Relationship of the quaternary structure of human secretory IgA to neutralization of influenza virus

Abstract

Secretory IgA (S-IgA) antibodies, the major contributors to humoral mucosal immunity to influenza virus infection, are polymeric Igs present in many external secretions. In the present study, the quaternary structures of human S-IgA induced in nasal mucosa after administration of intranasal inactivated influenza vaccines were characterized in relation to neutralization potency against influenza A viruses. Human nasal IgA antibodies have been shown to contain at least five quaternary structures. Direct and real-time visualization of S-IgA using high-speed atomic force microscopy (AFM) demonstrated that trimeric and tetrameric S-IgA had six and eight antigen-binding sites, respectively, and that these structures exhibited large-scale asynchronous conformational changes while capturing influenza HA antigens in solution. Furthermore, trimeric, tetrameric, and larger polymeric structures, which are minor fractions in human nasal IgA, displayed increased neutralizing potency against influenza A viruses compared with dimeric S-IgA, suggesting that the larger polymeric than dimeric forms of S-IgA play some important roles in protection against influenza A virus infection in the human upper respiratory tract.

Immune Responses Induced by Recombinant Bacillus Subtilis Expressing the Hemagglutinin Protein of H5N1 in chickens

“…In addition, avian influenza H5N1 has been detected in the nasal cavity mucosa, lungs, cloaca, and serum of aerosol-infected chickens38. Secretory IgA antibodies are the major contributors to humoral mucosal immunity against an influenza viral infection39. Our results show that oral administration of B.S.-HA increased the specific IgA antibody level in tracheal suspensions.…”

Intranasal Inactivated Influenza Vaccines: a Reasonable Approach to Improve the Efficacy of Influenza Vaccine?

“…The nasally administered inactivated WV vaccines also induced high levels of HI and NT Ab titers, together with a weaker IgG response, in the upper respiratory tract; however, nasal HI titers have not yet been evaluated in terms of vaccine efficacy because of the lack of available criteria for assessment. In addition, one clinical study demonstrated that the ability of human S-IgA Abs to neutralize influenza viruses increased with increasing polymerization of IgA (IgA Abs can form dimers, trimers, tetramers, and larger polymers), suggesting that polymeric S-IgA plays a crucial role in protecting against both homologous and variant influenza viruses (45).…”

“…Here, to demonstrate the utility of nasal-inactivated vaccines, we will present some of our own preclinical studies conducted in an influenza mouse model, along with the results of our clinical trials (43)(44)(45). Based on these studies, we propose that intranasal, inactivated vaccines should be developed to improve on influenza vaccine efficacy.…”

“…When used as a two-dose regimen, the intranasally administered SV vaccine failed to induce serum HI Ab titers that fulfilled the EMA criteria. Next, we obtained nasal wash samples from adult volunteers immunized intranasally in a five-dose regimen with an inactivated WV vaccine derived from an A/Victoria/210/2009 (H3N2)-like virus and examined the relationship between the structure of human S-IgA Abs and NT activity against influenza virus (45). The nasal wash samples were concentrated, separated by gel filtration chromatography, and then NT activity was measured.…”

More robust gut immune responses induced by combining intranasal and sublingual routes for prime-boost immunization

“…13 Higher quaternary structure SIgA induced by intranasal vaccination displayed increased neutralizing potency against influenza virus. 14 Antigen-specific IgA can be induced not only by immunization in the vicinity of corresponding mucosal tissues but also through common mucosal conduits such as oral, sublingual (SL), IN, or rectal routes. 15 Mucosa-administered antigens are generally less immunogenic and apt to induce tolerance since the host strives to maintain mucosal homeostasis by responding to mucosal antigens with tolerance.…”