Haemophilus Influenzae Type-b Conjugate Research Articles

Immunity and Control Analysis of H. Influenzae Type b Polysaccharide-protein Conjugate Vaccine

Haemophilus influenzae type b (HIb) is the widest known cause of bacterial meningitis and a leading cause of bacterial diseases in the United States and many areas of the world. It causes epiglotitis, pneumonia, septic arthritis, osteomylitis and penricarditis. Many sunvivors of meningitis experience in permanent mild hearing loss and mental retardation. The capsular polysaccharide of polyribosylribitol phosphate (PRP) is a major virulence facor of the organism. Antibody to PRP is the primary contributor to induce serum bactericidal activity. Three types of HIb-protein conjugate vaccines were prepared by different methods, using a different protein carrier, PS size, nature of linkage, and ratio of protein and PS: (1) The Connaught Laboratories combined diphtheria toxoid (DT)to HIb PS by cyanogen bromide activation of PS and conjugation of PS and DT by carbodiimide; (2)In the praxis Biologics, HIb oligosaccharides were conjugated to a mutant diphtheria toxin, CRM197, by the reductive amination; (3)The Merck, Sharp & Dohme conjugate vaccine utilized a 40 KD meningococcal outer membrane protein(OMP)and a mutiple synthetic procedure. HIb PS-protein oonjugate vaccine produced high antibody levels in infants 2-6 months of age and young children with no major adverse reactions. Control tests of HIb conjugate vaccine were carried out in two stages : (A) Each lot of PS shall be examined for(l) the chemical content, such as ribose and phosphorus;(2) contamination of cell components, such as protein, LPS and nucleic acids. The carrier protein was then examined for its purity. The conjugate bulk concentrate was next examined for free ribose content, ratio of PS and protein, molecular size, contamination of LPS and pyrogenicity. (B) The final conjugate vaccine contains 10-25 ug PRP per dose. The vaccine was tested for identity and amount of HIb PS, contents of free ribose, free protein, LPS, as well as sterility, general safety and pyrogenicity. Immunization of HIb PS-protein conjugate vaccine holds great promise for the prevention of HIb diseases in young children. An approach using similar technology can be applied to the prevention in the future of diseases caused by other encapsulated bacteria.

Antibody response to Haemophilus influenzae type-b conjugate vaccine in children and young adults with congenital asplenia or after undergoing splenectomy

Absence of the spleen constitutes a risk of infection caused by encapsulated bacteria. The aim of our study was to determine the immune response to Haemophilus influenzae type-b (Hib) conjugate vaccine (HibCV) in asplenic individuals, considering the cause of asplenia, the age when splenectomy was carried out, and previous Hib vaccinations. Twenty asplenic patients, aged five to 25 years, were immunized with a single dose of HibCV. The specific antibody concentrations against HibCV were measured by enzyme-linked immunosorbent assay. Before vaccinations, the geometric mean antibody concentration (GMC) had an average value of 3.21 μg/ml and was comparable for all of the patients, regardless of the causes of asplenia. After vaccinations, the GMC was significantly higher, with an average of 6.78 μg/ml. Further, 4.5 years after vaccinations, the GMC was comparable to that of previously unvaccinated children. Moreover, 17/20 patients had GMC ≥ 1.0 μg/ml, which included all of the children with congenital asplenia, children splenectomized before the age of six years, and only 57% of children splenectomized after that age. HibCV gives asplenic patients long-term protection. Hence, HibCV should be administered regardless of previous vaccinations and time from splenectomy, even if antibody evaluation is not available.

A comparative study to evaluate the safety and immunogenicity of two lots of Haemophilus influenzae type-B conjugate vaccine manufactured at different scales

ObjectiveTo compare the immunogenicity and safety of two different lots of SII Haemophilus influenzae type-B–tetanus toxoid conjugate (SII HibPRO) vaccine manufactured at different scales when given in 3-dose schedule. DesignPhase IV, open label, comparative, randomized parallel group study. SettingShirdi Sai Baba Hospital, Vadu Budruk, Pune and Pediatrics Department of King Edward Memorial Hospital Research Centre, Pune. Subjects204 normal healthy infants of age 6–8 weeks at the time of first vaccination. MethodsThe eligible subjects received 3 doses of 0.5ml of SII HibPRO vaccine of either lot depending upon randomization number, intramuscularly in right thigh in the EPI schedule of 6, 10 and 14 weeks. They also received concomitantly DTP-HB vaccine intramuscularly on left thigh and Oral Polio vaccine (OPV). Solicited reactions were captured for 7 days following each vaccination; the events beyond 7 days till day 28 were captured as unsolicited adverse events. Serious Adverse Events (SAEs) were looked for throughout the subject participation. Blood samples were collected at baseline (before the first dose) and one month after the third dose for anti-PRP (polyribosylribitol phosphate) antibodies. ResultsIn both groups, more than 98% subjects achieved short-term seroprotection (anti-PRP≥0.15μg/ml) after 3 doses. The long-term seroprotection (anti-PRP≥1μg/ml) was 87% and 80% in infants receiving lot manufactured at industrial scale and small scale respectively. Short and long term seroprotection and GMTs increased significantly as compared to baseline in both the groups. Overall local pain (52% and 58%), redness (30% and 41%), swelling (34% and 44%), fever (6% and 6%) and irritability (52% and 50%) were reported in infants receiving lot manufactured at industrial scale and small scale respectively. Majority of the reactions were mild and resoled without any sequelae. Four SAEs, none of them causally related to the study vaccine, occurred during study. ConclusionSII HibPRO vaccines manufactured in small and industrial scale are equally immunogenic, safe and confer adequate seroprotection to infants of 6–14 weeks of age. Scaling up production process has not affected the safety and immune response in the target population.

Associations between Vaccination and Childhood Cancers in Texas Regions

To determine whether children born in Texas regions with higher vaccination coverage had reduced risk of childhood cancer. The Texas Cancer Registry identified 2800 cases diagnosed from 1995 to 2006 who were (1) born in Texas and (2) diagnosed at ages 2 to 17 years. The state birth certificate data were used to identify 11 200 age- and sex-matched control subjects. A multilevel mixed-effects regression model compared vaccination rates among cases and control subjects at the public health region and county level. Children born in counties with higher hepatitis B vaccine coverage had lower odds of all cancers combined (OR = 0.81, 95% CI: 0.67 to 0.98) and acute lymphoblastic leukemia (ALL) specifically (OR = 0.63, 95% CI: 0.46 to 0.88). A decreased odds for ALL also was associated at the county level with higher rates of the inactivated poliovirus vaccine (OR = 0.67, 95% CI: 0.49 to 0.92) and 4-3-1-3-3 vaccination series (OR = 0.62, 95% CI: 0.44 to 0.87). Children born in public health regions with higher coverage levels of the Haemophilus influenzae type b-conjugate vaccine had lower odds of ALL (OR: 0.58; 95% CI: 0.42 to 0.82). Some common childhood vaccines appear to be protective against ALL at the population level.

Antibody Response to Polysaccharide Conjugate Vaccines after Nonmyeloablative Allogeneic Stem Cell Transplantation

After allogeneic stem cell transplantation with reduced-intensity conditioning regimens (allo-RIST) patients are susceptible to bacterial and viral infections for a period that may last several years. The efficacy of the recommended vaccination schedules, in terms of induction of a protective antibody response, is unknown. In this study, the reconstitution of humoral immunity after allo-RIST is determined by measuring the vaccination-induced antibody response against Streptococcus pneumoniae, Haemophilus influenzae type b (Hib), and tetanus toxoid (TT) 1 year posttransplantation. Patients who underwent allo-RIST were vaccinated according to a schedule starting at 12 months following transplantation with conjugated vaccines against S. pneumoniae, Hib, and TT. Of twenty-six patients both pre- and postvaccination sera were available. Patients were required to be off immunosuppression at the time of vaccination, and, therefore, 9 of the 26 patients did not start vaccination at 12 months post-stem cell transplantation but rather at a median range of 15 (12-36 months) posttransplantation. Except for pneumococcal serotype 6B, more than 73% of the patients developed antibody levels >or=0.35 microg/mL for all pneumococcal serotypes included in the vaccine. For Hib and TT, protective antibody levels were found in 77% and 96% of the patients, respectively. Vaccination of patients at a median of 15 months post-allo-RIST leads to significant rise in concentrations of pneumococcal, Hib, and TT antibodies in the majority of patients.

Simultaneous vaccination of Chinese applicants for a United States immigrant visa

Simultaneous vaccination is still uncommon in China, and many Chinese people are quite concerned about the adverse reactions because few data regarding the adverse reactions of simultaneous vaccination in Chinese people have been reported. The objective of this study was to evaluate the safety of simultaneous vaccination and the frequency of adverse reactions following simultaneous vaccinations in Chinese applicants for a United States immigrant visa. We conducted a prospective observational study in 772 applicants receiving required vaccination in Guangdong International Travel Healthcare Center. The vaccines required for vaccination included diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP), adult formulation tetanus and diphtheria toxoids (Td), haemophilus influenzae type-b conjugate vaccine (Hib), oral polio vaccine (OPV), hepatitis B vaccine (HepB), combined measles mumps rubella vaccine (MMR), varicella vaccine (Var), and influenza vaccine (Inf), pneumococcal polysaccharide vaccine (PPV). Data on adverse reactions were collected by questionnaires. Seven hundred and seventy-two participants have received a total of 2533 doses of different vaccines, and 49.6% of the participants reported adverse reactions within 7 days following vaccination, with 39.8%(307/772) local reactions and 20.2%(156/772) systemic reactions. There were no allergic reactions. Only one vaccinee visited hospital seeking treatment due to fever, and recovered well. The most frequent local reaction was pain at the injection site (260/772, 33.7%), especially in the case of PPV vaccination, 61.2% (63/103) vaccinees who received PPV complained of pain at the site of injection, while the most frequent systemic reaction was fever (84/772, 10.9%). Pain and fever were all temporary reactions and resolved within 72h. Logistic regression analysis found that females experienced adverse reactions more frequently than males [(local reactions: female:male=41.7%(187/448):37%(120/324), p=0.04; systemic reactions: female:male=23%(103/448):16.4%(53/324), p=0.026)]; vaccinees given PPV developed local reactions more frequently than those receiving the other vaccines. The number of vaccines has no significant influence on adverse reactions. Simultaneous vaccination is feasible for Chinese applicants for a United States immigrant visa because the adverse reactions are mostly mild and temporary. Our data suggest that more Chinese people should be encouraged to receive simultaneous vaccination if the time is limited so as to reduce the risk of vaccine-preventable diseases.

Bacteral Meningitis in Childhood at the Children's Hospital of Pittsburgh: 1988-1998

Bacterial meningitis is an important acute infectious disease of childhood that remains a source of substantial morbidity and mortality. The impact of the Haemophilus influenzae type b (HIB) conjugate vaccines on the epidemiology of the other bacterial causes of meningitis in childhood has received little attention. The objective of this study is to report the experience at a tertiary-care children's hospital with the occurrence of bacterial meningitis before and after the licensure of the HIB conjugate vaccine. With use of International Classification of Diseases diagnostic codes for bacterial meningitis, a list of all children admitted to Children's Hospital of Pittsburgh with a primary or secondary diagnosis of meningitis due to H. influenzae, Streptococcus pneumoniae, and Neisseria meningitidis from January 1, 1988, to December 31, 1998, was constructed. Medical records were examined for basic patient demographic information including age, gender, race, bacterial etiology of meningitis, receipt of vaccine for HIB, underlying conditions, and fatalities. Two hundred twenty-one cases of bacterial meningitis caused by H. influenzae, N. meningitidis, and S. pneumoniae were identified. The age of infected children ranged from 1 month to 18 years, with a mean and median age of 38.1 months and 13 months, respectively. Fifty-two percent of the children were female, 83% were Caucasian and 16% were African-American. Before the routine use of HIB conjugate vaccine, HIB was the bacterial species responsible for the greatest proportion of cases (average of 58%/year). The absolute number of cases of bacterial meningitis attributable to HIB declined after 1991 to an average of 2.5 cases/year. The number of cases of meningitis caused by S. pneumoniae and N. meningitidis have remained relatively stable between 1988 and 1998. The case fatality rates for children with meningitis caused by H. influenzae, S. pneumoniae, and N. meningitidis were 0.0%, 9.2%, and 7.5%, respectively. Most cases of meningitis due to HIB occurred in children who had not been immunized. Three children who received the polysaccharide vaccine developed meningitis due to HIB; there were no failures of the conjugate vaccine.

Epiglottitis and Haemophilus influenzae Immunization: The Pittsburgh Experience–A Five-Year Review

Current trends in the clinical presentation and management of children with epiglottitis at Children's Hospital of Pittsburgh were reviewed for the years 1988 to 1993. The medical records of all patients diagnosed as having epiglottitis between July 1988 and June 1993 at the Children's Hospital of Pittsburgh were reviewed. An additional telephone survey was conducted among the primary care physicians of those patients to collect information regarding administration of Haemophilus influenzae type b (HIB) vaccines. During the study period 28 children (age range, 11 months to 11 years, 10 months) were admitted with the diagnosis of epiglottitis. Cases declined remarkably in 1991. Fever, sore throat, and stridor were the usual symptoms. HIB was the most common cause of epiglottitis accounting for 21 cases. Candida albicans was recovered from the surface culture of the epiglottis in two patients. At least 11 children experienced vaccine failure: nine with polysaccharide vaccine and two with the conjugate vaccine for HIB. Cases of epiglottitis have declined dramatically since licensure of HIB conjugate vaccines for use in early infancy. At least 52% of the reported cases represent vaccine failures with the purified polysaccharide vaccine.

Impact of Immunization Against Haemophilus influenzae Type b (HIB) on the Incidence of HIB Meningitis Treated at Arkansas Childrenʼs Hospital

The newly available Haemophilus influenzae type b (HIB) protein conjugate vaccines are efficacious among study populations in which a high proportion of infants and children are vaccinated. In this retrospective study, we show the impact of the availability of HIB conjugate vaccines on the incidence of HIB meningitis at Arkansas Children's Hospital (ACH) in Little Rock. The Arkansas State Health Department estimates that only 43% of children in the state younger than 2 years of age have received the appropriate vaccinations. From 1985 through 1987, 27.3 +/- 4 HIB meningitis cases per year were treated at ACH. Although an HIB conjugate vaccine was licensed for 18-month-old children in December 1987, the incidence of HIB meningitis treated at ACH did not decrease significantly; there were 19.0 +/- 2 cases per year from 1988 through 1990. In December 1990, an HIB conjugate vaccine was licensed for use in infants beginning at 2 months of age. From that time through August 1992, there were five cases of HIB meningitis treated at ACH, representing a significant decrease over previous years. Four of these cases occurred in unimmunized infants younger than 6 months of age. The availability of HIB conjugate vaccines for infants has resulted in a dramatic decrease in the number of cases of HIB meningitis treated at ACH, despite a relatively low proportion of infants and children who are receiving vaccination.

IgG1, IgG2 and IgM responses to two Haemophilus influenzae type b conjugate vaccines in young infants.

PRP-meningococcal outer membrane protein complex (PRP-OMPC) and oligosaccharide linked to variant diphtheria toxin (HbOC) Haemophilus influenzae type b (HIB) conjugate vaccines have both been licensed for United States infants at 2 months of age. Differences in serologic responses for these vaccines have been noted with PRP-OMPC producing an early response at 2 months of age and HbOC producing a higher response after a third dose at 6 months of age. To further characterize the nature of these distinct responses, we measured the IgG1, IgG2 and IgM anti-HIB concentrations by enzyme-linked immunosorbent assay after administration of both vaccines. PRP-OMPC produced an IgM and IgG1 anti-HIB response following the initial dose at 2 months of age. After two doses of HbOC an increase in IgG1 and IgM were noted and after a third dose at 6 months of age an IgG2 anti-HIB response occurred. In addition 33 study subjects were boosted with PRP-OMPC at age 18 months and compared with 34 subjects who received only a primary dose. The anti-HIB IgG1 and IgG2 concentrations following the booster dose were both significantly higher for the primed group (P = 0.0001 and P = 0.001, respectively). Both HIB conjugate vaccines produce predominantly IgG1 anti-HIB antibody responses. The early response to PRP-OMPC vaccine at 2 months of age may result from adjuvant characteristics of the OMPC.