Q&A with Sir Brian Greenwood on Malaria Vaccines, Elimination Goals, & Implementation Challenges

Professor Sir Brian Greenwood, Emeritus Professor at the London School of Hygiene and Tropical Medicine, won a lifetime achievement award in May from the World Health Organization for his work in infectious diseases – particularly for his many decades of pioneering work on malaria. Over many years, he has contributed to the development, approval, and introduction of malaria vaccines, which have now been introduced in 18 countries via routine childhood immunization programs, ushering in a new era in malaria prevention. We recently connected with Sir Brian to understand what it will take to get to zero for malaria. 

You began working on malaria more than 50 years ago, but it was just in the last few years that the first safe and effective malaria vaccines were approved by the World Health Organization (WHO). Can you give a bit of history about malaria vaccine development?

The research to develop a malaria vaccine has been going on for about 100 years. It was first shown that a malaria vaccine was possible in the early 1900s, but that was in birds. Work towards development of a human malaria vaccine started in the 1960s by Professor Ruth Nussenzweig in New York. She found that irradiating the sporozoite — the part of the parasite that is injected when an infected mosquito bites somebody — partially decreases its ability to cause infections but also induces an immune response and thus could be used as a vaccine. This was shown to work first in animals, and then in humans but initially had to be delivered through the bite of many infected mosquitoes.

The breakthrough for the two malaria vaccines that we now have came from the work of Dr. Joe Cohen at GSK. He found a way of using a protein on the outside of the sporozoite to make a virus-like particle which could be injected in the same way that we do with other vaccines.

Around 1997, it was shown in volunteers in the U.S. that this vaccine provided protection against a malaria challenge infection. The first trial of the vaccine — now called RTS,S — in an area where malaria was endemic occurred in 1998 in the Gambia. I was involved in that project, and I’ve subsequently had more than 25 years of involvement in the development of this vaccine in different ways since that first study in the Gambia. It has taken a very long time to get RTS,S approved by WHO and I think we have lessons to learn from that experience.

What lessons?

We have learnt from the COVID experience that when there’s a real need, we can develop vaccines fast. It’s unfortunate that it’s taken such a long time for this to happen for malaria. But now we have two malaria vaccines in use, the RTS,S vaccine and the R21 vaccine developed in Oxford.

Clearly these vaccines have gone through extensive testing through clinical trials and there’s a great deal of evidence for their safety and efficacy. How have community partnerships contributed to the development and testing of these two malaria vaccines?

Community partnerships have been essential to the development of malaria and other vaccines; it’s very important that people living in an area where a trial is taking place are fully informed as to what is going to happen. We know that with some vaccines, like the COVID vaccine, there has been vaccine hesitancy and a lot of reaction against the vaccine. However, in Africa where malaria is such a big problem, vaccine hesitancy has not been much of a problem with the malaria vaccines because communities recognize the devastating effects that malaria may have. They may have seen a next-door neighbor’s child die from it, perhaps even one of their own children die, and they’ve seen their hospital wards full of children with severe malaria and with anemia, often due to malaria. There is an understanding that malaria is a horrible disease, and I think that this has helped with the acceptance of malaria vaccines.

When testing a vaccine, you often need to collect take blood samples and people have to turn up to the clinic regularly so that it is asking quite a lot of volunteers and their families to be involved in a vaccine trial. Participation in malaria vaccine trials has been very high because the population realizes how important development of an effective vaccine against malaria would be.

Malaria is still responsible for over 260 million cases and nearly 600,000 deaths, mostly among children, each year. What are some of the greatest and most urgent challenges facing malaria elimination today?

There are many challenges, including biological factors related to the parasite, as well as economic and social challenges. In addition, emergence and spread of resistance to the insecticides and treatments currently being used successfully in many malaria-endemic countries that are near to achieving elimination is a continuing treat.

Development of a highly effective vaccine that gives a prolonged period of protection would be a major step forward in achieving elimination. However, there are several challenges to doing this. The parasite has a complicated life cycle and has different methods of doing the same thing, such as trying to invade red blood cells and causing anemia. Developing a malaria vaccine is much more complicated than developing a vaccine against a virus like COVID.

What are some of the challenges to the implementation of vaccination programs and other control strategies that are used for malaria?

We now have two approved malaria vaccines, but money is needed to pay for them and deliver them effectively. Will poor countries, which are already struggling, be able to afford to buy a malaria vaccine? Wealthier countries can help through their aid programs, and Gavi helps many low-income countries with the purchase of their vaccines. However, many international aid programs are being cut, so this is a major concern. Some countries where malaria is endemic are now doing better than in the past at funding vaccines themselves, but in very poor ones it is hard to do this. Even after vaccines have been purchased, there needs to be a health system that is able to deliver the vaccine effectively.

Several countries across the world have been able to get to zero for malaria in recent years and be recognized by WHO as having eliminated malaria but it is difficult to see how this can be achieved in countries where there is no functioning health service, where people are fighting, or where there is a major civil disturbance. To get to zero for malaria, as well as having a good vaccine, needs financial support, either internally from a country that is doing well with its economy or, for the poorest countries, from outside and there needs to be a health system that can deliver the vaccine with very high coverage. In the case of measles vaccine, at least 90% coverage is needed for the vaccine to be effective at stopping transmission of the infection. I think that’s likely to be the case with the malaria vaccine as well.

Do you think it is important for this next generation of public health professionals to make a commitment to expanding efforts to reduce malaria to move this agenda forward?

A meeting held in Dakar, Senegal in 1997, the first meeting of the Multilateral Initiative on Malaria (MIM), was probably the most important meeting that I have been to in my career because it was at that meeting that malaria first came up as a major research priority in the international community.

The meeting was attended by Harold Varmus, the then-director of NIH and It was a real shock to some people that one of the most important people in the scientific world was taking malaria seriously. An exciting outcome of that meeting was a commitment from people working in many different areas of research that input from all these groups was needed if the problem of malaria was to be tackled effectively.

I was part of the organizing committee, and I encouraged the committee to include an economist at the meeting, which was unusual at that time. The meeting was attended by social scientists, molecular biologists, entomologists, and parasitologists, and there was an agreement that there was no magic bullet, and that we should not put all the research funding into just one area, but that research was needed in many different areas if malaria control was to be achieved effectively. I think that this was an important lesson, and that the situation is still the same now.

If we’re going to really get effective control, we need people working in many disciplines. There are huge advantages in having scientists involved who know the community in which they are working. There has been a big change in his area since I started my career. When I first went to work at the MRC unit in the Gambia in 1980, there were very few local scientists or technicians and even the reading of malaria blood films was done by expatriates. Now, the same institution hosts many African PhD students and postdoctoral fellows, and many of its key research programs are led by African scientists. I think that involvement of local scientists from many different disciplines working together will be essential to achieving elimination of malaria from sub-Saharan Africa.

How important would you say improving accessibility and access to not only malaria vaccines, but other tools for malaria prevention are going to be in the next few years?

It is possible that we will have a malaria vaccine that is 95% protective and gives protection for 10 years or another game-changer such as genetically modified mosquitoes that eliminate vector mosquitoes. We need to be aware that this is a possibility, but I don’t think that currently we should give up on all the other areas of research relevant to malaria control.

Now that we have a vaccine, we need to know how to deploy it most effectively in different epidemiological situations. How to do that in areas of Mali where malaria is only present for a few months in the year may be very different from what would be more appropriate in the Democratic Republic of Congo, where malaria transmission goes on all year.

I think there’s a lot of research needed on how best to deliver malaria vaccines and how best to use them in combination with other interventions. It is an exciting time for malaria control as we now have several control tools on the menu. We will not be able to afford to use all the interventions everywhere, so I think more research is needed in the coming years on learning how to use these combinations most effectively in different areas.

That opens up lot of research possibilities in terms of the public health strategies that can be tailored to different contexts and different epidemiological settings.

An example of such research, that we have just started in Guinea, is looking to see whether it is best to give a booster dose of malaria vaccine to children just before the rainy season or when they are 12 months old at any time of the year. This is a very straightforward study but it’s an important issue that could help in deciding which approach would prevent the most cases and give the best value for money. Similar studies are needed elsewhere.

As you probably know, a recent WHO analysis found that malaria control efforts have prevented more than 2 billion cases and saved more than 12 million lives since 2000. What would you say are the most important priorities that we should be focusing on right now to be able to reduce malaria cases further and to save even more lives in the years ahead?

One is to keep up the research on all the different aspects that we’ve talked about, and not just to focus on one.

The second is to make sure that there is the funding needed to eliminate malaria in the long-term. Some malaria-endemic countries are doing quite well now financially, so they should be putting more money into malaria control and some are doing that. However, the poorest countries will need support from the international community. It’s very sad to see a country like my own cut its aid budget, when the UK has made major contributions to malaria control in the past. We need to keep up the outside support for the countries that genuinely need it and will use these resources well.

And then finally, as we discussed, my number three is you have to have a health system that’s working and the money to support it.