The lead malaria vaccine under development by GlaxoSmithKline and the PATH Malaria Vaccine initiative can reduce the risk of infection in young children by 46% over a 15-month period compared with a rabies vaccine, the latest results of a Phase II clinical trial in Africa have shown.
Follow-up results from the trial in Kenya and Tanzania were published in The Lancet Infectious Diseases. The initial outcomes appeared in the New England Journal of Medicine in December 2008, showing that the vaccine, RTS,S/ASO1E, reduced malaria episodes by 53% over an eight-month period compared with the rabies vaccine.
The Phase II study involved healthy children aged between five and 17 months who were enrolled between March 2007 and October 2008 in Kilifi, Kenya and Korogwe, Tanzania, both malaria-endemic areas of Africa.
A total of 894 children were randomly assigned to three doses of either RTS,S/AS01E (447 children) or a human diploid-cell rabies vaccine (447). Blood samples were taken before vaccination and at regular intervals during the trial to test for antibodies. The primary trial endpoint was time to first clinical malaria episode, defined as the presence of fever (temperature _37•5°C) and a Plasmodium falciparum density of 2500/_L or more.
The follow-up period was 12 months for children from Korogwe and 15 months for those from Kilifi. Researchers led by Ally Olotu from the Kenya Medical Research Institute-Wellcome Trust Research Programme in Kilifi also conducted a post-hoc modelling analysis to determine the association between levels of anti-circumsporozoite antibodies and the vaccine’s efficacy.
In a per-protocol analysis, 82 of 415 children in the RTS,S/AS01E group and 125 of 420 children in the rabies vaccine group had their first or only clinical malaria episode within 12 months of treatment, a reduction of 39.2% in the risk of infection by the Plasmodium falciparum parasite.
At 15 months’ follow-up, 58 of 209 children in the RTS,S/AS01E group and 85 of 206 in the rabies vaccine group had their first or only clinical malaria episode, giving an efficacy score of 45.8% for the malaria vaccine.
Anti-circumsporozoite antibody titre data were available at 12 months after the first dose for 390 children in the RTS,S/AS01E group and for 391 in the rabies group. A mean of 15 months’ data were available for 172 children in the RTS,S/AS01E group and for 155 in the rabies group.
At one month after the third dose, the antibody titres were not associated with any protection against Plasmodium falciparum, but they were after 6•5 months, with the level of protection increasing abruptly over a narrow range of antibody concentrations.
The modelling analysis found that an antibody concentration in the range of 35-45 EU/mL provided the best distinction between children who were vulnerable to infection and those who were not.
The most common adverse events seen in the trial were pneumonia, febrile convulsion, gastroenteritis and P falciparum malaria, although fewer serious adverse events were reported in the RTS,S/AS01E group (11.4%) than in the rabies group (19.7%).
The RTS,S/AS01E vaccine “confers sustained efficacy for at least 15 months and shows promise as a potential public health intervention against childhood malaria in malaria endemic countries”, Olotu et al concluded.
“Further studies are needed to establish vaccine efficacy in, for example, children with HIV infection or those who are malnourished,” they said. “Furthermore, Phase III studies should include study sites at different transmission intensities to confirm how generalisable our results are.”
GlaxoSmithKline (GSK) and the PATH Malaria Vaccine Initiative launched a Phase III trial of RTS,S/ASO1E in seven countries across sub-Saharan Africa in November 2009. This study is evaluating the vaccine’s efficacy in two groups of children, one of which is being vaccinated as part of their regular schedule of infant immunisations while the other includes children aged five to 17 months.
In a comment piece for The Lancet Infectious Diseases, Professor Brian Greenwood from the London School off Hygiene and Tropical Medicine discusses how vaccine development for malaria has been hindered by a lack of a reliable immunological measurement to predict infection.
However, Greenwood notes, the need for a correlate will be less acute if the Phase III trial of RTS,S/AS01 confirms the promise shown in the Phase II results from Kenya and Tanzania, and “RTS,S/AS01 becomes the first malaria vaccine to be licensed and widely deployed”.