Different mechanisms of the protection against influenza A infection mediated by broadly reactive HA2-specific antibodies.

Influenza A viruses (IAVs) cause yearly repeating infections in humans. The current vaccination approach is based on the production of virus-neutralizing antibodies. Virus-neutralizing antibodies, however, are closely strain-specific due to the IAV variability. Therefore, antibodies produced during the previous influenza season do not provide sufficient protection against new infection, and, hence, annual revaccination is needed. The utilization of the influenza conserved stem domain of hemagglutinin (HA), the HA2 gp, led to a new vaccine design based on cross-reactive cellular and especially humoral immune responses represented by HA2-specific antibodies. The HA2-specific antibodies exhibit cross-reactivity with HA2 gp within one subtype or even among subtypes and play a role in protective immunity against influenza infection. There are several elimination mechanisms of viral replication mediated by HA2-specific antibodies. After recognition of the epitope, they prevent the conformational rearrangement of HA or the insertion of the fusion protein into the endosomal membrane and, consequently, the fusion pore formation. In this case, no release of viral genetic information into the target cell is enabled and virus cannot replicate. The HA2-specific antibodies are involved in the elimination of pathogen via the Fc fragment by activation of the cytotoxic mechanisms of innate immunity as are the antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent phagocytosis (ADP), or complement-dependent cytotoxicity (CDC), resulting in virus elimination and earlier recovery of the host from the infection. Though the protective effect of HA2-specific antibodies on the course of IAV infection was shown, few cases of worsening of IAV infection mediated by HA2-specific antibodies have been described. The identification of antigenic epitopes on HA2 gp that induce antibodies with such deteriorating effect on influenza infection can help to eliminate the unsuitable epitopes of HA2 gp as immunogens during the design of heteroprotective vaccine against influenza and can remove the side effects linked with the observations mentioned above. Keywords: influenza A virus; HA2 stem domain of hemagglutinin; immunization strategies; HA2-specific antibodies.