First results from a large-scale Phase III trial of RTS,S, published online in the New England Journal of Medicine (NEJM), show the malaria vaccine candidate to provide young African children with significant protection against clinical and severe malaria with an acceptable safety and tolerability profile.
RTS,S aims to trigger the immune system to defend against Plasmodium falciparum malaria parasite when it first enters the human host’s bloodstream and/or when the parasite infects liver cells. It is designed to prevent the parasite from infecting, maturing and multiplying in the liver, and from re-entering the bloodstream and infecting red blood cells, at which point the affected person would begin to show symptoms of the disease.
It is estimated that half the world’s population is at risk of malaria, which is responsible for close to 800,000 deaths each year, most of whom are children under five in sub-Saharan Africa. A child dies of malaria every 45 seconds in sub-Saharan Africa. According to the latest reports from 2009, children under five accounted for 85 per cent of the nearly 800,000 malaria deaths.
The trial, conducted at 11 trial sites in seven countries across sub-Saharan Africa, showed that three doses of RTS,S reduced the risk of children experiencing clinical malaria and severe malaria by 56 per cent and 47 per cent, respectively.
This analysis was performed on data from the first 6,000 children aged 5 to 17 months, over a 12-month period following vaccination. Clinical malaria results in high fevers and chills. It can rapidly develop into severe malaria, typified by serious effects on the blood, brain, or kidneys that can prove fatal. These first Phase III results are in line with those from previous Phase II studies.
The widespread coverage of insecticide-treated bed nets (75%) in this study indicated that RTS,S can provide protection in addition to that already offered by existing malaria control interventions.
According to the researchers, the trial is ongoing and efficacy and safety results in 6 to 12 week-old infants are expected by the end of 2012. These data will provide an understanding of the efficacy profile of the RTS,S malaria vaccine candidate in this age group, for both clinical and severe malaria.
An analysis of severe malaria episodes so far reported in all 15,460 infants and children enrolled in the trial at 6 weeks to 17 months of age has been performed. This analysis showed 35 per cent efficacy over a follow-up period ranging between 0 and 22 months (average 11.5 months).
The RTS,S malaria vaccine candidate is still under development. Further information about the longer-term protective effects of the vaccine, 30 months after the third dose, should be available by the end of 2014. This will provide evidence for national public health and regulatory authorities, as well as international public health organisations, to evaluate the benefits and risks of RTS,S.
The overall incidence of serious adverse events (SAEs) in this trial was comparable between the RTS,S candidate vaccine (18%) recipients and those receiving a control vaccine (22%). A serious adverse event refers to any medical event that occurs during the course of a clinical trial and that results in death, is life threatening, requires inpatient hospitalization, or results in a persistent or significant disability or incapacity needs, regardless of whether the SAE is considered to be caused by the study vaccination.
Differences in rates of SAEs were observed between the vaccine groups for specific events, such as seizures and meningitis, and were higher in the malaria vaccine group. Seizures were considered to be related to fever and meningitis was considered unlikely to be vaccine-related. These events will continue to be monitored and additional information about the safety profile of the RTS,S malaria vaccine candidate will become available over the next three years.
“The publication of the first results in children aged 5 to 17 months marks an important milestone in the development of RTS,S,” says Tsiri Agbenyega, a principal investigator of the trial and Chair of the Clinical Trials Partnership Committee. “These results confirm findings from previous Phase II studies and support ongoing efforts to advance the development of this malaria vaccine candidate.”
Bill Gates, co-chairman, Bill & Melinda Gates Foundation, says, “A vaccine is the simplest, most cost-effective way to save lives. These results demonstrate the power of working with partners to create a malaria vaccine that has the potential to protect millions of children from this devastating disease.”
The vaccine is being developed in partnership by GlaxoSmithKline (GSK) and the PATH Malaria Vaccine Initiative (MVI), together with prominent African research centres. Major funding for clinical development comes from a grant by the Bill & Melinda Gates Foundation to MVI.
In January 2010, GSK announced that the eventual price of RTS,S would cover the cost of manufacturing the vaccine together with a small return of around 5 per cent that will be reinvested in research and development for second-generation malaria vaccines or vaccines against other neglected tropical diseases.
If the required public health information, including safety and efficacy data from the Phase III programme, is deemed satisfactory, the World Health Organisation (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.