RESUMEN
SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2, and amino acid variation in Spike is increasingly appreciated. Given both vaccines and therapeutics are designed around Wuhan-1 Spike, this raises the theoretical possibility of virus escape, particularly in immunocompromised individuals where prolonged viral replication occurs. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences by both short and long read technologies over 23 time points spanning 101 days. Although little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days, N501Y in Spike was transiently detected at day 55 and V157L in RdRp emerged. However, following convalescent plasma we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and{Delta} H69/{Delta}V70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro, the Spike escape double mutant bearing{Delta} H69/{Delta}V70 and D796H conferred decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility, but incurred an infectivity defect. The{Delta} H69/{Delta}V70 single mutant had two-fold higher infectivity compared to wild type and appeared to compensate for the reduced infectivity of D796H. Consistent with the observed mutations being outside the RBD, monoclonal antibodies targeting the RBD were not impacted by either or both mutations, but a non RBD binding monoclonal antibody was less potent against{Delta} H69/{Delta}V70 and the double mutant. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with reduced susceptibility to neutralising antibodies.
RESUMEN
In 2013, the Robert Wood Johnson Foundation embarked on a pioneering effort to advance a Culture of Health. This report focuses on two questions that are central to understanding how individuals and sectors think about health and are motivated to promote it: How can the commonly understood concepts of cultural identity (e.g., ethnic or religious; lesbian, gay, bisexual, transgender plus; military) and organizational culture be harnessed to develop a Culture of Health? How can incentives be used to promote individual health and engage investors and leaders within organizations or governments to promote health and well-being broadly? This study draws on 43 one-hour semistructured interviews that RAND researchers conducted with stakeholders whose work focused on cultural alignment, incentives, or both to learn how organizations are addressing and leveraging culture and incentives to promote health and well-being, as well as to identify facilitators, barriers, potential best practices, and lessons learned. Key findings include the following: Equity is often addressed in silos, which impedes progress toward a unified goal of health equity for all; members of specific cultural groups need to be given a voice in health-related activities; systems are built around prevailing cultural norms, making it challenging for those working with specific cultures to make cultural adaptations; and not all incentives are monetary. Recommendations include institutionalizing practices that ensure ongoing input from marginalized populations, identifying ways to help smaller organizations overcome structural inequalities, and institutionalizing health promotion efforts in sectors other than public health or health care to sustain collaborative efforts.
