Malaria Vaccines: Where Next?

Abstract

A malaria vaccine for mass immuniza-tion, which could be delivered cheaply andwidely and provide long lasting protection,would have a massive effect on globalpublic health. However, such a vaccinedoes not currently exist. The reduction inglobal malaria incidence, in part due tothe ongoing introduction of mosquitocontrol measures such as insecticide-treat-ed nets and disease treatment with arte-mesinin combination drug therapy, raisesthe performance requirements for a futurevaccine, since the cost may be high relativeto that of other interventions and the scaleof the disease burden. Nevertheless, histo-ry teaches that complacency and an over-reliance on a small number of tools tocombat this disease are dangerous. Thereis therefore still a pressing need for avaccine to complement other control andpotential elimination tools. The big ques-tion is whether or not a malaria vaccinethat fulfills the above criteria can bedeveloped.RTS,S, the first malaria vaccine thattargets the so-called pre-erythrocytic stagesin humans, has just started in Phase 3 trials[1]; this is a major achievement based onnumerous trials (most recent trials in [2,3])and 40 years of research (reviewed in [4]).Although questions persist about whetherthis vaccine will be effective enough [5]and about the nature of the protectivemechanisms, does this achievement signalthe end for research on new vaccines andthe basic parasite biology and host immu-nology that underpins vaccine research?Other malaria vaccine candidates thattarget the asexual blood stages are not soadvanced, and without improvement maynot live up to hopes and expectations[6,7]; is it therefore time to reassess thestrategy on which they were developed[8]? For example, instead of subunit orvectored vaccines, the potential use of liveor live and attenuated parasite vaccineshas been proposed [9,10] and is beingpursued (http://www.sanaria.com/). Nowthat the international community is striv-ing to eliminate malaria, maybe therequirements for a malaria vaccine arechanging. Perhaps now is the time for agreater effort to research and develop thenext generation of malaria vaccines. If thisis the time for reinvigoration, what moredo we need to know to develop malariavaccines?Current vaccines are based on a handfulof proteins, several of which were firstdescribed several decades ago and beforeanalysis of the Plasmodium falciparum ge-nome indicated that there are about 5,400protein-coding genes, some of which areexpressed in an exquisitely stage-specificmanner and others that are not. Are anyof these other proteins antigens that areworth considering for vaccine develop-ment? It is unlikely that the level ofresources devoted to the circumsporozoitesurface protein (CSP) development thatled to RTS,S could be mustered to supportthe further development of any newantigen. If all new malaria vaccines needto be compared against RTS,S, this couldonly be done in an expensive clinical trialformat since alternative assays of efficacydo not exist. The cost and practicalities ofthis may inhibit vaccine-related researchand the development of next generationvaccines, because a company or public–private partnership may not be preparedto put in the resources to produce a newvaccine. We must, therefore, ask wherelimited resources are best placed; vaccinediscovery and development are bothexpensive. We have to take rationalapproaches; it’s the best we can do, andresources are not available for purelyempirical approaches. We need to en-hance efforts on basic science in combi-nation with clinical studies to provide astrong rationale for further vaccine devel-opment. This will need to be an integratedrather than a compartmentalized ap-proach; vaccine development from antigendiscovery to clinical trial is not a linearprocess. For example, clinical samplescollected as part of a vaccine evaluationtrial are essential for the development ofbetter and more appropriate methods andassays to understand relevant humanimmune responses.