Malaria Vaccine Progress

Vaccine development

  • Regarding vaccine development there exist several approaches, as immune responses could potentially target any stage of the parasite to which humans are exposed (Fig. 1)

Figure 1: Life cycle of P. falciparum. (A) During a mosquito blood meal Plasmodium sporozoites are injected into the dermis.(B) Through the vasculature the sporozoites are transported to the liver where they enter hepatocytes and develop within 7-10 days (P. falciparum) to schizonts which release tens of thousands merozoites into the vasculature.(C) The merozoites infest erythrocytes and perform a cycle of asexual schizogony by developing into trophozoites and subsequently schizonts which release merozoites.(D) A small part of merozoites develop into the sexual stages of the parasite, the male (microgamete) and female (macrogamete) gametocytes.(E) When a mosquito takes a blood meal containing both micro- and macrogametes, they emerge in the midgut of the mosquito and mate, thereby forming a zygote which transforms into an ookinete and finally into an oocyst (F) which releases, when mature, sporozoites which migrate into salivary glands where they can be transferred to a human host during next blood meal.[adapted from Cowman, A.F., et al., Malaria: Biology and Disease. Cell, 2016. 167(3): p. 610-624.]
Pre-erythrocytic vaccines (PEs)

  • The clinical vaccine development, however, has focused on the pre-erythrocytic stage which comprises sporozoites and liver stages of P.falciparum
  • Full protection would be achieved through stopping establishment of blood-stage infection and thereby preventing a clinical malaria infestation
  • For this both, T-cells and antibodies are needed to eradicate infected hepatocytes, target parasites and prevent sporozoites to enter the liver [4]
  • CD8+ and CD4+ T cells are required, as well as memory T cells for long term protection
  • The only licensed malaria vaccine so far is RTS,S [5], a PE that targets circumsporozoite (CS) protein, which is the major coat protein of sporozoites
  • It partly consists of the C-terminal end of P.falciparum CS which is fused with a hepatitis B surface antigen virus like particle (VLP)
  • CS-specific antibodies and CD4+ T cells are responsible for protection whereas CD8+ T cells play a minor part [6]
  • Unfortunately, the efficacy was poor in clinical trials, as only 28% of children aged 5-17 months were protected after three vaccine doses (at study end, after 48 months) [7]. After 18 months, efficacy was higher with 45% for 5-17 months old children.
  • Moreover, the protective antibodies wane over time, leading to a short duration of protection
  • Another approach is the combining of RTS,S with other malaria vaccine regimens to achieve improving of efficacy by eliciting more CD8+ T cells : The Chimp Adenovirus (ChAd)-MVA Prime Boost strategy in which probands are primed with chimpanzee adenovirus 63 (ChAd63) and boosted 8 weeks later with modified vaccinia virus Ankara (MVA) [8]
  • Highly immunogenic, inducing CD4+ and CD8+ T cells as well as anti-CS antibodies
  • But, sterile protection only in 1 out of 15 individuals [9]
  • Similar results using the antigen TRAP (thrombospondin related adhesion protein) instead of CS; it is safe and immunogenic but induced sterile protection in only 2 out of 15 individuals [9]
  • Use of radiation-attenuated, cryopreserved whole P.falciparum sporozoites (PfSPZ) as a vaccine, is another promising trial
  • After infesting hepatocytes, irradiated sporozoites do not initiate progress to blood stage development, if sterile protection is achieved [10]
  • PfSPZ vaccine induces antibodies and effector and memory T cells and is well tolerated [11, 12]
  • Sterile protection up to 100% (for > 1 year) was achieved in clinical trials after homologous 3-5 times CHMI (controlled human malaria infection) [13, 14]
  • Big challenges are the complexity of Plasmodium with its highly polymorphic antigens, resulting in problems with achieving heterologous protection (cross-strain or strain-transcendent protection) after vaccination, as well as the need of mass production of sporozoites and the obligation to maintain a liquid nitrogen cold chain for the parasites in remote areas

Pregnancy-associated malaria

  • P.falciparum parasites accumulating in the placental tissue during pregnancy cause placental malaria (PM)
  • PM is mostly asymptomatic but is associated with low birth weight or stillbirth and maternal anemia
  • Infection leads to almost a million low birth weight deliveries in Africa each year [15]
  • P. falciparum infected erythrocytes bind to chondroitin sulfate A (CSA), a glycosaminoglycan composed of disaccharides of N-acetylgalactosamine and D-glucuronic acid, fused to placental proteoglycans
  • Main proteoglycan responsible for parasite adhesion in the placenta is Syndecan-1 [16]
  • A study from 2003 identified the protein VAR2CSA, which is expressed on the surface of infected erythrocytes, to be associated with the binding to CSA [17] (Fig. 2)

 

Figure 2: Schematic structure of VAR2CSA with the CSA binding region underlined in blue [adapted from Pehrson, C., et al., Pre-clinical and clinical development of the first placental malaria vaccine. Expert Rev Vaccines, 2017. 16(6): p. 613-624.]
  • In 2004 it was shown that the infants born to women with naturally acquired high amounts of protective antibodies – specific against VAR2CSA – had a higher birth weight compared to those babies born to women with low antibody levels [18]
  • The VAR2CSA specific antibodies are associated with preventing parasite-infected erythrocytes from binding to CSA in the placenta
  • Therefore, a VAR2CSA-based vaccine would be a promising trial, as also strategies to prevent malaria in pregnancy are rather not successful: the use of insecticide-treated bed-nets (ITNs) during pregnancy is lower than 40% in sub-Saharan Africa and the administration or rather taking of intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is estimated to be only 17% in sub-Saharan Africa [19]
  • So far, a VAR2CSA-based vaccine has reached clinical phase I trials in Europe and Africa [20]
  • The vaccine candidate contains the N-terminally located CSA binding domains of VAR2CSA and should be administered before pregnancy because the antibodies should be present in maternal plasma before maternal circulation is established in the placenta
  • Challenges in the vaccine development are the sufficiently high and long-lasting responses, which are required because the vaccine will be administered before pregnancy, the non-protectiveness against non-falciparum malaria and the polymorphism of the antigen

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References
  1. Cowman, A.F., et al., Malaria: Biology and Disease. Cell, 2016. 167(3): p. 610-624.
  2. Pehrson, C., et al., Pre-clinical and clinical development of the first placental malaria vaccine. Expert Rev Vaccines, 2017. 16(6): p. 613-624.
  3. https://www.who.int/malaria/media/world-malaria-report-2018/en/, W., World Malaria Report 2018.
  4. Wilson, K.L., et al., Malaria vaccines in the eradication era: current status and future perspectives. Expert Rev Vaccines, 2019. 18(2): p. 133-151.
  5. Rts, S.C.T.P., Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet, 2015. 386(9988): p. 31-45.
  6. Cockburn, I.A. and R.A. Seder, Malaria prevention: from immunological concepts to effective vaccines and protective antibodies. Nat Immunol, 2018. 19(11): p. 1199-1211.
  7. Greenwood, B. and O.K. Doumbo, Implementation of the malaria candidate vaccine RTS,S/AS01. Lancet, 2016. 387(10016): p. 318-319.
  8. de Barra, E., et al., A phase Ia study to assess the safety and immunogenicity of new malaria vaccine candidates ChAd63 CS administered alone and with MVA CS. PLoS One, 2014. 9(12): p. e115161.
  9. Hodgson, S.H., et al., Evaluation of the efficacy of ChAd63-MVA vectored vaccines expressing circumsporozoite protein and ME-TRAP against controlled human malaria infection in malaria-naive individuals. J Infect Dis, 2015. 211(7): p. 1076-86.
  10. Doolan, D.L. and N. Martinez-Alier, Immune response to pre-erythrocytic stages of malaria parasites. Curr Mol Med, 2006. 6(2): p. 169-85.
  11. Epstein, J.E., et al., Live attenuated malaria vaccine designed to protect through hepatic CD8(+) T cell immunity. Science, 2011. 334(6055): p. 475-80.
  12. Luke, T.C. and S.L. Hoffman, Rationale and plans for developing a non-replicating, metabolically active, radiation-attenuated Plasmodium falciparum sporozoite vaccine. J Exp Biol, 2003. 206(Pt 21): p. 3803-8.
  13. Epstein, J.E., et al., Protection against Plasmodium falciparum malaria by PfSPZ Vaccine. JCI Insight, 2017. 2(1): p. e89154.
  14. Ishizuka, A.S., et al., Protection against malaria at 1 year and immune correlates following PfSPZ vaccination. Nat Med, 2016. 22(6): p. 614-23.
  15. Walker, P.G., et al., Estimated risk of placental infection and low birthweight attributable to Plasmodium falciparum malaria in Africa in 2010: a modelling study. Lancet Glob Health, 2014. 2(8): p. e460-7.
  16. Ayres Pereira, M., et al., Placental Sequestration of Plasmodium falciparum Malaria Parasites Is Mediated by the Interaction Between VAR2CSA and Chondroitin Sulfate A on Syndecan-1. PLoS Pathog, 2016. 12(8): p. e1005831.
  17. Salanti, A., et al., Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria. Mol Microbiol, 2003. 49(1): p. 179-91.
  18. Salanti, A., et al., Evidence for the involvement of VAR2CSA in pregnancy-associated malaria. J Exp Med, 2004. 200(9): p. 1197-203.
  19. van Eijk, A.M., et al., Coverage of intermittent preventive treatment and insecticide-treated nets for the control of malaria during pregnancy in sub-Saharan Africa: a synthesis and meta-analysis of national survey data, 2009-11. Lancet Infect Dis, 2013. 13(12): p. 1029-42.
  20. Institut National de la Santé Et de la Recherche Médicale, F., Trial to Evaluate the Safety and Immunogenicity of a Placental Malaria Vaccine Candidate (PRIMVAC) in healthy adults (PRIMALVAC). clinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US), 2000.