Why are some vaccines left outside the law, and what unites them?
Italy requires 10 vaccinations for children and adolescents up to 16 years of age. The rest of the Italian schedule is offered actively and free of charge, but it is not mandatory. The non-mandatory vaccines are pneumococcal conjugate, rotavirus, meningococcal B, meningococcal ACWY, HPV, influenza, and hepatitis A for risk groups and travel.
They prevent six diseases: pneumococcal disease, meningococcal disease, rotavirus gastroenteritis, HPV infection, influenza and hepatitis A. The six fall into three groups. For the first two groups, the kind of vaccine follows from the biology of the pathogen:
- Two bacteria with a polysaccharide capsule, pneumococcus and meningococcus. A capsule requires a conjugate vaccine.
- Two viruses whose biology dictates the vaccine. Rotavirus infects the gut, so it needs an oral live-attenuated vaccine with a narrow age window. HPV matters for the cancer it causes, so it must be prevented before exposure rather than treated afterwards.
The third group, influenza and hepatitis A, is defined differently, by who is offered the vaccine. Influenza vaccine is offered every year to young children and to those at risk. Hepatitis A vaccine is offered to risk groups and travellers.
First group: why do two bacteria need the same kind of vaccine?
Streptococcus pneumoniae and Neisseria meningitidis both have polysaccharide capsules. The capsule surrounds the cell wall and interferes with phagocytosis. In the meningococcus it also helps the bacterium survive while it invades the bloodstream and the central nervous system. The capsule is therefore both the way the organism defends itself and the part the immune system has to recognise, so it is the part the vaccine is built around.
There is a problem with using the capsule alone. Pure polysaccharide antigen produces little antibody and no reliable memory in children under 2 years. Because of this, both bacteria are prevented in infancy by conjugate vaccines rather than by polysaccharide alone. A conjugate vaccine joins the polysaccharide to a protein carrier. Pediatric Vaccines: Types and the Italian Schedule explains why the carrier fixes the problem.
Pneumococcus: who gets invasive disease, and what does the vaccine change?
S. pneumoniae causes otitis media, pneumonia, bacteraemia and meningitis. One organism gives all of these because it colonises the nasopharynx and from there can reach the ear, the lung, the blood and the meninges.
Why do some people develop invasive disease and others do not? The risk factors may be read as one pattern: weaker defences, a breach in a barrier, or chronic organ disease. The risk of invasive pneumococcal disease rises with:
- decreased immune function, including haematological malignancy and HIV infection
- asplenia
- chronic heart, lung, liver or kidney disease
- cigarette smoking in adults
- cerebrospinal fluid leak
- cochlear implant
Pneumococcal meningitis is the leading cause of lasting hearing loss among survivors of bacterial meningitis.
In infants, conjugate vaccines are used, and 13-valent and higher-valency conjugates are available. The product used can vary by region. The 23-valent polysaccharide vaccine is not effective below 2 years, so it is reserved for older children and adults.
The conjugate vaccine reduced invasive pneumococcal disease directly, in the vaccinated children. It also reduced invasive disease in the unvaccinated population. This is the herd effect: the protection of the unvaccinated by the immunity of those around them. A likely route is that the bacterium lives in the nasopharynx, so fewer carriers among vaccinated children means less transmission to others. The herd effect is not a property of the polysaccharide product. How much coverage it takes is a question for the coverage note.
Meningococcus: why is it so fast?
N. meningitidis is an aerobic Gram-negative diplococcus. It has 13 described polysaccharide capsules, and these define its serogroups. Serogroups A, B, C, W and Y cause almost all invasive disease. A vaccine has to match the capsule, so these are the serogroups the vaccines target.
Nasopharyngeal colonisation precedes invasion, so a person can carry the bacterium without being ill. A preceding upper respiratory infection may contribute. The incubation is 3 to 4 days, with a range of 2 to 10.
Then the picture changes abruptly. Once the bacterium is in the blood, the disease presents with fever, meningeal signs, hypotension and rash. This bloodstream phase explains why the disease is so fast and so dangerous. Overall mortality exceeds 10%, and death can occur within 24 to 48 hours. Case fatality is 10% to 15%, or up to 40% in meningococcaemia. About 20% of survivors have permanent complications, such as hearing loss, cutaneous necrosis or limb amputation. Incidence peaks in early childhood, adolescence and older age.
Two vaccines cover these serogroups. The recombinant serogroup B vaccine contains recombinant NHBA, fHbp and NadA fusion proteins, 50 micrograms each. It also contains outer membrane vesicles from strain NZ98/254, measured as total protein containing PorA, 25 micrograms. These are adsorbed onto aluminium hydroxide. The meningococcal ACWY conjugate vaccine is given at 12 months and again in adolescence.
Close contacts of a case need chemoprophylaxis. This is covered in Meningitis and Pediatric CNS Infections.
Rotavirus: why is a gut virus given by mouth, and why is there a deadline?
Rotavirus is the most common cause of gastroenteritis worldwide and the leading cause of severe dehydration in infancy. The virus enters by mouth and replicates in the cells lining the small intestine. Infection reduces absorption of salt, glucose and water and also provokes secretion, so the infant loses fluid, and an infant has little reserve. This is why dehydration is a danger.
The burden before the vaccine shows the scale. In the United States, 80% of children had had rotavirus by age 5. Each year there were roughly 410,000 physician visits, 205,000 to 272,000 emergency department visits and 55,000 to 70,000 hospitalisations. Rotavirus accounted for 30% to 50% of hospitalisations for gastroenteritis.
Incidence is highest between 6 and 24 months, and the mean age at infection is 9 to 15 months. Young infants are probably protected in part by maternal antibody, which fades. Cases cluster in winter and often coincide with respiratory infection. Etiology and Risk Factors of Acute Diarrhea in Children puts rotavirus in the context of other enteric pathogens.
The rotavirus vaccine is oral and live-attenuated. Because it is given by mouth, it meets the virus at the site where the virus infects. It is the one vaccine in the schedule whose age limits exist for safety rather than immunology. The first dose must be given by 12 to 15 weeks depending on the product, and the course is completed by 24 or 32 weeks. The reason is that the risk of intussusception is age-related. Intussusception is the telescoping of one segment of bowel into the next. Pediatric Vaccines: Types and the Italian Schedule gives the timing in the calendar.
HPV: why vaccinate against an infection that usually clears?
More than 200 HPV types have been described, on the basis of the outer capsid protein L1. About 40 of them infect the mucosal epithelium, and these are the ones that matter here.
Infection is very common: 50% to 80% of sexually active people are infected at some point. In the United States about 13 million people, including teenagers, become infected each year. Most infections are asymptomatic and clear. So why vaccinate? Because of the minority that do not clear. The carcinogenic role is what makes vaccination worthwhile. HPV is responsible for nearly all cervical cancers, and types 16 and 18 cause about 70% of them. HPV is implicated in around 90% of anal cancers and in a majority of vulvar, vaginal, penile and oropharyngeal cancers.
The vaccine prevents infection and does not treat it. It produces protection in advance, but it does not remove an infection already established. Hence the target is vaccination before exposure.
The 9-valent vaccine is given as two doses six months apart from 11 years of age and up to 14. From 15 years the course is three doses. The Italian catch-up offer continues into early adulthood.
Influenza: why are children the target?
Third group: influenza vaccination is defined by who is offered it. Influenza A viruses have animal reservoirs, wildfowl in particular, and influenza A is the usual source of epidemics and pandemics. Influenza B causes smaller, usually milder outbreaks. It circulates mainly in humans, and this is thought to be why its outbreaks are smaller. The Italian influenza season runs broadly from late November to the end of March.
Children are at higher risk of complications, and they are also a major driver of transmission to the rest of the population. Vaccinating them may therefore protect them and, by reducing spread, those around them. Complications include:
- acute otitis media in infants and preschool children
- febrile seizures
- myocarditis, myositis and toxic shock syndrome in school-aged children
Influenza myocarditis is rare but can cause sudden death in previously healthy children. Risk is increased in children under 5 years, particularly under 2, and in adults over 65.
Oseltamivir can be used from 2 weeks of age. It works best when started as soon as illness is recognised, because the virus replicates early. Later treatment still has a role, but with reduced efficacy.
Influenza vaccination is annual, because the virus changes, so protection from one season may not hold for the next. In Italy it is offered free of charge to all children from 6 months to 6 years, and also to older children with risk conditions.
Vaccinating a pregnant woman protects her, since pregnancy increases the risk of severe influenza. It also protects her infant during the first months of life.
Hepatitis A: who needs the vaccine?
Hepatitis A spreads by the faecal-oral route. In young children it is usually self-limiting, often asymptomatic or mild. Such children may therefore pass the virus on without being recognised. Severity increases with age, and hepatitis A can cause fulminant hepatitis.
The vaccine is inactivated, in a two-dose series. In Italy it is offered to risk groups, including people travelling to areas of high endemicity, because they meet the virus without prior immunity. Schedules for children with specific risk conditions and immunisation of immunocompromised children follow national guidance and specialist advice.
If none of this is required, what makes it work?
None of these vaccines is required by law. The protection each gives depends on how many people take it up. Uptake is a question about coverage rather than about the product, so how many people must take a vaccine before a whole population is protected?