World Health Organization World Malaria Report 2023 (World Health Organization, 2024).
Putrianti, E. D., Silvie, O., Kordes, M., Borrmann, S. & Matuschewski, K. Vaccine-like immunity against malaria by repeated causal-prophylactic treatment of liver-stage Plasmodium parasites. J. Infect. Dis. 199, 899–903 (2009).
Nunes-Cabaço, H., Moita, D. & Prudêncio, M. Five decades of clinical assessment of whole-sporozoite malaria vaccines. Front. Immunol. 13, 977472 (2022).
Nussenzweig, R., Vanderberg, J., Most, H. & Orton, C. Protective immunity produced by the injection of x-irradiated sporozoites of Plasmodium berghei. Nature 216, 160–162 (1967).
Weiss, W. R. & Jiang, C. G. Protective CD8+ T lymphocytes in primates immunized with malaria sporozoites. PLoS ONE 7, e31247 (2012).
Ishizuka, A. S. et al. Protection against malaria at 1 year and immune correlates following PfSPZ vaccination. Nat. Med. 22, 614–623 (2016).
Epstein, J. E. et al. Live attenuated malaria vaccine designed to protect through hepatic CD8+ T cell immunity. Science 334, 475–480 (2011).
Clyde, D. F., Most, H., McCarthy, V. C. & Vanderberg, J. P. Immunization of man against sporozite-induced falciparum malaria. Am. J. Med. Sci. 266, 169–177 (1973).
Fernandez-Ruiz, D. et al. Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection. Immunity 45, 889–902 (2016).
Valencia-Hernandez, A. M. et al. A natural peptide antigen within the Plasmodium ribosomal protein RPL6 confers liver TRM cell-mediated immunity against malaria in mice. Cell Host Microbe 27, 950–962.e957 (2020).
Lefebvre, M. N. et al. Expeditious recruitment of circulating memory CD8 T cells to the liver facilitates control of malaria. Cell Rep. 37, 109956 (2021).
Weiss, W. R., Sedegah, M., Beaudoin, R. L., Miller, L. H. & Good, M. F. CD8+ T cells (cytotoxic/suppressors) are required for protection in mice immunized with malaria sporozoites. Proc. Natl Acad. Sci. USA 85, 573–576 (1988).
de Menezes, M. N. et al. Long lived liver-resident memory T cells of biased specificities for abundant sporozoite antigens drive malaria protection by radiation-attenuated sporozoite vaccination. PLoS Pathog. 21, e1012731 (2025).
Doolan, D. L. & Hoffman, S. L. The complexity of protective immunity against liver-stage malaria. J. Immunol. 165, 1453–1462 (2000).
Guebre-Xabier, M., Schwenk, R. & Krzych, U. Memory phenotype CD8+ T cells persist in livers of mice protected against malaria by immunization with attenuated Plasmodium berghei sporozoites. Eur. J. Immunol. 29, 3978–3986 (1999).
Schmidt, N. W., Butler, N. S., Badovinac, V. P. & Harty, J. T. Extreme CD8 T cell requirements for anti-malarial liver-stage immunity following immunization with radiation attenuated sporozoites. PLoS Pathog. 6, e1000998 (2010).
Tinto, H. et al. Long-term incidence of severe malaria following RTS,S/AS01 vaccination in children and infants in Africa: an open-label 3-year extension study of a phase 3 randomised controlled trial. Lancet Infect. Dis. 19, 821–832 (2019).
Sissoko, M. S. et al. Safety and efficacy of PfSPZ vaccine against Plasmodium falciparum via direct venous inoculation in healthy malaria-exposed adults in Mali: a randomised, double-blind phase 1 trial. Lancet Infect. Dis. 17, 498–509 (2017).
Moita, D. & Prudêncio, M. Whole-sporozoite malaria vaccines: where we are, where we are going. EMBO Mol. Med. 16, 2279–2289 (2024).
Epstein, J. E. et al. Protection against Plasmodium falciparum malaria by PfSPZ vaccine. JCI Insight 2, e89154 (2017).
van Dorst, M. M. A. R. et al. Immunological factors linked to geographical variation in vaccine responses. Nat. Rev. Immunol. 24, 250–263 (2024).
Long, C. A. & Zavala, F. Malaria vaccines and human immune responses. Curr. Opin. Microbiol. 32, 96–102 (2016).
Ganley, M. et al. mRNA vaccine against malaria tailored for liver-resident memory T cells. Nat. Immunol. 24, 1487–1498 (2023).
Meibalan, E. & Marti, M. Biology of malaria transmission. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a025452 (2017).
Butler, N. S. et al. Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nat. Immunol. 13, 188–195 (2012).
Lin, J. W. et al. The subcellular location of ovalbumin in Plasmodium berghei blood stages influences the magnitude of T-cell responses. Infect. Immun. 82, 4654–4665 (2014).
Clarke, S. R. et al. Characterization of the ovalbumin-specific TCR transgenic line OT-I: MHC elements for positive and negative selection. Immunol. Cell Biol. 78, 110–117 (2000).
Shibui, A. et al. CD4+ T cell response in early erythrocytic stage malaria: Plasmodium berghei infection in BALB/c and C57BL/6 mice. Parasitol. Res. 105, 281–286 (2009).
Afonso, A. et al. Plasmodium chabaudi chabaudi malaria parasites can develop stable resistance to atovaquone with a mutation in the cytochrome b gene. Malar. J. 9, 135 (2010).
Dalapati, T. & Moore, J. M. Hemozoin: a complex molecule with complex activities. Curr. Clin. Microbiol. Rep. 8, 87–102 (2021).
Frita, R., Carapau, D., Mota, M. M. & Hänscheid, T. In vivo hemozoin kinetics after clearance of Plasmodium berghei infection in mice. Malar. Res. Treat. 2012, 373086 (2012).
Levesque, M. A., Sullivan, A. D. & Meshnick, S. R. Splenic and hepatic hemozoin in mice after malaria parasite clearance. J. Parasitol. 85, 570–573 (1999).
Shio, M. T. et al. Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. PLoS Pathog. 5, e1000559 (2009).
Pack, A. D. et al. Hemozoin-mediated inflammasome activation limits long-lived anti-malarial immunity. Cell Rep. 36, 109586 (2021).
Coban, C. et al. Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J. Exp. Med. 201, 19–25 (2005).
Wu, X., Gowda, N. M., Kumar, S. & Gowda, D. C. Protein–DNA complex is the exclusive malaria parasite component that activates dendritic cells and triggers innate immune responses. J. Immunol. 184, 4338–4348 (2010).
Coban, C. et al. Immunogenicity of whole-parasite vaccines against Plasmodium falciparum involves malarial hemozoin and host TLR9. Cell Host Microbe 7, 50–61 (2010).
Colin, M. et al. Haemoglobin interferes with the ex vivo luciferase luminescence assay: consequence for detection of luciferase reporter gene expression in vivo. Gene Ther. 7, 1333–1336 (2000).
Teijaro, J. R. & Farber, D. L. COVID-19 vaccines: modes of immune activation and future challenges. Nat. Rev. Immunol. 21, 195–197 (2021).
Wang, Z. et al. mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. Nature 592, 616–622 (2021).
Hassert, M. et al. Regenerating murine CD8+ lung tissue resident memory T cells after targeted radiation exposure. J. Exp. Med. https://doi.org/10.1084/jem.20231144 (2024).
Olsen, T. M., Stone, B. C., Chuenchob, V. & Murphy, S. C. Prime-and-trap malaria vaccination to generate protective CD8+ liver-resident memory T cells. J. Immunol. 201, 1984–1993 (2018).
MacMillen, Z. et al. Accelerated prime-and-trap vaccine regimen in mice using repRNA-based CSP malaria vaccine. npj Vaccines 9, 12 (2024).
Kurup, S. P. et al. Monocyte-derived CD11c+ cells acquire Plasmodium from hepatocytes to prime CD8 T cell immunity to liver-stage malaria. Cell Host Microbe 25, 565–577.e566 (2019).
Woodberry, T. et al. Low-level Plasmodium falciparum blood-stage infection causes dendritic cell apoptosis and dysfunction in healthy volunteers. J. Infect. Dis. 206, 333–340 (2012).
Schwarzer, E., Turrini, F., Giribaldi, G., Cappadoro, M. & Arese, P. Phagocytosis of P. falciparum malarial pigment hemozoin by human monocytes inactivates monocyte protein kinase C. Biochim. Biophys. Acta 1181, 51–54 (1993).
Sissoko, M. S. et al. Safety and efficacy of a three-dose regimen of Plasmodium falciparum sporozoite vaccine in adults during an intense malaria transmission season in Mali: a randomised, controlled phase 1 trial. Lancet Infect. Dis. 22, 377–389 (2022).
Tyberghein, A., Deroost, K., Schwarzer, E., Arese, P. & Van den Steen, P. E. Immunopathological effects of malaria pigment or hemozoin and other crystals. Biofactors 40, 59–78 (2014).
Schwarzer, E., Skorokhod, O. A., Barrera, V. & Arese, P. Hemozoin and the human monocyte—a brief review of their interactions. Parassitologia 50, 143–145 (2008).
Boura, M., Frita, R., Góis, A., Carvalho, T. & Hänscheid, T. The hemozoin conundrum: is malaria pigment immune-activating, inhibiting, or simply a bystander?. Trends Parasitol. 29, 469–476 (2013).
Millington, O. R., Di Lorenzo, C., Phillips, R. S., Garside, P. & Brewer, J. M. Suppression of adaptive immunity to heterologous antigens during Plasmodium infection through hemozoin-induced failure of dendritic cell function. J. Biol. 5, 5 (2006).
Pham, T.-T., Lamb, T. J., Deroost, K., Opdenakker, G. & Van den Steen, P. E. Hemozoin in malarial complications: more questions than answers. Trends Parasitol. 37, 226–239 (2021).
Harding, C. L., Villarino, N. F., Valente, E., Schwarzer, E. & Schmidt, N. W. Plasmodium impairs antibacterial innate immunity to systemic infections in part through hemozoin-bound bioactive molecules. Front. Cell. Infect. Microbiol. https://doi.org/10.3389/fcimb.2020.00328 (2020).
Wilson, N. S. et al. Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity. Nat. Immunol. 7, 165–172 (2006).
Ocaña-Morgner, C., Mota, M. M. & Rodriguez, A. Malaria blood stage suppression of liver stage immunity by dendritic cells. J. Exp. Med. 197, 143–151 (2003).
Schwarzer, E., Kuhn, H., Valente, E. & Arese, P. Malaria-parasitized erythrocytes and hemozoin nonenzymatically generate large amounts of hydroxy fatty acids that inhibit monocyte functions. Blood 101, 722–728 (2003).
Casals-Pascual, C. et al. Suppression of erythropoiesis in malarial anemia is associated with hemozoin in vitro and in vivo. Blood 108, 2569–2577 (2006).
Parroche, P. et al. Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9. Proc. Natl Acad. Sci. USA 104, 1919–1924 (2007).
Kalantari, P. et al. Dual engagement of the NLRP3 and AIM2 inflammasomes by Plasmodium-derived hemozoin and DNA during malaria. Cell Rep. 6, 196–210 (2014).
Franco, A. et al. Hemozoin-induced IFN-γ production mediates innate immune protection against sporozoite infection. Microbes Infect. https://doi.org/10.1016/j.micinf.2024.105343 (2024).
Kularatne, R. N., Crist, R. M. & Stern, S. T. The future of tissue-targeted lipid nanoparticle-mediated nucleic acid delivery. Pharmaceuticals https://doi.org/10.3390/ph15070897 (2022).
Eappen, A. G. et al. In vitro production of infectious Plasmodium falciparum sporozoites. Nature 612, 534–539 (2022).
Villarino, N. F. et al. Composition of the gut microbiota modulates the severity of malaria. Proc. Natl Acad. Sci. USA 113, 2235–2240 (2016).
Doll, K. L., Pewe, L. L., Kurup, S. P. & Harty, J. T. Discriminating protective from nonprotective Plasmodium-specific CD8+ T cell responses. J. Immunol. 196, 4253–4262 (2016).
Kurup, S. P. et al. Regulatory T cells impede acute and long-term immunity to blood-stage malaria through CTLA-4. Nat. Med. 23, 1220–1225 (2017).
Badovinac, V. P., Messingham, K. A. N., Jabbari, A., Haring, J. S. & Harty, J. T. Accelerated CD8+ T-cell memory and prime-boost response after dendritic-cell vaccination. Nat. Med. 11, 748–756 (2005).
Pisciotta, J. M., Scholl, P. F., Shuman, J. L., Shualev, V. & Sullivan, D. J. Quantitative characterization of hemozoin in Plasmodium berghei and vivax. Int. J. Parasitol. Drugs Drug Resist. 7, 110–119 (2017).
Shen, Z., Reznikoff, G., Dranoff, G. & Rock, K. L. Cloned dendritic cells can present exogenous antigens on both MHC class I and class II molecules. J. Immunol. 158, 2723–2730 (1997).
Rodriguez, F., Zhang, J. & Whitton, J. L. DNA immunization: ubiquitination of a viral protein enhances cytotoxic T-lymphocyte induction and antiviral protection but abrogates antibody induction. J. Virol. 71, 8497–8503 (1997).
Rosenblum, D. et al. CRISPR–Cas9 genome editing using targeted lipid nanoparticles for cancer therapy. Sci. Adv. 6, eabc9450 (2020).
