Bacteraemia in Kenyan children with sickle-cell anaemia: a retrospective cohort and case–control study Antibody responses to Haemophilus influenzae type b conjugate vaccine in sickle cell disease. Passive immunization against disease due to Haemophilus influenzae type b: concentrations of antibody to capsular polysaccharide in high-risk children. Haemophilus influenzae type b immunization of children with sickle cell diseases. Safety and immunogenicity of haemophilus influenzae type B polysaccharide or conjugate vaccines in an elderly adult population. Clinical and immunological risk factors associated with Haemophilus influenzae type b conjugate vaccine failure in childhood. Immunogenicity and tolerability of a virosome influenza vaccine compared to split influenza vaccine in patients with sickle cell anemia. Immunogenicity of Haemophilus influenzae type b conjugate vaccine in children with sickle cell disease. Biomarkers of splenic function in infants with sickle cell anemia: baseline data from the BABY HUG Trial.
Summary Background In sub-Saharan Africa , more than 90 % of children with sickle-cell anaemia die before the diagnosis can be made . The causes of death are poorly documented , but bacterial sepsis is probably important . We examined the risk of invasive bacterial diseases in children with sickle-cell anaemia . Methods This study was undertaken in a rural area on the coast of Kenya , with a case – control approach . We undertook blood cultures on all children younger than 14 years who were admitted from within a defined study area to Kilifi District Hospital between Aug 1 , 1998 , and March 31 , 2008 ; those with bacteraemia were defined as cases . We used two sets of controls : children recruited by r and om sampling in the same area into several studies undertaken between Sept 1 , 1998 , and Nov 30 , 2005 ; and those born consecutively within the area between May 1 , 2006 , and April 30 , 2008 . Cases and controls were tested for sickle-cell anaemia retrospectively . Findings We detected 2157 episodes of bacteraemia  in 38 441 admissions ( 6 % ) . 1749 of these children with bacteraemia ( 81 % ) were typed for sickle-cell anaemia  , of whom 108 ( 6 % ) were positive as were 89 of 13 492 controls ( 1 % ) . The organisms most commonly isolated from children with sickle-cell anaemia were Streptococcus pneumoniae ( 44/108 isolates ; 41 % ) , non-typhi Salmonella species ( 19/108 ; 18 % ) , Haemophilus influenzae type b ( 13/108 ; 12 % ) , Acinetobacter species ( seven of 108 ; 7 % ) , and Escherichia coli ( seven of 108 ; 7 % ) . The age-adjusted odds ratio for bacteraemia in children with sickle-cell anaemia was 26·3 ( 95 % CI 14·5–47·6 ) , with the strongest associations for S pneumoniae ( 33·0 , 17·4–62·8 ) , non-typhi Salmonella species ( 35·5 , 16·4–76·8 ) , and H influenzae type b ( 28·1 , 12·0–65·9 ) . Interpretation The organisms causing bacteraemia in African children with sickle-cell anaemia are the same as those in developed countries . Introduction of conjugate vaccines against S pneumoniae and H influenzae into the childhood immunisation schedules of African countries could substantially affect survival of children with sickle-cell anaemia . Funding Wellcome Trust , UK 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 From the pooled plasma of 54 adult donors immunized with Haemophilus influenzae type b capsular polysaccharide ( CP )  , a human hyperimmune globulin termed bacterial polysaccharide immune globulin ( BPIG ) was prepared . The pharmacokinetics of antibody to H. influenzae type b CP in high-risk children was compared after BPIG and conventional immune serum globulin ( ISG ) were administered intramuscularly at a dose of 0.5 - 0.6 ml/kg . The increase in antibody level four to seven days after injection was ninefold higher with BPIG than with ISG and remained higher throughout the three-month follow-up period . The mean half-life of antibody to H. influenzae type b CP was similar after BPIG ( 27 days ) and ISG ( 29 days ) . Antibody levels returned to baseline one to two months after ISG but remained significantly above baseline three months after BPIG ( mean concentration , 385 ng/ml ) . Based on the assumption that 150 ng of IgG antibody to H. influenzae type b CP/ml is the minimal protective level , it is concluded that a single intramuscular dose of 0.5 ml of BPIG/kg will protect children for four months Haemophilus influenzae type B vaccine is recommended for children 1.5 to 6 years of age with sickle cell anemia , but the adequacy of their response is unknown . A total of 69 children with sickle cell syndromes , 1.5 to 5.6 years of age , were immunized with two vaccines alternatively , single blind . PRP vaccine was given to 36 children and a diphtheria toxoid conjugated vaccine , PRP-D , was given to 36 . Coded pre- and postvaccine sera were tested by radioimmunoassay for anti-PRP antibody . The groups did not differ in age distribution or type of sickle hemoglobinopathy .  Preexisting antibody levels were low in both vaccine groups ; 65 % were less than 0.15 microgram/mL. The vaccines were safe but associated with frequent minor reactions .  PRP-D gave higher geometric mean titers and mean fold titer increase than PRP in all children ( 15.58 micrograms/mL [ 234-fold ] v 2.63 micrograms/mL [ 29-fold ] ) and in the subgroups 1.5 to 2.5 years of age or with pretiter values less than 0.15 microgram/mL. Titers for 64 % of children receiving PRP and 94 % receiving PRP-D were greater than or equal to 1.0 microgram/mL. Thus , both vaccines were useful in this population , but PRP-D was more immunogenic . Duration of antibody levels postvaccination , booster responses , and PRP-D immunogenicity in younger children with sickle cell syndromes all require further study OBJECTIVES To evaluate the safety and immunogenicity of unconjugated Haemophilus influenzae type b ( Hib ) polysaccharide ( PRP ) vaccine and two PRP-protein-conjugated vaccines as a model for the comparison of protein-conjugated versus plain polysaccharide vaccines in the elderly . DESIGN R and omized , double-blind , prospect i ve study . SETTING University-based center for vaccine research and development . PARTICIPANTS A total of 125 adults , aged 64 to 92 , who were judged to be in general good health and lacking any significant underlying medical conditions . INTERVENTION Subjects were r and omized to receive one of three vaccines : Group 1 ( n=39 ) , PRP ; Group 2 ( n=44 ) , PRP conjugated to an outer-membrane protein complex of Neisseria meningitidis ( PRP-OMP ) ; and Group 3 ( n=42 ) , PRP conjugated to diphtheria toxoid ( PRP-D ) . Sera were obtained before immunization and 1 and 12 months later . MEASUREMENTS Subjects maintained a diary of injection site and systemic reactions for 3 days after immunization . A radioantigen-binding assay was used to measure total concentrations of serum anticapsular antibody , and an enzyme-linked immunosorbent assay was used to measure immunoglobulin ( Ig ) G1 and IgG2 anticapsular antibody responses . Antibody functional activity was assessed using a complement-mediated bactericidal assay . RESULTS Before vaccination , the geometric mean serum anticapsular antibody concentration was 0.8 microg/mL , but fewer than 10 % of subjects had detectable bactericidal activity ( titer>1:4 ) . The magnitude , subclass distribution , and bactericidal activity of antibody responses to unconjugated PRP vaccine were similar to those observed in previous studies of younger adults immunized with PRP . The OMP conjugate , which is highly immunogenic after one dose in 2-month old infants , did not elicit anticapsular antibody responses in the elderly greater than those elicited by PRP vaccine ( P=.43 ) . In contrast , the D conjugate , which is poorly immunogenic in 2-month old infants , elicited higher anticapsular antibody responses than PRP vaccine in the elderly ( P=.01 ) and higher levels than the OMP-conjugate 1 year after vaccination ( P<.006 ) . CONCLUSION Elderly adults develop protective anticapsular antibody responses to unconjugated and conjugated PRP vaccine . The higher anticapsular antibody responses to the D conjugate but not to the OMP conjugate in the elderly , which is the reverse of that observed in immunized infants , implies fundamental differences in the immunological mechanisms by which the two age groups respond to PRP and by which the OMP and D conjugates elicit anticapsular antibody responses Haemophilus influenzae type b ( Hib ) conjugate vaccines have proved extremely efficacious in healthy children . True Hib vaccine failures are rare . Hib conjugate vaccines were introduced for routine immunization in the United Kingdom and the Republic of Irel and in 1992 . Coincident with this , active prospect i ve and national surveillance via pediatricians , microbiologists , and public health physicians was commenced to assess the clinical and immunological factors associated with vaccine failure . During the 6 years of the study , 115 children with true vaccine failure were reported . Of the children who were vaccinated before 12 months of age , a clinical risk factor was detected in 20 % , an immunological deficiency was detected in 30 % , and one or both were detected in 44 % . Children who were vaccinated after 12 months of age were more likely to have one or both factors ( 67 % ) . Thirty percent ( 33 of 105 ) of children with true vaccine failure had a low Hib antibody response ( concentration , < 1.0 microg/mL ) after disease , but the majority then responded to a further dose of Hib vaccine . Children who develop Hib disease despite vaccination deserve further clinical and immunological evaluation The immunogenicity and tolerability of virosome and of split influenza vaccines in patients with sickle cell anemia ( SS ) were evaluated . Ninety SS patients from 8 to 34 years old were r and omly assigned to receive either virosome ( n=43 ) or split vaccine ( n=47 ) . Two blood sample s were collected , one before and one 4 - 6 weeks after vaccination . Antibodies against viral strains ( 2006 ) A/New Caledonia ( H1N1 ) , A/California ( H3N2 ) , B/Malaysia were determined using the hemagglutinin inhibition test . Post-vaccine reactions were recorded over 7 days . Seroconversion rates for H1N1 , H3N2 and B were 65.1 % , 60.4 % and 83.7 % for virosome vaccine , and 68.0 % , 61.7 % and 68.0 % for split vaccine . Seroprotection rates for H1N1 , H3N2 e B were 100 % , 97.6 % and 69.7 % for virosome , and 97.8 % , 97.8 % and 76.6 % for split vaccine . No severe adverse reactions were recorded . Virosome and split vaccines in patients with sickle cell anemia were equally immunogenic , with high seroconversion and seroprotection rates . Both vaccines were well tolerated OBJECTIVE To determine the safety and immunogenicity of Haemophilus influenzae type b conjugate vaccine in children with sickle cell disease . RESEARCH DESIGN Prospect i ve , nonr and omized , nonblinded study . SETTING Hospital-based , comprehensive sickle cell center . PATIENTS Children with sickle cell disease aged 18 months to 18 years who were previously unvaccinated or had an inadequate or waning response to H influenzae type b polysaccharide vaccine .  SELECTION PROCEDURES Consecutive eligible patients . INTERVENTIONS Vaccination and observation for adverse effects . Blood sample s were taken before and 1 to 2 and 6 months after vaccination to measure anticapsular antibody levels . MEASUREMENTS AND RESULTS Vaccination was well tolerated . One hundred percent and 96 % of the 31 immunized children had postvaccination anticapsular antibody concentrations of greater than 0.15 and 1.0 mg/L , respectively . Six months after vaccination , 100 % and 89 % of children had these antibody concentrations . CONCLUSIONS H influenzae type b conjugate vaccines are safe and highly immunogenic in children with sickle cell disease . It is likely that these vaccines will be protective against invasive H influenzae type b disease We evaluated spleen function in 193 children with sickle cell anemia 8 to 18 months of age by (99m)Tc sulfur-colloid liver-spleen scan  and correlated results with clinical and laboratory parameters , including 2 splenic biomarkers :  pitted cell counts  ( PIT ) and  quantitative Howell-Jolly bodies  ( HJB ) enumerated by flow cytometry . Loss of splenic function began before 12 months of age in 86 % of infants in association with lower total or fetal hemoglobin and higher white blood cell or reticulocyte counts , reinforcing the need for early diagnosis and diligent preventive care . PIT and HJB correlated well with each other and liver-spleen scan results . Previously described biomarker threshold values did define patients with abnormal splenic function , but our data suggest that normal spleen function is better predicted by PIT of ≤1.2 % or HJB ≤55/10(6 ) red blood cells and absent function by PIT ≥4.5 % or HJB ≥665/10(6 ) . HJB is method ologically advantageous compared with PIT , but both are valid biomarkers of splenic function . This trial was registered at www . clinical trials.gov as # NCT00006400
BACKGROUND People affected with sickle cell disease are at high risk of infection from Haemophilus influenzae type b. Before the implementation of Haemophilus influenzae type b conjugate vaccination in high-income countries , this was responsible for a high mortality rate in children under five years of age .
In African countries , where coverage of this vaccination is still extremely low , Haemophilus influenzae type b remains one of the most common cause of bacteraemias in children with sickle cell disease .
The increased uptake of this conjugate vaccination may substantially improve the survival of children with sickle cell disease .
OBJECTIVES The primary objective was to determine whether Haemophilus influenzae type b conjugate vaccines reduce mortality and morbidity in children and adults with sickle cell disease .
The secondary objectives were to assess the following in children and adults with sickle cell disease : the immunogenicity of Haemophilus influenzae type b conjugate vaccines ; the safety of these vaccines ; and any variation in effect according to type of vaccine , mode of administration ( separately or in combination with other vaccines ) , number of doses , and age at first dose .