Basic immunology and vaccinology: Canadian Immunization Guide

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Last complete chapter revision: October 2024

This chapter has undergone a complete update to reflect current insights in the evolving fields of immunology and vaccinology. Building upon the foundational concepts previously introduced in the chapter, this update aims to capture the current state of understanding and provide general information on emerging research areas within these domains.

This information is captured in the table of updates.

On this page

• Introduction
• Components of the immune system
• Immune responses
• Immunizing agents
  • Vaccines
    • Table 1. Determinants of vaccine response in individuals
  • Immunoglobulins
    • Table 2. Types of immunizing agents
• Evolving landscape of vaccinology
• Acknowledgements
• Selected references

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. Furthermore, it aims to provide healthcare providers with the foundational knowledge essential for better understanding of the importance of vaccine recommendations in the Canadian Immunization Guide (CIG), the rationale behind them, and how these recommendations are rooted in immunological principles. A detailed review of immunology and vaccinology is beyond the scope of the CIG.

Components of the immune system

B Cells

B cells, or B lymphocytes, are a type of specialized white blood cell that recognizes and responds to antigens by producing antibodies. They contribute to the body's long-term ability to prevent disease through the establishment of memory B cells.

Antibodies

Specialized white blood cells known as B lymphocytes (B cells) produce proteins called antibodies in response to antigens introduced into the body. Antibodies are the main component of the humoral immune system. They travel throughout the body and are specific to sites of their corresponding antigens. There are many types of antibodies and they protect the body from disease by clearing pathogens through:

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

The specificity and strength of the binding interaction between an antibody and an antigen is known as antibody affinity. A higher affinity indicates a stronger and more stable binding between the antibody and the antigen, while a low affinity indicates a weaker and less stable binding between the antibody and its target antigen. Over time, the immune system adapts to improve the affinity of antibodies for their target antigens. This adaptive immune response is important for establishing long-lasting immunity and the effectiveness of immunizing agents. This is referred to as affinity maturation.

Monoclonal antibodies (mAbs) are synthetic antibodies that can be given to patients as preventative drugs or treatments.

T Cells

T cells, or T lymphocytes, are a type of specialized white blood cell that can directly kill infected cells and are involved in providing support to other components of the immune system, such as helping B cells produce antibodies.

Immune responses

Immunity is the ability of the human body to protect itself from infectious diseases. Immunogen or antigen is a substance that the body may recognize as foreign and that triggers an immune response. The terms immunogen and antigen are often used interchangeably. Antigens could be derived from infectious agents such as viruses or bacteria, or they can be designed synthetically to resemble an antigen. The same antigen may elicit different immune responses based on presentation to the immune system, including the platform, the site, the type of administration and alterations to the structure of the antigen itself.

Immunologic memory is the immune system's ability to remember its experience with an antigen and is the basis for the long-lasting protection provided by immunizing agents. Immunological memory is a key feature of the adaptive immune response and leads to effective and rapid immune responses upon subsequent exposure to the same or similar immunogen. Long-term immunity requires the persistence of antibody-producing plasma cells, 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. Development of complete immunologic memory requires participation of both B and T cells; memory B cell development and affinity maturation is dependent on the presentation of antigens by T cells.

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 molecular signatures of pathogens (i.e., pathogen associated molecular patterns), as well as phagocytic and humoral inflammatory responses. In general, innate immunity:
  • involves a generalized response (non-specific to a particular pathogen)
  • does not depend upon previous exposure to the pathogen
  • does not produce long-term immunologic memory
  • does not increase in strength and precision 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 (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.

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. The development of an immune response to an immunizing agent depends on several factors, including the type of agent, the recipient's age, prior exposure to the antigen, and the presence of immune-compromising conditions.

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. For many active immunizing agents, a protective immune response is typically achieved within a few weeks of vaccination. For example, it takes about two weeks after vaccination to reach the protective levels of humoral antibodies that are associated with immunity to influenza infection. Refer to vaccine-specific chapters in Part 4 for information about active vaccines. Passive immunization involves the transfer of pre-formed antibodies (including mAbs) to provide immediate, temporary protection from infection or to reduce the severity of illness caused by the infectious agent. Passive immunization can occur by transplacental transfer of maternal antibodies to the developing fetus, or it can be provided by administration of a passive immunizing agent. Protection provided by passive immunization is immediate upon administration but temporary and typically of shorter duration compared to active immunization because the transferred antibodies degrade more quickly over time. These general principles are important for health care providers to understand the timing of protection induced by both active and passive immunizing agents and to advise individuals appropriately, especially those at high risk of exposure to infectious diseases before or after immunization.

In addition to the active component (antigen in case of vaccines or antibody in case of immunoglobulins), immunizing agents may contain additional ingredients such as preservatives, additives, adjuvants and traces of other substances. Refer to Contents of immunizing agents authorized for use in Canada for more information.

Vaccines

Vaccines are complex biologic products designed to induce a protective immune response effectively and safely. They have historically been developed and tested for their ability to elicit a humoral (antibody-based) immune response. 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, risks, indications and contraindications, all vaccines offer protection against the disease for which they were created.

All 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 an important burden of disease in the population. Once the pathogen is identified, 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 participants. Vaccine safety and pharmacovigilance 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.

A vaccine is authorized based on its efficacy and/or ability to generate strong immune responses against the pathogen it was designed to target. Some pathogens change or evolve over time, resulting in new characteristics that were not present in the initial 'parent' virus; this is particularly true for rapidly changing viruses that are passed back and forth between humans and animals (i.e., zoonotic pathogens) or that infect large groups of people. In cases of pathogens that evolve over time and generate new variants, vaccine protection may not be as protective against new variant versions of the pathogen. If immune-evasive variants become prevalent enough to cause significant disease burden, this may warrant a change in the antigen composition of existing vaccines. This can make the vaccine development challenging as new iterations of the vaccine could be required periodically to target prevalent immune-evasive variants.

Vaccines can be classified according to the type of active component (antigen) they contain and their replication capacity. Generally, vaccines are most often categorized in two groups – live attenuated vaccines and non-live vaccines:

• Live attenuated vaccines contain whole, weakened bacteria or viruses that have the capacity to replicate within a host. Thus, the stimulus to the immune system of a vaccine recipient 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.
• Non-live vaccines contain whole inactivated (killed) bacteria or viruses, their parts, or products secreted by bacteria that are modified to remove their pathogenic effects (toxoids). Non-live vaccines also include messenger ribonucleic acid (mRNA) vaccines. Non-live vaccines cannot cause the disease they are designed to prevent. Because the immune response to non-live vaccines may be less than that induced by live organisms, they 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.

Vaccines can also be categorized into replicating and non-replicating:

• In non-replicating vaccines, the infectious agent or its components are incapable of replicating within the vaccinated individual. Non-replicating vaccines are often safer for individuals with weakened immune systems, as there is no risk of the vaccine strain causing disease.
• Replicating vaccines are typically live vaccines, where the weakened or attenuated bacteria or viruses have the ability to replicate within the vaccinated individual. A replicating immunogen elicits a more robust and prolonged immune response, contributing to longer-lasting immunity. To date, the majority of live attenuated vaccines are also replicating, and thus are usually contraindicated in individuals with weakened immune systems. However, some live vaccines are non-replicating as is the case for Imvamune^®, making them safe for administration in immunocompromised populations where the use of live vaccines would otherwise be contraindicated.

The distinction between live and non-live vaccines relates to whether the vaccine contains live forms of the infectious agent. Live vaccines can be further categorized into replicating and non-replicating vaccines. Replicating live vaccines contain live forms of the infectious agent capable of replicating within a vaccinated individual, while non-replicating live vaccines contain live forms of the infectious agent that cannot replicate within a vaccinated individual. Non-live vaccines do not contain any live infectious agents. These distinctions impact the nature of the immune response generated and pose important considerations for vaccine safety in special populations.

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.

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 have been studied to provide protection through the induction of humoral immunity (primarily through B cells), some vaccines, such as Bacille Calmette-Guérin (BCG) and live herpes zoster vaccines, act principally by inducing cell-mediated immunity (primarily though T cells). Long-term protection requires activation of both T and B cells. Although humoral immunity is the basis most often used as a marker of how well a vaccine works study of cellular immune markers of protection is an area of active research.

Vaccine efficacy refers to the vaccine's ability to prevent illness in people vaccinated in controlled studies that are carried out under strict clinical trial protocols, where participants are included or excluded based on pre-specified criteria and may be blinded as to whether or not they are receiving a vaccine or comparator (often a placebo). Vaccine effectiveness refers to the vaccine's ability to prevent illness in people in the "real world" and is often determined through observational studies, where participants who receive a vaccine or comparator have chosen to do so based on individual clinical decision making and are not blinded. Vaccine efficacy is a measure of how well a vaccine works when given in ideal, controlled conditions, while vaccine effectiveness is a measure of how well a vaccine works under normal use in the real world, including in populations that may have been excluded from clinical trials, and is subject to biases inherent to observational studies.

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.

Markers of protection induced by vaccination

Immunogenicity means the vaccine's ability to induce an immune response. A correlate of protection is a measure of a specific immune response that is 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. 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. Different correlate and surrogate correlate markers may be relevant across different populations.

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, above which the probability of infection is low. The seroprotective antibody concentration differs depending on the vaccine. The quantity and functional activity of antibodies can be measured using laboratory tests such as the enzyme-linked immunosorbent assays (ELISA), serum bactericidal antibody assays, virus neutralization assays and the opsonophagocytic activity assays. These assays are highly specific to the disease system. In addition, correlates of cellular immune responses may also provide valuable insight. These markers and mechanisms of protection may vary according to different attributes of the individual, including age, pregnancy, underlying medical condition and more.

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.

Immunoglobulins

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 people who are immunocompromised who may not be able to respond adequately 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. Refer to Table 2 in Contents of immunizing agents authorized for use in Canada in Part 1 for a list of all passive immunizing agents authorized for use in Canada and their contents.

There are two types of antibody preparations available:

• Standard immunoglobulin (Ig) of human origin – sometimes referred to as "immune serum globulin", "serum immune globulin" or "gamma globulin"
• Specific immunoglobulins of human or animal origin – containing high titres of specific antibodies against a particular microorganism or its toxin. Products of human origin are preferred over those of animal origin because of the high incidence of adverse reactions to animal sera and the longer lasting protection conferred by human immunoglobulins.

Standard immunoglobulin (human)

Standard human Ig, GamaSTAN^®, is a sterile, concentrated solution for intramuscular (IM) injection containing 15 to 18% Ig. It is obtained from pooled human plasma from screened donors and contains mainly IgG with small amounts of IgA and IgM.

Subcutaneous (SC) and intravenous (IV) Ig preparations are primarily used for continuous passive immunization for persons with selected congenital or acquired Ig deficiency states and as an immunomodulator in certain diseases.

Specific immunoglobulins

Specific immunoglobulins are derived from the pooled sera of people with antibodies to specific infectious agents; antisera from horses that are hyper-immunized against a specific organism when human products are not available; or recombinant DNA technology. Immunoglobulins from human or animal sources are made by more than one B cell clone (polyclonal) and can bind to heterogeneous antigens. Antibodies produced through recombinant DNA technology originate from a single clone of B cells (monoclonal) and are specific to only one antigen. Monoclonal antibody products are authorized for the prevention of various infectious diseases including respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Because of the relatively high risk of a specific type of immunological reaction (known as serum sickness) following the use of animal products, human Ig should be used whenever possible.

Evolving landscape of vaccinology

Ongoing scientific advances in biotechnology, genetics, immunology and virology, supported by novel Artificial Intelligence-based predictive technologies (e.g., for antigen design), 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. To ensure the effectiveness and safety of new products, scientific advances need to be accompanied by enhanced monitoring of new vaccine programs. Emerging areas in vaccinology, some of which are already being tested and used, include novel vaccine platforms and adjuvants.

Nucleic acid-based vaccines use nucleic acids, such as deoxyribonucleic acid (DNA) and messenger ribonucleic acid (mRNA), to provide cells with instructions for making an antigen. Viral vector vaccines typically use modified viruses to deliver the DNA sequence of an antigen into host cells, whereas lipid nanoparticles (LNPs) are the most used non-viral system for mRNA delivery into cells. Self-amplifying RNA (saRNA) vaccines are a type of mRNA vaccines that allow the nucleic acid to be replicated once the vaccine RNA has been delivered to the host cell, and can generate a robust immune responses when given at lower doses than conventional mRNA vaccines. Nucleic acid vaccines have been studied for their safety and effectiveness for decades. They offer numerous advantages to traditional vaccines such as faster development and adaptation to rapid antigenic changes (as demonstrated by the successful development of mRNA vaccines for new variants of viruses like SARS-CoV-2) and ability to generate long-term, B and T cell responses.

In addition to novel antigen-presenting technologies, new adjuvants are being developed with an aim of enhancing immune responses to vaccines. 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 towards a desired type of immune response (humoral versus cell-mediated) and allow for smaller amounts of antigen to be used in vaccines.

The evolving landscape of vaccinology, driven by ongoing scientific advances and novel technologies, holds promise for improving existing vaccines, developing new ones, and enhancing vaccine delivery systems, with ongoing monitoring and research efforts ensuring their safety and effectiveness.

For further information, please see the selected references below.

Acknowledgements

This chapter was prepared by R Krishnan, H Birdi, N Mohamed, and reviewed by A Killikelly, O Baclic and M Tunis.

NACI gratefully acknowledges the contribution of: N Haddad and C Jensen.

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.
• Canadian Paediatric Society in association with the Public Health Agency of Canada and Health Canada. Immunization Competencies Education Program. 2011.
• Kobiyama, K., Ishii, K.J. Making innate sense of mRNA vaccine adjuvanticity. Nat Immunol 23, 474–476 (2022). Accessed January 12 2024 at https://doi.org/10.1038/s41590-022-01168-4
• Pasquale AD, Press S, Silva FT, Garcon N. Vaccine Adjuvants: from 1920 to 2015 and beyond. Vaccines 2015; 3(2):320-34.
• Plotkin SA. Vaccines. 5th ed. Philadelphia, PA: Elsevier Health Sciences; 2023.
• Poland GA, Kennedy RB, McKinney BA et al. Vaccinomics, adversomics, and the immune response network theory: individualized vaccinology in the 21^st century. Semin Immunol 2013; 25(2):89-103.
• Pollard, A.J., Bijker, E.M. A guide to vaccinology: from basic principles to new developments. Nat Rev Immunol 21, 83–100 (2021). https://doi.org/10.1038/s41577-020-00479-7
• 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.

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