Immunotherapy and Vaccines
The definition, and the three ways to classify ★★★
The course opened with Jenner in 1796, and it closes with him too — this lecture's first slide is his portrait. Everything between has been an explanation of why his cowpox worked. This unit is what that understanding is for.
The treatment of a disease with therapeutic agents that potentiate or inhibit the immune response.Section I, 2019 AND 2020
Note the word inhibit. Immunotherapy is not only about strengthening immunity — suppressing it is equally immunotherapy, which is why anti-lymphocyte serum for graft rejection belongs in this unit alongside vaccines.
| Classification | The two halves |
|---|---|
| 1 · By direction | Immunopotentiation and immunosuppression |
| 2 · By specificity | Specific and non-specific immunotherapy |
| 3 · By what is given | Active immunotherapy — giving antigen Passive / adoptive immunotherapy — giving immune response products |
Look at classification 3 and you should recognise it immediately. Active immunotherapy gives antigen, so the patient makes their own response — slow, but with memory and lasting. That is a vaccine. Passive immunotherapy gives the products — antibody or cells — so protection is immediate but temporary and leaves no memory. That is antitoxin, immune globulin, monoclonal antibody.
Unit 1 taught the principle with von Behring's diphtheria antitoxin. Sections 2 and 4 below are simply the modern versions of the same two options.
- Define immunotherapy. → The treatment of a disease with therapeutic agents that potentiate or inhibit the immune response
- Name the three classifications. → Potentiation/suppression; specific/non-specific; active (antigen)/passive-adoptive (immune products)
- What does active immunotherapy give? → Antigen — the patient makes their own response
- What does passive immunotherapy give? → Immune response products — antibody or cells
Antigen-based therapy — vaccines ★★★
| Vaccine type | Detail | Advantages and problems |
|---|---|---|
| Purified antigen | Molecules purified directly from the pathogen — proteins, polysaccharides or exotoxins. E.g. vaccine against Streptococcus pneumoniae | + limited number of immunodominant molecules; no danger of replication or transmission − purification laborious and expensive; source may be hard to cultivate; only mildly immunogenic, so needs adjuvants and multiple immunisations |
| Synthetic peptide–carrier conjugate | Contains a B-cell epitope and a T-cell epitope. Used for prevention of measles and hepatitis B | Chemically defined, stable, safe. Problems: mimicking native conformation, susceptibility to proteolysis, MHC restriction |
| Recombinant antigen | The gene for an immunogenic protein is expressed in bacteria or yeast. The first was HBsAg — hepatitis B surface antigen, expressed in yeast | + large amounts cheaply; exotoxins can be genetically inactivated − response is primarily humoral; antigen is processed by the MHC class II pathway, so no cell-mediated response |
| DNA (genetic) vaccine | A gene encoding the antigen is inserted into a plasmid and delivered — e.g. on gold particles by 'gene gun'. Muscle cells express it endogenously | + elicits both humoral and cellular immunity; stable, heat-resistant, no cold chain needed; cheap; possible in neonates despite maternal antibody − foreign DNA might integrate and cause transformation; risk of anti-DNA antibodies and autoimmunity |
| Recombinant virus vaccine | Recombinant vaccinia or adenovirus vectors carrying the antigen gene | — |
Compare the last two rows and you are looking at Unit 11's two presentation pathways deciding a vaccine's usefulness.
A recombinant protein vaccine is injected from outside, so it is exogenous antigen — endocytosed, loaded onto MHC class II, presented to CD4⁺ cells. Result: antibody, and essentially no CTL response.
A DNA vaccine makes the host's own muscle cells synthesise the antigen, so it is endogenous — proteasome, TAP, MHC class I, presented to CD8⁺ cells. Result: both antibody and cytotoxic T cells.
That is why DNA vaccines are attractive against viruses and tumours, where you need CTLs and antibody alone will not do. The compartment in which the antigen appears determines what kind of immunity you get — Unit 11's rule, deciding vaccine design.
The features of an effective vaccine
Adjuvants — how a weak vaccine is made strong
Unit 2 defined an adjuvant; here is the mechanism spelled out. An adjuvant prolongs antigen persistence by releasing it slowly at the injection site; enhances co-stimulatory signals by increasing MHC and B7 expression and cytokine secretion, so antigen-presenting ability rises and Th activation is maximal; and induces granuloma formation and stimulates lymphocyte proliferation.
In animals, Freund's complete adjuvant; in humans, alum (aluminium hydroxide) is essentially the only one used. Modern adjuvants are TLR agonists such as CpG — which is Unit 9's PRR–PAMP system being deliberately triggered to supply signal 2.
- Name four vaccine types. → Purified antigen, synthetic peptide–carrier conjugate, recombinant antigen, DNA vaccine (and recombinant virus vector)
- What was the first recombinant vaccine? → Hepatitis B surface antigen (HBsAg), expressed in yeast
- Why does a recombinant protein vaccine give no cell-mediated response? → It is exogenous antigen, processed by the MHC class II pathway
- Why does a DNA vaccine give both? → Host cells make the antigen endogenously, so it enters the MHC class I pathway too
- Name the four features of an effective vaccine. → Safe, protective, sustained protection, practical
- Which adjuvant is used in human vaccines? → Alum (aluminium hydroxide)
Toxoid ★★★
A bacterial exotoxin which has been treated, usually with formaldehyde, so that it loses its toxic properties but retains its ability to stimulate an immune response against the toxin.
A toxin molecule has two functional parts: the toxin moiety that does the damage, and the antigenic determinants that the immune system recognises. Chemical modification with formaldehyde destroys the first while leaving the second intact.
So a toxoid is a molecule deliberately stripped of its function but not its shape — and because immunity is aimed at shape, the antibody produced still neutralises the real toxin. This is the basis of the tetanus and diphtheria vaccines, and it is why tetanus toxoid protects while tetanus antitoxin treats: active versus passive, from §1.
- Define toxoid. → A bacterial exotoxin treated (usually with formaldehyde) so that it loses toxicity but retains the ability to stimulate an immune response against the toxin
- What treatment is used? → Formaldehyde
- Which part is destroyed and which retained? → The toxin moiety is destroyed; the antigenic determinants are retained
- Toxoid vs antitoxin? → Toxoid is active immunisation (prevention); antitoxin is passive (treatment)
Antibody-based therapy ★★★
1 · Immune serum (antiserum)
| Preparation | Use |
|---|---|
| Antitoxins | Treatment of exotoxin-induced diseases — tetanus, diphtheria |
| Serum / placental gamma globulin | Prevention of viral infection (measles, viral hepatitis); treatment of hypogammaglobulinaemia |
| Anti-viral serum | Treatment of measles and rabies |
| Anti-lymphocyte serum | Inhibition of graft rejection and treatment of autoimmune diseases |
The last row is immunotherapy in the inhibit direction — the half of the definition students forget. Anti-lymphocyte serum suppresses immunity deliberately.
2 · Monoclonal antibodies
| Type | Use |
|---|---|
| Anti-CD3, anti-CD4 mAb | Prevention of graft rejection and graft-versus-host disease |
| mAb to cytokines | Anti-IL-1 and anti-TNF in rheumatoid arthritis and chronic inflammation |
| Antibody-guided therapy | Radioimmunotherapy (¹³¹I, ¹²⁵I) · chemotherapy conjugates · immunotoxin therapy (ricin, diphtheria toxin) |
3 · Engineered monoclonal antibodies
| Type | Structure |
|---|---|
| Chimeric antibody | Mouse V domain + human C domain |
| Humanized antibody | Only the CDRs remain of mouse origin |
| Single-chain antibody | VH – linker – VL |
| Bi-specific antibody | Two different binding specificities in one molecule |
Köhler and Milstein's hybridomas (Unit 3) are mouse cells, so the antibody they make is mouse protein. Inject it into a patient and you have done exactly what Unit 2 described for horse antitoxin: given a xenogeneic antigen. The patient makes antibody against it, the drug is cleared, and repeat dosing risks serum sickness.
The engineering ladder is one long retreat from that problem. A chimeric antibody keeps only the mouse variable domains; a humanized one keeps only the mouse CDRs — the six loops from Unit 3 that actually touch antigen. Each step removes more mouse while preserving the binding site.
That is why modern therapeutic antibody names end in -ximab (chimeric) or -zumab (humanized): rituximab is chimeric, trastuzumab is humanized. The suffix tells you how much mouse is left.
- Name four types of immune serum. → Antitoxin, gamma globulin, anti-viral serum, anti-lymphocyte serum
- Which is used to suppress immunity? → Anti-lymphocyte serum, for graft rejection
- Which mAbs treat rheumatoid arthritis? → Anti-IL-1 and anti-TNF
- Name the four engineered antibody types. → Chimeric, humanized, single-chain, bi-specific
- What is a single-chain antibody? → VH joined to VL by a linker
- Why engineer antibodies at all? → Mouse monoclonal antibody is a xenogeneic antigen in a patient
Immune checkpoint blockade ★★
Unit 7 introduced the accelerator and the brake. Here they become drugs. The checkpoint molecules targeted are CTLA-4, PD-1 and PD-L1, with newer targets BTLA, VISTA, TIM3 and LAG3. Monoclonal antibodies blocking CTLA-4, PD-1 and PD-L1 have been applied in immunotherapeutic clinical trials of many different tumours.
The logic is worth restating because it inverts the usual aim of therapy. You are not attacking the tumour and you are not boosting the immune system generally — you are removing an inhibition the tumour was exploiting. Many tumours over-express PD-L1 precisely to engage PD-1 on infiltrating T cells and switch them off; blocking that interaction restores a response the patient already had.
If checkpoints exist to prevent autoimmunity — which is what Unit 7 said CTLA-4 is for — then blocking them should cause autoimmunity. It does: colitis, thyroiditis, hepatitis, pneumonitis and dermatitis are the characteristic adverse effects of checkpoint inhibitors.
This is a good final illustration of the course's recurring theme. The side effects are not a flaw in the drug; they are the drug working, in tissues where you did not want it to. Every mechanism in immunology cuts both ways.
- Which checkpoint molecules are the main drug targets? → CTLA-4, PD-1 and PD-L1
- Name four newer targets. → BTLA, VISTA, TIM3, LAG3
- How does checkpoint blockade work? → It removes an inhibitory signal the tumour was exploiting, restoring T-cell activity
- What toxicity would you predict, and why? → Autoimmune effects — colitis, thyroiditis, hepatitis — because checkpoints normally prevent autoimmunity
Cytokine-related therapy ★★
1 · Cytokine supplementation
| Cytokine | Clinical use |
|---|---|
| IFN-α | Viral infections — hepatitis, herpes zoster |
| IFN-β | Multiple sclerosis |
| IFN-γ | Rheumatoid arthritis |
| IL-2 | Tumours |
| GM-CSF, G-CSF | Granulocytopenia |
| EPO | Nephritic anaemia |
| IL-11 | Thrombocytopenia |
2 · Cytokine antagonist therapy
| Agent | Use |
|---|---|
| IL-12 | Antagonises the effects of IL-4 — allergic diseases |
| Anti-TNF mAb | Septic shock |
| IL-1ra (receptor antagonist) | Inflammation, autoimmune disease |
The IL-12 entry is Unit 5's Th1/Th2 balance used therapeutically. IL-12 drives Th0 → Th1, and a Th1 response suppresses Th2 — so giving IL-12 pushes an allergic patient away from the IL-4/IgE axis that is causing their disease. You are not blocking a mediator; you are re-directing the lineage decision.
There is also a general caution in the deck worth carrying: cytokines are normally dedicated to act in a very localised microenvironment, as autocrine or paracrine factors at an immunological synapse. Giving them systemically is therefore working against their design — which is exactly Unit 5's point about containment, and why cytokine drugs are so often toxic.
- Which interferon treats multiple sclerosis? → IFN-β
- Which cytokine is used against tumours? → IL-2
- Which are used in granulocytopenia? → GM-CSF and G-CSF
- Why is IL-12 used in allergy? → It drives Th1 and so suppresses the Th2/IL-4/IgE axis
- Why are systemic cytokines often toxic? → Cytokines normally act locally, as autocrine or paracrine factors
Revision layer — and the end of the course
The exam map for this unit
| Section | Item | From |
|---|---|---|
| I. Definitions | Immunotherapy — set in BOTH years | §1 |
| IV. True/False Q8 | Toxoid definition — T | §3 |
| IV. True/False Q9 | Features of effective vaccines — T | §2 |
The whole unit on one screen
| Question | Answer |
|---|---|
| Define immunotherapy | Treatment of disease with agents that potentiate or inhibit the immune response |
| Three classifications? | Potentiation/suppression · specific/non-specific · active (antigen)/passive (products) |
| Vaccine types? | Purified antigen · peptide–carrier conjugate · recombinant · DNA · recombinant virus |
| First recombinant vaccine? | HBsAg, expressed in yeast |
| Why does DNA vaccine give CTLs? | Host cells make the antigen endogenously → MHC class I → CD8⁺ |
| Four features of an effective vaccine? | Safe · protective · sustained · practical |
| Human adjuvant? | Alum (aluminium hydroxide) |
| Define toxoid | Exotoxin treated with formaldehyde — loses toxicity, keeps immunogenicity |
| Four immune sera? | Antitoxin · gamma globulin · anti-viral serum · anti-lymphocyte serum |
| Four engineered antibodies? | Chimeric · humanized · single-chain · bi-specific |
| Checkpoint targets? | CTLA-4 · PD-1 · PD-L1 |
| IFN-β treats? | Multiple sclerosis |
| IL-12 in allergy works how? | Drives Th1, suppressing the Th2/IgE axis |
It is worth looking back from here. Jenner rubbed cowpox into a boy's arm in 1796 without knowing what an antigen was, that antibodies existed, or that lymphocytes could remember. Two centuries later, this unit designs a vaccine by choosing which presentation pathway the antigen should enter, engineers an antibody by keeping only its six CDR loops, and treats cancer by releasing a brake that exists to prevent autoimmunity.
Every one of those is an application of something in the preceding sixteen units. That is the argument for understanding the mechanisms rather than memorising the paper — and it is the same argument the Th1/Th2 true/false item makes on a single question.
- Define immunotherapy. → Treatment of a disease with agents that potentiate or inhibit the immune response
- Active vs passive immunotherapy? → Active gives antigen; passive gives immune response products
- Define toxoid. → A bacterial exotoxin treated with formaldehyde so it loses toxicity but keeps the ability to stimulate immunity
- Four features of an effective vaccine? → Safe, protective, sustained protection, practical considerations
- Why do recombinant protein vaccines give no CTL response? → Exogenous antigen enters only the MHC class II pathway
- Name the four engineered antibody types. → Chimeric, humanized, single-chain, bi-specific
- Which checkpoints are blocked therapeutically? → CTLA-4, PD-1, PD-L1
- What toxicity does checkpoint blockade cause, and why? → Autoimmunity, because checkpoints normally prevent it