Putative suppressing effect of IgG Fc-conjugated haemagglutinin (HA) stalk of influenza virus H7N9 on the neutralizing immunogenicity of Fc-conjugated HA head: implication for rational design of HA-based influenza vaccines

Abstract

The emergence of influenza A H7N9 in infection has posed a great threat to public health globally. Poor immunogenicity of H7N9 haemagglutinin (HA) is a major obstacle to the development of an effective H7N9 vaccine. Here, we found that the vaccine containing the H7HA head conjugated with IgG Fc (Hd-Fc) induced strong neutralizing antibody responses and protection against H7N9 infection, whilst the Fc-conjugated H7HA stalk (St-Fc)-based vaccine could not induce neutralizing antibodies, although the St-Fc-immunized mice were partially protected. The vaccines containing the full-length extracellular domain of HA conjugated with Fc and the mixture of Hd-Fc plus St-Fc induced significantly lower neutralizing antibody and haemagglutination inhibition titres than the Hd-Fc-based vaccine. These results suggest that the St-Fc may have inhibitory effects on the neutralizing immunogenicity of Hd-Fc. Therefore, the neutralizing domain(s), such as the receptor-binding domain, in the HA head should be kept and the non-neutralizing domain(s) in the HA stalk with the ability to potentially suppress the neutralizing immunogenicity of HA head should be removed from Fc-conjugated HA-based influenza vaccines to increase the neutralizing antibody response.

Immune-engineered H7N9 influenza hemagglutinin improves protection against viral influenza virus challenge

“…H7 HA stalk domains have inhibitory effects on the elicitation of neutralizing antibodies against the HA head domain. 20 Vaccine strategies that excluded the HA2 stalk domain from an Fc-conjugated HA-based influenza vaccine were more effective at eliciting neutralizing antibodies. 20 Replacing the transmembrane domain (TM) of H7 HA with a TM from an H3 HA antigen increased antibody titers and broadened the range of protection against H7N9 influenza virus infection.…”

“… 20 Vaccine strategies that excluded the HA2 stalk domain from an Fc-conjugated HA-based influenza vaccine were more effective at eliciting neutralizing antibodies. 20 Replacing the transmembrane domain (TM) of H7 HA with a TM from an H3 HA antigen increased antibody titers and broadened the range of protection against H7N9 influenza virus infection. 21 The replacement of immunosuppressive motifs in the HA2 stalk domain is an effective approach to improve the poor immunogenicity of H7 HA proteins.…”

Inhibition of influenza A virus and SARS-CoV-2 infection or co-infection by griffithsin and griffithsin-based bivalent entry inhibitor

“…The inhibition of infection by IAV PsVs or SARS-CoV-2 PsVs was performed as described previously ( 48 , 49 ). In brief, pseudotyped IAV or SARS-CoV-2 Omicron variant was mixed with an equal volume of the tested proteins or peptide at the indicated concentration and incubated for 30 min before being transferred to the target cells (MDCK cells for IAV PsVs and Caco-2 cells for SARS-CoV-2) for 12 h. Supernatants were removed, and target cells were cultured with fresh DMEM medium for 48 h. Target cells were lysed, and inhibitory activity was determined using a Luciferase Assay System (Promega, Madison, WI, USA).…”

Antibody Immunity Induced by H7N9 Avian Influenza Vaccines: Evaluation Criteria, Affecting Factors, and Implications for Rational Vaccine Design

“…It is noted that the inhibitory Treg epitope identified in the above immunoinformatics study localizes in the stalk region, indicating that the HA stalk may play a role in the regulation of the immune response. Intriguingly, the stalk region of H7N9 HA indeed had a suppressive effect on immunogenicity of the HA head (He et al, 2016 ). Different regions of HA, including the globular head, the stalk and the ectodomain (contains the head and stalk), fused with the intramolecular adjuvant IgG Fc were expressed.…”