Trillions of pounds have been spent during the Covid-19 pandemic supporting the economies of developed countries and yet only about 3 billion pounds has been spent in total trying to fight malaria. Why the difference? It could be that Covid-19 had the potential to cause more death and disease than malaria, but then why not spend the trillions on the health response rather than the economy? Could it have anything to do with the fact that 94% of cases and deaths from malaria occur in Africa rather than Europe and the USA?
Now we all know we should go and get our Covid-19 vaccine but wouldn’t it be great if there was an effective vaccine against malaria too? The WHO want a malaria vaccine that is at least 75% effective by the year 2030. Surely if there was something like that it would be all over the news; all that death and disease prevented. Well there is a promising vaccine… it just seems to have got a bit lost in all the Covid-19 noise… it is being trialled by those clever scientists from Oxford again, but it does have a rubbish name…!
I told you it had a rubbish name! Let’s just call it R21-MM like they do in the research paper. R21 refers to the bit of the vaccine that triggers the immune response. The MM bit (not the yellow and red chocolate sweets M&Ms) is an adjuvant based on the soap like chemical saponin, which makes the immune response stronger. The vaccine produces an immune response against proteins on the outside of the parasite and so is active against the parasite before it even gets into red bloods cells and causes disease.
What was the R21-MM study?
The R21-MM study was a Phase II double-blind, randomised, controlled trial of the malaria vaccine compared to a rabies vaccine. The rabies vaccine was used so that everyone in the study couldn’t tell who had the malaria vaccine because both vaccines would cause localised and systemic reactions. The researchers only knew who had had the malaria vaccine at the end of the study when all the results were in, and this is a good way to do a study as it eliminates a lot of bias. Proper process takes place when time is allowed for research!
The study has been done in the West African country of Burkina Faso (a great Pointless quiz show answer in case you’re ever struggling for an answer!). Burkina Faso has problems with high levels of seasonal malaria; it has malaria all year around, but the levels shoot up drastically in the rainy season from June to November.
In the study 450 children aged between 5 and 17 months were randomised to receive either R21 with two different strengths of adjuvant MM or a rabies vaccine. The two doses of adjuvant were to see how much of this was needed to produce a good immune response compared to any possible side effects from the MM. The children received 3 doses of vaccine four months apart and then a booster after another year.
The parents of the children were asked to report any episode of illness or fever >37.5oC during the study at which time the child would be tested for malaria using blood films looked at by 2 different microscopists who didn’t know either the vaccine status of the child nor the results from the other microscopist. If the 2 microscopists differed in their interpretation, then a third microscopist was used to give the casting vote.
No one who funded the project had a role in either the conduction of the study, the analysis of the data or the publication of the results. This was all done without any outside influence and conflicts of interest.
Dum, dum, dum! The results…
R21-MM was a success. The vaccine was able to prevent 77% of malaria cases; the first time any study has met the WHO goal of 75%. The higher adjuvant dose was a bit better than the lower dose, but not by much (77% versus 74% efficacy). This was great news.
The vaccine was also safe in this study. There were low levels of mild localised reactions at the injection site, with pain occurring in <10%, and systemic side effects such as fever occurred in 20%. These levels are very low. In comparison the Covid-19 vaccines had 80% localised side effects and 50-70% systemic side effects!
The study also looked at how long anti-malaria antibodies lasted and showed that levels did start to drop off by 1 year, but a dose of vaccine as a booster shot them back up to high levels again. This is reassuring as it suggests the immune system has remembered the earlier doses of vaccine and that either natural exposure or a program that involves a yearly booster would be effective in protecting from malaria.
Antibodies are important in fighting infection; they are the “bits” that stick to abnormal cells telling the body that they are foreign so the immune system can get rid of them. However, we need to keep in mind that antibodies aren’t everything. Another part of the immune response is known as cellular immunity which uses types of white blood cells that recognise the abnormal “stuff” and gobble it up e.g. phagocytes which eat up abnormal foreign material. This cellular immunity is not easy to measure in a laboratory but is as important as antibodies when it comes to fighting infections. The vaccine R21-MM stimulates cellular immunity as well as antibodies which means the recipient of the vaccine has a method of fighting infection even if their level of antibody looks like it is going down.
What was disappointing?
The one thing that was missing from the report that I would have liked to see is whether R21-MM prevented severe malaria (e.g. >2% parasitaemia, cerebral infection, hypoglycaemia). The R21-MM vaccine prevented 77% of cases of infection but the study couldn’t show how good it was at preventing severe, life threatening disease. Just as with the Covid-19 vaccines were the vaccine stops 60% of people catching SARS CoV2, 40% can still become infected. The value of the Covid-19 vaccine is that it prevents severe disease; the 40% who still catch it don’t come to any harm. If vaccines can prevent all infections this is ideal (MMR is very close to preventing all measles) but if they don’t they can still be hugely valuable if they prevent all the severe infections. It may just be that there weren’t enough cases in the study to show an effect on severe disease and mortality. Based on the WHO data of 229 million cases a year with 409,000 deaths, the mortality rate of malaria is 0.18%; the R21-MM study numbers are just too small, they only had 186 cases of malaria so there could only have been “on average” 0.33 deaths… yep, less than 1 person, or maybe just the legs… if you get my point. The study didn’t have enough cases to look at mortality. It’s the same as with blood clots and Covid-19 vaccines; there weren’t enough patients in the study to show the complication.
What happens now?
So, it is still early days for R21-MM, but it looks promising. This study is going into its second year to see how long the protection is sustained and whether yearly boosters are required.
The vaccine also now needs to be studied in different countries and populations to see if the results can be reproduced. This will involve different age groups and countries where malaria is around all the time and not just linked to seasons. I’d suggest countries like Malawi, Sierra Leone, Ghana, Rwanda and Mozambique… These are all actually great Pointless answers too, as well as fitting the criteria for endemic malaria!!!
Hat’s off to these researchers. It’s a really exciting development in the battle against malaria and a shame that it didn’t get more airtime on the news… but then malaria just isn’t sexy enough I suppose.
High efficacy of a low dose candidate malaria vaccine, R21 in adjuvant Matrix-MTM, with seasonal administration to children in Burkina Faso. Datoo M, Natam H, Some A, et al. The Lancet 2021. 397; 1809-1818