One of the most exciting papers I have seen for a long time was published in the New England Journal of Medicine yesterday. This describes a randomised controlled trial of a malaria vaccine in African children.
This is important. Malaria is a terrible disease, which kills almost a million people a year, most of them children, and almost all of them in developing countries. And over 200 million a year suffer non-fatal, but still thoroughly miserable malaria infection. Although various treatments for malaria exist, they are not always available to everyone who needs them in resource-poor countries, and drug-resistant strains of malaria represent a huge challenge for treatment. While mosquito control measures can have highly beneficial effects, they have not been anywhere near sufficient to provide adequate control of the disease in practice.
Clearly, a vaccine that would protect against malaria would be a huge advance, but an effective vaccine has long eluded researchers.
The results of this new study, with the not-very-snappily named RTS-S/AS01 vaccine, developed by GSK Biologicals with assistance from the Bill and Melinda Gates Foundation, are exciting because they show that the vaccine works.
The results of the trial do clearly show efficacy. It was a well conducted trial: it was randomised and double-blind, and used standardised definitions of malaria infection that included laboratory confirmation. The sample size of 6000 children gave good statistical power. The analysis was done in various different ways (using slightly different definitions of malaria infection, analysis of both intent-to-treat and per-protocol populations, and statistical adjustment for potential confounding variables) and the results of all analyses were remarkably consistent and highly statistically significant. It really doesn’t look possible that the lower rate of malaria infections seen in the malaria vaccine group could have been a chance effect.
Now, as a statistician, my first instinct is to be cautious. So that is what I’m going to do first. You’ll have to wait until the end of this post to find out what I’m going to do second.
One caveat to bear in mind is that, although the vaccine was effective, it did not offer complete protection against malaria. The vaccine efficacy was just a little over 50%, meaning that it only halved the risk of malaria, and did not eliminate the risk. Nonetheless, not only would a 50% reduction be clinically meaningful in itself, this is also a very important proof of concept study, showing that it is possible to protect against malaria. It is now reasonable to expect that improved vaccines, offering better efficacy, will be developed in the future.
It is also important to realise that this is a single study. It is seldom wise to get too excited about the results of a single study. Although the results are consistent with small, phase II studies of the same vaccine (for example this one), independent replication of the results in another large study, ideally in a different study population, would greatly increase our confidence in the results.
It’s also worth noting that this study did not show any reduction in deaths from malaria. That doesn’t mean that it would not be expected to reduce malaria deaths, it’s just that deaths were rare in the investigated population, and the study simply didn’t have enough statistical power to investigate whether the lower incidence of malaria infection translates into fewer deaths. It would be good to have evidence that it does before getting too excited about the vaccine.
My final note of caution is about the safety of the vaccine. Although the vaccine seemed reasonably safe in this study, it is hard to be too confident based on a study of this size. A much larger safety database will be necessary to confirm that there are no rare but nasty side effects lurking. The study did hint towards a possible association between the vaccine and meningitis, which is probably just a chance effect, but will certainly need to be monitored carefully in future studies before we can be sure. There also seemed to be a small risk of seizures following vaccination (about 1 per 1000 doses). All children in this study recovered from the seizures uneventfully, but again, we’ll need a larger safety database to be sure that there isn’t a meaningful risk of harm here.
Anyway, that’s the cautious stuff done. Now for my second reaction to the study.
WHOOOOOO HOOOOOOOO! A malaria vaccine that actually works! This is AWESOME!