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n e w e ng l a n d j o u r na l


m e dic i n e

edi t or i a l

A Vaccine for Malaria

Nicholas J. White, F.R.S. Its been a long time coming, and indeed we are still not there yet, but it is becoming increasingly clear that we really do have the first effective vaccine against a parasitic disease in humans. If there are no unforeseen disasters, the RTS,S/AS01 Plas modium falciparum malaria vaccine should become available in just over 3 years. The World Health Organization (WHO) has already taken the unusual step of indicating that it could recommend this first malaria vaccine for use in some African countries as early as 2015, depending on the full phase 3 trial results that will become available in 2014.1 The vaccine has been developed by a public private partnership between GlaxoSmithKline and the Program for Appropriate Technology in Health (PATH) Malaria Vaccine Initiative, supported by the Bill and Melinda Gates Foundation, primarily for use in infants and young children in sub-Saharan Africa. RTS,S/AS01 is a hybrid construct of the hepatitis B surface antigen fused with a recombinant antigen derived from part of the circumsporozoite protein. This is the protein coat of the sporozoite, the parasite stage that is inoculated by the feeding anopheline mosquito, which then invades liver cells and multiplies there before entering the bloodstream. Keys to the success of the vaccine are the immunogenic polymeric nature of RTS,S particles and the proprietary adjuvant AS01. A large number of other potential malaria vaccines are in various stages of development, but the RTS,S/AS01 vaccine is considerably further along the path to registration and potential deployment than the others. In this issue of the Journal, the RTS,S Clinical Trials Partnership provides an interim report of a large, multicenter phase 3 trial of this vaccine.2 A total of 15,460 children in two age categories 6 to 12 weeks and 5 to 17 months were enrolled. The report describes vaccine efficacy against P. falciparum malaria in the first 6000 of 8923 children in the older age category, together with an evaluation of the first 250 cases of severe malaria from the two age groups. It is not usual practice to publish the results of trials in pieces, and there does not seem to be a clear scientific reason why this trial has been reported with less than half the efficacy results available. The target population for this vaccine is young infants who would receive the malaria vaccine together with routine immunizations, but the critical efficacy results in this subgroup will not be reported for another year. Even then, only results on short-term efficacy will be available, findings that will be insufficient to assess the public health role of this vaccine. The interim results are broadly in line with those reported previously in extended phase 2 studies.3-5 Protective efficacy against P. falciparum malaria (55% protection against all malaria episodes) was at the upper end of expectations from earlier studies, whereas the overall reduction in severe malaria (35% protection) was slightly less than anticipated. Trials often throw up unexpected findings. In this trial, there were significantly more cases of meningitis among children receiving the RTS,S/AS01 vaccine than among those receiving the comparator vaccines. There seems to be no plausible explanation for this, and it may well turn out to be a chance finding, but it cannot be ignored. On the other hand, the increased risk of febrile reactions or seizures among RTS,S/AS01 recipients may be real, reflecting the reactogenicity of this highly immunogenic vaccine. Such questions highlight the importance of phase 4 studies of both safety


The New England Journal of Medicine Downloaded from on October 18, 2011. For personal use only. No other uses without permission. From the NEJM Archive. Copyright 2010 Massachusetts Medical Society. All rights reserved.


and effectiveness with active surveillance if this vaccine is deployed. What does this vaccine mean for the future of the control and elimination of malaria? The considerable increase in global funding is paying dividends. In places where effective interventions (insecticide-treated bed nets, insecticides, and artemisinin-combination treatments) are being intensively deployed, malaria morbidity and mortality are falling. Several new, simple, affordable interventions, such as seasonal chemoprevention among young children in areas of seasonally high malaria transmission and the use of artesunate in patients with severe malaria, can also provide substantial reductions in mortality. The very low rate of death from malaria in this large trial (only 10 deaths directly attributed to malaria) testifies to the benefits of providing early diagnosis and effective antimalarial treatment. But there are real dangers ahead. How will the necessary funding be sustained in the face of a global economic downturn, along with a reduction in political pressure associated with declining mortality from malaria? In addition, artemisinin resistance in malaria parasites and pyrethroid resistance in anopheline mosquito vectors pose very serious threats. All the investigators who have labored long and hard in the development and evaluation of this malaria vaccine deserve congratulations. It is a great achievement and an important advance, but they know that this partially protective vaccine is not the sole solution to the control and elimination of malaria. After registration, the definitive WHO guidance, expected in 2015, may

recommend that the inclusion of RTS,S/AS01 in the multipronged attack against malaria is justified. The key question of how long the protection against malaria lasts, particularly in the anticipated context of declining malaria transmission, remains open. An assessment of an 18-month booster dose will not be available until 2014. Another key issue is whether efficacy varies according to the intensity of transmission. We also do not know yet how much the vaccine will cost. All these factors are essential components of the objective assessments of cost-effectiveness that should form the basis of future global and national policy decisions.
Disclosure forms provided by the author are available with the full text of this article at From the Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. This article (10.1056/NEJMe1111777) was published on October 18, 2011, at
1. World Health Organization. Malaria. Initiative for vaccine re-

search (IVR) ( index.html). 2. The RTS,S Clinical Trials Partnership. First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. N Engl J Med 2011. DOI: 10.1056/NEJMoa1102287. 3. 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;359:2521-32. 4. Asante KP, Abdulla S, Agnandji S, et al. Safety and efficacy of the RTS,S/AS01(E) candidate malaria vaccine given with expandedprogramme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial. Lancet Infect Dis 2011; 11:741-9. 5. Olotu A, Lusingu J, Leach A, et al. Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania: a randomised controlled trial. Lancet Infect Dis 2011;11:102-9.
Copyright 2011 Massachusetts Medical Society.


The New England Journal of Medicine Downloaded from on October 18, 2011. For personal use only. No other uses without permission. From the NEJM Archive. Copyright 2010 Massachusetts Medical Society. All rights reserved.