The transition from field emission to collisional space-charge limited current with nonzero initial velocity.

Multiple electron emission mechanisms often contribute in electron devices, motivating theoretical studies characterizing the transitions between them. Previous studies unified thermionic and field emission, defined by the Richardson-Laue-Dushman (RLD) and Fowler-Nordheim (FN) equations, respectively, with the Child-Langmuir (CL) law for vacuum space-charge limited current (SCLC); another study unified FN and CL with the Mott-Gurney (MG) law for collisional SCLC. However, thermionic emission, which introduces a nonzero injection velocity, may also occur in gas, motivating this analysis to unify RLD, FN, CL, and MG. We exactly calculate the current density as a function of applied voltage over a range of injection velocity (i.e., temperature), mobility, and gap distance. This exact solution approaches RLD, FN, and generalized CL (GCL) and MG (GMG) for nonzero injection velocity under appropriate limits. For nonzero initial velocity, GMG approaches zero for sufficiently small applied voltage and mobility, making these gaps always space-charge limited by either GMG at low voltage or GCL at high voltage. The third-order nexus between FN, GMG, and GCL changes negligibly from the zero initial velocity calculation over ten orders of magnitude of applied voltage. These results provide a closed form solution for GMG and guidance on thermionic emission in a collisional gap.

A randomized study comparing the safety and immunogenicity of a conjugate vaccine combination containing meningococcal group C and pneumococcal capsular polysaccharide--CRM197 with a meningococcal group C conjugate vaccine in healthy infants: challenge phase.

BACKGROUND: A combination nonavalent pneumococcal-group C meningococcal conjugate vaccine (Pnc9-MenC) was previously found to be safe and immunogenic when administered to infants at 2, 3 and 4 months. This study describes the persistence of immunity at 12 months of age and the immunologic response to a challenge dose of either meningococcal polysaccharide vaccine (Meningivac A+C; MnA+C), or MenC. METHODS: A phase II, randomized, controlled trial of healthy infants. Subjects were given Pnc9-MenC or MenC vaccine at 2, 3 and 4 months of age and then challenged with either MenC or MnA+C. Group C meningococcal immunogenicity was measured by serum bactericidal assay (SBA) and an enzyme-linked immunosorbent assay (ELISA) adapted to measure antibody avidity pre- and post-challenge. RESULTS: The MenC vaccine was more immunogenic than the Pnc9-MenC vaccine in persistence of serogroup C meningococcal polysaccharide antibodies at 12 months of age. Post-challenge at 13 months there were significant differences between the four groups in the induction of serogroup C meningococcal polysaccharide antibodies. The responses to MenC/MenC were significantly higher than in the other groups (p<0.001) and the responses to Pnc9-MenC/MnA+C were significantly lower than in the other groups (p<0.001). There was no difference between the four groups in the proportions with geometric mean concentrations (GMC) greater than 2 microg/ml (p=0.18) or with SBA titres greater than or equal to the protective level of 1:8 (p=0.89). The SBA geometric mean ratio (GMR) between pre- and post-challenge was higher in the groups challenged with MenC than those challenged with MnA+C. Antibody avidity increased over time. CONCLUSION: We have shown that Pnc9-MenC primes effectively for immunological memory. At 13 months of age the highest immune responses were seen in the subjects primed and challenged with MenC alone. However, all groups achieved the threshold levels required for protection.

A survey of time management and particular tasks undertaken by consultant microbiologists in the UK.

BACKGROUND: Medical microbiology practice encompasses a diverse range of activities. Consultant medical microbiologists (CMMs) attribute widely differing priorities to, and spend differing proportions of time on various components of the job. AIM: To obtain a professional consensus on what are high-priority and low-priority activities, and to identify the time spent on low-priority activities. METHOD: National survey. RESULTS: Many respondents felt that time spent on report authorisation and telephoning of results was excessive, whereas time spent on ward-based work was inadequate. Timesaving could also be achieved through better prioritisation of infection-control activities. CONCLUSION: CMMs should apportion their time at work focusing on high-priority activities identified through professional consensus.

Reactogenicity of meningococcal C conjugate vaccines when administered at the same time as, or a month prior to or after, tetanus and diphtheria booster vaccinations.

INTRODUCTION: This single blind study was conducted to address safety concerns regarding coadministration of diphtheria/ tetanus (DT,Td) boosters and meningococcal C conjugate (MCC) vaccines containing diphtheria or tetanus conjugate proteins. METHODS: 1754 subjects (835 preschoolers and 919 school leavers) were randomised to receive one of three MCC products a month before, after or at the same as routine DT or Td boosters. They (or their parents) completed a health diary for 10 days to record local reactions and systemic symptoms after each vaccination. The effect of antibody levels pre and post-vaccination, preexisting allergies and medication taken before and for up to ten days after vaccination on reactogenicity was assessed. RESULTS: No relationship between prevaccination antibody levels and local reactions or systemic symptoms was found. Local reactions were more common after DT/Td than MCC vaccination and were related to post-vaccination diphtheria and tetanus antibody levels in younger children and to the post-vaccination tetanus only antibody levels in older children. Preexisting allergies were not related to reactogenicity. Use of analgesics/antipyretic medication significantly reduced the incidence of local reactions and of some systemic symptoms. In the first three days after vaccination there was an excess of some systemic symptoms including fatigue/malaise and headache for all ages, and crying/ irritability for younger children and nausea/vomiting and dizziness/faintness for older subjects. Eleven serious adverse events were reported, none of which was deemed related to vaccination. CONCLUSION: MCC vaccines can be given under the above schedules and safely in the presence of raised diphtheria and tetanus antibody levels without materially altering reactogenicity profiles of either vaccine.

Childhood empyema: limited potential impact of 7-valent pneumococcal conjugate vaccine.

During 2003-2004, locally presenting pleural empyema cases in children increased 3-fold. Antigen analysis of empyema fluid identified Streptococcus pneumoniae in 27 of 29 cases for whom samples were available and capsular polysaccharide type 1 in 18 of these. Use of a conjugate vaccine without serotype 1 antigen would have had limited impact on this morbidity in our region.

A randomised controlled study of the reactogenicity of an acellular pertussis-containing pentavalent infant vaccine compared to a quadrivalent whole cell pertussis-containing vaccine and oral poliomyelitis vaccine, when given concurrently with meningococcal group C conjugate vaccine to healthy UK infants at 2, 3 and 4 months of age.

Two hundred forty-one healthy infants were enrolled in an open randomised controlled study of three doses of DTaP-IPV-Hib (Group 1) or DTwP/Hib+OPV (Group 2) at 2, 3 and 4 months of age given concurrently with a meningitis C conjugate vaccine. After each dose, local reactions (any grade) were less common in Group 1 than Group 2 (p<0.03). Axillary temperature >37.5 degrees C, decreased feeding, reduced activity, irritability and crying in the week after vaccination were also less common in Group 1 than Group 2 (p<0.05 for each symptom, all doses combined). Severe local reactions and systemic symptoms were uncommon and occurred equally in both groups. The pentavalent DTaP-IPV-Hib vaccine was less reactogenic than the quadrivalent DTwP-Hib vaccine, as expected when changing from whole cell pertussis (wP) to an acellular pertussis (aP) component.

Immunogenicity and boosting after a reduced number of doses of a pneumococcal conjugate vaccine in infants and toddlers.

BACKGROUND: The minimum number of doses of pneumococcal conjugate vaccine required for protection is not known. We studied the immunogenicity of a reduced schedule in infants and toddlers. METHODS: U.K. infants were given either 2 or 3 doses (at 2 and 4 or 2/3/4 months of age) of a 9-valent pneumococcal conjugate vaccine (9VPCV) followed by boosting at 12 months of age. In a separate study, toddlers (12 months) received 1 or 2 doses (2 months apart) of 9VPCV followed by pneumococcal polysaccharide vaccine at 18 months of age. RESULTS: For infants, serotype-specific IgG geometric mean concentrations were similar post-primary immunization between the groups with both showing avidity maturation and similar booster responses. For toddlers, the primary response to 4 of the 9 serotypes was lower in the 1- compared with the 2-dose group (type 6B, 0.77 versus 7.1; type 14, 4.67 versus 14.98; type 19F, 5.05 versus 7.75; type 23F, 2.48 versus 5.05), although for all serotypes booster responses were similar between groups, and the postprimary responses in the 1-dose group were at least as high as those after infant immunization. CONCLUSIONS: The 2-dose infant priming schedule of 9VPCV is comparable with the 3-dose schedule and may thus be equally protective, whereas 1 dose in toddlers may suffice for a catch-up.

Diagnosis of invasive pneumococcal infection by serotype-specific urinary antigen detection.

Widespread use of conjugate pneumococcal polysaccharide-protein vaccines may alter the spectrum of pneumococci producing invasive disease. Novel sensitive diagnostic methods would be valuable for monitoring the epidemiology of pneumococcal disease within populations and vaccine recipients. Ideally, these methods should allow determination of the serotype of the infecting clone. Serotype-specific enzyme-linked immunosorbent assays (ELISA) for 13 capsular polysaccharides (types 1, 3, 4, 5, 6A, 6B, 7A, 9 V, 14, 18C, 19 A, 19F, and 23 F) were developed. Experiments with pure capsular polysaccharide demonstrated that the assays were sensitive (0.01 to 1.0 ng/ml) and specific. These assays were used to detect capsular polysaccharide in urine from 263 adult patients with proven (blood culture-positive) invasive pneumococcal disease and pneumonia of unknown etiology and from patients with positive blood cultures yielding bacteria other than pneumococci (control group). Among 76 patients with invasive pneumococcal disease from whom blood culture isolates had been serotyped, 62 (82%) had infections with pneumococci of serotypes represented in the ELISA panel. Capsular antigen matching the serotype of the blood culture isolate was detected in the urine of 52 of these patients, giving a sensitivity of 83.9% for the target serotypes. The tests were significantly more sensitive for urine from patients with pneumococcal pneumonia (89.8%) than for urine from patients with non-pneumonic invasive infection (61.5%; P<0.05). Data from the control group indicated a specificity of 98.8%. These assays should prove valuable in epidemiological investigation of invasive pneumococcal infection in adults, particularly if combined with a sensitive C-polysaccharide detection assay to screen for positive samples.

Immunogenicity and safety of a combination pneumococcal-meningococcal vaccine in infants: a randomized controlled trial.

CONTEXT: The success of conjugate vaccines in decreasing invasive disease due to Streptococcus pneumoniae and group C Neisseria meningitidis has placed pressure on crowded infant immunization schedules, making development of combination vaccines a priority. OBJECTIVE: To determine the safety and immunogenicity of a combination 9-valent pneumococcal-group C meningococcal conjugate candidate vaccine (Pnc9-MenC) administered as part of the routine UK infant immunization schedule at ages 2, 3, and 4 months. DESIGN, SETTING, AND PARTICIPANTS: Phase 2 randomized controlled trial conducted from August 2000 to January 2002 and enrolling 240 healthy infants aged 7 to 11 weeks from 2 UK centers, with home follow-up visits at ages 2, 3, 4, and 5 months. INTERVENTION: Pnc9-MenC (n = 120) or monovalent group C meningococcal conjugate vaccine (MenC) (n = 120) administered in addition to routine immunizations (diphtheria and tetanus toxoids and whole-cell pertussis [DTwP], Haemophilus influenzae type b [Hib] polyribosylribitol phosphate-tetanus toxoid protein conjugate, oral polio vaccine). MAIN OUTCOME MEASURES: Group C meningococcal immunogenicity measured by serum bactericidal titer (SBT) 1 month following the third dose; rates of postimmunization reactions. RESULTS: MenC component immunogenicity was reduced in the Pnc9-MenC vs the MenC group (geometric mean SBT, 179 [95% confidence interval {CI}, 133-243] vs 808 [95% CI, 630-1037], respectively; P<.001). The proportion with group C meningococcal SBT greater than 1:8 was lower in the Pnc9-MenC vs the MenC group (95% vs 100%, P = .05). The geometric mean concentration of antibodies to concomitantly administered Hib vaccine was reduced in the Pnc9-MenC vs the MenC group (2.11 [95% CI, 1.57-2.84] microg/mL vs 3.36 [95% CI, 2.57-4.39] microg/mL; P = .02), as were antibodies against diphtheria (0.74 [95% CI, 0.63-0.87] microg/mL vs 1.47 [95% CI, 1.28-1.69] microg/mL; P<.001). Pnc9-MenC was immunogenic for each of 9 contained pneumococcal serotypes, with responses greater than 0.35 microg/mL observed in more than 88% of infants. Increased irritability and decreased activity were observed after the third dose in the Pnc9-MenC group. CONCLUSIONS: Pnc9-MenC combination vaccine administered to infants at ages 2, 3, and 4 months demonstrated reduced group C meningococcal immunogenicity compared with MenC vaccine. The immunogenicity of concomitantly administered Hib and DTwP vaccines was also diminished. The Pnc9-MenC vaccine was safe and immunogenic for all contained pneumococcal serotypes. The reduced MenC immunogenicity may limit the development of the Pnc9-MenC vaccine.

Immunogenicity of, and immunologic memory to, a reduced primary schedule of meningococcal C-tetanus toxoid conjugate vaccine in infants in the United kingdom.

It has been previously shown that one of the three meningococcal C conjugate (MCC) vaccines introduced in the United Kingdom proved highly immunogenic after the first dose of a three-dose schedule, with evidence of immune memory after dose 3. Thus, in infants a one- or two-dose schedule of this MCC vaccine, conjugated to tetanus toxoid (TT), may suffice. Healthy infants (n = 586) were randomized to receive either one (group 1), two (group 2), or three (group 3) doses of MCC-TT vaccine with a 10- micro g polysaccharide booster given at 13 to 14 months of age. Serum bactericidal antibody (SBA) levels were measured by utilizing rabbit complement (rSBA), meningococcal C-specific immunoglobulin G (IgG), and avidity indices (AIs). For groups 1, 2, and 3, the percentages of infants with an rSBA level of > or =8 against strain C11 were 98.4, 100, and 99.4%, respectively. Infants in group 1 with prevaccination rSBA titers of > or =8 had post-primary MCC rSBA geometric mean titers (GMTs) significantly lower than those infants with prevaccination rSBA titers of <8. One dose of MCC-TT vaccine given to infants at 2 months of age yielded significantly lower SBA GMTs and geometric mean AIs (GMAIs) than two or three doses but elicited a significantly greater response after boosting, as reflected by rSBA levels and GMAI. This study provides the first evidence that the number of doses of MCC-TT used in infant immunization schedules could be decreased.

Rapid diagnosis of bacteremic pneumococcal infections in adults by using the Binax NOW Streptococcus pneumoniae urinary antigen test: a prospective, controlled clinical evaluation.

The diagnosis of severe pneumococcal infections is inadequate, relying heavily on culture of Streptococcus pneumoniae from blood or other normally sterile fluids, and is severely limited by prior administration of antibiotics. We evaluated prospectively the Binax NOW S. pneumoniae urinary antigen test, a rapid immunochromatographic assay, for the diagnosis of bacteremic pneumococcal infections in hospitalized adult patients. Antigen was detected in 88 of 107 cases overall, resulting in a test sensitivity of 82% (95% confidence interval [95% CI], 74 to 89%). Antigen detection was greater in those with pneumonia (67 of 77 [87%]) than in those without pneumonia (21 of 30 [70%]) (P = 0.04). Urinary antigen was also detected in 3 of 106 adult patients with community-acquired septicemic infections caused by other organisms, giving a test specificity of 97% (95% CI, 92 to 99%). For 45 pneumococcal bacteremia patients with a positive test on treatment day 1, urinary antigen excretion was monitored for the first week of antibiotic treatment. Antigen was still detectable in 83% (29 of 35 tested; 95% CI, 66 to 93%) on treatment day 3. Detection of urinary antigen is a valuable, sensitive, and rapid test for the early diagnosis of bacteremic pneumococcal infections in adult patients, even after antibiotic treatment has commenced.

Antibody persistence and immunological memory at age 4 years after meningococcal group C conjugate vaccination in children in the United kingdom.

Antibody persistence and immunological priming for 2 formulations of a meningococcal group C (menC) conjugate (MCC) vaccine (containing 2 or 10 microg of menC polysaccharide) administered at 2, 3, and 4 months of age was investigated by boosting vaccine recipients at age 13-16 months or 4 years with 10 microg of unconjugated menC polysaccharide. At age 4 years, geometric mean titers (GMTs) and concentrations of menC-specific immunoglobulin G and serum bactericidal antibody (SBA) had decreased to prevaccination levels. Geometric mean avidity indices increased after the primary vaccination until age 13-16 months and then remained constant until age 4 years. One month after boosting at age 4 years, menC immunoglobulin G and SBA levels increased significantly. The postbooster SBA GMT for the 2-microg vaccination (2181.2; 95% confidence interval [CI], 975.9-4875.1) was 2-fold higher than that for the 10-microg vaccination (931.6; 95% CI, 338.0-2568.1). This is the first demonstration of immunological memory at 4 years of age in children receiving MCC vaccine on the United Kingdom's 2/3/4-month immunization schedule.

Avidity maturation following vaccination with a meningococcal recombinant hexavalent PorA OMV vaccine in UK infants.

To date, there are no data assessing the utility of avidity indices as a surrogate marker for the induction of immunological memory following meningococcal serogroup B outer membrane vesicle (OMV) vaccination. We studied infants who had been immunized with three doses of a recombinant hexavalent PorA OMV vaccine at ages 2-4 months, together with a fourth dose at age 12-18 months. A control group had received a single dose of the same vaccine at age 12-18 months. As previously reported, serum bactericidal antibody (SBA) titres increased after each of the first three doses, with a significant increase observed from 6 months post third dose to 1 month post fourth dose. The geometric mean avidity indices (GMAI), against strain H44/76 OMVs, increased from 1 month post first dose to 1 month post third dose. Significant increases in GMAI were observed at 6 months post third dose and again following the fourth dose. At 32-42 months of age, though the SBA titres had returned to post first dose levels, the GMAI remained elevated. No increase in avidity was observed in the control group. Antibody avidity indices are useful laboratory markers for the priming of immunological memory following vaccination with meningococcal serogroup B OMV vaccines.

Epidemiology of meningococcal disease.

In the UK, serogroup A strains disappeared 50 years ago, but in the 1990s, numbers of cases rose again to a 50-year high. Following the very successful introduction of conjugated meningitis C vaccines, effective meningitis B vaccines are now the highest priority.

Neisseria lactamica protects against experimental meningococcal infection.

Immunological and epidemiological evidence suggests that the development of natural immunity to meningococcal disease results from colonization of the nasopharynx by commensal Neisseria spp., particularly with N. lactamica. We report here that immunization with N. lactamica killed whole cells, outer membrane vesicles, or outer membrane protein (OMP) pools and protected mice against lethal challenge by a number of diverse serogroup B and C meningococcal isolates in a model of bacteremic infection. Sera raised to N. lactamica killed whole cells, OMPs, or protein pools were found to cross-react with meningococcal isolates of a diverse range of genotypes and phenotypes. The results confirm the potential of N. lactamica to form the basis of a vaccine against meningococcal disease.

Pneumococcal disease in western Europe: burden of disease, antibiotic resistance and management.

UNLABELLED: Streptococcus pneumoniae- the pneumococcus- affects children and adults worldwide. Invasive pneumococcal disease, including pneumonia, meningitis and bacteraemia, has been linked annually to the deaths of millions of children. The pneumococcus is also a significant contributor to mucosal infections such as acute otitis media and sinusitis. Though pneumococcal infections can occur at any age, persons at greatest risk include children younger than 2 years of age and adults aged 65 years or more. Rates of pneumococcal disease and the prevalence of pneumococcal serotypes vary by geographic location and patient age. Accurate ascertainment and sound epidemiological data are essential for the rational development of effective programmes for prevention and treatment. Pneumococcal resistance to penicillin and other antibiotics has emerged rapidly in recent years, highlighting the importance of vaccine development. Newer pneumococcal vaccines, such as those conjugated to protein carriers, can now overcome the limitations of older polysaccharide vaccines. Such conjugated vaccines induce excellent immune responses even in infants and young children and they may also reduce asymptomatic nasopharyngeal carriage of pneumococci. Pneumococcal 7-valent conjugated vaccine PNCRM7 contains common prevalent serotypes coupled to a nontoxic diphtheria variant (CRM197). This vaccine has demonstrated high efficacy against invasive pneumococcal disease in clinical trials in infants and young children and is currently licensed for use in the United States and selected countries in Europe and Latin America. CONCLUSION: across Europe, pneumococcal infection is responsible for considerable morbidity and mortality, particularly in the very young and the elderly, groups whose members respond poorly to non-conjugated vaccines. The advent of new conjugated pneumococcal vaccines now offers an exciting opportunity in developed countries to reduce both the current burden of disease and the threat of rising antibiotic resistance. Rolling out the use of such vaccines across Europe must be accompanied by detailed ongoing surveillance in order to detect any changes that might occur in the pattern of pneumococcal serotypes.