Appearance
13.5 — Immunological Memory and Vaccines
Smallpox killed an estimated 300 million people in the twentieth century alone. The last natural case occurred in Somalia in 1977, and the disease was declared eradicated in 1980. It exists now only in two secure laboratories.
That is the only human disease ever deliberately eliminated from the planet, and it was done with a vaccine, on the basis of a mechanism that was not properly understood until long after it worked.
Memory
The whole point of the adaptive system is that the second encounter goes better.
Primary response: slow — 5 to 10 days before antibody appears. Low peak. Mostly IgM. Low-affinity antibody, because affinity maturation has not yet happened (Chapter 13.2).
Secondary response: fast — 1 to 3 days. Peak antibody 10 to 100 times higher. Mostly IgG. High affinity from the start, because the memory cells already carry the improved receptors selected during the first response.
And often the infection is cleared before any symptoms appear at all, which is why immunity usually looks like nothing happening.
Three changes underlie it.
More cells. A naive clone might be a few hundred cells; after an infection there may be a thousand times more.
Better cells. Memory B cells have already undergone class switching and affinity maturation.
Faster cells. Memory T and B cells activate at a lower threshold and divide sooner.
And there is a third population that matters and is often left out: long-lived plasma cells. These migrate to the bone marrow and secrete antibody continuously for decades without any further stimulation. They are why measurable antibody persists for a lifetime after some infections.
How long memory lasts varies enormously by pathogen, and the variation itself is informative:
| Infection | Duration of protection |
|---|---|
| Measles | Lifelong |
| Smallpox | Decades to lifelong |
| Tetanus (vaccine) | ~10 years |
| Pertussis (vaccine) | 4–12 years |
| Influenza | Season-limited — the virus changes |
| Common cold | Months, and there are hundreds of types |
| SARS-CoV-2 | Strong against severe disease; weaker against infection |
Two different reasons appear in that table, and they should not be confused.
Waning immunity — the memory itself declines, as with pertussis and tetanus. Solved by boosters.
Antigenic change — the memory is intact and the pathogen has changed, as with influenza. Not solved by boosters of the same vaccine; it requires reformulation.
Measles is the extreme of durability — one natural infection or two vaccine doses usually protects for life. The reason is not fully explained, and it is a genuinely interesting question.
And measles has a second property that is much less well known and is important. Measles infection causes "immune amnesia": it destroys a substantial proportion of existing memory cells, erasing immunity to other pathogens acquired over years.
Studies following unvaccinated children through measles outbreaks found losses of 11 to 73 percent of pre-existing antibody diversity, and increased susceptibility to other infections for two to three years afterwards. Measles vaccination therefore prevents more than measles, and the effect on overall childhood mortality in populations is larger than measles deaths alone would predict.
What a vaccine does
It presents the immune system with something that looks like a pathogen, without the disease.
Two things are needed, and this is why some early vaccine attempts failed.
Antigen — something specific to respond to.
A danger signal — otherwise the two-signal requirement of Chapter 13.1 means the T cell is switched off rather than on.
Live vaccines provide their own danger signal, because they replicate and behave like an infection.
Killed and subunit vaccines do not, which is why they need an adjuvant — a substance that stimulates innate immunity. Aluminium salts have been used for nearly a century, and newer adjuvants are designed to engage specific pattern recognition receptors.
The word comes from Latin adjuvare, to help, and for decades adjuvants were called "the immunologist's dirty little secret" because they worked and nobody knew why. The mechanism — providing the innate danger signal — is now understood.
The types
Live attenuated — a weakened organism that replicates but does not cause disease. MMR, chickenpox, oral polio, BCG, yellow fever.
Strongest and longest-lasting immunity, often from a single dose, because it most closely mimics real infection and generates both antibody and killer T cell responses.
And the drawbacks follow directly. Cannot be given to people with significantly suppressed immunity or in pregnancy, because a weakened organism can still cause disease in someone who cannot control it. And they require cold storage, which is a substantial obstacle in hot countries with unreliable electricity.
Inactivated (killed) — the whole organism, killed. Polio (injected), hepatitis A, rabies, some influenza vaccines.
Safe in immunosuppression. Weaker response, needing multiple doses and boosters.
Subunit, recombinant and conjugate — only the specific pieces that matter.
Hepatitis B uses a surface protein made in yeast. HPV uses proteins that self-assemble into empty virus-like particles containing no genetic material at all.
Conjugate vaccines solve the problem from Chapter 13.2: polysaccharide antigens produce weak, memory-free responses, particularly in infants under two. Chemically attaching the sugar to a carrier protein recruits T cell help.
And the impact was dramatic. Hib meningitis, once the commonest cause of bacterial meningitis in young children, has essentially disappeared where the conjugate vaccine is used — a reduction of over 95 percent.
Toxoid — an inactivated bacterial toxin. Tetanus, diphtheria.
Because the disease is caused by the toxin, not by the organism, immunity to the toxin is sufficient.
mRNA — the newest, and the one everyone now has an opinion about.
The mRNA instructs your own cells to make the antigen briefly (Chapter 2.3). The mRNA is degraded within days, it never enters the nucleus, and it cannot integrate into your DNA — there is no mechanism by which it could, since that would require reverse transcriptase and nuclear entry, neither of which is present.
They were developed rapidly for COVID-19 and were not invented then. The underlying research ran for over thirty years, and the key insight — chemically modifying one of the RNA bases so the innate system does not immediately destroy the message — was published in 2005 by Katalin Karikó and Drew Weissman, who shared the Nobel Prize in 2023.
Their advantage is speed and flexibility: the platform stays the same and only the sequence changes, so a new variant can be addressed in weeks rather than years.
Viral vector — a harmless virus carrying the gene for the antigen. Used in some COVID-19 and Ebola vaccines.
What vaccines have achieved
This deserves a section of its own, because the numbers are extraordinary and are rarely stated plainly.
Smallpox — eradicated. 300 to 500 million deaths in the twentieth century, now zero.
Polio — cases reduced by over 99 percent since 1988. Wild poliovirus now circulates in only two countries.
Measles — deaths reduced by over 80 percent since 2000, an estimated 60 million lives saved.
Hib meningitis, diphtheria, tetanus, pertussis, rubella — all reduced by 90 percent or more where coverage is good.
And congenital rubella syndrome is a particularly clear case. Before vaccination, a rubella epidemic in the United States in 1964 to 1965 caused around 20,000 babies to be born with deafness, blindness, heart defects or intellectual disability. It is now essentially unseen where coverage is maintained.
HPV vaccination is on course to eliminate cervical cancer. A Swedish study of 1.7 million women found an 88 percent reduction in invasive cervical cancer among those vaccinated before 17. This is a vaccine that prevents a cancer, which is a sentence worth pausing on.
The World Health Organization estimates vaccines prevent 3.5 to 5 million deaths a year.
Alongside clean water, vaccination is the intervention that has saved the most human lives.
Herd immunity
When enough people are immune, transmission cannot be sustained, and even unvaccinated people are protected.
The threshold depends on how transmissible the disease is, and it follows directly from the reproduction number R₀ — the average number of people one infected person infects in a fully susceptible population:
\text{Threshold} = 1 - \frac{1}{R_0}
| Disease | R₀ | Threshold |
|---|---|---|
| Measles | 12–18 | ~95% |
| Pertussis | 12–17 | ~94% |
| Polio | 5–7 | ~85% |
| Smallpox | 5–7 | ~85% |
| Influenza | 1.5–2 | ~35% |
Measles requires around 95 percent coverage, which is why it is always the first disease to return when coverage falls. It is the most transmissible common human infection — an infectious person leaves virus in the air of a room for up to two hours after leaving it.
And herd immunity protects the people who cannot be vaccinated: infants too young, people on chemotherapy or immunosuppression, transplant recipients, and the small proportion in whom the vaccine did not take.
Which is the ethical core of vaccination policy. Being vaccinated protects you, and it also protects the child with leukaemia in your child's class who cannot be.
Addressing the concerns honestly
Dismissing concerns does not work and is not respectful. Answering them does.
"Vaccines cause autism." This originated in a 1998 paper by Andrew Wakefield involving twelve children. The paper was retracted, the research was found to be fraudulent — data had been altered — and Wakefield was struck off the medical register.
Since then, studies involving many millions of children have found no association. A Danish study followed 657,461 children; a meta-analysis covered 1.27 million. No association, at any level of analysis, including in children with autistic siblings.
And the timing explains the persistence of the belief. Autism is typically recognised between 12 and 24 months, and the MMR is given at 12 to 13 months. Two things that happen at the same age look connected, and the human tendency to find causes in coincidence is strong. The association is real as an observation of sequence and absent as a matter of causation.
"Natural immunity is better." In one narrow sense it is often stronger and longer-lasting. And you have to get the disease to obtain it.
For measles that means a 1 in 1,000 risk of encephalitis, a 1 to 3 in 1,000 risk of death in developed countries, and the immune amnesia described above. For polio, paralysis. For rubella in pregnancy, a damaged baby. The vaccine gives most of the benefit without the toll, and that is the entire trade.
"Too many vaccines overwhelm the immune system." An infant's immune system responds to thousands of antigens daily from ordinary environmental exposure. The entire childhood schedule contains around 150 antigens in total — fewer than a single ear infection presents, and dramatically fewer than the older whole-cell vaccines contained. The number of vaccines has gone up and the number of antigens has gone down.
"There are ingredients I don't want." Thiomersal, a mercury-containing preservative, was removed from childhood vaccines in most countries around 2001 as a precaution, despite no evidence of harm — and autism rates continued to rise, which is itself informative. Aluminium adjuvants are present in microgram quantities, less than an infant receives from breast milk or formula over the same period. Formaldehyde is used in manufacturing and residual amounts are far below what the body produces naturally.
"Vaccines cause the disease." Killed and subunit vaccines cannot — there is no live organism. Live vaccines can rarely cause a mild version, which is why a small proportion of children get a brief rash and mild fever about a week after MMR.
Real side effects should be stated rather than minimised. Sore arm, mild fever and tiredness are common and expected — they are the immune response, which is the point. Serious adverse events are rare and are monitored actively. Anaphylaxis occurs in around 1 per million doses, which is why there is a 15-minute wait afterwards.
Some vaccines have specific rare associations: myocarditis after mRNA COVID vaccines, mostly in young men and mostly mild and self-limiting; a small increase in Guillain–Barré syndrome after some influenza vaccines. These are real, they are quantified, and in every case the same complication occurs more often after the disease than after the vaccine.
That last point is the one that resolves most individual decisions, and it is the one least often made.
The schedule, and why it is timed as it is
Every element of the timing has a reason.
Birth — BCG and hepatitis B where locally relevant. Given at birth because early exposure risk is real.
6 to 8 weeks — the first doses of most vaccines. Not earlier, because maternal antibody interferes (Chapter 13.3); not later, because pertussis is most dangerous in the first months.
Multiple doses — because inactivated and subunit vaccines need repeated exposure to generate a strong memory response.
12 to 13 months for MMR — waiting for maternal measles antibody to decline enough not to block the response.
Boosters at 3 to 4 years and in adolescence — countering waning immunity.
HPV at 12 to 13 — before sexual debut, because the vaccine prevents infection and does not treat it. And the antibody response is stronger at that age than later.
Pregnancy — pertussis, influenza, and RSV, to transfer IgG to the fetus (Chapter 13.3).
Older adults — influenza, pneumococcal, shingles, and COVID-19, because immune responses weaken with age and the diseases become more dangerous.
What the next page fixes
The system described so far is protective. Chapter 13.6 covers what happens when it goes wrong in three directions: reacting to harmless things, reacting to you, and failing to react at all.