NEJM malaria articles and duration of protection for the RTS,S malaria vaccine

The latest issue of the New England Journal of Medicine contains a large set of malaria articles  including results from the RTS,S vaccine phase 2 trials. RTS,S is the malaria vaccine furthest along in the development pipeline and is managed by a public-private partnership led by GlaxoSmithKline and the PATH Malaria Vaccine Initiative (the early research was a GSK and Walter Reed collaboration). In order to prevent infections, the vaccine targets the Plasmodium falciparum circumsporozoite protein which is expressed by the infectious stage of the parasite released from mosquito bites. The first trials of RTS,S conducted in children in The Gambia reported 30 percent efficacy in reducing clinical malaria over a period of 6 months though the range of this estimated effect was between 11 and 45 percent.

In this latest study RTS,S decreased malaria cases by 58 percent (range 35-73) in children of ages 5-17 months from sites in Kenya and Tanzania. Key differences in this study included the use of a different adjuvant (administered alongside a vaccine target to boost immune response) and a younger population (in which the previous trial was more efficacious). The trial was underpowered due to a lower than expected malaria incidence in both study arms (though it is unclear why exactly, cost comes to mind, the follow-up period could not have been extended). A longer duration of follow-up may have also shed light on the duration of protection for the vaccine.  What we know so far is that between the 3 month and the next followup (varies from 4.5-10m), circulating antibody against the target protein decreased by roughly an order of magnitude. However, the authors could not find any association between antibody titers and protection. I suspect there is some association which would be evident with more cases and a further decrease in antibody concentrations.

Duration of protection will be a key determinant for the vaccine’s utility. If the length of protection is limited, a 3 dose schedule can not be easily implemented at regular intervals, regardless of vaccine cost. Assuming RTS,S will primarily target infants, a possible delivery mechanism is through the staple Expanded Program on Immunization where the 3 dose schedule can be integrated with similar vaccines.  Is EPI delivery enough for protection through childhood? Will there be a rebound effect after immunity wanes? Many questions await, but looks like we will have to wait for phase 3 trial results to know the full story.

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