Haemophilus Influenzae Type B Conjugate Vaccine 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.

Clinical spectrum and complications of childhood pneumonia in the era of bacterial conjugate vaccines

Pneumonia remains a leading cause of under-5 childhood mortality, particularly in low and middle-income countries. The rollout of conjugate bacterial vaccines, including Haemophilus influenzae type b conjugate vaccine (HibCV) and particularly pneumococcal conjugate vaccine (PCV), into national immunization programs recently, has been associated with dramatic decline in all-cause pneumonia hospitalization in many developed countries where PCV immunization has been implemented. Also, PCV immunization has variably been associated with changes in incidence of hospitalization due to influenza virus and RSV-associated pneumonia in some settings. There is, however, limited data from low and middle-income countries on the effectiveness of PCV against pneumonia once introduced into immunization programs. A broader diversity of serotypes associated with pneumococcal disease and higher prevalence of underlying risk factors for pneumonia such as greater prevalence of malnutrition, HIV-infection and tuberculosis may affect the impact of PCV on all-cause pneumonia morbidity and mortality in children. Furthermore, early experience from few studies in developed countries with 7-valent PCV, suggested a temporal association between PCV-7 introduction and an increase in complicated pneumonia including that due to empyema due to few serotypes not included in PCV7, but which are now included in the 10 and 13-valent PCVs formulations currently used. The global public health value of PCV will be measured by its success in reducing all-cause childhood pneumonia morbidity and mortality in low and middle-income countries. Results on the impact of PCV immunization in early-adopting low and middle incoming countries are imminent and will contribute in determining the potential of PCV in improving child health globally.

Effect of HIV-1 exposure and antiretroviral treatment strategies in HIV-infected children on immunogenicity of vaccines during infancy

We studied the effect of maternal HIV-exposure and timing of antiretroviral treatment (ART) in HIV-infected infants on antibody responses to combined diphtheria-toxoid-tetanus-toxoid-whole cell pertussis and Haemophilus influenzae type b conjugate vaccine (HibCV) and monovalent hepatitis B vaccine (HBV). HIV-uninfected infants born to HIV-infected (HEU) or HIV-uninfected (HUU) mothers were enrolled in parallel with HIV-infected children with CD4⁺ ≥25%, who were randomized to initiate ART immediately upon confirmation of HIV-infection (ART-Immed) or when clinically and/or immunologically indicated (ART-Def). Infants received three doses of diphtheria-toxoid-tetanus-toxoid -wP-HibC/HBV at 7.3, 11.4 and 15.4 weeks of age. Antibody to diphtheria-toxoid, tetanus-toxoid, pertussis toxin, filamentous hemagglutinin (FHA) and hepatitis B surface antigen (HBsAg) were measured by Luminex multiplex-immunoassay and polyribosyl-ribitol phosphate (PRP) antibodies by standard ELISA and bactericidal assay. Prevaccination antibody geometric mean concentrations (GMCs) were higher in HUU than HEU infants for tetanus-toxoid, but lower for HBsAg, diphtheria-toxoid and FHA. Postvaccination GMCs and proportion with seroprotective antibody levels or sero-conversion rates were similar between HUU and HEU infants for all vaccines. Postvaccination GMCs were higher in HUU for tetanus-toxoid, diphtheria-toxoid, HBsAg and FHA than ART-Immed infants; and for tetanus-toxoid, HBsAg and pertussis-toxoid than ART-Def infants. Nevertheless, there was no difference in proportion of HUU and HIV-infected infants who developed sero-protective vaccine-specific antibody levels postvaccination. The timing of ART initiation generally did not affect immune responses to vaccines between HIV-infected groups. Vaccination with DTwP-HibCV/HBV of HEU and HIV-infected infants initiated on early-ART confers similar immunity compared with HUU children.

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.

A clinical trial examining the effect of increased total CRM 197 carrier protein dose on the antibody response to Haemophilus influenzae type b CRM 197 conjugate vaccine

CRM 197 is a carrier protein in certain conjugate vaccines. When multiple conjugate vaccines with the same carrier protein are administered simultaneously, reduced response to vaccines and/or antigens related to the carrier protein may occur. This study examined responses of infants who, in addition to diphtheria toxoid/tetanus toxoid/acellular pertussis vaccine (DTaP) received either diphtheria CRM 197-based Haemophilus influenzae type b conjugate vaccine (HbOC) or HbOC and a diphtheria CRM 197-based combination 9-valent pneumococcal conjugate vaccine/meningococcal group C conjugate vaccine. Administration of conjugate vaccines with CRM 197 carrier protein load >50 μg did not reduce response to CRM 197 conjugate vaccines or immunogenicity to immunologically cross-reactive diphtheria toxoid.

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.

Immunogenicity and reactogenicity of HbOC vaccine administered simultaneously with acellular pertussis vaccine (DTaP) into either arms or thighs of infants.

To evaluate the reactogenicity and immunogenicity of a Haemophilus influenzae type b conjugate vaccine (HbOC) and of a tricomponent acellular pertussis vaccine (DTaP) when injected simultaneously into either contralateral arms or into contralateral thighs, 110 infants were enrolled to receive three doses of DTaP at 3, 4, and 5 months and two HbOC doses at 3 and 5 months of age. Administration of either of the two vaccines into arms was associated with significantly more local side effects than administration into thighs. There was no difference in geometric mean concentration (GMC) values for any of the four vaccine antigens between subjects who had been vaccinated into arms or thighs. After immunization, all children had protective antibody titers to diphtheria toxin. While post vaccination the mean anti-tetanus toxoid GMC was > or = 1.25 IU/ml, there was no significant rise as compared to the GMC before vaccination. GMCs of antibodies against the various pertussis antigens were similar to those observed before with the same DTaP vaccine. The simultaneous administration of DTaP and HbOC was safe and immunogenic irrespective of the site of vaccine administration, but significantly more local reactions occurred when vaccines were injected into arms.

The immunogenicity of Haemophilus influenzae type b conjugate (HbOC) vaccine in human immunodeficiency virus-infected and uninfected infants.

Enzyme-linked immunosorbent assay polyribosyl ribitol phosphate (PRP) antibody responses to Haemophilus influenzae type b conjugate vaccine (HbOC) given at 2, 4 and 6 months of age were retrospectively compared in 23 human immunodeficiency virus (HIV) and 24 non-HIV-infected infants. HIV-infected infants were divided into those who were P1 (asymptomatic) or P2 (symptomatic) by 1 year of age. The P2 group was further divided into P2A (mildly symptomatic) and > P2A (rapidly symptomatic) by 1 year of age. The post-third HbOC dose geometric mean antibody titer to PRP was significantly lower in 12 P2 infants (0.43 microgram/ml) than either the 11 P1 infants (5.03 micrograms/ml, P < 0.05) or the 24 non-HIV infected infants (3.43 micrograms/ml, P < 0.05). Within the P2 group, the geometric mean antibody titer to PRP was significantly higher in 5 P2A infants (1.63 micrograms/ml) compared with 7 infants who were > P2A (0.17 microgram/ml, P < 0.05). After the third HbOC dose, PRP antibody titers were > or = 1.0 micrograms/ml for 4 of 12 P2 compared with 9 of 11 P1 infants (P < 0.05). Within the P2 group, PRP antibody titers were > 1.0 micrograms/ml for 4 of 5 P2A compared to 0 of 7 infants who were > P2A (P < 0.05). HIV-infected infants with PRP antibody titers > or = 1.0 micrograms/ml after the third HbOC dose had significantly higher mean CD4 counts (2842 cells/mm3) at the time of the third HbOC dose than those with lower PRP titers (1655 cells/mm3) (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

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.