James Maynard

Hepatitis B: global importance and need for control.

Hepatitis B is a disease of global importance, with greater than 300 million carriers of the virus world-wide. Hepatitis B virus (HBV) is the cause of up to 80% of cases of primary liver cancer, the single most important cause of mortality globally. In countries where HBV carrier rates reach 10%, HBV infection may account for 3% of total mortality, a level which exceeds polio-related mortality before the introduction of polio vaccine. The only means by which hepatitis B can be eventually eliminated is mass vaccination of infants with hepatitis B vaccine as part of the Expanded Programme on Immunization (EPI) in areas of the world where the HBV carrier rate exceeds 2.5%. With recent dramatic increases in hepatitis B vaccine production and decreases in per-dose price, there are grounds for optimism that global HBV infection rates may be reduced by as much as 90% over the next 10 years.

Incidences of vaccine-preventable Haemophilus influenzae type b pneumonia and meningitis in Indonesian children: hamlet-randomised vaccine-probe trial.

BACKGROUNDnMost 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.nnnMETHODSnTo 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.nnnFINDINGSnWe 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).nnnINTERPRETATIONnHib 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.

The introduction of new vaccines into developing countries.

The development and introduction of new vaccines is a costly and time consuming process. Unfortunately, those most in need--individuals in developing countries--are the last to receive these powerful disease preventing products. From the time a vaccine is first licensed in a developed country to the time most of the poor in developing countries have access to the vaccine can be 20-30 years. This delay is unacceptable. There is a great need to reduce this time span. This paper examines five ways of reducing the time span. Each of the five is essential and achieving success on all five will require a heightened level of international effort and coordination.

Improving birth dose coverage of hepatitis B vaccine

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.

At-birth immunisation against hepatitis B using a novel pre-filled immunisation device stored outside the cold chain

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.

Integration of hepatitis B vaccination into the expanded programme on immunization in Chonburi and Chiangmai provinces, Thailand.

Hepatitis B (HB) immunization was introduced as part of the expanded programme on immunization (EPI) in two provinces in Thailand and evaluated over a four year period. Three doses of HB vaccine were offered to 60,980 newborns at birth, 2 and 6 months of age. The overall coverage for complete HB immunization was 90.4%. Serosurveys of randomly selected children under the age of 5 years were undertaken before and at the end of the project. Levels of HBsAg positivity were reduced by 85%, and there was a corresponding 70% increase in protective immunity. These findings demonstrate that HB immunization can be successfully integrated into EPI without adverse effect on coverage rates of other antigens, and results in a marked reduction in the rate of chronic carriage of HB virus in preschool age children.

Comparative evaluation of a combined DTP–HB vaccine in the EPI in Chiangrai Province, 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.

Prevention of Hepatitis B Infection

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.