Correspondence

RTS,S/AS01E Vaccine against Malaria

N Engl J Med 2009; 360:1253-1254March 19, 2009

Article

To the Editor:

The results of the trial reported by Bejon et al. (Dec. 11 issue),1 in which the malaria vaccine RTS,S/AS01E was administered to children in Kilifi, Kenya, and Korogwe, Tanzania, are impressive. However, there are methodologic issues in the measurement of protective efficacy in sites where the transmission of malaria is falling. In such areas, transmission becomes overdispersed, and measuring protective efficacy against malaria over short periods may be inappropriate.2 For example, the high protective efficacy of intermittent preventive treatment for malaria in infants that was observed in the first clinical trial in Tanzania was probably exaggerated by a fall in transmission during the trial.3 Administration of the RTS,S vaccine in adults was shown to give short-lived protection,4 and in the study by Bejon et al.,1 the incidence of malaria was highest in the placebo group between 3 and 5 months after vaccination. This combination of decreasing transmission and protection over time could lead to an overestimate of efficacy.

Reassuringly, the high protective efficacy was seen in both sites; however, the study was small, the risk of malaria was highly variable, and transmission was falling. Similarly, the SPf66 vaccine showed high protective efficacy in low-transmission5 but not high-transmission settings. Testing RTS,S in high-transmission sites 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@lshtm.ac.uk

5 References

1. 1

   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
   Full Text | Web of Science | Medline

2. 2

   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 | Web of Science | Medline

3. 3

   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 | Web of Science | Medline

4. 4

   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

5. 5

   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

Author/Editor Response

In response to the comments by Gosling and Chandramohan: overdispersion in malaria is not necessarily limited to areas of falling transmission,1 and it also occurs in infectious diseases other than malaria.2 Our reading of the survival plots is of sustained transmission throughout the period of monitoring, although transmission has indeed been falling in the study areas.3,4 We certainly agree that estimates of efficacy during long-term follow-up are essential, and such estimates have been made for RTS,S/AS02A, with encouraging results.5 The data on vaccine efficacy for RTS,S are significantly more consistent and encouraging than the data available for SPf66 at any stage of its development. The comparison may not be informative. Nevertheless, we agree with Gosling and Chandramohan that point estimates of vaccine efficacy from phase 2b studies, such as the results we report, are surrounded by uncertainty. RTS,S/AS01E will be evaluated in a wide range of transmission sites and over longer periods of follow-up in a planned phase 3 multicenter efficacy trial.

Philip Bejon, Ph.D.
Kenya Medical Research Institute, Kilifi, Kenya
pbejon@kilifi.kemri-wellcome.org

Amanda Leach, M.R.C.P.C.H.
GlaxoSmithKline Biologicals, 1330 Rixensart, Belgium

Lorenz von Seidlein, Ph.D.
International Vaccine Institute, Seoul 1S1-500, Korea

5 References

1. 1

   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 | Web of Science | Medline

2. 2

   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
   CrossRef | Web of Science | Medline

3. 3

   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 | Web of Science | Medline

4. 4

   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

5. 5

   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