Protective neutralizing antibodies from human survivors of Crimean-Congo hemorrhagic fever.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a World Health Organization priority pathogen. CCHFV infections cause a highly lethal hemorrhagic fever for which specific treatments and vaccines are urgently needed. Here, we characterize the human immune response to natural CCHFV infection to identify potent neutralizing monoclonal antibodies (nAbs) targeting the viral glycoprotein. Competition experiments showed that these nAbs bind six distinct antigenic sites in the Gc subunit. These sites were further delineated through mutagenesis and mapped onto a prefusion model of Gc. Pairwise screening identified combinations of non-competing nAbs that afford synergistic neutralization. Further enhancements in neutralization breadth and potency were attained by physically linking variable domains of synergistic nAb pairs through bispecific antibody (bsAb) engineering. Although multiple nAbs protected mice from lethal CCHFV challenge in pre- or post-exposure prophylactic settings, only a single bsAb, DVD-121-801, afforded therapeutic protection. DVD-121-801 is a promising candidate suitable for clinical development as a CCHFV therapeutic.

Systematic Analysis of Monoclonal Antibodies against Ebola Virus GP Defines Features that Contribute to Protection.

Antibodies are promising post-exposure therapies against emerging viruses, but which antibody features and in vitro assays best forecast protection are unclear. Our international consortium systematically evaluated antibodies against Ebola virus (EBOV) using multidisciplinary assays. For each antibody, we evaluated epitopes recognized on the viral surface glycoprotein (GP) and secreted glycoprotein (sGP), readouts of multiple neutralization assays, fraction of virions left un-neutralized, glycan structures, phagocytic and natural killer cell functions elicited, and in vivo protection in a mouse challenge model. Neutralization and induction of multiple immune effector functions (IEFs) correlated most strongly with protection. Neutralization predominantly occurred via epitopes maintained on endosomally cleaved GP, whereas maximal IEF mapped to epitopes farthest from the viral membrane. Unexpectedly, sGP cross-reactivity did not significantly influence in vivo protection. This comprehensive dataset provides a rubric to evaluate novel antibodies and vaccine responses and a roadmap for therapeutic development for EBOV and related viruses.

Antibodies from a Human Survivor Define Sites of Vulnerability for Broad Protection against Ebolaviruses.

Experimental monoclonal antibody (mAb) therapies have shown promise for treatment of lethal Ebola virus (EBOV) infections, but their species-specific recognition of the viral glycoprotein (GP) has limited their use against other divergent ebolaviruses associated with human disease. Here, we mined the human immune response to natural EBOV infection and identified mAbs with exceptionally potent pan-ebolavirus neutralizing activity and protective efficacy against three virulent ebolaviruses. These mAbs recognize an inter-protomer epitope in the GP fusion loop, a critical and conserved element of the viral membrane fusion machinery, and neutralize viral entry by targeting a proteolytically primed, fusion-competent GP intermediate (GPCL) generated in host cell endosomes. Only a few somatic hypermutations are required for broad antiviral activity, and germline-approximating variants display enhanced GPCL recognition, suggesting that such antibodies could be elicited more efficiently with suitably optimized GP immunogens. Our findings inform the development of both broadly effective immunotherapeutics and vaccines against filoviruses.

Potently neutralizing and protective anti-human metapneumovirus antibodies target diverse sites on the fusion glycoprotein.

Human metapneumovirus (hMPV) is a leading cause of acute lower respiratory tract infections in high-risk populations, yet there are no vaccines or anti-viral therapies approved for the prevention or treatment of hMPV-associated disease. Here, we used a high-throughput single-cell technology to interrogate memory B cell responses to the hMPV fusion (F) glycoprotein in young adult and elderly donors. Across all donors, the neutralizing antibody response was primarily directed to epitopes expressed on both pre- and post-fusion F conformations. However, we identified rare, highly potent broadly neutralizing antibodies that recognize pre-fusion-specific epitopes and structurally characterized an antibody that targets a site of vulnerability at the pre-fusion F trimer apex. Additionally, monotherapy with neutralizing antibodies targeting three distinct antigenic sites provided robust protection against lower respiratory tract infection in a small animal model. This study provides promising monoclonal antibody candidates for passive immunoprophylaxis and informs the rational design of hMPV vaccine immunogens.

Infants Infected with Respiratory Syncytial Virus Generate Potent Neutralizing Antibodies that Lack Somatic Hypermutation.

Respiratory syncytial virus (RSV) is a leading cause of infant mortality, and there are currently no licensed vaccines to protect this vulnerable population. A comprehensive understanding of infant antibody responses to natural RSV infection would facilitate vaccine development. Here, we isolated more than 450 RSV fusion glycoprotein (F)-specific antibodies from 7 RSV-infected infants and found that half of the antibodies recognized only two antigenic sites. Antibodies targeting both sites showed convergent sequence features, and structural studies revealed the molecular basis for their recognition of RSV F. A subset of antibodies targeting one of these sites displayed potent neutralizing activity despite lacking somatic mutations, and similar antibodies were detected in RSV-naive B cell repertoires, suggesting that expansion of these B cells in infants may be possible with suitably designed vaccine antigens. Collectively, our results provide fundamental insights into infant antibody responses and a framework for the rational design of age-specific RSV vaccines.

A broad and potent neutralization epitope in SARS-related coronaviruses.

Many neutralizing antibodies (nAbs) elicited to ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through natural infection and vaccination have reduced effectiveness to SARS-CoV-2 variants. Here, we show that therapeutic antibody ADG20 is able to neutralize SARS-CoV-2 variants of concern (VOCs) including Omicron (B.1.1.529) as well as other SARS-related coronaviruses. We delineate the structural basis of this relatively escape-resistant epitope that extends from one end of the receptor binding site (RBS) into the highly conserved CR3022 site. ADG20 can then benefit from high potency through direct competition with ACE2 in the more variable RBS and interaction with the more highly conserved CR3022 site. Importantly, antibodies that are able to target this site generally neutralize a broad range of VOCs, albeit with reduced potency against Omicron. Thus, this conserved and vulnerable site can be exploited for the design of universal vaccines and therapeutic antibodies.

Foraminifera as a model of the extensive variability in genome dynamics among eukaryotes.

Knowledge of eukaryotic life cycles and associated genome dynamics stems largely from research on animals, plants, and a small number of "model" (i.e., easily cultivable) lineages. This skewed sampling results in an underappreciation of the variability among the many microeukaryotic lineages, which represent the bulk of eukaryotic biodiversity. The range of complex nuclear transformations that exists within lineages of microbial eukaryotes challenges the textbook understanding of genome and nuclear cycles. Here, we look in-depth at Foraminifera, an ancient (∼600 million-year-old) lineage widely studied as proxies in paleoceanography and environmental biomonitoring. We demonstrate that Foraminifera challenge the "rules" of life cycles developed largely from studies of plants and animals. To this end, we synthesize data on foraminiferal life cycles, focusing on extensive endoreplication within individuals (i.e., single cells), the unusual nuclear process called Zerfall, and the separation of germline and somatic function into distinct nuclei (i.e., heterokaryosis). These processes highlight complexities within lineages and expand our understanding of the dynamics of eukaryotic genomes.

Longitudinal associations between parents' prosocial behavior and media use and young children's prosocial development: The mediating role of children's media use.

Research has found that media is associated with children's prosocial behavior (PB) from an early age, and that parents play a key role in children's media use and behavior. However, few studies explore these relations as early as infancy while also controlling for well-established predictors of PB (e.g., empathic concern). Thus, the present study examined longitudinal associations between parents' PB and media use, and prosocial development during early childhood, mediated by children's own media use. Participants were 519 children (M age at Time 1 = 17.77 months) and parents who participated in three timepoints of an ongoing, longitudinal study. A longitudinal path model suggested that children's media use was still significantly associated with PB 1 year later after accounting for factors such as parents' PB, media use, and empathy. These findings have important implications for the early development of behaviors that serve as a foundation for social and moral development.

Microarray-guided evaluation of the frequency, B-cell origins, and selectivity of human glycan-binding antibodies reveals new insights and novel antibodies.

The immune system produces a diverse collection of antiglycan antibodies that are critical for host defense. At present, however, we know very little about the binding properties, origins, and sequences of these antibodies because of a lack of access to a variety of defined individual antibodies. To address this challenge, we used a glycan microarray with over 800 different components to screen a panel of 516 human monoclonal antibodies that had been randomly cloned from different B-cell subsets originating from healthy human subjects. We obtained 26 antiglycan antibodies, most of which bound microbial carbohydrates. The majority of the antiglycan antibodies identified in the screen displayed selective binding for specific glycan motifs on our array and lacked polyreactivity. We found that antiglycan antibodies were about twice as likely than expected to originate from IgG+ memory B cells, whereas none were isolated from naïve, early emigrant, or immature B cells. Therefore, our results indicate that certain B-cell subsets in our panel are enriched in antiglycan antibodies, and IgG+ memory B cells may be a promising source of such antibodies. Furthermore, some of the newly identified antibodies bound glycans for which there are no reported monoclonal antibodies available, and these may be useful as research tools, diagnostics, or therapeutic agents. Overall, the results provide insight into the types and properties of antiglycan antibodies produced by the human immune system and a framework for the identification of novel antiglycan antibodies in the future.

Prophylactic Administration of the Monoclonal Antibody Adintrevimab Protects against SARS-CoV-2 in Hamster and Non-Human Primate Models of COVID-19.

Adintrevimab is a human immunoglobulin G1 monoclonal antibody engineered to have broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and other SARS-like coronaviruses with pandemic potential. In both Syrian golden hamster and rhesus macaque models, prophylactic administration of a single dose of adintrevimab provided protection against SARS-CoV-2/WA1/2020 infection in a dose-dependent manner, as measured by significant reductions in lung viral load and virus-induced lung pathology, and by inhibition of viral replication in the upper and lower respiratory tract.

Longitudinal dynamics of the human B cell response to the yellow fever 17D vaccine.

A comprehensive understanding of the development and evolution of human B cell responses induced by pathogen exposure will facilitate the design of next-generation vaccines. Here, we utilized a high-throughput single B cell cloning technology to longitudinally track the human B cell response to the yellow fever virus 17D (YFV-17D) vaccine. The early memory B cell (MBC) response was mediated by both classical immunoglobulin M (IgM) (IgM+CD27+) and switched immunoglobulin (swIg+) MBC populations; however, classical IgM MBCs waned rapidly, whereas swIg+ and atypical IgM+ and IgD+ MBCs were stable over time. Affinity maturation continued for 6 to 9 mo following vaccination, providing evidence for the persistence of germinal center activity long after the period of active viral replication in peripheral blood. Finally, a substantial fraction of the neutralizing antibody response was mediated by public clones that recognize a fusion loop-proximal antigenic site within domain II of the viral envelope glycoprotein. Overall, our findings provide a framework for understanding the dynamics and complexity of human B cell responses elicited by infection and vaccination.

Microbial Diversity in the Eukaryotic SAR Clade: Illuminating the Darkness Between Morphology and Molecular Data.

Despite their diversity and ecological importance, many areas of the SAR-Stramenopila, Alveolata, and Rhizaria-clade are poorly understood as the majority (90%) of SAR species lack molecular data and only 5% of species are from well-sampled families. Here, we review and summarize the state of knowledge about the three major clades of SAR, describing the diversity within each clade and identifying synapomorphies when possible. We also assess the "dark area" of SAR: the morphologically described species that are missing molecular data. The majority of molecular data for SAR lineages are characterized from marine samples and vertebrate hosts, highlighting the need for additional research effort in areas such as freshwater and terrestrial habitats and "non-vertebrate" hosts. We also describe the paucity of data on the biogeography of SAR species, and point to opportunities to illuminate diversity in this major eukaryotic clade. See also the video abstract here: https://youtu.be/_VUXqaX19Rw.

Latent Growth in Self-Regulatory Subdimensions in Relation to Adjustment Outcomes in Youth Aged 12-19.

This study assessed latent growth in behavioral inhibition, anger regulation, and goal-setting from ages 12 to 18, as well as links between latent growth and depression, externalizing behavior, and prosocial behavior at age 19. A second goal included examining whether latent growth in these constructs and associations with distal outcomes varied by sex. Generally speaking, self-regulatory subdimensions displayed distinct patterns of developmental growth from ages 12 to 18. Growth in self-regulatory subdimensions did not vary by sex, though initial levels of anger regulation and goal-setting did vary by sex. In addition, self-regulatory subdimensions from ages 12 to 18 were differentially related to adjustment outcomes at age 19. However, sex did not moderate associations between growth in self-regulatory subdimensions and distal outcomes.

Can helping others strengthen teens? Character strengths as mediators between prosocial behavior and adolescents' internalizing symptoms.

INTRODUCTION: Identifying protective factors against internalizing behaviors during adolescence is a public health priority, as rates of depression and anxiety are rising. As such, the purpose of this study was to examine whether prosocial engagement toward strangers and family members is protective against depressive and anxiety symptoms, and whether this link is mediated by character strengths (i.e., hope, persistence, gratitude, and self-esteem). METHOD: The sample consisted of 500 US adolescents (52% female; 66% European American; 33% from single-parent families). Data across three consecutive yearly waves were utilized in the current study (Mage Time 1 = 13.32). RESULTS: Results of a longitudinal structural equation model revealed prosocial behavior toward strangers and family members were differentially related to character strengths, and that prosocial behavior toward strangers was indirectly associated with depressive symptoms via self-esteem. CONCLUSION: Taken together, findings extend the Developmental Cascades model and suggest that prosocial behavior and character strengths protect against depressive symptoms during the adolescent period. Findings are discussed in the context of relevant research and theory, and implications for future research and intervention programs are presented.

Intra-individual associations between intentional self-regulation and prosocial behavior during adolescence: Evidence for bidirectionality.

INTRODUCTION: Couched in Positive Youth Development (PYD) theory and relevant empirical work, this study investigated bidirectional associations between intentional self-regulation and prosocial behavior toward strangers from age 12 to age 18. METHOD: Participants included 500 adolescents (52% female, 77% European American; age Time 1 = 12 years, Time 2 = 14 years, Time 3 = 16 years, Time 4 = 18 years) from the Northwestern United States. Adolescents self-reported on their intentional self-regulation and prosocial behavior toward strangers across four time points. A random-intercept cross-lagged panel model (RICLPM) was estimated in order to assess bidirectionality while avoiding conflating intra- and inter-individual variability. RESULTS: Results revealed intentional self-regulation and prosocial behavior toward strangers were bidirectionally related during early adolescence (i.e., from age 12 to 14). During mid-to-late adolescence (i.e. age 14 to 18), prosocial behavior toward strangers facilitated intentional selfregulation, whereas intentional self-regulation did not drive the development of prosocial behavior toward strangers. CONCLUSIONS: Findings indicate that early adolescence may be a particularly plastic developmental period in terms of PYD. Findings also suggest that investigations of relations between adolescents' personal assets and contribution factors merit further scholarly attention. Several directions for future research are presented.

Associations between prosocial behavior, externalizing behaviors, and internalizing symptoms during adolescence: A meta-analysis.

INTRODUCTION: The purpose of this study was to conduct a meta-analysis investigating the consistency and strength of relations between prosocial behavior, externalizing behaviors, and internalizing symptoms from preadolescence (i.e., 1-9 years) to late adolescence (i.e., 19-25 years). This study directly addresses inconsistencies and gaps in the available literature by providing the field with a detailed, synthesized description of these associations. METHOD: Fifty-five studies met the inclusion criteria, containing 742 independent correlational effect sizes. Statistical information and other study information was coded and entered into Comprehensive Meta-analysis III software, which was used to analyze results. RESULTS: Results showed that higher levels of prosocial behavior were significantly associated with lower levels of externalizing behaviors, as expected. Additionally, more reported prosocial behavior was related to less reported internalizing symptoms. Follow-up analyses revealed specific relationships between prosocial behavior and aggression, deviant peer association, risky sexual behavior, substance use, delinquency/general externalizing behavior, depression, and general internalizing behaviors (i.e., emotional problems, negative emotionality). A variety of moderators of these associations were considered, including age and sex. CONCLUSIONS: Findings are discussed in the context of the broader research literature, weaknesses in the field are noted, and numerous meaningful directions for future research are presented.

Parent-child joint media engagement in infancy.

Early conversations are an important source in shaping children's cognitive and emotional development, and it is vital to understand how parents use media as a platform to engage in conversations with their young children and what might predict the quality of these interactions. Thus, in the current study we explored the nature of parent-child discourse while engaging in media (i.e., joint media engagement) with infants, and how parent (empathic concern and responsiveness) and child (negative emotionality and regulatory capacity) variables might be associated with the quality of engagement. The current study consisted of 269 infants (50% female, Mage  = 17.09 months, SD = 3.93; 59% White) and their primary caregiver (98% mothers) who engaged in a variety of in-home tasks and parental questionnaires. Results established three meaningful codes for both parent and child that assessed positive and negative joint media engagement. Further, results suggested that parental empathic concern was associated with positive parent and child media engagement, while child negative emotionality was associated with lower levels of distraction. Discussion focuses on the importance of studying parent-child discourse in the context of joint media engagement and recommends limiting media exposure before 18 months of age.

Trajectories of Perceived Parental Psychological Control across Adolescence and Implications for the Development of Depressive and Anxiety Symptoms.

Theory and research indicate considerable changes in parental control across adolescence (e.g., declining behavioral control), but the developmental course and significance of psychological control remains largely unknown. This study examined trajectories of adolescents' reports of mothers' and fathers' psychological control from ages 12 to 19, predictors of occupying distinct trajectories, and the developmental significance of these trajectories for adolescents' development of depressive and anxiety symptoms. It used eight waves of survey data on 500 adolescents (Mage = 11.83, SD = 1.03; 52% female; 67% White, 12% African American) and their parents from the Pacific Northwest United States. Most adolescents (about 90%) reported low but increasing levels of parental psychological control over time, with a small but significant subset (about 10%) perceiving perpetually elevated levels. Mothers' (but not fathers') depressive symptoms, reported at the age 12 assessment, predicted adolescents' membership in the elevated psychological control trajectory. Adolescents occupying these elevated trajectories showed more problematic growth in depressive and anxiety symptoms across adolescence. Taken together, the findings suggest that many adolescents experience increased parental psychological control as they age, and that variability in these trends indicates individual differences in their development of depressive and anxiety symptoms over time.

The Response of Litter-Associated Myxomycetes to Long-Term Nutrient Addition in a Lowland Tropical Forest.

Myxomycetes (plasmodial slime molds) are abundant protist predators that feed on bacteria and other microorganisms, thereby playing important roles in terrestrial nutrient cycling. Despite their significance, little is known about myxomycete communities and the extent to which they are affected by nutrient availability. We studied the influence of long-term addition of N, P, and K on the myxomycete community in a lowland forest in the Republic of Panama. In a previous study, microbial biomass increased with P but not N or K addition at this site. We hypothesized that myxomycetes would increase in abundance in response to P but that they would not respond to the sole addition of N or K. Moist chamber cultures of leaf litter and small woody debris were used to quantify myxomycete abundance. We generated the largest myxomycete dataset (3,381 records) for any single locality in the tropics comprised by 91 morphospecies. In line with our hypothesis, myxomycete abundance increased in response to P addition but did not respond to N or K. Community composition was unaffected by nutrient treatments. This work represents one of very few large-scale and long-term field studies to include a heterotrophic protist highlighting the feasibility and value in doing so.

Instagrowth: A Longitudinal Growth Mixture Model of Social Media Time Use Across Adolescence.

This study examined differential patterns of time spent using social media in a sample of 457 adolescents over a 6-year period. The majority of adolescents (83%), termed moderate users, reported steady social media use over time. A second group (increasers: 12%) reported low social media use that increased gradually and ended high at the end of the study. A third group, called peak users (6%), reported low social media that increased quickly after a few years and then returned to baseline levels. Low self-regulation predicted being an increaser or peak user. Being a moderate user tended to be related to lower levels of depression, aggression, delinquency, social media problems, and cyberbullying across time, as compared with the other groups.