Host Defense and Vaccination

Immune System & Host Defense

• Primary function: Host defense.
• Revision of major concepts: major immune cells, major mediators, immune response to different pathogens, vaccines, and adjuvants.

Cells of the Immune System

• Innate System:
  • Myeloid cells (e.g., neutrophils, macrophages).
  • NK cells.
• Adaptive Immune System:
  • Lymphocytes: T cells and B cells.
• Two systems must work together.

T Cell Activation Example

• Two signals needed for T cell activation.
  • Signal 1: TCR (T cell receptor) signaling through recognition of cognate peptide presented by dendritic cells.
  • Signal 2: CD28 on T cells engaging with co-stimulatory molecules (CD80 or CD86) on dendritic cells.
• Signal 2 is dependent on activation of the innate system.
• Innate system provides the second signal required for T cell activation.

Host-Pathogen Interaction

• Microbial entry, establishment of a niche, induction of host response, pathogen elimination or persistence (chronic infection).
• Acute infection example:
  • Innate immune response: Rapid (seconds, minutes, hours).
  • Recruitment of neutrophils and macrophages.
  • Adaptive immune system: Complete control of infection; more sophisticated mechanisms to combat infection.

Viral/Bacterial Control Phases

• Early phase:
  • Type I interferon, NK cells.
• Later phase:
  • Effector lymphocytes (T cells, B cells).
  • B cells produce antibodies to neutralize the virus.
  • CD8 T cells kill infected cells.
• Innate and adaptive systems are complementary.

Innate System: Pattern Recognition Receptors (PRRs)

• Sensing molecules expressed where microbes may be present (cell surface, endosomal, cytosolic).
• Examples:
  • Toll-like receptors (TLRs):
    • Surface: TLR2, TLR4 (sense extracellular bacteria).
    • Endosomal: TLR3, TLR8, TLR9 (sense viral infection).

Ligands Recognized by Sensing Molecules

• PAMPs: Pathogen-Associated Molecular Patterns (microbe-derived).
• DAMPs: Damage-Associated Molecular Patterns (host-derived).
• DAMPs are released by damaged cells during infection/inflammation, triggering inflammation.

Natural Killer (NK) Cells

• Innate lymphocytes that can kill infected cells.
• Produce inflammatory cytokines (interferon-gamma, TNF) to activate macrophages.
• Antibody-dependent cell-mediated cytotoxicity (ADCC): kill infected cells coated with antibodies via Fc receptor binding.
• Collaboration between adaptive and innate systems.

Soluble Mediators: Complement System

• Activated by classical, alternative, and lectin pathways.
• Mechanisms of action:
  • Membrane attack complex (MAC) formation leads to lysis of infected cells.
  • Release of cleaved components (C3a, C5a) triggers local inflammation and immune cell recruitment.
• Regulation of inflammation.

Adaptive System: B and T Cells

• B cells: antibody production.
• T cells:
  • CD4 T cells (helper cells).
  • CD8 T cells (cytotoxic T cells).

Immune Response to Pathogens

• Extracellular bacteria/pathogens:
  • Humoral response (antibody-dependent control).
• Intracellular bacteria/parasites:
  • Cell-mediated immunity.
  • Pathogens reside inside phagocytes.
  • Antibodies cannot penetrate cells.
  • Some pathogens live in the cytoplasm or in vacuoles of phagolysosomes.

Antigen Processing and Presentation

• Endogenous antigens (cancer cells, viral infection):
  • Processed and presented via MHC class I.
• Exogenous antigens:
  • Presented via MHC class II.
• MHC class I presents peptides to CD8 T cells.
• MHC class II presents antigens to CD4 T cells.
• Differential location of pathogens triggers different T cell responses due to different MHC processing and presentation pathways.

Immunopathology

• Host response to microbes can cause tissue damage.
• Example: Immunopathology of COVID-19.
  • Severe COVID: lymphocyte reduction (T and B cells), increased myeloid cells (neutrophils, macrophages, monocytes).
  • Massive cytokine production (inflammatory cytokines).
  • Increased antibody production.
  • Motor organ inflammation with rare virus detection in inflamed tissues.
  • Treatment: immunosuppression (e.g., anti-dexamethasone, anti-IL-6 receptor antibodies).

Characteristics of Adaptive Immunity

• Specificity and memory.
• Serum Antibody Data
  • Primary response: first exposure to antigen X produces a relatively small anti-X response.
  • Secondary response: second injection with antigens X and Y results in:
    • Enhanced anti-X antibody production (faster and greater magnitude).
    • Moderate anti-Y antibody production (primary response).
  • Memory cells (T and B cells) mediate enhanced secondary response.

CD8+ T Cell Response

• Viral growth kinetics:
  • Virus titer builds up quickly, peaks, and is eliminated by innate and adaptive immunity.
  • CD8+ T cells peak after viral infection peak.
• Three phases of CD8+ T cell response:
  • Expansion: rapid increase in CD8+ T cell number.
  • Contraction: most cells die.
  • Memory: few cells survive, providing long-lasting memory.
• Terminal effector T cells: expand dramatically but are eliminated after virus clearance.
• Memory cells: increase, but remain relatively stable, allowing for a stronger secondary response upon re-exposure.

Immunization

• Enhance immunity against infection.
• Two types of immunity:
  • Active Immunity: host response to microbe or microbial antigen (e.g., vaccination).
    • Exposure to infection or vaccination leads to memory cells.
    • Re-EXposure to pathogen triggers recall response.
  • Passive Immunity: adoptive transfer of antibodies or T cells.
    • Serum collected from immune individuals/animals and transferred to another individual.
    • Provides specificity but does not establish long-term memory.

Passive Immunity: Antibody Transfer

• Neutralizes toxins.
• Serum sickness: immune response against animal antibodies after repeated exposure.
• Solution: use human plasma or antigen-specific monoclonal human antibodies.

Mechanism of Transferred Antibody in Viral Infection

• Neutralize invading pathogens.
• Enhance uptake of virus via opsonization and phagocytosis.
• Activate complement cascade via the classical pathway.
• Bind to Fc receptor on NK cells, leading to killing of infected cells.

Adaptive Immunity and Vaccination Study (COVID-19)

• mRNA vaccines reduce viral incidence.
• Increased vaccination rate correlates to control of infection.
• Active immunity works better in younger individuals.

Vaccine Definition and Components

• Biological product that induces immune response to confer protection against infection/disease upon exposure to the same pathogen.
• Must contain antigens expressed by the pathogen.
• Clinical endpoint: protection against infection/disease severity.
• Immune correlates of protection: predict protection upon re-exposure.

Adjuvants

• Boost immune response, especially in recombinant vaccines.
• Essential in inducing primary T and B cell response.
• Many adjuvants are microbial products/PAMPs.
• Examples: alum, AS04 (modified LPS), CpG 118 (DNA from microbes).
• Activate innate immune response, upregulate co-stimulatory molecules (signal 2), and enhance T cell response.
• Increase immunogenicity of weak antigens.
• Enhance the speed and duration of immune response.
• Stimulate humoral and cell-mediated immune response.

Types of Vaccines

• RNA/DNA vaccine.
• Recombinant protein (protein + adjuvant).
• Viral vectors (adenovirus).
• Whole organism vaccines:
  • Inactivated vaccines (killed pathogens).
  • Live attenuated vaccines (weakened organisms).

COVID-19 Vaccines

• RNA vaccine.
• Viral vectors.
• Whole virus (inactivated).
• Protein subunit.

mRNA Vaccine Mechanism

• Spike protein construct in lipid nanoparticles.
• Cells uptake the construct and produce spike protein.
• Spike protein expressed on cell surface interacts with B cells.
• Spike protein picked up by dendritic cells, migrate to the lymph nodes.
• CD8 and CD4 T cells are activated.
• CD4 T cells differentiate into TFH cells, promote B cell activation and antibody production.

Summary

• Host defense against infection is the primary function of the immune system.
• Mediated by both innate and adaptive immunity.
• Different effective mechanisms control different types of microbes.
• Host response can sometimes cause disease (immunopathology).
• Vaccines save lives.