Ngui, Siew Lin; (1998) Molecular analysis of hepatitis B virus transmission events. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Selective percutaneous transmission by hepatitis B virus (HBV) and breakthrough perinatal HBV infection in fully immunized infants can occur. This study describes investigations into the virologic bases for these phenomena. The phenomoenon of selective percutaneous HBV transmission was discovered from the finding of transmitter/recipient HBV sequence discordance in two clusters of post-surgical HBV infection. Using limiting dilution, PCR-cloning, single-strand conformation polymorphism and nucleotide sequencing analyses, the discordance was found to be correlated with extreme viral diversity and low-level viraemia in the transmitters, and to transmission of minority variants. By contrast, in five cases where there was transmitter/recipient HBV sequence concordance, the transmitters carried relatively homogeneous HBV populations at high viraemia levels, and the most populous variant was transmitted. Fourteen fully immunized children born to HBV carrier mothers were found to have undergone breakthrough perinatal infection. In twelve infants, viral sequences were identical to those in their mothers. When these sequences were compared to 22 other mother/infant pairs in which the infants remained uninfected, a high maternal viral load (>108 genome copies/ml) and specific base changes in the HBV S gene (G365, A328, A479, C158, and C377) were found to be correlated with increased risk of infection. The two other HBV-positive infants were infected by putative vaccine-escape mutants, as there was sequence discordance between the S gene amplified from them and from their mothers. Specially developed amplification refractory mutation systems identifed the variants in these infants as having originated maternally. This study therefore shows that: (1) the degree of HBV heterogeneity in carriers can be extreme; (2) following percutaneous exposure, selective transmission is due to transmission of minor variants; (3) high maternal viraemia and specific base changes in the HBV S gene are associated with breakthough perinatal infection; and (4) vaccine- escape HBV mutants pre-exist in the mother.

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