High-affinity, neutralizing antibodies to SARS-CoV-2 can be made without T follicular helper cells

T follicular helper (Tfh) cells are the conventional drivers of protective, germinal center (GC)-based antiviral antibody responses. However, loss of Tfh cells and GCs has been observed in patients with severe COVID-19. As T cell-B cell interactions and immunoglobulin class switching still occur in these patients, non-canonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both Tfh-dependent and -independent antibodies were induced against SARS-CoV-2 infection, SARS-CoV-2 vaccination, and influenza A virus infection. Even though Tfh-independent antibodies to SARS-CoV-2 had evidence of reduced somatic hypermutation, they were still high-affinity, durable, and reactive against diverse spike-derived epitopes and were capable of neutralizing both homologous SARS-CoV-2 and the B.1.351 (beta) variant of concern. Indeed, we found by epitope mapping and BCR sequencing that Tfh cells focused the B cell response and therefore, in the absence of Tfh cells, a more diverse clonal repertoire was maintained. These data support an alternative pathway for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GC-derived antibodies that might compensate for GCs damaged by viral inflammation

Potent single-domain antibodies that arrest respiratory syncytial virus fusion protein in its prefusion state

Human respiratory syncytial virus (RSV) is the main cause of lower respiratory tract infections in young children. The RSV fusion protein (F) is highly conserved and is the only viral membrane protein that is essential for infection. The prefusion conformation of RSV F is considered the most relevant target for antiviral strategies because it is the fusion-competent form of the protein and the primary target of neutralizing activity present in human serum. Here, we describe two llama-derived single-domain antibodies (VHHs) that have potent RSV-neutralizing activity and bind selectively to prefusion RSV F with picomolar affinity. Crystal structures of these VHHs in complex with prefusion F show that they recognize a conserved cavity formed by two F protomers. In addition, the VHHs prevent RSV replication and lung infiltration of inflammatory monocytes and T cells in RSV-challenged mice. These prefusion F-specific VHHs represent promising antiviral agents against RSV

Closing the Gap in High-Risk Pregnancy Care Using Machine Learning and Human-AI Collaboration

Health insurers often use algorithms to identify members who would benefit from care and condition management programs, which provide personalized, high-touch clinical support. Timely, accurate, and seamless integration between algorithmic identification and clinical intervention depends on effective collaboration between the system designers and nurse care managers. We focus on a high-risk pregnancy (HRP) program designed to reduce the likelihood of adverse prenatal, perinatal, and postnatal events and describe how we overcome three challenges of HRP programs as articulated by nurse care managers; (1) early detection of pregnancy, (2) accurate identification of impactable high-risk members, and (3) provision of explainable indicators to supplement predictions. We propose a novel algorithm for pregnancy identification that identifies pregnancies 57 days earlier than previous code-based models in a retrospective study. We then build a model to predict impactable pregnancy complications that achieves an AUROC of 0.760. Models for pregnancy identification and complications are then integrated into a proposed user interface. In a set of user studies, we collected quantitative and qualitative feedback from nurses on the utility of the predictions combined with clinical information driving the predictions on triaging members for the HRP program

Prenatal Exposure to Organophosphates, Paraoxonase 1, and Cognitive Development in Childhood

Background: Prenatal exposure to organophosphate pesticides has been shown to negatively affect child neurobehavioral development. Paraoxonase 1 (PON1) is a key enzyme in the metabolism of organophosphates