Candidate malaria vaccine moves towards regulatory approval application

An application for regulatory approval for the most clinically advanced malaria candidate, RTS,S, could be submitted to the European Medicines Agency as early as next year following positive results from a late-stage clinical trial in African children.

The latest results – which were announced this week at a conference in South Africa – show that over 18 months of follow-up, the vaccine candidate cut the number of malaria cases in young children by almost half and reduced malaria cases in infants by around a quarter.

The results represent an interim analysis of an ongoing phase III clinical study that involves more than 15,000 infants (aged 6–12 weeks at first vaccination) and young children (aged 5–17 months at first vaccination). The trial is being conducted at 11 African research centres in seven African countries, including the Wellcome Trust's Major Overseas Programme at the Kenya Medical Research Institute in Kilifi, Kenya, together with GlaxoSmithKline, who initially developed the RTS,S vaccine, and the PATH Malaria Vaccine Initiative, with grant funding from the Bill and Melinda Gates Foundation.

Efficacy of the candidate vaccine was assessed separately at each of the trial sites, which represent a wide range of malaria transmission settings, and was found to be statistically significant at all sites in young children and at four sites in infants.

Dr Jimmy Whitworth, Head of International Activities at the Wellcome Trust, said: "This is good news for an experimental vaccine that has been in development for more than 20 years. The vaccine doesn't offer complete protection but if the level of protection we're seeing in these studies is repeated in other populations, it could have a significant effect in reducing the number of cases of falciparum malaria and easing the burden of the disease worldwide."

The efficacy and public health impact of RTS,S were evaluated in the context of existing malaria control measures, such as insecticide-treated bednets, which were used by 78 per cent of children and 86 per cent of infants in the trial. Participants in the trial received three doses of either RTS,S or a placebo 'control vaccine'.

In these latest results over 18 months of follow-up, children experienced 46 per cent fewer cases of clinical malaria, compared to children immunised with a control vaccine. An average of 941 cases of clinical malaria were prevented over 18 months of follow-up for every 1,000 children vaccinated in this age group, noting that a child can contract more than one case of malaria.

Severe malaria cases were reduced by more than one third; 21 cases of severe malaria were prevented over 18 months of follow-up for every 1,000 children vaccinated. Malaria hospitalisations were reduced by 42 per cent.

Infants had around a third fewer cases of clinical malaria. Over 18 months of follow-up, 444 cases of clinical malaria were prevented for every 1,000 infants vaccinated. The reduction of severe malaria cases and malaria hospitalisations by 15 per cent and 17 per cent, respectively, were not statistically significant.

Overall, the results reveal that vaccine efficacy had declined over time since the reporting of data from one year of follow-up of the phase III trial. The earlier results had reported that efficacy of RTS,S was 56 per cent against clinical malaria and 47 per cent against severe malaria for the 5–17 months age group and 31 per cent against clinical malaria and 37 per cent against severe malaria in the 6–12 weeks age group.

Dr Whitworth added: "Next year we'll have the results from 32 months of follow-up after vaccination with RTS,S, and they will be crucial for understanding the duration of protection offered by the vaccine. We'll also get the results of another study looking at the effect of a fourth 'booster' dose given 18 months after the initial three doses of vaccine. Once we have this information, the question for public health practitioners will be how the vaccine could fit with existing malaria prevention tools, such as insecticide-treated bednets.

"If the outcome of the European Medicines Agency regulatory approval application is successful, the World Health Organization (WHO) has indicated that a policy recommendation for the RTS,S malaria vaccine candidate is possible as early as 2015, paving the way for decisions by African nations regarding large-scale implementation of the vaccine through their national immunisation programmes.

"In Africa we experience nearly 600,000 deaths annually from malaria, mainly children under five years of age," said Dr Halidou Tinto from the Nanoro, Burkina Faso trial site and chair of the Clinical Trials Partnership Committee, which oversees the phase III programme.

"Preventing substantial numbers of malaria cases in a community would mean fewer hospital beds filled with sick children. Families would lose less time and money caring for these children and have more time for work or other activities. And of course the children themselves would reap the benefits of better health."