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n engl j med 359;24 www.nejm.org december 11, 2008 2521

Thenew englandjournalofmedicineestablished in 1812 december 11, 2008 vol. 359 no. 24

Efficacy of RTS,S/AS01E Vaccine against Malariain Children 5 to 17 Months of Age

Philip Bejon, Ph.D., John Lusingu, Ph.D., Ally Olotu, M.B., Ch.B., Amanda Leach, M.R.C.P.C.H., Marc Lievens, M.Sc.,Johan Vekemans, Ph.D., Salum Mshamu, M.D., Trudie Lang, Ph.D., Jayne Gould, Ph.D., Marie-Claude Dubois, M.Sc.,

Marie-Ange Demoiti, M.Sc., Jean-Francois Stallaert, B.Sc., Preeti Vansadia, M.H.S., Terrell Carter, M.H.S.,Patricia Njuguna, M.D., Ken O. Awuondo, H.N.D., Anangisye Malabeja, M.D., Omar Abdul, M.D., Samwel Gesase, M.D.,Neema Mturi, M.R.C.Paed., Chris J. Drakeley, Ph.D., Barbara Savarese, R.N., Tonya Villafana, Ph.D., W. Ripley Ballou, M.D.,

Joe Cohen, Ph.D., Eleanor M. Riley, Ph.D., Martha M. Lemnge, Ph.D., Kevin Marsh, F.R.C.P., and Lorenz von Seidlein, Ph.D.

Ab s t r ac t

From the Centre for Geographic Medi-cine Research (Coast), Kenya Medical Re-search Institute, Kilifi, Kenya (P.B., A.O.,T.L., P.N., K.O.A., N.M., K .M.); the Centrefor Clinical Vaccinology and Tropical Med-icine, Nuffield Department of Medicine,University of Oxford, Oxford, United King-dom (P.B., K.M.); the National Institutefor Medical Research, Tanga Centre (J.L.,S.M., A.M., O.A., S.G., M.M.L.), and the

Joint Malaria Programme, Korogwe ( J.L.,S.M., J.G., A.M., O.A., S.G., C.J.D., E.M.R.,M.M.L., L.S.) both in Tanzania; Centrefor Medical Parasitology, University ofCopenhagen, Denmark (J.L.); Glaxo-SmithKline Biologicals, Rixensart, Belgium(A.L., M.L., J.V., M.-C.D., M.-A.D., J.-F.S.,W.R.B., J.C.); the London School of Hy-giene and Tropical Medicine, London (J.G.,C.J.D., E.M.R., L.S.); Program for Appro-priate Technology in Health (PATH) Ma-laria Vaccine Initiative, Bethesda, MD (P.V.,T.C., B.S., T.V.); the International VaccineInstitute, Seoul, Korea (L.S.); and theMahidol Oxford Research Unit, Bangkok,Thailand (L.S.). Address reprint requests

to Dr. Bejon at KEMRI, P.O. Box 230,Mombasa, Kenya, or at [email protected].

This article (10.1056/NEJMoa0807381) waspublished on December 8, 2008, and up-dated on October 27, 2010, at NEJM.org.

N Engl J Med 2008;359:2521-32.Copyright 2008 Massachusetts Medical Society.

Background

Plasmodium falciparummalaria is a pressing global health problem. A previous studyof the malaria vaccine RTS,S (which targets the circumsporozoite protein), givenwith an adjuvant system (AS02A), showed a 30% rate of protection against clinicalmalaria in children 1 to 4 years of age. We evaluated the efficacy of RTS,S givenwith a more immunogenic adjuvant system (AS01E) in children 5 to 17 months of age,a target population for vaccine licensure.

Methods

We conducted a double-blind, randomized trial of RTS,S/AS01E vaccine as com-pared with rabies vaccine in children in Kilifi, Kenya, and Korogwe, Tanzania. Theprimary end point was fever with a falciparum parasitemia density of more than2500 parasites per microliter, and the mean duration of follow-up was 7.9 months(range, 4.5 to 10.5).

Results

A total of 894 children were randomly assigned to receive the RTS,S/AS01E vaccineor the control (rabies) vaccine. Among the 809 children who completed the study pro-cedures according to the protocol, the cumulative number in whom clinical malariadeveloped was 32 of 402 assigned to receive RTS,S/AS01E and 66 of 407 assigned toreceive the rabies vaccine; the adjusted efficacy rate for RTS,S/AS01E was 53% (95%confidence interval [CI], 28 to 69; P

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n engl j med 359;24 www.nejm.org december 11, 20082522

Worldwide, the mortality and

morbidity associated with Plasmodiumfalciparummalaria are high.1-3Progress

has been made in controlling malaria by intro-ducing insecticide-treated nets4and highly effec-tive artemisinin-based combination treatments.5There is evidence that the incidence of malaria is

falling in some areas.6-10These advances have re-newed interest in the prospects for the control ofmalaria and even its elimination in areas in whichP. falciparumwas previously endemic.11A safe andaffordable vaccine providing protection againstmalaria would be an important addition to con-trol strategies and should be assessed in the con-text of the use of insecticide-treated nets and theavailability of artemisinin-based combinationtreatments.

The candidate pre-erythrocytic malaria vaccineRTS,S targets the circumsporozoite protein and

has been evaluated in combination with two dif-ferent adjuvant systems: AS01 and AS02. Clinicaldevelopment of RTS,S in field trials began withthe AS02 adjuvant system. Preliminary estimatesof rates of efficacy against infection after curativeantimalarial treatment were 34% (95% confidenceinterval [CI], 8 to 53) in adults12and 66% (95%CI, 43 to 80) in infants.13The rate of efficacyagainst the more clinically relevant end point ofclinical malaria in children 1 to 4 years of agewas 30% (95% CI, 11 to 45).14

Planning is now under way for a multicenterphase 3 trial. However, since preliminary data sug-gested better immunogenicity with the AS01 ad-juvant,15-17there was a need to evaluate RTS,S ad-ministered with the AS01 adjuvant system beforeselecting the vaccine formulation for phase 3. Weevaluated the efficacy of RTS,S/AS01E against clin-ical malaria in children 5 to 17 months of age.

Methods

Study Design

The study was randomized, controlled, and dou-ble-blind and was prospectively registered atClinicalTrials.gov. Approval was obtained fromthe Kenyan Medical Research Institute NationalEthics Committee, the Tanzanian Medical Re-search Coordinating Committee, the Central Ox-ford Research Ethics Committee, the LondonSchool of Hygiene and Tropical Medicine Ethics

Committee, and the Western Institutional Review

Board in Seattle. An independent data and safetymonitoring board and local safety monitors wereappointed. The study was conducted in accordancewith the Helsinki Declaration of 1964 (revised in1996) and according to Good Clinical Practiceguidelines.

GlaxoSmithKline Biologicals was the studysponsor. The database was managed by the spon-sor and was opened to the principal investigatorsat the time of unblinding. Analysis was per-formed in parallel by an industry author who isan employee of the sponsor and an academic au-thor. Two academic authors and the industryauthor vouch for the data and analysis. The firstdraft of the manuscript was written by an aca-demic author, who subsequently implemented re-visions from all the authors after their review.

GlaxoSmithKline and both study sites (Kilifi,Kenya, and Korogwe, Tanzania) received fundingto undertake the work described in this reportfrom the Program for Appropriate Technology inHealth (PATH) Malaria Vaccine Initiative (MVI),which was involved in all aspects of the study

design. Permission to submit the manuscript forpublication was given by the directors of theKenya Medical Research Institute and the Nation-al Institute for Medical Research of Tanzania.More details of the investigators and sponsorsroles in the study are given in the SupplementaryAppendix, available with the full text of this articleat www.nejm.org.

Figure 1 (facing page).Screening, Randomization,and Follow-up of Study Participants.

The 177 children who were deemed ineligible at screen-ing had an age outside the acceptable range (67 children),

an acute disease at enrollment (23), a serious illness

on clinical screening (42), a laboratory result outsidethe acceptable limit (28), or another reason for ineligi-

bility: a parent or guardian who was judged by the in-vestigator to be unable to give consent, an inability to

follow the protocol, a planned administration of anothervaccination, or the use of blood products in the previ-

ous 3 months (17). The other reasons for ineligibilityor withdrawal from the study were enrollment in other

clinical trials (for the eight children excluded at screen-ing only), missed vaccinations because of hospital ad-

mission, contraindications to further vaccination, med-ical conditions not permitted according to the protocol,

and unavailability of documentation about concomitant

vaccination.

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RTS,S/AS01E Vaccine against Malaria in Children


894 Underwent randomization

1162 Children were assessed for e ligibility

177 Were ineligible57 Withdrew consent11 Were lost to follow-up15 Left study area

8 Had other reason for exclusion

447 Were assigned to receiveRTS,S/AS01E vaccine

447 Were assigned to receivecontrol (rabies vaccine)

2 Withdrew consent5 Left study area1 Had other reason

for withdrawal


for withdrawal

439 Received second dose 438 Received second dose

447 Received first dose 447 Received first dose

1 Withdrew consent4 Left study area


for withdrawal

434 Received third dose 433 Received third dose

3 Were lost to follow-up4 Were noncompliant

with dosing intervals12 Had other reason

for withdrawal

2 Were lost to follow-up3 Were noncompliant

with dosing intervals8 Had other reason

for withdrawal

415 Were included in theaccording-to-protocol cohort

420 Were included in theaccording-to-protocol cohort

13 Had missing covariates13 Had missing covariates

402 Underwent according-to-protocol analysis

407 Underwent according-to-protocol analysis

447 Were includedin intention-to-treat analysis

447 Were includedin intention-to-treat analysis

l

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blinded on August 4, 2008, after discussion amongthe investigators, sponsors, regulatory authorities,and data and safety monitoring board.

An analysis plan was agreed on by the dataand safety monitoring board, sponsor, and inves-tigators before the unblinding. The primary analy-sis was an estimate of the hazard ratio for the

first or only episode of malaria involving feverand a parasite density above 2500 per microliter(the primary end point) for the group that re-ceived the RTS,S/AS01E vaccine as compared withthe control group in the according-to-protocolcohort. Secondary analyses included episodes ofmalaria involving any parasitemia density withfever (a secondary end point) in the according-to-protocol cohort, as well as cases qualif ying asprimary and secondary end points in the inten-tion-to-treat cohort (i.e., all children randomlyassigned to receive vaccinations) and multiple epi-

sodes of malaria (analyzed by means of Poissonregression). The period for the according-to-protocol analysis was 2 weeks after the last vac-cination until the f inal blood test. The period forthe intention-to-treat analysis was the time fromthe first vaccination until the final blood test.More details are given in the Supplementary Ap-pendix.

The effect of anticircumsporozoite antibodieson the risk of clinical malaria was examined withthe use of titers measured 1 month after thethird dose. Log-transformed titers (with undetect-able levels scored as a value that was half thelower limit of detection) were used as a continu-ous variable in an adjusted Cox regression analy-sis for the children receiving the RTS,S/AS01Evaccine.

Safety data are presented for the intention-to-treat cohort, and efficacy data are presented forboth the according-to-protocol cohort and theintention-to-treat cohort. Data were analyzed fromthe time of the first vaccination until the time ofthe final blood test for efficacy, but all the avail-

able safety data up to August 4, 2008 (the timeof unblinding), were analyzed. Serious adverseevents are described with the use of the pre-ferred terms from the Medical Dictionary forRegulatory Activities (MedDRA).18

Results

A total of 1162 children were screened; 894 wererandomly assigned to a study group and receivedat least one vaccination, and data for 809 were

included in the according-to-protocol analysis ofeff icacy (Fig. 1). The demographic characteristicsof the participants were balanced between thetwo vaccine groups (Table 1).

Efficacy

In the according-to-protocol analysis (of dataover a mean of 8 months of follow-up, beginning2 weeks after the f inal vaccination), the cumula-tive incidence of the first or only malarial epi-sode, as defined for the primary end point, was8% (32 of 402 subjects) in the group that receivedthe RTS,S/AS01E vaccine, as compared with 16%(66 of 407 subjects) in the group that received therabies vaccine. Cox regression provided an adjust-ed efficacy of 53% (95% CI, 28 to 69; P

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and an unadjusted efficacy of 55% (95% CI, 31 to70; P

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Table2.EfficacyoftheRTS,S/AS01EVaccineagainstEpisodesofClinicalM

alaria.*

Episode

RTS,S/AS01EVaccine

RabiesVaccine

AdjustedEfficacy

UnadjustedEfficacy

No.of

Subjects

No.of

Episodes

Person-Yr

atRisk

Ev

ent

Rate

No.of

Subjects

No.of

Episodes

Person-Yr

atRisk

Event

Rate

%(

95%

CI)

PValue

%(

95%

CI)

PValue

According-to-protocolanalysis

Firstoronlyepisode

>2500parasites/l

402

32

245

0.1

3

407

66

239

0.2

8

53(2869)

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