ABSTRACT
Background: Reliable biomarkers of COVID-19 severity and outcomes are critically needed for clinical and research applications. We evaluated associations between anti-Spike IgG and SARS-COV-2 nucleocapsid antigen (N Ag) in plasma with clinical outcomes in outpatients with COVID-19. Method(s): We used data from 229 non-hospitalized, US-based adults with COVID-19 who enrolled between January and July 2021 into the placebo arm of the ACTIV-2/A5401 platform trial within 10 days of symptom onset. Pretreatment (day 0) plasma was analyzed by the quantitative Simoa SARS-CoV-2 IgG antibody (anti-Spike) assay (lower limit of quantification [LLoQ] 0.77ug/ mL), and the quantitative Simoa SARS-CoV-2 N Protein Advantage (Quanterix) measuring N Ag (LLoQ 3pg/mL). In addition to analyses for < LLoQ vs >=LLoQ anti-Spike and N Ag, we categorized participants into five N Ag groups (< 3 pg/ml;3-< 100 pg/ml;100-< 1,000 pg/ml;1,000-< 2,500 pg/ml;>=2,500 pg/ ml). Associations between SARS-CoV-2 anti-Spike and N Ag levels and clinical outcomes (all-cause hospitalization/death through day 28 and time to symptom improvement or resolution for two consecutive days from day 0 status) were estimated using log-binomial and Cox regression models, respectively. Result(s): At day 0, 40% had anti-Spike levels >=LLoQ and 64% of participants had plasma N Ag levels >=LLoQ. Participants with anti-Spike levels < LLoQ compared to those who had quantifiable anti-Spike at day 0, had an increased risk of hospitalization/death (16% vs 2%, RR [95% confidence interval (CI)]: 7.3 [1.8, 30.1]), and a significantly longer time to symptom improvement (median [Q1, Q3] 14 days [8, >27] vs 9 days [4, 16], hazard ratio [HR]: 0.6 [95%: CI: 0.4, 0.8], p< 0.001). Participants with higher N Ag levels at day 0 had an increased risk of hospitalization or death, ranging from 1% for < 3 pg/ml to 70% for >=2500 pg/ml (Figure). Compared to individuals who had N Ag levels < LLoQ at day 0, those in the highest category of N Ag levels (>=2500 pg/mL) experienced a significantly longer time to symptom improvement (median [Q1, Q3]: 25 days [13, >27] vs 10 days [5, 20];HR: 0.4 [95% CI: 0.2, 0.7];p=0.04). Conclusion(s): At study entry, the absence of Spike antibodies and higher levels of plasma SARS-CoV-2 N Ag predicted hospitalizations and death in untreated outpatients with COVID-19. These parameters may serve as informative biomarkers for risk stratification in the evaluation of outpatients with COVID-19. (Figure Presented).
ABSTRACT
Background. ACTT-1 demonstrated clinical efficacy of remdesivir (RDV) in hospitalized patients with COVID-19;subgroup analyses suggested those most likely to benefit presented with milder clinical illness. To further clarify what subsets of hospitalized patients might benefit from RDV, we analyzed virological and immunological biomarkers in this previously reported cohort. Methods. Serum and upper respiratory tract (URT) swabs were collected on Day 1, 3, 5, 8, and 11 while hospitalized;Day 15 and 29 as able were collected and tested for quantitative RNA (URT and plasma), serum nucleoprotein (NPR), IL-6, CRP through Day 6, and serostatus (baseline only). Participants with a baseline and at least one subsequent sample were used in this analysis. Associations of all these biomarkers with clinical outcomes (mortality, recovery) and response to therapy were assessed. Of the 1062 participants in ACTT-1, 642 had baseline and at least one subsequent sample within 6 days of randomization (Fig 1, Table 1). Results. RDV-treated patients with moderate/severe disease who had elevated baseline NPR levels recovered faster (RRR 1.95 vs 1.04, p = 0.01);similar trends were noted for plasma and URT RNA levels (Fig 2A);mortality treatment effects by viral load subgroups (high or low) were not seen (Fig 2B). In patients with less severe illness, RDV treatment was associated with an accelerated decline in NPR (difference -0.062 log10 pg/ml per day, p = 0.003) and plasma RNA levels (difference -0.040 log10 pg/ml per day, p = 0.004. Fig 3A), and a decrease in the proportion of patients with increasing and/or persistent viral loads (Fig 3B). Patients with increasing/persistent viral loads also took longer to recover than those with decreasing viral loads, irrespective of disease severity: RRR for plasma RNA 0.45, 95% CI 0.28-0.73, RRR for NPR 0.44, 95% CI 0.22-0.88 for moderate/severe disease;RRR for plasma RNA 0.26, 95% CI 0.10 - 0.70 , RRR for NPR n.e. (no recoveries) for critical disease (Fig 4). Conclusion. Our study demonstrates a systemic antiviral effect of remdesivir, shows the prognostic value of viral and immunologic biomarkers for mortality and failure to recover, and identifies a group of hospitalized patients with COVID-19 most likely to benefit from remdesivir treatment. (Figure Presented).
ABSTRACT
Reported cases of mumps infection in the United States (U.S.) have dropped since the introduction of the single-component mumps vaccine in 1967. After introduction of the multi-component measles, mumps, rubella (MMR) vaccine, cases in the U.S. and worldwide fell to the point where the International Task Force for Disease Eradication identified mumps for eventual global eradication. By 1991, all military recruits received an MMR vaccine. By 2010, the Department of Defense (DoD) had adopted a policy of immunizing recruits with MMR vaccine only if their antibody titers to measles or rubella had dropped below threshold levels established by the commercial testing laboratories as indicative of immunity. As part of a 2010 Defense Health Board (DHB) review of MMR immunization practices by the Department of the Navy, the DHB recommended that the Navy continue the practice of MMR immunization based on serosurveillance, but that universal MMR vaccination be re-instituted in the event of an increased risk of a mumps outbreak.