Zuckermann, Jane Nicola; (1996) Prevention of hepatitis A and B by immunisation. Doctoral thesis (M.D), UCL (University College London).

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Abstract

1. Hepatitis A Prevention of hepatitis A by immunisation is a high priority in many countries. Improvement in socio-economic conditions has resulted in a shift from asymptomatic infection in early life to clinically significant illness with increasing age. The immunogenicity, reactogenicity and safety of two inactivated vaccines were studied by three clinical trials; 1) A randomised, double blind, placebo-controlled study in 286 healthy volunteers of a vaccine containing 720 ELU antigen prepared from the HM 175 hepatitis A strain; 2) A study designed to protect susceptible patients with congenital coagulation disorders by subcutaneous administration of vaccine using a rapid immunisation schedule. 97 patients were enrolled; 3) A controlled, randomised, comparative open trial of the 720 ELU vaccine with a new vaccine prepared from the GBM strain of HAV in 210 volunteers, and 629 subjects enrolled in three other centres in France and Germany. All three vaccine preparations were found to be highly immunogenic and well-tolerated. A statistically significant effect of interaction between time and vaccine was observed indicating that the kinetics of antibody responses were different. The rapid immunisation schedule was found to be safe and immunogenic in children and adults with congenital coagulation disorders. CD4 counts indicated that patients with low counts did not seroconvert, although there was no absolute correlation. There were, as expected, lower seroconversion rates in patients infected with HIV in association with low CD4 counts. Serological testing 18 months after primary immunisation showed that all healthy subjects who received the 720 ELU antigen HM 175 vaccine and the 160 antigen units GBM vaccine had significant HAV antibody titres with a projected estimate of antibody persistence for 10 years or longer. The development of immunisation strategies is discussed. 2. Hepatitis B Between 5-15% of immunocompetent subjects do not produce protective surface antibody (anti-HBs) after immunisation with currently available S antigen vaccines. Non-responders remain susceptible to infection with HBV. A novel recombinant hepatitis B vaccine produced by transfection of mammalian cells and containing pre-S1, pre-S2 and S components of the viral coat protein of subtypes adw and ayw was evaluated in 86 true non-responder health care workers. 55/86 (64%) serconverted following a single dose of the vaccine. A single dose of 20 µg was as effective as two doses of 20 µg or 40 µg in terms of seroconversion, seroprotection or geometric mean titres using two different assays. As part of a separate collaborative study (which is not submitted with this thesis), a high frequency of HLA Class II allele DRB1*0701 and the phenotype B44;DRB1*0701 ;DQB1*0201 was found in non-responders compared to controls. All the initial non-responders expressing the phenotype B7;DRB1*1501 ;DQB1*0602 responded to the new vaccine. The majority of those who failed to mount an antibody response expressed two other phenotypes. Immunogenetic analysis thus confirmed that an initially distinct group of non-responders was indeed included in the vaccine study. The issues of repeated revaccination of non-responders and silent HBV infection are discussed.

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