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1.  Establishment of a New Human Pneumococcal Standard Reference Serum, 007sp ▿ 
Clinical and Vaccine Immunology : CVI  2011;18(10):1728-1736.
Lot 89SF has been the reference standard serum pool used in pneumococcal enzyme-linked immunosorbent assays (ELISAs) since 1990. In 2005, it was estimated that there remained between 2 and 5 years' supply of lot 89SF. Since lot 89SF was the reference standard used in the evaluation of the seven-valent pneumococcal conjugate vaccine Prevnar (PCV7), the link to clinical efficacy would be severed if stocks became completely depleted. Furthermore, demonstration of immune responses comparable to those elicited by PCV7 is a licensure approach used for new pneumococcal conjugate vaccines, so a replacement reference standard was required. A total of 278 volunteers were immunized with the 23-valent unconjugated polysaccharide vaccine Pneumovax II, and a unit of blood was obtained twice within 120 days following immunization. Plasma was prepared, pooled, and confirmed to be free from hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV. The pooled serum was poured at 6 ml per vial into 15,333 vials and lyophilized. Immunological bridging of 007sp to 89SF was used to establish equivalent reference values for 13 pneumococcal capsular serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F) by five independent laboratories. Antibody concentrations in 007sp were established relative to the lot 89SF reference preparation using the WHO reference ELISA. Subsequently, 12 existing WHO calibration sera had concentrations reassigned for 13 pneumococcal serotypes using new serum 007sp as the reference, and these were compared to concentrations relative to the original reference serum. Agreement was excellent for the 12 WHO calibration sera. The 007sp preparation has replaced 89SF as the pneumococcal reference standard. Sufficient quantity of this new preparation is available such that, with judicious use, it should be available for at least 25 years.
PMCID: PMC3187044  PMID: 21852547
2.  Hib IgG persistence following early booster dose 
PMCID: PMC1720312  PMID: 15723937
4.  Responses to a fourth dose of Haemophilus influenzae type B conjugate vaccine in early life 
Objective: To describe the immune response of preterm infants, with a reduced response to primary Haemophilus influenzae type B (Hib) immunisation, to a fourth dose of Hib conjugate vaccine given in early life.
Design: Prospective observational study.
Setting: Five Wessex Neonatal Units.
Patients: Infants born at < 32 weeks and immunised with three doses of combined acellular pertussis-Hib vaccine, with a Hib IgG geometric mean concentration (GMC) < 1.0 µg/ml after these primary immunisations.
Interventions: An additional fourth dose of Hib conjugate vaccine given before 1 year of age. Blood taken to assess Hib IgG concentration and avidity after immunisation.
Main outcome measures: Hib IgG GMC and avidity index.
Results: Ninety six infants (mean gestational age at birth 29.1 weeks) received a fourth dose of Hib at a mean age of 7.8 months. Hib IgG GMC after the primary immunisations was 0.17 µg/ml (95% confidence interval (CI) 0.14 to 0.20) rising to 4.68 µg/ml (95% CI 3.36 to 6.57) after the fourth dose (p < 0.0001). The IgG response to the fourth dose correlated positively with the response after the primary immunisations (p < 0.001). Hib IgG geometric mean avidity index (GMAI) after the primary immunisations was 30.87 (95% CI 20.40 to 46.73). This increased to 124.73 (95% CI 109.93 to 141.51) after the fourth dose (p < 0.0001).
Conclusion: Preterm infants with very low IgG responses to Hib after primary immunisations with a combined acellular pertussis-Hib vaccine mount a good response to a fourth dose of Hib. This study suggests that all infants will benefit from a fourth dose of Hib, regardless of the age at which it is given.
PMCID: PMC1721691  PMID: 15102734
5.  Correlation of Molecular Characteristics, Isotype, and In Vitro Functional Activity of Human Antipneumococcal Monoclonal Antibodies  
Infection and Immunity  2006;74(2):1025-1031.
Structure-function correlations of pneumococcal antibodies are important in predicting how changes in the pneumococcus (Pnc)-specific B-cell repertoire will influence humoral immunity against invasive Pnc disease. Using a unique panel of human hybridomas derived from memory B cells after pneumococcal conjugate vaccination, we analyzed the structure-function relationship of nine monoclonal antibodies (MAbs) reactive to Pnc polysaccharides. The avidities of the antibodies correlated with the avidity of donor immune serum (R, 0.7; P < 0.025), and this relationship was particularly strong for immunoglobulin A clones (R, 1; P < 0.0005), suggesting that the MAbs may represent important clones contributing to serological memory. Common heavy-light chain combinations and amino acid replacement mutations were seen for clones with the same serospecificity from different individuals. The two highest-avidity MAbs used Vh3-48, and two MAbs with the same serospecificity, using the same V gene pairings (Vh3-7 and Vk2A17), had similar avidities, suggesting that canonical V gene use makes an important contribution to avidity. Although all clones had mutation levels consistent with their being derived from memory B cells, low levels of replacement mutation were associated with high avidities. This relationship was strongest for Vh genes (R, 0.8; P < 0.01). Opsonophagocytosis was demonstrated for all clones, and there was a trend toward clones using canonical genes with low levels of mutation having high opsonophagocytic activities (R, 0.5). These data suggest that the use of canonical genes in the Pnc antibody response is associated with highly functional antibodies and that most somatic mutations seen in these genes are not antigen selected.
PMCID: PMC1360365  PMID: 16428749
6.  Effect of a fourth Haemophilus influenzae type b immunisation in preterm infants who received dexamethasone for chronic lung disease 
Aim: To assess whether a fourth Hib polysaccharide-tetanus protein conjugate vaccine (PRP-T) would improve antibody response in preterm infants previously treated with dexamethasone for chronic lung disease.
Methods: In a pilot study 12 infants born at less than 30 weeks gestation who had received corticosteroids were given a supplementary Hib dose six weeks after completion of the primary immunisation course. Serum samples obtained before and at eight weeks following the fourth Hib dose were analysed for total level and avidity of anti-PRP antibody.
Results: There was no significant increase in the geometric mean titre (GMT) of anti-PRP antibody resulting from the fourth Hib immunisation (GMT: pre 2.35 µg/ml, post 2.24 µg/ml, p = 0.79). A subgroup of six infants had subprotective antibody levels (<1.0 µg/ml) after the primary immunisation course, which remained subprotective following the extra Hib immunisation. Despite the poor response in total antibody level, the study group showed a significant rise in PRP specific IgG avidity following the fourth immunisation (GMAI: pre 0.076, post 0.138, p = 0.043).
Conclusion: An additional Hib immunisation given to recently steroid treated preterm infants six weeks after completion of the primary schedule did not augment primary immunogenicity. However, increasing avidity may imply successful priming and long term immunity to Hib.
PMCID: PMC1755995  PMID: 12496229
7.  Colitis in chronic granulomatous disease 
Archives of Disease in Childhood  2001;84(2):147-151.
BACKGROUND—Involvement of the gut in chronic granulomatous disease (CGD) has been previously described and colitis highlighted. However, the nature and histopathology of the colitis are unclear and have been thought to be non-specific or similar to Crohn's disease.
METHODS—Seven patients with CGD, suffering from gastrointestinal symptoms were prospectively studied.
RESULTS—All patients had anaemia; other symptoms were failure to thrive (5/7) and diarrhoea (5/7). Most had microcytic anaemia (5/7), increased platelets (7/7), and increased erythrocyte sedimentation rate (6/6). Endoscopically there was a friable erythematous mucosa in 6/7. The histological features present in all patients consisted of a colitis with paucity of neutrophils, increased numbers of eosinophils, eosinophilic crypt abscesses, pigmented macrophages, and nuclear debris. In some granulomas were present (2/7).
CONCLUSIONS—Colitis is a common cause of gastrointestinal symptoms in CGD and is caused by a non-infective inflammatory process. The histology has specific features, which are distinctive from those seen in Crohn's disease.

PMCID: PMC1718666  PMID: 11159292
9.  Antibody responses to Haemophilus influenzae type b conjugate vaccine in sickle cell disease. 
Archives of Disease in Childhood  1996;75(2):159-161.
OBJECTIVE: To investigate the immunogenicity of Haemophilus influenzae type b (Hib) conjugate vaccines in children with sickle cell disease. DESIGN: Open study. SETTING: Haemoglobinopathy clinic. SUBJECTS: Children with homozygous haemoglobin SS disease (HbSS), sickle haemoglobin C disease (HbSC), and sickle-beta thalassaemia disease (HbS-beta Thal). INTERVENTIONS: Children over the age of 2 years received a single dose of Hib-tetanus toxoid conjugate vaccine (PRP-T). MAIN OUTCOME MEASURES: Antibody response to Hib polysaccharide (PRP) approximately one month after vaccination. RESULTS: 77 children over the age of 2 years were studied,, 55 with HbSS, 16 with HbSC, and six with HbS-beta Thal. Before vaccination, 44% had anti-PRP IgG titres less than the level associated with long term protection (1.0 microgram/ml). After a single dose of PRP-T all children mounted an antibody titre > 1 microgram/ml. Geometric mean anti-PRP IgG titre achieved postvaccination (45.2 micrograms/ml 95% confidence interval (CI) 31.6 to 64.8) was comparable to that of a healthy population. Children with HbSC, however, had a significantly higher antibody titre postvaccination (91.1 micrograms/ml; 95% CI 32.7 to 254.4) than the children with HbSS (36.7 micrograms/ml; 95% CI 25.1 to 52.9). CONCLUSIONS: Children with a diagnosis of sickle cell disease who are over the age of 2 years make a vigorous antibody response to a single dose of PRP-T vaccine and hence we suggest unimmunised individuals in this group should receive a single dose of a Hib conjugate vaccine.
PMCID: PMC1511645  PMID: 8869201
11.  Decreased insulin sensitivity of forearm muscle in myotonic dystrophy. 
Journal of Clinical Investigation  1978;62(4):857-867.
Previous studies of patients with myotonic dystrophy have demonstrated hyperinsulinism after glucose loading. This hyperinsulinism has been attributed by some investigators to tissue insulin resistance. We have directly studied insulin sensitivity of forearm muscle in patients having such hyperinsulinism. The effect of an intrabrachial arterial insulin infusion (100 mu U/kg per min) on glucose uptake was determined in six cases of myotonic dystrophy, six normal subjects, and in seven disease control subjects with myotonia or wasting from other disorders. There was no significant difference in insulin tolerance comparing myotonic dystrophy patients to the normal and disease control groups. Glucose tolerance and basal insulin levels were normal in the myotonic dystrophy patients, but hyperinsulinism occurred after glucose ingestion. After 25 min of intra-arterial insulin, the mean peak muscle glucose uptake in myotonic dystrophy was 2.54 +/- 0.54 mu mol/min per 100 ml forearm compared to 5.24 +/- 0.86 mu mol/min per 100 ml for disease controls (P is less than 0.05). Myotonic dystrophy patients showed a peak glucose uptake increment of only 2.6 +/- 0.2-fold over basal contrasted with the disease control value of 6.5 +/- 1.0-fold (P is less than 0.02) and the normal control value of 8.8 +/- 1.1-fold (P is less than 0.01). Thus, there was an absolute as well as a relative decrease in muscle insulin sensitivity in myotonic dystrophy patients compared to both control groups. The peak increments in arterio-superficial venous glucose concentration differences after insulin infusion were not significantly different comparing myotonic dystrophy and control groups. These data suggest that in myotonic dystrophy, there is insulin insensitivity of skeletal muscle.
PMCID: PMC371838  PMID: 701484
12.  Assessment of Streptococcus pneumoniae pilus islet-1 prevalence in carried and transmitted isolates from mother–infant pairs on the Thailand–Burma border 
Clinical Microbiology and Infection  2011;18(10):970-975.
Streptococcus pneumoniae pilus islet-1 (PI-1)-encoded pilus enhances in vitro adhesion to the respiratory epithelium and may contribute to pneumococcal nasopharyngeal colonization and transmission. The pilus subunits are regarded as potential protein vaccine candidates. In this study, we sought to determine PI-1 prevalence in carried pneumococcal isolates and explore its relationship with transmissibility or carriage duration. We studied 896 pneumococcal isolates collected during a longitudinal carriage study that included monthly nasopharyngeal swabbing of 234 infants and their mothers between the ages of 1 and 24 months. These were cultured according to the WHO pneumococcal carriage detection protocol. PI-1 PCR and genotyping by multilocus sequence typing were performed on isolates chosen according to specific carriage and transmission definitions. Overall, 35.2% of the isolates were PI-1-positive, but PI-1 presence was restricted to ten of the 34 serotypes studied and was most frequently associated with serotypes 19F and 23F; 47.5% of transmitted and 43.3% of non-transmitted isolates were PI-1-positive (OR 1.2; 95% CI 0.8–1.7; p 0.4). The duration of first-ever infant pneumococcal carriage was significantly longer with PI-1-positive organisms, but this difference was not significant at the individual serotype level. In conclusion, PI-1 is commonly found in pneumococcal carriage isolates, but does not appear to be associated with pneumococcal transmissibility or carriage duration.
PMCID: PMC3469734  PMID: 22092910
Carriage; carriage duration; colonization; PI-1; pilus-1; Streptococcus pneumoniae; transmission
13.  Serum antibody responses to pneumococcal colonization in the first 2 years of life: results from an SE Asian longitudinal cohort study 
Clinical Microbiology and Infection  2013;19(12):E551-E558.
Assessment of antibody responses to pneumococcal colonization in early childhood may aid our understanding of protection and inform vaccine antigen selection. Serum samples were collected from mother-infant pairs during a longitudinal pneumococcal colonization study in Burmese refugees. Maternal and cord sera were collected at birth and infants were bled monthly (1–24 months of age). Nasopharyngeal swabs were taken monthly to detect colonization. Serum IgG titres to 27 pneumococcal protein antigens were measured in 2624 sera and IgG to dominant serotypes (6B, 14, 19F, 19A and 23F) were quantified in 864 infant sera. Antibodies to all protein antigens were detectable in maternal sera. Titres to four proteins (LytB, PcpA, PhtD and PhtE) were significantly higher in mothers colonized by pneumococci at delivery. Maternally-derived antibodies to PiuA and Spr0096 were associated with delayed pneumococcal acquisition in infants in univariate, but not multivariate models. Controlling for infant age and previous homologous serotype exposure, nasopharyngeal acquisition of serotypes 19A, 23F, 14 or 19F was associated significantly with a ≥2-fold antibody response to the homologous capsule (OR 12.84, 7.52, 6.52, 5.33; p <0.05). Acquisition of pneumococcal serotypes in the nasopharynx of infants was not significantly associated with a ≥2-fold rise in antibodies to any of the protein antigens studied. In conclusion, nasopharyngeal colonization in young children resulted in demonstrable serum IgG responses to pneumococcal capsules and surface/virulence proteins. However, the relationship between serum IgG and the prevention of, or response to, pneumococcal nasopharyngeal colonization remains complex. Mechanisms other than serum IgG are likely to have a role but are currently poorly understood.
PMCID: PMC4282116  PMID: 24255996
Antibody; capsule; colonization; polysaccharide; protein; Streptococcus pneumoniae; vaccine

Results 1-13 (13)