Il est recommande d'administrer aux nourrissons des leur naissance une dose de vaccin contre l'hepatite B (vaccin HepB) afin de prevenir une eventuelle transmission de la mere a l'enfant et l'infection chronique par le virus de l'hepatite B (VHB). Bien que les fabricants preconisent de maintenir le vaccin HepB a une temperature de 2 a 8 °C pendant sa distribution et sa conservation, la mise en evidence de la stabilite thermique des antigenes de surface du virus de l'hepatite B a encourage les recherches sur les possibilites d'utiliser ce vaccin apres un stockage ou une exposition a une temperature superieure ou egale a l'ambiante. La possibilite de stocker le vaccin HepB a la temperature ambiante permettrait son administration a la naissance aux nourrissons a domicile dans le cas des zones reculees ou dans des postes de sante non equipes d'un refrigerateur. Le present article examine les elements actuellement disponibles au sujet de la stabilite thermique de ce vaccin en cas de rupture de la chaine du froid pendant sa conservation. D'apres les rapports examines, les vaccins etudies etaient sans risque et efficaces, qu'ils aient ete stockes au froid ou en dehors de la chaine du froid. Les resultats d'etudes sur le terrain et en laboratoire confirment egalement que le HepB conserve son activite vaccinale apres une exposition a la chaleur. Les resultats de la fixation sur de nombreuses doses de vaccin HepB de divers dispositifs tres stables de controle de l'activite (mesurant l'exposition cumulee a la chaleur) viennent fortement etayer les politiques autorisant la conservation de ce vaccin en dehors de la chaine du froid, lorsque cette disposition favorise une meilleure couverture vaccinale des nouveaux-nes. La mise en place de cette pratique est donc recommandee afin d'etendre la couverture vaccinale des nouveaux-nes, notamment dans les zones rurales et eloignees. Il convient d'entreprendre en parallele un suivi et une evaluation pour confirmer l'absence de risque de cette disposition et estimer son cout, sa faisabilite et son effet sur la baisse des taux d'infection par le VHB. Entre temps, la publication par les fabricants de donnees confirmant l'activite des vaccins HepB actuellement disponibles apres une exposition a la chaleur pourrait renforcer la confiance dans l'utilisation d'etiquettes de controle de l'activite comme outil de gestion pour la conservation de ce vaccin en dehors de la chaine du froid.

The heat stability of hepatitis B vaccine (HepB vaccine) should enable its storage outside the cold chain (OCC), increasing access to the birth dose in areas lacking refrigeration. We compared the immunogenicity of a locally produced vaccine among infants who received three doses stored within the cold chain (n = 358) or for whom the first dose was stored OCC for up to one month (n = 748). Serum was collected from these infants at age 9-18 months. The vaccine was protective in 80.3% of all infants. There were no differences in the prevalence of a protective level of antibody or antibody titer among groups of infants according to storage strategy. Differences in antibody titer between certain groups of infants could be explained by different vaccination schedules. Where birth dose coverage will be improved, HepB vaccine can be taken OCC for up to one month without affecting its immunogenicity.

Administration of a birth dose of hepatitis B vaccine (HepB vaccine) to neonates is recommended to prevent mother-to-infant transmission and chronic infection with the hepatitis B virus (HBV). Although manufacturers recommend HepB vaccine distribution and storage at 2-8 degrees C, recognition of the heat stability of hepatitis B surface antigen stimulated research into its use after storage at, or exposure to, ambient or high temperatures. Storage of HepB vaccine at ambient temperatures would enable birth dosing for neonates delivered at home in remote areas or at health posts lacking refrigeration. This article reviews the current evidence on the thermostability of HepB vaccine when stored outside the cold chain (OCC). The reports reviewed show that the vaccines studied were safe and effective whether stored cold or OCC. Field and laboratory data also verifies the retained potency of the vaccine after exposure to heat. The attachment of a highly stable variety of a vaccine vial monitor (measuring cumulative exposure to heat) on many HepB vaccines strongly supports policies allowing their storage OCC, when this will benefit birth dose coverage. We recommend that this strategy be introduced to improve birth dose coverage, especially in rural and remote areas. Concurrent monitoring and evaluation should be undertaken to affirm the safe implementation of this strategy, and assess its cost, feasibility and effect on reducing HBV infection rates. Meanwhile, release of manufacturer data verifying the potency of currently available HepB vaccines after exposure to heat will increase confidence in the use of vaccine vial monitors as a managerial tool during storage of HepB vaccine OCC.

Voir page 70 le resume en francais. En la pagina 70 figura un resumen en espanol. Introduction The earliest effective formulation of B (HepB) vaccine was developed by Krugman et al. in the late 1960s. (1,2) Although the first commercial formulations of plasma-derived HepB vaccine were produced by largely chemical methods, (3) an alternative process developed by Prince et al. used a flash-heat inactivation method, which was far cheaper and yielded a vaccine of greater potency. (2) The immunogenic component of all HepB vaccines is the 22 nm B surface antigen (HBsAg) protein, which has extraordinary conformational integrity due to highly stable disulfide bridges between its cysteine residues. [his fact, and the use of in the production process used by Prince, suggested that these vaccines might be stable, enabling their storage outside the chain of refrigeration (outside the cold chain; OCC) normally required for vaccines used in the Expanded Programme on Immunization (EPI). This programme provides life-saving vaccination against at least six diseases for infants and young children all over the world. Storage of HepB vaccine OCC has long been advocated to improve availability of a birth dose for infants born in remote areas where refrigeration is not available. Birth dosing can prevent most perinatal infections with B virus (HBV), but is currently unavailable to many infants in developing nations because of the difficulty of keeping vials at the manufacturers' recommended temperature of 2-8 [degrees]C. (4) Indonesia allows OCC storage of HepB vaccine for the birth dose--but other nations seem reluctant to follow suit--and WHO does not yet unequivocally support such a strategy. This is presumably because of limited reported experience with vaccines used in this way, and the reluctance of manufacturers to support use of their products outside the conditions under which they were licensed. WHO guidelines on the introduction of HepB vaccine recommend storage of 2-8 [degrees]C (5) but according to another WHO publication, some vaccines, especially can be taken OCC if a vaccine vial monitor (WM) is properly used to monitor exposure. (6) WMs are small labels with a heat-sensitive central square that changes gradually from white to black upon to or light. (7) They are placed on vaccine vials by manufacturers before shipping. Most HepB vaccines procured by the United Nations Children's Fund (UNICEF) are now shipped with a VVM on each vial. To assist decision-makers considering use of OCC storage in nations where this will improve access to the birth dose of HepB we present the available data on the immunogenicity and potency of HepB vaccines exposed to and discuss the associated benefits, risks and possible costs of this strategy and the alternatives. Literature search strategy Research published since 1980 on the administration of heat-treated or heat-exposed HepB vaccine was sought using Medline, Embase, and a second Medline search through the New England Journal of Medicine. Finally, a search of the Cochrane Collaboration's systematic reviews was undertaken. The keywords were hepatitis B, HBsAg, hepatitis B vaccine, heat stability, heat, heat tolerance, and heat exposure in various combinations. For summaries of unpublished literature, we also referred to published reviews of vaccine thermostability (8) and HepB vaccines in clinical practice, (9) and overviews of the introduction of immunization against HBV. (5) We also gained information through email contact with experts in the field, including Dr Craig Shapiro and Dr Mark Kane (formerly at the US Centers for Disease Control), Dr David West (formerly of the Merck Laboratories in Virginia, USA), Dr Joseph Torresi (University of Melbourne, Australia) and Dr Alfred Prince (New York Blood Center, USA). …

BACKGROUND:Most studies of Haemophilus influenzae type b (Hib) disease in Asia have found low rates, and few Asian countries use Hib vaccine in routine immunisation programmes. Whether Hib disease truly is rare or whether many cases remain undetected is unclear.METHODS:To estimate incidences of vaccine-preventable Hib pneumonia and meningitis among children younger than 2 years in Lombok, Indonesia, during 1998-2002, we undertook a hamlet-randomised, controlled, double-blind vaccine-probe study (818 hamlets). Children were immunised (WHO schedule) with diphtheria, tetanus, pertussis (DTP) or DTP-PRP-T (Hib conjugate) vaccine. Vaccine-preventable disease incidences were calculated as the difference in rates of clinical outcomes between DTP and DTP-PRP-T groups. Analyses included all children who received at least one vaccine dose.FINDINGS:We enrolled 55073 children: 28147 were assigned DTP-PRP-T and 26926 DTP. The proportion of pneumonia outcomes prevented by vaccine ranged from less than 0 to 4.8%. Calculated incidences of vaccine-preventable Hib disease (per 10(5) child-years of observation) for outcome categories were: substantial alveolar consolidation or effusion, less than zero (-43 [95% CI -185 to 98]); all severe pneumonia, 264 (95% CI less than zero to 629); all clinical pneumonia, 1561 (270 to 2853); confirmed Hib meningitis, 16 (1.4 to 31); meningitis with cerebrospinal-fluid findings consistent with a bacterial aetiology, 67 (22 to 112); and admission for suspected meningitis or presenting to a clinic with convulsions, 158 (42 to 273).INTERPRETATION:Hib vaccine did not prevent the great majority of pneumonia cases, including those with alveolar consolidation. These results do not support a major role for Hib vaccine in overall pneumonia-prevention programmes. Nevertheless, the study identified high incidences of Hib meningitis and pneumonia; inclusion of Hib vaccine in routine infant immunisation programmes in Asia deserves consideration.

To ascertain hepatitis B virus (HBV) infection rates for Vietnam, we surveyed HBV markers in two districts of Thanh Hoa province. We randomly selected 536 infants (9- < or = 18 months old), 228 children (4 to < or = 6 years old), 219 adolescents (14 to < or = 16 years old), and 596 adults (25 to < or = 40 years old). On questioning, none of those surveyed had received vaccine against HBV. Hepatitis B virus surface antigen (HBsAg) and total HBV core antibody (anti-HBc) were measured in all specimens, and HBV e antigen (HBeAg) in those positive for HBsAg, and HBV surface antibody (anti-HBs) were measured in all others. Current infection (HBsAg+) rates were infants = 12.5%, children = 18.4%, adolescents = 20.5%, and adults = 18.8%. Current or previous infection (HBsAg+, anti-HBc+, or anti-HBs+) increased with age (infants = 19.6%, children = 36.4%, adolescents = 55.3%, adults = 79.2%). Rates of HBeAg among those HBsAg+ were infants = 85.1%, children = 88.1%, adolescents = 71.1%, and adults = 30.4%. The epidemiology of HBV in Vietnam resembles that of many southeast Asian nations before introduction of vaccine. Immunization of newborns will have enormous impact on HBV-related morbidity and mortality there.

There are limited prospective data for Haemophilus influenzae type b (Hib) disease in Asia, where some countries are considering vaccine introduction. A prospective population-based study was conducted to measure the incidence of Hib meningitis in children in two northern provinces of Thailand. Children <5 years with symptoms consistent with bacterial meningitis were enrolled in the study if inclusion criteria were met. The study enrolled 598 children with clinical meningitis, 76% of whom received lumbar puncture. The rate of probable bacterial meningitis was 26.6/100,000 children <5 years per year. There were four cases of laboratory confirmed Hib meningitis (rate 3.8/100,000 children <5 years per year). These findings suggest a relatively low incidence of Hib meningitis. However, additional data from studies of pneumonia are needed to define the Hib disease burden in Thailand.

Combined vaccines have been advocated as an efficient method of paediatric vaccine delivery. This study examined the performance and cost implications for the use of combined DTP–HB vaccine in the Thai immunisation program. Separate DTP and HB and then combined DTP–HB vaccines were used in the infant immunisation program in Chiangrai Province during a 4-year period. DTP vaccination coverage was maintained with the combined vaccine and HB coverage was improved (95.7% for DTP–HB1, 95.2% for DTP–HB2 and 93.8% for DTP–HB3). Seroconversion rates for anti-HBs rose from a baseline of 88.4 to 94.8% with use of the combined vaccine. Seroconversion rates for anti-D (97.5%) and anti-P (89.6%) were higher in the separate vaccine regimen. Although this study was not able to demonstrate that DTP–HB vaccine was more cost saving than the vaccines given separately as baseline vaccine coverage was already high, in settings where coverage rates are much lower the increased cost of combined vaccines may be more justifiable.

La presente invention porte sur des instruments analytiques efficaces par rapport au cout et permettant de determiner la presence ou quantite d'un analyte dans un echantillon. Les instruments analytiques utilisent une cartouche de dosage qui comporte un port accueillant les echantillons et un carrousel rotatif contenant une pluralite de puits de reactifs. Chaque puits de reactif comprend un element de piston qui permet d'administrer le reactif dans une surface de test. L'instrument peut indexer la cartouche de dosage pour administrer l'echantillon et les reactifs dans la surface de test, de maniere predeterminee et flexible, ce qui permet d'obtenir un protocole de dosage specifique au type de l'echantillon soumis a l'analyse. Cette invention porte egalement sur des composants, des dispositifs, des elements jetables, des systemes d'administration de reactifs, des accessoires et des procedes d'utilisation de ces instruments. Les instruments analytiques de cette invention sont appropries pour etre appliques dans les tests de maladies infectieuses, la detection et la surveillance du cancer, la pharmacovigilance therapeutique, les tests d'allergies, les tests d'environnement, les tests alimentaires, les tests diagnostiques d'echantillons humains et veterinaires, et les tests de traitement hors ligne.

We evaluated the immunogenicity of hepatitis B (HB) vaccine in UniJect, a pre-filled, non-reusable injection device, stored at tropical temperatures for up to one month and used to give the first dose of HB vaccine to newborns. Infants in Tabanan district, Bali, Indonesia, were given their first dose of HB vaccine with UniJect stored out of the cold chain, UniJect stored in the cold chain; or standard syringe, needle and multidose vial stored in the cold chain. Subsequent doses were given by usual means and blood samples drawn 4–6 weeks after the third dose. No significant differences were found in seroconversion rates or geometric mean titres of HB surface antibody between the three groups.

The control of infectious diseases generally involves three successive steps: first, the identification of the etiologic agent, second, the development of means for interruption of transmission, and, lastly the utilization of these means. Tremendous progress has been made in the first two of the above steps during the past 30 years. Hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV) have been identified and characterized to the level of nucleotide sequence. Safe and effective HBV and hepatitis A virus (HAV) vaccines have been developed and licensed. Sensitive and specific screening assays are available for the identification of blood donors infected with HBV and HCV. As described elsewhere at this meeting, progress is being made towards development of vaccines for HDV and HEV. However, progress in the utilization of these measures on a worldwide basis has been disappointingly slow. Indeed, it has become evident that implementation of control measures is a problem of greater magnitude and complexity than the development of the vaccines to be used in control of the disease. This report will illustrate this problem in the context of HBV control, and will describe efforts being made to accelerate the rate of progress.

Mortality was determined among 146 patients with chronic liver disease, with particular reference to hepatitis B viral (HBV) markers. Survival status at the end of the study period was known in 121 patients, of whom 52 died. Mortality correlated with hepatitis B surface antigen (HBsAg)-positive status (P < 0.001), age (P < 0.02), and cirrhosis (P < 0.05). Age adjustment did not affect the increased mortality in the HBsAg-positive (36 out of 60 patients) and HBV-immune (12 out of 29 patients) groups compared with the seronegative group (four out of 32 patients) (P < 0.02). When adjusted for cirrhosis, similar mortality rates were found in each of the HBV marker groups (P < 0.005). Likewise, when adjusted for the presence of clinical complications at presentation, there were similar mortality rates in each HBV marker group (P < 0.02). Life-table survival curves showed the best 5-year survival in seronegative patients (87%), followed by the HBV-immune group (62%), and the worst in the HBsAg-positive patients (38%) (P < 0.002). Moderate and severe degrees of portal inflammation (P < 0.002) and piecemeal necrosis (P < 0.03) were found more frequently in the HBsAg-positive and HBV-immune groups, while mild degrees of inflammation and necrosis were found more often in the seronegative patients. No significant changes in this analysis were noted after exclusion of hepatitis D-positive cases. Hepatitis B viral markers appear to be important prognostic indicators in chronic liver disease.

Hepatitis B is a disease that affects people throughout the world, and over 200 million are persistent carriers of the hepatitis B virus (HBV). The chronic sequelae of this infection include chronic active hepatitis, cirrhosis, and primary hepatocellular carcinoma. The development of safe and highly effective hepatitis B vaccines now provides the means by which HBV infection, including the HBV chronic carrier state, can be prevented and the related mortality significantly reduced. The cost of these vaccines has significantly decreased and will soon approach levels at which the cost-effectiveness (cost per death prevented) of hepatitis B vaccine will be similar to that of other childhood vaccines. Integration of hepatitis B vaccine into the Expanded Programme on Immunization for mass vaccination of infants in areas where HBV infection is endemic and morbidity is high would be the most effective means of providing the coverage necessary for effective control and prevention.

A nosocomial outbreak of fulminant hepatitis B infection at a medical center in Haifa, Israel, between 7 and 26 June 1986, involved five patients who had been hospitalized previously in the medical ward in late April and early May (first generation). This outbreak had an unusual clinical course, with fulminant hepatic failure associated with acute renal failure from acute glomerulonephritis, leading to death within a few days. The onset dates of hepatitis were tightly clustered temporally and incubation periods were short. Extensive laboratory and epidemiologic evaluation showed that the probable common-source vehicle of transmission was a multiple-dose vial of heparin and normal saline flush solution that may have been contaminated by blood of a known HBsAg carrier, who was positive for anti-HBe, hospitalized at the same time. A sixth patient died in August 1986 (second generation), after his initial admission in June that coincided with the terminal hospitalizations of three first-generation patients. Those patients had marked coagulopathies, and transmission to the sixth patient most probably occurred through environmental contamination by patients or through cross-contamination between patients through staff. The unusually high mortality rate (5 of 6) in this outbreak has not been definitely explained.

Transmission of the hepatitis B virus (HBV) during the perinatal period leads to the most devastating consequences of HBV infection. Women who test positive for hepatitis B surface antigen (HBsAg) at the time of delivery and who have hepatitis B e antigen in their sera have a 70% or greater chance of transmitting infection to their newborn infants. At least 90% of these infected infants become HBV chronic carriers. These HBV-carrier children have a 25% lifetime risk of dying from primary hepatocellular carcinoma or cirrhosis, usually during adulthood.1In addition, they serve as a reservoir of HBV infection in their families and communities. Many become carrier mothers themselves and perpetuate the cycle of perinatal transmission. Fortunately, treatment of these newborns shortly after birth with a combination of hepatitis B immune globulin and hepatitis B vaccine is 85% to 95% effective in preventing development of the HBV—chronic carrier state.2

Circulating immune complexes (CICs) were detected during the course of experimental hepatitis A virus (HAV) infection in 8 of 9 chimpanzees. In all cases, the predominant class of antibody detected in the CIC was IgM. The appearance of IgM‐CIC usually preceded the onset of liver enzyme elevations, and in all instances, the appearance of IgM‐CIC correlated with the presence of IgM anti‐HAV. Six of 8 animals tested had significant depression of C3 concentrations during the course of infection, and this depression occurred at the peak of CIC activity. Immunohistologic studies demonstrated granular deposits of IgM localized in sinusoidal cells during peak of IgM‐CIC activity. IgM‐CICs appear to be a fairly consistent finding during HAV infection and probably represent the viremic phase of the disease. However, they do not appear to mediate hepatocellular injury by direct action on hepatocytes.