Human antibody response to zoonotic influenza A viruses

Abstract

Annual outbreaks of influenza A viruses in humans are one of the major health problems worldwide, causing more than 250,000 deaths every year. In addition to yearly epidemics, novel influenza viruses that cross the species barrier to humans can cause deadly pandemics with high morbidity and mortality rates. Understanding the human antibody response to these novel viruses and identifying their structural and functional mode of protection is the key to designing effective vaccines against influenza A viruses. The goal of creating a universal influenza vaccine against all existing subtypes is severely hindered by the variability seen in the two viral surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), which are the major targets for neutralizing antibodies. From a large panel of human antibodies that were isolated from individuals that were either vaccinated or infected with different influenza A subtypes, we have identified monoclonal antibodies (mAbs) that target novel epitopes on HA conserved across subtypes and therefore exhibit broad influenza A activity. These mAbs function through a variety of neutralizing and non-neutralizing mechanisms including Fc-mediated effector functions. The identification of these broadly functional antibodies not only provides the basis for development of a universal influenza vaccine but also identifies potential candidates for treatment.