Prevenar 13

Prevenar 13 is the pneumococcal conjugate vaccine that set the standard for more than a decade – in immunisation programmes for infants as much as in adults at increased risk. It has since been superseded by vaccines with more serotypes. This page explains what it can do, what was learned from it and where it stands today.

What Prevenar 13 is

Prevenar 13 is a conjugate vaccine against thirteen serotypes of Streptococcus pneumoniae. It contains the sugar capsules of these thirteen types, each chemically coupled to a carrier protein – a detoxified diphtheria toxin called CRM197.

This coupling is the heart of the matter. Pure sugar structures produce practically no immune response in an infant and leave no memory behind. Through binding to a protein the sugar gets into a different recognition pathway – one that works from birth and produces a lasting memory. The principle comes from the Hib vaccination and is what made vaccinating infants against encapsulated bacteria possible in the first place.

One point that regularly prompts questions: the carrier protein is a detoxified diphtheria toxin, but the vaccine does not protect against diphtheria. The protein serves only as a vehicle; the quantity is too small for protection in its own right. The diphtheria vaccination remains separate and is part of the six-in-one vaccination and the dTpa booster.

From seven to thirteen

The history of this vaccine explains why pneumococcal vaccines change more often than others.

The first conjugate vaccine, introduced in 2000, covered seven serotypes. The effect was impressive: invasive disease due to these seven types disappeared almost entirely in small children, and because of the herd effect the frequency fell in adults as well, who had not been vaccinated at all.

Then what had been feared came to pass. The gap left by the vanished types was filled by others – most strikingly by serotype 19A, which had previously been rare, became commoner and is also insensitive to several antibiotics.

Prevenar 13 was the answer to this: the same seven types plus six more, including 19A. After its introduction this type too fell markedly.

The pattern is now repeating itself, and the answer once again consists of extension: there are conjugate vaccines with fifteen and with twenty serotypes. Which one is used in Austria in the childhood programme and for adults is set out in the immunisation schedule currently in force and changes faster than a website can follow – ask at the vaccination appointment.

What the vaccine prevents

The benefit is documented above all for invasive disease: blood poisoning, meningitis and pneumonia detectable in the blood. Here effectiveness against the covered serotypes is more than ninety per cent.

With pneumonia where no organism is detected in the blood – the commonest form – the effect is smaller but present. With middle ear infections it is smallest: the number of cases caused by the covered types falls, but the total number only moderately, because other organisms move in.

This gradation is part of honest advice. Anyone expecting the vaccination to produce a child without earache will be disappointed. Anyone who understands it as protection against the rare but severe courses gets exactly that. It is the same relationship as with many vaccinations: they prevent the rare and terrible more reliably than the common and annoying – which makes them less conspicuous in everyday life than they are.

The herd effect – the larger part of the benefit

With this vaccine something happened that had not been expected on this scale at its introduction and that is now regarded as its most important effect.

Conjugate vaccines prevent not only the illness but also colonisation of the nose and throat. A vaccinated small child carries the covered serotypes less often and passes them on less often. Because small children are the main source for the spread of pneumococci in the population, the frequency of illness thereby falls in all age groups.

In several countries invasive pneumococcal disease in people over 65 fell markedly after the introduction of the childhood programme – without that age group having been vaccinated. Arithmetically, in some analyses the larger part of the illness prevented falls to people who never received the vaccine.

For advice this is a remarkable point: vaccinating an infant measurably protects its grandparents too. It is one of the few cases in which this connection can be backed with figures and is not merely presented as an appeal.

The schedule for children

In Austria the pneumococcal conjugate vaccination is included in the free childhood immunisation programme. It is given in the third and fifth month of life and between the twelfth and the fourteenth – at the same appointments as the six-in-one vaccination, into the other thigh.

Premature babies and children at increased risk receive an additional dose, because in them the response to two doses is less reliable. The calculation follows actual age, not the calculated due date.

If the series is started later, the number of doses needed falls with increasing age. From the second birthday a single dose is as a rule enough in healthy children; from the fifth birthday no vaccination is provided for in them any more, because the illness becomes rare by then. For children with the underlying conditions named above this does not apply – there vaccination continues regardless of age.

Prevenar 13 in adults

The vaccine is also licensed for adults, and here the evidence is particularly interesting. In a Dutch study of around 85,000 people over 65 – the CAPiTA study – it reduced invasive pneumococcal disease due to the covered types by about 75 per cent and pneumonia due to these types by about 45 per cent.

That was the first robust evidence that a conjugate vaccine prevents pneumonia in older people as well – something the older polysaccharide vaccine could not convincingly show. The study was at the same time one of the largest vaccine trials ever conducted, and it changed the recommendations for adults in several countries.

For women of childbearing age vaccination is not routinely provided for. It is recommended with chronic illness, with immune deficiency, where the spleen is missing and in a number of other situations; the complete list is on the page pneumococcal disease.

Prevenar 13 and pregnancy

It is an inactivated vaccine with no organisms capable of multiplying. No harm to the child is known, and none is plausible.

Nevertheless the vaccination is not generally recommended for pregnant women in Austria – for a simple reason: systematic studies in this group are lacking, and a general benefit is not documented. Where one of the conditions named exists, the decision is taken case by case, and then little speaks against it.

Anyone planning a pregnancy who has an indication is best dealing with the vaccination beforehand. That is not an argument about safety but a practical one: before the pregnancy fewer things have to be weighed up, and protection is in place in good time.

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. Both also protect the child in the first months of life.

Conjugate and polysaccharide: which is given when

In adults at increased risk a combination of both kinds of vaccine is often used, and the order is not arbitrary.

First the conjugate vaccine, then – after an interval of at least a year – the polysaccharide vaccine with its 23 serotypes. This order matters: if the polysaccharide vaccine is given first, the response to a conjugate vaccine given later is weaker. The technical term for this is hyporesponsiveness, and it is the reason why the recommendations pay such close attention to the sequence.

Anyone who has already received a polysaccharide vaccine can still receive a conjugate vaccine later – only with an interval of at least a year and in the knowledge that the response will be somewhat smaller.

With the newer vaccines covering twenty serotypes this becomes simpler: where they are available, a single dose is enough in many recommendations and the combination is dropped. That is one of the reasons why these recommendations currently change more often than others.

What the abbreviations mean

In vaccination records and recommendations, abbreviations appear that are hard to read without explanation. They follow a simple logic.

PCV stands for pneumococcal conjugate vaccine; the number after it gives the number of serotypes covered. PCV7, PCV10, PCV13, PCV15 and PCV20 are accordingly the same kind of vaccine with differently wide coverage. Prevenar 13 is a PCV13.

PPSV23 stands for pneumococcal polysaccharide vaccine with 23 serotypes – the older vaccine without a carrier protein, which does not work in small children.

If you cannot place an entry in your vaccination record, the trade name is next to it. Bring the record with you; the matching up is done in a minute and saves a possibly unnecessary repeat.

Tolerability

In infants the commonest reactions are redness, swelling and tenderness on the thigh, together with fever, restlessness, reduced appetite and increased sleeping for one to two days.

If the six-in-one vaccination is given at the same time, fever occurs somewhat more often than with separate appointments. This is known, was so in the licensing studies and is accepted: two appointments mean more strain overall than one day with a little more fever.

In adults local reactions in the upper arm predominate, together with muscle pain and fatigue. Compared with the older polysaccharide vaccine the local reactions are as a rule milder.

The vaccination is not given where there has been a documented severe allergic reaction to one of its components or to a vaccine containing diphtheria toxoid. An acute febrile illness leads to postponement.

What the vaccine does not cover

Thirteen out of more than ninety serotypes – that sounds like few and is not, because the distribution is uneven: a small proportion of the types caused most of the serious illness before vaccination. It is precisely these that were selected.

Not covered are all the rest. Among them are types that have become commoner since the vaccines were introduced – a pattern that repeats itself with every extension. Invasive pneumococcal disease despite complete vaccination is therefore possible and is not a sign that the vaccination has failed.

Nor are the strains without capsules covered. They cause no invasive disease but do cause some of the middle ear and sinus infections – and are one reason why the effect on these illnesses remains limited.

And of course the vaccine protects against nothing but pneumococci. Pneumonia can be caused by numerous other organisms, and meningitis likewise – see meningitis. This obvious point deserves stating, because otherwise an illness after a vaccination easily leads to the wrong conclusion.

What is to be learned from serotype replacement

The history of Prevenar is instructive beyond pneumococci, because it shows how a biological system responds to intervention.

A vaccine that eliminates part of a family of organisms creates an ecological niche. Whoever can fill it, fills it. That is not a fault of the vaccine but a property of the system – and it does not mean the intervention was pointless: the total number of invasive infections has fallen markedly, because the types moving in cause severe courses less often.

It does mean, though, that surveillance never ends. This is why the serotype is determined in every case of invasive pneumococcal disease – not for treatment but so that it can be seen whether the vaccines still fit.

And it means that recommendations about vaccination change without the previous ones having been wrong. Anyone surprised that a different vaccine is used for a second child than for the first has the reason here.

How a conjugate vaccine is manufactured

The effort behind this vaccine explains why it is expensive and why extending it by further serotypes takes years.

For each individual serotype the organism is cultured separately, the capsule obtained and purified. The sugar is chemically activated and then bound to the carrier protein – for each type in a process of its own, because the capsules differ chemically. Only at the end are the thirteen finished conjugates mixed and combined with an aluminium salt as an adjuvant.

A vaccine with thirteen serotypes therefore consists of thirteen manufacturing lines run in parallel. Every additional component means another one – and at the same time the question of whether the new component weakens the response to the existing ones, which has to be tested.

That also explains why there are no arbitrarily broad vaccines. The amount of carrier protein is limited: too much of it leads to the immune system responding primarily to the protein instead of to the sugars. It is at this limit that the newer developments are working, and this is why the number of serotypes is not simply doubled.

What happens next

The child's vaccinations are given by the paediatrician; which pneumococcal vaccine is currently used follows the immunisation schedule in force. In this practice the subject is relevant if you yourself have an indication – above all before a planned pregnancy. Arranging an appointment.

If you are unsure whether an indication applies: the commonest are asthma, diabetes, chronic heart, lung, kidney or liver disease, immune deficiency or immunosuppressive treatment, a missing spleen and a cochlear implant. Smoking also markedly increases the risk. The complete list with the schedules provided for in each case is on the page pneumococcal disease and in the Austrian immunisation schedule.