Abstract
Background: Recently, several human monoclonal antibodies that target conserved epitopes on the stalk region of influenza hemagglutinin (HA) have shown broad reactivity to influenza A subtypes. Also, vaccination with recombinant chimeric HA or stem fragments from H3 influenza viruses induce broad immune protection in mice and humans. However, it is unclear whether stalk-binding antibodies can be induced in human memory B cells by seasonal H3N2 viruses. Methods:In this study, we recruited 13 donors previously exposed to H3 viruses, the majority (12 of 13) of which had been immunized with seasonal influenza vaccines. We evaluated plasma baseline strain-specific and stalk-reactive anti-HA antibodies and B cell recall responses to inactivated H3N2 A/Victoria/361/2011 virus in vitro using a high throughput multiplex (mPlex-Flu) assay. Results: Stalk-reactive IgG was detected in the plasma of 7 of the subjects. Inactivated H3 viral particles rapidly induced clade cross-reactive antibodies in B cell cultures derived from all 13 donors. In addition, H3 stalk-reactive antibodies were detected in culture supernatants from 7 of the 13 donors (53.8%). H3 stalk-reactive antibodies were also induced by H1 and H7 subtypes. Interestingly, broadly cross-reactive antibody recall responses to H3 strains were also enhanced by stimulating B cells in vitro with CpG 2006 ODN in the presence of IL-15. H3 stalk-reactive antibodies were detected in CpG 2006 ODN + IL-15 stimulated B cell cultures derived from 12 of the 13 donors (92.3%), with high levels detected in cultures from 7 of the 13 donors. Conclusions: Our results demonstrate that stalk-reactive antibody recall responses induced by seasonal H3 viruses and CpG 2006 ODN can be enhanced by IL-15.
Highlights
Worldwide, annual influenza epidemics are estimated to result in about 3 to 5 million cases of severe illness, and about 250,000 to 500,000 deaths[1,2]
Our results demonstrate that stalkreactive IgG antibodies induced by B cell exposure to H3 viruses in vitro, in the presence of CpG2006 ODN, are enhanced by IL-15 co-administration
Prevalence of H3-specific and stalk-reactive IgG To evaluate the anti-influenza antibodies in plasma from 13 subjects and further infer influenza-specific memory B cells in their peripheral blood, we examined H3 HA-specific IgG levels using our mPlex-Flu assay
Summary
Annual influenza epidemics are estimated to result in about 3 to 5 million cases of severe illness, and about 250,000 to 500,000 deaths[1,2]. Under the selective pressure of host immunity, H3N2 influenza virus HAs have undergone progressive antigenic drift This became problematic during the 2014–2015 influenza season, when H3N2 strains became predominant and were antigenically and genetically distinct from the A/Texas/50/2012 (A/Tex12) vaccine strain[10,11]. Vaccination with recombinant chimeric HA or stem fragments from H3 influenza viruses induce broad immune protection in mice and humans. It is unclear whether stalk-binding antibodies can be induced in human memory B cells by seasonal H3N2 viruses. Conclusions: Our results demonstrate that stalk-reactive antibody recall responses induced by seasonal H3 viruses and CpG2006 ODN can be enhanced by IL-15
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