Despite massive efforts to reduce the disease burden of malaria, it remains a significant cause of disease and death in parts of the world, most notably Sub-Saharan Africa. Now we have a new tool in the fight against malaria – two safe and effective vaccines. Cameroon is just beginning a program to give the vaccine for free to children in four doses from 5 month to two years, and other countries are soon to follow.
Malaria is a mosquito-born disease caused by five Plasmodium species of parasite, with P. falciparum being the most severe. People become infected by being bitten by a mosquito carrying the parasite. Infection causes fever and flu-like symptoms, and sometimes anemia and jaundice. Severe infection with P. falciparum can also cause seizures, delirium, kidney failure, coma and death. Eighty percent of people who die of malaria, 600,000 per year, are children under five.
Malaria mitigation has three components. The first is chemoprophylaxis – drug treatment to both prevent infection and treat infection. The three most common drugs used are atovaquone-proguanil, doxycycline, and mefloquine, which target the parasite at different states of its lifecycle. They are given based upon how high the risk of malaria is in specific regions.
The second approach is to reduce mosquito populations, especially in locations where people live. That was the primary approach taken by the CDC in the Southern US which essentially eliminated malaria there. In Africa the main measures are spraying to kill mosquito larvae and release of larvae eating predators. Spraying for adult mosquitoes is human-occupied areas is also used.
The third measure is personal protection. Mosquitoes that spread malaria mostly feed at night, so sleeping under nets is critical. Nets impregnated with insecticide are more effective. Using personal mosquito spray, wearing clothes to cover as much skin as possible, and spraying the location where you sleep are also effective.
Using these three approaches the incidence of malaria and malaria deaths have been significantly reduced, but this reduction has plateaued in recent years and may be ticking up a bit. The role of global warming in increasing the range and seasonal duration of malaria is still unclear, but is a question of concern and ongoing research.
Into this mix now comes two anti-malarial vaccines – RTS, S and R21, both now preapproved by the WHO. RTS (which stands for central Repeat units, T-cell epitopes, and Surface antigen) was first created in 1987, and took over 30 years of research and development by the British pharmaceutical company, GSK. R21 is produced by Oxford.
These are the first anti-parasite vaccines to be successfully developed. Anti-parasite vaccine are difficult because of their complex lifecycle, which offer many opportunities to escape the host’s immune system, and because the immune response is so complex. This is also why it took so long to get efficacious vaccines for malaria.
According to the WHO:
“Both prevent around 75% of malaria episodes when given seasonally in areas of highly seasonal transmission where seasonal malaria chemoprevention is provided.”
There are a couple of qualifiers in that statement, but it essentially means it is 75% effective when used optimally in areas of highest risk. That number depends on the population you study and the outcome measures used. A US-led study, by contrast, found:
“Results of Phase 3 testing show that among children aged 5–17 months who received 4 doses of RTS,S/AS01, vaccine efficacy against malaria was 36% over 4 years of follow-up.”
But that translates to one third fewer deaths from malaria in the vaccinated population. While overall that efficacy is modest, it is still highly significant, when talking about deaths in young children. It needs to be emphasized that the vaccines should become part of the existing malaria mitigation program – you still need the other three measures. But in combination, the WHO estimates this can prevent 90% of malarial deaths.
There are some logistical impediments to getting at-risk children fully vaccinated – funding, availability of enough doses to go around, and difficulty for some parents to get their children to a clinic where they can receive the vaccine. There are efforts to address all these factors. But there is also an additional factor – vaccine hesitancy. Some parents worry if the vaccine is safe.
Evidence so far from the pilot programs to test the vaccine rollout have found that it has an “acceptable safety profile”, is cost effective, and reduces the malarial burden on the population. In a phase III clinical trial overall adverse events were the same in the RTS group as the placebo group. However, there were more meningitis cases reported in the RTS group for children but not infants. This was a small number and not always temporally connected to vaccine dosing. Even taken at face value, assuming all such cases were caused by the vaccine, the benefits far outweigh this small risk.
RTS and R21 are great additions to the anti-malaria campaign in high risks parts of the world, specifically Sub-Saharan Africa. Like all vaccines, they are not risk-free, but the evidence (from phase III trials and now pilot use programs) show the benefits far outweigh the risks. Uptake has to overcome some vaccine hesitancy, but the early data shows that parent education is highly effective. That’s not always the case, but it is here, so we should take advantage of that.