Monoclonal Antibodies in Hospitalised Patients with COVID-19: The Role of SARS-COV-2 Serostatus in an Evolving Pandemic.

Appropriately selected neutralising monoclonal antibodies (nmAbs) are an effective treatment for patients with mild or moderate coronavirus disease 2019 (COVID-19) who are at high risk of progression to severe disease. In contrast, the efficacy of nmAbs in patients hospitalised with COVID-19 has been mixed, and clinical benefit has largely been restricted to seronegative patients [i.e. those lacking endogenous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies] in the trials with positive outcomes. This review summarises the major clinical trial data investigating nmAb treatment for hospitalised patients with COVID-19, and explores current definitions of seropositivity, what they mean in a late-pandemic context and discusses the current late-pandemic challenges associated with defining 'seroprotection' in a clinically meaningful way. We conclude that following widespread vaccination, increasing numbers of prior infections and emerging viral variants, seropositivity now reflects a range of immune coverage rather than a binary tool with which to aid decision-making on a clinically actionable timescale. Treatment decisions with nmAbs in a late-pandemic context would therefore likely best rely on information regarding clinical status, time since symptom onset, underlying patient condition(s) and the dominant circulating variant, should they be approved for future use in hospitalised patients with COVID-19.

Predictors of SARS-CoV-2 RNA From Nasopharyngeal Swabs and Concordance With Other Compartments in Nonhospitalized Adults With Mild to Moderate COVID-19.

Background: Identifying characteristics associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA shedding may be useful to understand viral compartmentalization, disease pathogenesis, and risks for viral transmission. Methods: Participants were enrolled August 2020 to February 2021 in ACTIV-2/A5401, a placebo-controlled platform trial evaluating investigational therapies for mild-to-moderate coronavirus disease 2019 (COVID-19), and underwent quantitative SARS-CoV-2 RNA testing on nasopharyngeal and anterior nasal swabs, oral wash/saliva, and plasma at entry (day 0, pretreatment) and days 3, 7, 14, and 28. Concordance of RNA levels (copies/mL) across compartments and predictors of nasopharyngeal RNA levels were assessed at entry (n = 537). Predictors of changes over time were evaluated among placebo recipients (n = 265) with censored linear regression models. Results: Nasopharyngeal and anterior nasal RNA levels at study entry were highly correlated (r = 0.84); higher levels of both were associated with greater detection of RNA in plasma and oral wash/saliva. Older age, White non-Hispanic race/ethnicity, lower body mass index (BMI), SARS-CoV-2 immunoglobulin G seronegativity, and shorter prior symptom duration were associated with higher nasopharyngeal RNA at entry. In adjusted models, body mass index and race/ethnicity associations were attenuated, but the association with age remained (for every 10 years older, mean nasopharyngeal RNA was 0.27 log10 copies/mL higher; P < .001). Examining longitudinal viral RNA levels among placebo recipients, women had faster declines in nasopharyngeal RNA than men (mean change, -2.0 vs -1.3 log10 copies/mL, entry to day 3; P < .001). Conclusions: SARS-CoV-2 RNA shedding was concordant across compartments. Age was strongly associated with viral shedding, and men had slower viral clearance than women, which could explain sex differences in acute COVID-19 outcomes.

Casirivimab and Imdevimab Treatment Reduces Viral Load and Improves Clinical Outcomes in Seropositive Hospitalized COVID-19 Patients with Nonneutralizing or Borderline Neutralizing Antibodies.

We conducted a post hoc analysis in seropositive patients who were negative or borderline for functional neutralizing antibodies (NAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at baseline from a phase 1, 2, and 3 trial of casirivimab and imdevimab (CAS+IMD) treatment in hospitalized coronavirus disease 2019 (COVID-19) patients on low-flow or no supplemental oxygen prior to the emergence of Omicron-lineage variants. Patients were randomized to a single dose of 2.4 g CAS+IMD, 8.0 g CAS+IMD, or placebo. Patients seropositive for anti-SARS-CoV-2 antibodies at baseline were analyzed by their baseline neutralizing antibody status. At baseline, 20.6% (178/864) of seropositive patients were negative or borderline for neutralizing antibodies, indicating negative or very low functionally neutralizing anti-SARS-CoV-2 antibodies. CAS+IMD reduced viral load in patients who were negative or borderline for neutralizing antibodies versus placebo, but not in patients who were positive for neutralizing antibodies. In patients who were negative or borderline for neutralizing antibodies, we observed a trend in reduction of the proportion of patients who died or required mechanical ventilation, as well as in all-cause mortality, by day 29 with CAS+IMD versus placebo. The proportions of patients who died or required mechanical ventilation from days 1 to 29 were 19.1% in the placebo group and 10.9% in the CAS+IMD combined-dose group, and the proportions of patients who died (all-cause mortality) from days 1 to 29 were 16.2% in the placebo group and 9.1% in the CAS+IMD combined-dose group. In patients who were positive for neutralizing antibodies, no measurable harm or benefit was observed in either the proportion of patients who died or required mechanical ventilation or the proportion of patients who died (all-cause mortality). In hospitalized COVID-19 patients on low-flow or no supplemental oxygen, CAS+IMD reduced viral load, the risk of death or mechanical ventilation, and all-cause mortality in seropositive patients who were negative or borderline for neutralizing antibodies. IMPORTANCE The clinical benefit of CAS+IMD in hospitalized seronegative patients with COVID-19 has previously been demonstrated, although these studies observed no clinical benefit in seropositive patients. As the prevalence of SARS-CoV-2-seropositive individuals rises due to both vaccination and previous infection, it is important to understand whether there is a subset of hospitalized patients with COVID-19 with antibodies against SARS-CoV-2 who could benefit from anti-SARS-CoV-2 monoclonal antibody treatment. This post hoc analysis demonstrates that there is a subset of hospitalized seropositive patients with inadequate SARS-CoV-2-neutralizing antibodies (i.e., those who were negative or borderline for neutralizing antibodies) who may still benefit from CAS+IMD treatment if infected with a susceptible SARS-CoV-2 variant. Therefore, utilizing serostatus alone to guide treatment decisions for patients with COVID-19 may fail to identify those seropositive patients who could benefit from anti-SARS-CoV-2 monoclonal antibody therapies known to be effective against circulating strains, dependent upon how effectively their endogenous antibodies neutralize SARS-CoV-2.

Pre-Existing Comorbidities Diminish the Likelihood of Seropositivity after SARS-CoV-2 Vaccination.

BACKGROUND: The impact of chronic health conditions (CHCs) on serostatus post-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is unknown. METHODS: We assessed serostatus post-SARS-CoV-2 vaccination among fully vaccinated adult residents of Jefferson County, Kentucky, USA, from April 2021 to August 2021. Serostatus was determined by qualitative analysis of SARS-CoV-2-specific Spike IgG antibodies via enzyme-linked immunoassay (ELISA) in peripheral blood samples. RESULTS: Of the 5178 fully vaccinated participants, 51 were seronegative and 5127 were seropositive. Chronic kidney disease (CKD) and autoimmune disease showed the highest association with negative serostatus in fully vaccinated individuals. The absence of any CHC was strongly associated with positive serostatus. The risk of negative serostatus increased as the total number of pre-existing CHCs increased. Similarly, the use of two or more CHC-related medications was associated with seronegative status. CONCLUSIONS: The presence of any CHC, especially CKD or autoimmune disease, increased the likelihood of seronegative status among individuals who were fully vaccinated to SAR-CoV-2. This risk increased with a concurrent increase in number of comorbidities, especially with multiple medications. The absence of any CHC was protective and increased the likelihood of a positive serological response. These results will help develop appropriate guidelines for booster doses and targeted vaccination programs.

Maternal SARS-CoV-2 sero-surveillance using newborn dried blood spot (DBS) screening specimens highlights extent of low vaccine uptake in pregnant women.

SARS-CoV-2 vaccine uptake in pregnant women is believed to be low and lags behind the general population contributing to increased hospital admissions, and poor maternal and fetal outcomes. However, there is a paucity of information on the SARS-CoV-2 serostatus of pregnant women to help inform policy planning and assess impact of interventions to improve vaccine uptake in this at-risk group. We analyzed 8,683 residual, anonymized newborn screening dried bloodspot (DBS) specimens during a 15-month period (October 2020 to December 2021) in Wales (UK) for SARS-CoV-2 IgG-antibodies. We compared newborn DBS antibody-positive rates to the percentage number of pregnant women vaccinated and the percentage number of antibody-positive adults. In December 2021, 47.8% of women in Wales had received two doses of the vaccine by their delivery date; however, only 41.1% of DBS specimens had high antibody concentrations. Results indicate that a proportion of pregnant women remain at higher-risk of COVID complications, particularly given the reduction in antibody neutralization of Omicron versus the Delta variant. Our study demonstrates the utility of newborn screening DBS specimens to monitor SARS-CoV-2 serostatus in pregnant women representing maternal vaccination and natural infection in almost real-time, defining the immunity gap and impact of any interventions.

SARS-CoV-2 mRNA vaccine induces robust specific and cross-reactive IgG and unequal neutralizing antibodies in naive and previously infected people.

Understanding vaccine-mediated protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is critical to overcoming the global coronavirus disease 2019 (COVID-19) pandemic. We investigate mRNA-vaccine-induced antibody responses against the reference strain, seven variants, and seasonal coronaviruses in 168 healthy individuals at three time points: before vaccination, after the first dose, and after the second dose. Following complete vaccination, both naive and previously infected individuals developed comparably robust SARS-CoV-2 spike antibodies and variable levels of cross-reactive antibodies to seasonal coronaviruses. However, the strength and frequency of SARS-CoV-2 neutralizing antibodies in naive individuals were lower than in previously infected individuals. After the first vaccine dose, one-third of previously infected individuals lacked neutralizing antibodies; this was improved to one-fifth after the second dose. In all individuals, neutralizing antibody responses against the Alpha and Delta variants were weaker than against the reference strain. Our findings support future tailored vaccination strategies against emerging SARS-CoV-2 variants as mRNA-vaccine-induced neutralizing antibodies are highly variable among individuals.

Infectious Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Virus in Symptomatic Coronavirus Disease 2019 (COVID-19) Outpatients: Host, Disease, and Viral Correlates.

BACKGROUND: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectious virus isolation in outpatients with coronavirus disease 2019 (COVID-19) has been associated with viral RNA levels and symptom duration, little is known about the host, disease, and viral determinants of infectious virus detection. METHODS: COVID-19 adult outpatients were enrolled within 7 days of symptom onset. Clinical symptoms were recorded via patient diary. Nasopharyngeal swabs were collected to quantitate SARS-CoV-2 RNA by reverse transcriptase polymerase chain reaction and for infectious virus isolation in Vero E6-cells. SARS-CoV-2 antibodies were measured in serum using a validated ELISA assay. RESULTS: Among 204 participants with mild-to-moderate symptomatic COVID-19, the median nasopharyngeal viral RNA was 6.5 (interquartile range [IQR] 4.7-7.6 log10 copies/mL), and 26% had detectable SARS-CoV-2 antibodies (immunoglobulin (Ig)A, IgM, IgG, and/or total Ig) at baseline. Infectious virus was recovered in 7% of participants with SARS-CoV-2 antibodies compared to 58% of participants without antibodies (prevalence ratio [PR] = 0.12, 95% confidence interval [CI]: .04, .36; P = .00016). Infectious virus isolation was also associated with higher levels of viral RNA (mean RNA difference +2.6 log10, 95% CI: 2.2, 3.0; P < .0001) and fewer days since symptom onset (PR = 0.79, 95% CI: .71, .88 per day; P < .0001). CONCLUSIONS: The presence of SARS-CoV-2 antibodies is strongly associated with clearance of infectious virus. Seropositivity and viral RNA levels are likely more reliable markers of infectious virus clearance than subjective measure of COVID-19 symptom duration. Virus-targeted treatment and prevention strategies should be administered as early as possible and ideally before seroconversion. CLINICAL TRIALS REGISTRATION: NCT04405570.

Postmortem Antigen-Detecting Rapid Diagnostic Tests to Predict Infectivity of SARS-CoV-2-Associated Deaths.

We investigated the infectivity of 128 severe acute respiratory disease coronavirus 2-associated deaths and evaluated predictive values of standard diagnostic procedures. Maintained infectivity (20%) did not correlate with viral RNA loads but correlated well with anti-S antibody levels. Sensitivity >90% for antigen-detecting rapid diagnostic tests supports their usefulness for assessment.