Long-term vaccine-induced heterologous protection against H5N1 influenza viruses in the ferret model

Abstract

Background: Highly pathogenic H5N1 influenza viruses reemerged in humans in 2003 and have caused fatal human infections in Asia and Africa as well as ongoing outbreaks in poultry. These viruses have evolved substantially and are now so antigenically varied that a single vaccine antigen may not protect against all circulating strains. Nevertheless, studies have shown that substantial cross-reactivity can be achieved with H5N1 vaccines. These studies have not, however, addressed the issue of duration of such cross-reactive protection.

Objectives: To directly address this using the ferret model, we used two recommended World Health Organization H5N1 vaccine seed strains - A/Vietnam/1203/04 (clade 1) and A/duck/Hunan/795/02 (clade 2.1) - seven single, double, or triple mutant viruses based on A/Vietnam/1203/04, and the ancestral viruses A and D, selected from sequences at nodes of the hemagglutinin and neuraminidase gene phylogenies to represent antigenically diverse progeny H5N1 subclades as vaccine antigens.

Results: All inactivated whole-virus vaccines provided full protection against morbidity and mortality in ferrets challenged with the highly pathogenic H5N1 strain A/Vietnam/1203/04 5 months and 1 year after immunization.

Conclusion: If an H5N1 pandemic was to arise, and with the hypothesis that one can extrapolate the results from three doses of a whole-virion vaccine in ferrets to the available split vaccines for use in humans, the population could be efficiently immunized with currently available H5N1 vaccines, while the homologous vaccine is under production.

Figure 1

Ferrets’ nasal wash titers after challenge with VN1203. Post‐challenge virus titers of ferrets vaccinated with (A) VN1203 (clade 1), (B) DKHUN795 (clade 2.1), (C) ancestral A antigen, or (D) ancestral D antigen are expressed as mean log₁₀ EID₅₀/ml (horizontal lines) ± standard error (vertical lines). Vaccinated ferrets are represented by black (challenged at 1 year) and gray (challenged at 5 months) circles. Control (PBS‐vaccinated) animals are represented by red (challenged at 1 year) and green (challenged at 5 months) symbols. All control ferrets died or were euthanized before day 7 post‐challenge.