Pharyngitis has no licensed vaccine against group A streptococcus, but many other infections of childhood can be prevented before they start. So what does a vaccine do, and why is one vaccine built differently from another?
What is a vaccine doing, and which kind do we choose?
A vaccine is the deliberate presentation of an antigen so that the immune system builds memory without the disease. The effect is large. Plotkin put it this way: apart from safe water, no other modality, not even antibiotics, has had such an effect on mortality reduction.
The clinician’s part is partly biological and partly operational. The biological part is knowing which vaccine suits which pathogen. The operational part is knowing the schedule well enough to notice when a child has fallen out of it. Those are the two questions that follow.
Three words are often used interchangeably, but they name different things:
- A vaccine is a product that produces immunity to a disease. It can be given by injection, by mouth or by aerosol.
- Vaccination is the act of administering a killed or weakened organism, or part of one, to produce immunity.
- Immunization is the process by which a person becomes protected.
Both vaccines and natural infection can immunize.
The choice of vaccine platform follows from the biology of the pathogen, not from convenience. The first question about any platform is whether the organism replicates. A live vaccine produces a strong, durable response with few doses, because the vaccine organism replicates. In a non-replicating vaccine the immune system sees only the antigen the product contains. Purified protein antigens usually need an adjuvant.
There are six vaccine types: live-attenuated, inactivated, subunit, conjugate, polysaccharide and recombinant.
What do the six kinds give the immune system?
The replication question separates the live-attenuated type from the rest.
| Type | What it is | Examples |
|---|---|---|
| Live-attenuated | The organism is alive and replicates, but is weakened so that it does not cause disease | Measles, mumps, rubella (MMR), varicella, rotavirus (oral), yellow fever, BCG, oral polio vaccine |
| Inactivated (“killed”) | The organism cannot replicate | Injected influenza vaccine, inactivated polio vaccine (IPV), hepatitis A |
| Subunit (toxoid, protein fragment) | Purified protein antigens or chemically inactivated toxins | Diphtheria and tetanus toxoids, acellular pertussis (in DTaP), recombinant hepatitis B |
| Conjugate | A polysaccharide antigen chemically joined to a protein carrier, so that the response becomes T-cell dependent | Hib conjugate, pneumococcal conjugate, meningococcal conjugate (MenACWY) |
| Polysaccharide | Long chains of surface sugar without a carrier protein | Pneumococcal polysaccharide vaccine (PPSV23), which does not work reliably in children under 2 years |
| Recombinant | The antigen is produced by another organism engineered to make it | Recombinant hepatitis B (the first genetically engineered vaccine), recombinant meningococcal B, HPV virus-like particles |
A live-attenuated vaccine replicates, and that replication produces a strong, durable response, usually with one or two doses. An inactivated vaccine cannot replicate, so the immune system sees a fixed dose of antigen. Subunit antigens are less immunogenic than a replicating organism and usually need an adjuvant.
Which of these is the clearest example of a platform chosen to match a pathogen’s biology? The conjugate vaccines.
Why can an infant not respond to a sugar, and how does conjugation fix it?
A pure polysaccharide antigen stimulates B cells without T-cell help. That T-independent response is adequate in an adult. In a child under 2 years it produces little antibody, no reliable memory, and no booster response when the dose is repeated.
The first Hib vaccine shows the problem. It was a pure polysaccharide product, available in the second half of the 1980s, and it was not consistently immunogenic in the under-twos.
Conjugating the polysaccharide to a protein carrier converts the response into a T-cell-dependent one. The carrier peptide is presented with T-cell help, which allows affinity maturation and memory. So infants mount protective antibody, and repeat doses boost it.
The same problem explains why the 23-valent pneumococcal polysaccharide vaccine is not effective below age 2 years. The conjugate pneumococcal vaccine is the one used in infants.
| Product | Construction | Use and response |
|---|---|---|
| Hib (current) | Polysaccharide conjugated to a protein carrier | Immunogenic in infants, with a booster response on repeat dosing |
| Hib (original, late 1980s) | Pure polysaccharide | Not consistently immunogenic under 2 years, no booster response |
| Pneumococcal conjugate (PCV) | Polysaccharide conjugated to a carrier protein | Used from 2 months of age |
| Pneumococcal polysaccharide (PPSV23) | Pure polysaccharide | Reserved for older children and adults |
What is different about a live vaccine?
A live-attenuated vaccine behaves differently in three ways, all because the organism replicates.
First, it is neutralised by pre-existing antibody. This is why MMR is not given before 12 months: maternal antibody would inactivate it. For the same reason, passively acquired immunoglobulin delays live vaccination.
Second, replication is the mechanism, so it matters where replication is unwelcome. Live-attenuated vaccines are contraindicated in severe immunodeficiency. They are avoided in pregnancy, because replication is the mechanism.
Third, a live vaccine organism can, rarely, revert. The oral polio vaccine can generate circulating vaccine-derived poliovirus. It was withdrawn in Italy and most high-income countries after it was recognised that it can cause vaccine-associated paralytic poliomyelitis.
What else is in the vial?
Two categories of additive come up in conversations with families: adjuvants and excipients.
The first category follows from the weakness of non-replicating antigens. Adjuvants encourage a stronger immune response to the antigen. Aluminium salts are the commonest adjuvants. They are needed mainly for subunit and toxoid vaccines, which are less immunogenic than a replicating organism.
Excipients are everything else in the product: preservatives, stabilisers, buffers, surfactants and emulsifiers, solvents, diluents and residuals from the manufacturing process. They are there for stability, sterility and solubility. The residual amounts in the finished product are typically far below clinically relevant thresholds, and the specific excipient list for any vaccine is in its product information.
How is the Italian schedule set?
The platform explains how each vaccine is built. The schedule decides when it is given. In Italy, part of the schedule is set by law.
Before 2017 most vaccination in Italy was recommended rather than required, and coverage was drifting. Law 119 of 31 July 2017, converting the decree-law of 7 June 2017, made ten vaccinations mandatory for children and adolescents up to 16 years:
- polio, diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type b, delivered as the hexavalent vaccine;
- measles, mumps, rubella and varicella, delivered as the quadrivalent MMRV vaccine or as MMR plus monovalent varicella.
The same law keeps a longer list of vaccinations offered actively and free of charge without being mandatory: pneumococcal conjugate, rotavirus, meningococcal B, meningococcal ACWY, HPV, influenza, and hepatitis A (for risk groups and travel).
The document that defines the current timetable is the National Vaccination Prevention Plan 2023–2025 (PNPV 2023–2025), published in the Gazzetta Ufficiale on 21 August 2023. Its national calendar separates mandatory from recommended offers. The regions implement the plan and can vary in some details. The influenza offer is restated each year in a Ministry of Health circular.
The calendar turns the mandatory and recommended lists into ages. Most doses fall in four periods: the first year of life, the first birthday, age 5, and early adolescence.
What is given when?
| Vaccine | Ages |
|---|---|
| Hexavalent (DTaP, IPV, hepatitis B, Hib; mandatory) | 2 months (from day 61), 4 months (from day 121), 10 months (from day 301) |
| Pneumococcal conjugate (PCV) | The same three visits: 2, 4 and 10 months |
| Rotavirus (oral, live-attenuated) | From 6 weeks; 2 or 3 doses depending on the product; course completed by 24 or 32 weeks of age depending on the product |
| Meningococcal B | 3 and 5 months, with a booster at 15 months; the first dose may be brought forward to 2 months |
| MMRV, or MMR plus varicella | 12 months, co-administered with MenACWY; second dose at 5 years |
| Meningococcal ACWY (conjugate, quadrivalent) | 12 months, co-administered with MMRV; again from 12 years |
| dTaP–IPV | Fourth dose at 5 years; adolescent booster from 12 years |
| HPV (9-valent) | From 11 years; 2 doses 6 months apart up to 14 years; 3 doses from 15 years; the catch-up offer continues into adolescence and early adulthood |
| Influenza | Annually; in Italy free for all children from 6 months to 6 years and for older children with risk conditions |
| Hepatitis A | Risk groups, including travel to high-endemicity areas |
The calendar lists ages, so why those ages? Each interval answers a question about the infant immune system.
Transplacental maternal antibody, acquired in the third trimester, protects the newborn. It wanes over the first months of life. Two months is the earliest age at which the immune system mounts a reliable response to conjugated and toxoid antigens while maternal antibody still provides some cover. The second dose at 4 months completes the primary series. The dose at 10 to 11 months is a booster that consolidates immunity before the second year.
The hexavalent and pneumococcal conjugate vaccines are given at the same visits, on different legs, so that the number of injections per visit stays manageable.
Why do measles and varicella wait until after the first birthday?
Maternal antibody is the reason, as it was for MMR in the section on live vaccines. Measles maternal antibody persists through most of the first year, and it neutralises the vaccine if the vaccine is given too early. So the first MMR dose waits until after the first birthday, when seroconversion becomes reliable. The second MMR dose at 5 years closes the gap for the small proportion of children who do not respond to the first.
Sometimes measles vaccination is brought forward during an outbreak. The anticipated dose then does not count towards the schedule. The child still needs two further doses: the next at 12 to 15 months, and another at least 28 days later.
Varicella follows the same timetable, and it can be given as the quadrivalent MMRV vaccine.
Why is the rotavirus window the only one that closes?
Rotavirus gastroenteritis is the leading cause of severe dehydrating diarrhoea in infancy. Its incidence is highest between 6 and 24 months, and the mean age at infection is about 9 to 15 months. The vaccine is oral and live-attenuated.
The licensed age windows are strict: the first dose by 12 to 15 weeks depending on the product, and the course completed by 24 or 32 weeks. The windows are strict because the risk of intussusception, the telescoping of one segment of bowel into the next, is related to age at vaccination. Rotavirus is the one vaccine in the schedule whose window closes rather than extends.
Why are the adolescent doses grouped?
The dTaP–IPV booster, the second MenACWY dose and the HPV series coincide in early adolescence. This is convenient, and it is also deliberate. Immunity to pertussis wanes. Meningococcal disease has a second incidence peak in the teenage years. HPV vaccine works best before exposure to the virus. The diseases themselves are taught in the notes that follow.
When is a vaccine not given?
The schedule is meant for almost every child, so exceptions need precise words.
A contraindication is a condition that makes a serious adverse reaction likely, so the vaccine should not be given. A precaution is a condition in which the vaccine may increase the chance or severity of a reaction, or may fail to produce immunity, so the decision needs to be weighed.
Permanent contraindications in the Italian and international schedules are few:
- a severe allergic reaction to a vaccine component or to a previous dose;
- encephalopathy (such as coma, decreased level of consciousness or prolonged seizures) not attributable to another cause and occurring within 7 days of a previous dose of a pertussis-containing vaccine. The seven-day window is the operative part.
A stable pre-existing neurological condition is not a contraindication. DTaP is deferred in a progressive neurological disorder until the child’s neurological status is clarified and stabilised.
Two contraindications are specific to the live oral rotavirus vaccine: severe combined immunodeficiency and a history of intussusception.
Minor illness is not a contraindication. A child with a low-grade fever or a mild upper respiratory infection can be vaccinated. Live vaccines require separate reasoning in immunocompromised children and in pregnancy, because replication is the mechanism.
Can vaccination protect a child before the first dose?
Yes, because vaccination in pregnancy can protect a child not yet born. Maternal antibody crosses the placenta, and two vaccines use this to protect the newborn before the schedule begins: Tdap and influenza.
Tdap (diphtheria, tetanus, acellular pertussis) is given in each pregnancy, ideally in the third trimester around 28 weeks. The maternal antibody then covers the infant during the months before the first pertussis dose at 2 months.
Influenza vaccination is recommended in any trimester during the influenza season. There are two reasons. Pregnancy increases the risk of severe influenza, and the transferred antibody protects the infant while it is too young to be vaccinated.
What does each line of the calendar answer?
Each line of the calendar answers a particular disease: a toxin that can damage the heart, a polysaccharide capsule the infant immune system barely responds to, a virus that harms the fetus. The ten diseases behind the mandatory vaccinations, each with its mechanism, the complication that justifies prevention and the vaccine detail, are set out in Pediatric Vaccine-Preventable Diseases: The Mandatory Schedule. Which ten diseases stand behind the mandatory vaccines, and why does each one need the kind of vaccine it gets?