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We present a deterministic model of the possible emergence of a vaccine escape variant of hepatitis B virus (HBV). The model identifies the key unknowns determining this process: the protection afforded by the current vaccines against particular HBV variants; the infectiousness of these variants; and the current prevalence of individuals infectious with the variants (each factor relative to wild-type). By making pessimistic assumptions about these unknowns we show that even a highly infectious variant, under a vaccine programme that affords no protection against the variant, would still take decades to emerge. Thus the current low prevalence of variants is not evidence for the cross-reactivity of the current vaccines or for a lack of infectiousness in the variants. As any vaccine failure will be inapparent for decades it may be sensible to recommend vaccine modifications now rather than later.

SUMMARYVaccine escape variants of hepatitis B virus (HBV) have been identified world-wide. A mathematical model of HBV transmission is used to investigate the potential pattern of emergence of such variants. Attention is focused on The Gambia as a country with high quality epidemiological data, universal infant immunization and in which escape mutants after childhood infections have been observed. We predict that a variant cannot become dominant for at least 20 years from the start of vaccination, even when using a vaccine which affords no cross protection. The dominant factor responsible for this long time scale is the low rate of infectious contacts between infected and susceptible individuals (we estimate the basic reproduction number of hepatitis B in The Gambia to be 1n7). A variant strain that achieves high prevalence will also take many years to control, and it is questionable whether emergence will be identifiable by sero-surveillance until of high prevalence. The sensitivity of the model predictions to epidemiological and demographic factors is explored.

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The prevention of viral infection by vaccination relies on stimulating an appropriate immune response in order to reduce the probability with which a virus can establish an infection. Post-vaccination antibody responses have therefore been associated with reducing the probability with which an individual can be infected (i.e., the vaccine's "impact"). Quantifying this relationship is essential in evaluating new vaccines, especially since comparisons between vaccines, and vaccine licensure, may be dependent on antibody responses alone. In this paper two principal questions are identified which need to be addressed in the evaluation of subunit vaccines: i) how do specific antibody levels relate to complete protection from infection or disease and ii) how do antigenic subunits interact in developing protection when combined together in a single vaccine. The aim is to identify explicitly certain assumptions that are frequently made implicitly in the discussion of vaccine action. First, antibody levels are related to levels of protection through a novel statistical analysis of incidence data from a published hepatitis B vaccine trial. The antibody response observed after influenza A virus infection is discussed in relation to the selection of neutralisation escape variants. Finally, by way of example, a theoretical situation is examined and three simple models of subunit vaccine action are constructed in order to describe how antibody levels may be related to population level phenomena such as the elimination of an infection by mass vaccination.