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Ring-infected erythrocytes are the predominant asexual stage in the peripheral circulation but are rarely investigated in the context of acquired immunity against Plasmodium falciparum malaria. Here we compare antibody-dependent phagocytosis of ring-infected parasite cultures in samples from a controlled human malaria infection (CHMI) study (NCT02739763). Protected volunteers did not develop clinical symptoms, maintained parasitaemia below a predefined threshold of 500 parasites/μl and were not treated until the end of the study. Antibody-dependent phagocytosis of both ring-infected and uninfected erythrocytes from parasite cultures was strongly correlated with protection. A surface proteomic analysis revealed the presence of merozoite proteins including erythrocyte binding antigen-175 and −140 on ring-infected and uninfected erythrocytes, providing an additional antibody-mediated protective mechanism for their activity beyond invasion-inhibition. Competition phagocytosis assays support the hypothesis that merozoite antigens are the key mediators of this functional activity. Targeting ring-stage parasites may contribute to the control of parasitaemia and prevention of clinical malaria. Here the authors show that antibody-dependent phagocytosis of ring-stage P. falciparum parasites is mediated by merozoite antigens and is a strong predictor of protection following challenge in a controlled human malaria infection study in semi-immune Kenyan adults.

Malaria remains a major global health priority, and monoclonal antibodies (mAbs) are emerging as potential new tools to support efforts to control the disease. Recent data suggest that Fc-dependent mechanisms of immunity are important mediators of protection against the blood stages of the infection, but few studies have investigated this in the context of mAbs. We aimed to isolate mAbs agnostic to cognate antigens that target whole merozoites and simultaneously induce potent neutrophil activity measured by the level of reactive oxygen species (ROS) production using an antibody-dependent respiratory burst (ADRB) assay. We used samples from semi-immune adults living in coastal Kenya to isolate mAbs that induce merozoite-specific ADRB activity. We then tested whether modifying the expressed IgG1 isotype to an IgG-IgA Fc region chimera would enhance the level of ADRB activity. We isolated a panel of nine mAbs with specificity to whole merozoites. mAb J31 induced ADRB activity in a dose-dependent fashion. Compared to IgG1, our modified antibody IgG-IgA bi-isotype induced higher ADRB activity across all concentrations tested. Further, we observed a negative hook effect at high IgG1 mAb concentrations (i.e., >200 µg/mL), but this was reversed by Fc modification. We identified MSP3.5 as the potential cognate target of mAb J31. We demonstrate an approach to engineer mAbs with enhanced ADRB potency against blood-stage parasites.

Transmission-blocking vaccines are among the novel tools under development for malaria control and elimination. Understanding the human immune response to the sexual stages of Plasmodium falciparum is essential for progressing transmission-blocking vaccine development. A serosurvey was conducted in Tanzania, from May to August 2022 among 290 participants, consisting of 114 children (5–12 years), 44 adolescents (13–17 years), and 132 adults (18–45 years). The participants were tested for malaria parasites using quantitative polymerase chain reaction, and standardized enzyme-linked immunosorbent assays were performed to detect the presence of IgG antibodies against transmission-blocking target antigens—Pfs230D1M, Pfs48/45, and Pfs25. A set of 10 plasma samples that were reactive to Pfs230DIM and/or Pfs48/45 were tested individually for transmission-reducing activity via standard membrane feeding assays. Of the participants tested, 56% (157/281) had detectable Pfs230D1M antibodies, and 49% (141/290) were positive for Pfs48/45 IgG. Approximately 30% were seropositive for both. However, Pfs25 IgG was not detected in any of the 117 participants tested. The seroprevalence for Pfs230D1M and Pfs48/45 IgG increased significantly with participants’ age, with adults more likely to have antibodies than children: Pfs230D1M (adjusted odds ratio: 3.16, 95% confidence interval: 1.81–5.53, p -value ≤ 0.0001) and Pfs45/48 (OR: 3.06, 95% CI: 1.79–5.25, p ≤ 0.0001). There was no significant difference in antibody titers for Pfs230D1M and Pfs48/45 antibodies across age groups. A significant transmission-reducing activity was observed in 2/10 participants, who were highly reactive to Pfs230D1M and Pfs48/45. Naturally acquired antibody responses to both full-length Pfs48/45 and Pfs230D1M proteins are prevalent and appeared to be stable, suggesting that semi-immune populations may be ideal to evaluate boosting transmission-blocking vaccine candidates.

Background Asymptomatic carriage of malaria parasites is common in high transmission intensity areas and confounds clinical case definitions for research studies. This is important for investigations that aim to identify immune correlates of protection from clinical malaria. The proportion of fevers attributable to malaria parasites is widely used to define different thresholds of parasite density associated with febrile episodes. The varying intensity of malaria transmission was investigated to check whether it had a significant impact on the parasite density thresholds. The same dataset was used to explore an alternative statistical approach, using the probability of developing fevers as a choice over threshold cut-offs. The former has been reported to increase predictive power. Methods Data from children monitored longitudinally between 2005 and 2017 from Junju and Chonyi in Kilifi, Kenya were used. Performance comparison of Bayesian-latent class and logistic power models in estimating malaria attributable fractions and probabilities of having fever given a parasite density with changing malaria transmission intensity was done using Junju cohort. Zero-inflated beta regressions were used to assess the impact of using probabilities to evaluate anti-merozoite antibodies as correlates of protection, compared with multilevel binary regression using data from Chonyi and Junju. Results Malaria transmission intensity declined from over 49% to 5% between 2006 and 2017, respectively. During this period, malaria attributable fraction varied between 27–59% using logistic regression compared to 10–36% with the Bayesian latent class approach. Both models estimated similar patterns of fevers attributable to malaria with changing transmission intensities. The Bayesian latent class model performed well in estimating the probabilities of having fever, while the latter was efficient in determining the parasite density threshold. However, compared to the logistic power model, the Bayesian algorithm yielded lower estimates for both attributable fractions and probabilities of fever. In modelling the association of merozoite antibodies and clinical malaria, both approaches resulted in comparable estimates, but the utilization of probabilities had a better statistical fit. Conclusions Malaria attributable fractions, varied with an overall decline in the malaria transmission intensity in this setting but did not significantly impact the outcomes of analyses aimed at identifying immune correlates of protection. These data confirm the statistical advantage of using probabilities over binary data.

A promising vaccine fails to provide durable protection against infection and clinical malaria in infants, a key malaria vaccine target population, in a phase 2b clinical trial. The need for a highly effective vaccine against malaria remains as urgent as ever.

Background Malaria is transmitted when infected Anopheles mosquitoes take a blood meal. During this process, the mosquitoes inject a cocktail of bioactive proteins that elicit antibody responses in humans and could be used as biomarkers of exposure to mosquito bites. This study evaluated the utility of IgG responses to members of the Anopheles gambiae D7 protein family as serological markers of human–vector contact. Methods The D7L2, D7r1, D7r2, D7r3, D7r4 and SG6 salivary proteins from An. gambiae were expressed as recombinant antigens in Escherichia coli . Antibody responses to the salivary proteins were compared in Europeans with no prior exposure to malaria and lifelong residents of Junju in Kenya and Kitgum in Uganda where the intensity of malaria transmission is moderate and high, respectively. In addition, to evaluate the feasibility of using anti-D7 IgG responses as a tool to evaluate the impact of vector control interventions, we compared responses between individuals using insecticide-treated bednets to those who did not in Junju, Kenya where bednet data were available. Results We show that both the long and short forms of the D7 salivary gland antigens elicit a strong antibody response in humans. IgG responses against the D7 antigens reflected the transmission intensities of the three study areas, with the highest to lowest responses observed in Kitgum (northern Uganda), Junju (Kenya) and malaria-naïve Europeans, respectively. Specifically, the long form D7L2 induced an IgG antibody response that increased with age and that was lower in individuals who slept under a bednet, indicating its potential as a serological tool for estimating human–vector contact and monitoring the effectiveness of vector control interventions. Conclusions This study reveals that D7L2 salivary antigen has great potential as a biomarker of exposure to mosquito bites and as a tool for assessing the efficacy of vector control strategies such as bednet use. Graphical abstract

The merozoite surface protein 1 (MSP1) is the most abundant protein on the surface of the invasive merozoite stages of Plasmodium falciparum and has long been considered a key target of protective immunity. We used samples from a single controlled human malaria challenge study to test whether the full-length version of MSP1 (MSP1 FL ) induced antibodies that mediated Fc-IgG functional activity in five independent assays. We found that anti-MSP1 FL antibodies induced complement fixation via C1q, monocyte-mediated phagocytosis, neutrophil respiratory burst, and natural killer cell degranulation as well as IFNγ production. Activity in each of these assays was strongly associated with protection. The breadth of MSP1-specific Fc-mediated effector functions was more strongly associated with protection than the individual measures and closely mirrored what we have previously reported using the same assays against merozoites. Our findings suggest that MSP1 FL is an important target of functional antibodies that contribute to a protective immune response against malaria.

Signaling by serine/threonine phosphorylation controls diverse processes in bacteria, and identification of the stimuli that activate protein kinases is an outstanding question in the field. Recently, we showed that nutrients stimulate phosphorylation of the protein kinase G substrate GarA in Mycobacterium smegmatis and Mycobacterium tuberculosis and that the action of GarA in regulating central metabolism depends upon whether it is phosphorylated. Here we present an investigation into the mechanism by which nutrients activate PknG. Two unknown genes were identified as co-conserved and co-expressed with PknG: their products were a putative lipoprotein, GlnH, and putative transmembrane protein, GlnX. Using a genetic approach, we showed that the membrane protein GlnX is functionally linked to PknG. Furthermore, we determined that the ligand specificity of GlnH matches the amino acids that stimulate GarA phosphorylation. We determined the structure of GlnH in complex with different amino acid ligands (aspartate, glutamate, and asparagine), revealing the structural basis of ligand specificity. We propose that the amino acid concentration in the periplasm is sensed by GlnH and that protein-protein interaction allows transmission of this information across the membrane via GlnX to activate PknG. This sensory system would allow regulation of nutrient utilization in response to changes in nutrient availability. The sensor, signaling, and effector proteins are conserved throughout the Actinobacteria , including the important human pathogen Mycobacterium tuberculosis , industrial amino acid producer Corynebacterium glutamicum , and antibiotic-producing Streptomyces species. IMPORTANCE Tuberculosis (TB) kills 5,000 people every day, and the prevalence of multidrug-resistant TB is increasing in every country. The processes by which the pathogen Mycobacterium tuberculosis senses and responds to changes in its environment are attractive targets for drug development. Bacterial metabolism differs dramatically between growing and dormant cells, and these changes are known to be important in pathogenesis of TB. Here, we used genetic and biochemical approaches to identify proteins that allow M. tuberculosis to detect amino acids in its surroundings so that it can regulate its metabolism. We have also shown how individual amino acids are recognized. The findings have broader significance for other actinobacterial pathogens, such as nontuberculous mycobacteria, as well as Actinobacteria used to produce billions of dollars of amino acids and antibiotics every year. Tuberculosis (TB) kills 5,000 people every day, and the prevalence of multidrug-resistant TB is increasing in every country. The processes by which the pathogen Mycobacterium tuberculosis senses and responds to changes in its environment are attractive targets for drug development. Bacterial metabolism differs dramatically between growing and dormant cells, and these changes are known to be important in pathogenesis of TB. Here, we used genetic and biochemical approaches to identify proteins that allow M. tuberculosis to detect amino acids in its surroundings so that it can regulate its metabolism. We have also shown how individual amino acids are recognized. The findings have broader significance for other actinobacterial pathogens, such as nontuberculous mycobacteria, as well as Actinobacteria used to produce billions of dollars of amino acids and antibiotics every year.

A promising vaccine fails to provide durable protection against infection and clinical malaria in infants, a key malaria vaccine target population, in a phase 2b clinical trial. The need for a highly effective vaccine against malaria remains as urgent as ever.

Pregnant women in malaria-endemic countries are at risk of placental malaria (PM), which can lead to adverse outcomes for both mothers and children. Histology of placental tissue is the gold standard for diagnosing PM, as it can detect current and past infections. Prior reviews focussed on malaria in pregnancy generally; in this systematic review, we specifically examine PM due to Plasmodium falciparum, its associated risk factors, and its impact on maternal and foetal outcomes. We included studies performed since 2013, reflecting important updates in WHO policy recommendations for PM control efforts and resistance to sufadoxine-primethamine resistance over the past decade. After extracting relevant data, we calculated the pooled prevalence, odds ratios (ORs), and risk ratios. We assessed the quality of the included studies using the Newcastle-Ottawa scale. The review included 50 studies, 45 of which were from sub-Saharan Africa (SSA), with 15 (33%) of them using histological diagnosis. Global PM prevalence was 17% (95% confidence interval (CI) = 12-21), rising to 23% (95% CI = 1-4) in histology-based studies. Prevalence was higher in SSA (19%; 95% CI = 14-24) than in other regions (4%; 95% CI = 1-9), with West Africa showing the highest rates. One study including only HIV-positive women reported a PM prevalence of 45% (95% CI = 38-52) compared to 17% (95% CI = 10-25) in HIV-negative women. One study on stillbirth showed an OR of 3.81 (95% CI = 1.22-11.94) and primigravidae had pooled ORs of 1.61 (95% CI = 0.91-2.84) compared to multigravidae. The ORs and CIs for congenital malaria, malaria in infancy, preterm birth, and low birth weight were wide, indicating imprecision. Our meta-analysis reveals a high PM burden in high- malaria transmission areas, especially among primigravidae and HIV-positive women. We note that PM remains high in SSA, with regional variation, with one in four pregnant women diagnosed by histological examination of the placenta, reflecting both current and past PM exposure. Reliance on non-histological methods may lead to underestimation of true PM prevalence. Due to wide confidence intervals and limited data, we could draw no conclusions on the impact of PM on maternal and foetal outcomes. Residual high heterogeneity reflects real-world diversity across populations, strengthening the generalisability of our findings.