Antibody persistence to diphtheria toxoid, tetanus toxoid, Bordetella pertussis antigens, and Haemophilus influenzae type b following primary and first booster with pentavalent versus hexavalent vaccines.

Thailand has incorporated the whole-cell (wP) pertussis vaccine into the expanded program on immunization since 1977 and has offered the acellular pertussis (aP) vaccine as an optional vaccine for infants since 2001. We followed healthy children from a clinical trial (ClinicalTrials.gov NCT02408926) in which children were randomly assigned to receive either pentavalent (DTwP-HB-Hib) or hexavalent (DTaP-IPV-HB-Hib) vaccines for their primary series (administered at 2, 4, and 6 months) and first booster vaccination (18 months). Both groups received Tdap-IPV as a second booster at the age of 4 y. Blood samples were collected for evaluation of antibody persistence to diphtheria toxoid (DT), tetanus toxoid (TT), and Bordetella pertussis (B. pertussis) between 2 and 6 y of age annually, and for the immunogenicity study of Tdap-IPV at 1 month after the second booster. Antibody persistence to Haemophilus influenzae type b (Hib) was followed until 3 y of age. A total of 105 hexavalent-vaccinated children and 91 pentavalent-vaccinated children completed this study. Both pentavalent and hexavalent groups demonstrated increased antibody levels against DT, TT, and B. pertussis antigens following the second booster with Tdap-IPV. All children achieved a seroprotective concentration for anti-DT and anti-TT IgG at 1 month post booster. The hexavalent group possessed significantly higher anti-pertactin IgG (adjusted p = .023), whereas the pentavalent group possessed significantly higher anti-pertussis toxin IgG (adjusted p < .001) after the second booster. Despite declining levels post-second booster, a greater number of children sustained protective levels of anti-DT and anti-TT IgG compared to those after the first booster.

Disparate kinetics in immune response of two different Haemophilus influenzae type b conjugate vaccines: Immunogenicity and safety observations from a randomized controlled phase IV study in healthy infants and toddlers using a 2+1 schedule.

Since the introduction of Haemophilus Influenzae type b (Hib) conjugate vaccines, invasive Hib disease has strongly declined worldwide, yet continued control of Hib disease remains important. In Europe, currently three different hexavalent combination vaccines containing Hib conjugates are marketed. In this phase IV, single-blind, randomized, controlled, multi-country study (NCT04535037), we aimed to compare, in a 2 + 1 vaccination schedule, the immunogenicity and safety and show non-inferiority, as well as superiority, of DTPa-HBV-IPV/Hib (Ih group) versus DTaP5-HB-IPV-Hib (Va group) in terms of anti-polyribosylribitol phosphate (PRP) antibody geometric mean concentrations (GMCs) and proportion of participants reaching anti-PRP antibody concentrations greater than or equal to a threshold of 5 µg/mL. One month after the booster vaccination, the anti-PRP antibody GMC ratio (Ih group/Va group) was 0.917 (95% CI: 0.710-1.185), meeting the non-inferiority criteria. The difference in percentage of participants (Ih group - Va group) reaching GMCs ≥5 µg/mL was -6.3% (95% CI: -14.1% to 1.5%), not reaching the predefined non-inferiority threshold. Interestingly, a slightly higher post-booster antibody avidity was observed in the Ih group versus the Va group. Both vaccines were well tolerated, and no safety concerns were raised. This study illustrates the different kinetics of the anti-PRP antibody response post-primary and post-booster using the two vaccines containing different Hib conjugates and indicates a potential differential impact of concomitant vaccinations on the anti-PRP responses. The clinical implications of these differences should be further studied.

Vaccination against Haemophilus influenzae type b (Hib) is included in the majority of national immunization programs worldwide and has shown to be effective in preventing Hib disease. In Europe, different vaccines containing Hib components are marketed. We compared the immune response and safety of 2 of these (DTPa-HBV-IPV/Hib, Ih group) and DTaP5-HB-IPV-Hib, Va group) in infants and toddlers, when used in a 2 + 1 schedule, i.e. two primary vaccination doses (at 2 and 4 months of age of the infant), followed by one booster dose at the age of one year. One month after the booster vaccination, the antibody concentration ratio between both groups (Ih group/Va group) was 0.917 (95% CI: 0.710­1.185) showing the DTPa-HBV-IPV/Hib vaccine was non-inferior to the DTaP5-HB-IPV-Hib vaccine; the difference in percentage of participants (Ih group ­ Va group) with antibody concentrations above 5 µg/mL was -6.3% (95% CI: −14.1% to 1.5%), which did not meet the pre-defined criterion for non-inferiority. In the Ih group, the quality of antibodies produced was somewhat higher versus the Va group. Both vaccines were well tolerated, and no safety concerns were raised. The kinetics of the immune response are different between the 2 vaccines. Since both vaccines contain different additional components (conjugated proteins), a possible effect of concomitant (simultaneously administered) vaccines was studied. Further investigations to confirm our findings are needed.

Immunogenicity and safety of adsorbed diphtheria-purified pertussis-tetanus-inactivated polio (Sabin strain)-Haemophilus type b conjugate combined vaccine (DPT-IPV-Hib) in healthy Japanese Infants ≥ 2 and < 43 months of Age: A phase III, multicenter, active controlled, assessor-blinded, randomized, parallel-group study.

OBJECTIVE: This study investigated the immunogenicity and safety of a pentavalent vaccine Gobik (DPT-IPV-Haemophilus influenzae type b [Hib]) in healthy Japanese infants aged ≥ 2 and < 43 months using a concomitant vaccination with ActHIB® (Hib) and Tetrabik (DPT-IPV) as a comparator. METHODS: This study was conducted as a phase 3, multicenter, active controlled, assessor-blinded, randomized, parallel-group study. Participants received a total of 4 subcutaneous doses (3 primary immunization doses and a booster dose) of either the experimental drug (DPT-IPV-Hib) or the active comparator (Hib + DPT-IPV). The primary endpoints were the anti-PRP antibody prevalence rate with ≥ 1 µg/mL, and the antibody prevalence rates against pertussis, diphtheria toxin, tetanus toxin, and attenuated poliovirus after the primary immunization. RESULTS: In 267 randomized participants (133 in the DPT-IPV-Hib group and 134 in the Hib + DPT-IPV group), the antibody prevalence rates after the primary immunization in both groups were 100.0 % and 88.7 % for anti-PRP antibody with ≥ 1 µg/mL, 99.2 % and 98.5 % against diphtheria toxin, and 100.0 % and 99.2 % against tetanus toxin, respectively. The antibody prevalence rates against pertussis and attenuated poliovirus were 100.0 % in both groups. The non-inferiority of the DPT-IPV-Hib group to the Hib + DPT-IPV group was verified for all measured antibodies. In both groups, all the GMTs of antibodies after the primary immunization were higher than those before the first dose, and those after the booster dose were higher than those after the primary immunization. No safety issues were identified. CONCLUSION: A single-agent Gobik, the first DPT-IPV-Hib pentavalent vaccine approved in Japan, was confirmed to simultaneously provide primary and booster immunizations against Hib infection, pertussis, diphtheria, tetanus, and poliomyelitis and to have a preventive effect and safety comparable to concomitant vaccination with Hib (ActHIB®) and DPT-IPV quadrivalent vaccine (Tetrabik).

Purpura Fulminans as a Rare Manifestation of Invasive Haemophilus influenzae Disease: A Case Report.

Haemophilus influenzae (Hi) is a bacterium usually found in the upper respiratory tract of humans. Though it is recognized as a naturally occurring element in the human bacterial reservoir, Hi infections have the potential to be severe and even fatal, particularly when they result in conditions such as meningitis or epiglottitis. Because of this, Hi invasive infections are considered a reportable disease in Portugal. We report a case of a 58-year-old female, chronically adrenally suppressed on long-term steroids, who developed an invasive Hi type b infection that led to purpura fulminans and multiorgan failure after an acute episode of epiglottitis. According to our review of the literature, only three previous cases of invasive Hi type b disease-causing purpura fulminans have been described.

Efficacy and Prolonged Safety of Haemophilus influenzae Type b Conjugate Vaccines.

OBJECTIVE: The purpose of this study was to find data proving the influence of the Haemophilus influenzae type b (Hib) conjugate vaccination on the frequency of invasive Hib illness. METHODOLOGY: A systematic literature search was conducted on the PubMed database to identify peerreviewed publications pertaining to the epidemiology of Haemophilus influenzae meningitis, both before and after the introduction of Haemophilus influenzae type b (Hib) conjugate vaccines. The search query employed a combination of relevant keywords, including "invasive," "Haemophilus," "influenzae," "meningitis," and specific serotype b (Hib). Additionally, terms related to epidemiology, burden, risk factors, impact, Hib vaccine, Hib conjugate vaccine, combination vaccine, vaccine production, efficacy, immunisation coverage, surveillance, review, clinical aspects, outcomes, and various age groups (adults and children) were incorporated. RESULT: The search encompassed articles published till now. Subsequently, relevant research papers concerning Haemophilus influenzae meningitis were subjected to a comprehensive review and analysis. CONCLUSION: The Hib conjugate vaccination has shown to be extremely effective when administered to the entire population. However, changes to the immunisation protocol appear to be required in order to effectively manage invasive Hib illness.

SEROPROTECTION RATE OF HAEMOPHILUS INFLUENZAE TYPE B CONJUGATE VACCINE AND ASSOCIATED CLINICAL OUTCOMES AMONG NIGERIAN CHILDREN AGED 6 TO 23 MONTHS.

Introduction: Haemophilus influenzae type b (Hib) causes invasive infections almost exclusively in under- fives with those aged 6-23 months being the most vulnerable. In Nigeria, it is estimated to cause nearly 400,000 annual infections and another 30,000 under-five mortality attributable to pneumonia and meningitis alone. The Hib Conjugate Vaccine (HCV) is in widespread use to combat these devastating infections. Data on its impact in Nigeria is grossly scanty. This study evaluated the seroprotection rates (SPR) of HCV and associated clinical outcomes among children aged 6-23 months in Obi L.G.A. of Nasarawa State, Nigeria. Methods: A cross-sectional study of 267 children aged 6-23 months who had completed three doses of HCV. They were enrolled via a two-staged household-level cluster sampling. Relevant sociodemographic and clinical data were obtained using structured questionnaires and serum samples collected were analysed serologically for antipolyribosylribitol phosphate (anti-PRP) antibodies using ELISA. Results: The overall SPRs against invasive Hib disease and Hib nasopharyngeal colonization were 74.2% and 26.2%, respectively. The overall geometric mean titre (GMT) of anti-PRP was 1.85 µg/mL (95%CI: 1.60-2.14) and across age groups, GMTs were >1 µg/mL-the threshold for long-term protection against invasive Hib disease. Rates/duration of healthcare admissions and average episodes of probable Hib disease syndromes were lower in seroprotected but not statistically different from non-seroprotected children. Conclusion: The demonstrated anti-PRP titres and Seroprotection Rates infer a very good HCV efficacy in Nigerian children. The lack of significant difference in clinical outcomes may be attributable to nonspecificity.

Consequences of a shortage and rationing: Evidence from a pediatric vaccine.

Shortages and rationing are common in health care, yet we know little about the consequences. We examine an 18-month shortage of the pediatric Haemophilus Influenzae Type B (Hib) vaccine. Using insurance claims data and variation in shortage exposure across birth cohorts, we find that the shortage reduced uptake of high-value primary doses by 4 percentage points and low-value booster doses by 26 percentage points. This suggests providers largely complied with rationing recommendations. In the long-run, catch-up vaccination occurred but was incomplete: shortage-exposed cohorts were 4 percentage points less likely to have received the ir booster dose years later. We also find that the shortage and rationing caused provider switches, extra provider visits, and negative spillovers to other care.

Prevalence and factors associated with pentavalent vaccination: a cross-sectional study in Southern China.

BACKGROUND: Immunization is one of the most far-reaching and cost-effective strategies for promoting good health and saving lives. A complex immunization schedule, however, may be burdensome to parents and lead to reduced vaccine compliance and completion. Thus, it is critical to develop combination vaccines to reduce the number of injections and simplify the immunization schedule. This study aimed to investigate the current status of the pentavalent diphtheria-tetanus-acellular pertussis inactivated poliomyelitis and Haemophilus influenzae type B conjugate (DTaP-IPV/Hib) vaccination in Southern China as well as explore the factors in the general population associated with uptake and the differences between urban and rural populations. METHODS: A cross-sectional study was conducted with recently enrolled kindergarten students in Hainan Province between December 2022 and January 2023. The study employed a stratified multistage cluster random sampling method. Information regarding the demographic characteristics and factors that influence decisions were collected from the caregivers of children via an online questionnaire. Multivariate logistic regression was used to determine the factors associated with the status of DTap-IPV/Hib vaccinations. RESULTS: Of the 4818 valid responses, 95.3% of children were aged 3-4 years, and 2856 (59.3%) held rural hukou. Coverage rates of the DTaP-IPV/Hib vaccine, from 1 to 4 doses, were 24.4%, 20.7%, 18.5%, and 16.0%, respectively. Caregivers who are concerned about vaccine efficacy [adjusted odds ratio (aOR) = 1.53, 95% confidence interval (CI): 1.30-1.79], the manufacturer (aOR = 2.05, 95% CI: 1.69-2.49), and a simple immunization schedule (aOR = 1.26, 95% CI: 1.04-1.54) are factors associated with a higher likelihood of vaccinating children against DTaP-IPV/Hib. In addition, caregivers in urban areas showed more concern about the vaccine price (P = 0.010) and immunization schedule (P = 0.022) in regard to vaccinating children. CONCLUSIONS: The DTaP-IPV/Hib vaccine coverage rate in Hainan Province remains low. Factors such as lower socioeconomic status, cultural beliefs, concerns about vaccine safety, and cost may hinder caregivers from vaccinating their children. Further measures, such as health education campaigns to raise knowledge and awareness, and encouragement of domestic vaccine innovation, which would reduce out-of-pocket costs, could be implemented to improve the coverage of DTap-IPV/Hib vaccination.

Enfermedad invasiva por Haemophilus influenzae: reporte de 14 casos luego de un año de iniciada la pandemia por COVID-19 / Invasive Haemophilus influenzae disease: A report of 14 cases one year after the COVID-19 pandemic outbreak

El Haemophilus influenzae (Hi) causa enfermedad invasiva (EI). Se distinguen cepas capsuladas, como el serotipo b (Hib), y cepas no tipificables (HNT). Al año de declarada la pandemia por COVID-19, observamos un aumento de casos. Se describen las características clínico-epidemiológicas de niños con EI por Hi internados en el hospital (julio 2021-julio 2022). Hubo 14 casos; 12 previamente sanos. Aislamientos: Hib (n = 6), Hi serotipo a (n = 2), HNT (n = 5), 1 no se tipificó. Mediana de edad: 8,5 meses (RIC 4-21). Manifestaciones: meningitis (n = 5), neumonía (n = 6), celulitis (n = 2), artritis (n = 1). Nueve presentaron vacunación incompleta para Hib. Observamos un incremento de EI por Hi de 2,5 veces respecto a años previos. Estos datos sugieren el resurgimiento de Hib por la caída de las coberturas de vacunación y porque otras cepas de Hi no b están en aumento.

Haemophilus influenzae (Hi) causes invasive disease. There are encapsulated strains, such as serotype b (Hib), and non-typeable strains (NTHi). One year after the outbreak of the COVID-19 pandemic, the number of cases increased. In this report we describe the clinical and epidemiological characteristics of children hospitalized with invasive Hi disease (July 2021-July 2022). There were 14 cases; 12 were previously healthy children. Isolations: Hib (n = 6), Hi serotype a (n = 2), NTHi (n = 5); 1 case was not typified. Median age: 8.5 months (IQR: 4­21). Manifestations: meningitis (n = 5), pneumonia (n = 6), cellulitis (n = 2), arthritis (n = 1). Incomplete Hib immunization was observed in 9 children. Invasive Hi disease increased 2.5 times from previous years. These data suggest the reemergence of Hib due to a decline in vaccination coverage and an increase in other non-b-type Hi serotypes.

Rates of Seroprotection against Vaccine-Preventable Infectious Diseases in HIV-Exposed and -Unexposed Malawian Infants.

BACKGROUND: The evaluation of seroprotection rates against vaccine-preventable infectious diseases allows for the identification of risk populations. HIV-exposed infants, even if not infected with HIV, have higher morbidity and mortality in comparison to unexposed counterparts. The aim of this study was to compare the specific IgG levels against Haemophilus influenzae type-B (HiB), Hepatitis-B (HBV), and Streptococcus pneumoniae (Spn) in two groups of infants (HIV-exposed and HIV-unexposed) living in Malawi. METHODS: Blood samples from 62 infants, 49 HIV-exposed, uninfected (HEU), and born to women living with HIV and 13 HIV-unexposed and uninfected (HUU), were collected at 6 months, and specific IgG levels were determined using ELISA tests. RESULTS: The antibody levels against HiB, HBV, and Spn were similar in the two groups. At six months, all HUU infants and 81.6% of HEU infants showed seroprotective levels against HiB, while a percentage of protection varying from 80.6 to 84.6% was observed for HBV and Spn regardless of HIV exposure. Only 59.2% of HEU and 69.2% of HUU infants showed antibody protection against all three pathogens. CONCLUSIONS: These results indicate similar rates of seroprotection among HEU and HUU infants but also suggest that a consistent fraction of infants received incomplete vaccinations. Strategies to enforce participation in immunization programs in Malawi should be a health priority.

Invasive Haemophilus influenzae disease: A report of 14 cases one year after the COVID-19 pandemic outbreak. / Enfermedad invasiva por Haemophilus influenzae: reporte de 14 casos luego de un año de iniciada la pandemia por COVID-19.

Haemophilus influenzae (Hi) causes invasive disease. There are encapsulated strains, such as serotype b (Hib), and non-typeable strains (NTHi). One year after the outbreak of the COVID-19 pandemic, the number of cases increased. In this report we describe the clinical and epidemiological characteristics of children hospitalized with invasive Hi disease (July 2021-July 2022). There were 14 cases; 12 were previously healthy children. Isolations: Hib (n = 6), Hi serotype a (n = 2), NTHi (n = 5); 1 case was not typified. Median age: 8.5 months (IQR: 4­21). Manifestations: meningitis (n = 5), pneumonia (n = 6), cellulitis (n = 2), arthritis (n = 1). Incomplete Hib immunization was observed in 9 children. Invasive Hi disease increased 2.5 times from previous years. These data suggest the reemergence of Hib due to a decline in vaccination coverage and an increase in other non-b-type Hi serotypes.

El Haemophilus influenzae (Hi) causa enfermedad invasiva (EI). Se distinguen cepas capsuladas, como el serotipo b (Hib), y cepas no tipificables (HNT). Al año de declarada la pandemia por COVID-19, observamos un aumento de casos. Se describen las características clínico-epidemiológicas de niños con EI por Hi internados en el hospital (julio 2021-julio 2022). Hubo 14 casos; 12 previamente sanos. Aislamientos: Hib (n = 6), Hi serotipo a (n = 2), HNT (n = 5), 1 no se tipificó. Mediana de edad: 8,5 meses (RIC 4-21). Manifestaciones: meningitis (n = 5), neumonía (n = 6), celulitis (n = 2), artritis (n = 1). Nueve presentaron vacunación incompleta para Hib. Observamos un incremento de EI por Hi de 2,5 veces respecto a años previos. Estos datos sugieren el resurgimiento de Hib por la caída de las coberturas de vacunación y porque otras cepas de Hi no b están en aumento.

Post-Marketing Safety Surveillance of a Childhood Pentavalent Diphtheria-Tetanus-Acellular Pertussis-Polio and Haemophilus influenzae Type B (DTaP-IPV//Hib) Vaccine in South Korea.

INTRODUCTION: PENTAXIM™ (Sanofi), DTaP-IPV//Hib, a pentavalent combination vaccine for protection against diphtheria, tetanus, pertussis, poliomyelitis, and invasive infections caused by Haemophilus influenzae type b, has been licensed in South Korea by the Ministry of Food and Drug Safety (MFDS) on May 9, 2016, and is currently used in routine vaccination. The aim of this phase IV study, conducted as a post-licensure commitment in South Korea, was to evaluate the safety of the DTaP-IPV//Hib vaccine when administered in infants at 2, 4, and 6 months of age in the real-world clinical practice. METHODS: This multicenter, observational, post-marketing surveillance (PMS) study was conducted in real-world practice in South Korea. Infants aged 2 months or older were enrolled across seven centers from July 31, 2018 to February 11, 2020. The study outcomes included occurrence, time to onset, duration, intensity, and causality assessment (for unsolicited adverse events [AEs] only) for several pre-listed solicited injection-site and systemic reactions, unsolicited AEs, and serious adverse events (SAEs). RESULTS: Data from 619 participants were included in the safety analysis. Overall, 618 AEs were reported by 273 (44.1%) participants consisting of 121 solicited injection-site reactions (15.4%), 344 solicited systemic reactions (24.6%), and 153 unsolicited AEs (15.7%) of which, 124 were unexpected AEs (12.9%) (regardless of intensity). None of the unsolicited AEs were reported to have a causal relationship with the study vaccine. One SAE of pyrexia (solicited reaction) was reported. Most AEs were of mild intensity, and all participants recovered. CONCLUSION: This PMS study of the DTaP-IPV//Hib vaccine confirmed its safety profile in a real-life setting in South Korea and justified that the vaccine is well tolerated when used in infants aged 2 months or older for the primary series.

Niveles de protección contra Haemophilus influenzae tipo b en niños, adolescentes y adultos cubanos / Levels of protection against Haemophilus influenzae type b in Cuban children, adolescents and adults

La concentración de los anticuerpos contra el polisacárido capsular polirribosilribitol fosfato del Haemophilus influenzae tipo b se considera un buen indicador serológico para evaluar protección contra la enfermedad invasiva. Existen pocos reportes que estudien la inmunidad serológica en Cuba. El objetivo general de este estudio fue determinar los niveles de protección séricos contra Haemophilus influenzae tipo b en niños, adolescentes y adultos cubanos, en una muestra de 575 individuos. Se cuantificó la concentración de IgG anti-polirribosilribitol fosfato de Haemophilus influenzae tipo b mediante un inmunoensayo enzimático estandarizado y validado en el laboratorio de inmunología del Centro Nacional de Genética Médica, La Habana, Cuba. Se determinaron las concentraciones medias geométricas de anticuerpos y los niveles de protección frente a la enfermedad invasiva por Haemophilus influenzae tipo b. La concentración media geométrica de IgG anti-polirribosilribitol fosfato fue de 1,94 μg/mL (IC95 por ciento 1,80; 2,08) y fue mayor en el grupo de 16 a 22 años. El porcentaje con protección de larga duración fue mayor para el sexo femenino que para el masculino (82,2 por ciento vs 71,4 por ciento; p=0,0339) entre los que poseían inmunidad natural. El grupo de sujetos nacidos en el periodo en que se vacunó con la vacuna conjugada cubana QUIMI-HIB® presentó concentraciones medias geométricas superiores (2,75 μg/mL, IC95 por ciento 2,00; 3,79). El 99,1 por ciento de los participantes presentó protección frente a la enfermedad invasiva por Haemophilus influenzae tipo b, el 19,8 por ciento a corto plazo y el 79,3 por ciento protección de larga duración. El inmunoensayo validado para la cuantificación de IgG anti-polirribosilribitol fosfato podría emplearse en estudios de seroprevalencia. En los sujetos estudiados, se encontró un predominio de elevadas concentraciones de IgG anti- polirribosilribitol fosfato del Haemophilus influenzae tipo b que confieren protección de larga duración(AU)

The levels of antibodies directed against the capsular polysaccharide polyribosylribitol phosphate of Haemophilus influenzae type b are considered a good serological indicator to assess the immunity against invasive disease. In Cuba, there are few reports that study serological immunity. The general objective was to determine serum protection levels against Haemophilus influenzae type b in Cuban children, adolescents and adults, in a sample of 575 Cuban individuals. The concentration of IgG against Haemophilus influenzae type b was quantified by means of an indirect ELISA standardized and validated in the immunology laboratory of the National Center of Medical Genetics, Havana, Cuba. The geometric mean concentration of IgG anti- polyribosylribitol phosphate and the levels of protection against invasive Haemophilus influenzae type b disease were determined. The geometric mean concentration of IgG anti- polyribosylribitol phosphate was 1.94 μg/mL (95percentCI 1.80;2.08) and the group from 16 to 22 years old presented the highest. Among those with natural immunity, the percentage with long-term protection was higher for females vs. males (82.2percent vs. 71.4percent; p=0.0339). The group of subjects born in the period in which they were vaccinated with the Cuban conjugate vaccine QUIMI-HIB® presented higher geometric mean concentration (2.75 μg/mL, CI95percent 2.00; 3.79). The 99.1percent of the participants had protection against invasive Haemophilus influenzae type b disease, 19.8percent short-term and 79.3percent long-term protection. The ELISA for the quantification of anti- Haemophilus influenzae type b IgG antibodies, developed and validated, could be used in seroprevalence studies. In the subjects studied, there was a predominance of high IgG anti- Haemophilus influenzae type b polyribosylribitol phosphate concentration values that confer long-term protection(AU)

Quantitative determination of cyanide residues in polysaccharide-protein conjugate vaccines based on flow injection analysis(FIA) with amperometric detector / 中国生物制品学杂志

@#Objective To develop and verify a method for determination of cyanide residues in polysaccharide-protein conjugate vaccines based on flow injection analysis(FIA)with amperometric detector.Methods After removing macromolecular substances in the samples by ultrafiltration,the cyanide residues were determined by a 3700 automatic chemical analyzer with the injection time of 35 s,injection volume of 200 μL,pump speed of 40%,sample cycle time of 140 s,ultraviolet wavelength of 312 nm and an Ampere detector.The developed method was verified for the specificity,matrix effect,linear range,limit of detection(LOD),limit of quantitation(LOQ),accuracy,presicion and stability.The cyanide residues in the polysaccharide derivative bulk(13 batches)and conjugate bulk(21 batches)of Haemophilus influenzae type b conjugate vaccine and group A and C meningococcal conjugate vaccine produced by 5 manufacturers were determined by the developed method.Results Blank samples showed no interference to detection;The recoveries of the matrix effector solution of Haemophilus influenzae type b conjugate vaccine polysaccharide derivative and conjugate bulk,group A and C meningococcal conjugate vaccine polysaccharide derivative and conjugate bulk were 97.4%,102.4%,96.8% and 99.8% respectively,with all CV values less than 15%;In the range of 0.312 5 ～ 80 ng/mL,cyanogroup concentration showed a good linear relationship with peak height with a regression equation of y = 133.13 x + 57.556,R2= 0.999 1;The LOD was 0.2 ng/mL,and the LOQ was 0.6 ng/mL.The average recoveries of the control solution were 108.9%,106.5%,103.5% respectively with RSD value of 6.4% in the groups added with 5,10 and 20 ng/mL of cyanogroup and the CV values of precision verification were all less than 15%;The average concentrations of the control solution injected 20 times continuously were 76,38,18and 5 ng/mL with all CV values less than 15%,when cyanogroup concentration was 80,40,20 and 5 ng/mL,respectively.Cyanide residues were detected in 13 batches of derivative bulk samples,while not in 2 batches of 21 batches of polysaccharide conjugate bulk samples,and were detected in the others.Conclusion The developed method had good accuracy,precision and stability,which might be applied to the quantitative determination of cyanide residues in polysaccharideprotein conjugate vaccines.

Inhibition of the different complement pathways has varying impacts on the serum bactericidal activity and opsonophagocytosis against Haemophilus influenzae type b.

Defense against Haemophilus influenzae type b (Hib) is dependent on antibodies and complement, which mediate both serum bactericidal activity (SBA) and opsonophagocytosis. Here we evaluated the influence of capsule-specific antibodies and complement inhibitors targeting the central component C3, the alternative pathway (AP; fB, fD), the lectin pathway (LP; MASP-2) and the terminal pathway (C5) on both effector functions. Findings may be relevant for the treatment of certain diseases caused by dysregulation of the complement system, where inhibitors of complement factors C3 or C5 are used. Inhibitors against other complement components are being evaluated as potential alternative treatment options that may carry a reduced risk of infection by encapsulated bacteria. Serum and reconstituted blood of healthy adults were tested for bactericidal activity before and after vaccination with the Hib capsule-conjugate vaccine ActHIB. Most sera had bactericidal activity prior to vaccination, but vaccination significantly enhanced SBA titers. Independently of the vaccination status, both C3 and C5 inhibition abrogated SBA, whereas inhibition of the LP had no effect. AP inhibition had a major inhibitory effect on SBA of pre- vaccination serum, but vaccination mitigated this inhibition for all disease isolates tested. Despite this, SBA-mediated killing of some Hib isolates remained retarded. Even for the most serum-resistant isolate, SBA was the dominating defense mechanism in reconstituted whole blood, as addition of blood cells to the serum did not enhance bacterial killing. Limited Fc receptor-mediated opsonophagocytosis was unmasked when bacterial killing by the membrane attack complex was blocked. In the presence of C3 or C5 inhibitors, addition of post-vaccination, but not of pre-vaccination serum to the blood cells triggered opsonophagocytosis, leading to suppression of bacterial multiplication. Taken together, our data indicate that for host defense against Hib, killing by SBA is more efficient than by blood cell opsonophagocytosis. However, additional defense mechanisms, such as bacterial clearance by spleen and liver, may play an important role in preventing Hib-mediated sepsis, in particular for Hib isolates with increased serum-resistance. Results indicate potentially improved safety profile of AP inhibitors over C3 and C5 inhibitors as alternative therapeutic agents in patients with increased susceptibility to Hib infection.

Vaccine Uptake to Prevent Meningitis and Encephalitis in Shanghai, China.

Multiple vaccines may prevent meningitis and encephalitis (M/E). In China, the meningococcal vaccine and Japanese encephalitis vaccine (JEV) have been included in the expanded program of immunization (EPI). The pneumococcal vaccine, Haemophilus influenzae type b (Hib) vaccine, rotavirus vaccine, and enterovirus 71 (EV-71) vaccine are non-EPI vaccines and are self-paid. We aim to investigate the uptake of these M/E vaccines in children and the related knowledge and health beliefs among family caregivers. A total of 1011 family caregivers with children aged 1-6 years in Shanghai, China were included in the study. The uptake of the pneumococcal vaccine, Hib-containing vaccine, rotavirus vaccine, and EV-71 vaccine remained at 44.0-48.1% in children, compared with the higher uptake of the meningococcal vaccine (88.8%) and JEV (87.1%). Moreover, family caregivers had limited knowledge on the M/E pathogens and possible vaccines. Their health beliefs were moderate to high. Then, a health belief model (HBM) and a structural equation model were established. The uptake of four non-EPI vaccines was significantly influenced by family income (ß = 0.159), knowledge (ß = 0.354), self-efficacy (ß = 0.584), and perceived susceptibility (ß = 0.212) within an HBM. Therefore, it warrants further improving the uptake rate for these non-EPI vaccines to prevent potential M/E in children. A specific health promotion may empower the caregivers' decision-making on childhood vaccination.

Monitoring bromide loss in bromoacetyl-derivatized polyribosylribitol polysaccharide in Haemophilus influenzae type b for PedvaxHIB® by capillary electrophoresis and NMR spectroscopy.

PedvaxHIB® is an effective pediatric vaccine for protecting infants from invasive gram-negative bacterium Haemophilus influenzae type b. It is a highly purified capsular polysaccharide, polyribosylribitol phosphate that is covalently linked to an outer membrane protein complex of Neisseria meningitidis. PRP is first derivatized with an organic linker, followed by the coupling of a butadiamine group, and then at the end terminal, a bromoacetyl group is attached for conjugation with thiolated OMPC. The stability of the bromide group in derivatized PRP is monitored by two different methods, capillary electrophoresis and NMR spectroscopy. The loss of the bromide group is detected by measuring the amount of free bromide ion liberated using capillary electrophoresis and by observing a change in amide proton peaks near the bromide group using NMR. The two methods give similar rate hydrolysis results, therefore both can be employed as quick stability tools for bromoacetylation PRP content during manufacturing.

Determination of ribose and phosphorus contents in Haemophilus influenzae type b capsular polysaccharide by a quantitative NMR method using a single internal standard.

The ribose and phosphorus contents in Haemophilus influenzae type b (Hib) capsular polysaccharide (CPS) are two important chemical indexes for the development and quality control of Hib conjugate vaccine. A quantitative 1H- and 31P-NMR method using a single internal standard was developed for simultaneous determination of ribose and phosphorus contents in Hib CPS. Hexamethylphosphoramide (HMPA) was successfully utilized as an internal standard in quantitative 1H-NMR method for ribose content determination. The ribose and phosphorus contents were found to be affected by the concentration of polysaccharide solution. Thus, 15-20 mg·L-1 was the optimal concentration range of Hib CPS in D2O solution for determination of ribose and phosphorus contents by this method. The ribose and phosphorus contents obtained by the quantitative NMR were consistent with those obtained by traditional chemical methods. In conclusion, this quantitative 1H- and 31P-NMR method using a single internal standard shows good specificity, accuracy and precision, providing a valuable approach for the quality control of Hib glycoconjugate vaccines.

Evaluating vaccination coverage and timeliness in American Indian/Alaska Native and non-Hispanic White children using state immunization information system data, 2015-2017.

Comprehensive estimates of vaccination coverage and timeliness of vaccine receipt among American Indian/Alaska Native (AI/AN) children in the United States are lacking. This study's objectives were to quantify vaccination coverage and timeliness, as well as the proportion of children with specific undervaccination patterns, among AI/AN and non-Hispanic White (NHW) children ages 0-24 months in Montana, a large and primarily rural U.S. state. Data from Montana's immunization information system (IIS) for children born 2015-2017 were used to calculate days undervaccinated for all doses of seven recommended vaccine series. After stratifying by race/ethnicity, up-to-date coverage at key milestone ages and the proportion of children demonstrating specific patterns of undervaccination were reported. Among n = 3,630 AI/AN children, only 23.1% received all recommended vaccine doses on-time (i.e., zero days undervaccinated), compared to 40.4% of n = 18,022 NHW children (chi-square p < 0.001). A greater proportion of AI/AN children were delayed at each milestone age, resulting in lower overall combined 7-vaccine series completion, by age 24 months (AI/AN: 56.6%, NHW: 64.3%, chi-square p < 0.001). As compared with NHW children, a higher proportion of AI/AN children had undervaccination patterns suggestive of structural barriers to accessing immunization services and delayed starts to vaccination. More than three out of four AI/AN children experienced delays in vaccination or were missing doses needed to complete recommended vaccine series. Interventions to ensure on-time initiation of vaccine series at age 2 months, as well initiatives to encourage completion of multi-dose vaccine series, are needed to reduce immunization disparities and increase vaccination coverage among AI/AN children in Montana.

Caracterización del polirribosilribitol fosfato por cromatografía de exclusión molecular de alta eficacia con detección ultravioleta / Characterization of polyribosylribitol phosphate by high efficiency size exclusion chromatography with ultraviolet detection

Haemophilus influenzae tipo b es un importante patógeno del hombre causante de varias de las enfermedades invasivas en niños menores de cinco años, contra el cual fueron autorizadas las vacunas glicoconjugadas a partir del polirribosilribitol fosfato. Quimi-Hib® es la primera y única vacuna contra este patógeno que utiliza el polisacárido obtenido por síntesis química. El Ingrediente Farmacéutico Activo es producido por el Centro de Ingeniería Genética y Biotecnología y se obtiene a partir de su conjugación al toxoide tetánico. En el presente reporte se hizo una caracterización del polirribosilribitol fosfato mediante la técnica de cromatografía de exclusión molecular de alta eficacia con detección ultravioleta a 215 nm. En el estudio se evaluaron tres lotes y se determinó el perfil de elución en una columna SuperdexTM 75 10/300 GL Increase con un porciento de pureza de 77,42 ± 8,97 y una masa molar promedio de 7.381 Da ± 210,93. La principal impureza presente en el polirribosilribitol fosfato es el dimetilsulfóxido, disolvente utilizado en la reacción de activación con el éster N-hidroxisuccinimidilo del ácido β-maleimidopropiónico. El polirribosilribitol fosfato se purificó por filtración con un Amicon Ultra-15 de 2.000 Da hasta una pureza de 99,1 por ciento y se conjugó al toxoide tetánico. El rendimiento de la reacción de conjugación con el polisacárido purificado fue de 30,0 por ciento 1,77 el cual no muestra diferencias significativas con el control que fue 33,7 por ciento ± 3,57 demostrándose que el dimetilsulfóxido no afecta el desempeño de la reacción de conjugación(AU)

Haemophilus influenzae type b is an important human pathogen causing some invasive diseases in children less than five years of age. Glycoconjugate vaccines based on polyribosylribitol phosphate have been licensed against this bacterium. Quimi-Hib® is the first and only vaccine against this pathogen using the chemically synthesized polysaccharide. The Active Pharmaceutical Ingredient is produced by the Center for Genetic Engineering and Biotechnology and is obtained from its conjugation to tetanus toxoid. In the present report a characterization of polyribosylribitol phosphate was performed by high performance molecular exclusion chromatography with ultraviolet detection at 215 nm. Three batches were evaluated in the study and the elution profile was determined on a SuperdexTM 75 10/300 GL Increase column with a purity percentage of 77.42 ± 8.97 and an average molecular weight of 7,381 Da ± 210.93. The main impurity present in polyribosylribitol phosphate was dimethylsulfoxide, the solvent used in the activation reaction with N-hydroxysuccinimidyl ester of β-maleimidopropionic acid. Polyribosylribitol phosphate was purified by filtration using a 2,000 Da cut-off Amicon Ultra-15 to a purity of 99.1 percent and conjugated to tetanus toxoid. The yield of the conjugation reaction with the purified polysaccharide was 30.0 percent ± 1.77 which shows no significant difference with the control which was 33.7 percent ± 3.57 demonstrating that dimethylsulfoxide does not affect the performance of the conjugation reaction(AU)