The R21 Malaria Vaccine : Standing On the Shoulders of Giants

WHO gives the green light to a second malaria vaccine hoping to solve the serious supply problems affecting the earlier vaccine.

[This text has been written by Matiana González Silva, coordinator of the ISGlobal's Malaria Elimination Initiative, and Regina Rabinovich, director of the ISGlobal's Malaria Elimination Initiative]

At a time when the fight against malaria is clearly in a state of emergency with the world struggling to obtain the millions of doses of vaccine needed to prevent this parasitic disease, the recommendation of a second malaria vaccine by the World Health Organisation (WHO) has been surrounded by a halo of extraordinary expectations. The new vaccine is not just a tool that can save tens of thousands of lives every year, it has arrived in the context of new dangers that threaten to exacerbate the already dramatic burden caused by a parasite that kills over 600,000 people every year, most of them small children living in sub-Saharan Africa.

The vaccine receiving this warm welcome is called R21/Matrix-M and its trajectory has been meteoric in both scientific and regulatory terms. Developed through a collaboration between Oxford University in the United Kingdom, the Serum Institute of India and researchers in malaria-endemic countries, R21 is based on the same principles as its predecessor, GlaxoSmithKline's RTS,S/AS01 vaccine.

Both vaccines are based on the same antigen and the vaccination regimen of three initial doses followed by a booster is also identical. There are however, some important differences between the two products: R21 uses much lower doses and a different adjuvant. This means that it can be manufactured more easily and faster than its predecessor, an important advantage in view of the obstacles faced by those currently trying to satisfy the huge demand for RTS,S.

The Importance of Supply

Two years after its approval by the WHO, an event hailed as an historic milestone, RTS,S is not yet being distributed on a massive scale in Africa. It will be 2024 before the countries affected will start to receive the first 18 million doses the suppliers estimate will be available over the next two years. This level of production is totally insufficient given the demand for 40 to 60 million doses just to fulfil orders from African countries.

Once it passes the WHO’s prequalification controls related to its manufacture at an industrial level, R21 will contribute to remedying this alarming situation. The Serum Institute has stated that it can produce 100 million doses annually, and WHO hopes that production of the two vaccines can fully cover the needs of the countries where malaria is caused by the Plasmodium falciparum species, and perhaps even extend vaccination coverage beyond the areas of high transmission, which WHO has asked to be prioritised.

Photo UN Women / Ryan Brown

This is very encouraging news at a conjuncture characterised by emerging resistance to drugs and insecticides by parasites and mosquitoes, respectively, and other competing health needs, wars and humanitarian emergencies, all of this in the context of limited resources. Against this backdrop, WHO has moved very quickly to recommend R21, undoubtedly prioritising public health needs and following a cultural change that took place during the COVID-19 pandemic. The pandemic allowed the world to see more clearly that malaria has been causing a permanent emergency in Africa for millennia, and that the urgency with which the world reacted to COVID-19 should also apply to other, much more ancient diseases.

What is clear is that the path followed by R21 has diverged at several points from the usual trajectories and timelines. The WHO recommended the use of R21 after reviewing the results of the most recent clinical trials of the vaccine (phase 3 trials) but before the results of this work had been published in any scientific journal. WHO’s assumption is that, used in similar settings, R21 will give similar results to RTS,S but this will not be confirmed until vaccination with R21 has been rolled out on a large scale. The logic followed appears to have been that the approval of an urgently needed tool should not be held back because of the absence of data in high malaria transmission settings since, as the well-known saying goes, the perfect is the enemy of the good.

Very High Interest in a Malaria Vaccine

The WHO has stressed the fact that the trial results of the two vaccines are not comparable and that there is no evidence that one is better than the other. All of the above, together with the avalanche of requests for RTS,S that GAVI received in response to its first call, undoubtedly helped to pave the way for the approval of R21 given the huge interest in malaria vaccines in African countries. For example, Ghana, Nigeria and Burkina Faso gave the green light to the vaccine before the summer following their own review of the data available and in anticipation of the WHO decision.

Supplies of RTS,S are very low because of a complex production process. However RTS,S was the product that demonstrated that it was possible to develop a vaccine against a parasitic disease and that such a vaccine could be effectively rolled out even in areas where the health systems are as fragile as those of most African countries. To paraphrase Isaac Newton, the developers of R21 could say that they were able to see further because they were standing on the shoulders of giants. And the best news of all is the confidence that both vaccines, used in conjunction with the existing preventive tools, have a truly extraordinary potential to have a beneficial effect.

Photo: UN Women / Ryan Brown

Given the relatively scant data available before the approval of R21, the WHO has made it very clear that further scientific research is needed to investigate certain important aspects of the new vaccine, especially its efficacy in areas of high transmission and the duration of the protective effect. It has also requested that safety be closely monitored until a much larger number of children have been vaccinated. It is therefore of great importance to ensure that, together with the resources needed to finance large-scale vaccination, funding also be made available for these evaluations and other implementation science research.

In the not too distant future, we may see a malaria vaccine based on RNA technology, which won its developers the Nobel Prize on the same day that R21 was recommended. And the future may also bring a new generation of vaccines targeting the life cycle stages that allow the parasite to pass from one person to another. But while we wait for this possible second generation malaria vaccine tomorrow, let’s hear it today for R21. Welcome!