Role of Vaccination-Induced Immunity and Antigenic Distance in Transmission Dynamics Investigated Using Highly Pathogenic Avian influenza (HPAI) H5N1 Virus Escape Mutants

Sitaras, I.; Peeters, B.P.H.; Jong, M.C.M. de


Evolution of avian influenza viruses – especially of the highly pathogenic avian influenza (HPAI) H5N1 subtype – is a major issue, since HPAI H5N1 epidemics are associated with huge economic losses and connected to human morbidity and mortality. Vaccination as a means to prevent transmission has oftentimes been reported as being ineffective and as a potential driving force in the selection of immune escape mutants. It is therefore essential to study how mutations are selected due to immune pressure, as well as, what is the effect on transmission given the antigenic distance between vaccine and challenge strains after selection has taken place.
We have selected for escape mutants of HPAI H5N1 A/turkey/Turkey/1/2005 by repeated in vitro exposure to homologous polyclonal sera. We characterised the mutants genetically and antigenically. We conducted two sets of transmission experiments to evaluate the transmission dynamics of the parent strains in animals vaccinated with high and low doses of our selected immune escape mutants. Finally, we employed mathematical models to examine the effect that antigenic distance between vaccine and challenge strains has on the vaccination-induced antibody level and therewith on virus transmission.
After 42 rounds of selection we identified 5 amino acid mutations, most of which located in areas of antigenic importance, also known to be prone to variation due to immune pressure. We show that genetic and antigenic distance increases with passage number. Our transmission experiments and mathematical analyses demonstrate that antigenic distance between vaccine and challenge strains is not a major factor in the transmission dynamics of the strains used in this study, as the effect of antibody levels against the challenge viruses is much larger than the small effect of antigenic distance. The reduction in transmission between animals with high antibody titres is mainly caused by lower infectivity and not by a change in susceptibility.
Although mutations take place early in the selection process, we demonstrate that vaccination will remain effective even in the face of virus changes caused by selection in vaccinated birds because sufficiently high antibody titres will still be attained. Considering the high transmission rate of HPAI H5N1 within and between flocks and its ability to transmit to humans, our results indicate that increasing the efficacy of vaccination should be aimed at in order to effectively curb the spread of HPAI H5N1.