EFFICACY OF RTS,S MALARIA VACCINE GIVEN WITH EPI VACCINES

Friday, 2nd of September 2011 Print

·         EFFICACY OF RTS,S MALARIA VACCINE GIVEN WITH EPI VACCINES

This discussion article, also accessible online at

http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(11)70186-4/fulltext

refers to an article in The Lancet Infectious Diseases by Asante et al., accessible at

http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=Search&term=10.1016/S1473-3099-11-70100-1[Doi]

If these results are confirmed by Phase 3 trial results, likely to appear in 2011, then the licensing and prequalfication of a malaria vaccine as part of EPI may be closer than even the optimists have believed.

Good reading.

BD

Efficacy of RTS,S malaria vaccine given with EPI vaccines

Original Text

Alassane Dicko a, Ogobara Doumbo a

Despite widespread use of effective drugs and vector control with insecticide-treated bednets (ITNs) and indoor residual spraying, hundreds of millions of people have malaria and nearly a million die every year.1 Children aged less than 5 years living in sub-Saharan Africa are disproportionally affected; accounting for 80% of malaria deaths worldwide.1 The disease is an important constraint to the development of sub-Saharan Africa. Severe malaria caused by Plasmodium falciparum is the most common form of the disease in this region. New methods such as intermittent preventive treatment in children have reduced the incidence of uncomplicated and severe malaria by between 67% and 86%.2—6 An effective P falciparum malaria vaccine has been long awaited and would be a major additional intervention for improved control and elimination of malaria in sub-Saharan Africa.

Malaria vaccine research has been intensified over the past few years with several vaccines tested in trials. RTS,S vaccine has been the most promising of these candidates. The vaccine consists of P falciparum circumsporozoite protein fused to hepatitis B virus surface antigen, expressed in Saccharomyces cerevisiae yeast cells. After initial studies of safety and immunogenicity in American volunteers and a phase 2b study in Gambian adults,7 a phase 2b study in Mozambican children showed that the RTS,S vaccine adjuvanted with ASO2A reduced the incidence of severe malaria episodes in children aged 1—4 years by 49% over 18·5 months; a groundbreaking step in the development of a malaria vaccine.8 The reduction in all clinical episodes in this study was a modest 30%. Since then, further phase 2b trials of RTS,S have been done in younger children in different areas of sub-Saharan Africa. Two studies assessed the efficacy of the vaccine adjuvanted with ASO1E against all clinical episodes over a period longer than 10 months in young children. A study of children aged 5—17 months in Kenya and Tanzania, showed a reduction of 54% in all clinical episodes over 10·5 months of follow-up.9 In Gabon, Ghana, and Tanzania, another study delivered the vaccine alongside vaccines given as part of the expanded programme on immunisation (EPI) with two schedules: 0, 1, and 2 months or 0, 1, and 7 months. As in previous studies, the safety profile of the vaccine was good and the vaccine was well tolerated.10, 11

In this issue of The Lancet Infectious Diseases, Asante and colleagues12 report the results of nearly 2 years of follow-up in the children in Gabon, Ghana, and Tanzania. Vaccine efficacy against all clinical episodes was 59% over 19 months of follow-up with a 0, 1, 2 month schedule. The 0, 1, 7 month schedule did not improve the anticircumsporozoite antibody titres at 19 months or the efficacy of the vaccine compared with the 0, 1, 2 month schedule, as might have been anticipated with a long gap between vaccine doses.

Efficacy against clinical malaria was not a primary endpoint of this trial but a secondary analysis with more than 20% of the efficacy data gathered retrospectively. Furthermore, the open design raises the potential for observer bias. Hence, the results need to be treated with caution. However, the results of this follow-up study are very encouraging: they confirm the good safety profile of the vaccine and its immunogenicity when given with the EPI vaccines in infants, and they suggest that efficacy above 50% against all clinical episodes was maintained for 19 months.

The efficacy against severe malaria was not assessed in either of the two studies of infants, but by showing a 59% efficacy against all clinical episodes for a period longer than a year when given with EPI vaccines, the study by Asante and colleagues reinforces the hope that RTS,S will meet the criteria set for licensure of the first generation of malaria vaccines.

If the safety and efficacy results obtained in phase 2b studies are confirmed in the ongoing phase 3 study of nearly 16 000 children in 11 sites in sub-Saharan Africa, the vaccine will be approved by regulators and WHO for use along with current malaria interventions and will save hundreds of thousands of lives. As the first results from the phase 3 trial are expected later this year, planning for how to make the vaccine available to children in sub-Saharan Africa should be underway.

We declare that we have no conflicts of interest.

References

1 WHO. World Malaria Report. http://libdoc.who.int/publications/2009/9789241563901_eng.pdf. (accessed June 27, 2011).

2 Cissé B, Sokhna C, Boulanger D, et al. Seasonal intermittent preventive treatment with artesunate and sulfadoxine-pyrimethamine for prevention of malaria in Senegalese children: a randomised, placebo-controlled, double-blind trial. Lancet 2006; 367: 659-667. Summary | Full Text | PDF(136KB) | CrossRef | PubMed

3 Dicko A, Sagara I, Sissoko MS, et al. Impact of intermittent preventive treatment with sulphadoxine-pyrimethamine targeting the transmission season on the incidence of clinical malaria in children in Mali. Malar J 2008; 7: 123. CrossRef | PubMed

4 Kweku M, Liu D, Adjuik M, et al. Seasonal intermittent preventive treatment for the prevention of anaemia and malaria in Ghanaian children: a randomized, placebo controlled trial. PLoS One 2008; 3: e4000. CrossRef | PubMed

5 Dicko A, Diallo AI, Tembine I, et al. Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Mali: a randomised, double-blind, placebo-controlled trial. PLoS Med 2011; 8: e1000407. CrossRef | PubMed

6 Konaté AT, Yaro JB, Ouédraogo ZA, et al. Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide treated bednet in Burkina Faso: a randomized, double blind, placebo-controlled trial. PLoS Med 2011; 8: e10004008. PubMed

7 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. Summary | Full Text | PDF(118KB) | CrossRef | PubMed

8 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. Summary | Full Text | PDF(119KB) | CrossRef | PubMed

9 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. CrossRef | PubMed

10 Abdulla S, Oberholzer R, Juma O, et al. Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N Engl J Med 2008; 359: 2599-2601. CrossRef | PubMed

11 Agnandji ST, Asante KP, Lyimo J, et al. Evaluation of the safety and immunogenicity of the RTS,S/AS01E malaria candidate vaccine when integrated in the Expanded Program of Immunization. J Infect Dis 2010; 202: 1076-1087. CrossRef | PubMed

12 Asante KP, Abdulla S, Agnandji S, et al. Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial. Lancet Infect Dis 201110.1016/S1473-3099(11)70100-1. published online July 21. PubMed

a Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Medicine, Pharmacy and Dentistry, University of Bamako, PO Box 1805, Point G, Bamako, Mali

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