COMMENTARY
COMMENTARY
Mastering malaria: What helps and what hurts Sunetra Gupta1 Department of Zoology, University of Oxford, Oxford OX1 3PS, United Kingdom
Paul Russell’s Man’s Mastery of Malaria (1), written in 1955, opens with these wistful words: “While keeping in mind the realities, one can nevertheless be confident that malaria is well on its way toward oblivion. Already as a malariologist, I feel premonitory twinges of lonesomeness, and in my own organization I am now a sort of ‘last survivor’.” However, Russell was misguided in thinking that the possibilities that had opened up with Ronald Ross’s discovery of the life cycle of the malaria parasite in 1897 (not to mention his remarkable attempts thereafter to understand the dynamics of infection through a simple mathematical model) were to be realized so soon. We are still struggling to conquer malaria, but now have at our disposal some very sophisticated methods of attacking the mosquito vectors, such as with bacterial larvicides and entomopathogenic fungi; new drugs like artemisinin have replaced those to which the parasite has become resistant, and candidate malaria vaccines are reaching
a new stage of maturity. An important question to pose at this stage is how some of these control strategies will combine in their impact and, in PNAS, Artzy-Randrup et al. (2) warn that bednets and vaccines may interact in ways that either make the situation a whole lot better (synergistically) or actually much worse (antagonistically), depending on which stage of the malaria life cycle the vaccine targets. Malaria has a complex life cycle and vaccines are now being developed to attack it at both its pre-erythrocytic stages and erythrocytic (blood) stages, as well as those that are specifically tailored to prevent onward transmission (Fig. 1). It is broadly envisaged that blood-stage vaccines will mainly impact on disease severity rather than infection, whereas pre-erythrocytic vaccines are being held to the higher standard of preventing infection as well as disease. A handful of pre-erythrocytic vaccines have shown partial efficacy, and others that target either the asexual
Fig. 1. The malaria parasite, Plasmodium falciparum, is injected by the mosquito vector into its human host in the form of sporozoites. These sporozoites quickly hone in on the liver and set up intracellular infections of hepatocytes. Vaccines targetting these stages are known as “pre-erythrocytic” vaccines. After an incubation period of ∼1 wk, merozoites burst out of the liver and go on to invade RBCs (erythrocytes). Infected RBCs produce further merozoites that can invade uninfected RBCs: this highly proliferative stage of the life cycle is specifically associated with malarial disease, and vaccines targeting the blood stages could conceivably have an effect on disease severity without impacting on infection or transmission. The differentiation of infected RBCs into sexual stages or gametocytes completes the life cycle, as these can be taken up by the mosquito to mate within its gut. Vaccines targeting these stages can block transmission without interfering with either infection or disease and, therefore, be of no immediate personal benefit to the vaccinee but afford significant long-term benefits. Bednets can prevent both infection of the human host and transmission of parasites from an infected host to the mosquito vector.
www.pnas.org/cgi/doi/10.1073/pnas.1501786112
blood-stage parasites or the transmissible forms (gametocytes, and also the zygotes within the mosquito) are in various stages of development. When it comes to elimination, a clear case can be made for synergistic interactions between pre-erythrocytic and transmissionblocking vaccines and bednets. The vaccines and bednets may act in concert to diminish the availability of susceptibles as well as to reduce the per capita rate of infection, thereby tipping the system into negative growth. In contrast, vaccine-induced immunity against the blood stages may neither prevent infection nor impact on onward transmission, and Artzy-Randrup et al. (2) emphasize that, under these circumstances, blood-stage vaccines will offer very little other than personal protection against clinical symptoms. This result is certainly possible, although many blood-stage antigens bear the signature of immune selection (3, 4), suggesting that antibodies against them have some impact on the success of the parasite. Therefore, if a vaccine were to be developed against a conserved target, such as Rh5 (5), then there is no reason to believe that it would not be fully effective against blood cell invasion. Because this would effectively render it identical to an infection-blocking vaccine, it is worth drawing our attention to the other extreme where its effects are limited to the individual rather than the community. However, it is also important to bear in mind that, in reality, a blood-stage vaccine will occupy a point somewhere in the continuum between having no effect on transmission and having as much of an impact as a pre-erythrocytic or transmissionblocking vaccine. A much trickier question is how the combination of bednets and vaccines will impact on malarial disease. As ArtzyRandrup et al. (2) are careful to point out, malaria is a complex clinical phenomenon that cannot be linked to parasite densities or past exposure in a simple way. Immunity Author contributions: S.G. wrote the paper. The author declares no conflict of interest. See companion article on page 3014. 1
Email: [email protected].
PNAS | March 10, 2015 | vol. 112 | no. 10 | 2925–2926
to infection (sometimes called “sterile immunity”) is difficult to acquire through natural infection: the prevalence of parasites remains at high levels even in age-classes where disease is rarely seen, dropping only in older age classes but very rarely to zero. In contrast, immunity to severe forms of malarial disease tends to be acquired upon a relatively small number of exposures. The incidence of nonsevere malarial disease declines in a manner that is compatible with the progressive acquisition of clinical immunity upon each exposure and appears to be complete in most endemic areas by late childhood. Any intervention or combination of interventions that reduces the per capita risk of infection will cause a shift in average age of first and subsequent infections, potentially delaying the acquisition of clinical immunity into adulthood. This result could have a detrimental effect if adult malaria were worse in symptoms than malaria in childhood (there is some evidence that symptoms are different but it is hard to say yet when it is worst to get malaria) or, as underscored by ArtzyRandrup et al. (2), if it erodes the earning capacity of the family unit. An age-shift in malaria incidence also opens up the potential for HIV coinfection, with its attendant costs for the outcome of both (6). Any combination of interventions can also shift the age of first infection upwards, and this may have the perverse consequence of increasing severe disease for reasons to do with postnatal protection against disease offered by maternal antibodies (7). Postnatal protection offers the infant the opportunity to acquire immunity without suffering severe symptoms, and delaying first infection beyond this period could leave them at risk for severe malarial anemia. Similar considerations apply to another severe syndrome known as cerebral malaria (8), although in this case, postnatal protection is likely offered by some other mechanism such as delay in receptor maturation.
2926 | www.pnas.org/cgi/doi/10.1073/pnas.1501786112
diverse antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) (10), which is expressed on the surface of infected red blood cells (RBCs) and plays
a role in the adhesion of infected RBCs to the lining of blood vessels, a process that is important to the survival of the malaria parasite. PfEMP1 is encoded by the var multigene family, with ∼60 copies present in each parasite genome. The degree to which boosting plays a role in maintenance of immunity will depend on the extent of overlap between the PfEMP1 repertoires of different strains (11–13) and its precise effects on incidence of different clinical syndromes will also be affected by their different propensities to cause severe disease (14–16). The dynamics of boosting of CD8+ T-cell responses against the liver stages will also differ in important ways from boosting of antibodies to sporozoite or merozoite antigens. Furthermore, vaccine immunity itself may be boosted by natural infection (17), introducing further nonlinearities. Artzy-Randrup et al. (2) provide an object lesson in how such questions may be tackled by using simple conceptual mathematical models.
1 Russell P (1955) Man’s Mastery of Malaria (Oxford Univ Press, Oxford, UK). 2 Artzy-Randrup Y, Dobson AP, Pascual M (2015) Synergistic and antagonistic interactions between bednets and vaccines in the control of malaria. Proc Natl Acad Sci USA 112:3014–3019. 3 Polley SD, et al. (2007) Plasmodium falciparum merozoite surface protein 3 is a target of allele-specific immunity and alleles are maintained by natural selection. J Infect Dis 195(2): 279–287. 4 Amambua-Ngwa A, et al. (2012) Population genomic scan for candidate signatures of balancing selection to guide antigen characterization in malaria parasites. PLoS Genet 8(11):e1002992. 5 Douglas AD, et al. (2015) A PfRH5-based vaccine is efficacious against heterologous strain blood-stage Plasmodium falciparum infection in aotus monkeys. Cell Host Microbe 17(1):130–139. 6 Berg A, et al. (2014) Increased severity and mortality in adults co-infected with malaria and HIV in Maputo, Mozambique: A prospective cross-sectional study. PLoS ONE 9(2):e88257. 7 Snow RW, et al. (1998) Risk of severe malaria among African infants: Direct evidence of clinical protection during early infancy. J Infect Dis 177(3):819–822. 8 Gupta S, Snow RW, Donnelly C, Newbold C (1999) Acquired immunity and postnatal clinical protection in childhood cerebral malaria. Proc Biol Sci 266(1414):33–38.
9 Aron JL, May RM (1982) The population dynamics of malaria. The Population Dynamics of Infectious Diseases: Theory and Applications, ed Anderson RM (Springer, London). 10 Bull PC, et al. (1998) Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria. Nat Med 4(3):358–360. 11 Gupta S, Trenholme K, Anderson RM, Day KP (1994) Antigenic diversity and the transmission dynamics of Plasmodium falciparum. Science 263(5149):961–963. 12 Buckee CO, Recker M (2012) Evolution of the multi-domain structures of virulence genes in the human malaria parasite, Plasmodium falciparum. PLOS Comput Biol 8(4):e1002451. 13 Artzy-Randrup Y, et al. (2012) Population structuring of multi-copy, antigen-encoding genes in Plasmodium falciparum. eLife 1:e00093. 14 Jensen ATR, et al. (2004) Plasmodium falciparum associated with severe childhood malaria preferentially expresses PfEMP1 encoded by group A var genes. J Exp Med 199(9):1179–1190. 15 Warimwe GM, et al. (2012) Prognostic indicators of lifethreatening malaria are associated with distinct parasite variant antigen profiles. Sci Transl Med 4(129):29ra45. 16 Claessens A, et al. (2012) A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells. Proc Natl Acad Sci USA 109(26):E1772–E1781. 17 Halloran ME, Struchiner CJ, Spielman A (1989) Modeling malaria vaccines. II: Population effects of stage-specific malaria vaccines dependent on natural boosting. Math Biosci 94(1):115–149.
A final feature highlighted by ArtzyRandrup et al. (2) is the increase in intervals between infections because of the reduction in per capita risk of infection. This is particularly relevant if immunity is maintained by boosting (9). Once again, the crucial question is what type of immunity is under discussion. The acquisition of immunity to nonsevere disease, for example, is linked to the highly
As Artzy-Randrup et al. are careful to point out, malaria is a complex clinical phenomenon that cannot be linked to parasite densities or past exposure in a simple way.
Gupta
COMMENTARY
Mastering malaria: What helps and what hurts Sunetra Gupta1 Department of Zoology, University of Oxford, Oxford OX1 3PS, United Kingdom
Paul Russell’s Man’s Mastery of Malaria (1), written in 1955, opens with these wistful words: “While keeping in mind the realities, one can nevertheless be confident that malaria is well on its way toward oblivion. Already as a malariologist, I feel premonitory twinges of lonesomeness, and in my own organization I am now a sort of ‘last survivor’.” However, Russell was misguided in thinking that the possibilities that had opened up with Ronald Ross’s discovery of the life cycle of the malaria parasite in 1897 (not to mention his remarkable attempts thereafter to understand the dynamics of infection through a simple mathematical model) were to be realized so soon. We are still struggling to conquer malaria, but now have at our disposal some very sophisticated methods of attacking the mosquito vectors, such as with bacterial larvicides and entomopathogenic fungi; new drugs like artemisinin have replaced those to which the parasite has become resistant, and candidate malaria vaccines are reaching
a new stage of maturity. An important question to pose at this stage is how some of these control strategies will combine in their impact and, in PNAS, Artzy-Randrup et al. (2) warn that bednets and vaccines may interact in ways that either make the situation a whole lot better (synergistically) or actually much worse (antagonistically), depending on which stage of the malaria life cycle the vaccine targets. Malaria has a complex life cycle and vaccines are now being developed to attack it at both its pre-erythrocytic stages and erythrocytic (blood) stages, as well as those that are specifically tailored to prevent onward transmission (Fig. 1). It is broadly envisaged that blood-stage vaccines will mainly impact on disease severity rather than infection, whereas pre-erythrocytic vaccines are being held to the higher standard of preventing infection as well as disease. A handful of pre-erythrocytic vaccines have shown partial efficacy, and others that target either the asexual
Fig. 1. The malaria parasite, Plasmodium falciparum, is injected by the mosquito vector into its human host in the form of sporozoites. These sporozoites quickly hone in on the liver and set up intracellular infections of hepatocytes. Vaccines targetting these stages are known as “pre-erythrocytic” vaccines. After an incubation period of ∼1 wk, merozoites burst out of the liver and go on to invade RBCs (erythrocytes). Infected RBCs produce further merozoites that can invade uninfected RBCs: this highly proliferative stage of the life cycle is specifically associated with malarial disease, and vaccines targeting the blood stages could conceivably have an effect on disease severity without impacting on infection or transmission. The differentiation of infected RBCs into sexual stages or gametocytes completes the life cycle, as these can be taken up by the mosquito to mate within its gut. Vaccines targeting these stages can block transmission without interfering with either infection or disease and, therefore, be of no immediate personal benefit to the vaccinee but afford significant long-term benefits. Bednets can prevent both infection of the human host and transmission of parasites from an infected host to the mosquito vector.
www.pnas.org/cgi/doi/10.1073/pnas.1501786112
blood-stage parasites or the transmissible forms (gametocytes, and also the zygotes within the mosquito) are in various stages of development. When it comes to elimination, a clear case can be made for synergistic interactions between pre-erythrocytic and transmissionblocking vaccines and bednets. The vaccines and bednets may act in concert to diminish the availability of susceptibles as well as to reduce the per capita rate of infection, thereby tipping the system into negative growth. In contrast, vaccine-induced immunity against the blood stages may neither prevent infection nor impact on onward transmission, and Artzy-Randrup et al. (2) emphasize that, under these circumstances, blood-stage vaccines will offer very little other than personal protection against clinical symptoms. This result is certainly possible, although many blood-stage antigens bear the signature of immune selection (3, 4), suggesting that antibodies against them have some impact on the success of the parasite. Therefore, if a vaccine were to be developed against a conserved target, such as Rh5 (5), then there is no reason to believe that it would not be fully effective against blood cell invasion. Because this would effectively render it identical to an infection-blocking vaccine, it is worth drawing our attention to the other extreme where its effects are limited to the individual rather than the community. However, it is also important to bear in mind that, in reality, a blood-stage vaccine will occupy a point somewhere in the continuum between having no effect on transmission and having as much of an impact as a pre-erythrocytic or transmissionblocking vaccine. A much trickier question is how the combination of bednets and vaccines will impact on malarial disease. As ArtzyRandrup et al. (2) are careful to point out, malaria is a complex clinical phenomenon that cannot be linked to parasite densities or past exposure in a simple way. Immunity Author contributions: S.G. wrote the paper. The author declares no conflict of interest. See companion article on page 3014. 1
Email: [email protected].
PNAS | March 10, 2015 | vol. 112 | no. 10 | 2925–2926
to infection (sometimes called “sterile immunity”) is difficult to acquire through natural infection: the prevalence of parasites remains at high levels even in age-classes where disease is rarely seen, dropping only in older age classes but very rarely to zero. In contrast, immunity to severe forms of malarial disease tends to be acquired upon a relatively small number of exposures. The incidence of nonsevere malarial disease declines in a manner that is compatible with the progressive acquisition of clinical immunity upon each exposure and appears to be complete in most endemic areas by late childhood. Any intervention or combination of interventions that reduces the per capita risk of infection will cause a shift in average age of first and subsequent infections, potentially delaying the acquisition of clinical immunity into adulthood. This result could have a detrimental effect if adult malaria were worse in symptoms than malaria in childhood (there is some evidence that symptoms are different but it is hard to say yet when it is worst to get malaria) or, as underscored by ArtzyRandrup et al. (2), if it erodes the earning capacity of the family unit. An age-shift in malaria incidence also opens up the potential for HIV coinfection, with its attendant costs for the outcome of both (6). Any combination of interventions can also shift the age of first infection upwards, and this may have the perverse consequence of increasing severe disease for reasons to do with postnatal protection against disease offered by maternal antibodies (7). Postnatal protection offers the infant the opportunity to acquire immunity without suffering severe symptoms, and delaying first infection beyond this period could leave them at risk for severe malarial anemia. Similar considerations apply to another severe syndrome known as cerebral malaria (8), although in this case, postnatal protection is likely offered by some other mechanism such as delay in receptor maturation.
2926 | www.pnas.org/cgi/doi/10.1073/pnas.1501786112
diverse antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) (10), which is expressed on the surface of infected red blood cells (RBCs) and plays
a role in the adhesion of infected RBCs to the lining of blood vessels, a process that is important to the survival of the malaria parasite. PfEMP1 is encoded by the var multigene family, with ∼60 copies present in each parasite genome. The degree to which boosting plays a role in maintenance of immunity will depend on the extent of overlap between the PfEMP1 repertoires of different strains (11–13) and its precise effects on incidence of different clinical syndromes will also be affected by their different propensities to cause severe disease (14–16). The dynamics of boosting of CD8+ T-cell responses against the liver stages will also differ in important ways from boosting of antibodies to sporozoite or merozoite antigens. Furthermore, vaccine immunity itself may be boosted by natural infection (17), introducing further nonlinearities. Artzy-Randrup et al. (2) provide an object lesson in how such questions may be tackled by using simple conceptual mathematical models.
1 Russell P (1955) Man’s Mastery of Malaria (Oxford Univ Press, Oxford, UK). 2 Artzy-Randrup Y, Dobson AP, Pascual M (2015) Synergistic and antagonistic interactions between bednets and vaccines in the control of malaria. Proc Natl Acad Sci USA 112:3014–3019. 3 Polley SD, et al. (2007) Plasmodium falciparum merozoite surface protein 3 is a target of allele-specific immunity and alleles are maintained by natural selection. J Infect Dis 195(2): 279–287. 4 Amambua-Ngwa A, et al. (2012) Population genomic scan for candidate signatures of balancing selection to guide antigen characterization in malaria parasites. PLoS Genet 8(11):e1002992. 5 Douglas AD, et al. (2015) A PfRH5-based vaccine is efficacious against heterologous strain blood-stage Plasmodium falciparum infection in aotus monkeys. Cell Host Microbe 17(1):130–139. 6 Berg A, et al. (2014) Increased severity and mortality in adults co-infected with malaria and HIV in Maputo, Mozambique: A prospective cross-sectional study. PLoS ONE 9(2):e88257. 7 Snow RW, et al. (1998) Risk of severe malaria among African infants: Direct evidence of clinical protection during early infancy. J Infect Dis 177(3):819–822. 8 Gupta S, Snow RW, Donnelly C, Newbold C (1999) Acquired immunity and postnatal clinical protection in childhood cerebral malaria. Proc Biol Sci 266(1414):33–38.
9 Aron JL, May RM (1982) The population dynamics of malaria. The Population Dynamics of Infectious Diseases: Theory and Applications, ed Anderson RM (Springer, London). 10 Bull PC, et al. (1998) Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria. Nat Med 4(3):358–360. 11 Gupta S, Trenholme K, Anderson RM, Day KP (1994) Antigenic diversity and the transmission dynamics of Plasmodium falciparum. Science 263(5149):961–963. 12 Buckee CO, Recker M (2012) Evolution of the multi-domain structures of virulence genes in the human malaria parasite, Plasmodium falciparum. PLOS Comput Biol 8(4):e1002451. 13 Artzy-Randrup Y, et al. (2012) Population structuring of multi-copy, antigen-encoding genes in Plasmodium falciparum. eLife 1:e00093. 14 Jensen ATR, et al. (2004) Plasmodium falciparum associated with severe childhood malaria preferentially expresses PfEMP1 encoded by group A var genes. J Exp Med 199(9):1179–1190. 15 Warimwe GM, et al. (2012) Prognostic indicators of lifethreatening malaria are associated with distinct parasite variant antigen profiles. Sci Transl Med 4(129):29ra45. 16 Claessens A, et al. (2012) A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells. Proc Natl Acad Sci USA 109(26):E1772–E1781. 17 Halloran ME, Struchiner CJ, Spielman A (1989) Modeling malaria vaccines. II: Population effects of stage-specific malaria vaccines dependent on natural boosting. Math Biosci 94(1):115–149.
A final feature highlighted by ArtzyRandrup et al. (2) is the increase in intervals between infections because of the reduction in per capita risk of infection. This is particularly relevant if immunity is maintained by boosting (9). Once again, the crucial question is what type of immunity is under discussion. The acquisition of immunity to nonsevere disease, for example, is linked to the highly
As Artzy-Randrup et al. are careful to point out, malaria is a complex clinical phenomenon that cannot be linked to parasite densities or past exposure in a simple way.
Gupta
