Host Defense & Vaccination Lecture Notes

Host Defense & Vaccination Vaccination

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  • Major Immune Cells and Mediators

    • Innate immunity:

      • Dendritic cells, mast cells, macrophages, natural killer cells, complement proteins, basophils, eosinophils, neutrophils.

    • Adaptive immunity:

      • γδ T cells, B cells, antibodies, natural killer T cells, CD4+ T cells, CD8+ T cells.

  • Effector Mechanisms Controlling Different Types of Microbes

    • Extracellular vs. intracellular pathogens

    • Humoral vs. cell-mediated immunity

  • Vaccines and Adjuvants

Cells of the Immune System

  • Innate Immunity (Rapid Response)

    • Cells involved:

      • Dendritic cells

      • Mast cells

      • Macrophages

      • Natural killer cells

      • Basophils

      • Eosinophils

      • Neutrophils (Granulocytes)

    • Other components:

      • Complement proteins

  • Adaptive Immunity (Slow Response)

    • Cells involved:

      • γδ T cells

      • B cells (produce antibodies)

      • Natural killer T cells

      • CD4+ T cells

      • CD8+ T cells

Stimulation of Adaptive Immunity by Innate Signals

  • Signal 1:

    • Antigen binding to lymphocyte receptor.

  • Signal 2:

    • Costimulatory molecules (e.g., CD28) on antigen-presenting cells (APCs) binding to receptors on lymphocytes.

    • Molecules induced by the innate response (e.g., complement fragments).

  • Process:

    • Microbial antigen triggers an innate immune response.

    • The innate immune response induces molecules required for lymphocyte activation.

    • Lymphocyte proliferation and differentiation lead to an adaptive immune response.

Time Course of Infection

  • Microbe Entry:

    • Infection is established.

  • Innate Immune Response:

    • Rapid initial response.

  • Adaptive Immune Response:

    • Slower, but more specific and effective.

  • Adaptive Immune Memory:

    • Allows for a faster and stronger response upon subsequent exposure.

  • Infection Ended:

    • Immune system clears the infection.

Innate and Adaptive Immune Response

  • Innate Immunity

    • Mediated by NK cells and Type I Interferons (IFNs).

    • Results in an antiviral state.

  • Adaptive Immunity

    • Involves B cells producing antibodies for neutralization and protection against infection.

    • CD8+ cytotoxic T lymphocytes (CTLs) kill infected cells, eradicating established infection.

Soluble Effector Molecules of Innate Immunity

  • Complement System

    • Initiation:

      • Classical pathway (antibody-mediated)

      • Alternative pathway (direct activation by microbe)

      • Lectin pathway (mannose-binding lectin)

    • Early Steps:

      • C3 convertase cleaves C3 into C3a and C3b.

      • C3b is deposited on the microbe surface.

    • Late Steps (Membrane Attack Complex - MAC pathway):

      • C5 convertase cleaves C5 into C5a and C5b.

      • Formation of the MAC, leading to lysis of the microbe.

    • Effector Functions:

      • C3a and C5a: Inflammation

      • C3b: Opsonization and phagocytosis

      • MAC: Lysis of microbe

Pattern Recognition Receptors (PRR)

  • Expressed where microbes may be present.

  • Types:

    • TLR: Toll-like receptor (TLR1-13)

    • NLR: NOD-Like Receptors (NOD 1 and 2)

  • Ligands:

    • PAMP: Pathogen-associated molecular patterns (pathogen-derived)

    • DAMP: Damage-associated molecular patterns (host-derived)

Functions of Natural Killer (NK) Cells

  • NK cell-mediated cytotoxicity:

    • Direct killing of infected or abnormal cells.

  • NK cell-derived IFN-γ:

    • Increases the capacity of macrophages to kill phagocytosed bacteria.

  • Antibody-dependent cell-mediated cytotoxicity (ADCC):

    • NK cells bind to antibody-coated cells via Fc receptors and destroy these cells.

Types of Adaptive Immunity

  • Cell-mediated immunity (CMI)

  • Humoral immunity

How do T cells combat different infections? Division of Labor

  • Class II MHC Pathway (Antigen Presentation to Helper T Cells)

    • Antigen uptake or synthesis by macrophages.

    • Extracellular microbes in endosomes are presented to CD4+ helper T lymphocytes.

    • T cell effector functions include macrophage activation and cytokine secretion.

    • Macrophage activation leads to killing of phagocytosed microbes.

    • Cytokines also stimulate antigen-specific B cells.

    • B cell activation results in antibody secretion, which binds to extracellular antigens.

  • Class I MHC Pathway (Antigen Presentation to Cytotoxic T Lymphocytes)

    • Cytosolic antigens are presented to CD8+ cytotoxic T lymphocytes.

    • CTLs kill antigen-expressing target cells.

Different Effector Mechanisms Control Different Types of Microbes

  • Cell-mediated immunity (CMI) and humoral immunity are distinct immune responses required to control microbes with different lifestyles.

Different Microbes Activate Distinct Arms of Adaptive Immune System

  • MHC-I presentation activates cytotoxic T cells.

  • MHC-II presentation activates T helper (Tfh) cells.

Host Response and Tissue Injury

  • Host response to a microbe, rather than the microbe itself, may cause tissue injury and disease.

The Immunopathology of COVID-19

  • COVID-19 cytokine storm syndrome (CSS)

    • High IL-6 level is the best laboratory predictor of respiratory failure and death.

    • Autopsy studies of lethal COVID-19 cases showed extensive multiorgan inflammation with only sporadic presence of virus.

    • Dysregulated immune response results in continuous neutrophil activation and organ damage.

    • Some COVID-19 patients benefit from immunosuppression, e.g., reduced mortality in patients treated with dexamethasone, anti-IL-6 receptor mAb, or JAK kinase inhibitors.

Adaptive Immunity: Specificity and Memory

Primary and Secondary Immune Responses

  • Primary Response:

    • Naive B cells encounter antigen X and differentiate into plasma cells, resulting in a primary anti-X response.

    • Memory B cells are also generated.

  • Secondary Response:

    • Upon subsequent exposure to antigen X, memory B cells differentiate into plasma cells, resulting in a faster and stronger secondary anti-X response.

    • If antigen Y is encountered, a primary anti-Y response occurs.

Kinetics of a T Cell Response and Distribution of Memory Cell Potential

Enhancing Immunity Against Infection: Immunization

Active and Passive Immunity

  • Active Immunity:

    • A host response to a microbe or microbial antigen.

  • Passive Immunity:

    • Adoptive transfer of antibodies or T cells specific for the microbe.

Antibodies and Passive Immunization

  • Passive immunization involves infusion of antigen-specific mAbs or polyclonal antibodies derived from non-human or human blood products.

  • The first major success in immunological intervention was a therapeutic serum from animals actively immunized against diphtheria toxin, 125 years ago.

  • Polyclonal antibodies collected from immunized animals are the primary source of antisera, but there is a risk of ‘serum sickness’, especially after repeated exposures, as the recipient may generate an immune response against antibodies of non-human origin.

  • These risks are mitigated with the use of convalescent plasma from human patients or antigen-specific monoclonal human antibodies.

Mechanism of Action of Transferred Monoclonal Antibodies for Viral Infection

Active Immunity: Vaccination Saves Lives

  • Graphs showing the impact of vaccination on SARS-CoV-2 incidence in different age groups.

Vaccines

  • A vaccine is a biological product used to safely induce an immune response that confers protection against infection and/or disease on subsequent exposure to a pathogen.

  • The vaccine must contain antigens that are either derived from the pathogen or produced synthetically to represent components of the pathogen.

  • The essential component of most conventional vaccines is one or more protein antigens that induce protective immune responses.

  • Protection conferred by a vaccine is measured in clinical trials that relate immune responses to the vaccine antigen to clinical endpoints (such as prevention of infection, a reduction in disease severity, or a decreased rate of hospitalization).

  • Finding an immune response that correlates with protection can accelerate the development of and access to new vaccines.

Adjuvants

  • An agent used in a vaccine to enhance the immune response against the antigen.

  • Adjuvants play an essential role in inducing primary T cell responses to protein antigens included in the vaccines.

  • Many adjuvants are products of microbes or mimic molecules produced by microbes and necrotic cells, and thus elicit innate immune responses.

  • FDA-approved adjuvants:

    • Aluminum salts

    • AS04 (Monophosphoryl lipid A (MPL) + aluminum salt)

    • MF59 (Oil in water emulsion composed of squalene)

    • CpG 1018 (a synthetic form of DNA)

How Does an Adjuvant Work?

  • Adjuvants affect the immune response in various ways:

    • To increase the immunogenicity of weak antigens.

    • To enhance the speed and duration of immune response.

    • To stimulate and modulate humoral responses.

    • To stimulate cell-mediated immunity.

  • One of their major functions in T cell activation is to stimulate the expression of costimulators on APCs.

Types of Vaccines

  • RNA Vaccines:

    • RNA encoding the spike antigen from SARS-CoV-2 is taken up by host cells and translated, inducing an immune response towards the antigen.

  • DNA Vaccines:

    • DNA encoding the spike antigen is taken up, transcribed, and the mRNA is translated, inducing an immune response towards the antigen.

  • Recombinant Protein Vaccines:

    • Protein antigen is produced via yeast or baculovirus expression systems and injected (usually with an adjuvant).

    • Examples: Human Papillomavirus, Hepatitis B Virus, Influenza vaccines.

  • Viral Vector Vaccines:

    • Viruses (e.g., adenovirus) encoding SARS-CoV-2 antigen in their DNA enter host cells and transcribe the antigen. The virus also acts as an adjuvant.

    • Example: Ebolavirus vaccine (VSV vector).

  • Inactivated Vaccines:

    • Killed virus is injected as the immunogen and can be combined with an adjuvant if necessary.

    • Examples: Influenza, Polio, Hepatitis A vaccines.

  • Live Attenuated Vaccines:

    • A weakened form of the virus is used to induce a strong antiviral immune response.

    • Examples: MMR, Chickenpox, Yellow Fever vaccines.

How Some of the Different Covid-19 Vaccines Compare

  • List of vaccines by technology/company, suitability for people with weak immune systems, number of doses, and storage requirements.

How mRNA Vaccine Elicits Immunity to SARS-CoV-2

  • Pfizer-BioNTech and Moderna SARS-CoV-2 mRNA vaccines.

    • mRNA in lipid nanoparticles is injected.

    • Vaccinated cells present the spike protein-fragment.

    • Induces B cell production of antibodies to the virus's spike protein.

    • T cells are also elicited, particularly CD4+ and CD8+ against the SARS-CoV-2 spike protein.

    • Antibodies bind to target sites on the SARS-CoV-2 surface glycoprotein and either neutralize it or inactivate virions for destruction and clearance by the immune system.

Summary

  • Defense against infectious microbes is the principal function of the immune system.

  • Mediated by the effector mechanisms of innate and adaptive immunity.

  • Different effector mechanisms control different types of microbes.

  • Host response to a microbe, rather than the microbe itself, may cause tissue injury and disease.

  • Vaccination saves lives.