Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine

Abstract

The target of neutralizing antibodies that protect against influenza virus infection is the viral protein HA. Genetic and antigenic variation in HA has been used to classify influenza viruses into subtypes (H1-H16). The neutralizing antibody response to influenza virus is thought to be specific for a few antigenically related isolates within a given subtype. However, while heterosubtypic antibodies capable of neutralizing multiple influenza virus subtypes have been recently isolated from phage display libraries, it is not known whether such antibodies are produced in the course of an immune response to influenza virus infection or vaccine. Here we report that, following vaccination with seasonal influenza vaccine containing H1 and H3 influenza virus subtypes, some individuals produce antibodies that cross-react with H5 HA. By immortalizing IgG-expressing B cells from 4 individuals, we isolated 20 heterosubtypic mAbs that bound and neutralized viruses belonging to several HA subtypes (H1, H2, H5, H6, and H9), including the pandemic A/California/07/09 H1N1 isolate. The mAbs used different VH genes and carried a high frequency of somatic mutations. With the exception of a mAb that bound to the HA globular head, all heterosubtypic mAbs bound to acid-sensitive epitopes in the HA stem region. Four mAbs were evaluated in vivo and protected mice from challenge with influenza viruses representative of different subtypes. These findings reveal that seasonal influenza vaccination can induce polyclonal heterosubtypic neutralizing antibodies that cross-react with the swine-origin pandemic H1N1 influenza virus and with the highly pathogenic H5N1 virus.

Prevalence and Predictors for Homo- and Heterosubtypic Antibodies Against Influenza A Virus

“…These findings corroborate previous findings made by biochemical analysis of a limited number of samples [4,8]. We have found that vaccination not only enhanced antibody responses to subtypes that are currently circulating, and are therefore included in the vaccine, but also augmented binding and neutralizing antibody titers to Reference age: 0-40 years.…”

Influenza virus A(H1N1)2009 antibody-dependent cellular cytotoxicity in young children prior to the H1N1 pandemic

“…Notably, the highest induction of ADCC in response to HA1 or the HA trimer was detected in the pre-pandemic samples (#3 and #51, Fig. 5 Several studies have shown pre-existing immunity against A(H1N1)2009 in adults (Corti et al, 2010(Corti et al, , 2011Ekiert et al, 2009;Throsby et al, 2008), whereas little or no preexisting cross-reactive antibodies were detected in a group of 124 children aged 6 months to 9 years (Hancock et al, 2009) the HA2 domain, which is not presented in our array (Greenbaum et al, 2009;Li et al, 2012).…”

“…Persons born before the 1940s were most protected against the A (H1N1)2009, which has been related to the similarity between the HA1 of the 1918 and 2009 pandemic strains Xu et al, 2010); however, some protection was also observed in younger adults. Cross-neutralizing antibodies have been implicated in this immune protection, possibly resulting from the boosting of antibodies that had developed against previous seasonal strains ( Corti et al, 2010Corti et al, , 2011Ekiert et al, 2009;Li et al, 2012;Throsby et al, 2008;Wrammert et al, 2011). However, cross-reactive antibodies were hardly detected among children aged 6 months to 9 years (Hancock et al, 2009).…”

Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells

“…These Abs were shown to have neutralizing activity against multiple influenza subtypes and were identified using a number of systems including phage display (2-4) and immortalization of memory B cells (5). We then demonstrated that these stem-reactive Abs were readily detected in patients infected with the pandemic H1N1 2009 influenza (referred to as pH1N1 2009 from here on) (7).…”