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We have determined the mechanism of neutralization of influenza virus infectivity by three antihemagglutinin monoclonal antibodies, the structures of which we have analyzed before as complexes with hemagglutinin. The antibodies differ in their sites of interaction with hemagglutinin and in their abilities to interfere in vitro with its two functions of receptor binding and membrane fusion. We demonstrate that despite these differences all three antibodies neutralize infectivity by preventing virus from binding to cells. Neutralization occurs at an average of one antibody bound per four hemagglutinins, a ratio sufficient to prevent the simultaneous receptor binding of hemagglutinins that is necessary to attach virus to cells.

The structure of a complex of influenza hemagglutinin (HA) with a neutralizing antibody shows that the antibody binds to HA at a distance from the virus receptor binding site. Comparison of the properties of this antibody and its Fab with those of an antibody that recognizes an epitope overlapping the receptor binding site leads to two main conclusions. First, inhibition of receptor binding is an important component of neutralization. Second, the efficiency of neutralization by the antibodies ranks in the same order as their avidities for HA, and their large size makes these antibodies highly efficient at neutralization, regardless of the location of their epitope in relation to the virus receptor binding site. These observations provide rationales for the range of antibody specificities that are detected in immune sera and for the distribution of sequence changes on the membrane-distal surface of influenza HAs that occur during 'antigenic drift.'

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