Immunogenicity, safety and tolerability of inactivated trivalent influenza vaccine in overweight and obese children.

Obesity may be a risk factor for increased hospitalization and deaths from infections due to respiratory pathogens. Additionally, obese patients appear to have impaired immunity after some vaccinations. To evaluate the immunogenicity, safety and tolerability of an inactivated trivalent influenza vaccine (TIV) in overweight and obese children, 28 overweight/obese pediatric patients and 23 healthy normal weight controls aged 3-14 years received a dose of TIV. Four weeks after vaccine administration, significantly higher seroprotection rates against the A/H1N1 strain were observed among overweight/obese children compared with normal weight controls (p<0.05). Four months after vaccination, similar or slightly higher seroconversion and seroprotection rates against the A/H1N1 and A/H3N2 strains were detected in overweight/obese than in normal weight children, whereas significantly higher rates of seroconversion and seroprotection against the B strain were found in overweight/obese patients than in normal weight controls (p<0.05 for seroconversion and seroprotection). Geometric mean titers (GMTs) and fold increase against B strains were significantly higher in overweight/obese patients than in normal weight controls 4 months after vaccine administration (p<0.01 for GMT values and p<0.05 for fold increase). The frequency of local and systemic reactions was similar between the groups, and there were no serious adverse events. The results of this study indicate that in overweight and obese children, antibody response to TIV administration is similar or slightly higher than that evidenced in normal weight subjects of similar age and this situation persists for at least 4 months after vaccine administration in the presence of a favorable safety profile.

Loss of Either Rac1 or Rac3 GTPase Differentially Affects the Behavior of Mutant Mice and the Development of Functional GABAergic Networks.

Rac GTPases regulate the development of cortical/hippocampal GABAergic interneurons by affecting the early development and migration of GABAergic precursors. We have addressed the function of Rac1 and Rac3 proteins during the late maturation of hippocampal interneurons. We observed specific phenotypic differences between conditional Rac1 and full Rac3 knockout mice. Rac1 deletion caused greater generalized hyperactivity and cognitive impairment compared with Rac3 deletion. This phenotype matched with a more evident functional impairment of the inhibitory circuits in Rac1 mutants, showing higher excitability and reduced spontaneous inhibitory currents in the CA hippocampal pyramidal neurons. Morphological analysis confirmed a differential modification of the inhibitory circuits: deletion of either Rac caused a similar reduction of parvalbumin-positive inhibitory terminals in the pyramidal layer. Intriguingly, cannabinoid receptor-1-positive terminals were strongly increased only in the CA1 of Rac1-depleted mice. This increase may underlie the stronger electrophysiological defects in this mutant. Accordingly, incubation with an antagonist for cannabinoid receptors partially rescued the reduction of spontaneous inhibitory currents in the pyramidal cells of Rac1 mutants. Our results show that Rac1 and Rac3 have independent roles in the formation of GABAergic circuits, as highlighted by the differential effects of their deletion on the late maturation of specific populations of interneurons.

Genetic polymorphisms and the development of invasive bacterial infections in children.

To evaluate the associations between single nucleotide polymorphisms (SNPs) of factors involved in the development of invasive bacterial disease (IBD) in children, 47 SNPs of 18 candidate genes were analysed in 49 children with IBD and 100 controls. The G/T genotype of TLR2 rs2149356 and the C genotype of LTA rs2229094 were associated with significantly reduced risk of developing IBD (P=0.04 and P=0.05, respectively), whereas the C/T genotype of RFP175 rs1585110 was associated with a significantly higher risk of developing IBD (P=0.02). These results support the evidence that some genetic variants of factors involved in innate immunity may influence IBD risk in children.

Impact of genetic polymorphisms on paediatric atopic dermatitis.

In order to investigate whether polymorphisms of genes encoding some factors of innate and adaptive immunity play a role in the development of, or protection against atopic dermatitis (AD) and condition its severity, we genotyped 33 candidate genes and 47 single nucleotide polymorphisms (SNPs) using Custom TaqMan Array Microfluidic Cards and an ABI 7900HT analyser (Applied Biosystems, Foster City, CA, USA). The study involved 104 children with AD (29 with mild-to-moderate and 75 with severe disease; 42 girls; mean age ± SD, 5.8 ± 3.3 years) and 119 healthy controls (49 girls; mean age, 4.8 ± 3.0 years). IL10-rs1800872T, TG and MBL2-rs500737AG were all significantly more frequent among the children with AD (P = 0.015, P = 0.004 and P = 0.030), whereas IL10-rs1800896C and TC were more frequent in those without AD (P = 0.028 and P = 0.032). The VEGFA-rs2146326A and CTLA4-rs3087243AG SNPs were significantly more frequent in the children with mild/moderate AD than in those with severe AD (P = 0.048 andP = 0.036). IL10-rs1800872T and TG were significantly more frequent in the children with AD and other allergic diseases than in the controls (P = 0.014 and P = 0.007), whereas IL10-rs1800896TC and C were more frequent in the controls than in the children with AD and other allergic diseases (P = 0.0055 and P = 0.0034). These findings show that some of the polymorphisms involved in the immune response are also involved in some aspects of the development and course of AD and, although not conclusive, support the immunological hypothesis of the origin of the inflammatory lesions.

Pharyngeal colonization by Streptococcus pneumoniae in older children and adolescents in a geographical area characterized by relatively limited pneumococcal vaccination coverage.

BACKGROUND: The aim of this study was to evaluate the relation between colonization and vaccination status with pneumococcal conjugate vaccine (PCV) in older children and adolescents living in an area characterized by relatively limited vaccination coverage. METHODS: Oropharyngeal swabs were obtained from 2076 randomly selected healthy school-age children and adolescents, and the extracted genomic DNA was tested for Streptococcus pneumoniae by means of real-time polymerase chain reaction. All of the positive cases were subsequently serotyped, and the association between vaccination status with the heptavalent PCV (PCV7) and pneumococcal colonization was determined. RESULTS: S. pneumoniae was identified in the oropharyngeal swabs of 1201 subjects (57.9%), and its prevalence declined with age (74.9% in subjects aged <10 years, 51.8% in those aged 10-14 years and 32.7% in those aged ≥15 years; P < 0.001). There were more carriers of any pneumococcal serotype, any of the serotypes in PCV7, or any of the 6 additional serotypes in 13-valent PCV (PCV13) among the vaccinated than the unvaccinated subjects, but no association emerged after adjustment for age and other selected covariates. Sub-analyses by serotype and age groups revealed significant differences in the case of serotypes 3 and 19A among children aged <10 years (odds ratios of 2.03 and 2.18, respectively). CONCLUSIONS: These results show the absence of any long-term effect of PCV7 on colonization, and raise doubts concerning the recent suggestion to use carriage to evaluate the efficacy of PCVs. The high prevalence of carriers in all of the age groups independent of previous pneumococcal vaccination indicates that further studies are needed to evaluate whether the extensive use of PCVs in healthy older children and adolescents might reduce pharyngeal colonization of these subjects thereby increasing herd immunity.

Streptococcus pneumoniae and Staphylococcus aureus carriage in healthy school-age children and adolescents.

Streptococcus pneumoniae and Staphylococcus aureus are common commensals of the upper respiratory tract in children and adolescents. Understanding the relationship between these two pathogens, including their potential for mutual interference, is needed to evaluate the epidemiology of the diseases they cause, the factors that condition acquisition and carriage, and the impact of related preventative measures. We obtained oropharyngeal and nasal swabs from 497 healthy subjects aged 6-17 years. S. pneumoniae detection and serotyping were performed using a real-time PCR and S. aureus detection was performed using the RIDAGENE MRSA system. We found that 136 (27.3%) of the children were carriers of both species, 121 (24.3%) of the children carried S. pneumoniae alone and 128 (25.7%) of the children carried S. aureus alone. S. aureus carriage was similar between children who carried S. pneumoniae (136/257, 52.9 %, 95% confidence interval [CI]: 46.8-58.9%) vs those who did not (128/240, 53.3%, 95% CI: 47.0 -59.5%) and was independent of age and vaccination with 7-valent pneumococcal conjugate vaccine (PCV7). Vaccination with PCV7 did not affect S. aureus carriage [S. pneumoniae: 84/143 (58.7%, 95% CI: 50.5 -66.5%) vaccinated children vs 171/351 (48.7%, 95% CI: 43.5 -53.9%) unvaccinated children; S. aureus: 67/143 (46.9%, 95% CI: 38.9-55.0 %) vaccinated children vs 195/351 (55.6%, 95% CI: 50.3 -60.7%) unvaccinated children]. Pneumococcal serotype also did not appear to affect S. aureus carriage. These findings suggested that the carriage of S. pneumoniae did not affect that of S. aureus in older children and adolescents, regardless of age, PCV7 vaccination and pneumococcal serotype.

Human rhinovirus infection in children with cystic fibrosis.

Nasopharyngeal swabs obtained from 78 pediatric patients with cystic fibrosis (CF), including 47 with acute pulmonary exacerbation and 31 in a stable clinical condition, were evaluated for 17 respiratory viruses. Human rhinovirus (HRV) was the most frequently detected virus in patients with pulmonary exacerbation and in those who were clinically stable (21.3% vs. 12.9%; P = 0.52). HRV-A was the main RV detected in patients with pulmonary exacerbations. However, no prevalence of particular HRV-A subtypes was found. This study highlights that RV is frequently found in the respiratory secretions of patients with CF and the impact of HRV-A appears higher than that of the other HRV types in patients with pulmonary exacerbations.

Impact of air pollution on respiratory diseases in children with recurrent wheezing or asthma.

BACKGROUND: Air pollution has many negative health effects on the general population, especially children, subjects with underlying chronic disease and the elderly. The aims of this study were to evaluate the effects of traffic-related pollution on the exacerbation of asthma and development of respiratory infections in Italian children suffering from asthma or wheezing compared with healthy subjects and to estimate the association between incremental increases in principal pollutants and the incidence of respiratory symptoms. METHODS: This prospective study enrolled 777 children aged 2 to 18 years (375 with recurrent wheezing or asthma and 402 healthy subjects). Over 12 months, parents filled out a daily clinical diary to report information about respiratory symptoms, type of medication used and healthcare utilization. Clinical data were combined with the results obtained using an air pollution monitoring system of the five most common pollutants. RESULTS: Among the 329 children with recurrent wheezing or asthma and 364 healthy subjects who completed follow-up, children with recurrent wheezing or asthma reported significantly more days of fever (p=0.005) and cough (p<0.001), episodes of rhinitis (p=0.04) and tracheitis (p=0.01), asthma attacks (p<0.001), episodes of pneumonia (p<0.001) and hospitalizations (p=0.02). In the wheezing/asthma cohort, living close to the street with a high traffic density was a risk factor for asthma exacerbations (odds ratio [OR]=1.79; 95% confidence interval [CI], 1.13-2.84), whereas living near green areas was found to be protective (OR=0.50; 95% CI, 0.31 -0.80). An increase of 10 µg/m3 of particulates less than 10 microns in diameter (PM10) and nitrogen dioxide (NO2) increased the onset of pneumonia only in wheezing/asthmatic children (continuous rate ratio [RR]=1.08, 95% CI: 1.00-1.17 for PM10; continuous RR=1.08, 95% CI: 1.01-1.17 for NO2). CONCLUSIONS: There is a significant association between traffic-related pollution and the development of asthma exacerbations and respiratory infections in children born to atopic parents and in those suffering from recurrent wheezing or asthma. These findings suggest that environmental control may be crucial for respiratory health in children with underlying respiratory disease.

Rac1 and rac3 GTPases control synergistically the development of cortical and hippocampal GABAergic interneurons.

The intracellular mechanisms driving postmitotic development of cortical γ-aminobutyric acid (GABA)ergic interneurons are poorly understood. We have addressed the function of Rac GTPases in cortical and hippocampal interneuron development. Developing neurons express both Rac1 and Rac3. Previous work has shown that Rac1 ablation does not affect the development of migrating cortical interneurons. Analysis of mice with double deletion of Rac1 and Rac3 shows that these GTPases are required during postmitotic interneuron development. The number of parvalbumin-positive cells was affected in the hippocampus and cortex of double knockout mice. Rac depletion also influences the maturation of interneurons that reach their destination, with reduction of inhibitory synapses in both hippocampal CA1 and cortical pyramidal cells. The decreased number of cortical migrating interneurons and their altered morphology indicate a role of Rac1 and Rac3 in regulating the motility of cortical interneurons, thus interfering with their final localization. While electrophysiological passive and active properties of pyramidal neurons including membrane capacity, resting potential, and spike amplitude and duration were normal, these cells showed reduced spontaneous inhibitory currents and increased excitability. Our results show that Rac1 and Rac3 contribute synergistically to postmitotic development of specific populations of GABAergic cells, suggesting that these proteins regulate their migration and differentiation.

Genetic characteristics of Neisseria meningitidis serogroup B strains carried by adolescents living in Milan, Italy: implications for vaccine efficacy.

Before a protein vaccine is introduced into a country, it is essential to evaluate its potential impact and estimate its benefits and costs. The aim of this study was to determine the genetic characteristics of Neisseria meningitidis B (NmB) in the pharyngeal secretions of 1375 healthy adolescents aged 13-19 y living in Milan, Italy, in September 2012, and the possible protection offered by the two currently available NmB protein vaccines. Ninety-one subjects were Nm carriers (6.6%), 29 (31.9%) of whom carried the NmB capsular gene. The 29 identified strains belonged to eight clonal complexes (CCs), the majority of which were in the ST-41/44/Lin.3 CC (n = 11; 37.9%). All of the identified strains harboured ƒHbp alleles representing a total of 15 sub-variants: the gene for NHBA protein was found in all but three of the studied strains (10.3%) with 13 identified sub-variants. There were 15 porA sub-types, seven of which were identified in just one CC. The findings of this study seem to suggest that both of the protein vaccines proposed for the prevention of invasive disease due to NmB (the 4-protein and the 2-protein products) have a composition that can evoke a theoretically effective antibody response against the meningococcal strains currently carried by adolescents living in Northern Italy. The genetic characteristics of NmB strains can be easily evaluated by means of molecular methods, the results of which can provide an albeit approximate estimate of the degree of protection theoretically provided by the available vaccines, and the possible future need to change their composition.

The immunogenicity and safety of a single 0.5 mL dose of virosomal subunit influenza vaccine administered to unprimed children aged ≥6 to <36 months: data from a randomized, Phase III study.

This study evaluated the immunogenicity, safety and tolerability of a single 0.5 mL dose of the seasonal virosomal subunit influenza vaccine (Inflexal V, Crucell, Switzerland) in 205 healthy, unprimed children aged at least 6 to <36 months, evaluated at four weeks post-vaccination and seven months from baseline. Of the enrolled children, 102 received one single 0.5 mL dose and 103 received the standard two 0.25 mL doses given four weeks apart. Both treatments evoked an immune response that satisfied the EMA/CHMP criteria for yearly vaccine licensing for all three vaccine strains. Exploratory analyses revealed no differences between the groups at four weeks post-vaccination. Furthermore, immunogenicity was maintained seven months after the first vaccination after both the 0.5 mL and standard two 0.25 mL doses. Adverse events were comparable between groups and were as expected according to the safety profile of the vaccine; overall, the vaccine was well tolerated. Our results show that a single 0.5 mL dose effectively and safely provided long-term immunogenicity to all three influenza strains in unprimed children aged at least 6 to <36 months.

Live attenuated intranasal influenza vaccine.

Annual vaccination is the most effective means of preventing and controlling influenza epidemics, and the traditional trivalent inactivated vaccine (TIV) is by far the most widely used. Unfortunately, it has a number of limitations, the most important of which is its poor immunogenicity in younger children and the elderly, the populations at greatest risk of severe influenza. Live attenuated influenza vaccine (LAIV) has characteristics that can overcome some of these limitations. It does not have to be injected because it is administered intranasally. It is very effective in children and adolescents, among whom it prevents significantly more cases of influenza than the traditional TIV. However, its efficacy in adults has not been adequately documented, which is why it has not been licensed for use by adults by the European health authorities. LAIV is safe and well tolerated by children aged > 2 y and adults, but some concerns arisen regarding its safety in younger children and subjects with previous asthma or with recurrent wheezing. Further studies are needed to solve these problems and to evaluate the possible role of LAIV in the annual vaccination of the general population.

Recommendations for the use of influenza vaccine in pediatrics.

Every year for the last few decades, the health authorities of most countries throughout the world have issued specific recommendations for the prevention and treatment of pediatric influenza, including recommendations concerning the use of vaccines. However, different evaluations of the importance of the disease and the efficacy of influenza vaccination frequently lead to conflicting recommendations. This is clearly demonstrated not only by the differences in the subjects for whom the vaccine is recommended, but also by the inaccurate manner in which subjects at risk of influenza-related complications are defined. Only further studies that consider the burden of the disease and vaccine efficacy in adequate numbers of healthy children and high-risk children with different chronic underlying diseases can overcome all of the current limitations and significantly improve vaccination coverage in both categories.

Immunogenicity and safety of intradermal influenza vaccine in children.

In order to compare the immunogenicity and safety of different doses of trivalent influenza vaccine (TIV) administered intradermallly (ID) with those evoked by a full dose of intramuscular (IM) virosomal-adjuvanted influenza vaccine (VA-TIV), 112 previously primed healthy children aged ≥ 3 years were randomised to receive 9 µg or 15 µg of each strain of ID-TIV, or a full IM dose (15 µg of each strain) of VA-TIV. The A/H1N1 and A/H3N2 seroconversion and seroprotection rates were ≥ 90% and geometric mean titres (GMTs) increased 3.2-14.9 times without any statistically significant between-group differences; however, the seroconversion and seroprotection rates against the B strain were significantly higher in the children receiving either ID-TIV dose (p<0.05) without any differences between them. GMT against B virus was significantly higher in the children receiving the highest dose (p<0.05). Local reactions were significantly more common among the children receiving either ID-TIV dose (p<0.05), but systemic reactions were relatively uncommon in all three groups. Our findings suggest that ID-TIV with 15 µg of each viral antigen can confer a significant better protection against influenza than that obtained with the same dose of IM TIV in already primed children aged ≥ 3 years with an acceptable safety profile. The lower dose of ID-TIV needs further evaluation to analyze persistence of protection.