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Development of malaria blood-stage vaccines: learning from mosquitoes
Transactions of the Royal Society of Tropical Medicine and Hygiene (2007) 101, 530—531
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/trst
MINI-REVIEW
Development of malaria blood-stage vaccines: learning from mosquitoes G.A. Butcher ∗ Division of Cell and Molecular Biology, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK Available online 30 March 2007
KEYWORDS Malaria vaccines; Plasmodium; Macaque monkey; Immunity; Mosquito; Infection
Summary If current methods of vaccine development for malaria continue to result in vaccines with only relatively limited degrees of protection, what is the alternative? Here, a totally different approach to blood-stage vaccine research is suggested, focusing on malarial immunity as it develops in macaque monkeys, but using methodology already well established in mosquito research. © 2007 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
After many years of neglect in terms of research as well as practical efforts at control, malaria is now receiving the attention it deserves and some authorities claim that it can be controlled, if not eliminated, by concerted, well funded programmes, particularly those based on the provision of insecticide-impregnated bed nets in conjunction with artemisinin-based combination therapy. These authors downplay the importance of malaria vaccines, disregarding the fact that, in the absence of protective immunity that a vaccine would provide, the populations of endemic areas would be vulnerable to any new outbreak that might occur. Despite much publicity at each step in the progress of vaccine research, no current human malaria vaccine has yet achieved the kind of results in experimental animals, and occasionally in humans, first observed in the 1940s and later in the 1970s. Using various preparations of sporozoites, including crude parasite extracts, UV, Xirradiation or formal treatment, a degree of immunity was induced that delayed patency and in a few experiments rendered hosts parasite-negative. Similarly, various treatments of blood-stage parasites also stimulated a
∗
Tel.: +44 20 8942 3467. E-mail address: [email protected]
protective response, although these vaccines were considerably more immunogenic when combined with Freund’s Complete Adjuvant (FCA). The most successful of these different procedures, often giving complete protection against live challenge, were with attenuated sporozoites from Xirradiated mosquitoes in animals and humans (Hoffman and Doolan, 2000), and with FCA plus merozoites in monkeys (Mitchell et al., 1974). Efforts to translate these encouraging results to the human host using subunit vaccines based on the identification and characterisation of proteins that were potentially protective, expressed in a variety of carriers combined with modern adjuvants, have been far less successful. Indeed, this has led some researchers to return to the concept of using attenuated live vaccines, clearly an impractical proposition for the populations of malaria-endemic countries. It is possible that the limited protection currently achieved by the RTS,S/ASO2A vaccine developed by GlaxoSmithKline (Alonso et al., 2004) can be gradually improved upon, but if this is not going to be the case what alternatives are there? Will the concept of a malaria vaccine fade from the scene in favour of other remedies? The most commonly used laboratory models for malaria research are mice, although there has been a considerable increase in recent years in immunological data obtained
0035-9203/$ — see front matter © 2007 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.trstmh.2007.02.019
Development of malaria blood-stage vaccines: learning from mosquitoes from human infections. Notwithstanding the very large number of papers on the immune responses of mice to rodent malaria, it is recognised that there are significant differences from human responses, particularly in the initial stages of antigen presentation. One group of animals genetically closer to humans than mice, and that are natural carriers of a dozen malarial parasites, are the Asian macaques, but, with one or two exceptions, these have been ignored by the current generation of malaria researchers and study of their responses has been almost entirely neglected (Butcher, 1996). Despite the considerable ethical and administrative problems relating to experimentation on monkeys, in my view renewed examination of immunity to malaria in the macaques using modern techniques could lead to a novel and more successful route to vaccine development than those currently being pursued. A suitable starting point would be to use the methodology of those engaged in studying the responses of different mosquito species to Plasmodium infection (Dimopoulos, 2003). Comparison of the patterns of gene expression in response to a malarial infection in susceptible and nonsusceptible mosquitoes has provided information on the types of immune effector mechanisms that limit parasite multiplication. Similar methodology could be applied to analysis of immune responses of two species of macaque—– Macaca mulatta and M. fascicularis. The limited information available on malaria in these animals has been reviewed previously (Butcher, 1996), but there are two relevant points that need stating here. First, their ability to resist infection by plasmodia, especially P. knowlesi, is completely different. Macaca mulatta is extremely susceptible to this parasite, dying sometimes within a week after infection if untreated, often with almost every red cell infected. In contrast, M. fascicularis, the natural host of this and several other malaria parasites, exhibits peak parasitaemias rarely above 3% and appears to suffer no illness or pathology. The second significant factor is that this species can interbreed with M. mulatta where their ranges overlap and, very occasionally and unexpectedly, in the laboratory (Butcher, 1996). The genome of M. mulatta, recently published in
531
draft form (http://www.eurekalert.org/pub releases/200602/nhgr-ras020906.php), is presumably very similar to that of M. fascicularis although, regrettably, the genome of that species has yet to be described. Comparison of genes activated by a malaria infection in these closely related susceptible and non-susceptible hosts could, as with the mosquitoes, reveal valuable information on immune mechanisms and indicate which are protective. Once this is established, it would be a comparatively small step to identify the antigens concerned and therefore those that are potential vaccine candidates.
Acknowledgements I am grateful for the continued use of the library and computer facilities at Imperial College London, UK. Funding: None. Conflict of interest: None declared. Ethical approval: Not required.
References Alonso, P.L., Sacarlal, J., Aponte, J.J., Leach, A., Macete, E., Milman, J., Mandomando, I., Spiessens, B., Guinovart, C., Espasa, M., et al., 2004. Efficacy of the RTS,S/ASO2A vaccine against Plasmodium falciparum infection and disease in young African children: randomized controlled trial. Lancet 364, 1411— 1420. Butcher, G.A., 1996. Models for malaria: nature knows best. Parasitol. Today 12, 378—382. Dimopoulos, G., 2003. Insect immunity and its implication in mosquito—malaria interactions. Cell. Microbiol. 5, 3—14. Hoffman, S.L., Doolan, D.L., 2000. Malaria vaccines—–targeting infected hepatocytes. Nature Med. 6, 1218—1219. Mitchell, G.H., Butcher, G.A., Cohen, S., 1974. A merozoite vaccine effective against Plasmodium knowlesi malaria. Nature 252, 311—313.
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/trst
MINI-REVIEW
Development of malaria blood-stage vaccines: learning from mosquitoes G.A. Butcher ∗ Division of Cell and Molecular Biology, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK Available online 30 March 2007
KEYWORDS Malaria vaccines; Plasmodium; Macaque monkey; Immunity; Mosquito; Infection
Summary If current methods of vaccine development for malaria continue to result in vaccines with only relatively limited degrees of protection, what is the alternative? Here, a totally different approach to blood-stage vaccine research is suggested, focusing on malarial immunity as it develops in macaque monkeys, but using methodology already well established in mosquito research. © 2007 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
After many years of neglect in terms of research as well as practical efforts at control, malaria is now receiving the attention it deserves and some authorities claim that it can be controlled, if not eliminated, by concerted, well funded programmes, particularly those based on the provision of insecticide-impregnated bed nets in conjunction with artemisinin-based combination therapy. These authors downplay the importance of malaria vaccines, disregarding the fact that, in the absence of protective immunity that a vaccine would provide, the populations of endemic areas would be vulnerable to any new outbreak that might occur. Despite much publicity at each step in the progress of vaccine research, no current human malaria vaccine has yet achieved the kind of results in experimental animals, and occasionally in humans, first observed in the 1940s and later in the 1970s. Using various preparations of sporozoites, including crude parasite extracts, UV, Xirradiation or formal treatment, a degree of immunity was induced that delayed patency and in a few experiments rendered hosts parasite-negative. Similarly, various treatments of blood-stage parasites also stimulated a
∗
Tel.: +44 20 8942 3467. E-mail address: [email protected]
protective response, although these vaccines were considerably more immunogenic when combined with Freund’s Complete Adjuvant (FCA). The most successful of these different procedures, often giving complete protection against live challenge, were with attenuated sporozoites from Xirradiated mosquitoes in animals and humans (Hoffman and Doolan, 2000), and with FCA plus merozoites in monkeys (Mitchell et al., 1974). Efforts to translate these encouraging results to the human host using subunit vaccines based on the identification and characterisation of proteins that were potentially protective, expressed in a variety of carriers combined with modern adjuvants, have been far less successful. Indeed, this has led some researchers to return to the concept of using attenuated live vaccines, clearly an impractical proposition for the populations of malaria-endemic countries. It is possible that the limited protection currently achieved by the RTS,S/ASO2A vaccine developed by GlaxoSmithKline (Alonso et al., 2004) can be gradually improved upon, but if this is not going to be the case what alternatives are there? Will the concept of a malaria vaccine fade from the scene in favour of other remedies? The most commonly used laboratory models for malaria research are mice, although there has been a considerable increase in recent years in immunological data obtained
0035-9203/$ — see front matter © 2007 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.trstmh.2007.02.019
Development of malaria blood-stage vaccines: learning from mosquitoes from human infections. Notwithstanding the very large number of papers on the immune responses of mice to rodent malaria, it is recognised that there are significant differences from human responses, particularly in the initial stages of antigen presentation. One group of animals genetically closer to humans than mice, and that are natural carriers of a dozen malarial parasites, are the Asian macaques, but, with one or two exceptions, these have been ignored by the current generation of malaria researchers and study of their responses has been almost entirely neglected (Butcher, 1996). Despite the considerable ethical and administrative problems relating to experimentation on monkeys, in my view renewed examination of immunity to malaria in the macaques using modern techniques could lead to a novel and more successful route to vaccine development than those currently being pursued. A suitable starting point would be to use the methodology of those engaged in studying the responses of different mosquito species to Plasmodium infection (Dimopoulos, 2003). Comparison of the patterns of gene expression in response to a malarial infection in susceptible and nonsusceptible mosquitoes has provided information on the types of immune effector mechanisms that limit parasite multiplication. Similar methodology could be applied to analysis of immune responses of two species of macaque—– Macaca mulatta and M. fascicularis. The limited information available on malaria in these animals has been reviewed previously (Butcher, 1996), but there are two relevant points that need stating here. First, their ability to resist infection by plasmodia, especially P. knowlesi, is completely different. Macaca mulatta is extremely susceptible to this parasite, dying sometimes within a week after infection if untreated, often with almost every red cell infected. In contrast, M. fascicularis, the natural host of this and several other malaria parasites, exhibits peak parasitaemias rarely above 3% and appears to suffer no illness or pathology. The second significant factor is that this species can interbreed with M. mulatta where their ranges overlap and, very occasionally and unexpectedly, in the laboratory (Butcher, 1996). The genome of M. mulatta, recently published in
531
draft form (http://www.eurekalert.org/pub releases/200602/nhgr-ras020906.php), is presumably very similar to that of M. fascicularis although, regrettably, the genome of that species has yet to be described. Comparison of genes activated by a malaria infection in these closely related susceptible and non-susceptible hosts could, as with the mosquitoes, reveal valuable information on immune mechanisms and indicate which are protective. Once this is established, it would be a comparatively small step to identify the antigens concerned and therefore those that are potential vaccine candidates.
Acknowledgements I am grateful for the continued use of the library and computer facilities at Imperial College London, UK. Funding: None. Conflict of interest: None declared. Ethical approval: Not required.
References Alonso, P.L., Sacarlal, J., Aponte, J.J., Leach, A., Macete, E., Milman, J., Mandomando, I., Spiessens, B., Guinovart, C., Espasa, M., et al., 2004. Efficacy of the RTS,S/ASO2A vaccine against Plasmodium falciparum infection and disease in young African children: randomized controlled trial. Lancet 364, 1411— 1420. Butcher, G.A., 1996. Models for malaria: nature knows best. Parasitol. Today 12, 378—382. Dimopoulos, G., 2003. Insect immunity and its implication in mosquito—malaria interactions. Cell. Microbiol. 5, 3—14. Hoffman, S.L., Doolan, D.L., 2000. Malaria vaccines—–targeting infected hepatocytes. Nature Med. 6, 1218—1219. Mitchell, G.H., Butcher, G.A., Cohen, S., 1974. A merozoite vaccine effective against Plasmodium knowlesi malaria. Nature 252, 311—313.