Antibody-mediated protection against symptomatic COVID-19 can be achieved at low serum neutralizing titers.

Multiple studies of vaccinated and convalescent cohorts have demonstrated that serum neutralizing antibody (nAb) titers correlate with protection against coronavirus disease 2019 (COVID-19). However, the induction of multiple layers of immunity after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure has complicated the establishment of nAbs as a mechanistic correlate of protection (CoP) and hindered the definition of a protective nAb threshold. Here, we show that a half-life-extended monoclonal antibody (adintrevimab) provides about 50% protection against symptomatic COVID-19 in SARS-CoV-2-naïve adults at serum nAb titers on the order of 1:30. Vaccine modeling results support a similar 50% protective nAb threshold, suggesting that low titers of serum nAbs protect in both passive antibody prophylaxis and vaccination settings. Extrapolation of adintrevimab pharmacokinetic data suggests that protection against susceptible variants could be maintained for about 3 years. The results provide a benchmark for the selection of next-generation vaccine candidates and support the use of broad, long-acting monoclonal antibodies as alternatives or supplements to vaccination in high-risk populations.

Antibody-mediated protection against symptomatic COVID-19 can be achieved at low serum neutralizing titers.

Multiple studies of vaccinated and convalescent cohorts have demonstrated that serum neutralizing antibody (nAb) titers correlate with protection against COVID-19. However, the induction of multiple layers of immunity following SARS-CoV-2 exposure has complicated the establishment of nAbs as a mechanistic correlate of protection (CoP) and hindered the definition of a protective nAb threshold. Here, we show that a half-life extended monoclonal antibody (adintrevimab) provides approximately 50% protection against symptomatic COVID-19 in SARS-CoV-2-naive adults at low serum nAb titers on the order of 1:30. Vaccine modeling supports a similar 50% protective nAb threshold, suggesting low levels of serum nAb can protect in both monoclonal and polyclonal settings. Extrapolation of adintrevimab pharmacokinetic data suggests that protection against susceptible variants could be maintained for approximately 3 years. The results provide a benchmark for the selection of next-generation vaccine candidates and support the use of broad, long-acting monoclonal antibodies as an alternative or supplement to vaccination in high-risk populations.

Model-Based Approach for Optimizing Ceftobiprole Dosage in Pediatric Patients.

Ceftobiprole is an advanced-generation cephalosporin for intravenous administration with activity against Gram-positive and Gram-negative organisms. A population pharmacokinetic (PK) model characterizing the disposition of ceftobiprole in plasma using data from patients in three pediatric studies was developed. Model-based simulations were subsequently performed to assist in dose optimization for the treatment of pediatric patients with hospital-acquired or community-acquired pneumonia. The population PK data set comprised 518 ceftobiprole plasma concentrations from 107 patients from 0 (birth) to 17 years of age. Ceftobiprole PK was well described by a three-compartment model with linear elimination. Ceftobiprole clearance was modeled as a function of glomerular filtration rate; other PK parameters were scaled to body weight. The final population PK model provided a robust and reliable description of the PK of ceftobiprole in the pediatric study population. Model-based simulations using the final model suggested that a ceftobiprole dose of 15 mg/kg of body weight infused over 2 h and administered every 12 h in neonates and infants <3 months of age or every 8 h in older pediatric patients would result in a ceftobiprole exposure consistent with that in adults and good pharmacokinetic-pharmacodynamic target attainment. The dose should be reduced to 10 mg/kg every 12 h in neonates and infants <3 months of age who weigh <4 kg to avoid high exposures. Extended intervals and reduced doses may be required for pediatric patients older than 3 months of age with renal impairment.

Quantification of mitochondrial membrane potential in the isolated rat lung using rhodamine 6G.

Mitochondrial membrane potential (Δψm) plays a key role in vital mitochondrial functions, and its dissipation is a hallmark of mitochondrial dysfunction. The objective of this study was to develop an experimental and computational approach for estimating Δψm in intact rat lungs using the lipophilic fluorescent cationic dye rhodamine 6G (R6G). Rat lungs were excised and connected to a ventilation-perfusion system. The experimental protocol consisted of three single-pass phases, loading, washing, and uncoupling, in which the lungs were perfused with R6G-containing perfusate, fresh R6G-free perfusate, or R6G-free perfusate containing the mitochondrial uncoupler FCCP, respectively. This protocol was carried out with lung perfusate containing verapamil vehicle or verapamil, an inhibitor of the multidrug efflux pump P-glycoprotein (Pgp). Results show that the addition of FCCP resulted in an increase in R6G venous effluent concentration and that this increase was larger in the presence of verapamil than in its absence. A physiologically based pharmacokinetic (PBPK) model for the pulmonary disposition of R6G was developed and used for quantitative interpretation of the kinetic data, including estimating Δψm. The estimated value of Δψm [-144 ± 24 (SD) mV] was not significantly altered by inhibiting Pgp with verapamil and is comparable with that estimated previously in cultured pulmonary endothelial cells. These results demonstrate the utility of the proposed approach for quantifying Δψm in intact functioning lungs. This approach has potential to provide quantitative assessment of the effect of injurious conditions on lung mitochondrial function and to evaluate the impact of therapies that target mitochondria.NEW & NOTEWORTHY A novel experimental and computational approach for estimating mitochondrial membrane potential (Δψm) in intact functioning lungs is presented. The isolated rat lung inlet-outlet concentrations of the fluorescent cationic dye rhodamine 6G were measured and analyzed by using a computational model of its pulmonary disposition to determine Δψm. The approach has the potential to provide quantitative assessment of the effect of injurious conditions and their therapies on lung mitochondrial function.