Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Alonso PL, Sacarlal J, Aponte JJ, Leach A, Macete E, Milman J, Mandomando I, Spiessens B, Guinovart C, Espasa M et al. Lancet 2004;364(9443):1411-1420.
Explanatory note: Malaria is a life-threatening disease transmitted by mosquitoes, and caused by four species of parasites from the genus Plasmodium—the most deadly being P. falciparum. An estimated 700,000-2.7 million persons die of malaria each year, 75% of them African children.
There is currently no vaccine for the prevention of malaria, although several candidate vaccines are undergoing clinical trials. This article reports the results of a phase II clinical trial of a vaccine against P. falciparum. The vaccine consists of a molecularly constructed molecule of a protein from the parasite fused with the hepatitis B antigen and adjuvants designed to stimulate cellular immunity.
What are the efficacy, immunogenicity, and safety of the RTS,S/AS02A malaria vaccine candidate in young African children?
This trial included 2,022 children 1 to 4 years of age from two separate areas of Mozambique. The vaccine being tested targets the malaria parasite before it enters the red blood cell. Researchers gave the children 3 doses of either RTS,S/AS02A malaria vaccine or other control vaccines (not protective against malaria) at 0, 1 and 2 months. The children were followed for 6 months after the last dose using a previously established surveillance system.
The researchers estimated the time to first clinical episode of P. falciparum malaria in 1,605 children; they determined that their case definition was both specific and sensitive. The different categories of severe disease were considered together.
In an additional group of 417 children, they examined the vaccine efficacy against developing P. falciparum infection by looking for the parasite in blood samples.
The vaccine provided a good immune response, especially in children younger than 24 months of age. The time to first episode of clinical illness was longer in vaccine recipients than control children, although the number of parasites in the blood was not different in those who had a first clinical episode.
While there were few who had severe disease the researchers reported that the vaccine demonstrated some efficacy at preventing severe forms of malaria.
In a group of children in whom any P. falciparum infection was sought by performing blood smears, the time to first infection was delayed for those who had received the RTS,S/AS02A vaccine. At the end of 6 months, 94% of control children and 87% of vaccine recipients demonstrated parasites, however, only suggesting a low level of vaccine efficacy.
Adverse events were mostly mild although there were 429 serious adverse events reported and 15 children died during the study period. Four of the children who died were judged to have had severe malaria and these four were all in the control group. None of the serious adverse events were judged to have been related to vaccination.
The RTS,S/AS02A candidate malaria vaccine some short term protection in a proportion of young African children against uncomplicated malaria, against P. falciparum infection, and severe malaria.
The RTS,S/AS02A vaccine had low levels of efficacy against multiple endpoints. While reductions in clinical disease of these amounts would have little impact on a population in an area of high malaria transmission, these findings are sufficiently encouraging that additional studies of larger numbers of children in areas of higher P. falciparum transmission are warranted. In addition, if other studies confirm there observations, it may be possible to use detection of infection (parasites in the blood) as a surrogate endpoint for vaccine efficacy against clinical disease which would greatly simplify study design and conduct.