Safety of recombinant VSV-Ebola virus vaccine vector in pigs.

The ongoing Ebola outbreak in West Africa has resulted in fast-track development of vaccine candidates. We tested a vesicular stomatitis virus vector expressing Ebola virus glycoprotein for safety in pigs. Inoculation did not cause disease and vaccine virus shedding was minimal, which indicated that the vaccine virus does not pose a risk of dissemination in pigs.

Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques.

The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) is of global concern: the virus has caused severe respiratory illness, with 111 confirmed cases and 52 deaths at the time of this article's publication. Therapeutic interventions have not been evaluated in vivo; thus, patient management relies exclusively on supportive care, which, given the high case-fatality rate, is not highly effective. The rhesus macaque is the only known model organism for MERS-CoV infection, developing an acute localized to widespread pneumonia with transient clinical disease that recapitulates mild to moderate human MERS-CoV cases. The combination of interferon-α2b and ribavirin was effective in reducing MERS-CoV replication in vitro; therefore, we initiated this treatment 8 h after inoculation of rhesus macaques. In contrast to untreated, infected macaques, treated animals did not develop breathing abnormalities and showed no or very mild radiographic evidence of pneumonia. Moreover, treated animals showed lower levels of systemic (serum) and local (lung) proinflammatory markers, in addition to fewer viral genome copies, distinct gene expression and less severe histopathological changes in the lungs. Taken together, these data suggest that treatment of MERS-CoV infected rhesus macaques with IFN-α2b and ribavirin reduces virus replication, moderates the host response and improves clinical outcome. As these two drugs are already used in combination in the clinic for other infections, IFN-α2b and ribavirin should be considered for the management of MERS-CoV cases.

A Hendra virus G glycoprotein subunit vaccine protects African green monkeys from Nipah virus challenge.

In the 1990s, Hendra virus and Nipah virus (NiV), two closely related and previously unrecognized paramyxoviruses that cause severe disease and death in humans and a variety of animals, were discovered in Australia and Malaysia, respectively. Outbreaks of disease have occurred nearly every year since NiV was first discovered, with case fatality ranging from 10 to 100%. In the African green monkey (AGM), NiV causes a severe lethal respiratory and/or neurological disease that essentially mirrors fatal human disease. Thus, the AGM represents a reliable disease model for vaccine and therapeutic efficacy testing. We show that vaccination of AGMs with a recombinant subunit vaccine based on the henipavirus attachment G glycoprotein affords complete protection against subsequent NiV infection with no evidence of clinical disease, virus replication, or pathology observed in any challenged subjects. Success of the recombinant subunit vaccine in nonhuman primates provides crucial data in supporting its further preclinical development for potential human use.

A neutralizing human monoclonal antibody protects african green monkeys from hendra virus challenge.

Hendra virus (HeV) is a recently emerged zoonotic paramyxovirus that can cause a severe and often fatal disease in horses and humans. HeV is categorized as a biosafety level 4 agent, which has made the development of animal models and testing of potential therapeutics and vaccines challenging. Infection of African green monkeys (AGMs) with HeV was recently demonstrated, and disease mirrored fatal HeV infection in humans, manifesting as a multisystemic vasculitis with widespread virus replication in vascular tissues and severe pathologic manifestations in the lung, spleen, and brain. Here, we demonstrate that m102.4, a potent HeV-neutralizing human monoclonal antibody (hmAb), can protect AGMs from disease after infection with HeV. Fourteen AGMs were challenged intratracheally with a lethal dose of HeV, and 12 subjects were infused twice with a 100-mg dose of m102.4 beginning at either 10, 24, or 72 hours after infection and again about 48 hours later. The presence of viral RNA, infectious virus, and HeV-specific immune responses demonstrated that all subjects were infected after challenge. All 12 AGMs that received m102.4 survived infection, whereas the untreated control subjects succumbed to disease on day 8 after infection. Animals in the 72-hour treatment group exhibited neurological signs of disease, but all animals started to recover by day 16 after infection. These results represent successful post-exposure in vivo efficacy by an investigational drug against HeV and highlight the potential impact a hmAb can have on human disease.

Inhibitory effects and mechanisms of intestinal electrical stimulation on gastric tone, antral contractions, pyloric tone, and gastric emptying in dogs.

The aim of this study was to investigate the effects and mechanisms of intestinal electrical stimulation (IES) on gastric tone, antral and pyloric contractions, and gastric emptying in dogs. Female hound dogs were equipped with a duodenal or gastric cannula, and one pair of serosal electrodes was implanted in the small intestine. The study consisted of five different experiments. Liquid gastric emptying was assessed by collection of chyme from the duodenal cannula in a number of sessions with and without IES and with and without N-nitro-l-arginine (l-NNA). Postprandial antral and pyloric contractions were measured with and without IES and in the absence and presence of l-NNA or phentolamine by placement of a manometric catheter into the antrum and pylorus via the duodenal cannula. Gastric tone was assessed by measurement of gastric volume at a constant pressure. Gastric emptying was substantially and significantly delayed by IES or l-NNA compared with the control session. IES-induced delay of gastric emptying became normal with addition of l-NNA. IES reduced gastric tone, which was blocked by l-NNA. IES also inhibited antral contractions (frequency and amplitude), and this inhibitory effect was not blocked by l-NNA but was blocked by phentolamine. IES alone did not affect pyloric tone or resistance, but IES + l-NNA decreased pyloric tone. In conclusion, IES reduces gastric tone via the nitrergic pathway, inhibits antral contractions via the adrenergic pathway, does not affect pyloric tone, and delays liquid gastric emptying. IES-induced delay of gastric emptying is attributed to its inhibitory effects on gastric motility.

Rectal distension inhibits postprandial small intestinal motor activity partially via the adrenergic pathway in dogs.

OBJECTIVE: Rectal distension is known to induce numerous upper gastrointestinal symptoms. The aim of this study was to investigate the effects and mechanisms of rectal distension on small intestinal myoelectrical and motor activities in 8 dogs using a pair of intestinal electrodes and an intestinal fistula. MATERIAL AND METHODS: Experiment 1 entailed a 30-min baseline recording and a 30-min recording during rectal balloon distension at various volumes (60, 80, 100 and 120 ml) randomly. Experiment 2 comprised three sessions, each including a 30-min baseline recording, a 20-min recording after intravenous infusion of saline, phentolamine (3 mg/kg) or propranolol (3 mg/kg), respectively, and another 30-min recording during rectal balloon distending. RESULTS: 1) Rectal distension resulted in reduced intestinal motility in a dose-dependent manner (r=0.68, p<0.001). 2) The reduction in intestinal motility was significantly diminished when infusions of phentolamine (2.7+/-1.0 versus 8.4+/-1.5, p<0.01) or propranolol (3.7+/-1.4 versus 8.4+/-1.5, p<0.05) were given, suggesting partial involvement of the alpha- and beta-adrenergic pathways. 3) Rectal distension did not affect the percentage of normal 17-22 cycles/min intestinal slow waves (97.5+/-2.5 versus 93.0+/-5.3, p>0.05), or their dominant frequency (17.2+/-1.2 counts per minute (cpm) versus 17.7+/-1.0 cpm, p>0.05), or dominant power (-4.8+/-2.5 versus -8.2+/-2.9 dB, p>0.05). CONCLUSIONS: Rectal distension inhibits postprandial small intestinal motor activity in a distension volume-dependent manner in dogs, and this inhibitory effect is at least partially mediated via the alpha and beta adrenergic pathways and does not involve any alterations in intestinal slow waves.

Effects of enhanced viscosity on canine gastric and intestinal motility.

BACKGROUND AND AIM: The aim of this study was to investigate the effect of enhanced viscosity on gastric emptying and gastrointestinal motor and myoelectrical activities in dogs. METHOD: The study was performed in eight healthy female hound dogs chronically implanted with four pairs of gastric and two pairs of intestinal serosal electrodes and a duodenal fistula. Each dog was studied in three sessions and fed with three test meals with different viscosity. Gastric emptying was monitored for 2 h simultaneously with gastric and intestinal myoelectrical recordings. RESULTS: The liquid test meal containing either 0.78% or 1.21% of galactomannan significantly delayed gastric emptying but had no effect on postprandial blood glucose levels in comparison with the meal containing no galactomannan. The liquid test meal containing either 0.78% or 1.21% of galactomannan significantly increased the frequency and strength of intestinal motility but had no effect on intestinal slow wave rhythms. The product with enhanced viscosity had no effect on gastric motor activity or gastric slow waves. CONCLUSION: It was concluded that enhanced viscosity delays gastric emptying, increases postprandial intestinal but not gastric motility, and has no effects on gastric or intestinal slow waves.