Protective capacity of neutralizing and non-neutralizing antibodies against glycoprotein B of cytomegalovirus.

Human cytomegalovirus (HCMV) is an important, ubiquitous pathogen that causes severe clinical disease in immunocompromised individuals, such as organ transplant recipients and infants infected in utero. Antiviral chemotherapy remains problematic due to toxicity of the available compounds and the emergence of viruses resistant to available antiviral therapies. Antiviral antibodies could represent a valuable alternative strategy to limit the clinical consequences of viral disease in patients. The envelope glycoprotein B (gB) of HCMV is a major antigen for the induction of virus neutralizing antibodies. However, the role of anti-gB antibodies in the course of the infection in-vivo remains unknown. We have used a murine CMV (MCMV) model to generate and study a number of anti-gB monoclonal antibodies (mAbs) with differing virus-neutralizing capacities. The mAbs were found to bind to similar antigenic structures on MCMV gB that are represented in HCMV gB. When mAbs were used in immunodeficient RAG-/- hosts to limit an ongoing infection we observed a reduction in viral load both with mAbs having potent neutralizing capacity in-vitro as well as mAbs classified as non-neutralizing. In a therapeutic setting, neutralizing mAbs showed a greater capacity to reduce the viral burden compared to non-neutralizing antibodies. Efficacy was correlated with sustained concentration of virus neutralizing mAbs in-vivo rather than their in-vitro neutralizing capacity. Combinations of neutralizing mAbs further augmented the antiviral effect and were found to be as potent in protection as polyvalent serum from immune animals. Prophylactic administration of mAbs before infection was also protective and both neutralizing and non-neutralizing mAbs were equally effective in preventing lethal infection of immunodeficient mice. In summary, our data argue that therapeutic application of potently neutralizing mAbs against gB represent a strategy to modify the outcome of CMV infection in immunodeficient hosts. When present before infection, both neutralizing and non-neutralizing anti-gB exhibited protective capacity.

Development and validation of an improved mechanical thorax for simulating cardiopulmonary resuscitation with adjustable chest stiffness and simulated blood flow.

Investigations of compressive frequency, duty cycle, or waveform during CPR are typically rooted in animal research or computer simulations. Our goal was to generate a mechanical model incorporating alternate stiffness settings and an integrated blood flow system, enabling defined, reproducible comparisons of CPR efficacy. Based on thoracic stiffness data measured in human cadavers, such a model was constructed using valve-controlled pneumatic pistons and an artificial heart. This model offers two realistic levels of chest elasticity, with a blood flow apparatus that reflects compressive depth and waveform changes. We conducted CPR at opposing levels of physiologic stiffness, using a LUCAS device, a motor-driven plunger, and a group of volunteers. In high-stiffness mode, blood flow generated by volunteers was significantly less after just 2min of CPR, whereas flow generated by LUCAS device was superior by comparison. Optimal blood flow was obtained via motor-driven plunger, with trapezoidal waveform.