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Immunity to malaria has been linked to the availability and function of helper CD4+ T cells, cytotoxic CD8+ T cells and γδ T cells that can respond to both the asymptomatic liver stage and the symptomatic blood stage of Plasmodium sp. infection. These T cell responses are also thought to be modulated by regulatory T cells. However, the precise mechanisms governing the development and function of Plasmodium-specific T cells and their capacity to form tissue-resident and long-lived memory populations are less well understood. The field has arrived at a point where the push for vaccines that exploit T cell-mediated immunity to malaria has made it imperative to define and reconcile the mechanisms that regulate the development and functions of Plasmodium-specific T cells. Here, we review our current understanding of the mechanisms by which T cell subsets orchestrate host resistance to Plasmodium infection on the basis of observational and mechanistic studies in humans, non-human primates and rodent models. We also examine the potential of new experimental strategies and human infection systems to inform a new generation of approaches to harness T cell responses against malaria.John Harty and colleagues explain how different subsets of CD4+ T cells, CD8+ T cells and γδ T cells respond to the Plasmodium parasites that cause malaria. They discuss the major challenges that need to be overcome in order to harness T cell responses for malaria vaccines and therapies.

Malaria killed over 600,000 people in 2022, a death toll that has not improved since 2015. Additionally, parasites and mosquitoes resistant to existing interventions are spreading across Africa and other regions. Vaccines offer hope to reduce the mortality burden: the first licensed malaria vaccines, RTS,S and R21, will be widely deployed in 2024 and should substantially reduce childhood deaths. In this Review, we provide an overview of the malaria problem and the Plasmodium parasite, then describe the RTS,S and R21 vaccines (the first vaccines for any human parasitic disease), summarizing their benefits and limitations. We explore next-generation vaccines designed using new knowledge of malaria pathogenesis and protective immunity, which incorporate antigens and platforms to elicit effective immune responses against different parasite stages in human or mosquito hosts. We describe a decision-making process that prioritizes malaria vaccine candidates for development in a resource-constrained environment. Future vaccines might improve upon the protective efficacy of RTS,S or R21 for children, or address the wider malaria scourge by preventing pregnancy malaria, reducing the burden of Plasmodium vivax or accelerating malaria elimination.In this Review, Duffy et al. examine the malaria vaccine landscape, showcasing both achievements and setbacks over the past decades. They discuss approaches and assays for different parasite stages, summarize recent advancements, propose a decision-making process for the field and identify future priorities to address unmet needs.

Development of a malaria vaccine remains a critical priority to decrease clinical disease and mortality and facilitate eradication. Accordingly, RTS,S, a protein-subunit vaccine, has completed phase III clinical trials and confers ~30% protection against clinical infection over 4 years. Whole-attenuated-sporozoite and viral-subunit vaccines induce between 20% and 100% protection against controlled human malaria infection, but there is limited published evidence to date for durable, high-level efficacy (>50%) against natural exposure. Importantly, fundamental scientific advances related to the potency, durability, breadth and location of immune responses will be required for improving vaccine efficacy with these and other vaccine approaches. In this Review, we focus on the current understanding of immunological mechanisms of protection from animal models and human vaccine studies, and on how these data should inform the development of next-generation vaccines. Furthermore, we introduce the concept of using passive immunization with monoclonal antibodies as a new approach to prevent and eliminate malaria. Malaria remains a disease of global importance, and a fully protective vaccine is elusive. In this Focus Review, Cockburn and Seder describe how insights into the biology of malaria biology may lead to the design of an effective vaccine.

Geo-seq combines laser capture microdissection and single-cell RNA-seq technology to enable transcriptome analysis of small quantities of cells from defined geographical locations. Conventional gene expression studies analyze multiple cells simultaneously or single cells, for which the exact in vivo or in situ position is unknown. Although cellular heterogeneity can be discerned when analyzing single cells, any spatially defined attributes that underpin the heterogeneous nature of the cells cannot be identified. Here, we describe how to use geographical position sequencing (Geo-seq), a method that combines laser capture microdissection (LCM) and single-cell RNA-seq technology. The combination of these two methods enables the elucidation of cellular heterogeneity and spatial variance simultaneously. The Geo-seq protocol allows the profiling of transcriptome information from only a small number cells and retains their native spatial information. This protocol has wide potential applications to address biological and pathological questions of cellular properties such as prospective cell fates, biological function and the gene regulatory network. Geo-seq has been applied to investigate the spatial transcriptome of mouse early embryo, mouse brain, and pathological liver and sperm tissues. The entire protocol from tissue collection and microdissection to sequencing requires ∼5 d, Data analysis takes another 1 or 2 weeks, depending on the amount of data and the speed of the processor.

The identification of antibodies targeting a conserved site of vulnerability in the Plasmodium falciparum circumsporozoite protein reveals opportunities for passive prevention of malaria in vulnerable individuals and provides insights for rational vaccine design. Development of a highly effective vaccine or antibodies for the prevention and ultimately elimination of malaria is urgently needed. Here we report the isolation of a number of human monoclonal antibodies directed against the Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) from several subjects immunized with an attenuated Pf whole-sporozoite (SPZ) vaccine (Sanaria PfSPZ Vaccine). Passive transfer of one of these antibodies, monoclonal antibody CIS43, conferred high-level, sterile protection in two different mouse models of malaria infection. The affinity and stoichiometry of CIS43 binding to PfCSP indicate that there are two sequential multivalent binding events encompassing the repeat domain. The first binding event is to a unique 'junctional' epitope positioned between the N terminus and the central repeat domain of PfCSP. Moreover, CIS43 prevented proteolytic cleavage of PfCSP on PfSPZ. Analysis of crystal structures of the CIS43 antigen-binding fragment in complex with the junctional epitope determined the molecular interactions of binding, revealed the epitope's conformational flexibility and defined Asn-Pro-Asn (NPN) as the structural repeat motif. The demonstration that CIS43 is highly effective for passive prevention of malaria has potential application for use in travelers, military personnel and elimination campaigns and identifies a new and conserved site of vulnerability on PfCSP for next-generation rational vaccine design.

In the malaria parasite Plasmodium falciparum , the switch from asexual multiplication to sexual differentiation into gametocytes is essential for transmission to mosquitos. The transcription factor PfAP2-G is a key determinant of sexual commitment that orchestrates this crucial cell fate decision. Here we identify the direct targets of PfAP2-G and demonstrate that it dynamically binds hundreds of sites across the genome. We find that PfAP2-G is a transcriptional activator of early gametocyte genes, and identify differences in PfAP2-G occupancy between gametocytes derived via next-cycle and same-cycle conversion. Our data implicate PfAP2-G not only as a transcriptional activator of gametocyte genes, but also as a potential regulator of genes important for red blood cell invasion. We also find that regulation by PfAP2-G requires interaction with a second transcription factor, PfAP2-I. These results clarify the functional role of PfAP2-G during sexual commitment and early gametocytogenesis. The transcription factor PfAP2-G is a key determinant of sexual commitment in Plasmodium falciparum . Here, Josling et al. define the transcriptional regulatory network of PfAP2-G by identifying its DNA binding sites genome-wide, which vary depending on the route of sexual conversion and rely on interactions with the PfAP2-I transcription factor.

Endothelial protein C receptor is shown to be the receptor for Plasmodium falciparum erythrocyte membrane protein 1 variants associated with severe malaria. Drug target in childhood malaria Severe childhood malaria, still causing about a million deaths every year, is triggered by the binding of red blood cells infected with the parasite Plasmodium falciparum to the walls of the host's blood vessels. P. falciparum erythrocyte membrane protein 1 (PfEMP1) containing domain cassettes 8 and 13 is known to be associated with severe malaria, and here Thomas Lavstsen and colleagues identify the receptor for PfEMP1 as endothelial protein C receptor (EPCR), a protein involved in regulating blood coagulation and the inflammatory response. This work could help to explain why some episodes of malaria are life-threatening and involve severe inflammation and suggests a target for future antimalarials. Sequestration of Plasmodium falciparum -infected erythrocytes in host blood vessels is a key triggering event in the pathogenesis of severe childhood malaria, which is responsible for about one million deaths every year 1 . Sequestration is mediated by specific interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and receptors on the endothelial lining 2 . Severe childhood malaria is associated with expression of specific PfEMP1 subtypes containing domain cassettes (DCs) 8 and 13 (ref. 3 ), but the endothelial receptor for parasites expressing these proteins was unknown 4 , 5 . Here we identify endothelial protein C receptor (EPCR), which mediates the cytoprotective effects of activated protein C 6 , as the endothelial receptor for DC8 and DC13 PfEMP1. We show that EPCR binding is mediated through the amino-terminal cysteine-rich interdomain region (CIDRα1) of DC8 and group A PfEMP1 subfamilies, and that CIDRα1 interferes with protein C binding to EPCR. This PfEMP1 adhesive property links P. falciparum cytoadhesion to a host receptor involved in anticoagulation and endothelial cytoprotective pathways, and has implications for understanding malaria pathology and the development of new malaria interventions.

Immunization with Plasmodium falciparum sporozoites under chemoprophylaxis can protect against controlled human malaria infection with the same strain for at least 10 weeks, and protection correlates with polyfunctional T-cell memory. The search for a malaria vaccine The best candidates for a malaria vaccine so far have been radiation-attenuated Plasmodium falciparum sporozoites (PfSPZ) inoculated by mosquitos, intravenous injection of radiation-attenuated, cryopreserved PfSPZ, and infectious PfSPZ inoculated by mosquitos in people taking chloroquine or mefloquine. Here Stephen Hoffman, Peter Kremsner and colleagues report that inoculation of volunteers taking chloroquine with direct intravenous injection of aseptic, cryopreserved, non-irradiated PfSPZ can induce protection against infection with the same strain for at least ten weeks. The authors show that protection correlates with polyfunctional T-cell memory. A highly protective malaria vaccine would greatly facilitate the prevention and elimination of malaria and containment of drug-resistant parasites 1 . A high level (more than 90%) of protection against malaria in humans has previously been achieved only by immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (PfSPZ) inoculated by mosquitoes 2 , 3 , 4 ; by intravenous injection of aseptic, purified, radiation-attenuated, cryopreserved PfSPZ (‘PfSPZ Vaccine’) 5 , 6 ; or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine 7 , 8 , 9 , 10 or mefloquine 11 (chemoprophylaxis with sporozoites). We assessed immunization by direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated PfSPZ (‘PfSPZ Challenge’ 12 , 13 ) to malaria-naive, healthy adult volunteers taking chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as PfSPZ-CVac) 14 . Three doses of 5.12 × 10 4 PfSPZ of PfSPZ Challenge 12 , 13 at 28-day intervals were well tolerated and safe, and prevented infection in 9 out of 9 (100%) volunteers who underwent controlled human malaria infection ten weeks after the last dose (group III). Protective efficacy was dependent on dose and regimen. Immunization with 3.2 × 10 3 (group I) or 1.28 × 10 4 (group II) PfSPZ protected 3 out of 9 (33%) or 6 out of 9 (67%) volunteers, respectively. Three doses of 5.12 × 10 4 PfSPZ at five-day intervals protected 5 out of 8 (63%) volunteers. The frequency of Pf-specific polyfunctional CD4 memory T cells was associated with protection. On a 7,455 peptide Pf proteome array, immune sera from at least 5 out of 9 group III vaccinees recognized each of 22 proteins. PfSPZ-CVac is a highly efficacious vaccine candidate; when we are able to optimize the immunization regimen (dose, interval between doses, and drug partner), this vaccine could be used for combination mass drug administration and a mass vaccination program approach to eliminate malaria from geographically defined areas.

Malaria is a vector-borne disease of global importance, with the vast majority of its life-threatening cases caused by infection with Plasmodium falciparum parasites. Repeated exposure to P. falciparum leads to naturally occurring immunity, but this is not sterilizing and is relatively short-lived. However, antibodies can protect from the disease, as has been shown by serum transfer studies in humans and in animal models. Recent advances in single-cell antibody cloning technologies have enabled the characterization of recombinant monoclonal antibodies against parasite antigens at the molecular level. This work has significantly advanced our understanding of how protective antibodies against P. falciparum are generated, what their molecular features are, their epitope specificity and binding modes, and the formation of memory B cell responses. Here we review these recent advances, with a particular emphasis on human antibody responses. We discuss how these discoveries have laid the foundation for the development of novel intervention strategies, as well as having conceptual implications beyond the malaria field.

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family members mediate receptor- and tissue-specific sequestration of infected erythrocytes (IEs) in malaria. Antibody responses are a central component of naturally acquired malaria immunity. PfEMP1-specific IgG likely protects by inhibiting IE sequestration and through IgG-Fc Receptor (FcγR) mediated phagocytosis and killing of antibody-opsonized IEs. The affinity of afucosylated IgG to FcγRIIIa is up to 40-fold higher than fucosylated IgG, resulting in enhanced antibody-dependent cellular cytotoxicity. Most IgG in plasma is fully fucosylated, but afucosylated IgG is elicited in response to enveloped viruses and to paternal alloantigens during pregnancy. Here we show that naturally acquired PfEMP1-specific IgG is strongly afucosylated in a stable and exposure-dependent manner, and efficiently induces FcγRIIIa-dependent natural killer (NK) cell degranulation. In contrast, immunization with a subunit PfEMP1 (VAR2CSA) vaccine results in fully fucosylated specific IgG. These results have implications for understanding protective natural- and vaccine-induced immunity to malaria. Here, Larsen et al. describe differences in Fc fucosylation of P. falciparum PfEMP1-specific IgG produced in response to natural infection versus VAR2CSA-type subunit vaccination, which leads to differences in the ability to induce FcγRIIIa-dependent natural killer cell degranulation.