Evaluation of an inactivated Ross River virus vaccine in active and passive mouse immunization models and establishment of a correlate of protection

Ross River Virus has caused reported outbreaks of epidemic polyarthritis, a chronic debilitating disease associated with significant long-term morbidity in Australia and the Pacific region since the 1920s. To address this public health concern, a formalin- and UV-inactivated whole virus vaccine grown in animal protein-free cell culture was developed and tested in preclinical studies to evaluate immunogenicity and efficacy in animal models. After active immunizations, the vaccine dose-dependently induced antibodies and protected adult mice from viremia and interferon α/β receptor knock-out (IFN-α/βR(-/-)) mice from death and disease. In passive transfer studies, administration of human vaccinee sera followed by RRV challenge protected adult mice from viremia and young mice from development of arthritic signs similar to human RRV-induced disease. Based on the good correlation between antibody titers in human sera and protection of animals, a correlate of protection was defined. This is of particular importance for the evaluation of the vaccine because of the comparatively low annual incidence of RRV disease, which renders a classical efficacy trial impractical. Antibody-dependent enhancement of infection, did not occur in mice even at low to undetectable concentrations of vaccine-induced antibodies. Also, RRV vaccine-induced antibodies were partially cross-protective against infection with a related alphavirus, Chikungunya virus, and did not enhance infection. Based on these findings, the inactivated RRV vaccine is expected to be efficacious and protect humans from RRV disease

Development and feasibility of a smartphone, ECG and GPS based system for remotely monitoring exercise in cardiac rehabilitation

Background Despite its efficacy and cost-effectiveness, exercise-based cardiac rehabilitation is undertaken by less than one-third of clinically eligible cardiac patients in every country for which data is available. Reasons for non-participation include the unavailability of hospital-based rehabilitation programs, or excessive travel time and distance. For this reason, there have been calls for the development of more flexible alternatives. Methodology and Principal Findings We developed a system to enable walking-based cardiac rehabilitation in which the patient's single-lead ECG, heart rate, GPS-based speed and location are transmitted by a programmed smartphone to a secure server for real-time monitoring by a qualified exercise scientist. The feasibility of this approach was evaluated in 134 remotely-monitored exercise assessment and exercise sessions in cardiac patients unable to undertake hospital-based rehabilitation. Completion rates, rates of technical problems, detection of ECG changes, pre- and post-intervention six minute walk test (6 MWT), cardiac depression and Quality of Life (QOL) were key measures. The system was rated as easy and quick to use. It allowed participants to complete six weeks of exercise-based rehabilitation near their homes, worksites, or when travelling. The majority of sessions were completed without any technical problems, although periodic signal loss in areas of poor coverage was an occasional limitation. Several exercise and post-exercise ECG changes were detected. Participants showed improvements comparable to those reported for hospital-based programs, walking significantly further on the post-intervention 6 MWT, 637 m (95% CI: 565–726), than on the pre-test, 524 m (95% CI: 420–655), and reporting significantly reduced levels of cardiac depression and significantly improved physical health-related QOL. Conclusions and Significance The system provided a feasible and very flexible alternative form of supervised cardiac rehabilitation for those unable to access hospital-based programs, with the potential to address a well-recognised deficiency in health care provision in many countries. Future research should assess its longer-term efficacy, cost-effectiveness and safety in larger samples representing the spectrum of cardiac morbidity and severity.

Zoledronic acid preserves bone structure and increases survival but does not limit tumour incidence in a prostate cancer bone metastasis model

Background The bisphosphonate, zoledronic acid (ZOL), can inhibit osteoclasts leading to decreased osteoclastogenesis and osteoclast activity in bone. Here, we used a mixed osteolytic/osteoblastic murine model of bone-metastatic prostate cancer, RM1(BM), to determine how inhibiting osteolysis with ZOL affects the ability of these cells to establish metastases in bone, the integrity of the tumour-bearing bones and the survival of the tumour-bearing mice. Methods The model involves intracardiac injection for arterial dissemination of the RM1(BM) cells in C57BL/6 mice. ZOL treatment was given via subcutaneous injections on days 0, 4, 8 and 12, at 20 and 100 µg/kg doses. Bone integrity was assessed by micro-computed tomography and histology with comparison to untreated mice. The osteoclast and osteoblast activity was determined by measuring serum tartrate-resistant acid phosphatase 5b (TRAP 5b) and osteocalcin, respectively. Mice were euthanased according to predetermined criteria and survival was assessed using Kaplan Meier plots. Findings Micro-CT and histological analysis showed that treatment of mice with ZOL from the day of intracardiac injection of RM1(BM) cells inhibited tumour-induced bone lysis, maintained bone volume and reduced the calcification of tumour-induced endochondral osteoid material. ZOL treatment also led to a decreased serum osteocalcin and TRAP 5b levels. Additionally, treated mice showed increased survival compared to vehicle treated controls. However, ZOL treatment did not inhibit the cells ability to metastasise to bone as the number of bone-metastases was similar in both treated and untreated mice. Conclusions ZOL treatment provided significant benefits for maintaining the integrity of tumour-bearing bones and increased the survival of tumour bearing mice, though it did not prevent establishment of bone-metastases in this model. From the mechanistic view, these observations confirm that tumour-induced bone lysis is not a requirement for establishment of these bone tumours.