Safety and immunogenicity of a plant-produced recombinant monomer hemagglutinin-based influenza vaccine derived from influenza A (H1N1)pdm09 virus: a Phase 1 dose-escalation study in healthy adults.

BACKGROUND: Novel influenza viruses continue to pose a potential pandemic threat worldwide. In recent years, plants have been used to produce recombinant proteins, including subunit vaccines. A subunit influenza vaccine, HAC1, based on recombinant hemagglutinin from the 2009 pandemic A/California/04/2009 (H1N1) strain of influenza virus, has been manufactured using a plant virus-based transient expression technology in Nicotiana benthamiana plants and demonstrated to be immunogenic and safe in pre-clinical studies (Shoji et al., 2011). METHODS: A first-in-human, Phase 1, single-center, randomized, placebo-controlled, single-blind, dose escalation study was conducted to investigate safety, reactogenicity and immunogenicity of an HAC1 formulation at three escalating dose levels (15 µg, 45 µg and 90 µg) with and without Alhydrogel(®), in healthy adults 18-50 years of age (inclusive). Eighty participants were randomized into six study vaccine groups, a saline placebo group and an approved monovalent H1N1 vaccine group. Recipients received two doses of vaccine or placebo (except for the monovalent H1N1 vaccine cohort, which received a single dose of vaccine, later followed by a dose of placebo). RESULTS: The experimental vaccine was safe and well tolerated, and comparable to placebo and the approved monovalent H1N1 vaccine. Pain and tenderness at the injection site were the only local solicited reactions reported following vaccinations. Nearly all adverse events were mild to moderate in severity. The HAC1 vaccine was also immunogenic, with the highest seroconversion rates, based on serum hemagglutination-inhibition and virus microneutralization antibody titers, in the 90 µg non-adjuvanted HAC1 vaccine group after the second vaccine dose (78% and 100%, respectively). CONCLUSIONS: This is the first study demonstrating the safety and immunogenicity of a plant-produced subunit H1N1 influenza vaccine in healthy adults. The results support further clinical investigation of the HAC1 vaccine as well as demonstrate the feasibility of the plant-based technology for vaccine antigen production.

Nocturnal polysomnographic correlates of daytime sleepiness.

The relations of nighttime polysomnographic sleep variables with daytime sleepiness scores on the Epworth Sleepiness Scale were assessed in a retrospective chart review of 38 patients referred to a sleep clinic. Of the variables assessed, only slow wave sleep was statistically significantly correlated with daytime sleepiness, regardless of whether the analysis was based on absolute minutes of slow wave sleep or percentage of total sleep time spent in slow wave sleep. Stepwise linear regression suggested that other polysomnographic variables did not provide additional predictive value beyond the two indices of slow wave sleep. Apparently, reduced quantity of slow wave sleep was weakly but significantly related to increased daytime sleepiness among these sleep-clinic patients.

Sleep disruptions among returning combat veterans from Iraq and Afghanistan.

BACKGROUND: Post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI) are common injuries among returning combat veterans from the wars in Iraq and Afghanistan. Although these combat injuries have been associated with increased sleep disruption, little is known about the nature and specificity of sleep problems within these common injury categories. METHOD: A retrospective chart review of 69 consecutive referrals to the Waiter Reed Army Medical Center sleep clinic was conducted. All cases were active duty soldiers who had recently returned from combat deployment in Iraq or Afghanistan. Data from polysomnographically (PSG) recorded sleep stages, sleepiness scales, and documented medical diagnoses were extracted from medical records. Sleep data were compared across diagnoses of PTSD, TBI, and other clinical conditions. RESULTS: As expected, clinical sleep disturbances, including rates of obstructive sleep apnea, excessive awakenings, daytime sleepiness, and hypoxia, were high for the sample as a whole. However, no differences across diagnostic groups were found. Differences were observed, however, on PSG measures of sleep quality, suggesting more frequent arousals from sleep among patients with PTSD and greater slow wave sleep among those with TBI. Except for REM latency, medication status had virtually no effect on sleep variables. CONCLUSIONS: Among recently redeployed combat veterans, clinically significant sleep disturbances and problems with sleep-disordered breathing are common but nonspecific findings across primary diagnoses of PTSD, TBI, major depression, and anxiety disorder, whereas more subtle differences in sleep architecture and arousals as measured by overnight PSG recordings were modestly, but significantly, effective at distinguishing among the diagnostic groups.

Oral appliance titration in patients with obstructive sleep apnea induces the appearance of periodic limb movements.

STUDY OBJECTIVES: Oral appliance (OA) therapy is considered a first line choice of therapy for some patients with mild or moderate obstructive sleep apnea (OSA) and an alternative form of treatment in those intolerant of continuous positive airway pressure (CPAP) use. According to several studies, periodic limb movements (PLM) appear during effective treatment of OSA with CPAP, but a similar phenomenon has not been described with the use of oral appliance. Herein, we describe the incidence of PLM in patients with OSA who underwent oral appliance therapy titration. DESIGN: This is a retrospective, [corrected] observational study set in a six-bed sleep center in an academic, military referral hospital. PATIENTS AND METHODS: Patients with OSA (n=21; 15 men and six women; mean age, 43 years; and age range, 25 to 53 years) treated with OA during a 1-year period were analyzed. [corrected] Patients were categorized according to the severity of sleep apnea and incidence of PLM on diagnostic polysomnography. Effective treatment of OSA and appearance or disappearance of PLM with arousal on subsequent oral appliance titration polysomnography were recorded and compared. RESULTS: Twenty-one patients were included in the analysis. [corrected] During baseline polysomnography, three of 21 (14%) patients had five or more PLM with arousal per hour while 11 of 21 (52%) patients had PLM with arousal during the oral appliance titration trial. CONCLUSION: Oral appliance therapy for obstructive sleep apnea is an effective treatment and ideal for use in military recruits. The appearance of periodic limb movements with arousal during oral appliance use should be considered as a cause of persistent daytime sleepiness despite effective treatment of obstructive sleep apnea in this subset of patients.

Airway function in women: bronchial hyperresponsiveness, cough, and vocal cord dysfunction.

Bronchial hyperreactivity and cough are common medical problems that occur more frequently in women. Differences in size, hormonal effects, density, and sensitivity to receptors and psychologic factors may all play a role, which results in increased expression of upper and lower airway disease. The reason that VCD occurs more commonly in women is not clear but many of the same explanations regarding bronchial hyperreactivity and cough may apply.