Antibodies and vaccination

Antibody structure

An antibody is a glycoprotein called an immunoglobulin. It is Y-shaped and made of four polypeptide chains: two identical long heavy chains and two identical short light chains, held together by disulfide bonds.

Each arm of the Y ends in a variable region. This is the part whose amino acid sequence differs between antibodies, and it forms the antigen binding site. There are two binding sites per antibody, one on each arm, and both are the same shape.

The rest of the molecule is the constant region, which is the same in all antibodies of a class. It is what phagocytes recognise and bind to.

The hinge region between the arms gives flexibility, so an antibody can bind two antigens that are not exactly the right distance apart.

The specificity comes from exactly the same place as in an enzyme: the variable region folds into a shape complementary to one antigen, and the shape comes from the tertiary structure, which comes from the sequence, which comes from the gene.

How antibodies work

Antibodies do not destroy pathogens themselves. They mark them and immobilise them, and something else does the destroying.

• Agglutination. Because each antibody has two binding sites, it can bind two pathogens at once, clumping them together. Clumped pathogens cannot enter cells, and a clump is easier for a phagocyte to engulf than many separate cells.
• Neutralisation. Antibodies bind to toxins, or to the binding sites a virus uses to attach to a host cell, so neither can act. An antibody used this way is an antitoxin.
• Opsonisation. The constant region acts as a marker. Phagocytes have receptors for it, so a coated pathogen is recognised and engulfed far more readily.
• Lysis. Antibodies bound to a bacterium activate a set of blood proteins that punch holes in its membrane.

Types of immunity

The two questions to ask are: did the body make the antibodies itself, and did it happen naturally or through medicine.

Active immunity is slow to develop, because clonal selection and expansion take days, but it is long-lasting, because memory cells remain.

Passive immunity is immediate, because the antibodies are already there, but it is short-lived. The antibodies are broken down within weeks and no memory cells are made, so there is no lasting protection.

That trade-off decides which is used. Somebody bitten by a venomous snake has no time to develop their own antibodies, so they are given antibodies directly. Somebody who might meet a pathogen in the future is vaccinated.

Vaccination

A vaccine contains antigens from a pathogen, in a form that cannot cause the disease. It may be a killed pathogen, a weakened live one, a fragment such as a surface protein, or an inactivated toxin.

The antigens trigger a primary immune response: clonal selection, clonal expansion, plasma cells and, crucially, memory cells. The person feels little or nothing because the antigens cannot multiply or cause harm.

If the real pathogen is met later, the secondary response is fast and large enough to destroy it before symptoms appear. The person is immune.

Many vaccines need a booster, a second dose that provokes a secondary response during the vaccination itself, raising memory cell numbers much higher and extending protection.

Herd immunity

If a large enough proportion of a population is immune, the pathogen cannot find enough susceptible hosts to spread from one to the next, and transmission dies out. That protects the people who are not immune: babies too young to be vaccinated, people whose immune systems are suppressed, and those for whom the vaccine did not work.

The proportion needed depends on how infectious the disease is. Measles is very infectious and needs around 95 per cent coverage; less infectious diseases need less.

This is why falling vaccination rates cause outbreaks even among the vaccinated population's unvaccinated minority, and why coverage rather than individual choice is what public health programmes measure.

Why some diseases are hard to vaccinate against

Smallpox was eradicated and polio nearly has been. Others resist, for reasons worth being able to name:

• Antigenic variation. The pathogen changes its surface antigens, so memory cells from a previous exposure no longer recognise it. Influenza does this every year, which is why the vaccine is reformulated annually. HIV does it within a single patient.
• Many strains or species. Plasmodium has several species and a life cycle with several stages, each with different antigens.
• Hiding inside cells, where antibodies cannot reach, as tuberculosis does inside phagocytes.
• Practical obstacles: vaccines that need refrigeration, populations that are hard to reach, war and displacement, cost, and refusal.

Monoclonal antibodies

A monoclonal antibody is a preparation of identical antibody molecules, all specific to one antigen, produced from a single clone of cells.

How they are made

The problem is that plasma cells make exactly the antibody wanted but die within days, while cancerous cells divide indefinitely but make nothing useful. The hybridoma method combines the two.

1. An animal, usually a mouse, is injected with the antigen.
2. Its plasma cells producing the wanted antibody are collected from the spleen.
3. These are fused with myeloma cells, a type of cancerous cell that divides indefinitely.
4. The fused cells are hybridomas, which both produce the antibody and divide indefinitely.
5. Hybridomas are separated, and the one producing the wanted antibody is cultured to produce a clone.
6. The antibody is harvested and purified.

The word "clone" is what the process is producing and is often the answer a question is looking for: what is grown by cell culture is a clone of hybridoma cells.

Uses

Diagnosis. A monoclonal antibody binds one specific molecule and nothing else, so it can detect that molecule in a sample. A pregnancy test uses antibodies specific to the hormone HCG, bound to coloured particles: HCG in the urine is captured by antibodies at the test line, and the colour accumulates there.

Monoclonals are also used to detect prostate specific antigen, to identify the exact type of a leukaemia, and to match tissue before transplant.

Treatment. An antibody specific to a protein on cancer cells can be used to attack them directly, or to carry a drug or radioactive isotope straight to the tumour. Because it binds only cells carrying that antigen, healthy cells are largely spared, so side effects are far fewer than with conventional chemotherapy.

Other monoclonals block molecules involved in disease, such as those used against the inflammation of rheumatoid arthritis.

Research. Locating a specific protein within a tissue by tagging an antibody with a fluorescent marker.

Common mistakes

• Saying antibodies kill pathogens. They agglutinate, neutralise and mark them; phagocytes and other mechanisms do the killing.
• Saying an antibody has one binding site. It has two, which is what makes agglutination possible.
• Calling breast milk antibodies active immunity. Antibodies received ready-made are passive.
• Saying a vaccine gives immediate protection. It takes days, because a primary response has to happen first.
• Saying myeloma cells are cultured to make the antibody. The hybridoma clone is; myeloma cells alone make nothing useful.

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