In the 14 years of SBM we only have written two articles about malaria, both in 2021. At first this may be surprising as malaria is a serious worldwide illness, with an estimated 241 million cases per year and 627,000 deaths (although likely an underestimate). However, there hasn’t been much in the way of innovation to write about, until recently. Last year Harriet wrote about a monoclonal antibody for malaria, and Clay Jones wrote about the first malaria vaccine.
Already there is an update, with the recent announcement of another anti-malaria vaccine claiming greater efficacy. I don’t think this is a coincidence. I think we are seeing the results of advancing biotechnology. Monoclonal antibodies, for example, are finally coming into their own, with multiplying applications in almost every field of medicine. Vaccine technology has also been steadily advancing, which the world witnessed with the rapid roll-out of many anti-COVID vaccines within a year of its emergence.
The RTS,S/AS01 vaccine (now named Mosquirix and manufactured by GlaxoSmithKline):
…had a vaccine efficacy of 68% over a period of 6 months following administration of the initial three doses, but this efficacy waned over time. At 6 months after a fourth dose, administered 18 months following the third dose, vaccine efficacy was 44% (95% CI 40–48).
As Clay pointed out, this is still not at the WHO’s goal of 75% efficacy, but it is still good. Even at 44% efficacy this will prevent many deaths. Also, we need to keep in mind that (as with COVID) death is not the only bad outcome from serious infections. Malaria mostly affect sub-Saharan African children, who often have multiple infections by age 5. Those who survive can still suffer malnutrition, poor development, and increased susceptibility to other infections. It is a massive disease and societal burden. Even with modest efficacy, an effective vaccine has a huge ROI in terms of outcomes and healthcare dollars.
The new vaccine, R21/Matrix-M, is being developed at Oxford and manufactured by the Serum Institute of India, which is the largest vaccine manufacturer in the world. There has actually already been a preliminary phase I trial of this vaccine using a three-dose schedule in a cohort of children aged 5–17 months in Nanoro, Burkina Faso. The results showed an efficacy of 75% at 12 months, reaching the WHO goal. The new study in the same cohort uses a booster shot at 12 months following the initial three-dose regimen, and finds:
Vaccine efficacy was maintained in the high-dose adjuvant group, at 80% following the booster vaccine over 12 months, and 75% over 24 months after the primary three-dose regimen. Furthermore, vaccine efficacy against multiple episodes of clinical malaria was similar (78%) over 2 years of follow-up. R21/Matrix-M has a favourable safety profile and also induces high levels of malaria-specific anti-NANP antibodies that correlate with the observed protection against clinical malaria.
This is a significant improvement over the Mosquirix vaccine, and meets the WHO goal. The caveat is that this was only a phase II trial involving 409 children. The researchers are already beginning a phase III trial with 4,800 children. If this shows similar results that would likely be enough to get regulatory approval.
The other advantage to this vaccine, especially given the target population, is that it is cheap to produce, at only a few dollars per dose. The Serum Institute of India claims they can produce 100 million doses a year, which is a lot but not nearly enough. A full booster course is four doses, so that is enough for 25 million children, yet there are over 240 million cases a year. Hopefully production can be ramped up significantly.
The good news is that it seems we are on the cusp of significantly reducing cases of malaria. Malaria is likely the deadliest disease in all history, and remains a significant killer. The CDC in the US was founded essentially to fight malaria in the southeast, which was accomplished mainly through getting rid of mosquito breeding grounds. In Africa the mainstay of fighting malaria is through pesticides to reduce mosquito populations, mosquito netting, and drugs to treat infection once it occurs. But we have been lacking the single most effective tool in our infectious disease toolkit – a vaccine. That is now changing.
But why has it taken so long to develop an anti-malaria vaccine? Some infectious organisms are challenging to target with a vaccine, because they have a complex lifecycle or are able to evade immunity. Malaria is caused by a parasite, several Plasmodium species, that reproduce in the gut of mosquitos then migrate to the salivary glands and are injected during feeding on humans. The parasites then reproduce in the liver and in the final stage move onto red blood cells, where they cause serious illness.
The vaccines both work by targeting the initial phase of human infection, preventing them from infecting liver cells. They combine malarial proteins with the Hepatitis B virus, so essentially they work like a typical anti-viral vaccine, but the malarial proteins allow the resulting antibodies to target the Plasmodium parasite. The Oxford vaccine incorporates more malarial proteins, which they believe is the reason it has higher efficacy than the GSK vaccine. It was a clever approach that ultimately bore fruit.
Vaccine technology remains arguably the most effective medical intervention developed by humans. We are also seeing the results of advancing vaccine technology, and biotechnology in general. In a generation malaria, one of the greatest scourges of humanity, may become a thing of the past due to vaccine technology.