To the Editor: The results of the trial reported by Bejon etal. (Dec. 11 issue),1 in which the malaria vaccine RTS,S/AS01Ewas administered to children in Kilifi, Kenya, and Korogwe,Tanzania, are impressive. However, there are methodologic issuesin the measurement of protective efficacy in sites where thetransmission of malaria is falling. In such areas, transmissionbecomes overdispersed, and measuring protective efficacy againstmalaria over short periods may be inappropriate.2 For example,the high protective efficacy of intermittent preventive treatmentfor malaria in infants that was observed in the first clinicaltrial in Tanzania was probably exaggerated by a fall in transmissionduring the trial.3 Administration of the RTS,S vaccine in adultswas shown to give short-lived protection,4 and in the studyby Bejon et al.,1 the incidence of malaria was highest in theplacebo group between 3 and 5 months after vaccination. Thiscombination of decreasing transmission and protection over timecould lead to an overestimate of efficacy.
Reassuringly, the high protective efficacy was seen in bothsites; however, the study was small, the risk of malaria washighly variable, and transmission was falling. Similarly, theSPf66 vaccine showed high protective efficacy in low-transmission5but not high-transmission settings. Testing RTS,S in high-transmissionsites is a priority in order to refine estimates of SPf66.
Roly D. Gosling, M.D. Daniel Chandramohan, M.D., Ph.D. London School of Hygiene and Tropical Medicine London WC1E 7HT, United Kingdom roly.gosling{at}lshtm.ac.uk
References
Bejon P, Lusingu J, Olotu A, et al. Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age. N Engl J Med 2008;359:2521-2532. [Free Full Text]
Mwangi TW, Fegan G, Williams TN, Kinyanjui SM, Snow RW, Marsh K. Evidence for over-dispersion in the distribution of clinical malaria episodes in children. PLoS ONE 2008;3:e2196-e2196. [CrossRef][Medline]
Gosling RD, Ghani AC, Deen JL, von Seidlein L, Greenwood BM, Chandramohan D. Can changes in malaria transmission intensity explain prolonged protection and contribute to high protective efficacy of intermittent preventive treatment for malaria in infants? Malar J 2008;7:54-54. [CrossRef][Medline]
Bojang KA, Milligan PJ, Pinder M, et al. Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial. Lancet 2001;358:1927-1934. [CrossRef][Web of Science][Medline]
Valero MV, Amador LR, Galindo C, et al. Vaccination with SPf66, a chemically synthesised vaccine, against Plasmodium falciparum malaria in Colombia. Lancet 1993;341:705-710. [CrossRef][Web of Science][Medline]
The authors reply: In response to the comments by Gosling and Chandramohan: overdispersion in malaria is not necessarily limitedto areas of falling transmission,1 and it also occurs in infectiousdiseases other than malaria.2 Our reading of the survival plotsis of sustained transmission throughout the period of monitoring,although transmission has indeed been falling in the study areas.3,4We certainly agree that estimates of efficacy during long-termfollow-up are essential, and such estimates have been made forRTS,S/AS02A, with encouraging results.5 The data on vaccineefficacy for RTS,S are significantly more consistent and encouragingthan the data available for SPf66 at any stage of its development.The comparison may not be informative. Nevertheless, we agreewith Gosling and Chandramohan that point estimates of vaccineefficacy from phase 2b studies, such as the results we report,are surrounded by uncertainty. RTS,S/AS01E will be evaluatedin a wide range of transmission sites and over longer periodsof follow-up in a planned phase 3 multicenter efficacy trial.
Philip Bejon, Ph.D. Kenya Medical Research Institute Kilifi, Kenya pbejon{at}kilifi.kemri-wellcome.org
Lorenz von Seidlein, Ph.D. International Vaccine Institute Seoul 1S1-500, Korea
References
Smith DL, Dushoff J, Snow RW, Hay SI. The entomological inoculation rate and Plasmodium falciparum infection in African children. Nature 2005;438:492-495. [CrossRef][Medline]
Woolhouse ME, Dye C, Etard JF, et al. Heterogeneities in the transmission of infectious agents: implications for the design of control programs. Proc Natl Acad Sci U S A 1997;94:338-342. [Free Full Text]
Okiro EA, Hay SI, Gikandi PW, et al. The decline in paediatric malaria admissions on the coast of Kenya. Malar J 2007;6:151-151. [CrossRef][Medline]
O'Meara WP, Bejon P, Mwangi TW, et al. Effect of a fall in malaria transmission on morbidity and mortality in Kilifi, Kenya. Lancet 2008;372:1555-1562. [CrossRef][Web of Science][Medline]
Alonso PL, Sacarlal J, Aponte JJ, et al. Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial. Lancet 2005;366:2012-2018. [CrossRef][Web of Science][Medline]
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