In observation of World Malaria Day 2021, News-Medical interviews Sir Brian Greenwood about raising awareness for malaria in the times of the COVID-19 pandemic and how we can achieve elimination of the disease.
Please can you introduce yourself and tell us about your incredible career in malaria and other tropical diseases in Africa?
I am Brian Greenwood and I work at the London School of Hygiene and Tropical Medicine. Before this, I spent 30 years working and living in West Africa. I trained in medicine in the UK and after doing a couple of years of internships, I thought that it would be exciting to go and spend some time in Africa. So I went to Ibadan in Nigeria, thinking this would be a one or two-year trip as part of my career before coming back to the UK and progressing along the more usual route to become a medical specialist.
However, I found that I really enjoyed my time in Nigeria. It was a bit difficult at that time because the Biafran War came along, and although I stayed through parts of the war, I thought I should come back to the UK and get some more expert training if I was really going to contribute to medical research in Africa. I came back to the UK and I did some immunology training as clinical immunology was quite a trendy thing to do at that time. Because I had done an internship in joint disease in the UK, whilst I was in Nigeria I thought that it might be interesting to look at the incidence of autoimmune diseases in Nigeria for my thesis because not much was known about autoimmune diseases in the tropics.
I found that there were few autoimmune diseases among patients seen at the hospital in Ibadan, especially systemic lupus erythematosus, which is quite common in people of African origin living in the United States and the Caribbean and I thought, "Well, why might that be the case?". The idea was that perhaps malaria was doing something to the immune system and protecting people from some of these autoimmune diseases. When I got back to the UK we did some experiments in mice that were going to get an autoimmune disease like systemic lupus erythematosus and gave them malaria.
Much to my surprise, we found that malaria did stop them from getting their autoimmune disease. That was how I first got into malaria. After my training in the UK, in 1970, I had the chance to go back to Nigeria after the Biafran War to help start a new medical school at Ahmadu Bello University in Zaria in northern Nigeria.
One of the striking things about infectious diseases in places like Zaria in the region of Africa called the Sahel and sub-Sahel is their seasonality. There is a long dry season from about November to June, when it hardly rains, and then a wet season when it rains quite heavily. During the dry season, meningitis and pneumonia are common, and during the rainy season, when the mosquito population increases, malaria takes off. This characteristic seasonality has formed the two main areas of my research, malaria the wet season problem and meningitis and pneumonia the dry season problems.
After 10 years in Zaria, I was appointed director of the MRC research unit in The Gambia and was able to continue my research there. I spent 15 years working in The Gambia and the unit expanded a lot during that time. I think there were about 200 people when I first went there, and now there is a team of well over 1,000 staff. It was not clear what would happen to the MRC units in Uganda and The Gambia when the UK decided that MRC units needed to be linked to a university. It was decided the best thing for The Gambia’s unit was to be linked formally to the London School of Hygiene and Tropical Medicine (LSHTM) with which it had links going back many years. It has been nice for me to see how this link has happened as the next stage of my career has been working at LSHTM.
I took up a job at LSHTM in 1995, thinking that I would do a few years before I retired, and somehow that has gone on for over 20 years now! I have still been quite busy keeping up my links in Africa and for a lot of this time, I have focused on research capacity training of African scientists. We had grants from the Gates Foundation and the Wellcome Trust to help with that.
Until COVID came along, I had been able to travel almost every month to Africa, which is where my heart still is. When Ebola came along, I was asked by Peter Piot, the director of LSHTM, to go with him to Sierra Leone and help to set up an Ebola vaccine trial there. So for the last five years, I have spent a lot of time in Sierra Leone helping with Ebola vaccine trials.
My two main research projects at the moment are malaria vaccines in Burkina Faso and Mali and the Ebola vaccine in Sierra Leone. This keeps me busy!
Back when I was starting out on my career, going to America was the typical way to progress one’s research career. Instead, I went to Africa, which was fairly unusual at the time. I found I liked it - the people were so kind and friendly and I felt really at home there. That is why I decided to spend most of my career in Africa, and I have no regrets about that. I have had a much more interesting life than I would have had if I had stayed in the UK.
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The theme of World Malaria Day 2021 is “Reaching the zero malaria target” and aims to celebrate countries around the world that are reaching or approaching malaria eradication. Are you hoping for elimination across the world in the not-so-distant future?
I have a call about this later on today because I am chair of the WHO's committee (the MECP) that has the task of recommending whether a country has eliminated malaria. I have been quite involved in that for the past few years.
Several countries have done this. There was an old committee called the Malaria Expert Committee, which used to certify malaria, but that committee lapsed and nothing much happened for a long time. Then about 10 years ago, countries got much more interested in trying to eliminate malaria and getting that officially approved by WHO.
Since our committee was set up in 2017, we have recommended certification of malaria elimination for Paraguay, Argentina, El Salvador, Algeria, and Azerbaijan. The list is increasing. Next month I will be going to China to see if China has eliminated malaria, and there are about another six countries on the potential list for review. However, nearly all of these countries have been countries where malaria transmission was not very high and where people were not getting bitten very often by infected mosquitoes. So far, no country in the heartland of malaria in sub-Saharan Africa has achieved elimination.
I think that elimination in sub-Saharan Africa will happen first around the edges. We will perhaps see that in southern Africa, perhaps in Botswana, or maybe in Mauritania and perhaps even in The Gambia. Elimination is going to be very difficult in the Sahel areas and in the forest areas where people get bitten nearly every night by an infected mosquito. It is also going to be very difficult to eliminate malaria in countries where there is civil unrest. I think we will see this progress in big countries like China, Iran and possibly one day, India. But getting rid of the last malaria parasite (malaria eradication) is going to be very difficult, and I think it is probably wrong to give people expectations of when that might happen. I just don't think we know when this might be.
There may be some exciting new developments such as genetically modified mosquitoes that cannot transmit malaria or a vaccine that is extremely effective that will accelerate progress to malaria eradication and we cannot say that eradication of malaria will not happen, but the probability is that this is going to take a long time.
In recent years you have contributed to many landmark vaccination studies including trials of candidate malaria vaccine RTS,S-AS01. How far do you think we are from widespread vaccination for malaria?
I think we are a little way away. The RTS,S/AS01E vaccine was developed by GSK 30 years ago. When I was in the Gambia we did the first trial in Africa of this vaccine in a malaria-endemic area and this was around 25 years ago. It has been a very slow process. This vaccine is now in pilot studies in three countries - Malawi, Kenya, and Ghana and around 600,000 children have had the vaccine in these countries - this is a large-scale pilot study.
The aim of the pilot study is to see if the vaccine can be given through the routine immunization program like other vaccines. There will be an answer to that at the end of this year or early next year. The vaccine may then be recommended in the areas where malaria is worst because of a very high level of transmission.
The trial we have been doing in Burkina Faso and Mali is using the RTS,S/AS01E vaccine as a seasonal vaccine, as malaria is very seasonal in those countries as I have mentioned before. About 300 million people live in countries of the Sahel and sub-Sahel, which have seasonal malaria and where malaria is still a major problem killing many children.
We use seasonal vaccination for the prevention of flu: people have their vaccine just before the winter. And so we had the idea of doing this for malaria because malaria vaccines like RTS,S/ASO1E only give a high level of protection for a short time. We have been trying to see if we vaccinate children first when they are young and then give them a booster before each rainy season this will protect them through the four months of the malaria transmission season.
We have finished the first part of that trial. I cannot say what the results are because they are not published yet, but the results will come out in the next few months and they are very encouraging. So this is a possible route of malaria vaccination for this part of Africa. I don't think we will suddenly get a recommendation by WHO that every child in sub-Saharan Africa should have a malaria vaccine as we do with measles, pertussis or tetanus vaccines. But RTS,S/AS01E may get used in areas where vaccination coverage is high and the malaria problem is still really bad.
We might see selective vaccination in some countries, for example around Lake Victoria, Kenya. I don't think Kenya would choose to vaccinate all children in Kenya because in lots of parts of Kenya there is now no malaria or very little malaria.
There are a couple of other vaccines which are quite advanced in development. One of these is R21 which was developed in Oxford by the Jenner Institute. R21 is quite like RTS,S/AS01E but may be a bit better in some respects. There is also a different one developed in the USA by Sanaria, which uses the whole sporozoite, the part of the parasite that the mosquito injects when it bites somebody.
This vaccine is based on work that was done many years ago which showed that if you irradiate sporozoites and inject them, they could still stay alive for a bit in the liver and develop an immune response, but they do not go on to develop fully and cause malaria. So those are the three main vaccines at the moment, and they are at the stage of going from quite big trials to looking to see, "Well, could you actually use them in the routine program? Would it be useful to do that? Would it be cost-effective?".
Malaria vaccine development has so far been a slow process but I think COVID may have helped that situation. Development of Ebola vaccines took about five years instead of the 30 years for RTS.S/AS01E, and COVID has shown you can produce a vaccine within a year. Hopefully, some of the lessons that have been learned from the development of COVID vaccines are going to help the development of other vaccines like malaria.
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You have been involved in other trials on seasonal malaria chemoprevention. How can work on malaria drugs such as this change the course of malaria control in Africa?
I have always been interested in using drugs for preventing malaria in people who are long-term residents of malaria-affected areas and not just visitors. I brought up my kids in high-malaria areas from very early on in their life, and they took their antimalarials every week. We made sure that happened, and neither of the girls ever had malaria.
So the question was: if the ex-patriots and some of the more wealthy Africans could do that, why would we not do that for the rest of the population? Around 30 years ago or so, that might have been difficult to do because there was not enough money or a sufficient distribution system to do this but this situation has changed.
In The Gambia, we did some studies in the 1980s that showed this approach was very effective using community volunteers to give the drugs but these results got forgotten as things do sometimes in science. They were resurrected again in the 2000s when more trials were done. These more recent trials have shown that giving antimalarials to young children during the few months of the malaria transmission season, now called seasonal malaria chemoprevention (SMC), was very effective and gave 70% protection against malaria. The question after that was: whilst it is all very well if you can do that in a trial when you have money and support, could you actually do that in reality? To my surprise, this has been achieved successfully and last year over 20 million children living in counties of the Sahel and sub-Sahel got SMC.
What we are doing now in the trial in Burkina Faso and Mali is seeing what happens when you give the malaria vaccine and SMC together, trying to give the children everything we have got an insecticide-treated net, SMC and the malaria vaccine as well.
In nearly every country in Africa, malaria epidemiology is very varied. You have the Sahel countries, and countries like Nigeria, where part of it is in the Sahel and part of it is in the forest. The recommendation some years ago in countries like Nigeria was that everybody should have the same malaria treatment and control measures but now with more resources and more surveillance, we can have more structured programs. SMC is an example of that because that was one of the first interventions to be given in just a restricted part of a country. Nigeria gives SMC in certain states in the north and not in the rest of the country. We might see the same stratified approach happening with malaria vaccines, with it being cost-effective to use them in some parts of a country, but not in others.
This approach has put more emphasis on having good malaria surveillance so that you know what is happening in your country. Circumstances are changing: you might be using spraying at one stage and then after 10 years of doing this, it might not be the useful thing to do. You can only make the right decisions if you have got surveillance and you know what is actually happening at the current time. The WHO has rightly been putting a lot of emphasis on the importance of surveillance.
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Antimalarial drug resistance is a significant threat to malaria. How does this need to be tackled?
It is true that antimalaria drug resistance is a threat. There was a big spike in malaria deaths about 20 years ago or so ago because the falciparum parasite had become resistant to chloroquine, the standard treatment. The community was very slow, including me, in picking that up and taking that seriously.
Fortunately, we did have the new Artemisinin combination drugs, ACTs to replace chloroquine and these have been a huge success for treatment, both for severe disease and mild disease.
Then, artemisinin resistance appeared in southeast Asia and there was a real worry that those resistant parasites would come to Africa and cause havoc again like the situation when parasites became resistant to chloroquine. So far, fortunately, that has not happened, but it could happen still. That is a real threat, and the best thing to do would be to get rid of those resistant parasites in southeast Asia and stop them from being available to come to Africa.
There has been a big effort on that front by the Mekong Project. Unfortunately, there is still some malaria in that area and some of the malaria parasites have become very resistant but the number of cases is now very small, and countries like Vietnam and Cambodia have brought their numbers right down. The big risk is probably Myanmar where there is still quite a lot of malaria and resistant parasites. Getting rid of those resistant parasites by getting rid of malaria parasites altogether is an important aim of treatment and control measures.
We cannot assume that eradication of resistant parasites will happen so it is important to continue work on developing new antimalarials. That cannot stop just because we are doing well because you never know when resistance is going to appear and spread to the drugs responsible for the current successful control.
I think the Medicines for Malaria Venture, a public-private partnership, has been very successful over the last 20 years in bringing together big pharma, academia and donors to develop new antimalarials.
These might never need to be used but it is important to have them, ready to scale up production if needed, rather than having to start from scratch when there is a problem.
Furthermore, some of the new antimalarials might be easier to use than the current ones, for example, you might only have to take one tablet for one day instead of three days. Improvements like that can happen. It is really important that research continues and supports the development of new drugs, especially if antimalarial drugs are going to be used widely for prevention in Africa as well as treatment. The drugs we are currently using for SMC are two very old drugs, sulfadoxine/pyrimethamine (SP) and amodiaquine. They are still working now, but any day that could stop happening.
Drug development has to be ahead of the game and prepared for what might be needed in the future. The benefits of this can be seen in the Ebola vaccine. No company was going to sell an Ebola vaccine and make money years ago, but there was public money in developing it, and so when it was urgently needed, some of the background work had been done, and it was possible to have an effective vaccine much more quickly than in the past. The same has been the case with COVID vaccines.
This year the world has been fixated on the COVID-19 pandemic, and so it is more important than ever to raise awareness for other infectious diseases such as malaria, that still have devastating effects on the world's most vulnerable populations. How can international agendas be pushed to pay attention to these diseases?
COVID is a pandemic – it is a global problem, and everybody is at risk from that. Diseases like malaria or leprosy mainly affect the poorest people not living in wealthy countries.
Wealthy countries have been very generous in the past in supporting research and distribution of interventions for diseases of primarily poor people, like malaria. Being UK-based, I know that the UK has a very strong record in doing that.
But when there are problems at home and the rich countries themselves are threatened, it is not surprising that the attention is moved to that. I think all we can do is just keep on plugging away, and not just give up and say, "Forget malaria," or, "Forget TB" and keep trying to get the message heard that these diseases have not gone away because of COVID.
I think it is really important that the press and the media help us with that by giving some time to other problems and not just being repetitious about COVID.
The UK government has made major cuts to the Official Development Assistance funding (ODA). Whilst the UK has been a leading partner in scientific research on problems of poorer countries and has received a lot of praise for malaria work and support, suddenly a lot of the funding enabling this is being cut.
The money has gone and it has been absolutely disastrous for some research projects. The cut to the ODA budget has overall been by 30%. but for a lot of research projects for LMICs, it has been a cut of 70%.
For example, this has impacted the very promising trial combining the RTS,S/AS01E and SMC trials in Burkina and Mali already mentioned. About six weeks ago we got an email saying, "The money that we promised you to continue this trial will not be coming and you will have to stop your study."
This is unethical because you are putting people at risk. Furthermore, it is very damaging to the reputation of everybody involved, damaging to the UK, damaging to our science. The cut has fallen particularly hard on the research projects. We have tried desperately hard and have managed to find money from elsewhere to keep the RTS,S/AS01E trial going, but others are not being as successful.
There is a petition going to parliament but this is unlikely to change the current situation but at least making a fuss might make people realize what is going on and what that means. I know that some MPs are trying to stop this from becoming a permanent cut. If it can be made awkward for the minister of finance then he will realize that this has not been popular with the general public. That may deter the government from making this a permanent approach, and I think that this is the best we can hope for in the UK at the moment.
Because of COVID, the UK government has lots of debt now and the money pot is not limitless. Maybe you can make a case for cutting your aid budget and your support for diseases like malaria when the UK is threatened with a crisis itself. But, this should not be a permanent cut when things are better. We need to see that money and support for diseases affecting primarily poor countries come back again.
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COVID-19 has proved that when international agendas are aligned, scientific and medical progress can be made incredibly quickly. The concept that no one is safe until everyone is safe has also been a key element of this crisis. How can we learn from this pandemic to fight other diseases successfully, and make global health fairer and more accessible to all?
Not many people know about diseases like podoconiosis or mycetoma, a couple of horrible tropical diseases. But when something threatens your family, for example, Ebola when people started coming back from Sierra Leone and dying, it certainly galvanizes things.
Epidemics show what can happen and make everybody work harder. But if the epidemic does not threaten people in the wealthier countries, it is not seen as a major health threat. The argument then needs to be made which wealthy countries should support research on diseases affecting primarily poor countries. There are ethical grounds for wealthy countries supporting work on diseases like malaria but also more selfish ones for if countries do not have malaria, they are going to be more prosperous, and then wealthy countries will have a better chance for trading with them and making more money.
Any new drug or vaccine has to go through a complicated procedure before it can be used: clinical trials, ethical approval and a complex registration process. Sometimes we have to wait for months to get permission to do a trial, for example, an important committee may only meet once every three months. COVID has shown that this process can be accelerated and done in days when everybody pulls together. I hope some of the lessons learned on how to do this in the development of COVID drugs and vaccines will last for the development of other drugs and vaccines including those for malaria.
Climate change is an influence on the development of new infectious diseases as cases of both vector-borne and zoonotic diseases are predicted to rise. How can the world work together to stop preventable deaths from climate change-induced spread of disease, particularly in vulnerable populations?
Climate change is very important for all sorts of reasons. However, its impact on malaria may have been over-exaggerated by some. Perhaps some malaria may get transmitted in southern Europe because the temperature has gone up a couple of degrees, but that is not going to be a disaster. Or maybe it will go a bit higher up the mountains in Africa but this is likely to affect only a relatively small number of people.
Dengue is probably more of a worry because the mosquitoes that carry that infection can spread into areas where the temperature has increased. There are risks there, and surveillance is needed to watch that.
There are other things like chopping down the Amazon and changing the environment in ways which seem to be important in precipitating outbreaks of nasty virus infections. These viruses can emerge when you change the ecosystem, which is linked to climate change.
Climate change is going to have a lot of impact on health in all sorts of ways, for example, people dying from heat stress. But it is perhaps not such a major issue for malaria.
You are an internationally recognized expert in tropical medicine, have even received a knighthood for your services to malaria research in Africa. What has been the highlight of your career?
I think the aspect of public recognition of my career that I enjoyed most was the award of the Hideyo Noguchi Africa Prize. This prestigious prize was set up by the Japanese government in memory of Doctor Noguchi who died in Ghana whilst investigating the cause of yellow fever. I was the first recipient of the prize, set up to award people who have contributed the most to Africa, and It would be silly not to say that I am proud of that recognition by my peers.
But what really switches me on, is when you have an idea, do a study, do a trial, and you find it works. That is very special, and it does not happen many times in a person’s career. For me, it has happened about three or four times, when I have done something that has really had an impact. If something you do gets recommended by WHO, adopted and found to be useful this is amazing.
Science has two purposes. First, it is important to know about the world we live in. But the other part is doing something that is going to improve mankind and how we live. To me, that was one of the attractions of working in Africa as when I started out there, there were so many things that needed to be done and few trained people to do so.
I remember early during my time in Zaria, we had these huge meningitis epidemics that happened every few years. We found that the antibiotic being used was not working, and we did a study and showed that it should be changed to a different antibiotic that worked. Based on this finding the state governor went on the local TV program and said, "I will not have this drug in use in my state. You have got to change your drug." And suddenly, as a young scientist, one could see how one’s work could have a direct impact on people’s health.
Hopefully, I have made a difference, but it is not just me, it is the wonderful people I have worked with. In particular, working with Africans, helping with their careers and seeing them able to take responsibility and run things has been very rewarding.
JHSPH World Malaria Day 2019 – Brian Greenwood – Malaria Elimination in Africa
With continued research and funding, are you hopeful for a future without malaria?
I think it is possible. One problem is Plasmodium knowlesi. That is the fifth malaria species that affects man and has come from monkeys. In Malaysia, they have done very well at getting rid of all the classic human malaria parasites which are transmitted from person to person. But last year, I think there were 1,000 or 2,000 cases of Plasmodium knowlesi, so there is a problem there.
Theoretically, there is no reason why we should not get rid of malaria but that will only happen when we have better tools than we have now, and when we have stability. If people go on fighting and destroying their societies, it is going to be really difficult to eliminate malaria. You cannot have good public health programs without political stability.
Once we have the tools and political stability in the last areas where the parasite is thriving, hopefully, malaria eradication will be possible. However, I think it is very dangerous to predict exactly when that will be and this is going to be a long process.
It does not help to say, "We'll eradicate malaria by 2035", because expectations are then raised. It might not be possible, and then funding will stop and people will feel that they have been let down. It is better to be more cautious.
Have you got anything else you want to make people aware of?
I want to stress the point about the decrease in UK funding - the ODA cut. The UK should be proud of its record in areas like malaria and other global health problems, and that is universally recognized across the world. We have a record of doing things that are useful in the developing world, and to cut that off is a really bad thing. We are a wealthy country. Okay, there are problems now, but we still need to keep that support sustained.
The studies on bed nets in The Gambia showing their effectiveness did amazing things. Those trials cost around two or three million dollars and look what has happened in terms of the dissemination of bed nets. That modest spending on research has provided massive benefits. When the idea of rolling out bed nets to everybody was put forward, there was a lot of support from the media and then from the public. From all parts of society, people were raising money to make bed nets available. Stopping research on projects that are going to help people who really need help is shameful.
There is now more money coming from within the countries where malaria is a major problem, as it should do. As they get wealthier, these countries should become less dependent on outside money. But for the really poor countries, the need for financial support is likely to continue for a while. The people who do the sums think that the current level of funding for malaria needs to double if we are going to have a major, final impact on malaria and this is the goal that we should be aiming for.
Where can readers find more information?
The London School of Hygiene & Tropical Medicine (LSHTM)
About Sir Brian Greenwood
Sir Brian Greenwood's main research interests concern the prevention of acute infectious diseases which are still responsible for the deaths of many young children in Africa, in particular those from malaria, meningitis, and pneumonia.
In The Gambia, he initiated studies of Haemophilus influenzae type b (Hib) and Streptocococus pneumoniae vaccines after these bacteria were identified in epidemiological studies as being major causes of serious illness and death in young Gambia children. Hib and pneumococcal vaccine studies in The Gambia started with pilot safety and immunogenicity studies and progressed to pivotal phase 3 trials.
The results of these trials played an important role in recommendations by international organizations for the introduction of these vaccines into the routine immunization programs of countries with high child mortality. Sir Brian has also had many years of experience with the development and evaluation of meningococcal vaccines including an evaluation of the group A meningococcal conjugate vaccine MenAfriVac in sub-Saharan Africa, demonstrating its ability to halt an epidemic in Chad and to provide both direct and indirect protection through prevention of carriage.
Sir Brian coordinated some of the first studies that showed the value of insecticide-treated bednets and of malaria chemoprevention. He has also been involved over many years in the difficult task of developing a malaria vaccine, participating in a number of phase 2 trials of the RTS,S/AS01 and the large phase 3 trial whose results resulted in a positive recommendation for this vaccine from the European Medicines Agency.
Sir Brian Greenwood is an author of over 800 publications in peer-reviewed journals more than a half of which relate to studies on malaria.