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n engl j med 365;20 nejm.org november 17, 20111926

T h e  n e w e n g l a n d j o u r n a l o f   medicine

A Vaccine for MalariaNicholas J. White, F.R.S.

It’s been a long time coming, and indeed we arestill not there yet, but it is becoming increasingly clear that we really do have the first effective vac-cine against a parasitic disease in humans. If thereare no unforeseen disasters, the RTS,S/AS01 Plas-

modium falciparum malaria vaccine should becomeavailable in just over 3 years. The World HealthOrganization (WHO) has already taken the un-usual step of indicating that it could recommendthis f irst malaria vaccine for use in some Africancountries as early as 2015, depending on the fullphase 3 trial results that will become available in2014.1 The vaccine has been developed by a public–private partnership between GlaxoSmithKline andthe Program for Appropriate Technology in Health(PATH) Malaria Vaccine Initiative, supported by theBill and Melinda Gates Foundation, primarily foruse in infants and young children in sub-SaharanAfrica. RTS,S/AS01 is a hybrid construct of thehepatitis B surface antigen fused with a recom-binant antigen derived from part of the circum-sporozoite protein. This is the protein coat of thesporozoite, the parasite stage that is inoculatedby the feeding anopheline mosquito, which theninvades liver cells and multiplies there before en-tering 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 vac-cines are in various stages of development, but the RTS,S/AS01 vaccine is considerably furtheralong the path to registration and potential de-ployment than the others.

In this issue of the  Journal, the RTS,S Clini-cal Trials Partnership provides an interim re-port of a large, multicenter phase 3 trial of this vaccine.2 A total of 15,460 children in two agecategories — 6 to 12 weeks and 5 to 17 months

— were enrolled. The report describes vaccine ef-ficacy against P. falciparum malaria in the first 6000of 8923 children in the older age category, together with an evaluation of the first 250 cases of severemalaria 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 scientificreason why this trial has been reported with lessthan half the efficacy results available. The target population for this vaccine is young infants who would receive the malaria vaccine together withroutine immunizations, but the critical efficacy results in this subgroup will not be reported foranother year. Even then, only results on short-termefficacy will be available, findings that will beinsufficient to assess the public health role of this vaccine.

The interim results are broadly in line withthose reported previously in extended phase 2studies.3-5 Protective efficacy against P. falciparum malaria (55% protection against all malaria epi-sodes) was at the upper end of expectations fromearlier studies, whereas the overall reduction insevere malaria (35% protection) was slightly lessthan anticipated.

Trials often throw up unexpected findings.In this trial, there were signif icantly more cas-es of meningitis among children receiving the

RTS,S/AS01 vaccine than among those receiv-ing the comparator vaccines. There seems tobe 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, theincreased risk of febrile reactions or seizuresamong RTS,S/AS01 recipients may be real, re-flecting the reactogenicity of this highly im-munogenic vaccine. Such questions highlight the importance of phase 4 studies of both safety 

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and effectiveness with active surveillance if this vaccine is deployed.

What does this vaccine mean for the futureof the control and elimination of malaria? Theconsiderable increase in global funding is payingdividends. In places where effective interven-tions (insecticide-treated bed nets, insecticides, and

artemisinin-combination treatments) are being in-tensively deployed, malaria morbidity and mortal-ity are falling. Several new, simple, affordable in-terventions, such as seasonal chemopreventionamong young children in areas of seasonally high malaria transmission and the use of artesu-nate in patients with severe malaria, can also pro- vide 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 diagno-sis and effective antimalarial treatment. But there

are real dangers ahead. How will the necessary funding be sustained in the face of a global eco-nomic downturn, along with a reduction in politi-cal pressure associated with declining mortality from malaria? In addition, artemisinin resistancein malaria parasites and pyrethroid resistancein anopheline mosquito vectors pose very seriousthreats.

All the investigators who have labored longand hard in the development and evaluation of this malaria vaccine deserve congratulations. It isa great achievement and an important advance,but they know that this partially protective vac-cine is not the sole solution to the control andelimination of malaria. After registration, the de-finitive WHO guidance, expected in 2015, may 

recommend that the inclusion of RTS,S/AS01 inthe multipronged attack against malaria is justi-fied. The key question of how long the protectionagainst malaria lasts, particularly in the antici-pated context of declining malaria transmission,remains open. An assessment of an 18-monthbooster dose will not be available until 2014.

Another key issue is whether efficacy varies ac-cording to the intensity of transmission. We alsodo not know yet how much the vaccine will cost.All these factors are essential components of theobjective assessments of cost-effectiveness that should form the basis of future global and na-tional policy decisions.

Disclosure forms provided by the author are available with thefull text of this article at NEJM.org.

From the Faculty of Tropical Medicine, Mahidol University,Bangkok, Thailand.

This article (10.1056/NEJMe1111777) was published on Octo-

ber 18, 2011, at NEJM.org.

1. Malaria: initiative for vaccine research (IVR). Geneva: WorldHealth Organization (http://www.who.int/vaccine_research/Malaria/en/index.html).2. The RTS,S Clinical Trials Partnership. First results of phase 3 tr ial of RTS,S/AS01 malaria vaccine in African children.N Engl J Med 2011;365:1863-75.3. 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 eff icacy of the RTS,S/AS01(E) candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 tria l. Lancet Infect Dis 2011;11:741-9.

5. Olotu A, Lusingu J, Leach A, et al. Efficacy of RTS,S/AS01Emalaria vaccine and exploratory analysis on anti-circumsporozo-ite antibody titres and protection in children aged 5-17 monthsin Kenya and Tanzania: a randomised controlled trial. Lancet Infect Dis 2011;11:102-9.Copyright © 2011 Massachusetts Medical Society.

Childhood Obesity and Coronary Heart DiseaseAlbert P. Rocchini, M.D.

Obesity is the most common nutritional problem

among children in both developed and under-developed countries. Despite efforts over the past decade to prevent and control obesity, data fromthe 2003–2006 National Health and Nutrition Ex-amination Surveys (NHANES) show that 16.3%of children and adolescents, 2 to 19 years of age,are obese (i.e., have a body-mass index [BMI] abovethe 95th percentile for age and sex).1

There is strong epidemiologic evidence that obesity in childhood is associated with an in-

creased incidence of atherosclerosis in adulthood.

Postmortem studies have shown that obesity inchildhood and adolescence is associated with in-creased evidence of atherosclerosis at autopsy, es-pecially in males.2 Epidemiologic studies involvingchildren have documented a strong associationbetween the major known atherosclerosis risk fac-tors (elevated blood pressure, dyslipidemia, in-flammatory markers, and insulin resistance) andchildhood obesity.3 Baker et al.,4 using data onchildhood BMI z scores and information from

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