Fc or not Fc; that is the question: Antibody Fc-receptor interactions are key to universal influenza vaccine design

Abstract

A universal vaccine that provides long-lasting protection from both epidemic and pandemic influenza viruses remains the "holy grail" of influenza vaccine research. Though virus neutralization assays are the current benchmark of measuring vaccine effectiveness, it is clear that Fc-receptor functions can drastically improve the effectiveness of antibodies and vaccines in vivo. Antibodies that kill virus-infected cells and/or elicit an antiviral environment, termed antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies, provide a link between the innate and adaptive immune response. New technologies allowing the rapid isolation and characterization of monoclonal antibodies (mAb) have yielded a plethora of mAbs which target conserved regions of influenza virus, such as the hemagglutinin (HA) stem region. Many such mAbs have been used to gain a better understanding of Fc-receptor functions in vivo. In parallel, several studies have characterized the induction of polyclonal ADCC following influenza vaccination and infection in humans. Taken together, these studies suggest that ADCC-mediating antibodies (ADCC-Abs) significantly contribute to host immunity against influenza virus and may be a mechanism to exploit for rational vaccine and therapeutic design. We discuss recent research on influenza-specific ADCC and potential future avenues to extend our understanding.

Keywords: antibody-dependent cellular cytotoxicity; influenza; monoclonal antibodies; universal vaccine.

Figure 1.

Possible mechanisms of influenza-specific ADCC. (A) Differential ability of HA-specific mAbs to mediate ADCC. Mabs targeting regions of influenza virus HA (stem or head region) have the ability to mediate ADCC (HAI⁻ head-specific mAbs or stem-specific mAbs), cannot mediate ADCC (HAI⁺ head-specific mAbs) or inhibit ADCC (HAI ⁺ head-specific with stem-specific mAbs). (B) Potential role of neutralizing and non-neutralizing (including ADCC-Abs) antibodies against seasonal influenza viruses that antigenically drift through influenza seasons. High concentractions of neutralizing antibodies against seasonal influenza virus entry before infection is established, such as following "matched" seasonal influenza vaccination or homologous influenza control of virus infection. Moderate neutralization and cross-reactive non-nuetralizing antibodies may lead to some infection but provide rapid control of virus infection and clearance, as maybe the case following vaccine miss-match or heterologous influenza infection. Low neutralizing and high cross-reactive non-neutralizing antibodies may not prevent influenza virus infection but reduce the severity of influenza infection.