ABSTRACT
COVID-19 convalescent plasma (CCP), a passive polyclonal antibody therapeutic, has exhibited mixed results in the treatment of COVID-19. Given that the therapeutic effect of CCP may extend beyond the ability of SARS-CoV-2-specific antibody binding and neutralization to influence the evolution of the endogenous antibody response, we took a systematic and comprehensive approach to analyze SARS-CoV-2 functional antibody profiles of participants in a randomized controlled trial of CCP treatment of individuals hospitalized with COVID-19 pneumonia where CCP was associated with both decreased mortality and improved clinical severity. Using systems serology, we found that the clinical benefit of CCP is related to a shift towards reduced inflammatory Spike (S) responses and enhanced Nucleocapsid (N) humoral responses. We found CCP had the greatest clinical benefit in participants with low pre-existing anti-SARS-CoV-2 antibody function, rather than S or N antibody levels or participant demographic features. Further, CCP induced immunomodulatory changes to recipient humoral profiles persisted for at least two months, marked by the selective evolution of anti-inflammatory Fc-glycan profiles and persistently expanded nucleocapsid-specific humoral immunity following CCP therapy. Together, our findings identify a novel mechanism of action of CCP, suggest optimal patient characteristics for CCP treatment, identify long-last immunomodulatory effects of CCP, and provide guidance for development of novel N-focused antibody therapeutics for severe COVID-19 hyperinflammation.
ABSTRACT
There is growing evidence that racial and ethnic minorities bear a disproportionate burden from COVID-19. Temporal changes in the pandemic epidemiology and diversity in the clinical course require careful study to identify determinants of poor outcomes. We analyzed 6255 individuals admitted with PCR-confirmed COVID-19 to one of 5 hospitals in the University of Pennsylvania Health System between March 2020 and March 2021, using electronic health records to assess risk factors and outcomes through 8 weeks post-admission. Discharge, readmission and mortality outcomes were analyzed in a multi-state model with multivariable Cox models for each transition. Mortality varied markedly over time, with cumulative incidence (95% CI) 30 days post-admission of 19.1% (16.9, 21.3) in March-April 2020, 5.7% (4.2, 7.5) in July-October 2020 and 10.5% (9.1,12.0) in January-March 2021; 26% of deaths occurred after discharge. Average age (SD) at admission varied from 62.7 (17.6) to 54.8 (19.9) to 60.5 (18.1); mechanical ventilation use declined from 21.3% to 9-11%. Compared to Caucasian, Black race was associated with more severe disease at admission, higher rates of co-morbidities and low-income resident zip code. Between-race risk differences in mortality risk diminished in multivariable models; while admitting hospital, increasing age, admission early in the pandemic, and severe disease and low blood pressure at admission were associated with increased mortality hazard. Hispanic ethnicity was associated with fewer baseline co-morbidities and lower mortality hazard (0.57, 95% CI: 0.37, .087). Multi-state modeling allows for a unified framework to analyze multiple outcomes throughout the disease course. Morbidity and mortality for hospitalized COVID-19 patients varied over time but post-discharge mortality remained non-trivial. Black race was associated with more risk factors for morbidity and with treatment at hospitals with lower mortality. Multivariable models suggest there are not between-race differences in outcomes. Future work is needed to better understand the identified between-hospital differences in mortality.
ABSTRACT
The SARS-CoV-2 Spike protein acquired a D614G mutation early in the COVID-19 pandemic that appears to confer on the virus greater infectivity and is now the globally dominant form of the virus. Certain of the current vaccines entering phase 3 trials are based on the original D614 form of Spike with the goal of eliciting protective neutralizing antibodies. To determine whether D614G mediates neutralization-escape that could compromise vaccine efficacy, sera from Spike-immunized mice, nonhuman primates and humans were evaluated for neutralization of pseudoviruses bearing either D614 or G614 Spike on their surface. In all cases, the G614 pseudovirus was moderately more susceptible to neutralization. The G614 pseudovirus also was more susceptible to neutralization by monoclonal antibodies against the receptor binding domain and by convalescent sera from people known to be infected with either the D614 or G614 form of the virus. These results indicate that a gain in infectivity provided by D614G came at the cost of making the virus more vulnerable to neutralizing antibodies, and that the mutation is not expected to be an obstacle for current vaccine development.
