[Prevention of respiratory syncytial virus infection in infants. What has been done and where are we today?] / Prevención de la infección por virus respiratorio sincicial en lactantes. ¿Qué se ha hecho y en qué estamos hoy?

Respiratory syncytial virus (RSV) infection is a frequent cause of morbidity and mortality in children. Recently, great advances have been made in the development of new monoclonal antibodies and vaccines thanks to the recognition of the structural conformation of virus proteins. The objective of this study was to review the advances related to the prevention of RSV infection in the first 6 months of life. Advances in structural biology have shown that the RSV fusion protein (F-Protein) in its prefusion state (Pre-F) is an excellent antigen for developing monoclonal antibodies and vaccines to prevent respiratory syncytial virus (RSV) infections. A new single-dose monoclonal antibody, Nirsevimab, has greater neutralizing power than currently available Palivizumab, and prolonged protection for 5 to 6 months. Nirsevimab has demonstrated an efficacy of 76.8% (95% CI, 49.4 to 89.4) in preventing lower respiratory infection 150 days after vaccination, decreasing the risk of ICU admission by 90.1% (95% CI: 16.4-98.8). Clesrovimab is another single-dose monoclonal antibody that has also shown promising results in phase 1b-2a trials. More recently, a bivalent vaccine against RSV A and B (Bivalent Prefusion F) has also been developed by replicating the F-protein stabilized in its Pre-F state as an antigen, using genetic engineering. This antigen, when administered to pregnant women between 24-36 weeks of gestation, induces high levels of antibodies in the mother with high transplacental transfer to the fetus. This vaccine has demonstrated an efficacy of 81.8% (95% CI: 40.6-96.3) at 90 days and 69.4% (95% CI: 44.3-84.1) at 180 days to prevent severe RSV disease (primary endpoint) without safety events detected so far. Nirsevimab and the Pre-F vaccine for pregnant women confer effective protection through passive immunity against RSV that lasts for the first 5 to 6 months of life and have already been approved for use in Europe by the EMA and in Canada and the United States by the FDA.

Suptavumab for the Prevention of Medically Attended Respiratory Syncytial Virus Infection in Preterm Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of childhood medically attended respiratory infection (MARI). METHODS: We conducted a randomized, double-blind, placebo-controlled phase 3 trial in 1154 preterm infants of 1 or 2 doses of suptavumab, a human monoclonal antibody that can bind and block a conserved epitope on RSV A and B subtypes, for the prevention of RSV MARI. The primary endpoint was proportion of subjects with RSV-confirmed hospitalizations or outpatient lower respiratory tract infection (LRTI). RESULTS: There were no significant differences between primary endpoint rates (8.1%, placebo; 7.7%, 1-dose; 9.3%, 2-dose). Suptavumab prevented RSV A infections (relative risks, .38; 95% confidence interval [CI], .14-1.05 in the 1-dose group and .39 [95% CI, .14-1.07] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .0499), while increasing the rate of RSV B infections (relative risk 1.36 [95% CI, .73-2.56] in the 1-dose group and 1.69 [95% CI, .92-3.08] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .12). Sequenced RSV isolates demonstrated no suptavumab epitope changes in RSV A isolates, while all RSV B isolates had 2-amino acid substitution in the suptavumab epitope that led to loss of neutralization activity. Treatment emergent adverse events were balanced across treatment groups. CONCLUSIONS: Suptavumab did not reduce overall RSV hospitalizations or outpatient LRTI because of a newly circulating mutant strain of RSV B. Genetic variation in circulating RSV strains will continue to challenge prevention efforts. CLINICAL TRIALS REGISTRATION: NCT02325791.

Four-year antibody persistence and response to a booster dose of a pentavalent MenABCWY vaccine administered to healthy adolescents and young adults.

This open-label, multicenter extension study (NCT02451514) assessed persistence of Neisseria meningitidis serogroups ABCWY antibodies 4 years after primary vaccination. Adolescents and young adults who previously received 2 doses of MenABCWY+OMV (Group III), 1 dose of MenACWY-CRM (Group VI), or newly-recruited vaccine-naïve participants (Group VII) were administered 1 (Group III) or 2 doses (Groups VI and VII) of MenABCWY+OMV, 1 month apart. Immunogenicity was assessed by human serum bactericidal assay (hSBA). Safety and reactogenicity were also evaluated. Percentages of participants with hSBA titers ≥8 (serogroups ACWY), ≥5 (serogroup B) and hSBA geometric mean titers (GMTs) were evaluated in all 129 enrolled participants (Group III: 33; Group VI: 46; Group VII: 50). Anti-ACWY antibody concentrations waned over 4 years post-vaccination, but remained above pre-vaccination concentrations. Similarly, levels of antibodies against serogroup B test strains also waned over 4 years post-vaccination, but remained above pre-vaccination concentrations for some strains. MenABCWY+OMV booster induced a robust anamnestic anti-ACWY response in Group III and VI and a good response against serogroup B test strains (≥82%) in Group III. In serogroup B-naïve participants (Groups VI and VII), anti-B responses to 2 doses of MenABCWY+OMV were less homogenous and lower than in Group III. MenABCWY+OMV was reactogenic, but well-tolerated. No safety concerns were identified. These findings indicate that although antibodies against N. meningitidis serogroups ABCWY waned over 4 years post-vaccination, exposure to a MenABCWY+OMV booster dose elicits an anamnestic response in adolescents previously exposed to the same or another multivalent meningococcal vaccine.

Temporospatial angiogenesis-associated gene expression profiles in rat ischemic skin flaps.

OBJECTIVES: Emerging therapies designed to improve soft tissue flap survival include the use of angiogenic factors. However, endogenous expression patterns for these factors have not been characterized. The purpose of this study was to identify spatial and temporal variations in expression patterns of angiogenesis-associated genes in ischemic rat skin flaps. STUDY DESIGN: This is an observational animal study characterizing spatial and temporal angiogenesis associated gene expression patterns in rat ischemic skin flaps. METHODS: Dorsal skin flaps were created on 15 male Sprague-Dawley rats. The flap tissue was harvested and sectioned at 1, 3, or 7 days postsurgery. Total RNA was isolated, amplified, labeled with biotin, and hybridized to microarrays containing probes for 113 angiogenesis-associated genes. Microarray analysis revealed unique spatial and temporal patterns with statistically significant gene modulation over the length of the flap (P<.05). RESULTS: The molecular analysis performed in this study correlates with the hemodynamic profile previously published. Expression patterns associated with blood flow were markedly different from patterns associated with stasis and avascularity. CONCLUSIONS: To our knowledge, this study is the first to characterize endogenous spatial and temporal angiogenesis-associated gene expression in rat ischemic skin flaps. Further characterization of expression patterns may allow clinicians to differentiate ischemic tissue that may be rescued via pharmacological or surgical intervention from tissue destined to succumb. Additionally, comparison of the expression profiles observed in this study with profiles generated from pharmacologically treated rats may suggest mechanisms for enhanced healing.

Repeated exposure to sublethal doses of the organophosphorus compound VX activates BDNF expression in mouse brain.

The highly toxic organophosphorus compound VX [O-ethyl S-[2-(diisopropylamino)ethyl]methylphosphonate] is an irreversible inhibitor of the enzyme acetylcholinesterase (AChE). Prolonged inhibition of AChE increases endogenous levels of acetylcholine and is toxic at nerve synapses and neuromuscular junctions. We hypothesized that repeated exposure to sublethal doses of VX would affect genes associated with cell survival, neuronal plasticity, and neuronal remodeling, including brain-derived neurotrophic factor (BDNF). We examined the time course of BDNF expression in C57BL/6 mouse brain following repeated exposure (1/day × 5 days/week × 2 weeks) to sublethal doses of VX (0.2 LD(50) and 0.4 LD(50)). BDNF messenger RNA expression was significantly (p < 0.05) elevated in multiple brain regions, including the dentate gyrus, CA3, and CA1 regions of the hippocampal formation, as well as the piriform cortex, hypothalamus, amygdala, and thalamus, 72 h after the last 0.4 LD(50) VX exposure. BDNF protein expression, however, was only increased in the CA3 region of the hippocampus. Whether increased BDNF in response to sublethal doses of VX exposure is an adaptive response to prevent cellular damage or a precursor to impending brain damage remains to be determined. If elevated BDNF is an adaptive response, exogenous BDNF may be a potential therapeutic target to reduce the toxic effects of nerve agent exposure.

Effect of combined nicotine and shrapnel exposure on pain measures and gait after nerve injury.

A significant fraction of military soldiers sustain nerve injury and use tobacco or nicotine containing products. Healing of nerve injuries is influenced by many factors, such as degree of original injury, healing potential of the nerve, and general health of patient. However, recently, it has been demonstrated that the presence of retained insoluble metal fragments decreases healing. The effects of systemic nicotine administration, with or without metal fragments at the site of nerve injury, were evaluated. Both the nicotine-administered groups (nicotine, nicotine + shrapnel) showed significant increase in the peroneal function compared with untreated controls, as assessed by paw area (p < 0.05). Furthermore, to test possible role of altered sensory function, we used the hot plate assay. Latency to withdraw paw from a hot plate was significantly shorter in nicotine groups (p < 0.05). These data indicate that nicotine improves sensory and motor aspects of nerve function, in the presence or absence of shrapnel.

Effect of intermittent systemic administration of recombinant parathyroid hormone (1-34) on mandibular fracture healing in rats.

PURPOSE: To establish a rat mandibular fracture model and investigate the short- and long-term effects of recombinant parathyroid hormone (PTH 1-34) on mandibular fracture healing in rats. MATERIALS AND METHODS: A controlled unilateral mandibular fracture was created surgically in 29 male Sprague-Dawley rats and then stabilized using an external fixation device. The rats were divided into 2 groups: 1 group received daily subcutaneous injections of 10 microg/kg of PTH(1-34) and 1 group served as the vehicle control. The rats were killed on postoperative days 7 and 21, and radiographic densitometry and histologic evaluation of new bone formation were performed. RESULTS: A novel unilateral mandibular fracture model was established that has significant differences from previously published models, both in the location of the osteotomy site and in the rigid external stabilization device. The PTH(1-34) treated rats showed a statistically significant difference (P < .05) in callous formation compared with the control animals. Radiographic densitometry evaluation of the injury site revealed an increase in bone density, apparent at day 7 in the experimental group. Visual inspection of the histologic sections stained with Masson's trichrome blue showed an apparent increase in new bone formation at 21 days in the PTH-treated group compared with the control group. CONCLUSIONS: Intermittent systemic administration of PTH(1-34) might enhance the healing of mandibular fractures in the early phase (7-day period). Long-term administration (21-day period) showed no statistically significant differences between the control and experimental group by radiographic densitometry.

Effects of metal fragments on nerve healing in extremity injuries using a rat peroneal nerve model.

BACKGROUND: On the modern battlefield, the majority of injuries currently seen are to the extremities, often involving a large number of metallic fragments. Although they are typically left in place, the effects of these retained metal fragments on nerve healing have not been studied. STUDY DESIGN: In a rat model, the right peroneal nerve was surgically sectioned and reanastomosed (control group). In the study group, metal fragments from an artillery casing were placed around the reanastomosed peroneal nerve. Functional recovery in both groups was evaluated over a 4-week period by measuring maximum ankle dorsiflexion captured on video as the animals walked through a tunnel. Morphologic analyses included distal and proximal axon counts, measurement of nerve fiber and axon diameter ratios, and myelin thickness. RESULTS: A significant decrease (p < 0.05) in return toward baseline for the rats' ankle angle in the nerves exposed to metal fragments was noted at weeks 2 through 4. Distal axon counts were significantly less (p < 0.05) in the metal fragment group for weeks 1 through 4. Proximal axon counts were increased in both groups, with a greater (p < 0.05) increase in the metal fragment group. CONCLUSIONS: Functional recovery after rat peroneal nerve transection and repair is decreased when metal fragments are placed in and around the injury site. Select histologic indicators of nerve regeneration showed decreased healing when exposed to metal fragments. Further studies of functional recovery in patients sustaining penetrating injuries from bullets or explosive devices are indicated.

Evaluation of the effect of sildenafil and vascular endothelium growth factor combination treatment on skin flap survival in rats.

BACKGROUND: Distal ischemic necrosis of surgical flaps remains a challenging problem for the reconstructive surgeon. Recent studies have shown that either sildenafil or vascular endothelium growth factor (VEGF) treatment significantly improves ischemic skin flap viability. In this study, the effect of the combination of sildenafil and VEGF165 was evaluated on a rat skin flap model using orthogonal polarization spectral imaging and histologic analysis. METHODS: Rats were assigned to either a sham (n = 31), vehicle (n = 24), sildenafil (n = 24), VEGF (n = 23), or sildenafil and VEGF combination treatment (n = 21) groups. Distances from the distal end of the flap to avascular, stasis, and normal capillary blood flow zones were determined using orthogonal polarization spectral imaging on a skin flap model. Vessel density assessment was done at 7 days post surgery. RESULTS: Imaging analysis showed significant reduction in avascular and stasis areas in sildenafil and VEGF combination-treated groups at 7 days post surgery (p < 0.05). The combination-treated group, however, was not significantly different when compared to the group treated with sildenafil only. The sildenafil-treated group showed a significant (p < 0.05) reduction in both areas at day 7 compared to the VEGF and control groups. Histologic analysis showed no significant differences in vessel density between the groups. CONCLUSION: The combination of sildenafil and VEGF decreases the extent of avascular and stasis zones in skin flaps. The skin flap improvement seen with the combination treatment was similar to the sildenafil treatment alone suggesting that enhanced flap survival was due solely to the effect of sildenafil.

Acute social defeat reduces neurotrophin expression in brain cortical and subcortical areas in mice.

Acute social defeat in mice activates the hypothalamic-pituitary-adrenal axis (HPA) and induces long-term behavioral changes, including exaggerated fear responses and inhibition of territorial behavior. Stress-induced hormonal and neurotransmitter release may contribute to disruption of expression of genes important for cell survival, neuronal plasticity, and neuronal remodeling. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor associated with structural cellular changes that occur during nervous system development and contributes to neural plasticity in the adult brain. In rats, acute (1-2 h) restraint stress transiently reduces BDNF mRNA expression in the hippocampus, a region important in the memory and in HPA regulation; restraint stress also decreases BDNF expression in the basolateral amygdala (BLA), a region important for fear consolidation and emotional memory. We hypothesized that a brief (10 min) exposure to intense social stress, a more naturalistic stressor than restraint stress, would also reduce BDNF mRNA in the hippocampus and BLA of mice. In the present study, we examined the time course of expression of BDNF mRNA expression in the hippocampus and amygdala, as well as other subcortical and cortical brain regions, following acute social stress. In situ hybridization analysis for BDNF mRNA expression showed that there was a significant decrease in BDNF mRNA expression in all regions studied in mice 24 h after social defeat when compared to control (naive) mice (P<0.05). These findings support our hypothesis that BDNF mRNA levels are reduced by social stress, and may have implications for brain plasticity and behavioral changes following social stress.

Learning associated increase in heat shock cognate 70 mRNA and protein expression.

The Morris water maze is a task widely used to investigate cellular and molecular changes associated with spatial learning and memory. This task has both spatial and aversive (swimming related stress) components. It is possible that stress may influence cellular modifications observed after learning the Morris water maze spatial task. Heat shock proteins, also known as stress proteins, are up-regulated in response to thermal stress, trauma, or environmental insults. In the rat hippocampus, psychophysiological stress increases the levels of heat shock protein 70 (HSC70). In this study, we investigated whether the expression of the hsc70 gene is modulated in the hippocampus during learning of the Morris water maze task. Five groups of rats were trained in the Morris water maze task for varying amounts of time (either 1, 2, 3, 4, or 5 days). Training consisted of 10 trials/day in which the animals were given 60s to find a submerged platform. Rats were sacrificed 24h after their last training trial. Results showed a significant increase in hsc70 mRNA and protein levels in the hippocampal formation after two and three days of training, respectively. The increase in mRNA and protein was associated with learning but not stress because the increase was not observed in the yoked control animals. These findings suggest that cellular and molecular changes can occur independent of stress. Moreover, the results are the first to implicate hsc70 expression in spatial learning.