Subcutaneous Administration of a Monoclonal Antibody to Prevent Malaria.

BACKGROUND: Subcutaneous administration of the monoclonal antibody L9LS protected adults against controlled Plasmodium falciparum infection in a phase 1 trial. Whether a monoclonal antibody administered subcutaneously can protect children from P. falciparum infection in a region where this organism is endemic is unclear. METHODS: We conducted a phase 2 trial in Mali to assess the safety and efficacy of subcutaneous administration of L9LS in children 6 to 10 years of age over a 6-month malaria season. In part A of the trial, safety was assessed at three dose levels in adults, followed by assessment at two dose levels in children. In part B of the trial, children were randomly assigned, in a 1:1:1 ratio, to receive 150 mg of L9LS, 300 mg of L9LS, or placebo. The primary efficacy end point, assessed in a time-to-event analysis, was the first P. falciparum infection, as detected on blood smear performed at least every 2 weeks for 24 weeks. A secondary efficacy end point was the first episode of clinical malaria, as assessed in a time-to-event analysis. RESULTS: No safety concerns were identified in the dose-escalation part of the trial (part A). In part B, 225 children underwent randomization, with 75 children assigned to each group. No safety concerns were identified in part B. P. falciparum infection occurred in 36 participants (48%) in the 150-mg group, in 30 (40%) in the 300-mg group, and in 61 (81%) in the placebo group. The efficacy of L9LS against P. falciparum infection, as compared with placebo, was 66% (adjusted confidence interval [95% CI], 45 to 79) with the 150-mg dose and 70% (adjusted 95% CI, 50 to 82) with the 300-mg dose (P<0.001 for both comparisons). Efficacy against clinical malaria was 67% (adjusted 95% CI, 39 to 82) with the 150-mg dose and 77% (adjusted 95% CI, 55 to 89) with the 300-mg dose (P<0.001 for both comparisons). CONCLUSIONS: Subcutaneous administration of L9LS to children was protective against P. falciparum infection and clinical malaria over a period of 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT05304611.).

Holistic processing is modulated by the probability that parts contain task-congruent information.

Holistic processing of face and non-face stimuli has been framed as a perceptual strategy, with classic hallmarks of holistic processing, such as the composite effect, reflecting a failure of selective attention, which is a consequence of this strategy. Further, evidence that holistic processing is impacted by training different patterns of attentional prioritization suggest that it may be a result of learned attention to the whole, which renders it difficult to attend to only part of a stimulus. If so, holistic processing should be modulated by the same factors that shape attentional selection, such as the probability that distracting or task-relevant information will be present. In contrast, other accounts suggest that it is the match to an internal face template that triggers specialized holistic processing mechanisms. Here we probed these accounts by manipulating the probability, across different testing sessions, that the task-irrelevant face part in the composite face task will contain task-congruent or -incongruent information. Attentional accounts of holistic processing predict that when the probability that the task-irrelevant part contains congruent information is low (25%), holistic processing should be attenuated compared to when this probability is high (75%). In contrast, template-based accounts of holistic face processing predict that it will be unaffected by manipulation given the integrity of the faces remains intact. Experiment 1 found evidence consistent with attentional accounts of holistic face processing and Experiment 2 extends these findings to holistic processing of non-face stimuli. These findings are broadly consistent with learned attention accounts of holistic processing.

NK cell-induced damage to P.falciparum-infected erythrocytes requires ligand-specific recognition and releases parasitophorous vacuoles that are phagocytosed by monocytes in the presence of immune IgG.

Natural killer (NK) cells lyse virus-infected cells and transformed cells through polarized delivery of lytic effector molecules into target cells. We have shown that NK cells lyse Plasmodium falciparum-infected red blood cells (iRBC) via antibody-dependent cellular cytotoxicity (ADCC). A high frequency of adaptive NK cells, with elevated intrinsic ADCC activity, in people chronically exposed to malaria transmission is associated with reduced parasitemia and resistance to disease. How NK cells bind to iRBC and the outcome of iRBC lysis by NK cells has not been investigated. We applied gene ablation in inducible erythrocyte precursors and antibody-blocking experiments with iRBC to demonstrate a central role of CD58 and ICAM-4 as ligands for adhesion by NK cells via CD2 and integrin αMß2, respectively. Adhesion was dependent on opsonization of iRBC by IgG. Live imaging and quantitative flow cytometry of NK-mediated ADCC toward iRBC revealed that damage to the iRBC plasma membrane preceded damage to P. falciparum within parasitophorous vacuoles (PV). PV were identified and tracked with a P.falciparum strain that expresses the PV membrane-associated protein EXP2 tagged with GFP. After NK-mediated ADCC, PV were either found inside iRBC ghosts or released intact and devoid of RBC plasma membrane. Electron microscopy images of ADCC cultures revealed tight NK-iRBC synapses and free vesicles similar in size to GFP+ PV isolated from iRBC lysates by cell sorting. The titer of IgG in plasma of malaria-exposed individuals that bound PV was two orders of magnitude higher than IgG that bound iRBC. This immune IgG stimulated efficient phagocytosis of PV by primary monocytes. The selective NK-mediated damage to iRBC, resulting in release of PV, and subsequent phagocytosis of PV by monocytes may combine for efficient killing and removal of intra-erythrocytic P.falciparum parasite. This mechanism may mitigate the inflammation and malaria symptoms during blood-stage P. falciparum infection.

Backward masking implicates cortico-cortical recurrent processes in convex figure context effects and cortico-thalamic recurrent processes in resolving figure-ground ambiguity.

Introduction: Previous experiments purportedly showed that image-based factors like convexity were sufficient for figure assignment. Recently, however, we found that the probability of perceiving a figure on the convex side of a central border was only slightly higher than chance for two-region displays and increased with the number of display regions; this increase was observed only when the concave regions were homogeneously colored. These convex figure context effects (CEs) revealed that figure assignment in these classic displays entails more than a response to local convexity. A Bayesian observer replicated the convex figure CEs using both a convexity object prior and a new, homogeneous background prior and made the novel prediction that the classic displays in which both the convex and concave regions were homogeneous were ambiguous during perceptual organization. Methods: Here, we report three experiments investigating the proposed ambiguity and examining how the convex figure CEs unfold over time with an emphasis on whether they entail recurrent processing. Displays were shown for 100 ms followed by pattern masks after ISIs of 0, 50, or 100 ms. The masking conditions were designed to add noise to recurrent processing and therefore to delay the outcome of processes in which they play a role. In Exp. 1, participants viewed two- and eight-region displays with homogeneous convex regions (homo-convex displays; the putatively ambiguous displays). In Exp. 2, participants viewed putatively unambiguous hetero-convex displays. In Exp. 3, displays and masks were presented to different eyes, thereby delaying mask interference in the thalamus for up to 100 ms. Results and discussion: The results of Exps. 1 and 2 are consistent with the interpretation that recurrent processing is involved in generating the convex figure CEs and resolving the ambiguity of homo-convex displays. The results of Exp. 3 suggested that corticofugal recurrent processing is involved in resolving the ambiguity of homo-convex displays and that cortico-cortical recurrent processes play a role in generating convex figure CEs and these two types of recurrent processes operate in parallel. Our results add to evidence that perceptual organization evolves dynamically and reveal that stimuli that seem unambiguous can be ambiguous during perceptual organization.

Understanding the encoding of object locations in small-scale spaces during free exploration using eye tracking.

Navigation is instrumental to daily life and is often used to encode and locate objects, such as keys in one's house. Yet, little is known about how navigation works in more ecologically valid situations such as finding objects within a room. Specifically, it is not clear how vision vs. body movements contribute differentially to spatial memory in such small-scale spaces. In the current study, participants encoded object locations by viewing them while standing (stationary condition) or by additionally being guided by the experimenter while blindfolded (walking condition) after viewing the objects. They then retrieved the objects from the same or different viewpoint, creating a 2 × 2 within subject design. We simultaneously recorded participant eye movements throughout the experiment using mobile eye tracking. The results showed no statistically significant differences among our four conditions (stationary, same viewpoint as encoding; stationary, different viewpoint; walking, same viewpoint; walking, different viewpoint), suggesting that in a small real-world space, vision may be sufficient to remember object locations. Eye tracking analyses revealed that object locations were better remembered next to landmarks and that participants encoded items on one wall together, suggesting the use of local wall coordinates rather than global room coordinates. A multivariate regression analysis revealed that the only significant predictor of object placement accuracy was average looking time. These results suggest that vision may be sufficient for encoding object locations in a small-scale environment and that such memories may be formed largely locally rather than globally.

Rare, convergent antibodies targeting the stem helix broadly neutralize diverse betacoronaviruses.

Humanity has faced three recent outbreaks of novel betacoronaviruses, emphasizing the need to develop approaches that broadly target coronaviruses. Here, we identify 55 monoclonal antibodies from COVID-19 convalescent donors that bind diverse betacoronavirus spike proteins. Most antibodies targeted an S2 epitope that included the K814 residue and were non-neutralizing. However, 11 antibodies targeting the stem helix neutralized betacoronaviruses from different lineages. Eight antibodies in this group, including the six broadest and most potent neutralizers, were encoded by IGHV1-46 and IGKV3-20. Crystal structures of three antibodies of this class at 1.5-1.75-Å resolution revealed a conserved mode of binding. COV89-22 neutralized SARS-CoV-2 variants of concern including Omicron BA.4/5 and limited disease in Syrian hamsters. Collectively, these findings identify a class of IGHV1-46/IGKV3-20 antibodies that broadly neutralize betacoronaviruses by targeting the stem helix but indicate these antibodies constitute a small fraction of the broadly reactive antibody response to betacoronaviruses after SARS-CoV-2 infection.

BOLD activation on the groundside of figures: More suppression of grounds that competed more for figural status.

A fundamental aspect of object detection is assigning a border to one (figure) side but not the other (ground) side. Figures are shaped; grounds appear shapeless near the figure border. Accumulating evidence supports the view that the mechanism of figure assignment is inhibitory competition with the figure perceived on the winning side. Suppression has been observed on the groundside of figure borders. One prediction is that more suppression will be observed when the groundside competes more for figural status. We tested this prediction by assessing BOLD activation on the groundside of two types of stimuli with articulated borders: AEnov and AEfam stimuli. In both stimulus types, multiple image-based priors (symmetry, closure, small area, enclosure by a larger region) favored the inside as the figure. In AEfam but not AEnov stimuli, the figural prior of familiar configuration present on the outside competes for figural status. Observers perceived the insides of both types of stimuli as novel figures and the outsides as shapeless grounds. Previously, we observed lower BOLD activation in early visual areas representing the grounds of AEfam than AEnov stimuli, although unexpectedly, activation was above baseline. With articulated borders, it can be difficult to exclude figure activation from ground ROIs. Here, our ground ROIs better excluded figure activation; we also added straight-edge (SE) control stimuli and increased the sample size. In early visual areas representing the grounds, we observed lower BOLD activation on the groundside of AEfam than AEnov stimuli and below-baseline BOLD activation on the groundside of SE and AEfam stimuli. These results, indicating that greater suppression is applied to groundsides that competed more for figural status but lost the competition, support a Bayesian model of figure assignment in which proto-objects activated at both low and high levels where image features and familiar configurations are represented, respectively, compete for figural status.

Safety and Efficacy of a Monoclonal Antibody against Malaria in Mali.

BACKGROUND: CIS43LS is a monoclonal antibody that was shown to protect against controlled Plasmodium falciparum infection in a phase 1 clinical trial. Whether a monoclonal antibody can prevent P. falciparum infection in a region in which the infection is endemic is unknown. METHODS: We conducted a phase 2 trial to assess the safety and efficacy of a single intravenous infusion of CIS43LS against P. falciparum infection in healthy adults in Mali over a 6-month malaria season. In Part A, safety was assessed at three escalating dose levels. In Part B, participants were randomly assigned (in a 1:1:1 ratio) to receive 10 mg of CIS43LS per kilogram of body weight, 40 mg of CIS43LS per kilogram, or placebo. The primary efficacy end point, assessed in a time-to-event analysis, was the first P. falciparum infection detected on blood-smear examination, which was performed at least every 2 weeks for 24 weeks. At enrollment, all the participants received artemether-lumefantrine to clear possible P. falciparum infection. RESULTS: In Part B, 330 adults underwent randomization; 110 were assigned to each trial group. The risk of moderate headache was 3.3 times as high with 40 mg of CIS43LS per kilogram as with placebo. P. falciparum infections were detected on blood-smear examination in 39 participants (35.5%) who received 10 mg of CIS43LS per kilogram, 20 (18.2%) who received 40 mg of CIS43LS per kilogram, and 86 (78.2%) who received placebo. At 6 months, the efficacy of 40 mg of CIS43LS per kilogram as compared with placebo was 88.2% (adjusted 95% confidence interval [CI], 79.3 to 93.3; P<0.001), and the efficacy of 10 mg of CIS43LS per kilogram as compared with placebo was 75.0% (adjusted 95% CI, 61.0 to 84.0; P<0.001). CONCLUSIONS: CIS43LS was protective against P. falciparum infection over a 6-month malaria season in Mali without evident safety concerns. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04329104.).

Broadly neutralizing antibodies target the coronavirus fusion peptide.

The potential for future coronavirus outbreaks highlights the need to broadly target this group of pathogens. We used an epitope-agnostic approach to identify six monoclonal antibodies that bind to spike proteins from all seven human-infecting coronaviruses. All six antibodies target the conserved fusion peptide region adjacent to the S2' cleavage site. COV44-62 and COV44-79 broadly neutralize alpha- and betacoronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants BA.2 and BA.4/5, albeit with lower potency than receptor binding domain-specific antibodies. In crystal structures of COV44-62 and COV44-79 antigen-binding fragments with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine residue at the S2' cleavage site. COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings highlight the fusion peptide as a candidate epitope for next-generation coronavirus vaccine development.

Atypical B cells up-regulate costimulatory molecules during malaria and secrete antibodies with T follicular helper cell support.

Several infectious and autoimmune diseases are associated with an expansion of CD21-CD27- atypical B cells (atBCs) that up-regulate inhibitory receptors and exhibit altered B cell receptor (BCR) signaling. The function of atBCs remains unclear, and few studies have investigated the biology of pathogen-specific atBCs during acute infection. Here, we performed longitudinal flow cytometry analyses and RNA sequencing of Plasmodium falciparum (Pf)-specific B cells isolated from study participants before and shortly after febrile malaria, with simultaneous analysis of influenza hemagglutinin (HA)-specific B cells as a comparator. At the healthy baseline before the malaria season, individuals had similar frequencies of Pf- and HA-specific atBCs that did not differ proportionally from atBCs within the total B cell population. BCR sequencing identified clonal relationships between Pf-specific atBCs, activated B cells (actBCs), and classical memory B cells (MBCs) and revealed comparable degrees of somatic hypermutation. At the healthy baseline, Pf-specific atBCs were transcriptionally distinct from Pf-specific actBCs and classical MBCs. In response to acute febrile malaria, Pf-specific atBCs and actBCs up-regulated similar intracellular signaling cascades. Pf-specific atBCs showed activation of pathways involved in differentiation into antibody-secreting cells and up-regulation of molecules that mediate B-T cell interactions, suggesting that atBCs respond to T follicular helper (TFH) cells. In the presence of TFH cells and staphylococcal enterotoxin B, atBCs of malaria-exposed individuals differentiated into CD38+ antibody-secreting cells in vitro, suggesting that atBCs may actively contribute to humoral immunity to infectious pathogens.

Broadly neutralizing antibodies target the coronavirus fusion peptide.

The potential for future coronavirus outbreaks highlights the need to develop strategies and tools to broadly target this group of pathogens. Here, using an epitope-agnostic approach, we identified six monoclonal antibodies that bound to spike proteins from all seven human-infecting coronaviruses. Epitope mapping revealed that all six antibodies target the conserved fusion peptide region adjacent to the S2' cleavage site. Two antibodies, COV44-62 and COV44-79, broadly neutralize a range of alpha and beta coronaviruses, including SARS-CoV-2 Omicron subvariants BA.1 and BA.2, albeit with lower potency than RBD-specific antibodies. In crystal structures of Fabs COV44-62 and COV44-79 with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine at the S2' cleavage site. Importantly, COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings identify the fusion peptide as the target of the broadest neutralizing antibodies in an epitope-agnostic screen, highlighting this site as a candidate for next-generation coronavirus vaccine development. One-Sentence Summary: Rare monoclonal antibodies from COVID-19 convalescent individuals broadly neutralize coronaviruses by targeting the fusion peptide.

Semantic Expectation Effects on Object Detection: Using Figure Assignment to Elucidate Mechanisms.

Recent evidence suggesting that object detection is improved following valid rather than invalid labels implies that semantics influence object detection. It is not clear, however, whether the results index object detection or feature detection. Further, because control conditions were absent and labels and objects were repeated multiple times, the mechanisms are unknown. We assessed object detection via figure assignment, whereby objects are segmented from backgrounds. Masked bipartite displays depicting a portion of a mono-oriented object (a familiar configuration) on one side of a central border were shown once only for 90 or 100 ms. Familiar configuration is a figural prior. Accurate detection was indexed by reports of an object on the familiar configuration side of the border. Compared to control experiments without labels, valid labels improved accuracy and reduced response times (RTs) more for upright than inverted objects (Studies 1 and 2). Invalid labels denoting different superordinate-level objects (DSC; Study 1) or same superordinate-level objects (SSC; Study 2) reduced accuracy for upright displays only. Orientation dependency indicates that effects are mediated by activated object representations rather than features which are invariant over orientation. Following invalid SSC labels (Study 2), accurate detection RTs were longer than control for both orientations, implicating conflict between semantic representations that had to be resolved before object detection. These results demonstrate that object detection is not just affected by semantics, it entails semantics.

Environmental and organizational correlates and motivations for provider-sponsored health plan ownership in the post-reform era.

BACKGROUND: The 1980s to 1990s saw many health systems in the United States enter and exit the insurance market in the form of provider-sponsored health plans (PSHPs). Reforms and value-based reimbursement methods have stimulated health care organizations to reconsider PSHP as a logical strategy. PURPOSE: The aim of this study was to examine market and organizational factors associated with PSHP ownership and motivations for engaging in PSHP after health care reforms. The resource dependence theory was used as a theoretical lens. METHODOLOGY/APPROACH: A sequential quantitative to qualitative mixed-methods design was used. The quantitative analysis examined data for 5,849 U.S. hospitals. Results were synthesized with qualitative findings from 10 semistructured interviews representing eight health systems in five states. RESULTS: Organizational and environmental characteristics were significantly associated with PSHP ownership. Hospital and payer concentration, Medicare penetration, income, unemployment rate, government, and for-profit and metro area hospitals were associated with a lower likelihood of PSHP ownership. Salaried physician arrangements, clinically integrated network membership and adoption of other risk-bearing arrangements were associated with higher odds of PSHP ownership. Interviewees described PSHP as the culmination of the journey to value-based care and as a strategy to improve patient care, compete, and diversify revenue streams. CONCLUSIONS: Both market and organizational factors are important considerations for hospitals contemplating PSHP ownership, and motivations for ownership cover a broad range of financial, competitive, strategic, and mission-based goals. PRACTICE IMPLICATIONS: Hospitals considering PSHP ownership must carefully evaluate their competitive landscapes and organizational resources to ensure optimal conditions for this strategy. PSHP ownership has high start-up costs and requires a long-term organizational commitment.

Bispecific antibodies targeting distinct regions of the spike protein potently neutralize SARS-CoV-2 variants of concern.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern threatens the efficacy of existing vaccines and therapeutic antibodies and underscores the need for additional antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells collected from patients with coronavirus disease 2019. The three most potent antibodies targeted distinct regions of the receptor binding domain (RBD), and all three neutralized the SARS-CoV-2 Alpha and Beta variants. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the angiotensin-converting enzyme 2 receptor, and has limited contact with key variant residues K417, E484, and N501. We designed bispecific antibodies by combining nonoverlapping specificities and identified five bispecific antibodies that inhibit SARS-CoV-2 infection at concentrations of less than 1 ng/ml. Through a distinct mode of action, three bispecific antibodies cross-linked adjacent spike proteins using dual N-terminal domain­RBD specificities. One bispecific antibody was greater than 100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a dose of 2.5 mg/kg. Two bispecific antibodies in our panel comparably neutralized the Alpha, Beta, Gamma, and Delta variants and wild-type virus. Furthermore, a bispecific antibody that neutralized the Beta variant protected hamsters against SARS-CoV-2 expressing the E484K mutation. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.

Functional human IgA targets a conserved site on malaria sporozoites.

Immunoglobulin (Ig)A antibodies play a critical role in protection against mucosal pathogens. However, the role of serum IgA in immunity to nonmucosal pathogens, such as Plasmodium falciparum, is poorly characterized, despite being the second most abundant isotype in blood after IgG. Here, we investigated the circulating IgA response in humans to P. falciparum sporozoites that are injected into the skin by mosquitoes and migrate to the liver via the bloodstream to initiate malaria infection. We found that circulating IgA was induced in three independent sporozoite-exposed cohorts: individuals living in an endemic region in Mali, malaria-naïve individuals immunized intravenously with three large doses of irradiated sporozoites, and malaria-naïve individuals exposed to a single controlled mosquito bite infection. Mechanistically, we found evidence in an animal model that IgA responses were induced by sporozoites at dermal inoculation sites. From malaria-resistant individuals, we isolated several IgA monoclonal antibodies that reduced liver parasite burden in mice. One antibody, MAD2-6, bound to a conserved epitope in the amino terminus of the P. falciparum circumsporozoite protein, the dominant protein on the sporozoite surface. Crystal structures of this antibody revealed a unique mode of binding whereby two Fabs simultaneously bound either side of the target peptide. This study reveals a role for circulating IgA in malaria and identifies the amino terminus of the circumsporozoite protein as a target of functional antibodies.

Task set and instructions influence the weight of figural priors: A psychophysical study with extremal edges and familiar configuration.

In figure-ground organization, the figure is defined as a region that is both "shaped" and "nearer." Here we test whether changes in task set and instructions can alter the outcome of the cross-border competition between figural priors that underlies figure assignment. Extremal edge (EE), a relative distance prior, has been established as a strong figural prior when the task is to report "which side is nearer?" In three experiments using bipartite stimuli, EEs competed and cooperated with familiar configuration, a shape prior for figure assignment in a "which side is shaped?" task." Experiment 1 showed small but significant effects of familiar configuration for displays sketching upright familiar objects, although "shaped-side" responses were predominantly determined by EEs. In Experiment 2, instructions regarding the possibility of perceiving familiar shapes were added. Now, although EE remained the dominant prior, the figure was perceived on the familiar-configuration side of the border on a significantly larger percentage of trials across all display types. In Experiment 3, both task set (nearer/shaped) and the presence versus absence of instructions emphasizing that familiar objects might be present were manipulated within subjects. With familiarity thus "primed," effects of task set emerged when EE and familiar configuration favored opposite sides as figure. Thus, changing instructions can modulate the weighing of figural priors for shape versus distance in figure assignment in a manner that interacts with task set. Moreover, we show that the influence of familiar parts emerges in participants without medial temporal lobe/ perirhinal cortex brain damage when instructions emphasize that familiar objects might be present.

Ultrapotent bispecific antibodies neutralize emerging SARS-CoV-2 variants.

The emergence of SARS-CoV-2 variants that threaten the efficacy of existing vaccines and therapeutic antibodies underscores the urgent need for new antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells of COVID-19 patients. The three most potent antibodies targeted distinct regions of the RBD, and all three neutralized the SARS-CoV-2 variants B.1.1.7 and B.1.351. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the ACE2 receptor, and has limited contact with key variant residues K417, E484 and N501. We designed bispecific antibodies by combining non-overlapping specificities and identified five ultrapotent bispecific antibodies that inhibit authentic SARS-CoV-2 infection at concentrations of <1 ng/mL. Through a novel mode of action three bispecific antibodies cross-linked adjacent spike proteins using dual NTD/RBD specificities. One bispecific antibody was >100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a 2.5 mg/kg dose. Notably, six of nine bispecific antibodies neutralized B.1.1.7, B.1.351 and the wild-type virus with comparable potency, despite partial or complete loss of activity of at least one parent monoclonal antibody against B.1.351. Furthermore, a bispecific antibody that neutralized B.1.351 protected against SARS-CoV-2 expressing the crucial E484K mutation in the hamster model. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.

Plasmodium falciparum-specific IgM B cells dominate in children, expand with malaria, and produce functional IgM.

IgG antibodies play a role in malaria immunity, but whether and how IgM protects from malaria and the biology of Plasmodium falciparum (Pf)-specific IgM B cells is unclear. In a Mali cohort spanning infants to adults, we conducted longitudinal analyses of Pf- and influenza-specific B cells. We found that Pf-specific memory B cells (MBCs) are disproportionally IgM+ and only gradually shift to IgG+ with age, in contrast to influenza-specific MBCs that are predominantly IgG+ from infancy to adulthood. B cell receptor analysis showed Pf-specific IgM MBCs are somatically hypermutated at levels comparable to influenza-specific IgG B cells. During acute malaria, Pf-specific IgM B cells expand and upregulate activation/costimulatory markers. Finally, plasma IgM was comparable to IgG in inhibiting Pf growth and enhancing phagocytosis of Pf by monocytes in vitro. Thus, somatically hypermutated Pf-specific IgM MBCs dominate in children, expand and activate during malaria, and produce IgM that inhibits Pf through neutralization and opsonic phagocytosis.

Learned value and predictiveness affect gaze but not figure assignment.

Many factors affect figure-ground segregation, but the contributions of attention and reward history to this process is uncertain. We conducted two experiments to investigate whether reward learning influences figure assignment and whether this relationship was mediated by attention. Participants learned to associate certain shapes with a reward contingency: During a learning phase, they chose between two shapes on each trial, with subsets of shapes associated with high-probability win, low-probability win, high-probability loss, and low-probability loss. In a test phase, participants were given a figure-ground task, in which they indicated which of two regions that shared a contour they perceived as the figure (high-probability win and low-probability win shapes were pitted against each other, as were high-probability loss and low-probability loss shapes). The results revealed that participants had learned the reward contingencies and that, following learning, attention was reliably drawn to the optimal stimulus. Despite this, neither reward history nor the resulting attentional allocation influenced figure-ground organization.