Combination Ad26.RSV.preF/preF protein vaccine induces superior protective immunity compared with individual vaccine components in preclinical models.

Respiratory syncytial virus (RSV) is a leading cause of severe respiratory disease for which no licensed vaccine is available. We have previously shown that a prefusion (preF) conformation-stabilized RSV F protein antigen and an adenoviral vector encoding RSV preF protein (Ad26.RSV.preF) are immunogenic and protective in animals when administered as single components. Here, we evaluated a combination of the 2 components, administered as a single injection. Strong induction of both humoral and cellular responses was shown in RSV-naïve and pre-exposed mice and pre-exposed African green monkeys (AGMs). Both components of the combination vaccine contributed to humoral immune responses, while the Ad26.RSV.preF component was the main contributor to cellular immune responses in both mice and AGMs. Immunization with the combination elicited superior protection against RSV A2 challenge in cotton rats. These results demonstrate the advantage of a combination vaccine and support further clinical development.

Lipocalin-2 is an anorexigenic signal in primates.

In the mouse, the osteoblast-derived hormone Lipocalin-2 (LCN2) suppresses food intake and acts as a satiety signal. We show here that meal challenges increase serum LCN2 levels in persons with normal or overweight, but not in individuals with obesity. Postprandial LCN2 serum levels correlate inversely with hunger sensation in challenged subjects. We further show through brain PET scans of monkeys injected with radiolabeled recombinant human LCN2 (rh-LCN2) and autoradiography in baboon, macaque, and human brain sections, that LCN2 crosses the blood-brain barrier and localizes to the hypothalamus in primates. In addition, daily treatment of lean monkeys with rh-LCN2 decreases food intake by 21%, without overt side effects. These studies demonstrate the biology of LCN2 as a satiety factor and indicator and anorexigenic signal in primates. Failure to stimulate postprandial LCN2 in individuals with obesity may contribute to metabolic dysregulation, suggesting that LCN2 may be a novel target for obesity treatment.

Obesity has reached epidemic proportions worldwide and affects more than 40% of adults in the United States. People with obesity have a greater likelihood of developing type 2 diabetes, cardiovascular disease or chronic kidney disease. Changes in diet and exercise can be difficult to follow and result in minimal weight loss that is rarely sustained overtime. In fact, in people with obesity, weight loss can lower the metabolism leading to increased weight gain. New drugs may help some individuals achieve 5 to 10% weight loss but have side effects that prevent long-term use. Previous studies in mice show that a hormone called Lipocalin-2 (LCN2) suppresses appetite. It also reduces body weight and improves sugar metabolism in the animals. But whether this hormone has the same effects in humans or other primates is unclear. If it does, LCN2 might be a potential obesity treatment. Now, Petropoulou et al. show that LCN2 suppressed appetite in humans and monkeys. In human studies, LCN2 levels increased after a meal in individuals with normal weight or overweight, but not in individuals with obesity. Higher levels of LCN2 in a person's blood were also associated with a feeling of reduced hunger. Using brain scans, Petropoulou et al. showed that LCN2 crossed the blood-brain barrier in monkeys and bound to the hypothalamus, the brain center regulating appetite and energy balance. LCN2 also bound to human and monkey hypothalamus tissue in laboratory experiments. When injected into monkeys, the hormone suppressed food intake and lowered body weight without toxic effects in short-term studies. The experiments lay the initial groundwork for testing whether LCN2 might be a useful treatment for obesity. More studies in animals will help scientists understand how LCN2 works, which patients might benefit, how it would be given to patients and for how long. Clinical trials would also be needed to verify whether it is an effective and safe treatment for obesity.

Radiosynthesis and in Vivo Evaluation of [11C]A1070722, a High Affinity GSK-3 PET Tracer in Primate Brain.

Dysfunction of glycogen synthase kinase 3 (GSK-3) is implicated in the etiology of Alzheimer's disease, Parkinson's disease, diabetes, pain, and cancer. A radiotracer for functional positron emission tomography (PET) imaging could be used to study the kinase in brain disorders and to facilitate the development of small molecule inhibitors of GSK-3 for treatment. At present, there is no target-specific or validated PET tracer available for the in vivo monitoring of GSK-3. We radiolabeled the small molecule inhibitor [11C]1-(7-methoxy- quinolin-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea ([11C]A1070722) with high affinity to GSK-3 (Ki = 0.6 nM) in excellent radiochemical yield. PET imaging experiments in anesthetized vervet/African green monkey exhibited that [11C]A1070722 penetrated the blood-brain barrier (BBB) and accumulated in brain regions, with highest radioactivity binding in frontal cortex followed by parietal cortex and anterior cingulate, and with the lowest bindings found in caudate, putamen, and thalamus, similarly to the known distribution of GSK-3 in human brain. Our studies suggest that [11C]A1070722 can be a potential PET radiotracer for the in vivo quantification of GSK-3 in brain.

Age-related degenerative functional, radiographic, and histological changes of the shoulder in nonhuman primates.

BACKGROUND: Nonhuman primates have similar shoulder anatomy and physiology compared to humans, and may represent a previously underutilized model for shoulder research. This study sought to identify naturally occurring bony and muscular degeneration in the shoulder of nonhuman primates and to assess relationships between structural and functional aspects of the shoulder and measures of physical function of the animals. We hypothesized that age-related degenerative changes in the shoulders of nonhuman primates would resemble those observed in aging humans. METHODS: Middle-aged (n = 5; ages 9.4-11.8 years) and elderly (n = 6; ages 19.8-26.4 years) female vervet monkeys were studied for changes in mobility and shoulder function, and radiographic and histologic signs of age-related degeneration. RESULTS: Four out of 6 (4/6) elderly animals had degenerative changes of the glenoid compared to 0/5 of the middle-aged animals (P = .005). Elderly animals had glenoid retroversion, decreased joint space, walked slower, and spent less time climbing and hanging than middle-aged vervets (P < .05). Physical mobility and shoulder function correlated with glenoid version angle (P < .05). Supraspinatus muscles of elderly animals were less dense (P = .001), had decreased fiber cross-sectional area (P < .001), but similar amounts of nuclear material (P = .085). Degenerative rotator cuff tears were not observed in any of the eleven animals. DISCUSSION AND CONCLUSION: The vervet monkey naturally undergoes age-related functional, radiographic and histological changes of the shoulder, and may qualify as an animal model for selected translational research of shoulder osteoarthritis.