vaccines contain whole, weakened bacteria or viruses. Since the agent replicates within the vaccine recipient, the stimulus to the immune system more closely resembles that associated with natural infection, resulting in longer lasting and broader immunity than can be achieved with other vaccine types. Because of the strong immunogenic response, live attenuated vaccines, except those administered orally, typically produce immunity in most recipients with one dose; however, a second dose helps to make sure that almost all vaccine recipients are protected, because some individuals may not respond to the first dose. Live vaccines require careful storage and handling to avoid inadvertent inactivation. 
  • Inactivated vaccines contain whole or parts of an inactivated (killed) bacteria or viruses; products secreted by bacteria that are modified to remove their pathogenic effects (toxoids); or parts of a bacteria or virus obtained through recombinant technology. Inactivated vaccines cannot cause the disease they are designed to prevent. Because the immune response to inactivated vaccines may be less than that induced by live organisms, inactivated vaccines often require adjuvants and multiple doses. The initial doses prime the immune system and are called primary vaccination or the primary series. As protection following primary vaccination diminishes over time, periodic supplemental doses (booster doses) may be required to increase or boost antibody levels.
    • In addition to the active component (antigen in case of vaccines or antibody in case of immune globulins), immunizing agents may contain additional ingredients such as preservatives, additives, adjuvants and traces of other substances. Refer to Contents of Immunizing Agents Available for Use in Canada for more information.

Immune globulins

Passive immunization with immune globulins provides protection when vaccines for active immunization are unavailable or contraindicated, or in certain instances when unimmunized individuals have been exposed to the infectious agent and rapid protection is required (post-exposure immunoprophylaxis). Passive immunization also has a role in the management of immunocompromised people who may not be able to respond fully to vaccines or for whom live vaccines may be contraindicated. The duration of the beneficial effects provided by passive immunizing agents is relatively short and protection may be incomplete.

Vaccine Development

How vaccines are developed

New vaccines undergo a very rigorous development process.  The first steps in the development of a vaccine include the identification of the microorganism or toxin that causes a significant burden of disease in the population, and an understanding of the biological mechanisms occurring in the development of the disease (pathogenesis). Once the pathogen and pathogenesis are understood, research is initiated into the possibility of developing a vaccine to reduce the disease incidence, or severity, or both. Pre-clinical laboratory testing is carried out to ensure that the candidate vaccine produces the immune response needed to prevent disease and has no toxicities that would prevent its use in people. Clinical trials (human studies) then proceed through several phases involving progressively more study subjects. Vaccine Safety in Part 2 describes pre-clinical and clinical research throughout the vaccine life cycle and the accompanying regulatory requirements to ensure data and product quality.

How Vaccines Work

Vaccines work at an individual level to protect the immunized person against the specific disease, as well as at a population level to reduce the incidence of the disease in the population, thereby reducing exposure of susceptible persons and consequent illness. Although the primary measure of effectiveness occurs at an individual level, there is also interest in decreasing or even eliminating disease at a population level.

How vaccines work at the individual level

Administration of a vaccine antigen triggers an inflammatory reaction that is initially mediated by the innate immune system and subsequently expands to involve the adaptive immune system through the activation of T and B cells. While the majority of vaccines provide protection through the induction of humoral immunity (primarily through B cells), some vaccines, such as BCG and herpes zoster vaccines, act principally by inducing cell-mediated immunity (primarily though T cells). Many vaccines probably work through both, although humoral immunity is the basis most often used as a marker of how well a vaccine works.

Long-term immunity requires the persistence of antibodies, or the creation and maintenance of antigen-specific memory cells (priming) that can rapidly reactivate to produce an effective immune response upon subsequent exposure to the same or similar antigen.

Markers of protection induced by vaccination

A correlate of protection is a specific immune response that is responsible for and statistically linked to protection against infection or disease. Following administration of most vaccines, prevention of infection has been shown to correlate predominantly with the production of antigen-specific antibodies. The quantity and functional activity of antibodies can be measured using serological assays such as the enzyme-linked immunosorbent assay (ELISA), serum bactericidal antibody assay (SBA), and the opsonophagocytic assay (OPA). In cases when a correlate of protection cannot be determined, a substitute (surrogate) immune marker is used. Surrogate markers may not be directly linked to protection against infection or disease. For example, vaccines against rotavirus produce both mucosal and serum antibodies. Whereas serum antibodies are not directly protective against rotavirus infection, they serve as a surrogate of protection since mucosal antibodies are difficult to measure.

Immunogenicity means the vaccine’s ability to induce an immune response. Vaccine-induced seroconversion is the development of detectable antigen-specific antibodies in the serum as a result of vaccination; seroprotection is a predetermined antibody concentration as a result of vaccination, above which the probability of infection is low. The seroprotective antibody concentration differs depending on the vaccine.

How vaccines work at the population-level

Vaccine efficacy refers to the vaccine’s ability to prevent illness in people vaccinated in controlled studies. Vaccine effectiveness refers to the vaccine’s ability to prevent illness in people in the “real world”.

Herd immunity refers to the immunity of a population against a specific infectious disease. The resistance of that population to the spread of an infectious disease is based on the percentage of people who are immune and the probability that those who are still susceptible will come into contact with an infected person. The proportion of the population required to be immune to reach herd immunity depends on a number of factors, the most important one being the transmissibility of the infectious agent either from a symptomatically infected person or from an asymptomatically colonized person.

The reproduction number (R0), also called the basic reproductive rate, is defined as the average number of transmissions expected from a single primary case introduced into a totally susceptible population. Diseases that are highly infectious have a high R0 (for example, measles) and require higher immunization (vaccine) coverage to attain herd immunity than a disease with a lower R0 (for example, rubella, Haemophilus influenzae type b). Immunization coverage refers to the proportion of the population (either overall or for particular risk groups) that has been immunized against a disease. To stop transmission of a given disease, there needs to be at least a specified percentage (1 minus 1/R0) of the population immune to the disease. For example, measles has an estimated R0 of 15; therefore, at least 94% (1 minus 1/15 = 94%) of the population needs to be immune to prevent transmission of measles. 

Determinants of vaccine response in individuals

The strength and duration of the immune system’s response to a vaccine is determined by a number of factors as outlined in Table 1.

Table 1: Determinants of Vaccine Response in Individuals
Determinants of Vaccine Response Explanation
Vaccine type

The type of vaccine antigen and its immunogenicity directly influence the nature of the immune response that is induced to provide protection:

  • Live attenuated vaccines generally induce a significantly stronger and more sustained antibody response.
  • Inactivated vaccines often require adjuvants to enhance antibody responses, usually require multiple doses to generate high and sustained antibody responses, and induce vaccine antibodies that decline over time below protective thresholds unless repeat exposure to the antigen reactivates immune memory. Pure polysaccharide vaccines induce limited immune response and do not induce immunologic memory.
Vaccine adjuvants and carrier proteins
  • The addition of adjuvants to inactivated vaccines enhances the immune response and extends the duration of B and T cell activation.
  • Conjugating (linking) a polysaccharide with a carrier protein (protein that is easily recognized by the immune system such as diphtheria or tetanus) leads to a significantly higher immune response.
Optimal dose of antigen
  • Higher doses of inactivated antigens, up to a threshold, elicit higher antibody responses.
Interval between doses
  • The recommended interval between doses allows development of successive waves of antigen-specific immune system responses without interference, as well as the maturation of memory cells.
Age of vaccine recipient
  • In early life, the immune system is immature, resulting in limited immune responses to vaccines. For example, children less than 2 years of age do not respond to polysaccharide-based vaccines.
  • In general, antibody responses to vaccines received early in life decline rapidly for most, but not all (for example, hepatitis B) vaccines.
  • In older age, immune responses decline (immunosenescence) and can result in a reduction in the strength and persistence of antibody responses to vaccines and in an increased incidence and severity of infectious diseases.
Pre-existent antibodies
  • The immune response to vaccines received early in life may be influenced by the presence of maternal antibodies transferred across the placenta.
  • The immune response to live vaccines will be influenced by passively transferred antibodies, such as after blood product transfusion or receipt of immune globulins. Refer to Blood Products, Human Immune Globulin and Timing of Immunization in Part 1 for additional information.
Status of the immune system

Epidemiology and Immunization

Epidemiology provides data on the distribution and determinants of diseases. Epidemiology informs the first steps in vaccine development by describing the diseases caused by a pathogen in a particular population and indicating the need for vaccine development. As a vaccine is introduced into the population, epidemiology monitors the effect of the vaccine in the population by describing changes in the disease burden and the pathogens causing that disease. Epidemiology can also provide information regarding immunization coverage and vaccine safety.

Surveillance is the process of systematic collection, orderly analysis, evaluation and reporting of epidemiological data to inform disease control measures or policy decisions, or both. Surveillance of vaccine preventable diseases, including immunization coverage and vaccine safety, is needed to:

  • identify and quantify risk factors to enable appropriate control of communicable diseases.
  • assist in the investigation, containment and management of vaccine preventable disease outbreaks or a signal of adverse events following immunization.
  • monitor progress toward the achievement of set goals and targets in disease control programs.
  • provide up-to-date information to assist in the development of evidence-based guidelines.

Determining the burden of disease is important in setting immunization priorities. Burden of disease includes: the prevalence (total number of cases of a disease in a geographic area); the incidence (number of new cases of a disease in a geographic area over a specified period of time); the age or risk group that is most affected (for example, infants, children, adults, the elderly, immunocompromised persons); the severity of the disease (for example, as measured by time missed from work, hospitalization, complications or death); and the risk factors for disease that should be considered. These factors are particularly important when making vaccine recommendations regarding:

  • populations who are susceptible to the disease and who require the direct protection of a vaccine; and
  • populations who require indirect protection through herd immunity because they are susceptible to the disease but may not be the ideal target group to receive the vaccine.

Evaluation of vaccine programs is the systematic investigation of the structure, activities, or outcomes of public health programs. It explores whether or not activities are implemented as planned and outcomes have occurred as intended, and why. Evaluation can help to support program implementation and build on the program monitoring activities that immunization programs currently conduct to assess whether program objectives have been met.

Future of Vaccinology

Ongoing scientific advances in biotechnology, genetics, immunology and virology are providing new tools for vaccine development. This knowledge provides the basis for improving the effectiveness of existing vaccines, as well as the development of new vaccines and vaccine delivery systems. These ongoing scientific advances in vaccine development need to be accompanied by scientific advances in epidemiological methods which can continue to inform the development and monitoring of new vaccines.  The following are a few emerging areas in vaccinology, some form the foundation of basic research studies and some are already being tested in clinical trials around the world:

  • Reverse vaccinology and bioinformatics: the broad sequencing of pathogen genomes allows the development of experimental vaccines for new candidate proteins/antigens that had not been previously identified.
  • Viral or bacterial vector vaccines: a few genes coding for pathogen antigens can be inserted into a completely different benign virus or bacteria, which can then be used to infect the host and provide a safe active supply of the target antigens to promote strong immunity.
  • DNA vaccines: DNA sequences coding for pathogen antigens can be stored on a bacterial plasmid, which is then taken into host cells upon injection of the DNA plasmid.  The harmless vaccine antigens can then be actively produced by host cells.
  • Recombinant subunit vaccines: several vaccines are currently produced in chicken eggs, but recombinant DNA technologies have been developed that allow vaccine proteins to be expressed by alternative cell types in controlled settings, including insect, plant, yeast, and mammalian cells.  These provide good avenues for the rapid large-scale production of antigens to be used in vaccines.
  • Personalized vaccinomics: different populations and individuals have different immune profiles, for example infants versus the elderly, and different adjuvant-vaccine combinations may be necessary to optimize individual vaccine responses.  As new screening technologies are developed it may be possible to provide individuals with vaccines tailored to their immune system, thus improving vaccine immunogenicity or effectiveness, and preventing vaccine failure or adverse events.
  • Adjuvant technologies: new adjuvants are being developed that can enhance the type of immune response (humoral versus cell-mediated) desired to eliminate specific pathogens; these adjuvants provide better immunity and can allow for a lower dose of antigen within the vaccine.  Furthermore, new research into the innate immune system is informing the development of adjuvants that make better use of innate immune mechanisms to direct adaptive immunity.

For further information please see the selected references below.

Selected References

  • Andre FE, Booy R, Bock HL et al. Vaccination greatly reduces disease, disability, death and inequity worldwide. Bull World Health Organ 2008;86(2):140-6.
  • BC Centre for Disease Control. Immunization Coverage. Accessed July 2015 at: http://www.bccdc.ca/imm-vac/BCImmunizationCov/default.htm.
  • Canadian Paediatric Society in association with the Public Health Agency of Canada and Health Canada. Immunization Competencies Education Program. 2011.
  • Centers for Disease Control and Prevention. Immunization: The Basics. Accessed December 2016 at http://www.cdc.gov/vaccines/vac-gen/imz-basics.htm.
  • Loomis RJ and Johnson PR. Emerging Vaccine Technologies. Vaccines 2015; 3(2):429-47.
  • Nabel GJ. Designing Tomorrow’s Vaccines. N Eng J Med 2013;368(6): 551-60.
  • Pasquale AD, Press S, Silva FT, Garcon N. Vaccine Adjuvants: from 1920 to 2015 and beyond. Vaccines 2015; 3(2):320-34.
  • Plotkin SA. Correlates of protection induced by vaccination. Clin Vaccine Immunol 2010;17(7):1055-65.
  • Plotkin SA. Correlates of vaccine-induced immunity. Clin Infect Dis 2008;47 (3):401-09.
  • Plotkin SA, Orenstein WA, Offit PA, eds. Vaccines. 5th ed. Philadelphia, PA: Elsevier Health Sciences; 2008.
  • Poland GA, Kennedy RB, McKinney BA et al.  Vaccinomics, adversomics, and the immune response network theory: individualized vaccinology in the 21stcentury. Semin Immunol 2013; 25(2):89-103.
  • Public Health Agency of Canada. Immunization Competencies for Health Professionals. 2008. Accessed July 2015 at: http://healthycanadians.gc.ca/publications/healthy-living-vie-saine/immunization-competencies-competences-immunisation/index-eng.php
  • Pulendran B, Ahmed R. Immunological mechanisms of vaccination. Nat Immunol 2011;12(6):509-17.
  • Warrington R, Watson W, Kim HL et al. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol 2011;7 Suppl 1:S1.
  • Weinberger B, Herndler-Brandstetter D, Schwanninger A et al. Biology of Immune Responses to Vaccines in Elderly Persons. Clin Infect Dis. 2008;46(7):1078-84.
  • World Health Organization. Protocol for the Assessment of National Communicable Disease Surveillance and Response Systems, Annex 1.0 Surveillance Definitions. Accessed July 2015 at: http://www.who.int/csr/resources/publications/surveillance/whocdscsrisr20012.pdf. 
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