Cross‐neutralisation of antibodies elicited by an inactivated split‐virion influenza A/Vietnam/1194/2004 (H5N1) vaccine in healthy adults against H5N1 clade 2 strains

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Abstract
Background Highly pathogenic avian influenza A H5N1 viruses are widespread in different parts of the world and have evolved into clade 1 and 2 lineages. Their continuing circulation represents serious pandemic threat, spurring human vaccine development efforts. Initial clinical trials tested vaccines prepared from clade 1 strains circulating in 2004. Methods Post‐vaccination sera from a phase I trial of an inactivated split‐virion vaccine based on A/Vietnam/1194/2004/NIBRG14 (H5N1) were analysed in vitro for cross‐reactivity against highly pathogenic, wild‐type clade 2 H5N1 strains isolated from human cases, and their corresponding reverse genetics derived vaccine candidate strains. Results Neutralisation of clade 1 and 2 wild‐type and reverse‐genetics viruses was seen, with highest titres observed for viruses most closely related to the vaccine strain. There was no consistent relationship between vaccine dose given, or presence of aluminium adjuvant and cross‐neutralising antibody titre, possibly because of small sample size. Use of wild‐type highly pathogenic strains compared with antigenically equivalent reverse‐genetics viruses suggests presence of a higher level of cross‐neutralising antibody. Conclusion Vaccination with a clade 1 H5N1 virus elicited antibodies capable of neutralising diverse clade 2 H5N1 strains. This data underlines that while a close match between vaccine virus and circulating virus is important to achieve maximum protection, population priming with a ‘pre‐pandemic’ vaccine may be beneficial for the protection of a naïve population. The data suggests that use of reverse‐genetic viruses in neutralisation assays may underestimate the extent of cross‐protective antibody present following H5N1 vaccination.