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Contributions toward assesing and optimizing immunization against viral hepatitis B

Author: Vrânceanu-Beneş Angela
Degree:doctor of medicine
Speciality: 14.00.30 - Epidemiology
Scientific adviser: Petru Iarovoi
doctor habilitat, associate professor (docent)
Scientific consultant: Constantin Spînu
doctor habilitat, professor
Scientific council:


The thesis was presented on the 25 February, 2009
Approved by NCAA on the 23 April, 2009


Adobe PDF document0.36 Mb / in romanian


CZU 616.36-002-036.22-097

Adobe PDF document 0.82 Mb / in romanian
121 pages


Viral hepatitis B, booster doses, immune responses, immune memory, antibody anti-HBs, subclinical infection, breakthrough infection, postvaccination immunity.


This work represents a thesis of the results of the evaluation of the longevity and of the level of the immune response following the primary vaccination, of the extent of hepatitis B virus (HBV) burden among immunized children from general population and from some groups exposed to increased infection risk (children born from HIV infected and HBsAg positive mothers), evaluation of the risk of perinatal and afterbirth transmission of HBV, as well as the argumentation of the need for optimizing the existing vaccination schemes.

The results were produced following a national study performed in the Republic of Moldova during 2004-2006, based on a representative, random, stratified sample of 620 children 6-11 years old from the general population and of 114 pregnant women and HIV infected mothers and their children (70).

Study of the level of anti-HBs antibodies 6-11 years after beginning the VHB immunization revealed that only 33% of children, having completed the 3-dose primary vaccination course before their first birthday and following the vaccination scheme 0, 1, 6 months, showed a protective level ( 10 IU/L ) of anti-HBs, with no significant variation by age groups and geographical areas.

Identification of specific hepatitis B virus infection markers (AgHBs, anti-HBc, anti-HBc IgM) revealed occurrence of sub-clinic infection (anti-HBc positive) in 2% and of the breakthrough infection (AgHBs positive) in 1% of apparently healthy children from general population, that have received a three dose course of hepatitis B vaccine during their infancy.

Presence of the immunological memory was confirmed for 91% of children, based on the increase of titres of anti-HBs antibodies  10 IU/L following administration of one booster dose of the vaccine. Among children showing non-protective levels of anti-HBs antibodies before the booster dose, 87% reached a post-booster level of anti-HBs antibodies  10 IU/L. High, durable titres of anti-HBs  250 IU/L were reached by 95% of children with pre-booster level of anti-HBs varying from 10 IU/L to 250 IU/L and by 57% of children with non protective pre-booster level of anti-HBs (<10 IU/L).

High prevalence of the AgHBs among pregnant women and HIV infected mothers (16%) as well as among uninfected HIV mothers (10%) revealed a persisting risk for perinatal and afterbirth transmission of HBV infection. Investigation of acute symptomatic VHB cases among vaccinated children, showed that the majority of children developing the disease (11 out of 14) were born from AgHBs positive mothers, the others were exposed to different risk factors such as surgical and stomatologic interventions, fresh dried plasma transfusion, erythrocytes transfusion. Exposure to the above mentioned risk factors was associated with lack of application of the vaccination scheme 0, 1, 2 months and unjustified prescribed contraindications to vaccination.

Among children born from HIV positive mothers, 25% missed a protective level of anti-HBs 2-6 months after finalization of a complete 3 dose course of primary HepB vaccination. These results prove the importance of assessing the level of post-vaccine anti-HBs antibodies at 8-12 months of age to identify cases of seroconversion failure following primary vaccination course and to decide on additional immunization needs.

Testing infants born from HIV positive mothers for specific hepatitis B virus infection markers (AgHBs, anti-HBc, anti-HBc IgM) revealed none of the children got infected with HBV.

Identification in infants serums of the presence of anti-HBc while missing anti-HBc IgM or AgHBs and their disappearance before the age of 12 months allowed to highlight the passive transmission of the above mentioned antibodies from mother to child when she is positive for anti-HBc. In order to facilitate differential diagnosis of viral hepatitis B infection during the first year of life from passive transmission of anti-HBc from mother to child there was proposed and implemented a diagnosis algorithm.

In order to optimize immunization against hepatitis B there was proposed to vaccinate children born from AgHBs positive mothers using the vaccination scheme 0, 1, 2, 12 months, to apply a booster dose to children vaccinated 6-11 years ago or to introduce the fourth dose in the primary immunization schedule against VHB, to assess the level of post-vaccination anti-HBs following the primary vaccination against hepatitis B virus of children born from AgHBs positive mothers as well as for those born from HIV infected mothers and to establish a monitoring system for pregnant women positive for AgHBs.