Vasee S Moorthy, Michael F Good, Adrian V S Hill Large gains in the reduction of malaria mortality in the early 20th century were lost in subsequent decades. Malaria nowkills 2–3 million people yearly. Implementation of malaria control technologies such as insecticide-treated bednets andchemotherapy could reduce mortality substantially, but an effective malaria vaccine is also needed. Advances invaccine technology and immunology are being used to develop malaria subunit vaccines. Novel approaches that mightyield effective vaccines for other diseases are being evaluated first in malaria. We describe progress in malaria vaccinedevelopment in the past 5 years: reasons for cautious optimism, the type of vaccine that might realistically beexpected, and how the process could be hastened. Although exact predictions are not possible, if sufficient fundingwere mobilised, a deployable, effective malaria vaccine is a realistic medium-term to long-term goal.
In 1955, a book entitled Man’s Mastery of Malaria1 We summarise the life cycle of malaria, describe the reflected the generally held views of that time. Half a differences between naturally acquired and vaccine century later, malaria kills 2–3 million people a year.2 Most induced immunity, discuss the relevance of the of these deaths are in children younger than 5 years living elucidation of the Plasmodium falciparum in sub-Saharan Africa; one African child dies from malaria sequence14 to vaccine development, and highlight some every 30 seconds.3 Rarely has scientific optimism been so vaccine candidates that have reached clinical evaluation. misplaced. With the advent of resistance to chloroquineand dichlorodiphenyltrichloroethane (DDT), malaria re- emerged in many parts of the world. In recent years, the Which statement speaks to your instinct: Plutarch’s burden of disease and death has increased substantially in “history repeats itself” or Robert Walpole’s “anything but malaria-endemic countries,4 and transmission has spread history, for history must be false”? Your answer could to new areas.5 The major causes of this resurgence are the determine your level of optimism in malaria vaccine development of resistance to affordable drugs6 and development. 1973 saw the first report of human protection from malaria by vaccination.15 However, the grammes,8 increasing human migration,9 and tourism.10 vaccination consisted of the bites of about a thousand The rise in malaria deaths contrasts with falls in all-cause mosquitoes infected with malaria parasites that had been mortality in children in many developing countries.11 Since X irradiated.16 This demonstration was obviously unlikely economic prospects for countries in which malaria is to be a practical means of mass vaccination. For about endemic are closely linked to the disease burden, a strong
20 years, progress occurred mainly in experimental economic and political case can be made for increasing models rather than in human vaccine trials.17,18 Much speculation and excitement was generated by the Spf66 candidate vaccine, despite uncertainty about how such a coordinating improved case management, insecticide- construct could work. Eventually, phase III trials showed treated bednets, and other control measures for reduction that Spf66 lacked efficacy.19–23 During the past 5 years, of malaria mortality. Malaria drug development is a many candidate vaccine approaches have been tested in research priority. Vaccine development is only one aspect clinical trials (table).24 Many potential candidate vaccines of efforts to control malaria, but an effective vaccine should transform prospects for reducing the burden of thisdisease. There are three intermediate goals of vaccine The life cycle of P falciparum
research: induction of strong, strain-transcending, durable A female anopheline mosquito requires a blood meal for immune responses;13 identification of protective antigens egg production (figure 1). During such a meal, a mosquito for stage-specific immunity; and successful combination of candidate immunogens. Worldwide funding for malaria 20 sporozoites,25,26 which invade hepatocytes within vaccines has increased recently from below US$50 million minutes. Sporozoites migrate through several hepatocytes to around $60–70 million, but remains an order of before entering one; this is the start of the liver stage.27,28 magnitude below that for HIV vaccine development.
The sporozoite and liver stages are the pre-erythrocytic Nonetheless, substantial advances have been made in parts of the life cycle. Over an average of 6·5 days, We searched PubMed using the phrase “malaria and vaccine”with a limit for clinical trials. We also searched for papers that MRC Laboratories, Banjul, The Gambia (V S Moorthy MRCP); Nuffield detailed antigen characterisation or vaccine platform Department of Clinical Medicine, University of Oxford, John evaluation by use of in-vitro assays and animal models. The Radcliffe Hospital, Oxford, UK (V S Moorthy, Prof A V S Hill DM); phrase for the second search was “malaria vaccines[MeSH]”.
The Cooperative Research Centre for Vaccine Technology, We reviewed all abstracts and selected relevant articles. We Queensland Institute of Medical Research, Brisbane, Australia (Prof M F Good also identified relevant articles from the reference lists in articles from these two searches. Searches were done in Correspondence to: Dr Vasee S Moorthy, Malaria Vaccine Initiative, November, 2002, and May, 2003. We did not restrict the 6290 Montrose Road, Rockville, MD 20852, USA THE LANCET • Vol 363 • January 10, 2004 • For personal use. Only reproduce with permission from The Lancet.
GlaxoSmithKline Biologicals, Belgium; and WRAIR, USA (Medical Research Council [MRC] Laboratories, The Gambia; Centro de Investigacao em Saude de Manhica [CISM], Mozambique)Malaria Vaccine Development Unit, National Institutes Of Health, USA Naval Medical Research Center (NMRC), USA; Vical, USA Oxford University, UK (MRC Laboratories, The Gambia; Wellcome-Kenya Medical Research Institute [KEMRI] collaboration, Kilifi, Kenya) FP9 ME-TRAP, MVA-CS (DNA and recombinant viral) Statens Serum Institut (SSI), Copenhagen; Institut Pasteur; Institute of Lausanne, Switzerland Walter and Eliza Hall Institute of Medical Research, Melbourne; Queensland Institute of Medical MSP-1, MSP-2, RESA (protein) Research (QIMR), Brisbane; Swiss Tropical Institute; Biotech Australia Pty (Papua New Guinea Institute Of Medical Research)Walter Reed Army Institute of Research (WRAIR), USA (KEMRI, Kisumu, Kenya) EXP=exported protein. LSA=liver stage antigen. MAP=multiple antigen peptide. Pvs=Plasmodium vivax surface protein. AMA-1=apical membrane antigen-1. RESA=ringinfected erythrocyte surface antigen. SSP2 and TRAP are synonyms: sporozoite surface protein 2 and thrombospondin-related adhesion protein. Only vaccines beingtested in clinical trials as of May, 2003, are listed. Field collaborations are only listed if field trials of the candidate had begun as of May, 2003.
Candidate malaria vaccines in clinical trials parasites develop within the liver into schizonts. The erythrocyte, and starts a 48-h cycle of replication.
schizonts rupture, releasing 20 000–30 000 merozoites Replication is followed by schizont rupture and invasion per original sporozoite into the hepatic venous circulation, of new red blood cells—the blood stage of malaria. The from where they disseminate systemically. Each merozoite blood stage culminates either in death of the human host that is not picked up by phagocytic cells invades an or control by the immune system. Some merozoites differentiate into male or femalegametocytes, which can be ingestedby an anopheline mosquito.
mosquito midgut, leading tocompletion of the life cycle, withsporozoites migrating to the salivaryglands, and becoming infective.
Gametocytes are ingestedwhen mosquito takes killed inactivated vaccines is notpractical for many diseases. In subunitvaccination, part or complete antigensare identified from a pathogen’s induce protective immunity to thewhole pathogen on vaccination. Thehepatitis B vaccine is an effectiverecombinant protein subunit vaccine.29This vaccine was designed to induce the maximum antibody (humoral)immune response. in their immunogenicity. Moreover,induced antibodies must have thecorrect avidity (ability to bind), adjuvants, and their effects on innateimmunity, genetic engineering tech- niques, and novel delivery systems are gradually increasing antibody Targets: 1 (sporozoites)=RTS,S, ICC-1132, NYU CS, Lausanne CS; 2 (liver stage)=DNA and viral vectors (NMRC, Vical, and Oxford), ?RTS,S, ?Lausanne CS; 3 (blood stages)=MSP1, MSP2, RESA, MSP3, GLURP, FMP1, AMA-1; 4 (sexual stages)=Pvs25. The ? in front of RTS,S and Lausanne CS indicates that these vaccines might also partly act against the liver stage as well as againstsporozoites. THE LANCET • Vol 363 • January 10, 2004 • For personal use. Only reproduce with permission from The Lancet.
elimination of intracellular pathogens such as liver-stage The ideal vaccine for this stage would induce high titres of The newest generation of subunit vaccines are DNA functional antibodies against sporozoites to prevent all based.30,31 DNA sequences from P falciparum parasites parasites entering the liver stage, and induce potent have been inserted into plasmid DNA molecules (DNA cytotoxic T-lymphocyte immunogenicity against the liver vaccines) or various recombinant attenuated DNA stage to kill infected hepatocytes, while not harming the viruses (recombinant viral vaccines) to generate human host. The lead candidate vaccine of this type is candidate vaccines.32,33 DNA vaccines are taken up by RTS,S—a recombinant protein vaccine.46 Hepatitis B host cells, protein is expressed, and T-cell epitopes surface antigen DNA was fused to DNA encoding a large bound to HLA molecules prime naive T cells to form part of the best characterised pre-erythrocytic malaria memory T-cell populations.34 Recombinant viral vaccines antigen, the circumsporozoite (CS) protein.47,48 When work in a similar way, but actively infect cells and express expressed in yeast, the fusion product (RTS) binds the recombinant malaria proteins before aborting hepatitis B surface antigen (S) to form RTS,S particles.
infection.35 DNA and recombinant viral subunit vaccines These particles are mixed with an adjuvant, AS02—a can induce high levels of effector T-cell immune mixture of deacylated monophosphoryl lipid A, QS21, responses, although antibody responses have been poor and an emulsion—and given intramuscularly on two to three occasions. RTS,S vaccination induces high titre Assessment of T-cell responses has been revolutionised antibodies to CS and to hepatitis B, and gives 30–60% by the enzyme-linked immunospot (ELISPOT) assay and protection against parasites of the same strain as the the tetramer assay.37–39 ELISPOT is a highly sensitive vaccine in a sporozoite challenge model.49 In this model, means of quantitatively detecting functional antigen- vaccinees from developed countries (USA and Europe) specific T cells. Tetramer assays allow detailed are bitten by five mosquitoes infected with the 3D7 strain characterisation of antigen-specific T cells. These of P falciparum, which is sensitive to chloroquine.
advances in assays, together with those of subunit Volunteers are monitored closely by malaria blood smears vaccination in malaria, raise the possibility of identifying or PCR techniques, and treated promptly once blood robust antibody and T-cell immune correlates of protection or, in other words, of understanding how partly Proof of the efficacy of RTS,S/AS02 followed years of effective vaccines provide their level of protection. Such iterative development of CS-based vaccines—trials either an understanding should allow tailoring of vaccine design with no challenge component, or resulting in very limited around immune correlates of protection to systematically protection.51–58 Several adjuvants used with the RTS,S improve vaccine efficacy—a process dubbed iterative construct were far less protective than AS02. In a randomised controlled field trial of three-dose RTS,S inGambian adults, vaccine efficacy was 34% (p=0·014) during the 15-week surveillance period, but with 71% Natural exposure to P falciparum gradually elicits, in efficacy in the first 9 weeks and 0% in the next 6 weeks.59 human hosts, short-lived strain-specific malaria Protection was not strain-specific.60 Although the duration immunity: first to severe disease and death, and then to of efficacy was short, RTS,S is the first pre-erythrocytic mild disease.40 Repeated infections are required to vaccine to show clear protection against natural maintain immunity, which is both antibody and T-cell P falciparum infection. Development of RTS,S has been based, although evidence is most clear for antibody- accelerated by the Malaria Vaccine Initiative, which is mediated immunity to blood-stage malaria.41–43 Exactly funding an efficacy trial of RTS,S in children aged which of the 5300 antigens encoded by the P falciparum 1–4 years in Mozambique. Phase-I trials of varying doses parasite produces the key protective immune responses is of RTS,S in children aged 1–11 years have already been not known, although some evidence implicates about 20.
Immunity acquired in malaria-endemic areas is likely to Several other pre-erythrocytic candidates have reached be mediated by an integration of low to moderate the clinical evaluation stage: ICC-1132 is being tested in responses to many antigens. Immunity to one stage of the different formulations in the USA, Germany, and the UK.
parasite is restricted to that part of the life cycle; this ICC-1132 is a hepatitis B core particle, genetically complicates vaccine development—although sporozoite engineered to include a region of CS for high titre and liver-stage immunity overlap to some extent.
antibody induction. High titres of biologically active CS However, proteomics techniques have detected antigens antibody have been noted in preclinical studies,61 and thought to be specific to one stage of the life cycle to be Another approach is heterologous prime-boost The aim with most vaccines is to induce antibody and vaccination. Two different vaccine vectors encoding the T-cell responses to one or a few antigens, but for effective same antigen are given sequentially. Viral vectors can be vaccination these will need to be of greater magnitude, given first (priming) or second (boosting); DNA vaccines duration, and strain-transcendence than in naturally are efficient priming vaccines but do not boost acquired immunity. Antigenic variation occurs in some efficiently.62 Three carriers have been clinically tested: important blood-stage malaria antigens, and there is a DNA; modified vaccinia virus Ankara (MVA); and possibility that vaccination could select for escape attenuated poxvirus FP9, once used to vaccinate chickens mutants, but this is less of a concern than with viruses against fowlpox.24 The insert includes thrombospondin- such as HIV-1. T-cell responses have been neglected, in related adhesive protein (TRAP), a well characterised pre- particular for blood-stage vaccine development; which erythrocytic antigen, and a string of T-cell epitopes (called responses are necessary is little known or understood, ME for multiple epitope); these ME-TRAP vaccines are except for the need to produce T-cell help for an antibody given in prime-boost sequence—ie, DNA then MVA, or response. An alternative, ambitious, long-term approach FP9 then MVA.63,64 This approach has induced high is to use a cocktail of many antigens to attempt to mimic T-cell responses and some protection, manifest by a natural immunity, but this could lead to a complex and substantial delay to parasitaemia in sporozoite challenge studies.65 A randomised controlled trial of the efficacy of THE LANCET • Vol 363 • January 10, 2004 • For personal use. Only reproduce with permission from The Lancet.
DNA and ME-TRAP followed by MVA and ME-TRAP Another approach to blood-stage vaccine design has has been completed in The Gambia with 372 adult been suggested by the demonstration that vaccine induced volunteers. MVA encoding the CS protein and given before T-cell responses to blood-stage antigens can be protective or after RTS,S is being assessed in phase I and IIa studies in in animal models, and by the finding that human volunteers can be protected against infection by Intense efforts have been made to develop effective immunisation with low doses of blood-stage parasites that DNA-based vaccines to the liver stage and blood stages.
do not induce detectable antibodies.77,78 Development of Various DNA vaccines, each encoding a pre-erythrocytic blood-stage challenge models, and the increasing antigen, have undergone phase-I studies.45,66 A mixture of availability of new antigens, should lead to a growing five pre-erythrocytic DNA vaccines has been administered number of clinical studies of blood-stage candidate in phase-I studies, but no evidence of protection was noted in sporozoite challenge tests. DNA vaccines require viral Sequestration of P falciparum by adherence to vascular boosting to induce strong T-cell immunogenicity in endothelial cells in the brain, kidneys, and placenta is an macaques as well as in human beings; antibody induction in important cause of severe malaria. The PfEMP-1 human beings is generally very low after DNA vaccination, antigen (erythrocyte membrane protein-1), the main by contrast with some animal models.32,65,67,68 ligand for such adherence, is being researched as a Other CS-based candidate vaccines that have been tested vaccine candidate. However, its high degree of in phase-I studies include a multiple antigen peptide, a type variability, rapid rate of antigenic variation, and high of synthetic delivery system, which induced strong antibody copy number within each parasite complicate vaccine responses; a polyoxime construct, containing a universal T- development, although some researchers think that use cell epitope; and a long synthetic peptide in an oil-based of a conserved part of the antigen could be a promising adjuvant, which induced detectable antibody and CD4+ approach. At schizont rupture, inflammatory mediators and CD8+ T-cell responses with a good safety profile.69–71 are released, leading to many severe manifestations ofmalaria disease. The P falciparum glycosyl phosphatidyl inositol (GPI) molecule is a lead candidate for this mediator, the so-called malaria toxin. Immunisation There are two possible classes of blood-stage vaccine: anti- with P falciparum GPI protected mice from severe invasion and anticomplication. A vaccine that could disease manifestations on malaria challenge, although prevent invasion of red blood cells by merozoites would this finding was not reproducible by other investigators, prevent malaria disease. Development of such vaccines has and the pathway from this work to an effective clinical been hampered by the lack of an established human challenge model, by the limitations of available animalmodels, and by unclear immunological correlates of Sexual-stage vaccines: the altruistic vaccine protection. Merozoite surface protein-1 (MSP-1) is the Induction of antibodies to gametocyte antigens can most well characterised antigen involved in invasion, and is prevent fertilisation in the mosquito; as well as its blood the basis of several candidate vaccines. However, vaccine meal, the mosquito ingests antibodies that block development has been complicated by the discovery of fertilisation. As a result, assessment of the efficacy of parallel pathways for invasion, and by the elegant gametocyte vaccines is possible with a simple ex-vivo demonstration that some antibodies to MSP-1 can block assay. Mosquitoes are fed on gametocytes with or without the activity of malaria-protective antibodies.72 In a small the addition of human serum samples from vaccinated efficacy study in Papua New Guinea, a blood-stage vaccine volunteers. The US National Institute for Allergy and incorporating the antigen MSP-2 and two other blood- Infectious Disease Malaria Vaccine Development Unit stage antigens reduced parasite density in vaccine plans clinical assessment of a P falciparum gametocyte candidate vaccine, Pfs25, a recombinant protein. There is infection with the vaccine strain of malaria, suggesting that little commercial funding for sexual-stage vaccine for polymorphic antigens such as MSP2, a vaccine candidates, since they have no market in developed including just one allelic form of the antigen is not likely to countries. Such vaccines could, however, contribute to malaria control, especially if linked with other A recombinant viral vaccine, NYVAC Pf-7 (P falciparum- interventions. A sexual-stage vaccine consisting of an 7), has been developed that encodes seven antigens from antigen not expressed in human beings during natural various life-cycle stages.74 Results of a sporozoite challenge infection would not select for escape mutants. Therefore, study of NYVAC Pf-7 showed encouraging delays in time combination of such a vaccine with a blood-stage or pre- to parasitaemia, and some antibody and cytotoxic erythrocytic vaccine could prevent potential immune T-lymphocyte immunogenicity, but this candidate has not selection. Sexual-stage vaccination would not protect been further developed. An anti-invasion vaccine based on vaccinated individuals from disease but would protect MSP-1 known as falciparum malaria protein (FMP-1) is being clinically assessed and has progressed quickly to anadult phase-I study in western Kenya. Vaccine development in the post-genomic era Two blood-stage candidates, glutamate rich protein Results of whole-genome sequencing indicate that there (GLURP) and MSP3, have been clinically assessed in are probably 5300 P falciparum antigens. Genome Europe.75,76 A key issue with all such protein candidates is databases can be used for identifying hundreds of the identification of a safe, immunogenic adjuvant, since candidates for vaccination. However, the number of the traditional adjuvant, alum, seems to be insufficiently possible antigens is not rate-limiting for malaria vaccine immunogenic for many malaria proteins. Additionally, development. Identification of antigens does not help vaccines with an alum adjuvant induce a Th2 response, solve some key problems in malaria vaccine development: rather than the generally more desirable Th1 response.
how to induce strong, durable immune responses; and Induction of biologically-relevant antibodies is a further how to combine multiple antigens without interference or challenge, and it is uncertain how often this will require a competition. Post-genomic antigen identification should native conformation of the recombinant protein. generate a wealth of information of long-term value to THE LANCET • Vol 363 • January 10, 2004 • For personal use. Only reproduce with permission from The Lancet.
Figure 2: A simplified timeline for assessment of a hypothetical candidate malaria vaccineRegulatory and ethics approval must be obtained before the first clinical trial. The first trial has always occurred to date in a non-malaria-endemic country.
With safety data and ethics approval from country of origin and locally, the vaccine can be tested in a malaria-endemic country. Once safety, immunogenicity,and perhaps artificial challenge efficacy data warrant field efficacy testing, the candidate moves to a phase IIb trial. This is a malaria-specific term indicatinga small-scale safety, immunogenicity, and efficacy study usually involving a few hundred participants. At some point the candidate will probably requirecombination with other antigens—the earlier this occurs, the sooner a final combined product can be licensed. *If efficacy in the laboratory challenge modelis sufficient and safety requirements allow, it may be possible to bypass adults entirely in malaria-endemic countries. Safety and efficacy will usually need tobe shown in children aged 1–5 years before progressing to infants. Before efficacy studies in infants, coadministration studies with vaccines routinelyadministered to infants would be done. A safe and efficacious vaccine would move to critical prelicensing safety and efficacy assessment in severalthousand infants. In this timeline, the vaccine candidate enters the clinic in 2003; some current candidate vaccines entered trials earlier and could reachlicensure sooner.
vaccine development, but solving other problems could be a vaccine. Currently, it can take more than a decade a faster means to developing an effective vaccine. Clearly, between first demonstration of high-level efficacy of a new diversion of funding from clinical development of the well vaccine and licensing for use in young children. The characterised antigens already available would be availability of trained, motivated, local investigators to do counterproductive. A distinction can be made here efficacy studies is a further limiting factor. Funds are between vaccine and drug development, in which there needed to train and support developing country are likely to be shorter-term promising applications of investigators to work with sponsors and take a leading role The cost of vaccines should be considered before large- scale efficacy trials are planned. Estimation of cost is Development of an effective and deployable malaria complicated by the unpredictable but anticipated decrease vaccine seems technically feasible in the view of most in price of a vaccine over time. The establishment of a malaria researchers. New vaccine delivery methods and global purchase fund could be essential to spur industrial adjuvants could continue to increase the antibody and interest in late-stage vaccine development. Increasing cellular immunogenicity of subunit vaccination. The rate numbers of trials will result in increasing numbers of of clinical assessment of candidate malaria vaccines is study participants who should be followed up in the long increasing; in the past 5 years, the number of groups doing term. However, funding rarely exists for more than such research has increased from three to 11. Careful 1–2 years per trial; thus, the best way to maintain long- clinical expansion is needed to translate immunogenicity term follow-up is to do sequential trials in the same into efficacy against malaria parasites in people resident in setting, and to include demographic surveillance malaria-endemic countries. Artificial challenge models infrastructures. As occurred in The Gambia in phase-III and improved in-vitro assays should speed up this process.
trials of hepatitis B and Haemophilus influenzae type b However, development of an effective vaccine also vaccines, a plan should be made in conjunction with local requires research into antigenic polymorphism, duration governments for provision of vaccine to the country or of efficacy, and means of antigen combination. A practical region participating in key prelicensing field trials.
limitation is the lack of worldwide Good Manufacturing Increasingly, cessation of vaccinations once such a trial Practice (GMP) manufacturing facilities for some new has ended is seen as unacceptable if the intervention has technologies such as recombinant viral vaccines. An effective vaccine is urgently needed. Efficacy studies Informed consent is a complex issue in efficacy studies.
often have to progress through adults and children aged In many rural African settings, community consent is as 1–5 years before reaching their target age group of infants important as individual consent, and rates of literacy can (figure 2). There will probably be a need for combination be poor. The American-European-Japanese ICH-GCP vaccines, and therefore vaccine development efforts of (International Committee on Harmonisation-Good several groups will almost certainly have to be combined.
Clinical Practice) guidelines are moving towards the Although one candidate vaccine has moved from first use status of law in much of the developed world. The in human participants to a phase-I trial in developing guidelines were drawn up by regulatory authorities and countries within months, a greater challenge is speeding pharmaceutical companies with little contribution from the progression from demonstrated efficacy to licensing of developing countries. GCP consent forms may be very THE LANCET • Vol 363 • January 10, 2004 • For personal use. Only reproduce with permission from The Lancet.
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THE LANCET • Vol 363 • January 10, 2004 • For personal use. Only reproduce with permission from The Lancet.


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