Published online 26 October 2011 | Nature 478, 439-440 (2011) | doi:10.1038/478439a

Corrected online:

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Experts question early release of incomplete trial data.

The RTS,S/AS01 candidate vaccine offers poor protection against severe malaria. Reuters/J. Okanga

"Malaria vaccine could save millions of children's lives"; "World's first malaria vaccine works in major trial"; "Malaria vaccine almost here". To judge from last week's headlines, scientists had made a big breakthrough in the long campaign to create a malaria vaccine, proving its effectiveness with interim results from a huge phase III clinical trial in Africa1.

Yet several leading vaccine researchers, who are critical of the unusual decision to publish partial trial data, argue that the results raise questions about whether the RTS,S/AS01 candidate vaccine can actually win approval.

RTS,S has been in development for some 25 years, initially by the US military, and since 2001 by a public–private venture between the PATH Malaria Vaccine Initiative (MVI) and the drug-maker GlaxoSmithKline (GSK), supported by US$200 million in funding from the Bill & Melinda Gates Foundation. Bill Gates himself announced the interim results at the Gates Malaria Forum in Seattle, Washington.

Gates' speech and the MVI's public-relations material were suitably circumspect about the results, but they were "immediately translated into headlines about [reductions] in death and mortality", says Andrew Farlow, an economist at the University of Oxford, UK, who has previously assessed the RTS,S programme2. "But the data are not telling you that at all."

Some researchers question whether the results should have been published before all the data were available; full results are expected in 2014. Interim trial data are usually reported only to regulatory authorities, and clinical trials published only once all the data are in, noted Nicholas White, a malaria expert at Mahidol University in Bangkok, in an editorial3 accompanying the interim results. "There does not seem to be a clear scientific reason why this trial has been reported with less than half the efficacy results available," he wrote.

The publication presents vaccine-efficacy data for infants aged 5–17 months, but not for those aged 6–12 weeks, who are the stated target of the trial: it is this group that would receive the malaria vaccine alongside routine immunizations. The aim of the trial is to provide the World Health Organization (WHO) with the information it needs to consider licensing the vaccine, and recommend it for use in that age group. "What is the point of publishing the interim data on the 5–17-month-olds?" asks Stephen Hoffman, a veteran malaria researcher and chief executive of a rival vaccine effort, Sanaria, based in Rockville, Maryland.

The MVI's director, Christian Loucq, argues that the results were "robust enough to be published. We decided this before we knew the results; we felt it was our scientific and ethical duty to make the results public when they become available."

One of the biggest claims made in the paper is that RTS,S reduced the total number of episodes of clinical malaria in the older group by 55.1%, compared to controls. This measure of efficacy is recommended for assessing a partially effective vaccine4. But the public expects vaccine efficacy to describe protection over a period of time, argues Judith Epstein, a captain and paediatrician at the US Military Malaria Vaccine Program in Silver Spring, Maryland. Recalculating the trial data shows that RTS,S protected just 35–36% after 12 months, she says, adding that the paper should have presented both numbers. The study also showed no detectable impact on mortality, and it is too early to tell whether RTS,S actually protects against malaria, or merely delays infection.

The paper did report that RTS,S reduced severe malaria by 47% in the older group. But combining that result with available data from the younger age group cut that number to 34.8% — meaning that for the youngest children, the benefit must be even smaller. "The real question mark is the 34.8% efficacy in severe disease," says Blaise Genton of the Swiss Tropical and Public Health Institute in Basel, and a member of the WHO technical advisory group for RTS,S. The results suggest that the vaccine might fall short of expectations, laid out in 2006 by a WHO-led consortium5, that it should have a "protective efficacy of more than 50% against severe disease and death and lasts longer than one year". "If it doesn't reduce deaths, and has only a modest effect on severe malaria, these are going to be big questions for decision-makers at WHO, GSK and the Gates Foundation," says Hoffman.

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Another worrying finding is that the frequency of serious adverse events, such as convulsions and meningitis, was significantly higher in the vaccinated group, although the data are too preliminary to draw firm conclusions.

But Hoffman, like many researchers contacted by Nature, says that RTS,S still marks a significant achievement. It is the first vaccine against a parasite, Plasmodium falciparum, to consistently show a significant protective effect in large-scale trials. The phase III trial of RTS,S resulted in groundbreaking cooperation with African scientists, who led the 11 trials in 7 countries, says Hoffman. "I think that those teams deserve an incredible amount of recognition and congratulation."

Corrected: This article originally described Plasmodium falciparum as multicellular instead of unicellular. The error has now been removed from the text.