By Dr Seth Berkley, Gavi& Dr Mark Dybul, Global Fund
The first malaria vaccine is set to be given the green light by regulators on Friday, opening the door for the World Health Organization to recommend its use in developing countries. But in this week's Scrubbing Up, By Dr Seth Berkley, chief executive officer of Gavi (the Vaccine Alliance), and Dr Mark Dybul, executive director of the Global Fund to Fight Aids, Tuberculosis and Malaria, say it won't be a straightforward decision.
How effective does a vaccine have to be before it should be made available?
This is far from straightforward. Clearly it needs to be capable of preventing disease, but to what extent?
None are 100% effective. So in the cold light of day, for most countries it comes down to a complex calculation based on the cost effectiveness, lives saved, illness avoided and the availability of other effective interventions.
For highly effective vaccines - ones which offer a high level of immunity - this normally proves uncontentious, but what about ones that are less effective?
How much protection do they need to provide in order to justify their use?
Such is the question World Health Organization (WHO) experts will now be preparing to ask themselves as they consider whether or not to recommend the world's first malaria vaccine for use in affected countries in Africa.
That's because, on Friday, the European Medicines Agency is effectively giving the GlaxoSmithKline (GSK) vaccine - called Mosquirix - a green light, meaning that the 250,000-page application has now passed every regulatory bar required of it for WHO to consider it. The decision is expected in October.
With nearly 200m cases of malaria every year, resulting in the deaths of around 1,200 children every day, this may seem like a no brainer. However the decision is a complex one. Clinical trial data suggests that Mosquirix offers only partial protection, preventing one in three cases of clinical malaria, a relatively low success rate compared to other approved vaccines.
What's more, the clinical trials were carried out with the vaccine used in conjunction with high use of other interventions, such as long-lasting insecticide treated bed-nets and anti-malarial drugs.
So we don't really know how effective the vaccine is by itself or how well it would perform outside the controlled setting of a clinical trial.
In fact there are still many unknowns.
We don't know, for example, if the vaccine will give people a false sense of security and lead to reduction in the use of bed-nets and other interventions.
Given the progress that has been made since 2000 in halving the number of malaria deaths, that would be tragic.
Similarly, the effectiveness is very much dependent upon children receiving an additional booster shot, after an initial three doses.
Without this protection starts to wane significantly from 36% efficacy with the booster to around 28% in older children, the equivalent of preventing one in four cases, and even lower in younger children.
The obvious answer is to make sure everyone gets that booster, but that's easier said than done.
With vaccinations half the challenge is making sure everyone gets the full course.
That's all very well in the controlled setting of clinical trials, but in practice what sort of dropout rate can we expect for that booster shot, particularly since this will be given outside of the normal childhood immunisation schedule?
So, with such unanswered questions it may seem more prudent to hold off, focus on current tools with known cost effectiveness and wait for a better alternative.
The problem is that there currently aren't any. Mosquirix is about five to 10 years ahead of any other candidate malaria vaccines, and there's no guarantee any of them will be better.
Moreover, in clinical trials Mosquirix still prevented on average 1,774 cases of malaria per 1,000 children (with more than one malaria episode per child), meaning that in areas of high burden it prevented several episodes of malaria per child per year.
So, if Mosquirix can potentially save lives or reduce illness now - even if only in one in three cases - then can we really justify holding off? Indeed, governments of malaria-affected countries are keen to see a malaria vaccine soon.
For many countries malaria is a hugely important issue and a big drain on their economies.
Not only does it kill 584,000 people every year, the vast majority being African children under the age of five, but through recurring sickness it takes many adults out of work for prolonged periods.
All these factors conspire to make the WHO decision incredibly complex.
The best way to get any clarity on these issues is to see how the vaccine performs in a real-life setting, in high and low transmission areas, with and without high coverage of other interventions.
Normally this kind of post-market surveillance, or phase four trial, is used to gather additional long-term safety data.
But for Mosquirix it now seems clear that this is the only way to find out definitively the role this vaccine has to play in reducing the disease burden of malaria.
Currently, several phase four trials have been proposed for Mosquirix, some of which aim to shed more light on its effectiveness and the issues around the booster dose, yet none of these studies are fully-funded.
That has to change. Most of the uncertainty surrounding this important vaccine concern questions that can be answered.
Given the vast scale of the number of people affected, we have a duty to fill these gaps in our knowledge.