Cell-Mediated Immunity, Active & Passive Immunity, and Principles of Immunization

The adaptive (acquired) immune system has two synergistic arms
- Humoral immunity – production of soluble antibodies & activation of complement.
- Cell-mediated immunity (CMI) – activation of cells that directly destroy other cells without relying on antibodies or complement.
Both arms are triggered simultaneously by the same antigen, employ clonal selection, and generate memory that yields an accelerated secondary response.

Helper T cells (TH1 subset) – express CD4; release cytokines (e.g. interleukin-2, interferon-α) that coordinate the response.
Cytotoxic T lymphocytes (CTLs, “killer T cells”) – become antigen-specific and cytotoxic once activated; destroy target cells.
Antigen-presenting cells (APCs) – mainly macrophages; ingest antigen, process it, and present peptide–MHC complexes to TH1 cells.
Natural killer (NK) cells & additional activated macrophages – recruited and up-regulated by TH1-derived cytokines.

Cells harbouring intracellular pathogens:
- Virus-infected cells (e.g.
  COVID-19 respiratory epithelial cells).
- Intracellular bacteria: Mycobacterium tuberculosis, Listeria monocytogenes, etc.
Cancer (tumour) cells displaying neoantigens.
Fungi & protozoa that survive inside phagocytes.
Transplanted tissues/organs – non-self MHC evokes CTL-mediated rejection.

Antigen uptake & presentation
- Macrophage/APC engulfs pathogen → displays peptide on MHC II.
TH1 activation
- Specific TH precursor recognises peptide–MHC → differentiates into TH1.
Cytokine burst
- TH1 secretes $\text{IL-2}$ & \text{IFN-\alpha} ➔
  - Proliferation of that TH1 clone.
  - Activation/expansion of CTLs & NK cells.
  - “Angry” macrophages with enhanced microbicidal power.
CTL differentiation (clonal expansion)
- Naïve CD8 T cells receive signals → become antigen-specific CTLs.
Effector phase: target-cell lysis
- CTL binds target via T-cell receptor (TCR) recognising peptide–MHC I.
- Releases perforin → forms pores in the target-cell membrane.
- Injects granzymes → trigger intracellular caspases & apoptosis.
- Secretes cytokines that curb viral replication & attract phagocytes to clean up.
Memory formation
- Subset becomes long-lived memory T cells to ensure a faster, larger response upon re-exposure.

COVID-19-infected airway cell displays viral peptide → CTL docks → perforin pore → granzymes enter → infected cell dies, halting viral replication.

Feature	Cell-Mediated	Humoral
Main weapons	CTLs, NK cells, activated macrophages	Antibodies & complement
Best against	Intracellular pathogens, viruses, TB, cancer cells, transplant tissue	Toxins, extracellular bacteria (e.g. Staph. aureus, Strep.), free viruses
Site of action	Inside infected cell cytoplasm or within vesicles	Extracellular fluid, bloodstream
Outcome	Kills infected/abnormal cells; activates macrophages	Neutralises toxins, opsonises microbes, activates complement

Natural – exposure to pathogen in the environment.
Artificial – vaccination with antigenic material.
Characteristics:
- Body performs the full clonal-selection cascade.
- Usually long-lasting, often lifelong (especially natural infections).
- Vaccines may require boosters when the memory wanes.

Natural passive – maternal antibodies:
- Placental transfer of $\text{IgG}$ before birth.
- $\text{IgA}$ in breast milk/colostrum after birth.
Artificial passive – injection of pre-formed antibodies (immune serum, “specific immunoglobulin”).
- Sources: human convalescent plasma or animal serum.
- Examples:
- Tetanus antitoxin from horse serum.
- Hepatitis B immune globulin (HBIG) after needle-stick $\text{NSI}$ , especially in $5!\text{–}!10\%$ of people who fail to seroconvert after Hep-B vaccination.
- Provides immediate but transient protection (antibodies cleared in ≈2 wk, no memory produced).

Smallpox mortality ≈ $30\%$ .
COVID-19 mortality ≈ $1\%$ .
Seasonal influenza mortality ≈ $0.1\%$ .
Some vaccines (e.g. an mRNA COVID-19 vaccine) induce antibodies in ≈ $70\%$ of recipients — meaning $30\%$ remain non-responsive and may rely on boosters or passive measures.

Observed that milkmaids exposed to cowpox rarely contracted deadly smallpox.
Inoculated an 8-year-old boy with cowpox fluid; later challenged with smallpox ➔ boy remained well.
- Ethically dubious, but founded modern vaccinology.
- Principle: antigenic similarity can confer cross-protection.

Vaccination – administration of antigenic material.
Immunization – broader; includes active (antigen) and passive (antibody) administration.

Mimics natural protective response.
Does not cause disease.
Induces robust, long-lasting immunity (humoral &/or CMI).
Easy to administer & store.
- Cold-chain challenges: one COVID-19 mRNA vaccine requires storage at $-85^{\circ}\text{C}$ .
- Oral doses (e.g. polio, rotavirus) simplify delivery by bypassing needles/sterile technique.

Killed / Inactivated Whole-Cell or Virus
- Cholera, typhoid (bacteria).
- Influenza, rabies, inactivated-polio (Salk).
Live Attenuated Bacteria – Mycobacterium bovis BCG for tuberculosis.
Live Attenuated Viruses – measles, mumps, rubella (MMR), varicella, yellow fever, oral-polio (Sabin).
Toxoids (Inactivated Toxins) – tetanus, diphtheria.
Subunit / Fragment Vaccines – hepatitis B surface antigen, acellular pertussis, HPV L1 proteins.
Nucleic-Acid (mRNA/DNA) Vaccines – COVID-19 mRNA platforms (new 5th category).

Live attenuated vaccines require strict cold chain; risk of reversion to virulence in immunocompromised hosts.
Passive antibody therapy is lifesaving yet temporary; possible serum sickness if derived from animal.
Public-health scheduling & boosters ensure herd immunity when individual responses vary.

The immune system’s dual nature delivers both antibody-mediated and cell-mediated protection, each targeting different pathogen niches.
CMI relies on TH1-driven activation of antigen-specific CTLs that induce apoptosis with perforin/granzyme; crucial against viruses, intracellular bacteria, cancer, and transplants.
Active vs Passive immunity – understand sources, longevity, metabolic cost, and clinical scenarios (needle-stick, maternal Ig).
Vaccination artificially triggers active immunity; vaccines vary by composition (killed, live-attenuated, toxoid, subunit, nucleic-acid) and must be safe, effective, long-lasting, and logistically feasible.
Remember key percentages (e.g. smallpox $30\%$ mortality, vaccine effectiveness figures) and classic examples (BCG, MMR, HBIG) to illustrate principles.