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.

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.

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)

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)

Epiglotitis por Haemophilus influenzae tipo b en la era de la vacunación: caso clínico pediátrico / Epiglottitis due to Haemophilus influenzae type b in the vaccination era: pediatric clinical case

La epiglotitis aguda infecciosa es infrecuente en la actualidad, debido a la vacunación contra su principal agente etiológico, el Haemophilus influenzae b. Se requiere alto índice de sospecha ante el cuadro clínico de dificultad respiratoria, estridor, disfonía y fiebre. Se presenta a un niño de 2 años, previamente sano, con esquema de vacunas completas, con dificultad respiratoria aguda y estridor laríngeo, en el que, al momento de realizar la intubación, se realizó el diagnóstico de epiglotitis aguda. Con hemocultivos positivos para Haemophilus influenzae b, cumplió 13 días de tratamiento con ceftriaxona, con hemocultivos de control y cultivo de líquido cefalorraquídeo negativo.

Acute infectious epiglottitis is infrequent at present due to vaccination for its main etiologic agent, Haemophilus influenzae b (Hib). It must be taken into account when we make a differential diagnosis in a child whose clinical symptoms are respiratory distress, stridor, dysphonia and fever. We report a 2-year-old child, previously healthy, whose vaccination calendar was complete, and whose clinical presentation included respiratory distress and stridor; at the moment of the intubation the laryngoscopy showed an acute epiglottitis. Blood cultures were taken, which were positive for Hib. He was treated with ceftriaxone during 13 days, and the control blood cultures and cerebrospinal fluid were negative.

Meningitis por Haemophilus influenzae b: ¿estamos ante una reemergencia? 24 años de experiencia en un hospital pediátrico / Haemophilus influenzae type B meningitis: Is there a re-emergence? 24 years of experience in a children's hospital

Introducción. Haemophilus influenzae b era la principal causa de meningitis bacteriana en menores de 5 años. Después de la introducción de la vacuna al calendario (1998), se observó un descenso significativo de la incidencia, pero, en los últimos años, hubo un aumento. Los objetivos de este estudio fueron describir las características y analizar la curva epidémica de los casos de meningitis por Haemophilus influenzae b (MHib) comparando los períodos pre- y posvacunación. Material y métodos. Estudio de series temporales. Se incluyeron todos los pacientes internados por MHib en el Hospital de Niños "R. Gutiérrez" (enero de 1992-mayo de 2016). Se compararon las tasas de hospitalización antes (prevacunación) y después (posvacunación) de la introducción de la vacuna. Se dividió la etapa posvacunación en tres períodos similares. Resultados. Fueron admitidos 85 pacientes con MHib (73,3% prevacunación). Las características clínicas y sociodemográficas de los casos en ambos períodos no mostraron diferencias. Prevacunación: 10,5 casos/año; y posvacunación: 0,7 casos/año. A partir de 2014, se observó un aumento. Tasa de letalidad: 4,8% (todos prevacunación). Datos posvacunación (n= 15): 40% del esquema primario completo, 40% del esquema atrasado para la edad. Reducción global de la tasa hospitalaria de MHib de 89,8% (IC 95%: -82,79-93,96%; p < 0,001) en el período posvacunación. Al analizar los diferentes períodos posvacunación, se observa una caída en la reducción a lo largo del tiempo. Conclusiones. Se observó una disminución muy importante de las hospitalizaciones por MHib pos introducción de la vacuna, pero, en los últimos años, se evidenció un aumento de estos casos sin modificaciones en las características de los pacientes.

Introduction. Haemophilus influenzae type B (Hib) used to be the main cause of bacterial meningitis in children younger than 5 years old. Following the introduction of the Hib vaccine in the immunization schedule (1998), its incidence reduced significantly but it has increased over the last years. The objectives of this study included describing the characteristics and analyzing the epidemic curve of Haemophilus influenzae type B (Hib) meningitis by comparing the pre- and postimmunization periods. Material and methods. Time-series study. All patients hospitalized with Hib meningitis at Hospital de Niños "R. Gutiérrez" (January 1992-May 2016). Hospitalization rates were compared before (pre-immunization) and after (post-immunization) the introduction of the Hib vaccine. The post-immunization period was divided into three similar periods. Results. Eighty-five patients with Hib meningitis were admitted (73.3% in the pre-immunization period). No differences were observed in relation to the clinical and sociodemographic characteristics of cases in both periods. Pre-immunization: 10.5 cases/year; postimmunization: 0.7 cases/year. As of 2014, the rate has increased. Lethality rate: 4.8% (all preimmunization). Post-immunization data (n= 15): 40% had completed their primary immunization schedule, 40% were delayed on the immunization schedule for their age. Overall reduction in the hospital rate of Hib meningitis by 89.8% (95% confidence interval: -82.79-93.96%, p < 0.001) in the post-immunization period. The analysis of the different post-immunization periods shows a decline in reduction over time. Conclusions. A very significant reduction in hospitalizations due to Hib meningitis was observed after the Hib vaccine was introduced; however, over the past years, the number of cases has increased although no changes have been observed in patient characteristics.

Evaluation of Antibodies Against Haemophilus influenzae Type b in Korean Adults

PURPOSE: After the introduction of Haemophilus influenzae type b (Hib) vaccine in 1995 in Korea, it was included in the national immunization program in 2013. In the post-Hib vaccine era, some studies in other countries reported that invasive Hib disease affects adults, especially the elderly and immunocompromised persons, more often than it affects children. To evaluate disease susceptibility, quantitative and qualitative analysis of anti-polyribosylribitol phosphate (PRP) antibodies were carried out in Korean adults aged 20 to 85 years. METHODS: Sera were collected from 39 healthy adults (20 to 50 years of age) and from 30 elderly adults (75 to 85 years of age) who did not have immune-compromising conditions. The concentration of anti-PRP immunoglobulin G (IgG) and serum bactericidal indices (SBIs) were measured by enzyme-linked immunosorbent assay and serum bactericidal assay. RESULTS: Geometric mean concentrations of anti-PRP IgG and geometric mean SBIs were 0.88 µg/mL (95% confidence interval [CI], 0.17 to 3.85) and 354 (95% CI, 50 to 2,499) in young adults and 1.67 µg/mL (95% CI, 0.53 to 5.24) and 449 (95% CI, 146 to 1,376) in elderly adults, respectively. When the threshold of seropositivity for anti-PRP IgG was applied as 0.15 or 1.0 µg/mL, which is the protective antibody level in children, seropositive rates were 87.2% or 53.8% in young adults and 100% or 60% in elderly adults. The seropositivity rates of the SBI (SBI ≥4) were 82.1% and 100% in the groups, respectively. CONCLUSIONS: Most subjects in the adult and elderly adult groups display immunity to Hib based on quantitative and qualitative antibody levels, but not all. Because high immunization and low Hib circulation rates may reduce the natural Hib immunity in the population, monitoring Hib immunity as well as disease are needed continuously.

Effect ofβ-defensin 2 gene silencing on the inflammatory response induced by Haemophilus influenzae type B combined vaccine immunization in rats / 中华传染病杂志

Objective To investigate the effect of β‐defensin 2 (rBD‐2 ) silencing on the inflammatory response induced by Haemophilus influenzae type B vaccine immunization in rats .Methods A total of 144 SPF Sprague Dawley (SD) rats were divided into four groups .Group 1 were immunized with Haemophilus influenzae type B vaccine .Group 2 were immunized with Haemophilus influenzae type B vaccine and administered with lentivirus Lv‐shRNA‐rBD‐2 by intratracheal instillation .Group 3 were administered with the lentivirus Lv‐shRNA‐rBD‐2 by intratracheal instillation .Group 4 were blank controls .Each group was set with 12 rats . The serum was collected at 12 ,24 and 72 hours after immunization ,and tumor necrosis factor (TNF)‐α,interleukine (IL)‐1β and IL‐10 were assessed by enzyme‐linked immuno sorbent assay (ELISA ) .Expression levels of rBD‐2 in lung tissues of rats were measured by western blotting . Results The recombinant virus was successfully produced by a lipofectmaine transfection method .At 12 ,24 ,and 72 h of immunization ,serum levels of TNF‐αof rats in group 1 were (82 .0 ± 8 .0) ,(155 .0 ± 18 .2) ,and (272 .0 ± 32 .5) pg/mL ,respectively ,which were all higher than those in group 4 ([55 .0 ± 6 .2] ,[52 .0 ± 5 .8] ,and [56 .0 ± 4 .8] pg/mL ,respectively ;t=16 .034 ,P=0 .043 ;t=12 .411 ,P=0 .035 ;t=10 .530 ,P=0 .018 ,respectively) .Serum levels of TNF‐αat 12 ,24 ,and 72 h of immunization in group 2 were (66 .0 ± 8 .2) ,(90 .0 ± 12 .6) ,and (108 .0 ± 13 .6) pg/mL ,respectively ,which were all significantly lower than group 1 (t=12 .115 ,P=0 .039 ;t=12 .830 , P=0 .033 ;t=15 .522 ,P=0 .012 ,respectively) .At each time point ,serum levels of IL‐1βand IL‐10 in group 1 were all significantly higher than those in group 4 (IL‐1β:t=18 .032 , P=0 .048 ;t=15 .824 , P=0 .039 ;t=13 .518 , P=0 .021 ,respectively ;IL‐10 :t=15 .410 , P=0 .045 ;t=14 .294 , P=0 .032 ;t=13 .375 ,P=0 .013 ,respectively) .Serum levels of IL‐1βand IL‐10 at each time points in group 2 were all significantly lower than those in group 1 (IL‐1β:t=19 .012 , P=0 .043;t=16 .991 , P=0 .034;t=14 .862 , P=0 .027 ,respectively ;IL‐10 :t=15 .134 , P=0 .048 ;t=15 .264 , P=0 .036 ;t=11 .408 , P=0 .024 ,respectively) .Seventy‐two hours after immunization of SD rats ,the relative content of rBD‐2 protein in lung tissue of rats significantly increased .Protein level in group 1 was significantly higher than that in group 4 (t=10 .582 ,P=0 .035) ,while protein level in group 2 was significantly lower than that in group 1 (t=13 .250 ,P=0 .027) .Conclusions rBD‐2 gene silencing can improve the inflammatory response induced by Haemophilus inf luenzae type B combined vaccine in rats.

Prospective multi-centre sentinel surveillance for Haemophilus influenzae type b & other bacterial meningitis in Indian children.

Background & objectives: Haemophilus influenzae type b (Hib) is one of the leading bacterial causes of invasive disease in populations without access to Hib conjugate vaccines (Hib-CV). India has recently decided to introduce Hib-CV into the routine immunization programme in selected States. Longitudinal data quantifying the burden of bacterial meningitis and the proportion of disease caused by various bacteria are needed to track the impact of Hib-CV once introduced. A hospital-based sentinel surveillance network was established at four places in the country and this study reports the results of this ongoing surveillance. Methods: Children aged 1 to 23 months with suspected bacterial meningitis were enrolled in Chennai, Lucknow, New Delhi, and Vellore between July 2008 and June 2010. All cerebrospinal fluid (CSF) samples were tested using cytological, biochemical, and culture methods. Samples with abnormal CSF (≥10 WBC per μl) were tested by latex agglutination test for common paediatric bacterial meningitis pathogens. Results: A total of 708 patients with abnormal CSF were identified, 89 of whom had a bacterial pathogen confirmed. Hib accounted for the majority of bacteriologically confirmed cases, 62 (70%), while Streptococcus pneumoniae and group B Streptococcus were identified in 12 (13%) and seven (8%) cases, respectively. The other eight cases were a mix of other bacteria. The proportion of abnormal CSF and probable bacterial meningitis that was caused by Hib was 74 and 58 per cent lower at Christian Medical College (CMC), Vellore, which had a 41 per cent coverage of Hib-CV among all suspected meningitis cases, compared to the combined average proportion at the other three centres where a coverage between 1 and 8 per cent was seen (P<0.001 and P= 0.05, respectively). Interpretation & conclusions: Hib was found to be the predominant cause of bacterial meningitis in young children in diverse geographic locations in India. Possible indications of herd immunity was seen at CMC compared to sites with low immunization coverage with Hib-CV. As Hib is the most common pathogen in bacterial meningitis, Hib-CV would have a large impact on bacterial meningitis in Indian children.

Prevención / Prevention

En la actualidad, se cuenta con un grupo de vacunas desarrolladas para la prevención de infecciones bacterianas, incluso para realizar profilaxis. En la década de los 80 del siglo XX apareció la primera vacuna contra Haemophilus influenzae tipo b que redujo y prácticamente eliminó la enfermedad invasiva por esta bacteria. A inicios del año 2000 se observó una dramática reducción de enfermedad invasiva por neumococo, gracias a la introducción de la vacuna PCV-7 contra este germen. Sin embargo, surgieron serotipos no incluidos en esta vacuna, por lo cual se desarrollaron la PHiD-CV 10 y la PCV-13, con 10 y 13 serotipos, respectivamente. En contra del meningococo se han desarrollado vacunas polisacáridas que han demostrado efectividad, así como las conjugadas que pueden ser monovalentes y tetravalentes. La quimioprofilaxis se indica en casos específicos que se explican en forma detallada en este capítulo

Nowadays, several vaccines have been developed for the prevention of bacterial infections, and also for prophylaxis. In the 80's of the twentieth century came the first vaccine against Haemophilus influenzae type b, which reduced and virtually eliminated invasive disease by this bacterium. In early 2000, there was a dramatic reduction in invasive pneumococcal disease, with the introduction of PCV-7 vaccine against this germ. However, there were serotypes not included in the vaccine, which was developed by the Phido-CV 10 and PCV-13, 10 and 13 serotypes, respectively. Against meningococcus, polysaccharide vaccines have been developed that have demonstrated effectiveness, as well as the conjugate vaccines, which may be monovalent and tetravalent. Chemoprophylaxis is indicated in specific cases that are reviewed in detail in this chapter

Multi-center surveillance for pneumonia & meningitis among children (<2 yr) for Hib vaccine probe trial preparation in India.

Background & objectives: Severe clinical pneumonia and meningitis caused by Haemophilus influenzae type b in children less than 5 yr old is preventable by use of Hib vaccine. However, data on Hib burden in India are limited. To support an evidence-based decision for Hib vaccine introduction in India, a vaccine probe study was planned. This paper presents the results of the preparatory phase for such a study, which aimed to determine the feasibility of conducting a randomized vaccine probe study and to estimate the incidence of all causes of pneumonia and meningitis. The preparatory study included population-based, hospital-based and carriage surveillance. Methods: Children aged 18-24 months and were enrolled at PGIMER, Chandigarh, CMC, Vellore and NICED, Kolkata, from July 2005 to December 2006. At the time of enrollment, parents were informed about the signs and symptoms of pneumonia and meningitis, and were encouraged to take the child to study hospitals for treatment. Hospitalized children less than two years of age suspected of having pneumonia and/or meningitis were enrolled in study hospitals, whether or not they were from the cohort population. Patients were examined clinically and received chest radiograph for suspected cases of pneumonia or lumbar puncture for suspected cases of meningitis. Blood culture was done for both pneumonia and meningitis patients. Cerebrospinal fluid (CSF) was tested for biochemistry, culture, latex agglutination test and polymerase chain reaction. Nasopharyngeal swabs were collected from healthy children less than 2 yr of age at immunization clinics to estimate Hib carriage. Results: A cohort of 17,951 children were recruited for the population-based arm. The incidence of severe clinical pneumonia ranged from 2717 to 7890 per 100,000 child-years of observation; suspected meningitis ranged from 1971 to 2433 per 100,000 child-years of observation. In the hospital-based study 7/90 (7.8%), 29/98 (29.6%) and 38/181 (21.0%) of CSF samples with cell count ≥100 WBCs/mm3 were purulent at Chandigarh, Kolkata and Vellore respectively. Of these purulent CSF samples, Hib was detected in 2, 6 and 11 cases, respectively. The Hib nasopharyngeal carriage prevalence ranged from 6.0 - 7.6 per cent. Interpretation & conclusions: Incidence of severe clinical pneumonia is comparable with other studies from India but that of suspected meningitis is higher. Although rates of Hib meningitis cannot be calculated from a hospital-based study, there is evidence of Hib meningitis in these study settings. Hib carriage prevalence indicates that Hib is present and circulating in these study areas. There is a significant burden of pneumonia and meningitis among children in India. Continued strengthening of laboratory capacity and bacterial surveillance systems are necessary.

Pattern of functional antibody activity against Haemophilus influenzae type b (Hib) in infants immunized with diphtheria-tetanus-pertussis/Hib Brazilian combination vaccine

We evaluated the functional activity of Haemophilus influenzae B (Hib) antibodies elicited in a group of infants immunized with the diphtheria-tetanus-pertussis vaccine combined with an Hib vaccine produced totally in Brazil after technological transfer of Hib vaccine production from Glaxo SmithKline, Belgium. Blood samples from immunized infants (N = 985) were collected for the determination of Hib antibodies. Total Ig and IgM and IgG subclasses of antibodies against polyribosyl ribitol phosphate (PRP) were analyzed by ELISA. Almost all vaccinees (97.56 percent, 961/985) developed a strong anti-PRP IgG antibody response (¡Ý1.0 ¦Ìg/mL), while an anti-PRP IgM response was observed in 64.24 percent (634/985) of them (¡Ý0.15 ¦Ìg/mL). Only 18.88 percent (186/985) of the infants in the group with high PRP antibody IgG concentrations (¡Ý1.0 ¦Ìg/mL) developed a high IgM antibody response. Anti-PRP IgG antibody levels were significantly higher than anti-PRP IgM. These results demonstrate the predominance of IgG antibodies over IgM antibodies in response to PRP, with a ratio of 17:1. IgG antibodies were predominantly of the IgG1 subclass. An increase in IgG avidity was also observed during the course of immunization.

Impact of Haemophilus influenzae type b conjugate vaccine on bacterial meningitis in the Dominican Republic / Impacto de la vacuna conjugada contra Haemophilus influenzae tipo b sobre la meningitis bacteriana en la República Dominicana

OBJECTIVES: Widespread use of Haemophilus influenzae type b (Hib) vaccines has dramatically reduced the burden of Hib disease throughout the Americas. Few studies have evaluated the impact of Hib vaccination on non-culture-confirmed disease. This study analyzed trends in probable bacterial meningitis before and after the introduction of Hib vaccine in the Dominican Republic and estimated vaccine effectiveness against Hib meningitis. METHODS: Meningitis cases among children < 5 years of age were identified from admission records of the main pediatric hospital in Santo Domingo during 1998-2004. Laboratory criteria were used to classify meningitis cases with probable bacterial etiology; confirmed cases had positive bacterial culture or antigen detection in cerebrospinal fluid. Cumulative incidence rates of confirmed and probable bacterial meningitis were calculated for children living in the National District. Confirmed cases of Hib meningitis were enrolled in a case-control study with age- and neighborhood-matched control children to calculate vaccine effectiveness. RESULTS: Before vaccine introduction, annual rates of meningitis with probable bacterial etiology were 49 cases per 100 000 children < 5 years old; Hib accounted for 60 percent of confirmed bacterial cases. During 2002-2004, after vaccine introduction, annual rates of probable bacterial meningitis were 65 percent lower at 16 cases per 100 000, and Hib accounted for 26 percent of confirmed cases. Rates of Hib meningitis and probable bacterial meningitis with no determined etiology declined by 13 and 17 cases per 100 000, respectively. CONCLUSIONS: Introduction of Hib vaccine substantially reduced the incidence of confirmed and probable bacterial meningitis in the Dominican Republic. The estimated impact of Hib vaccination was twice as great when non-culture-confirmed disease was included.

OBJETIVOS: El uso generalizado de la vacuna contra Haemophilus influenzae tipo b (Hib) ha permitido reducir radicalmente la carga de enfermedad por Hib en las Américas. Pocos estudios han evaluado el impacto de la vacunación contra Hib sobre los casos no confirmados mediante cultivo. En este estudio se analizaron las tendencias en el número de casos probables de meningitis bacteriana antes y después de la introducción de la vacuna contra Hib en la República Dominicana y se estimó la eficacia de la vacuna contra la meningitis. MÉTODOS: Se identificaron los casos de meningitis en niños menores de 5 años a partir de los registros de ingreso del principal hospital pediátrico de Santo Domingo entre 1998 y 2004. Los casos de meningitis con probable etiología bacteriana se clasificaron según criterios de laboratorio; los casos confirmados contaban con cultivo bacteriano positivo o detección de antígenos específicos en el líquido cefalorraquídeo. Se calcularon las tasas de incidencia acumulada de casos confirmados y probables de meningitis en los niños que vivían en el Distrito Nacional. Los casos confirmados de meningitis por Hib se incorporaron a un estudio de casos y controles -pareados según la edad y el barrio de residencia- para calcular la eficacia de la vacuna. RESULTADOS: Antes de la introducción de la vacuna, la tasa anual de meningitis de posible etiología bacteriana era de 49 casos por 100 000 niños menores de 5 años; de los casos confirmados de origen bacteriano, 60 por ciento fue por Hib. En el período 2002-2004, después de la introducción de la vacuna, la tasa anual de meningitis de posible etiología bacteriana fue de 16 casos por 100 000, es decir 65 por ciento más baja, y 26 por ciento de los casos confirmados correspondieron a Hib. Las tasas de meningitis por Hib y de posible origen bacteriano de etiología desconocida se redujeron en 13 y 17 casos por 100 000, respectivamente. CONCLUSIONES: La introducción de la vacuna...

Placental transfer of Haemophilus influenzae type b antibodies in malnourished pregnant women

This study evaluated the vaccination response to Haemophilus influenzae type b (Hib) in malnourished pregnant women (MN), cord blood (CB) and in infants at two and six months of age for comparison with a control group (C). Twenty-eight malnourished pregnant women and 29 pregnant controls were immunized with conjugated Act-HIB® in the third trimester of pregnancy. Blood samples were collected from all before the immunization, during labor (post immunization), and from CB. All infants were immunized with Hib vaccine according to normal vaccine schedule and sera were collected at two and six months of age. Antibody levels to polyribosylribitol phosphate (PRP) were similar for both groups. Preimmunization: MN 1.94 µg/mL, C 1.68 µg/mL; post-vaccination: MN 18.53 µg/mL and C 17.55 µg/mL; in CB from MN 14.46 µg/mL and from C 17.04 µg/mL. Infants from MN and C mothers presented respectively at two months: 5.18 µg/mL and 8.60 µg/mL and at six months: MN 3.42 µg/mL and C 2.18 µg/mL. Antibody levels were similar in both groups studied (p = 0.485), however the vertical transmission rate was 14 percent lower in the MN pregnant group. Levels of antibodies > 0.15 µg/mL were found in all newborns from the MN pregnant group. Pregnant MN presented an immunological response to Hib vaccine similar to group C, however, vertical transmission rate of antibodies to PRP in the MN pregnant group was 14 percent lower than that in C, suggesting a less efficient passage of antibodies within this group.

Cost-Benefit Analysis of Haemophilus Influenzae Type B Immunization in Korea

An economic evaluation of Haemophilus influenzae type b (Hib) immunization was conducted to examine whether Hib immunization should be included in the Korea's national immunization program. The costs and benefits included direct and indirect values and an estimation of the economic efficiency. We determined that a universal Hib immunization program in Korea would prevent 17 deaths and 280 invasive Hib cases. When we assumed the one Hib immunization cost as 26,000 won, the national Hib immunization would cost 34.6 billion won. Costs for various Hib diseases were estimated at 26.8 billion won (11.8 billion won from direct costs and 14.9 billion won from indirect costs). A benefit-cost ratio of 0.77 showed that the economic efficiency of the integration of Hib immunization in Korea is low because of the low incidence rate of Hib disease and high price of vaccine. However, if the Hib immunization cost decrease to less than 20,000 won, a benefit-cost ratio increase to 1.0 and above, integrating Hib immunization into the national immunization program with economic efficiency can be considered.

Antibody prsistence after Haemophilus influenzae type b (Hib) primary vaccination and response to boosters in Korean children / 소아과

PURPOSE: Antibody persistence after primary series of Haemophilus influenzae type b (Hib) vaccine and responses to boosters are seldom studied in Korean children. We performed this study to evaluate the antibody titer in relation to booster immunization of Hib vaccine in Korean children. METHOD: One hundred forty four children aged 12-23 months were enrolled in three university hospitals. The immunogenicity of boosters with Hib vaccine was assessed in children previously primed with Hib vaccine. Antibody persistence was also assessed in children who had received 3 doses of Hib vaccine without a booster. Anti-polyribosylribitol phosphate (PRP) IgG antibody levels and bactericidal titers were determined by enzyme immunoassay and bactericidal assay at the Center for Vaccine Evaluation and Study, Medical Research Institute, Ewha Womans University. RESULTS: Prior to a booster in the second year of life, geometric mean antibody concentrations were 2.39 microgram/mL and the percent of subjects who had a anti-PRP antibody level > or =1 microgram/mL was 68.6%. After boosting, antibody concentration was 19.09 microgram/mL and the percent of subjects who had a anti- PRP antibody level > or =1 microgram/mL was 96.5%, which reflects previous immune priming. In subjects who had finished primary immunization only, the bactericidal titer was 3,946 and in subjects who had a booster, it was 11,205. Anti-PRP antibody level was correlated with serum bactericidal titer. CONCLUSION: Many children aged 12-23 month old still had protective antibodies after recommended primary immunization only. A booster dose seemed to induce good anamnestic antibody responses in Korean children.

Validation of enzyme immunoassay for the quantitative measurement of human IgG antibodies specific for Haemophilus influenzae Type b capsular polysaccharide / 소아과

PURPOSE: This study was conducted to validate enzyme immunoassay (EIA) for the quantitative measurement of human IgG antibodies specific for Haemophilus influenzae type b (Hib) capsular polysaccharide. METHOD: We evaluated specificity, repeatability, intermediate precision, accuracy, lower limit of quantification (LLOQ), and stability to validate standardized EIA for the quantitative measurement of human anti-polyribosylribitol phosphate (PRP) IgG antibodies. RESULTS: The results indicated that this EIA showed specificity to HbO-HA antigen and repeatability and intermediate precision were within acceptance criteria (repeatability: CV < or =15%, intermediate precision: CV < or =20%). The EIA-derived results from this laboratory were equivalent to those obtained by the standard radioactive antigen binding assay (RABA) for quantitation of anti-PRP antibodies in the 28 sera. Spiking recovery result was within acceptance criteria (100+/-20%). The precision and accuracy of samples in LLOQ were from -14.7 to -4.7% in nominal values, which were within acceptance criteria (precision: CV < or =25%, accuracy: +/-25%). Freeze-thaw stability and short term temperature stability were within +/-20% of acceptance criteria. CONCLUSIONS: The EIA which is performed at the Center for Vaccine Evaluation and Study Ewha Medical Research Institute, is an appropriate serologic assay which can be used for quantitation of anti-PRP IgG antibodies in human sera.

Present status and prospects of Haemophilus influenzae type b(Hib) immunization / 소아과

Haemophilus influenzae type b(Hib) conjugate vaccines prevent Hib disease in individuals and reduce the carriage and transmission of the organism in the community. The incidence of Hib disease has been decreased dramatically in a diverse range of countries through the use of a variety of conjugate vaccines and vaccine schedules. In some countries, the vaccine has caused a near-disappearance of invasive Hib disease through a combination of direct protection and herd immunity. The effectiveness of the vaccine was not modified by the type of conjugate vaccine, the number of doses given(two, three or four), age at first vaccination(two months, 42 to 90 days, three months) and whether the vaccine was tested in an industrialized or developing country. Over 15 years of international experience with vaccines has also demonstrated that they are safe. In 2004, Hib vaccines were adapted in routine immunization in 92 countries in the world. Decisions regarding the use of the Hib vaccine in routine immunization schedules depend not only on the effectiveness and efficacy of the vaccine but also on factors such as burden of disease, vaccine cost, and competing priorities. In Korea, Hib disease burden seemed to be lower than other developed countries(~10/100,000). Moreover Hib vaccines showed excellent immunogenicity in Korean children in many studies. Therefore, a potential approach to economize the cost of Hib vaccines could be to explore the possibilities of using reduced vaccine doses for immunization as some other countries.

Familial factor in contagiousness of Haemophilus influenzae type B meningitis in children

Seventy-nice pediatric patient - family pairs were detected for Hib or Hib-antigen. The study also examined 22 pairs of H. influenzae strains isolated from CSF of patients and from upper respiratory tract of the family members of the patients to determine serotype, biotype, presence of Beta-lactamase, PCR with Hib-specified primers, and PFGE with SmaI restriction enzyme. The results showed that 44.4% of the patients` families had Hib carriers; all of 22 H. influenzae isolated pairs from patients and their families had serotype b; 17 of 22 pairs had characteristics of biotype II; 16 of 22 pairs had Beta-lactamase; and 9 of 22 pairs had both the PCR pattern and PFGE pattern. Close contact with Hib carriers was a factor of Hib meningitis contagiousness in children under 5 years of age

Haemophilus influenzae type b (Hib) molecular relationship of Hib pathogenous strains isolated in Hanoi

34 Haemophilus influenzae type b (Hib) strains isolated from cerebrospinal fluids (CSFs) of meningitis patients at National Hospital of Pediatrics, Hanoi, between 11/2002 and 12/2003 were biotyped, serotyped and analyzed by using PCR with specific primers, Pulsed field gel electrophoresis (PFGE) with Smal restriction enzyme. The results showed that 24 of 34 Hib strains (70.6%) belong to biotype II; 8 of 34 (23.5%) belong to biotype I. PCR patterns with capsular polysaccharide type b specified primers of the 34 Hib strains were identical. DNA restriction patterns generated by PFGE (so-called PFGE patterns) of the 34 Hib strains were mainly distributed into 2 PFGE patterns. DNA restriction patterns had close relationship to biotype. The presence of PFGE patterns of Hib strains was not related to season