Structural Basis of Influenza Virus Inhibition by Broadly Neutralizing Antibodies

Vaccines are the gold standard for the control and prevention of infectious diseases. Widespread vaccination efforts led to the eradication of smallpox, near elimination of polio, and the effective control of many other human maladies, such as measles and pertussis. Despite these successes, a number of important human diseases remain challenging targets for vaccine development, including HIV, malaria, tuberculosis, and influenza. Traditional strategies based upon inactivated/attenuated pathogens or major antigenic subunits have been largely unsuccessful, and other approaches to vaccine design need to be explored. For many of these pathogens, such as HIV and influenza, neutralizing antibodies are key to protective immunity, but vaccination typically induces a fairly narrow, strain-specific response. Consequently, little protection is conferred against heterologous challenge with an antigenically distinct virus strain. However, more broadly neutralizing antibodies have been identified that protect against multiple HIV or influenza virus clades or subtypes, and a vaccine that re-elicited such broadly neutralizing antibodies may lead to immunity to a larger number of virus lineages. Towards this end, we have set out to understand the molecular basis for the neutralizing activity of a panel of antibodies against influenza viruses. Crystal structures of several neutralizing antibodies in complex with hemagglutinin, the major influenza surface antigen, have revealed the presence of at least 3 conserved epitopes on HA, and antibodies targeting these epitopes are broadly neutralizing. Our understanding of the molecular details of these antibody-antigen interactions has suggested new strategies for the rational design of improved influenza vaccines, and inspired the development of new antivirals for the treatment of influenza infections.