All of the vaccines currently recommended in Europe have been through a rigorous series of clinical trials. We speak to a leading expert about what it takes to develop new vaccines.
Prof Adam Finn is the David Baum Professor of Paediatrics at the University of Bristol in the UK and heads the Bristol Children’s Vaccine Centre (BCVC) research group. In a detailed interview, Prof Finn explains how researchers study viruses and bacteria which cause infection before developing a potential vaccine.
“You have to understand the structure of the bug because in order to create a vaccine you need to know enough about the infection to be able to mimic it. A vaccine is essentially a mimicked infection,” he says.
Following pre-clinical research, the vaccine is tested in a very small group of people – sometimes as few as half a dozen – in what is called a ‘Phase I’ clinical study. This helps to rule out major safety problems and also helps doctors to work out the right dose for the next step in the testing process.
Phase II trials involve giving the vaccine to a larger number of people (often 100 or 200 but sometimes in the 1,000s). At this point, researchers want to see whether the vaccine gives a consistent immune response and they watch for any side effects that might occur.
Where a disease is reasonably common, phase III trials can be conducted to test how the vaccine protects against natural infection. These studies often include tens of thousands of healthy volunteers so that doctors have a better chance of discovering rare problems which did not show up in smaller Phase II studies and prove that the vaccine prevents the disease.
Prof Finn says vaccine trials differ from studies of new medicines in a number of crucial ways. For one thing, a much larger number of people are included in Phase III trials for vaccines because researchers want to detect any very rare side effects caused by the vaccine.
Another thing that makes the tolerance for side effects in vaccine trials lower than for medicines trials is the fact that the volunteers – and the future target group for the vaccine – are healthy to begin with.
It doesn’t end there. After a vaccine is approved by regulators it can be made available to the public – either via funded national immunisation programmes or to purchase privately. At this point, ongoing monitoring of the vaccine’s effect takes place as part of what can be called Phase IV trials and doctors are encouraged report any unexpected apparent side-effects.
Read the full interview with Adam Finn, Professor of Paediatrics at the University of Bristol
Vaccines Today: Can you talk us through the process of developing new vaccines?
Adam Finn: To develop a vaccine there first has to be research done to understand the nature of the infection you’re trying to prevent. You need to know enough about virus or bacterium that causes the infection; you have to understand the structure of the bug because in order to create a vaccine you need to know enough about the infection to be able to mimic it. A vaccine is essentially a mimicked infection.
Vaccines Today: What is the next step once that work has been done?
Adam Finn: There are a number of different ways to create a vaccine. One way is to actually make a vaccine that is in itself an infection but with a version of the original microbe that doesn’t make you sick. There you’re stimulating the immune system by causing an infection – but a really mild one. Then the next time the body is exposed to that bug the immune system will be primed and can respond quickly.
Another way is to generate material from the bug which doesn’t actually cause infection but stimulates a response. That is referred to as a non-live vaccine. Earlier versions of vaccines were killed bugs. More recent vaccines use more sophisticated ways of creating those ‘antigens’, as they are called.
So we have either live or non-live vaccines. The way you give the vaccine when you start using it will be affected by that because you can give live vaccines in a number of ways whereas non-live tend to be given by injection.
Vaccines Today: Are these potential vaccines then tested in people?
Adam Finn: The next step is usually a series of studies done using cell cultures and animal models so that we can test that they are safe and induce an immune response and protection. At that point plans can be made for human studies. Before anything can be given to humans, careful steps must be taken to ensure that all material is manufactured in an entirely safe and strictly controlled way so you know exactly what it is that you’re giving to people. In particular, efforts are made to ensure that there’s absolutely no chance of contamination with other infectious or toxic material.
The first stage of human research is referred to as phase 1 studies. Material is given at different doses to each of a small number of healthy volunteers. The objective is to ensure that the material is safe and to test the immune response to get some idea of the appropriate dose.
Vaccines Today: How many people would be included in phase I clinical trials for a vaccine?
Adam Finn: It can be as few as half a dozen initially, then more the exact depending on the disease, the vaccine and initial results. It’s unusual for more than 100 people to be involve in phase I.
Next, phase II involves giving an established dose of the vaccine, often alongside other routine vaccines, to larger number of people, often children if they are the target population, the aim being to see how reproducible and consistent the immune response is. At this stage you can establish rates of common adverse events like local swelling and fever as well as some of the slightly less common ones. There are typically hundreds of subjects involved in each phase II trial but the total will usually be in the 1000s as several studies are normally done.
Vaccines Today: Are these subjects paid to take part?
Adam Finn: There are no absolute rules in terms of payment. Vaccine studies are often done in young children as many vaccines are predominantly used in that age group and in most places it is unusual to pay them or their parents although payments might be provided to cover travel costs and inconvenience. There a balance here to be struck between appropriate compensation and inappropriate inducements.
Vaccines Today: What happens next?
Adam Finn: For most vaccines, except where the disease to be prevented is very rare, trials are required to show prevention of disease. In all cases studies looking for rare unexpected side-effects have to be done. At this point, much larger numbers of people need to be immunised. The primary aim is to demonstrate that the people receiving the vaccine are protected against disease. For this to be possible, the disease must be common enough in the population for differences between vaccinated and unvaccinated people to be detectable within a reasonable time frame. There are often tens of thousands of people included in such phase III trials which also pick up rare side effects and adverse events that might not be noticed in small trials.
Vaccine Today: How does the number of participants in vaccine studies compare with the number of people included in clinical trials for new medicines?
Adam Finn: There are generally much larger numbers involved in vaccine studies. Drugs are usually used to treat illness rather than prevent it. To see a treatment effect you don’t need to study so many people unless you are looking for a small difference between two similar treatments. When you test a vaccine in a healthy population you need a larger group of patients especially if the infection you are trying to prevent is rare and to rule out rare side effects.
Vaccines Today: Is it difficult to recruit so many people?
Adam Finn: Recruitment rates vary a lot and are influenced, amongst other things, by the perception of importance and danger of the disease. If you take a particularly unpleasant disease like meningitis where the condition is rare but many parents have concerns, parents are often very glad to have their children participate due to the potential benefit of being protected against the disease. Vaccine studies have the advantage that any healthy person of the right age can take part.
Vaccines Today: When medicines are tested, one group is often given the drug while another is given a placebo or another drug to which the new medicines can be compared. How does this work for vaccines?
Adam Finn: For vaccines, it is exactly the same – there will normally be some kind of comparison group. Nobody is comfortable with the idea of injecting children with a placebo, but a comparator vaccine is alright and, in Phase III efficacy studies normally another vaccine is given which prevents something else. In children, if the vaccine is given via a nasal spray or administered orally then it is typically acceptable to use a placebo provided that a vaccine against the disease under study is not already in routine use and placebo injections can be used in consenting adults.
Vaccines Today: This leads to the question of getting approval from research ethics committees which decide whether clinical trials may proceed. Is it difficult to get approval when you are working with healthy children?
Adam Finn: This kind of research is often done in centres with considerable expertise and experience with vaccine trials. The ethics committees in these centres are very familiar with the principles involved. Provided the protocol is properly designed and presented, approval can usually be obtained.
Vaccines Today: Once phase III trials are successfully completed, is that the end of the story?
Adam Finn: No. After phase III – and sometimes even without phase III if the disease is so rare that it can’t be studied even in very large populations – then a file is prepared by the manufacturer and submitted to the regulator for a license to sell the vaccine. If that’s obtained, national experts decide whether to recommend the vaccine for all children, high risk groups or just to make it available without adding it to the routine immunisation schedule. The ways in which the costs of purchase and delivery of vaccines are covered vary between countries and regions. Once that has been done, phase IV surveillance studies may be done to look for trends in disease – hopefully downward trends! Ideally, a large proportion of the population – usually young children – is offered and receives the vaccine. In many cases vaccines prevent illness not only among those who have received them but also reduce transmission to others who have not been vaccinated as well. If you carefully count the number of cases coming through your health system you can track the disease as it becomes rare or even disappears completely in some cases.
Vaccines Today: At this point are other rare side effects discovered?
Adam Finn: There are examples of very rare side effects not picked up in phase III which become clear when the vaccine is in general use in a very large population. Normally that does not happen but it can occur. For example, it happened with the first licensed vaccine against rotavirus gastroenteritis which was launched in the US in the 1990s. A very small proportion of babies given the vaccine were found to develop a rare, although treatable, condition which causes the intestine to be turned inside out like a sock. It is treatable and curable but potentially serious so that vaccine was withdrawn.
Vaccines Today: Is the level of tolerance of such problems lower with vaccines because they are given to healthy children?
Adam Finn: Yes, there is a very different tolerance for any kind of severe adverse events for vaccines compared to medicines used to treat illness for the simple reason that the recipients are all healthy and many would never have got seriously ill with vaccine preventable diseases even if unimmunised. This doesn’t undermine the importance of vaccines, it just means they have to be safe as well as effective.
Vaccines Today: The whole process sounds long and expensive. How much does it cost to develop a vaccine?
Adam Finn: It varies but nowadays may cost hundreds of millions of dollars, particularly for the late-stage studies which must be very carefully monitored and involve careful manufacturing processes and recorded keeping. It takes an enormous amount of time. These programmes are vastly expensive and costs have risen as we become ever more safety conscious.
Vaccines Today: Have the regulations covering clinical trials made it more challenging?
Adam Finn: The right balance has to be struck between the complexity of the regulation processes and making it easy to get things done. The balance has shifted towards caution and care against any kind of safety issues. But in the case of vaccines that’s unavoidable as you’re offering them to healthy individuals. One of the fundamental guiding principles of medicine is First, Do No Harm.