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In this article from Southeast Asia and Africa, the emergence of widespread decreased susceptibility of Plasmodium falciparum to artemisinins, detected throughout Southeast Asia, is associated with a point mutation in the kelch protein on chromosome 13. Artemisinin derivatives are highly potent, rapidly eliminated antimalarial drugs with a broad stage specificity of action. They clear parasitemia more rapidly than all other currently available antimalarial agents. In the 1990s, resistance to available antimalarial drugs such as chloroquine and sulfadoxine–pyrimethamine worsened across areas of the world where malaria is endemic. As a direct consequence, morbidity and mortality associated with malaria increased, especially among African children, who account for most deaths from malaria. 1 The artemisinin-based combination therapies were introduced in the mid-1990s, when there was an imminent prospect of untreatable malaria in Southeast Asia, where resistance to all available antimalarial . . .

Dihydroartemisinin-piperaquine has been adopted as first-line artemisinin combination therapy (ACT) for multidrug-resistant Plasmodium falciparum malaria in Cambodia because of few remaining alternatives. We aimed to assess the efficacy of standard 3 day dihydroartemisinin-piperaquine treatment of uncomplicated P falciparum malaria, with and without the addition of primaquine, focusing on the factors involved in drug resistance. In this observational cohort study, we assessed 107 adults aged 18–65 years presenting to Anlong Veng District Hospital, Oddar Meanchey Province, Cambodia, with uncomplicated P falciparum or mixed P falciparum/Plasmodium vivax infection of between 1000 and 200 000 parasites per μL of blood, and participating in a randomised clinical trial in which all had received dihydroartemisinin-piperaquine for 3 days, after which they had been randomly allocated to receive either primaquine or no primaquine. The trial was halted early due to poor dihydroartemisinin-piperaquine efficacy, and we assessed day 42 PCR-corrected therapeutic efficacy (proportion of patients with recurrence at 42 days) and evidence of drug resistance from the initial cohort. We did analyses on both the intention to treat (ITT), modified ITT (withdrawals, losses to follow-up, and those with secondary outcomes [eg, new non-recrudescent malaria infection] were censored on the last day of follow-up), and per-protocol populations of the original trial. The original trial was registered with ClinicalTrials.gov, number NCT01280162. Between Dec 10, 2012, and Feb 18, 2014, we had enrolled 107 patients in the original trial. Enrolment was voluntarily halted on Feb 16, 2014, before reaching planned enrolment (n=150) because of poor efficacy. We had randomly allocated 50 patients to primaquine and 51 patients to no primaquine groups. PCR-adjusted Kaplan-Meier risk of P falciparum 42 day recrudescence was 54% (95% CI 45–63) in the modified ITT analysis population. We found two kelch13 propeller gene mutations associated with artemisinin resistance—a non-synonymous Cys580Tyr substitution in 70 (65%) of 107 participants, an Arg539Thr substitution in 33 (31%), and a wild-type parasite in four (4%). Unlike Arg539Thr, Cys580Tyr was accompanied by two other mutations associated with extended parasite clearance (MAL10:688956 and MAL13:1718319). This combination triple mutation was associated with a 5·4 times greater risk of treatment failure (hazard ratio 5·4 [95% CI 2·4–12]; p<0·0001) and higher piperaquine 50% inhibitory concentration (triple mutant 34 nM [28–41]; non-triple mutant 24 nM [1–27]; p=0·003) than other infections had. The drug was well tolerated, with gastrointestinal symptoms being the most common complaints. The dramatic decline in efficacy of dihydroartemisinin-piperaquine compared with what was observed in a study at the same location in 2010 was strongly associated with a new triple mutation including the kelch13 Cys580Tyr substitution. 3 days of artemisinin as part of an artemisinin combination therapy regimen might be insufficient. Strict regulation and monitoring of antimalarial use, along with non-pharmacological approaches to malaria resistance containment, must be integral parts of the public health response to rapidly accelerating drug resistance in the region. Armed Forces Health Surveillance Center/Global Emerging Infections Surveillance and Response System, Military Infectious Disease Research Program, National Institute of Allergy and Infectious Diseases, and American Society of Tropical Medicine and Hygiene/Burroughs Wellcome Fund.

There is a tremendous need for a malaria vaccine. By means of a sieve analysis, the RTS,S/AS01 candidate vaccine, which is in advanced clinical development, was shown to have improved vaccine efficacy against genetically matched versus mismatched infecting malaria strains. Malaria induces substantial morbidity and mortality worldwide 1 and has proved to be a challenge for vaccine-development efforts. The recently renewed effort to control, eliminate, and hopefully eradicate malaria will have a greater likelihood of success if a vaccine can be combined with other intervention methods, such as drug-administration campaigns and insect-vector control. 2 , 3 The most advanced candidate vaccine for protection against Plasmodium falciparum malaria infection, RTS,S/AS01, is a monovalent recombinant protein vaccine that targets a fragment of the circumsporozoite protein parasite antigen. RTS,S/AS01 was evaluated in a large randomized, controlled, phase 3 trial, conducted at 11 study sites in Africa . . .

The current epidemic of artemisinin resistant Plasmodium falciparum in Southeast Asia is the result of a soft selective sweep involving at least 20 independent kelch13 mutations. In a large global survey, we find that kelch13 mutations which cause resistance in Southeast Asia are present at low frequency in Africa. We show that African kelch13 mutations have originated locally, and that kelch13 shows a normal variation pattern relative to other genes in Africa, whereas in Southeast Asia there is a great excess of non-synonymous mutations, many of which cause radical amino-acid changes. Thus, kelch13 is not currently undergoing strong selection in Africa, despite a deep reservoir of variations that could potentially allow resistance to emerge rapidly. The practical implications are that public health surveillance for artemisinin resistance should not rely on kelch13 data alone, and interventions to prevent resistance must account for local evolutionary conditions, shown by genomic epidemiology to differ greatly between geographical regions. Malaria is an infectious disease caused by a microscopic parasite called Plasmodium, which is transferred between humans by mosquitos. One species of malaria parasite called Plasmodium falciparum can cause particularly severe and life-threatening forms of the disease. Currently, the most widely used treatment for P. falciparum infections is artemisinin combination therapy, a treatment that combines the drug artemisinin (or a closely related molecule) with another antimalarial drug. However, resistance to artemisinin has started to spread throughout Southeast Asia. Artemisinin resistance is caused by mutations in a parasite gene called kelch13, and researchers have identified over 20 different mutations in P. falciparum that confer artemisinin resistance. The diversity of mutations involved, and the fact that the same mutation can arise independently in different locations, make it difficult to track the spread of resistance using conventional molecular marker approaches. Here, Amato, Miotto et al. sequenced the entire genomes of more than 3,000 clinical samples of P. falciparum from Southeast Asia and Africa, collected as part of a global network of research groups called the MalariaGEN Plasmodium falciparum Community Project. Amato, Miotto et al. found that African parasites had independently acquired many of the same kelch13 mutations that are known to cause resistance to artemisinin in Southeast Asia. However the kelch13 mutations seen in Africa remained at low levels in the parasite population, and appeared to be under much less pressure for evolutionary selection than those found in Southeast Asia. These findings demonstrate that the emergence and spread of resistance to antimalarial drugs does not depend solely on the mutational process, but also on other factors that influence whether the mutations will spread in the population. Understanding how this is affected by different patterns of drug treatments and other environmental conditions will be important in developing more effective strategies for combating malaria.

Artemisinin therapy is a first-line approach to malaria treatment in many parts of the world. Resistance to this class of agents is an emerging threat to malaria treatment and control. In two studies conducted in Thailand and Cambodia, P. falciparum was found to have reduced in vivo susceptibility to artesunate, characterized by slow parasite clearance. In two studies conducted in Thailand and Cambodia, P. falciparum was found to have reduced in vivo susceptibility to artesunate, characterized by slow parasite clearance. Artemisinins are established antimalarial agents with an excellent safety profile. 1 Artemisinin-based combination therapies are now recommended by the World Health Organization (WHO) as first-line treatment of uncomplicated falciparum malaria in all areas in which malaria is endemic. 2 Replacing ineffective, failing treatments (chloroquine and sulfadoxine–pyrimethamine) with artemisinin-based combination therapies has reduced the morbidity and mortality associated with malaria. 3 – 5 Parenteral artesunate is replacing quinine for the treatment of severe malaria. 6 Recently, there have been signs that the efficacy of artemisinin-based combination therapy and artesunate monotherapy have declined in western Cambodia. 7 – 10 Artemisinin resistance would be disastrous for global malaria control. To . . .

Efforts to develop a live-attenuated malaria vaccine are advancing. In this report, an engineered sporozoite-based vaccine is presented in a human challenge model, with associated immunologic assessments.

Plasmodium parasite–specific antibodies are critical for protection against malaria, yet the development of long-lived and effective humoral immunity against Plasmodium takes many years and multiple rounds of infection and cure. Here, we report that the rapid development of short-lived plasmablasts during experimental malaria unexpectedly hindered parasite control by impeding germinal center responses. Metabolic hyperactivity of plasmablasts resulted in nutrient deprivation of the germinal center reaction, limiting the generation of memory B cell and long-lived plasma cell responses. Therapeutic administration of a single amino acid to experimentally infected mice was sufficient to overcome the metabolic constraints imposed by plasmablasts and enhanced parasite clearance and the formation of protective humoral immune memory responses. Thus, our studies not only challenge the current model describing the role and function of blood-stage Plasmodium -induced plasmablasts but they also reveal new targets and strategies to improve anti- Plasmodium humoral immunity. Early humoral responses to malaria fail to induce durable protective antibodies. Butler and colleagues report that low-affinity, short-lived plasmablasts become nutrient sinks for glutamine and starve germinal center B and T cells, thereby reducing the generation of high-affinity B cells and long-lived plasma cells and memory B cells.

The pathogenesis of Plasmodium falciparum malaria is linked to the variant surface antigen PfEMP1, which mediates tethering of infected erythrocytes to the host endothelium and is encoded by approximately 60 var genes per parasite genome. Repeated episodes of malaria infection result in the gradual acquisition of protective antibodies against PfEMP1 variants. The antibody repertoire is believed to provide a selective pressure driving the clonal expansion of parasites expressing unrecognized PfEMP1 variants, however, due to the lack of experimental in vivo models there is only limited experimental evidence in support of this concept. To get insight into the impact of naturally acquired immunity on the expressed var gene repertoire early during infection we performed controlled human malaria infections of 20 adult African volunteers with life-long malaria exposure using aseptic, purified, cryopreserved P. falciparum sporozoites (Sanaria PfSPZ Challenge) and correlated serological data with var gene expression patterns from ex vivo parasites. Among the 10 African volunteers who developed patent infections, individuals with low antibody levels showed a steep rise in parasitemia accompanied by broad activation of multiple, predominantly subtelomeric var genes, similar to what we previously observed in naïve volunteers. In contrast, individuals with intermediate antibody levels developed asymptomatic infections and the ex vivo parasite populations expressed only few var gene variants, indicative of clonal selection. Importantly, in contrast to parasites from naïve volunteers, expression of var genes coding for endothelial protein C receptor (EPCR)-binding PfEMP1 that are associated with severe childhood malaria was rarely detected in semi-immune adult African volunteers. Moreover, we followed var gene expression for up to six parasite replication cycles and demonstrated for the first time in vivo a shift in the dominant var gene variant. In conclusion, our data suggest that P. falciparum activates multiple subtelomeric var genes at the onset of blood stage infection facilitating rapid expansion of parasite clones which express PfEMP1 variants unrecognized by the host's immune system, thus promoting overall parasite survival in the face of host immunity.

Malaria vaccines consisting of metabolically active Plasmodium falciparum ( Pf ) sporozoites can offer improved protection compared with currently deployed subunit vaccines. In a previous study, we demonstrated the superior protective efficacy of a three-dose regimen of late-arresting genetically attenuated parasites administered by mosquito bite (GA2-MB) compared with early-arresting counterparts (GA1-MB) against a homologous controlled human malaria infection. Encouraged by these results, we explored the potency of a single GA2-MB immunization in a placebo-controlled randomized trial. Primary outcomes were safety and tolerability, time-to-parasitemia and protective efficacy. Humoral and cellular immunological results were considered secondary outcomes. Here we report the safe administration of GA2-MB with no breakthrough malaria and sterile protection in nine of ten participants at 6 weeks after a single immunization with 50 GA2-infected mosquitoes, compared with none of five mock-immunized participants, against a homologous controlled human malaria infection. Immunization increased circulating Pf -specific polyfunctional effector memory CD4 + T cells coexpressing tumor necrosis factor and interleukin-2. This unprecedented 90% protective efficacy after a single low-dose immunization holds great promise for the potency of GA2 immunization. Future studies should demonstrate whether GA2 is similarly efficacious in pre-exposed populations and whether the favorable safety profile reported here holds up in larger groups. ClinicalTrials.gov registration: NCT05468606 . In a small randomized controlled clinical trial, a single immunization for malaria using mosquitoes infected with attenuated parasites showed unprecedented 90% protective efficacy and did not lead to breakthrough disease.