Antibody-Dependent Cell-Mediated Cytotoxicity to Hemagglutinin of Influenza A Viruses After Influenza Vaccination in Humans

Hemagglutinin (HA) is the major glycoprotein expressed on the surface of influenza A viruses. A total of 18 antigenically different HA subtypes have been identified so far, with each sharing 40%–60% amino acid sequence identity [1]. Seasonal H1 and H3 subtypes of influenza A viruses have been circulating among human populations for decades and cause annual influenza epidemics. Recently, emerging avian influenza A viruses, including H5, H7, and H9 subtypes, have caused serious infections in humans and pose a new threat for public health. Vaccination is an efficient approach to prevent human influenza illness. The current seasonal trivalent inactivated influenza vaccines (TIVs) are highly immunogenic in inducing neutralizing antibodies (nAbs) to the HA antigens [2]. Two types of HA-specific nAbs have been identified so far: conventional nAbs (cnAbs) and broadly nAbs (bnAbs). Conventional nAbs primarily recognize antigenic sites located within the HA globular head [3]. Whereas the globular head undergoes constant antigenic drift, cnAbs are often strain-specific [4]. Nevertheless, detection of cnAbs by conventional serological assays such as hemagglutination inhibition (HI) assay and/or microneutralization (MN) assay is currently the main way of assessing protection after influenza virus infection or vaccination. In addition to strain-specific cnAbs, bnAbs to HA antigens have been identified [5]. These bnAbs primarily target amino acid sequences within the membrane proximal HA stem region that are conserved among diverse HA subtypes [5]. Levels of bnAbs are extremely low or undetectable in human sera after seasonal influenza vaccination [6]. In contrast to seasonal TIV, prepandemic avian influenza vaccines containing H5, H7, or H9 subtypes are poorly immunogenic in inducing nAbs [7, 8]. Multiple dosing or coadministration with an adjuvant is generally required to elicit detectable levels of nAbs after immunization [9]. However, it has been shown in animal models that avian influenza vaccines can provide considerable protection despite no or low levels of nAbs induced [10]. This raises an important question of whether detection of cnAbs alone can fully reflect the protective capacity of antiavian HA Abs after vaccination with current avian influenza vaccines. In a recent study, Jegaskanda et al [11] reported that pre-existing HA-specific Abs in normal human sera (NHS) possessed cross-reactive Ab-dependent cell-mediated cytotoxicity (ADCC) against a wide range of HA subtypes, including both seasonal and avian HA subtypes. Notably, they found that ADCC activities toward H1 antigen of the 2009 pandemic H1N1 virus was inversely correlated with the age of the patients [12], a finding that is in line with the epidemiological data [13]. Further study in a rhesus macaque model suggested that influenza virus-specific ADCC may be associated with control of pandemic H1N1 virus infection [14]. Taken together, current evidence clearly suggests potential involvement of HA-specific ADCC in protection against influenza illness. Despite recent progress, several important questions remain unanswered, partially due to the lack of a robust ADCC assay. First, what is the relation between HA-associated virus neutralization (VN) and ADCC activities after seasonal versus avian influenza vaccination? Second, which factors primarily determine the strength of HA-specific ADCC activities in human sera? Third, what potential values could in vitro measurement of HA-specific ADCC add to immune correlates of protection after influenza vaccination? In the present study, we demonstrate that a combination of both nAbs and ADCC-mediating Abs (adccAbs) may provide a better correlate of protection than nAbs alone in assessment of protective efficacy of avian influenza vaccines.