IgA polymerization contributes to efficient virus neutralization on human upper respiratory mucosa after intranasal inactivated influenza vaccine administration

Abstract

Unlike the current injectable influenza vaccines, intranasally administered influenza vaccines induce influenza virus-specific IgA antibodies in the local respiratory mucosa as well as IgG antibodies in the systemic circulation. Our previous study showed that after five volunteers underwent intranasal administration with inactivated H3N2 or H5N1 vaccines, their IgA antibodies on the upper respiratory tract were present as monomers, dimers, and multimers (trimers and tetramers). Moreover, the multimers associated with the highest virus neutralizing activity. However, it has remained elusive whether a more practical intranasal vaccination strategy could induce the high-performance IgA multimers in the nasal mucosa. In the present study, volunteers were administered with two doses of the intranasal trivalent whole-virus inactivated influenza vaccine and showed that in nasal wash samples the amount of multimeric IgA correlated positively with virus neutralizing titers, indicating that the multimeric IgA antibodies play an important role in the antiviral activity at the nasal mucosa. Surface plasmon resonance analysis of the binding dynamics of nasal wash derived IgA monomers, dimers, and multimers against recombinant trimeric influenza virus HA showed that sample fractions containing IgA multimers dissociated from HA less well than sample fractions without IgA multimers. Thus, IgA multimers may "stick" to the antigen more tightly than the other structures. In summary, intranasal administration of two doses of multivalent inactivated influenza vaccines induced multimeric IgA. Multimerization of mucosal IgA antibodies conferred higher neutralizing activity against viruses in the nasal mucosa, possibly by increasing their cohesion to virus antigens.

Vaccines to Prevent Infectious Diseases in the Older Population: Immunological Challenges and Future Perspectives

“…Although data suggest that i.m. and s.c. vaccination is able to induce limited amounts of mucosal IgA mucosal (intranasal) administration of the influenza vaccine can improve this effect (181). An intranasally administered virosomal influenza vaccine adjuvanted with LT (heat labile enterotoxin of Escherichia coli) has been withdrawn during the 2000/2001 season shortly after marketing due to safety issues as Bell palsy cases increased 19-fold (due to accumulation of LT in the olfactory bulb) (182,183).…”

How to assess the effectiveness of nasal influenza vaccines? Role and measurement of sIgA in mucosal secretions

“…It has been hypothesized that pIgA may have a higher ability than mIgA to neutralize intracellular viral particle assembly by binding newly synthesized viral proteins . It has also been demonstrated that the polymeric nature of sIgA was responsible for their elevated cross‐reactivity, thereby increasing the avidity of this antibody subclass in comparison with mIgA and serum IgG …”

“…5,17,26 It has also been demonstrated that the polymeric nature of sIgA was responsible for their elevated cross-reactivity, thereby increasing the avidity of this antibody subclass in comparison with mIgA and serum IgG. 27,28 The best neutralizing activity and the higher avidity of human pIgA than mIgA can be attributed to the presence of multiple antigen-binding sites located on each Ig polymer, indicating that the quaternary structure plays a key role for their potency. 25 This result is in accordance with previous researches conducted on mice.…”

Human immune responses elicited by an intranasal inactivated H5 influenza vaccine

“…S‐IgA antibodies in the nasal mucosa are cross‐protective against not only antigenically homologous viruses but also antigenically heterologous viruses, and exist in the form of multimers such as trimers and tetramers. These multimeric S‐IgA antibodies display superior neutralizing potency against influenza A viruses compared with dimeric S‐IgA antibodies 8,9 . We previously showed that in the case of seasonal influenza vaccination, two doses of an intranasal inactivated whole‐virion vaccine could successfully induce S‐IgA and IgG responses in the nasal mucosa and serum, respectively, in healthy adults 9,10 .…”