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Human infection with the highly pathogenic avian influenza A virus H5N1 is associated with a high mortality and morbidity. H5N1 continues to transmit from poultry to the human population, raising serious concerns about its pandemic potential. Current influenza H5N1 vaccines are based upon the elicitation of a neutralizing antibody (Ab) response against the major epitope regions of the viral surface glycoprotein, hemagglutinin (HA). However, antigenic drift mutations in immune-dominant regions on the HA structure allow the virus to escape Ab neutralization. Epitope mapping using neutralizing monoclonal antibodies (mAb) helps define mechanisms of antigenic drift, neutralizing escape and can facilitate pre-pandemic vaccine design. This review explores the current knowledge base of the antigenic sites of the H5N1 HA molecule. The relationship between the epitope architecture of the H5N1 HA, antigenic evolution of the different H5N1 lineages and the antigenic complexity of the H5N1 virus lineages that constitute potential pandemic strains are discussed in detail.

The induction of neutralising antibodies to the viral surface glycoprotein, haemagglutinin (HA) is considered the cornerstone of current seasonal and pandemic influenza vaccines. Mapping of neutralising epitopes using monoclonal antibodies (mAbs) helps define mechanisms of antigenic drift, neutralising escape and facilitates pre-pandemic vaccine design. In the present study we reverse engineered the antigenic structure of the HAs of two highly pathogenic H5N1 vaccine strains representative of currently circulating clade 1 and 2.2 H5N1 viruses. The HA sequence of the A/Vietnam/1194/04 clade 1 virus was progressively mutated into the HA sequence of the clade 2.2 virus, A/Bar-headed Goose/Qinghai/1A/05. Fine mapping of clade-specific neutralising epitopes was performed by examining the cross-reactivity of mAbs raised against the native HA of each parent virus. The reactivity across all clade specific mAbs centred around a constellation of mutations at positions 140, 145, 171 and 172, all of which are proximal to the receptor binding site on the membrane distal globular head of the HA. Overlapping cross-reactivity of these antigenic sites suggests that these amino acid positions relate to the antigenic evolution of the H5 clade 1 and 2.2 viruses. This finding may prove useful for the design of vaccines with broader neutralising cross-reactivity against the different H5 HA sublineages currently in circulation. These findings provide important information about the amino acid changes involved in the cross-clade evolution of H5N1 viruses and their potential for human to human transmission; and facilitates a greater understanding of the pandemic potential of H5N1 isolates.