Volume 7 Supplement 1
Malaria vaccines and their potential role in the elimination of malaria
© Targett and Greenwood; licensee BioMed Central Ltd. 2008
Published: 11 December 2008
Research on malaria vaccines is currently directed primarily towards the development of vaccines that prevent clinical malaria. Malaria elimination, now being considered seriously in some epidemiological situations, requires a different vaccine strategy, since success will depend on killing all parasites in the community in order to stop transmission completely.
The feature of the life-cycles of human malarias that presents the greatest challenge to an elimination programme is the persistence of parasites as asymptomatic infections. These are an important source from which transmission to mosquitoes can occur. Consequently, an elimination strategy requires a community-based approach covering all individuals and not just those who are susceptible to clinical malaria.
The progress that has been made in development of candidate malaria vaccines is reviewed. It is unlikely that many of these will have the efficacy required for complete elimination of parasites, though they may have an important role to play as part of future integrated control programmes. Vaccines for elimination must have a high level of efficacy in order to stop transmission to mosquitoes. This might be achieved with some pre-erythrocytic stage candidate vaccines or by targeting the sexual stages directly with transmission-blocking vaccines. An expanded malaria vaccine programme with such objectives is now a priority.
Development of a malaria vaccine has been difficult. Greatly expanded investment in malaria vaccine research and development in recent years has resulted in the identification of a substantial number of vaccine candidates that are now in clinical trials or in the late stages of preclinical development. Now the malaria vaccine community is faced with a new challenge. Do the vaccine development plans developed several years ago, when the main target of malaria vaccine development was reduction in the burden of clinical malaria, fit with the new and ambitious aim of achieving malaria elimination. Here the current situation with respect to malaria control, the particular challenges elimination strategies present, and the progress being made in vaccine development are considered. An assessment is made of what vaccines are needed and how they could be used most effectively as part of a malaria elimination programme.
The much quoted figures for malaria deaths and clinical cases – around 1 million deaths and 300–500 million clinical cases per annum, are still the best estimates available. The majority of these deaths are due to Plasmodium falciparum malaria and occur in sub-Saharan Africa . The importance of Plasmodium vivax infection, in particular in South-East Asia, and the severity of some infections caused by this malaria parasite have been underestimated but are now receiving more attention .
There are, however, encouraging recent reports that show that a very significant improvement in the malaria situation is possible using existing control tools. Effective malaria control in high transmission areas seemed a remote possibility, even just a few years ago, but, with the substantial increase in political commitment and financial investment in control measures over the past 5–6 years, some dramatic results have been obtained. Some of the reported successes have occurred in countries or regions where malaria transmission was already low  but, in other cases, a significant downward trend has been achieved in places where transmission is stable; Zanzibar , Eritrea , The Gambia  and Kenya [7, 8] are good examples.
These successes have involved scaling up of existing control measures, notably treatment with artimisinin-based combination therapy (ACT) or other effective drug combinations, insecticide-treated nets (ITNs) and, increasingly, a return to insecticide-residual spraying (IRS). There has also been increased use of intermittent preventive treatment in pregnancy , and this approach to malaria control is being explored in infants and older children. A high level of commitment to the discovery of new drugs and insecticides is essential to ensure that these gains are not lost when the drugs and insecticides in current use lose their effectiveness.
Effective malaria control is defined as a reduction in cases of clinical malaria and mortality to a level at which malaria ceases to be a major problem. The malaria parasite still persists in the community, country or region and, if the control measures are not sustained, there is every likelihood that transmission and numbers of cases will increase rapidly again. However, the somewhat surprising impact of scaling-up the use of existing control measures has prompted the call, first by the Bill and Melinda Gates Foundation, quickly endorsed by WHO, and then by the Roll Back Malaria partnership, for malaria elimination to become the new goal. This has a very different and far more challenging aim of stopping transmission completely within a defined region, so that the only cases of malaria that occur are through importation from outside the region . Elimination by this definition can be achieved only by killing all of the parasites within the target population.
It is clear that, despite the successes achieved by scaling-up use of existing tools, additional or alternative strategies will be needed if malaria elimination is to be achieved – a possible exception being some island situations .
Persistence of infection
The focus of enhanced research and malaria control has, understandably, been primarily on P. falciparum malaria, given the mortality and severity of disease associated with this species. However, there is increasing recognition that the risk of infection and the burden of disease due to P. vivax malaria is substantial and, although of limited importance in sub-Saharan Africa, this parasite is often the dominant one in the other major endemic regions of the world. Frequently, P. vivax and P. falciparum occur sympatrically and elimination programmes, in such cases, must take account of the different challenges presented by the two species, especially in terms of persistence of infection, and the complex interactions between the species. This complex balance may be disturbed by vaccination against either P. falciparum or P. vivax in areas where both parasites are prevalent. Eliminating P. falciparum but not P. vivax would be a step forward, but if this was all that was achieved could damage the reputation of a malaria elimination programme.
Malaria elimination means stopping infection. This may be achieved if the measures directed against asexual parasites are fully effective, or by targeting sexual stages directly with drugs or vaccines.
Transmission of P. falciparum
In areas of high transmission, asexual parasite densities are highest in young children, and it is in this age group that microscopic detection of gametocytes is most common. Both asexual blood stage and gametocyte densities then decline with age, though the patterns of decline are somewhat different . Epidemiological studies show, however, that transmission of P. falciparum is as dependent on the parasites not detected by routine blood screening as on those that are readily seen. The cumulative evidence for the importance of low-grade asymptomatic infections as a reservoir for infection of mosquitoes is strong. In areas of highly seasonal malaria, where there is often a long dry season in which little or no transmission occurs, persisting very low gametocytaemias are the source from which transmission occurs at the onset of the subsequent rainy season . In areas where the endemicity of malaria allows acquired immunity to develop, there are many asymptomatic individuals, particularly adults, who are an important source of infection for mosquitoes [14, 15].
Detection of gametocytes using molecular techniques, such as reverse transcriptase polymerase chain reaction (RT-PCR)  and quantitative nucleic acid sequence-based amplification (QT-NASBA) has shown that gametocytaemias can persist at sub-microscopic levels for months and that the prevalence of gametocytaemic individuals is much higher than was assumed from blood film examinations . Of particular relevance to consideration of malaria elimination, Shekalaghe et al , in a study of parasite prevalence in an area of low, seasonal transmission in Tanzania, showed that, while microscopically the parasite rates were low (1.9% asexual parasites, 0.4% gametocytes), QT-NASBA revealed much higher prevalence rates (32.5% asexual parasites and 15.0% gametocytes).
These observations indicate the need to adopt a community-based approach to elimination; any selective interventions used should be based more on the focality of malaria , rather than on particular groups especially at risk from the clinical consequences of malaria infection, such as young children or pregnant women. Those at low risk clinically may still be important transmitters of infection.
Transmission of P. vivax
A key factor in the persistence of P. vivax is the fundamental difference in the life cycle shown by P. vivax and Plasmodium ovale, compared with P-. falciparum and Plasmodium. malariae, namely the occurrence of dormant hypnozoites in the liver, from which relapse infections can emerge, weeks, months or years after infection.
There is some evidence from use of PCR techniques, that, as for P. falciparum, the number of P. vivax infections in an affected community is generally significantly underestimated . Though the pattern of gametocyte production in P. vivax is different from that of P. falciparum, low grade asymptomatic infections are equally likely to give rise to infectious gametocytes.
Progress with vaccine development
The challenges set to vaccine developers  by those who drew up the malaria vaccine road map are first, by 2015, to produce a licensed vaccine that has a protective efficacy of more than 50% against severe disease and death from malaria which lasts longer than one year. Secondly, by 2025, to develop a vaccine with a protective efficacy greater than 80% against clinical disease and death that lasts longer than four years.
These targets focus on the prevention of clinical disease, especially its severe and life-threatening form, valid objectives for vaccines that are to be introduced into areas of medium or high transmission. A vaccine that conformed to the 2015 objective, providing protection to half of those vaccinated, would be valuable as part of an integrated control programme alongside vector control and chemo-preventative measures. That level of efficacy would not justify its use alone as an alternative to other means of malaria control.
The expanding programme of experimental vaccine-related research has two broad but overlapping approaches. One is to achieve a much needed better understanding of the nature of protective immune mechanisms against malaria, thus providing a basis for rational vaccine design . The other approach is more empirical and involves issues of design and presentation as vaccines of antigens that have been recognised for a long time and which are known to have an important role in the parasite's life cycle.
Pre-erythrocytic stage vaccines
The primary objective of pre-erythrocytic stage vaccines is provision of a level of protection that prevents any invasion of the blood and hence any clinical malaria. This has been achieved readily in experimental malarias by vaccination with radiation-attenuated sporozoites; this formed the starting point for the extensive investigations into pre-erythrocytic vaccines. Complete protection was also achieved in humans against P. falciparum and P. vivax by exposing them to the bites of mosquitoes that had been irradiated to attenuate their sporozoites. However, this delivery procedure was totally impractical and the research emphasis shifted to the synthetic design and genetic-engineering of sub-unit vaccines .
There has, however, been a renewal of interest in the development of attenuated-sporozoite vaccines. Given the high level of sterile protection these whole organism vaccines can induce, this is a very welcome development. Stephen Hoffman established and directs Sanaria Inc. specifically to produce radiation-attenuated sporozoites of P. falciparum from infected mosquitoes in sufficient quantity and in a way that meets the regulatory standards required for their use as a vaccine . This has been achieved and phase I/2a clinical trials will begin shortly using irradiation-attenuated sporozoites delivered by intradermal or subcutaneous injection.
Genetic attenuation of sporozoites is also being investigated. Mueller et al  produced sporozoites from Plasmodium berghei deficient in the vis3 gene. These gave complete protection when used for vaccination. Sporozoites lacking 6-cysteine secretory proteins required for parasitophorous vacuole formation are equally effective vaccines . The immune responses of importance following vaccination with attenuated sporozoites are CD8+T cell-mediated with production of interferon gamma [26–28].
Synthetic and genetically-engineered sub-unit vaccines have generally been based on the two surface proteins, circumsporozoite protein (CSP) and thrombospondin-related anonymous protein (TRAP) involved in sporozoite motility and invasion of liver cells. Most of the phase 2 trials of vaccines based on these antigens, using a variety of vaccine constructs, have given poor results and it is perhaps surprising that the RTS, S vaccine candidate has proved to be much more promising. This vaccine is a hybrid molecule expressed in yeast, that consists of the tandem repeat tetra-peptide (R) and C-terminal T-cell epitope containing (T) regions of CSP fused to the hepatitis B surface antigen (S), plus unfused S antigen. The adjuvant ASO2, which consists of an oil in water emulsion containing immunostimulants monophosphoryl lipid A and QS-21, a fraction of Quillaia saponaria, is an essential component of the vaccine. Variants of ASO2 have been tested successfully , and an alternative adjuvant, ASO1, where a liposomal formulation replaces the oil in water emulsion, has given very encouraging results [30, 31].
The first challenge trials with RTS, S/ASO2 gave impressive, but short-lived, protection in naïve adults . Similarly, in a trial in Gambian adults, there was greater than 70% protection against parasitaemia in the nine weeks post-vaccination, but the immunity waned rapidly . The most comprehensive study of RTS, S/AS02 has been in children in Mozambique, who have been followed up for two years. Over this period, there was 30% protection against clinical malaria and close to 50% protection against severe malaria . Most recently, in a small-scale trial in infants designed primarily to test safety and immunogenicity, RTS, S/AS02D had a vaccine efficacy of 65.9% against new infections in the six months of follow-up . A series of phase 2 studies preparatory to a large phase 3 trial and potential licensure of this vaccine are in progress.
RTS, S is several years ahead of any other vaccine in terms of assessment of its efficacy in clinical trials. Trials of other pre-erythrocytic stage vaccines, based on CSP, TRAP and other liver stage antigens, several of which have used viral vector delivery systems, have shown some initial promise, but are not sufficiently advanced or effective to be considered yet for evaluation in phase 3 trials [36, 37].
Asexual blood-stage candidate vaccines
A range of blood stage antigens have progressed to phase 1 and phase 2 trials. Most are molecules that have been identified as being involved in the process of invasion of erythrocytes by merozoites . Promising results from studies with rodent malarias are proving difficult to transfer to human infections [39–43], though some early encouraging results with MSP-3 antigen have been reported . The expectation is that such candidate vaccines might give protection against disease, but not against infection. This was the case with one phase 2 clinical trial of a vaccine containing MSP-1, MSP-2 and RESA antigens which reduced parasite density, but not prevalence of infection . It was also strain-specific in its effect and the polymorphism of these antigens, coupled with the variability in invasion pathways P. falciparum can adopt [46, 47] are a severe challenge to the design of this kind of vaccine. Blocking invasion of reticulocytes by P. vivax merozoites might be a more hopeful strategy, given that the Duffy antigen is thought to be the obligatory receptor on the erythrocyte surface  yet, even here an alternative invasion strategy has been proposed .
Plasmodium falciparum-infected erythrocytes express highly variable parasite molecules on the red blood cell surface. Naturally-acquired immunity involves variant-specific responses to these antigens and the very complexity of these responses may limit the potential of these antigens as vaccine candidates. However, this variability might be exploitable for specifically targeted vaccines. The P. falciparum-infected erythrocytes that sequester in the placenta of pregnant women have a very selected sub-set of variant surface antigens, notably one coded VAR2CSA, through which they bind to chondroitin sulphate A (CSA) in the placenta. This opens the possibility of designing a vaccine that would be beneficial to pregnant women , but which would probably not affect the other variants that circulate and sequester elsewhere using different receptor-ligand interactions. Another postulated approach to vaccination, much less studied, is to block parasite molecules that mediate disease by inducing pro-inflammatory responses. Glycosylphosphotidyl-inositol (GPI) is strongly implicated , but any vaccine effect would alleviate symptoms of disease without affecting infection. The immunity induced by such a vaccine might prevent some of the severe complications of malaria mediated by cytokine-induced response to infection. Use of vaccines of this kind, however, has the potential disadvantage of damping down the early clinical features of malaria, such as fever, which could delay the time before a patient sought treatment whilst still allowing parasite multiplication to occur.
The concept of a malaria vaccine that could provide an effective immune response when the antibodies induced had been ingested by blood-feeding mosquitoes, was developed thirty years ago . The target antigens of the passively transferred antibodies that blocked transmission were shown to be sexual-stage specific surface molecules (Pfs 48/45 and Pfs 230 in P. falciparum), that are involved in the process of fertilization of macrogametocytes by microgametes. Subsequently, other antigens (P25 and P28 proteins), that are uniquely expressed in the mosquito by zygotes and ookinetes (i.e. after fertilization), were shown to be equally good for induction of transmission-blocking immunity (TBI). The end result in each case is to prevent sporogonic development in the vector.
Experimental studies with animal models have shown that it is possible to induce a highly effective TBI [22, 53]. The most extensive studies have focused on Pfs 48/45, Pfs 230, Pfs 25, Pfs 28 of P. falciparum and orthologues in other Plasmodium species, but more potential vaccine candidates have been identified .
The gamete surface molecules (48/45 and 230) are also expressed in gametocytes circulating in the blood. This has made it possible to study the nature and duration of naturally-acquired sexual-stage specific immunity, and has contributed importantly to an understanding of the epidemiology of gametocytes in comparison with that of the much more comprehensively studied asexual blood stages . The P25 and P28 proteins are not expressed in gametocytes and hence there is no natural infection-related immunity to them. However, the mRNA that encodes these proteins is measurable in gametocytes and is used as the basis of highly sensitive means of detecting gametocytes .
The transmission-blocking activity of sera from vaccinated animals or humans, or from individuals naturally infected, has mostly been assessed by an ex vivo assay, during which mosquitoes feed through a membrane on blood containing gametocytes and a serum under test. Comparison with controls of the numbers of mosquitoes that become infected, and the number of oocysts they carry, gives a measure of the potency of the serum under test.
Experimentally, sera from rabbits, monkeys and mice vaccinated with vaccine candidates Pfs25 from P. falciparum and Pvs25 from P. vivax contained antibodies with transmission-blocking activity. The antibody levels measured by ELISA correlated with both oocyst reduction and the number of mosquitoes that failed to become infected ; antibody levels persisted at a high level for months after a second or third injection in mice . Phase 1 human vaccine trials were also effective , though not yet at the level that will be required and can be achieved experimentally.
Alternatives to the membrane-feeding assay are also being assessed for evaluation of transmission-blocking activity. Transmission of the transgenic P. berghei expressing the P25 antigens of either P. falciparum  or P. vivax  was blocked by antibodies obtained from animal vaccination and phase 1 clinical trials.
Though Pfs48/45 has been clearly shown to induce antibodies that prevent fertilization and correlate with transmission-blocking activity, the conformational nature of the epitopes, and the cysteine-rich nature of the protein has made production of a correctly folded recombinant molecule difficult. Encouragingly, production of a stable, properly folded C terminal portion of the molecule that induces transmission-blocking antibodies has recently been described [60, 61].
Use of vaccines in an elimination programme
Since elimination of malaria requires complete removal of all parasites, the focus of measures used to accomplish this goal is quite different from that for disease control. Whether the measures used for parasite elimination involve drugs  or vaccines, or a combination of the two, what is required are tools that prevent production of gametocytes or that render them non-infective to mosquitoes.
The ideal vaccine would be one that induces complete sterilizing immunity or which is fully effective at blocking transmission. Nothing approaching induction of a sterile immunity has been shown so far and it seems unlikely that this will be achieved with sub-unit vaccines. This does not rule out the use of such vaccines as part of an integrated approach to malaria-elimination, but they are unlikely to induce an anti-parasite immunity of sufficient efficacy to eliminate all parasites. It remains to be seen whether attenuated sporozoites, which, in small-scale studies with a demanding and unusable vaccination regime, did give full protection, will be as effective in the trials now beginning.
The transmission-blocking vaccines currently being tested induce good, but certainly not complete, transmission-blocking immunity. Since the membrane-feeding and the transgenic rodent malaria assays allow sera from clinical trials to be tested for efficacy, it is possible to set up a series of small-scale phase 1/2a trials with different vaccine constructs and vaccination regimes. It should then be possible to make speedy progress towards improving vaccine efficacy and selecting the best vaccine for development. There is an urgency to do this.
Acquired immunity, persistence of gametocytes, and transmission.
Acquired immunity to asexual blood stages increases with exposure but allows the persistence of low level parasitaemias from which gametocytes develop.
Anti-parasitic immunity will persist after interruption of transmission and may allow the occurrence of asymptomatic infections and hence gametocytaemias for a number of years.
Transmission-blocking immunity to gametocytes develops rapidly then wanes so that adults carrying small numbers of gametocytes are less likely to have antibodies that render them non-infective.
Low levels of transmission-blocking antibodies have been shown to enhance transmission.
The gametocyte reservoir is much larger than that determined by blood film examination even in areas where transmission is low. Transmission of infection can occur from individuals with very low numbers of gametocytes.
Gametocyte infectivity is broadly related to gametocyte density but small numbers of infectious gametocytes in adults are as important in maintaining transmission as larger numbers of gametocytes in children susceptible to clinical attacks of malaria.
A vaccine for elimination of malaria must ensure everyone susceptible to malaria infection is protected completely or that all gametocytes are made non-infective.
Naturally acquired immune responses to the sexual stages of the malaria parasite develop rapidly (in individuals with little or no previous exposure to malaria) and have transmission-blocking activity . However, in endemic areas, the ability of sera to reduce transmission decreases in older age groups, corresponding to a reduction in gametocyte numbers . The biological significance of this loss of immunity has been reviewed  and further supports evidence that adults with few parasites are nevertheless important as a reservoir of infection. There is evidence too, particularly for P. vivax, that a low level of immunity can enhance transmission to mosquitoes .
It is frequently stated that, as malaria control and elimination programmes progress, the population no longer has any immunity and becomes highly susceptible to epidemic infections. While this is true to some extent, especially for younger age groups, there is another aspect of immunity to consider. It is well known that those who had immunity to malaria quite rapidly lose their clinical immunity if no longer exposed and may develop a symptomatic infection at low parasite densities on subsequent exposure. However, the anti-parasite immunity they had acquired can persist for many years [66–68]. In other words, there is immunological memory directed against the infection. The relevance of this to malaria elimination is that, for many years, there may be a proportion of the population capable of supporting low grade infections from which gametocytes can be derived.
Elimination programmes are focused on populations, not individuals, and, optimally, a herd immunity that is sustained and prevents transmission is required. The current vaccine development programmes are largely concerned with disease control and must be sustained, but, from the results obtained so far in clinical trials of the RTS, S vaccine, the impact is not dissimilar to that of ITNs, i.e. there is a greater impact on severe disease than on infection. It is difficult to imagine partially effective asexual blood stage vaccines being very useful for parasite elimination. Given that all age groups can potentially provide a source of infection to mosquitoes, a high proportion of the population will need to be given a vaccine. However, there is much evidence to show that malaria is a highly focal disease and, initially at least, it might be beneficial to vaccinate those at greatest risk of being bitten by vector mosquitoes. Whatever vaccine is employed, pre-erythrocytic or transmission-blocking, its efficacy would need to be very high to achieve elimination .
A transmission-blocking vaccine has no direct effect on clinical malaria, but would break the life-cycle between human and malaria. It might be used as a stand-alone vaccine, but, more appropriately, as part of an integrated programme involving drug-treatment and vector control. The concept of a multi-component, multi-stage vaccine  with an effect from one component mainly on disease and from another on infection is intuitively appealing though the type of vaccine design required to kill parasites or render gametocytes non-infective to mosquitoes might be quite different from vaccines whose beneficial effect is mainly against disease severity. What is needed is an expanded malaria vaccine programme targeting the particular requirements of malaria elimination.
This article has been published as part of Malaria Journal Volume 7 Supplement 1, 2008: Towards a research agenda for global malaria elimination. The full contents of the supplement are available online at http://www.malariajournal.com/supplements/7/S1
- Guerra CA, Gikandi PW, Tatem AJ, Noor AM, Smith DL, Hay SI, Snow RW: The limits and intensity of Plasmodium falciparum transmission: implications for malaria control and elimination worldwide. PLoS Med. 2008, 5: e38-10.1371/journal.pmed.0050038.PubMed CentralView ArticlePubMedGoogle Scholar
- Baird JK: Neglect of Plasmodium vivax malaria. Trends Parasitol. 2007, 23: 533-539.View ArticlePubMedGoogle Scholar
- Barnes KI, Durrheim DN, Little F, Jackson A, Mehta U, Allen E, Dlamini SS, Tsoka J, Bredenkamp B, Mthembu DJ, White NJ, Sharp BL: Effect of artemether-lumefantrine policy and improved vector control on malaria burden in KwaZulu-Natal, South Africa. PLoS Med. 2005, 2: e330-10.1371/journal.pmed.0020330.PubMed CentralView ArticlePubMedGoogle Scholar
- Bhattarai A, Ali AS, Kachur SP, Martensson A, Abbas AK, Khatib R, Al-Mafazy AW, Ramsan M, Rotllant G, Gerstenmaier JF, Molteni F, Abdulla S, Montgomery SM, Kaneko A, Björkman A: Impact of artemisinin-based combination therapy and insecticide-treated nets on malaria burden in Zanzibar. PLoS Med. 2007, 4: e309-10.1371/journal.pmed.0040309.PubMed CentralView ArticlePubMedGoogle Scholar
- Nyarango PM, Gebremeskel T, Mebrahtu G, Mufunda J, Abdulmumini U, Ogbamariam A, Kosia A, Gebremichael A, Gunawardena D, Ghebrat Y, Okbaldet Y: A steep decline of malaria morbidity and mortality trends in Eritrea between 2000 and 2004: the effect of combination of control methods. Malar J. 2006, 5: 33-10.1186/1475-2875-5-33.PubMed CentralView ArticlePubMedGoogle Scholar
- Ceesay SJ, Casals-Pascual C, Erskine J, Anya SE, Duah NO, Fulford AJ, Sesay SS, Abubakar I, Dunyo S, Sey O, Palmer A, Fofana M, Corrah T, Bojang KA, Whittle HC, Greenwood BM, Conway DJ: Changes in malaria indices between 1999 and 2007 in The Gambia: a retrospective analysis. Lancet. 2008, 372: 1545-1554. 10.1016/S0140-6736(08)61654-2.PubMed CentralView ArticlePubMedGoogle Scholar
- Okiro EA, Hay SI, Gikandi PW, Sharif SK, Noor AM, Peshu N, Marsh K, Snow RW: The decline in paediatric malaria admissions on the coast of Kenya. Malar J. 2007, 6: 151-10.1186/1475-2875-6-151.PubMed CentralView ArticlePubMedGoogle Scholar
- O'Meara WP, Bejon P, Mwangi TW, Okiro EA, Peshu N, Snow RW, Newton CR, Marsh K: Effect of a fall in malaria transmission on morbidity and mortality in Kilifi, Kenya. Lancet. 2008, 372: 1555-1562. 10.1016/S0140-6736(08)61655-4.PubMed CentralView ArticlePubMedGoogle Scholar
- Greenwood BM: From malaria control to elimination: implications for the research agenda. Trends Parasitol. 2008, 24: 449-454. 10.1016/j.pt.2008.07.002.View ArticlePubMedGoogle Scholar
- Feachem R, Sabot O: A new global malaria eradication strategy. Lancet. 2008, 371: 1633-1635. 10.1016/S0140-6736(08)60424-9.View ArticlePubMedGoogle Scholar
- Kaneko A, Taleo G, Kalkoa M, Yamar S, Kobayakawa T, Bjorkman A: Malaria eradication on islands. Lancet. 2000, 356: 1560-1564. 10.1016/S0140-6736(00)03127-5.View ArticlePubMedGoogle Scholar
- Drakeley C, Sutherland C, Bousema JT, Sauerwein RW, Targett GA: The epidemiology of Plasmodium falciparum gametocytes: weapons of mass dispersion. Trends Parasitol. 2006, 22: 424-430. 10.1016/j.pt.2006.07.001.View ArticlePubMedGoogle Scholar
- Abdel-Wahab A, Abdel-Muhsin AM, Ali E, Suleiman S, Ahmed S, Walliker D, Babiker HA: Dynamics of gametocytes among Plasmodium falciparum clones in natural infections in an area of highly seasonal transmission. J Infect Dis. 2002, 185: 1838-1842. 10.1086/340638.View ArticlePubMedGoogle Scholar
- Drakeley CJ, Akim NI, Sauerwein RW, Greenwood BM, Targett GA: Estimates of the infectious reservoir of Plasmodium falciparum malaria in The Gambia and in Tanzania. Trans R Soc Trop Med Hyg. 2000, 94: 472-476. 10.1016/S0035-9203(00)90056-7.View ArticlePubMedGoogle Scholar
- Schneider P, Bousema JT, Gouagna LC, Otieno S, Vegte-Bolmer van de M, Omar SA, Sauerwein RW: Submicroscopic Plasmodium falciparum gametocyte densities frequently result in mosquito infection. Am J Trop Med Hyg. 2007, 76: 470-474.PubMedGoogle Scholar
- Bousema JT, Schneider P, Gouagna LC, Drakeley CJ, Tostmann A, Houben R, Githure JI, Ord R, Sutherland CJ, Omar SA, Sauerwein RW: Moderate effect of artemisinin-based combination therapy on transmission of Plasmodium falciparum. J Infect Dis. 2006, 193: 1151-1159. 10.1086/503051.View ArticlePubMedGoogle Scholar
- Shekalaghe SA, Bousema JT, Kunei KK, Lushino P, Masokoto A, Wolters LR, Mwakalinga S, Mosha FW, Sauerwein RW, Drakeley CJ: Submicroscopic Plasmodium falciparum gametocyte carriage is common in an area of low and seasonal transmission in Tanzania. Trop Med Int Health. 2007, 12: 547-553.View ArticlePubMedGoogle Scholar
- Woolhouse ME, Dye C, Etard JF, Smith T, Charlwood JD, Garnett GP, Hagan P, Hii JL, Ndhlovu PD, Quinnell RJ: Heterogeneities in the transmission of infectious agents: implications for the design of control programs. Proc Natl Acad Sci USA. 1997, 94: 338-342. 10.1073/pnas.94.1.338.PubMed CentralView ArticlePubMedGoogle Scholar
- Kasehagen LJ, Mueller I, McNamara DT, Bockarie MJ, Kiniboro B, Rare L, Lorry K, Kastens W, Reeder JC, Kazura JW, Zimmerman PA: Changing patterns of Plasmodium blood-stage infections in the Wosera region of Papua New Guinea monitored by light microscopy and high throughput PCR diagnosis. Am J Trop Med Hyg. 2006, 75: 588-596.PubMed CentralPubMedGoogle Scholar
- Malaria Vaccine Technology Roadmap. [http://www.malariavaccineroadmap.net]
- Stevenson MM, Zavala F: Immunology of malaria infections – implications for the design and development of malaria vaccines. Parasite Immunol. 2006, 28: 1-60. 10.1111/j.1365-3024.2006.00797.x.View ArticlePubMedGoogle Scholar
- Targett GA: Malaria vaccines 1985–2005: a full circle?. Trends Parasitol. 2005, 21: 499-503. 10.1016/j.pt.2005.08.018.View ArticlePubMedGoogle Scholar
- Sanaria. [http://www.sanaria.com]
- Mueller AK, Labaied M, Kappe SH, Matuschewski K: Genetically modified Plasmodium parasites as a protective experimental malaria vaccine. Nature. 2005, 433: 164-167. 10.1038/nature03188.View ArticlePubMedGoogle Scholar
- Labaied M, Harupa A, Dumpit RF, Coppens I, Mikolajczak SA, Kappe SH: Plasmodium yoelii sporozoites with simultaneous deletion of P52 and P36 are completely attenuated and confer sterile immunity against infection. Infect Immun. 2007, 75: 3758-3768. 10.1128/IAI.00225-07.PubMed CentralView ArticlePubMedGoogle Scholar
- Jobe O, Lumsden J, Mueller AK, Williams J, Silva-Rivera H, Kappe SH, Schwenk RJ, Matuschewski K, Krzych U: Genetically attenuated Plasmodium berghei liver stages induce sterile protracted protection that is mediated by major histocompatibility complex Class I-dependent interferon-gamma-producing CD8+ T cells. J Infect Dis. 2007, 196: 599-607. 10.1086/519743.PubMed CentralView ArticlePubMedGoogle Scholar
- Mueller AK, Deckert M, Heiss K, Goetz K, Matuschewski K, Schluter D: Genetically attenuated Plasmodium berghei liver stages persist and elicit sterile protection primarily via CD8 T cells. Am J Pathol. 2007, 171: 107-115. 10.2353/ajpath.2007.060792.PubMed CentralView ArticlePubMedGoogle Scholar
- Tarun AS, Dumpit RF, Camargo N, Labaied M, Liu P, Takagi A, Wang R, Kappe SH: Protracted sterile protection with Plasmodium yoelii pre-erythrocytic genetically attenuated parasite malaria vaccines is independent of significant liver-stage persistence and is mediated by CD8+ T cells. J Infect Dis. 2007, 196: 608-616. 10.1086/519742.View ArticlePubMedGoogle Scholar
- Barbosa A, Naniche D, Manaca MN, Aponte JJ, Mandomando I, Aide P, Renom M, Sacarlal J, Ballou WR, Moris P, Cohen J, Dubovsky F, Millman J, Alonso PL: Assessment of cellular immune responses in infants participating in a RTS, S/ASO2D phase I/IIB trial in Mozambique. Am J Trop Med Hyg. 2007, 77 (Abstr 9): 2-3.Google Scholar
- Lell B, Agnandji S, von Glasenapp I, Oyakhiromen S, Haertle S, Kremsner PG, Ramboer I, Lievens M, Ballou WR, Vekemans J, Dubois M-C, Demoitie M-A, Cohen J, Villafana T, Carter T, Petersen T: A randomized, observer-blind trial to compare safety and immunogenicity of two adjuvanted RTS, S anti-malaria vaccine candidates in Gabonese children. Am J Trop Med Hyg. 2007, 77 (Abstr 10): 3-Google Scholar
- Anyona SB, Hunja CW, Kifude CM, Polhemus ME, Heppner DG, Leach A, Lievens M, Ballou WR, Cohen J, Sutherland C: Impact of RTS, S/ASO2A and RTS, s/ASO1B on multiplicity of infections and CSP T-cell epitopes of Plasmodium falciparum in adults participating in a malaria vaccine clinical trial. Am J Trop Med Hyg. 2007, 77 (Abstr 578): 166-Google Scholar
- Kester KE, McKinney DA, Tornieporth N, Ockenhouse CF, Heppner DG, Hall T, Krzych U, Delchambre M, Voss G, Dowler MG, Palensky J, Wittes J, Cohen J, Ballou WR, RTS S Malaria Vaccine Evaluation Group: Efficacy of recombinant circumsporozoite protein vaccine regimens against experimental Plasmodium falciparum malaria. J Infect Dis. 2001, 183: 640-647. 10.1086/318534.View ArticlePubMedGoogle Scholar
- Bojang KA, Milligan PJ, Pinder M, Vigneron L, Alloueche A, Kester KE, Ballou WR, Conway DJ, Reece WH, Gothard P, Yamuah L, Delchambre M, Voss G, Greenwood BM, Hill A, McAdam KP, Tornieporth N, Cohen JD, Doherty T, RTS S Malaria Vaccine Trial Team: Efficacy of RTS, S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial. Lancet. 2001, 358: 1927-1934. 10.1016/S0140-6736(01)06957-4.View ArticlePubMedGoogle Scholar
- Alonso PL, Sacarlal J, Aponte JJ, Leach A, Macete E, Aide P, Sigauque B, Milman J, Mandomando I, Bassat Q, Guinovart C, Espasa M, Corachan S, Lievens M, Navia MM, Dubois MC, Menendez C, Dubovsky F, Cohen J, Thompson R, Ballou WR: Duration of protection with RTS, S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial. Lancet. 2005, 366: 2012-2018. 10.1016/S0140-6736(05)67669-6.View ArticlePubMedGoogle Scholar
- Aponte JJ, Aide P, Renom M, Mandomando I, Bassat Q, Sacarlal J, Manaca MN, Lafuente S, Barbosa A, Leach A, Lievens M, Vekemans J, Sigauque B, Dubois MC, Demoitié MA, Sillman M, Savarese B, McNeil JG, Macete E, Ballou WR, Cohen J, Alonso PL: Safety of the RTS, S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial. Lancet. 2007, 370: 1543-1551. 10.1016/S0140-6736(07)61542-6.View ArticlePubMedGoogle Scholar
- Hill AV: Pre-erythrocytic malaria vaccines: towards greater efficacy. Nat Rev Immunol. 2006, 6: 21-32. 10.1038/nri1746.View ArticlePubMedGoogle Scholar
- Walther M: Advances in vaccine development against the pre-erythrocytic stage of Plasmodium falciparum malaria. Expert Rev Vaccines. 2006, 5: 81-93. 10.1586/14760518.104.22.168.View ArticlePubMedGoogle Scholar
- Hu J, Chen Z, Gu J, Wan M, Shen Q, Kieny MP, He J, Li Z, Zhang Q, Reed ZH, Zhu Y, Li W, Cao Y, Qu L, Cao Z, Wang Q, Liu H, Pan X, Huang X, Zhang D, Xue X, Pan W: Safety and immunogenicity of a malaria vaccine, Plasmodium falciparum AMA-1/MSP-1 chimeric protein formulated in montanide ISA 720 in healthy adults. PLoS ONE. 2008, 3: e1952-10.1371/journal.pone.0001952.PubMed CentralView ArticlePubMedGoogle Scholar
- Greenwood BM, Fidock DA, Kyle DE, Kappe SH, Alonso PL, Collins FH, Duffy PE: Malaria: progress, perils, and prospects for eradication. J Clin Invest. 2008, 118: 1266-1276. 10.1172/JCI33996.PubMed CentralView ArticlePubMedGoogle Scholar
- Dicko A, Sagara I, Ellis RD, Miura K, Guindo O, Kamate B, Sogoba M, Niambele MB, Sissoko M, Baby M, Dolo A, Mullen GE, Fay MP, Pierce M, Diallo DA, Saul A, Miller LH, Doumbo OK: Phase 1 study of a combination AMA1 blood stage malaria vaccine in Malian children. PLoS ONE. 2008, 3: e1563-10.1371/journal.pone.0001563.PubMed CentralView ArticlePubMedGoogle Scholar
- Malkin E, Long CA, Stowers AW, Zou L, Singh S, MacDonald NJ, Narum DL, Miles AP, Orcutt AC, Muratova O, Moretz SE, Zhou H, Diouf A, Fay M, Tierney E, Leese P, Mahanty S, Miller LH, Saul A, Martin LB: Phase 1 study of two merozoite surface protein 1 (MSP1(42)) vaccines for Plasmodium falciparum malaria. PLoS Clin Trials. 2007, 2: e12-10.1371/journal.pctr.0020012.PubMed CentralView ArticlePubMedGoogle Scholar
- Richie T: High road, low road? Choices and challenges on the pathway to a malaria vaccine. Parasitology. 2006, 133 (Suppl S1): 13-144.Google Scholar
- Remarque EJ, Faber BW, Kocken CH, Thomas AW: Apical membrane antigen 1: a malaria vaccine candidate in review. Trends Parasitol. 2008, 24: 74-84. 10.1016/j.pt.2007.12.002.View ArticlePubMedGoogle Scholar
- Druilhe P, Spertini F, Soesoe D, Corradin G, Mejia P, Singh S, Audran R, Bouzidi A, Oeuvray C, Roussilhon C: A malaria vaccine that elicits in humans antibodies able to kill Plasmodium falciparum. PLoS Med. 2005, 2: e344-10.1371/journal.pmed.0020344.PubMed CentralView ArticlePubMedGoogle Scholar
- Genton B, Betuela I, Felger I, Al-Yaman F, Anders RF, Saul A, Rare L, Baisor M, Lorry K, Brown GV, Pye D, Irving DO, Smith TA, Beck HP, Alpers MP: A recombinant blood-stage malaria vaccine reduces Plasmodium falciparum density and exerts selective pressure on parasite populations in a phase 1–2b trial in Papua New Guinea. J Infect Dis. 2002, 185: 820-827. 10.1086/339342.View ArticlePubMedGoogle Scholar
- Baum J, Maier AG, Good RT, Simpson KM, Cowman AF: Invasion by P. falciparum merozoites suggests a hierarchy of molecular interactions. PLoS Pathog. 2005, 1: e37-10.1371/journal.ppat.0010037.PubMed CentralView ArticlePubMedGoogle Scholar
- Takala SL, Coulibaly D, Thera MA, Dicko A, Smith DL, Guindo AB, Kone AK, Traore K, Ouattara A, Djimde AA, Sehdev PS, Lyke KE, Diallo DA, Doumbo OK, Plowe CV: Dynamics of polymorphism in a malaria vaccine antigen at a vaccine-testing site in Mali. PLoS Med. 2007, 4: e93-10.1371/journal.pmed.0040093.PubMed CentralView ArticlePubMedGoogle Scholar
- Devi YS, Mukherjee P, Yazdani SS, Shakri AR, Mazumdar S, Pandey S, Chitnis CE, Chauhan VS: Immunogenicity of Plasmodium vivax combination subunit vaccine formulated with human compatible adjuvants in mice. Vaccine. 2007, 25: 5166-5174. 10.1016/j.vaccine.2007.04.080.View ArticlePubMedGoogle Scholar
- Cavasini CE, Mattos LC, Couto AA, Bonini-Domingos CR, Valencia SH, Neiras WC, Alves RT, Rossit AR, Castilho L, Machado RL: Plasmodium vivax infection among Duffy antigen-negative individuals from the Brazilian Amazon region: an exception?. Trans R Soc Trop Med Hyg. 2007, 101: 1042-1044. 10.1016/j.trstmh.2007.04.011.View ArticlePubMedGoogle Scholar
- Duffy PE: Plasmodium in the placenta: parasites, parity, protection, prevention and possibly preeclampsia. Parasitology. 2007, 134: 1877-1881. 10.1017/S0031182007000170.View ArticlePubMedGoogle Scholar
- Schofield L, Hewitt MC, Evans K, Siomos MA, Seeberger PH: Synthetic GPI as a candidate anti-toxic vaccine in a model of malaria. Nature. 2002, 418: 785-789. 10.1038/nature00937.View ArticlePubMedGoogle Scholar
- Carter R: Transmission blocking malaria vaccines. Vaccine. 2001, 19: 2309-2314. 10.1016/S0264-410X(00)00521-1.View ArticlePubMedGoogle Scholar
- Saul A: Efficacy model for mosquito stage transmission blocking vaccines for malaria. Parasitology. 2008, 135: 1497-1506. 10.1017/S0031182008000280.View ArticlePubMedGoogle Scholar
- Saul A: Mosquito stage, transmission blocking vaccines for malaria. Curr Opin Infect Dis. 2007, 20: 476-481. 10.1097/QCO.0b013e3282a95e12.View ArticlePubMedGoogle Scholar
- Miura K, Keister DB, Muratova OV, Sattabongkot J, Long CA, Saul A: Transmission-blocking activity induced by malaria vaccine candidates Pfs25/Pvs25 is a direct and predictable function of antibody titer. Malar J. 2007, 6: 107-10.1186/1475-2875-6-107.PubMed CentralView ArticlePubMedGoogle Scholar
- Kubler-Kielb J, Majadly F, Wu Y, Narum DL, Guo C, Miller LH, Shiloach J, Robbins JB, Schneerson R: Long-lasting and transmission-blocking activity of antibodies to Plasmodium falciparum elicited in mice by protein conjugates of Pfs25. Proc Natl Acad Sci USA. 2007, 104: 293-298. 10.1073/pnas.0609885104.PubMed CentralView ArticlePubMedGoogle Scholar
- Malkin EM, Durbin AP, Diemert DJ, Sattabongkot J, Wu Y, Miura K, Long CA, Lambert L, Miles AP, Wang J, Stowers A, Miller LH, Saul A: Phase 1 vaccine trial of Pvs25H: a transmission blocking vaccine for Plasmodium vivax malaria. Vaccine. 2005, 23: 3131-3138. 10.1016/j.vaccine.2004.12.019.View ArticlePubMedGoogle Scholar
- Mlambo G, Maciel J, Kumar N: Murine model for assessment of Plasmodium falciparum transmission-blocking vaccine using transgenic Plasmodium berghei parasites expressing the target antigen Pfs25. Infect Immun. 2008, 76: 2018-2024. 10.1128/IAI.01409-07.PubMed CentralView ArticlePubMedGoogle Scholar
- Ramjanee S, Robertson JS, Franke-Fayard B, Sinha R, Waters AP, Janse CJ, Wu Y, Blagborough AM, Saul A, Sinden RE: The use of transgenic Plasmodium berghei expressing the Plasmodium vivax antigen P25 to determine the transmission-blocking activity of sera from malaria vaccine trials. Vaccine. 2007, 25: 886-894. 10.1016/j.vaccine.2006.09.035.View ArticlePubMedGoogle Scholar
- Outchkourov N, Vermunt A, Jansen J, Kaan A, Roeffen W, Teelen K, Lasonder E, Braks A, Vegte-Bolmer van de M, Qiu LY, Sauerwein R, Stunnenberg HG: Epitope analysis of the malaria surface antigen pfs48/45 identifies a subdomain that elicits transmission blocking antibodies. J Biol Chem. 2007, 282: 17148-17156. 10.1074/jbc.M700948200.View ArticlePubMedGoogle Scholar
- Outchkourov NS, Roeffen W, Kaan A, Jansen J, Luty A, Schuiffel D, van Gemert GJ, Vegte-Bolmer van de M, Sauerwein RW, Stunnenberg HG: Correctly folded Pfs48/45 protein of Plasmodium falciparum elicits malaria transmission-blocking immunity in mice. Proc Natl Acad Sci USA. 2008, 105: 4301-4305. 10.1073/pnas.0800459105.PubMed CentralView ArticlePubMedGoogle Scholar
- Molineaux L, Gramiccio G: The Garki project: research on the epidemiology and control of malaria in the Sudan savanna of West Africa. 1980, WHO GenevaGoogle Scholar
- Ong CS, Zhang KY, Eida SJ, Graves PM, Dow C, Looker M, Rogers NC, Chiodini PL, Targett GA: The primary antibody response of malaria patients to Plasmodium falciparum sexual stage antigens which are potential transmission blocking vaccine candidates. Parasite Immunol. 1990, 12: 447-456. 10.1111/j.1365-3024.1990.tb00980.x.View ArticlePubMedGoogle Scholar
- Bousema JT, Drakeley CJ, Sauerwein RW: Sexual-stage antibody responses to P. falciparum in endemic populations. Curr Mol Med. 2006, 6: 223-229. 10.2174/156652406776055140.View ArticlePubMedGoogle Scholar
- Peiris JS, Premawansa S, Ranawaka MB, Udagama PV, Munasinghe YD, Nanayakkara MV, Gamage CP, Carter R, David PH, Mendis KN: Monoclonal and polyclonal antibodies both block and enhance transmission of human Plasmodium vivax malaria. Am J Trop Med Hyg. 1988, 39: 26-32.PubMedGoogle Scholar
- Deloron P, Chougnet C: Is immunity to malaria really short-lived?. Parasitol Today. 1992, 8: 375-378. 10.1016/0169-4758(92)90174-Z.View ArticlePubMedGoogle Scholar
- Struik SS, Riley EM: Does malaria suffer from lack of memory?. Immunol Rev. 2004, 201: 268-290. 10.1111/j.0105-2896.2004.00181.x.View ArticlePubMedGoogle Scholar
- Filipe JA, Riley EM, Drakeley CJ, Sutherland CJ, Ghani AC: Determination of the processes driving the acquisition of immunity to malaria using a mathematical transmission model. PLoS Comput Biol. 2007, 3: e255-10.1371/journal.pcbi.0030255.PubMed CentralView ArticlePubMedGoogle Scholar
- Saul A, Fay MP: Human immunity and the design of multi-component, single target vaccines. PLoS ONE. 2007, 2: e850-10.1371/journal.pone.0000850.PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.