By David Tellett
Children in many regions of Sub-Saharan Africa are regularly and repeatedly subjected to infection from the malaria parasite Plasmodium falciparum. While only a small proportion of these infections are fatal, they are frequent and dangerous enough to make malaria one of the largest causes of child mortality in the world. Decades of development have finally yielded two effective malaria vaccines at nearly the same time.
The WHO has approved both the RTS,S and the R21 malaria vaccines for use in routine childhood immunization programs in areas with high malaria prevalence. Both vaccines have only been used in a limited number of sites so far, so their life saving potential must be estimated from measures of their efficacy during clinical trials.
Children in trial sites are frequently bitten by mosquitos carrying the malaria parasite, so the efficacy of the vaccine is measured by its ability to reduce episodes of clinical malaria experienced by vaccinated children relative to a control group. Vaccines are rarely 100% effective against infection or symptoms, and protective benefits tend to wane over time. Long-term data from the RTS,S Phase 3 trial, for example, suggested that initial vaccine efficacy for children aged 5-17 months was around 57%,1RTS,S Clinical Trials Partnership (2015) dropping to 36% in year four.2Laurens (2019) Protection was also highly dependent on a booster dose delivered one year after the initial three-course dose.
Phase 3 trials of R21 started more recently, so the same long-term data is not yet available. Results suggest that a standard (non-seasonal) vaccination program targeting the same age group had efficacy of 67% and seasonal vaccination had efficacy of up to 75% in the first 12 months.3Datoo et al. (2024) This also appears to wane over time, but as the trials were conducted more recently, long term durability is unknown and some estimation is required to fill in the gaps.4This is consistent with both expectations and trial data, which implied a decline in efficiency over the course of the first year (p=0·037). See Datoo et al. (2024)
The only long-term data available so far for R21 is from the Phase 2b clinical trials, carried out at a handful of sites with different patterns of malaria infection. Working with members of the Oxford R21 team, researchers at Imperial College fitted granular data on clinical malaria infections and local seasonal malaria characteristics during these trials to a complex model predicting the effect of the vaccine on antibody levels, which are assumed to rise after each vaccination and decline over time.5Schmit et al. (2024) They used this to project how R21 will perform long-term and with different background levels of malaria infection, and they sanity-checked this against the data from the Phase 3 trials.6The Phase 3 trial only has short term data available so far. They found the model was a good fit, but overestimated efficacy in two sites with low incidences of malaria transmission and no chemoprevention (with high uncertainty due to the low number of observations).
The Imperial paper estimates a three-vaccine course plus booster could lead to 40% reduction in cases of clinical malaria per fully vaccinated child in an area with average parasite prevalence for malarial regions of sub-Saharan Africa. As repeated malaria infections are common, this represented over 180,000 cases of malaria prevented per 100,000 fully vaccinated children.
As the number of actual deaths during the medical trials is very low (due to small sample sizes and good access to treatment for symptomatic cases) the ability of the vaccines to avert deaths when scaled up for wider distribution can be inferred from their efficacy at preventing cases of clinical malaria.7This was based on 0.215% of modeled cases of severe malaria resulting in death. Severe malaria cases are in turn inferred from as a proportion of clinical malaria cases adjusted for treatment coverage. See p.19 of Supplementary Appendix 1 in Schmit et al. (2024). The Imperial model estimates that R21 could prevent over a third of deaths, saving 629 deaths per 100,000 fully vaccinated children in a region with moderate malaria parasite prevalence.
| Proportion of clinical cases averted in children younger than five | 40.2% |
| Proportion of deaths averted in children younger than five | 33.6% |
| Clinical cases averted per 100,000 fully vaccinated children | 181,825 |
| Deaths averted per 100,000 fully vaccinated children | 629 |
From the Imperial study, Schmit et al. (2024). Figures are based on a four dose course of the R21 vaccine in a region with PfPR2, 10 of 20%, where PfPR2, 10 is the prevalence rate of P. falciparum among children aged between two and ten (20% is approximately average for malarial regions of sub-Saharan Africa, defined as those with PfPR2, 10 >1%).
The size of the reduction in malaria cases and deaths depends on a variety of other factors: the prevalence of malaria in the region, the use of other suppression techniques such as bednets and seasonal malaria chemoprevention, and the standard of medical care available. Vaccination prevents more deaths overall where parasite prevalence is higher, which occurs in areas with higher background levels of malaria and fewer children sleeping under bednets (use of insecticide-treated nets was very common among trial participants under five in Burkina Faso,8Datoo et al. (2024) reports that 97% had access to an insecticide-treated bednet during the month of investigation. but is less common in children under five in other African countries9For example, Aheto et al. (2023) report that only 57% of children under five in Ghana used insecticide-treated bednets.). The model also predicted that the vaccine would have a slightly larger impact on deaths in settings where malaria transmission is seasonal, particularly if a (more expensive) seasonal or hybrid vaccination program was used.
Impact on lives saved would be lower in areas with low levels of malaria, but there are millions of children living in regions of sub-Saharan Africa where malaria prevalence is equal to or greater than 20%.
There remains a high level of uncertainty about these figures, but trials can underestimate as well as overestimate the potency of vaccines as a weapon against childhood mortality. There are now indications from longer-term follow-up studies of the Phase 2b trials of R21 that protection from a four-dose booster course is maintained at levels over 60% into the fourth year after transmission, implying protection may be longer-lasting than predicted by the Imperial model, which would result in a greater number of lives saved than predicted.10Natama et al. (2023), abstract #6949. The Imperial model, by contrast, projects a decline to 49% protective efficacy.
There are also lessons from scaling up the trials of RTS,S to a much larger pilot program (the Malaria Vaccine Implementation Programme, or MVIP) which delivered 6 million vaccinations and produced much more impressive results than expected. In the regions where the pilot was rolled out, there was a 13% fall in all-cause mortality for toddlers (excluding deaths related to injuries) and a 22% fall in hospitalization for malaria over the 46 months of the study11This data was presented at the October 2023 conference of the American Society of Tropical Medicine and Hygiene and has been reported widely in the medical and scientific press (e.g Meredith Wadman, First malaria vaccine slashes early childhood mortality. Unfortunately, the raw data for this is not yet available for further analysis and the 95% confidence intervals for the reported figures are wide, see here. – all in a real world setting in regions where less than half of children eligible received a full course of the vaccine. By reducing malaria infection rates and strengthening the immune response to malaria, the vaccine may reduce the tendency for infants to succumb to other diseases following malaria infection.12First malaria vaccine slashes early childhood mortality Gavi now expects that RTS,S will result in one life saved for every 200 children vaccinated in high risk areas targeted for initial rollout.13Hope spreads as 18 million doses of the first malaria vaccine are allocated to 12 African countries
The current generation of vaccines alone cannot prevent all malaria casualties, but they can significantly reduce them and complement other options to prevent and treat malaria which also offer imperfect protection (for example, studies of RTS,S found that it performed marginally better than chemoprevention and that the two worked particularly well in combination).14Chandramohan et al. (2021) Aside from protecting against deaths, a significant reduction in episodes of clinical malaria and severe malaria will reduce long term health issues caused by malaria. Vaccines may also reduce the risk of drug-resistant strains of malaria becoming prevalent.15Hamilton et al. (2023)
Rollout of anti-malarial vaccine programs
RTS,S was approved by the WHO for wider use after a large-scale pilot program which has already vaccinated 2 million children. 6 million RTS,S doses have been allocated to be administered in 2024,16Hope spreads as 18 million doses of the first malaria vaccine are allocated to 12 African countries enough to provide a course of three vaccinations for 2 million more children.17This assumes they also receive a booster vaccination from next year’s vaccination production. In practice, 18m vaccines won’t sum exactly to 6m fully vaccinated children, as some will drop out before completing a full course of vaccination (still receiving some protection) and there will be some level of wastage. At an estimated one life saved for every 200 children vaccinated, this could save up to 10,000 lives in the priority target regions. With demand outstripping supply, however, difficult decisions have to be made about who does and does not get the vaccine.
R21 was approved by the WHO only towards the end of 2023 and still awaits some local approvals. R21 is cheaper and easier to manufacture, and the Serum Institute of India says it can produce 100 million doses of R21 per annum,18Oxford R21/Matrix-M™ malaria vaccine receives WHO recommendation for use paving the way for global roll-out and had a stock of at least 20 million produced in 2023.19WHO recommends malaria vaccine that will be rolled out next year Initial indications are that R21 has a similar level of protective effect.
- Under an optimistic scenario, this could be used to provide a three-course vaccination for nearly 40m children starting this year. Based on the vaccine efficacy figures from the Imperial study, and assuming they also received a booster in 2025, this would represent around 250,000 young lives saved over the next couple of years (the Imperial paper estimates 629 deaths averted per 100,000 fully vaccinated children for a 3 course plus single booster vaccination program, starting with children around 6 months old in regions with perennial transmission of malaria at median rates for malarial sub-Saharan regions. Extrapolated to 33m vaccinations in Year 1 this translates to 208,860 lives saved. In practice, these numbers will vary considerably due to a variety of factors). Combined with RTS,S, the figure would be about 260,000.
- Under a less optimistic scenario based on current projections in which only the first 10 million doses of R21 were distributed, mostly towards the end of 2024, and less than 3 million children received a full course of vaccinations, fewer than 20,000 lives would be saved. The combined R21 and RTS,S 2024 vaccination programs would save under 30,000 lives.
Lives lost to malaria infection in the next year cannot be recovered in the future, and trials found the protective effect of R21 vaccination was much stronger when administered to infants under the age of 18 months.20Vaccine efficacy was higher in younger children (5-17 months) than older children (18-36 months), with first year vaccine efficiency of 75% achieved for a standard (non-seasonal) vaccination program targeting the former age group, which is the primary target for EPI vaccinations (Datoo et al., 2024). Delivering antimalarial vaccines while children are still young is also more cost-effective than delaying vaccination, as they can be delivered alongside routine immunizations this age group already receives. An accelerated rollout of R21 can therefore be expected to save over 4-5x as many young lives in the near term as a slower rollout.