Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please could you give a brief introduction to malaria?
Malaria is an infection caused by a parasite called plasmodium, which is transmitted from person to person by females of some species of mosquito. It is primarily a disease of tropical countries. However, it is seen occasionally in many other countries in visitors who have brought the infection back from a trip to the tropics.
Malaria is still the most important parasitic infection. Although there have been considerable improvements in the past 10 years or so, it still kills around 650,000 people every year – an unacceptable number. Most of those 650,000 are children in Africa.
What treatments are currently available for malaria?
There are several drugs that are effective at treating malaria, but the drugs that are currently used most frequently come from a plant called Artemisia. This group of drugs has been used in China for about 2000 years for treating people with fever, but more recently Chinese scientists found the active principle in the plant and these pure compounds are now used as the basis for most treatments for malaria.
The malaria community used to rely on treating people with one drug – chloroquine, which was initially very effective drug and was used for about 50 years by itself. Then resistance developed to this drug, first in South East Asia and then in Africa. Chloroquine isn’t used anymore and artemisinins have taken its place. Malariologists have learnt from people treating TB and HIV that you shouldn’t use your best drugs by themselves, but in a combination. This helps to stop development of resistance because if that happens for one of the drugs in the combination, then the other drug will kill the parasite.
So for treating uncomplicated malaria we use an artemisinin drug in combination with another antimalarial – these are called ACTs – Artemisinin Combination Therapies.
Are these treatments effective?
ACTs are very effective and they kill malaria parasites faster than other antimalarials do – this is very important for the patient. With the old drugs that we used to use, such as quinine, it takes a few days for the patient to feel better and for their fever to come down; with ACTs patients are often better within 24 hours.
We do have a problem,however, as the malaria parasite is very clever at developing resistance to drugs and there are now early reports that the parasite is developing resistance to artemisinins in Cambodia and perhaps in Thailand as well. This is very worrying. Because the biggest burden of malaria is still in Africa, if these resistant parasites got to Africa that would really be very serious. This is why we need to keep up research to develop new drugs as we know that for any drug that we use it is likely that eventually the parasite will develop resistance to it. We need to be sure that we have 1 or 2 drugs in reserve, so the they could come into use rapidly if we get widespread resistance to artemisinins.
Why is there a need for a malaria vaccine?
The simplest answer to this question is that prevention is always better than cure. If we rely just on treatment, then there is a risk that when a person gets sick with malaria they may be too ill to travel to the hospital, or there may not be a clinic near enough which has the drugs needed to treat them. Malaria can progress very fast so that children can die within 24 hours of first getting ill. So, if at all possible, we want to prevent the infection rather than relying on treatment when it has developed.
The main approaches to the prevention of malaria at the moment are stopping mosquitoes biting people or killing the mosquitoes. We have two main ways of doing this, one is using bed nets that have been treated with an insecticide(ITNs). An ITN works in two ways: it acts as a mechanical barrier stopping the mosquito from biting somebody, unless they are leaning right against the net, and if it does land on the net and tries to bite somebody the mosquito will pick up some insecticide off the net and be killed. This is the main tool we have at the moment for preventing malaria in Africa.
Insecticides can also be sprayed on the walls of houses. When a mosquito has bitten someone, it will often rest on the bedroom wall and there it picks up some insecticide that kills it. This is a slightly more complicated approach to malaria control than just giving someone a bed net.People like bed nets as they stop them getting bitten by other insects and bedbugs.
However, there are problems for ITNs as a bed net only lasts 3 years or so and has to be renewed every few years, and resistance is beginning to develop to the insecticides that are used to treat bednets and to spray on walls. So, like the parasite developing resistance to the drugs, the mosquito is developing resistance to the insecticides that we use to try and kill it. For these reasons malaria control would be easier if there was a vaccine that we could give, like the measles vaccine, which would protect for life. We wouldn’t have to worry then so much about drug and insecticide resistance.
For most infectious diseases, the most cost-effective way of controlling them is through a vaccine, but it has been really difficult to make a malaria vaccine that is highly effective.
How was the RTS,S vaccine developed?
RTS,S was developed on the basis of work done by Professor Nussenzweig and her colleagues at New York University (NYU) in experimental animals. She found that there was an antigen, something that stimulates the immune response, on the surface of malaria sporozoites called circumsporozoite protein (CSP) and that this protein induced a very good immune response when injected into animals and protected them against malaria. Sporozoites are the form of the parasite injected by an infected mosquito when it bites somebody; sporozoites travel via the blood to the liver where they multiply in the first stage of the malaria parasite’s life-cycle.
Scientists at the Walter Reed Army Institute in Washington then took up this work in humans and did various experiments. They showed that a proportion of healthy people who volunteered to be given malaria experimentally, could be protected against malaria by the CSP protein when it was given in different ways as Professor Nussenzweig had shown to be the case in experimental animals. This was the second stage in development of the vaccine -transferring research from animals to humans volunteers.
Then the company GlaxoSmithKline (GSK) picked up the research and scientists working for the company found a very effective way of presenting the CSP antigen to the body: they combined it with a hepatitis virus to make a particle that is very good at inducing an immune response, much better than if the protein is given by itself in solution. The RTS,S vaccine is what is known as a virus-like particle – it looks like a virus but it has the malaria parasite antigen CSP on its surface. The particle is injected with a powerful adjuvant AS01, an adjuvant being a substance that provides an overall stimulus to the immune system.
Initial experiments looked promising so GSK went into partnership with the Malaria Vaccine Initiative, a part of PATH – a non-governmental agency which receives a lot of support from the Bill and Melinda Gates Foundation. Thus the development of RTS,S became a partnership between a pharmaceutical company and a non-governmental organisation, both of whom have put a heavy investment into testing the vaccine in Africa.
Development of a vaccine for widespread use re quires initial safety studies starting in small numbers of subjects with trials increasing is size in order to show that the vaccine is effective. The trial of RTS,S that is currently going on is the final stage of this process; it involves 16,000 children and is what is called a Phase III trial, the final stage of testing which, if successful, might lead to a vaccine being licensed. Development of a malaria vaccine takes a long time – progressing from animal experiments to early experiments in volunteers, small experiments in adults, then into children and finally into a big trial to confirm its safety and to show that it is effective.
How does the RTS,S vaccine differ from other malaria vaccines that have previously been tested?
There is only one previous malaria vaccine (SPf66) that has been tested on a large scale in humans. This was developed by a Columbian scientist, Dr Manuel Patarroyo. SPf66 gave some initial encouraging results in South America, in Columbia in particular, but when when the vaccine was trialled in Africa, it provided little protection to African children, so that vaccine was not developed further.
RTS,S is, therefore, only the second malaria vaccine that has gone into large-scale trials, but there are a lot of other ones coming along that have been tested in humans but so far in only relatively small numbers of subjects.
Please can you outline the latest international study on the RTS vaccine?
The big trial of RTS,S that is now under way is the last stage before the vaccine is considered for possible licensure and use. It is being conducted in 11 centers in 7 countries in Africa and about 16,000 children and many scientists are involved.
The first results from the trial, reported last year, came from children who were 5-17 months old when they were vaccinated. In these children, the malaria vaccine was given just by itself – they were not given any other vaccines at the same time. These children were followed for one year after vaccination and the results of this initial follow-up were reported in the New England Journal of Medicine a year ago. The results were very encouraging with the vaccine giving about 50% protection against severe malaria and less severe malaria.
The results that have been reported recently come from younger children who were given the RTS,S vaccine at the same time as their other routine vaccines. This is logistically much easier as the mother doesn’t have to bring the child many times to the clinic. The results in these younger children weren’t as positive as they had been in the older children – the vaccine gave only about 30% protection against severe and less severe malaria.
There have been various discussions in the scientific community on why these different levels of protection have been seen:
Was it because the vaccines were interfering with each other?
Was it because the children were a bit younger than in the previous group of children studied?
In the New England Journal of Medicine paper which reports these new results, some of the reasons why the vaccine may not have done so well in younger children are discussed.
Why was it important that the malaria vaccine was given together with other routine vaccines?
Children now receive around 10 or 12 vaccines and we don’t want them having to come to the clinic every week to get another vaccine. For this reason one of the vaccines that is used very widely, called Pentavalent vaccine, or Penta, combines 5 vaccines into one injection. It would be easiest practically if the malaria vaccine could be given at the same time as the pentavalent vaccine, as was the case in the current trial, but maybe we can’t do that and, as we get more vaccines, we may have to space them out and children will just have to come to the clinic more often than they did when we only had 5 or 6 vaccines to give them.
Is the trial still on-going?
The trial will continue for another 2 years. It is very important to find out how long the vaccine will protect against malaria for if it is just for a year or so and children need to be vaccinated repeatedly this could be difficult. Measles vaccine protects a child for life but other vaccines like influenza do have to have to be given more often so a malaria vaccine that needed to be given every few years could still be useful. Nevertheless, a malaria vaccine is much more likely to be used if it gives children 5 or 10 years protection. So part of the reason for continuing the study is to see for how long the protection provided by RTS,S lasts.
How did the recent results of this study compare to what was expected?
They were not as good as we expected. We had previously seen 50% protection in the slightly older children, the 5 to 17 month olds, and there had been some previous small studies done in younger infants in which RTS,S was given with other routine vaccines but which had given about 50% protection. So we were a bit surprised that we got 30% and not 50%. However, one of the reasons why we need to do big trials is because small trials may give an indication of whether or not a vaccine is working but are unable to give an exact accurate figure of the level of protection that the vaccine provides So that may be why the earlier trials, which showed better protection in the very young infants but were quite small, gave different results from the current study. Overall though, I think we were all hoping that we would get 50% protection.
What further research is planned on this malaria vaccine?
For this particular vaccine the plan is to go on and follow the children in the trial for another 2 years. About half the children are getting a booster dose when they are a 18 months old, because that may help them to get a longer duration of protection, and we will get results on how effective the booster dose has been in another couple of years’ time.
It is also important to know whether the risk of infection is important in determining how effective the vaccine is. The level of infection with malaria varies a lot across Africa and in some parts, like around Lake Victoria, children may be bitten every night by an infected mosquito. In other parts, like the coastal region of Kenya, children may be bitten only once or twice a year by an infected mosquito. So we need to know whether the vaccine will be equally effective in those two situations; we will know this in next year or the year after that. We will be able to look at how effective the vaccine was in each of the 11 sites where it has been tested, the ability to do this is a very important feature of the current RTS,S trial.
There are about 10 or 15 other malaria vaccines using other malaria parasite antigens and different ways of presenting these to the immune system of the body that are in clinical trials, so that this is a very active field of research.
Would you like to make any further comments?
A malaria vaccine that gives 50% protection is not the end of the story and for the longer term we are looking for something better than that. If the RTS,S vaccine does get licensed, all of the studies done so far show that it is safe, and used that will be a major step forward but we are looking for a vaccine that gives more than 50% protection. This may achieved by combining malaria vaccines, mixing different parasite components to give a more complex vaccine, and probably a more expensive one, but one that gives a higher level of protection.
A lot has been learnt from the RTS,S phase 3 vaccine trial. The trial has been done almost completely by African scientists - they have taken the lead in this. An enormous effort has gone into strengthening the ability of the African centres where the trial is being done; providing training; upgrading the clinical services; improving laboratories and so on. So the trial has had an enormous stimulus in increasing the capacity of scientists in Africa to do vaccine trials. Other groups are going to benefit from this because whatever happens to RTS,S, whether it gets used or not, there will be other vaccines coming along that need to be tested and the RTS,S trial will have shown how to do this most effectively. The phase 3 RTS,S malaria vaccine has had many indirect benefits in addition to showing how effective the vaccine is in preventing malaria.
Where can readers find more information?
They can find our paper here: http://www.nejm.org/doi/full/10.1056/NEJMoa1208394?query=featured_home
The malaria vaccine initiative has a website which gives more information on malaria in general: http://malariavaccine.org/
Also if readers want more information there is a very useful Rainbow chart of all the different malaria vaccines and the stages they are at produced by the WHO: http://www.who.int/vaccine_research/links/Rainbow/en/index.html
About Professor Sir Brian Greenwood
Brian Greenwood qualified in medicine at the University of Cambridge in 1962. He then spent 13 years in Nigeria at University College, Ibadan and at Ahmadu Bello University, Zaria, followed by 16 years in The Gambia, where he directed the UK’s Medical Research Council Laboratories.
Since 1996, he has been based at LSHTM where from 2000 - 2008 he co-ordinated the Gates Malaria Partnership, a programme of malaria research and capacity development in several countries in Africa.
In 2008, he became the co-ordinator of a new malaria capacity development initiative supported by the Bill & Melinda Gates Foundation and the Wellcome Trust, the Malaria Capacity Development Consortium (MCDC), which supports PhD and post-graduate training in malaria in five universities in sub-Saharan Africa.
He also co-ordinates the African Meningococcal Carriage Consortium (MenAfriCar), also supported by the Bill & Melinda Gates Foundation and the Wellcome Trust, which is studying meningococcal carriage in Africa before and after introduction of a new meningococcal conjugate vaccine.
He is an investigator in a trial of a new combined pneumococcal protein and conjugate vaccine currently underway in The Gambia and in a phase 3 trial of the malaria vaccine RTS,S.
He has published over 700 papers in peer-reviewed journals on a variety of infectious disease but especially malaria. He is an advisor to WHO, the Bill and Melinda Gates Foundation and several other philanthropic organisations.