Bexsero

Bexsero is the vaccine against meningococci of group B – the serogroup that causes most illness in Europe and against which a conventional vaccine does not work. Its development took a route that had not existed before, and it has one property that regularly occupies parents: it causes fever.

Why a conventional vaccine did not work

Against meningococci of groups A, C, W and Y there are conjugate vaccines. They contain the sugar capsule of the organism, coupled to a carrier protein, and work very well – the same principle as with Hib and pneumococci.

With group B this route fails because of a biological peculiarity. Its sugar capsule consists of polysialic acid – a structure that occurs in the human body, particularly on nerve cells during development. The immune system therefore does not recognise it as foreign. A vaccine made from it would be ineffective, and the theoretical possibility of a reaction against the body's own tissue made the route unattractive in any case.

For decades meningococcus B therefore remained the gap in the immunisation programme. There were vaccines against individual outbreak strains – New Zealand and Cuba developed such vaccines for their own epidemics – but none that would have worked broadly. They were tailor-made and could not be transferred: a vaccine against the New Zealand strain was of little use in Europe.

Reverse vaccinology

The solution came from a direction that had not existed before. Instead of starting from the organism and looking for usable components, its complete genome was decoded and searched by computer for proteins meeting two conditions: they sit on the surface, and they occur in as many strains as possible.

Out of more than two thousand candidates, a handful remained after testing in the laboratory. The method was given the name reverse vaccinology, and Bexsero was the first vaccine to arise this way.

It contains three surface proteins produced recombinantly as well as outer membrane vesicles of a New Zealand outbreak strain, which contribute a fourth antigen. “Recombinant” means that the proteins are not obtained from meningococci but produced by harmless bacteria from the transferred set of instructions. The vaccine contains no organisms capable of multiplying; it is an inactivated vaccine.

This composition also explains its limit. Because it uses not the capsule but surface proteins, its effectiveness depends on whether the strain in question carries these proteins and displays them in sufficient quantity. Estimates for Europe lie at about seventy to eighty per cent of circulating B strains – not at a hundred.

How well it works

Because meningococcal disease is rare, effectiveness could not be shown in a classic trial: it would have meant observing hundreds of thousands of children over years. The vaccine was therefore licensed on the basis of the immune response.

Confirmation came from use. The United Kingdom was the first country to take Bexsero into its infant programme in 2015, and subsequent observation showed a fall in meningococcal B disease in the vaccinated birth cohorts of about seventy-five per cent. Effectiveness against the covered strains was about eighty per cent.

A remarkable incidental finding: several studies showed a degree of protection against gonorrhoea. The organism causing gonorrhoea is closely related to meningococci and shares some of the surface proteins. The effect is moderate – of the order of thirty per cent – but it was large enough to prompt the development of vaccines against gonorrhoea in their own right.

For gynaecology this incidental finding is notable, because there has been no vaccination against gonorrhoea so far and treatment is becoming more difficult through increasing antibiotic resistance. No recommendation can be derived from it at present – but the development is worth following.

The immunisation schedule

Bexsero is licensed from the completed second month of life. The number of doses needed depends on the age at the start.

The early start has a reason: the first peak of the illness lies in the first and second year of life, with a maximum around the fifth month. Anyone starting only at the age of one already has the most vulnerable period behind them – the vaccination is then not pointless, but it comes too late for the stretch in which it would have achieved most.

In Austria the vaccination is recommended from the second month of life. Whether and to what extent it is free of charge has changed several times – that is set out in the immunisation schedule in force and should be asked about at the vaccination appointment. This information changes faster than a website can follow, which is why no amounts are given here.

The matter of the fever

Bexsero causes fever in infants considerably more often than other vaccines. Given on its own, about thirty per cent of vaccinated infants develop a fever above 38 degrees; together with other vaccinations it is considerably more – more than half in studies.

The fever appears in the first hours after the vaccination, reaches its peak after about six hours and is over after twenty-four to forty-eight hours. It is an expression of the immune reaction and not an illness.

With this vaccine an exception therefore applies to a rule that otherwise holds: paracetamol is recommended preventively – one dose shortly before or immediately after the vaccination, then two more at intervals of four to six hours each. Studies have shown that this approach markedly reduces the frequency of fever without impairing the response to the vaccination to any relevant extent.

With all other vaccinations, preventive antipyretics are advised against, because they damp down the immune response slightly with no discernible benefit. With Bexsero the benefit outweighs this – not least because high fever in an infant would otherwise lead to investigations that can be avoided.

Ask about it expressly at the vaccination appointment. This recommendation is not widely known, and it makes a considerable difference to the evening after the vaccination.

The other reactions

Besides fever, local reactions are common and more pronounced than with other vaccines: redness, swelling and marked tenderness on the thigh, often over two to three days. Some children temporarily do not want to put weight on the leg concerned.

Added to this are restlessness, unusual crying, loss of appetite, sleepiness and diarrhoea. These reactions too subside within one to two days.

What belongs with a doctor: fever above 39.5 degrees, fever lasting more than 48 hours, a seizure, unusually shrill crying over hours, swelling involving the whole leg, or striking listlessness.

The vaccination is not given where there has been a documented severe allergic reaction to one of its components. An acute febrile illness leads to postponement – here with particular emphasis, because the fever caused by the vaccine could otherwise not be distinguished from that of the illness.

Bexsero in pregnancy

It is an inactivated vaccine. No harm to the child is known, and none is plausible.

There is no general recommendation for pregnant women in Austria: the risk of illness in this age group is low, and systematic studies in pregnant women are lacking. Where there is a clear indication – absence of the spleen, certain immune deficiencies, an outbreak situation, travel to a risk area – the decision is taken case by case.

Protection carried over to the child from vaccinating the mother is not to be expected to any appreciable extent. Precisely for that reason the child's own vaccination begins earlier than almost any other – from the second month of life.

What is expressly recommended in pregnancy, by contrast, are two other vaccinations: dTpa against whooping cough between weeks 27 and 36 and the influenza vaccination in every trimester. With both, protection carried over to the child is the purpose.

Fever in an infant: what is normal and what is not

Because this vaccine practically guarantees the question, here is what is needed. In infants the temperature is measured rectally – that is the only method giving reliable values at this age. Ear and forehead thermometers are too imprecise in children under six months to base a decision on.

From 38 degrees one speaks of fever. After a vaccination it is to be expected in the first forty-eight hours and needs no investigation as long as the child feeds, can be settled and is alert in between.

What is treated is not the thermometer but the child. An infant with 38.8 degrees who feeds contentedly needs no antipyretic; one with 38.3 degrees who is fretful and does not sleep benefits from it. With this vaccine the preventive administration described above comes on top.

The age limit matters. In infants under three months any temperature above 38 degrees counts as a reason for medical assessment – regardless of whether a vaccination has been given. At this age a serious infection can run its course without further signs, and the distinction cannot be made from the outside. If a vaccination falls in this age range, how to proceed in such a case should be discussed beforehand.

Febrile convulsions practically do not occur in infants under six months; they are a matter of early childhood. If a seizure occurs, it should be assessed regardless of age.

When several vaccinations are given on one day

In Austria Bexsero often falls on the same appointment as the six-in-one vaccination and the pneumococcal vaccination. Three injections in one day sounds like a lot, and the question about splitting them comes up regularly.

Little speaks against giving them together and a good deal for it. The immune response to the individual vaccines is not substantially impaired by giving them at the same time – that has been tested for the usual combinations. The stress for the child arises from the situation and not from the number of injections: three appointments with one injection each mean three occasions of tension instead of one.

What does increase is the frequency of fever, and markedly so – this is the reason for the paracetamol recommendation. Arranging the appointment so that the evening afterwards is free makes the whole thing easier for everyone involved.

The injections are given into different muscles, usually into both thighs. With three vaccines, two are given into one thigh, a few centimetres apart, so that local reactions can be attributed.

For whom the vaccination is particularly important

Beyond the general recommendation in infancy, it applies with particular emphasis to people at increased risk of a severe course.

• people without a spleen or with a non-functioning spleen
• congenital defects of the complement system
• treatment with certain medicines that inhibit the complement system
• people working in laboratories with contact with meningococci
• travellers to risk areas and people in outbreak situations

For women planning a pregnancy who meet one of these conditions, the same applies as with other vaccinations: it is more straightforward to deal with beforehand than during it.

Why coverage is not a hundred per cent

With vaccines containing a sugar capsule the question of coverage is easy to answer: either a serotype is included or it is not. With Bexsero it is more complicated, and that is worth explaining, because it is where the “seventy to eighty per cent” mentioned above comes from.

The vaccine contains four antigens. A meningococcus B strain is covered by it if it carries at least one of these antigens – in a form similar enough to the antibodies, and in sufficient quantity on the surface.

To test this, a laboratory method of its own was developed which determines for each strain examined whether and through which antigen it is covered. The results differ by country and period, because different strains circulate; for Europe they lie in the range given.

This imprecision is not a weakness of the studies but a property of the approach. In practical terms it means that illness remains possible despite vaccination – and that continual surveillance of the circulating strains is needed in order to recognise whether coverage is falling.

What the vaccination does not do

It does not protect against serogroups A, C, W and Y – a separate vaccination is needed for that; see meningococcal disease. Nor does it protect against all B strains, but against those carrying the surface proteins it contains.

And it prevents colonisation of the throat less reliably than the conjugate vaccines. A pronounced herd effect is therefore not to be expected from it – which means that the protection is essentially individual.

Illness despite complete vaccination is therefore possible. The warning signs remain the same, and they apply regardless of vaccination status: fever with pain in the legs, cold hands and feet and an unusual skin colour should be looked at; bleeding into the skin that does not blanch means 144.

What happens next

The child's vaccination is given by the paediatrician. In this practice it belongs among the questions discussed before the birth – together with the other appointments of the first year of life, so that the decision does not fall into the first weeks with a newborn. Arranging an appointment.

Bexsero is the vaccination for which this preparation pays off most. It begins earlier than almost any other – in the second month of life, that is, at a time when many parents are still occupied with the basics. It was long, and in part still is, a question of cost. And it brings with it an evening with fever, which you can prepare for if you know about it. Three things that can be settled beforehand in ten minutes and can cost a restless night afterwards.