Biology › Pathogens, disease and immunity › Antibodies, vaccination and the four kinds of immunity
Antibodies, vaccination and the four kinds of immunity
An antibody is four polypeptide chains folded so that two ends of it fit one antigen and nothing else. From that single structural fact come agglutination, vaccination, pregnancy tests and a class of cancer drugs — and also the reason the flu vaccine has to be reformulated every year.
Before this Protein tertiary and quaternary structure · Disulfide bridges between cysteine side chains · The specific immune response
Before you start
Antibodies kill pathogens. They do not, and no mark scheme will accept that they do. An antibody is a protein with two binding sites and no enzymic activity whatever; it cannot lyse a cell, digest a wall or poison anything. What it does is bind — clumping pathogens together, blocking the parts of them that would otherwise attach to your cells, and flagging them so that a phagocyte engulfs them. The destroying is done inside a phagocyte; the antibody is what puts the pathogen in its way.
What you should be able to do
- Describe the structure of an antibody and relate each feature to what it does.
- Explain agglutination, neutralisation and opsonisation without claiming that antibodies destroy pathogens.
- Classify an example of immunity as active or passive and natural or artificial, and justify the classification.
- Explain how vaccination protects an unvaccinated person, and why a threshold coverage exists.
- Explain why the influenza vaccine changes annually and the measles vaccine does not.
- Set out both sides of an ethical question about vaccine trials without asserting a conclusion.
What an antibody is made of
An antibody is a protein — an immunoglobulin — with a quaternary structure of four polypeptide chains: two identical long heavy chains and two identical short light chains, held together by disulfide bridges into a Y.
The tips of the two arms are the variable regions. Their amino acid sequence differs between one antibody and the next, so the tertiary structure there differs, so the shape of the binding site differs. Each arm carries one antigen-binding site, formed where a heavy chain and a light chain meet, and the two sites on any one antibody are identical to each other. Two sites, one shape.
Everything else is the constant region, and it is constant in the strict sense: the same sequence in every antibody of a given class. That is what makes it useful. Phagocytes have receptors for the constant region, so they can bind any antibody regardless of what it is attached to, which is how one receptor deals with millions of different pathogens.
- Antibody
- A protein with a quaternary structure of four polypeptide chains, produced by plasma cells, with variable regions forming two binding sites complementary to one antigen.
- Variable region
- The part of an antibody whose amino acid sequence differs between antibodies, forming the antigen-binding site.
- Constant region
- The part of an antibody that is the same in all antibodies of a class, and that binds to receptors on phagocytes.
- Antigen-antibody complex
- The structure formed when an antigen binds to the complementary binding site of an antibody.
The hinge between the arms and the stem is flexible, so the arms can move to reach antigens at different spacings on a pathogen's surface. Structural questions here follow one pattern: name the feature, then say what it lets the molecule do.
What an antibody does, and what it does not
An antibody binds an antigen, forming an antigen-antibody complex. Everything else follows from that, and there are three consequences worth naming.
Agglutination. Because each antibody has two binding sites, one antibody can bind two pathogens at once. Repeat that across thousands of antibodies and the bacteria are clumped into a mass. The clump cannot move about the body, and a single phagocyte can engulf many cells in one go rather than chasing them individually. Note the dependence: agglutination needs at least two binding sites, so 'why does an antibody have two?' has a real answer rather than a symmetrical one.
Neutralisation. Antibodies bound over a bacterial toxin cover the part of it that would otherwise fit a host receptor, so it cannot act. The same works on viruses: an antibody covering the attachment proteins of an influenza virus stops it binding to and entering a host cell, and a virus that cannot get into a cell can do nothing at all.
Marking for phagocytosis. With antibody bound, the constant regions stick outwards from the pathogen's surface, and phagocytes have receptors that bind them. The pathogen is far more readily engulfed than it would be otherwise.
In none of those does the antibody destroy anything. Hydrolysis happens inside a phagocyte's phagosome, as it did in the first lesson. Write 'the antibody destroys the bacterium' and you have described a chemical event that does not occur.
A structure-to-function question, answered fully
Explain how the structure of an antibody allows it to cause agglutination of bacteria and to be engulfed together with them by a phagocyte. (4 marks)
Each antibody has two identical antigen-binding sites, formed by the variable regions at the tips of the two arms. Both are complementary to the same antigen.
One antibody can therefore bind an antigen on one bacterium with one site and an identical antigen on a second bacterium with the other, so many antibodies cross-link many bacteria into a clump. The flexible hinge lets the arms move to reach antigens that are not conveniently spaced.
The constant regions are identical in all antibodies of that class and project outwards from the clump. Receptors on the phagocyte's cell-surface membrane are complementary to them, so the phagocyte attaches to the clump and engulfs the whole thing by endocytosis.
Four marks, four structural features doing four jobs — and notice that the phagocyte never identifies the bacterium at all. It recognises the antibody, which is why one kind of receptor on one kind of cell can deal with every pathogen you will ever meet.
Four ways to end up immune
Immunity gets classified on two independent axes: whether your own immune system did the work, and whether you met the antigen by living your life or because someone arranged it. Two axes give four combinations, and questions ask you to place an example in one of them.
Active immunity means your own lymphocytes met the antigen, underwent clonal selection and expansion, and left memory cells behind. It takes days or weeks to establish and then lasts for years. Passive immunity means ready-made antibody was introduced from outside. It works immediately, because the antibody is already there, and it fails within weeks, because antibodies are proteins that get broken down and nothing was made to replace them.
| Natural | Artificial | |
|---|---|---|
| Active | Catching measles and recovering; your plasma cells made the antibody | The MMR vaccine: antigen without the disease |
| Passive | Antibody crossing the placenta before birth, and in breast milk | Anti-tetanus or anti-rabies immunoglobulin, injected after exposure |
The passive examples are worth thinking about rather than memorising. A newborn cannot mount a decent specific response for some months, so it borrows its mother's antibodies, and the protection fades over roughly six months. Someone bitten by a possibly rabid animal cannot wait the eight days a primary response takes, so they are given antibodies directly and vaccinated at the same time: passive protection now, active protection later.
Vaccination and herd immunity
A vaccine puts antigen into the body in a form that provokes a primary response without causing the disease. Depending on the vaccine, that antigen may be a weakened (attenuated) strain, an inactivated pathogen, a purified surface protein, a harmless toxin derivative, or the mRNA instructions for making one viral protein. What all of them have in common is antigen; what none of them contains is a full dose of virulent pathogen.
It is worth naming the misconception because it is so widely half-held: a vaccine is often described as giving you a mild version of the disease. For most vaccines that is simply not what is happening. The sore arm and the day of feeling rough after a vaccination are the primary immune response — inflammation, cytokines, a slight fever — not the disease itself. A tetanus vaccine contains no tetanus and could not give it to you.
The response to a first dose is a primary response: slow, small, and leaving memory cells. A booster is deliberately arranged to be a secondary response, producing much more antibody and many more memory cells, which is why schedules involve several doses rather than one.
Herd immunity is the protection unvaccinated people get from being surrounded by vaccinated ones. An infected person can only pass the pathogen to someone susceptible, and if nearly everyone they meet is immune, the chain of transmission breaks before an outbreak can build. This matters because some people cannot be vaccinated: babies below the recommended age, people receiving chemotherapy or immunosuppressants, and anyone with a genuine allergy to a component.
There is a threshold because transmission is a multiplication. If each infected person would on average infect R₀ others in a fully susceptible population, then a proportion of them being immune reduces that number proportionally; once the average falls below one, each case leads to fewer than one new case and the outbreak shrinks. That happens when the immune proportion exceeds 1 − 1/R₀. Measles is extremely transmissible, with R₀ around 15 to 18. Put the two ends in and do the arithmetic: 1 − 1/15 is 93.3%, and 1 − 1/18 is 94.4%, so the threshold is 93 to 94%. Coverage of 90% sounds high and is not high enough, which is why measles returns in communities where uptake slips by a few per cent.
The figure quoted in public health is 95%, and it is worth being clear about why that is a different number rather than a rounding of the same one. The threshold is the bare point at which transmission stops on average, in a population where everyone mixes with everyone and every immunised person is genuinely immune. Real populations are not like that: the unvaccinated cluster in particular schools and neighbourhoods, a small fraction of those vaccinated never respond properly, and R₀ is higher in a crowded city than on a farm. The 95% coverage target is the threshold with a deliberate margin on top, so that a region can drift a little and still be above the line. If a question gives you R₀ and asks for the threshold, calculate it and quote 93 to 94%; if it asks what health services aim for, that is the 95%.
- Vaccine
- A preparation containing antigens from a pathogen, given to produce a primary immune response and memory cells without causing the disease.
- Herd immunity
- The protection of unvaccinated individuals that results when a large enough proportion of a population is immune for transmission not to be sustained.
- Antigenic variation
- Change in the antigens on a pathogen's surface, so that memory cells and antibodies produced against the previous form are no longer complementary to it.
Why the flu vaccine changes and the measles one does not
Immunity is immunity to a shape. Memory cells specific to one antigen recognise that antigen and nothing else, so a pathogen that changes its surface antigens is effectively a new pathogen to an immune system that has met the old one.
Influenza does this constantly. Its surface proteins, haemagglutinin and neuraminidase, accumulate mutations, and occasionally two strains infecting the same animal exchange whole segments of genome. Your memory cells from last year carry receptors complementary to last year's haemagglutinin. Against this year's they bind poorly or not at all, so the response to infection is essentially primary again. That is why the vaccine is reformulated annually against the strains predicted to circulate, and why the prediction is sometimes wrong.
Measles virus has stable surface antigens, so antibodies and memory cells raised against it in 1985 still fit the virus circulating today. Two doses in childhood give protection that generally lasts for life. The difference between the two vaccines is nothing to do with vaccine quality; it is a property of the viruses.
HIV goes further still, mutating rapidly within a single infected person, so antibodies effective at one stage of the infection are useless months later. That, and the fact that it infects the very cells that would co-ordinate the response, is why an HIV vaccine has proved so much harder to make than a measles one.
Monoclonal antibodies
A monoclonal antibody is a population of identical antibody molecules produced by a clone of identical cells, and therefore specific to one antigen. A molecule that binds one shape and ignores everything else in a sample of blood is a very precise tool.
Targeted cancer treatment. Roughly one breast cancer in five over-produces a receptor protein called HER2 on its cell surfaces. Trastuzumab is a monoclonal antibody with binding sites complementary to HER2: it blocks the growth signal those receptors carry and marks the cells for destruction. Healthy cells carry far less HER2, so the drug affects them much less than a conventional cytotoxic agent would, and the side effects are correspondingly narrower — though not absent.
Pregnancy testing. The placenta produces the hormone hCG, which appears in urine. A test strip carries mobile anti-hCG antibodies attached to coloured beads, and a second set fixed in a line further up. Urine carrying hCG picks up the mobile antibodies and carries them to the fixed line, where they are trapped and the colour concentrates. No hCG, no trapping, no line.
ELISA uses the same logic in a laboratory, with an enzyme attached to the second antibody so a colour change reports a positive result. Diagnosing HIV infection is the standard example, and note what is detected: antibodies against HIV, which is why a test taken very soon after exposure can be negative in an infected person.
The ethics, stated evenly
Questions on this section ask you to discuss, and discussion means presenting the considerations on both sides and being clear about which are factual and which are value judgements. A conclusion is optional; the reasoning is not.
Testing. A new vaccine is tested on animals before humans, raising the question of whether harm to the animals is justified by benefit to people, and on humans before licensing, raising questions about consent and about who bears the risk. Trials often run in the countries where the disease is common, which are frequently poorer countries: an argument that the trial goes where the disease is, and an argument that consent means less where the alternative is no medical care at all.
Control groups. A trial needs a comparison group, and giving that group a placebo means deliberately leaving people without protection during an epidemic. Using the existing vaccine as the comparison avoids that but makes the trial larger, slower and more expensive, which delays the new vaccine for everyone.
Individual and population. Vaccination carries a small risk of side effects to the individual and a large benefit to the population through herd immunity. Someone who declines is protected by others' uptake without accepting the risk themselves. Some countries make certain vaccinations a condition of school entry; others do not, and the disagreement is about how far a state may compel a medical procedure for a collective benefit rather than about the immunology.
Write these as claims and counter-claims. An answer that argues one way throughout is marked down for the same reason as an answer that lists facts without weighing them. Nothing in the biology settles any of it, and saying so is part of a good answer.
TRY IT — A coverage figure that is not good enough
In a region, 88% of children are vaccinated against measles. Public health officials describe this as insufficient and campaign to raise it to 95%. Using your knowledge of transmission, explain why 88% is insufficient, and suggest two reasons why a small group of unvaccinated children still matters.
Check your answer
Measles is highly transmissible: one infected person would infect something like 15 to 18 others in a fully susceptible population. The proportion immune has to exceed 1 − 1/R₀ before the average number of new cases per case falls below one. That is 1 − 1/15 = 93.3% at one end and 1 − 1/18 = 94.4% at the other, so the threshold is 93 to 94%.
The 95% the officials are campaigning for is not that threshold but a target set above it. The threshold assumes everyone mixes evenly and every vaccinated child is immune, and neither holds, so the target carries a margin to absorb the difference.
At 88%, roughly one child in eight is still susceptible, and each case therefore still produces more than one further case on average. Transmission is sustained and an outbreak can grow rather than fade.
The unvaccinated children matter first because they are clustered — in particular schools or communities — so the local proportion susceptible is far higher than the regional average and transmission runs freely inside the cluster.
They matter second because they include children who could not be vaccinated rather than were not: infants below the recommended age, and children immunosuppressed by treatment for leukaemia or after a transplant. Measles is most dangerous to exactly those individuals, and the only protection available to them is everyone else's.
In the exam
- Antibodies bind. They agglutinate, they neutralise, and they mark pathogens for phagocytosis. They do not kill, lyse or destroy, and writing that they do costs the mark every time.
- Structure-to-function questions want the feature and the consequence in the same sentence: two binding sites so pathogens can be clumped together; constant region so phagocytes can bind it.
- Classify immunity on both axes. 'Passive' alone is half an answer; 'passive natural, because ready-made antibody crossed the placenta' is a whole one.
- For herd immunity, name the mechanism: transmission stops when an infected person is unlikely to meet a susceptible one. Saying 'more people are protected' restates the question.
- A vaccine contains antigens. Say so. Answers that describe injecting 'a weak version of the disease' are describing something that is usually untrue and always vague.
- In ethics questions, give at least one point on each side and label value judgements as such. Marks are for the balance, not the verdict.
Check yourself
A person recovering from a severe bacterial infection is given an injection of antibodies taken from a donor who has recovered from the same infection. They improve within a day. Six months later they are infected again and become seriously ill. Explain both outcomes, and state what should have been done differently if long-term protection was the aim.
Answer
The injection gave artificial passive immunity. Ready-made antibodies with binding sites complementary to the bacterium's antigens were already present in the blood, so agglutination, neutralisation of toxins and marking for phagocytosis began at once, with no lag for clonal selection or expansion. That is why the improvement was so fast.
No memory cells were produced. The patient's own B cells were not selected and did not undergo clonal expansion, because the donor's antibodies bound the antigens and cleared them before the patient's response had developed. The injected antibodies are proteins and were broken down over the following weeks, leaving nothing behind.
Six months later there were therefore no memory cells specific to that antigen. The second infection provoked a primary response — around eight days to detectable antibody, at a low concentration — so the bacteria reproduced freely in the meantime and the patient became seriously ill.
For long-term protection they should have been vaccinated as well as given the antibodies: passive immunity for immediate control, and antigen to provoke an active response and leave memory cells. That is exactly the combined treatment used after a possible rabies exposure.
Questions
Question 14 marks
An antibody has no enzymic activity of any kind. Explain how antibodies nevertheless help to clear a bacterial infection.
Mark scheme
- B1 an antibody has two binding sites and cannot lyse a cell, digest a wall or poison anything; all it does is bind an antigen to form an antigen-antibody complex
- B1 agglutination: because each antibody has two identical binding sites it can bind two bacteria at once, clumping them so they cannot spread and so one phagocyte can engulf many at a time
- B1 neutralisation: antibody bound over a toxin, or over the attachment proteins of a pathogen, covers the part that would otherwise fit a host receptor, so it cannot act or enter a cell
- B1 marking for phagocytosis: the constant regions project outwards and phagocytes carry receptors complementary to them, so the pathogen is engulfed and hydrolysed inside the phagocyte
Question 24 marks
Compare active immunity with passive immunity, referring to how each arises, how quickly it acts and how long it lasts.
Mark scheme
- B1 in active immunity the person's own lymphocytes meet the antigen and respond, whereas in passive immunity ready-made antibody is introduced from outside
- B1 active immunity takes days or weeks to become established, whereas passive immunity works immediately because the antibody is already present
- B1 active immunity leaves memory cells behind, whereas passive immunity produces none
- B1 active immunity therefore lasts for years, whereas passive immunity fails within weeks as the introduced antibodies are broken down and nothing replaces them
Question 34 marks
An ELISA test for HIV detects antibodies against the virus rather than the virus itself. Suggest why a person infected two weeks ago may still test negative, and suggest what follows for the screening of donated blood.
Mark scheme
- B1 after infection the specific response takes time: antigen must be presented, a B cell selected, and clonal expansion must run before plasma cells exist
- B1 a primary response takes about eight days to produce detectable antibody and the concentration rises slowly, so it may still be below what the test can detect
- B1 the person is infected, and infectious, despite the negative result, which is a false negative
- B1 donated blood could therefore transmit HIV despite passing the screen, so an antibody test alone is not sufficient and a further test or a repeat test after an interval is needed
Question 44 marks
A new vaccine is trialled during an epidemic, with one group given the vaccine and a control group given a placebo. Evaluate the use of a placebo control group in a trial of this kind.
Mark scheme
- B1 in favour: a placebo group provides a valid comparison, so any difference in infection rate between the groups can be attributed to the vaccine rather than to other factors
- B1 against: the control group is deliberately left without protection during an epidemic, so people who could have been protected may catch the disease
- B1 the alternative of comparing against an existing vaccine avoids that, but makes the trial larger, slower and more expensive, which delays the new vaccine for everyone
- B1 a judgement supported by the points made, for example that a placebo group is defensible only where no effective vaccine already exists and consent is genuinely informed, with the recognition that this is a value judgement the biology does not settle
Question 53 marks
A virus has a basic reproduction number R₀ of 12 in a fully susceptible population. Calculate the percentage of that population which must be immune before transmission is no longer sustained.
Mark scheme
- M1 uses the threshold proportion 1 − 1/R₀
- M1 substitutes correctly: 1 − 1/12 = 1 − 0.0833
- A1 0.917, that is 91.7 per cent (accept 92 per cent), of the population must be immune
Question 63 marks
Explain why the influenza vaccine has to be reformulated every year while the measles vaccine does not.
Mark scheme
- B1 immunity is immunity to a shape: memory cells and antibodies are complementary to one antigen and to no other
- B1 the surface proteins of influenza, haemagglutinin and neuraminidase, accumulate mutations and whole genome segments can be exchanged, so its antigens change from year to year, which is antigenic variation
- B1 memory cells raised against last year's antigens bind this year's poorly or not at all, whereas measles has stable surface antigens, so the same memory cells still fit and childhood doses last for life
Question 72 marks
A baby receives antibodies in its mother's breast milk. A child of five is given the MMR vaccine. Identify the type of immunity produced in each case, naming both axes of the classification.
Mark scheme
- B1 the breast milk gives natural passive immunity
- B1 the MMR vaccine gives artificial active immunity
Worth remembering
- An antibody is four chains, two identical binding sites, variable regions at the tips and a constant region below.
- Antibodies agglutinate, neutralise and mark for phagocytosis. Phagocytes do the destroying.
- Active immunity makes memory cells and lasts; passive immunity supplies antibody and fades.
- A vaccine supplies antigen, provokes a primary response, and leaves memory cells so that the real infection meets a secondary one.
- Herd immunity has a threshold of 1 − 1/R₀, which for measles is 93 to 94%. The 95% coverage target is that threshold plus a deliberate margin, not the same figure.