Hemagglutinin stem reactive antibody response in individuals immunized with a seasonal influenza trivalent vaccine

Protein & Cell, May 2015

Xiaopeng Zhao, Kun Qin, Jinlei Guo, Donghong Wang, Zi Li, Wenfei Zhu, Liqi Liu, Dayan Wang, Yuelong Shu, Jianfang Zhou

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Hemagglutinin stem reactive antibody response in individuals immunized with a seasonal influenza trivalent vaccine

The Author(s) 2015. This article is published with open access at Springerlink.com and journal.hep.com.cn Hemagglutinin stem reactive antibody response in individuals immunized with a seasonal influenza trivalent vaccine Dear Editor - Influenza is a contagious, acute respiratory disease caused by influenza viruses. Type A influenza virus has a broad host range and has caused substantial human morbidity and mortality. There are sixteen subtypes of influenza A virus so far, which are divided into two distinct groups: group 1 (H1, H2, H5, H6, H8, H9, H11, H12, H13 and H16) and group 2 (H3, H4, H7, H10, H14 and H15) (Corti et al., 2011). Seasonal H1 and H3 subtype influenza viruses are circulating in the human population. Vaccination is widely used for the prophylaxis and the antibodies (Abs) induced by the vaccine were conventionally thought to be mainly directed against the variable head region in HA. Those Abs could block viral binding to the sialic acid receptors on cell surface (Skehel and Wiley, 2000). They are typically effective against antigenically close-related strains and thus need to be updated annually. Recently, a number of broadly neutralizing monoclonal antibodies (BnAbs) directed against the HA stem have been identified, including CR6261, F10, FI6v3, FE43 and FE17 and so on (Corti et al., 2010; Corti et al., 2011; Sui et al., 2009; Throsby et al., 2008). The stem-reactive Abs also performed neutralizing activity by either blocking viral fusion or preventing the cleavage by host protease (Ekiert et al., 2009). Furthermore, the development of those BnAbs is not only correlated with antigen immunogenicity but also with the host genetic background (Ellebedy et al., 2014; Li et al., 2012; Pappas et al., 2014). However, whether human serum has such kind of Abs and the frequency or magnitude of the Abs in peripheral blood are not fully answered. BnAbs against Group 1 HA have been discovered from 4 out of 24 donors vaccinated by seasonal-flu vaccine (Corti et al., 2010). Here, we focused on the Chinese adults vaccinated by a seasonal trivalent vaccine in 2009 containing A/Brisbane/59/2007 (Br59, H1N1), A/Brisbane/10/2007 (H3N2), and B/Florida/4/2006. The serum Ab profile on Day 0 and Day 21 from 49 volunteers was determined. Initially, the Ab response to homologous Br59-HA was measured by enzyme-linked immunosorbent assay (ELISA). Most donors had detectable Br59-HA binding antibody titer before vaccination and the geometric mean titer (GMT) was 105.93 1.17. As expected, the strain-specific Ab titer increased dramatically after vaccination (P < 0.0001) and the GMT was up to 772.68 1.18 (Fig. 1A). In consistent with the Hemagglutination-inhibition (HI) titers reported in the previous study (Wu et al., 2011), a more than 2.5-fold increase of Br59HA binding Ab titer was detected in 87.8% of the cohort after immunization (Fig. 1B), suggesting that the vaccine was efficient to induce homologous H1 subtype Ab response. To determine the cross-reactive Abs after vaccination, we then screened the 49 paired sera using recombinant HA derived from A/California/04/2009 (CA04, H1N1). As shown in the Fig. 1C, a low level of CA04-HA binding Abs, around 97.27 1.18 was observed, the Ab response was boosted after vaccination and the GMT was 200.45 1.14. Among them, 17 donors had a more than 2.5-fold increase of CA04HA binding Ab titer after immunization (Fig. 1D). We further measured if there were any heterosubtypic Abs against H5HA in the 17 paired sera. Among them, only 6 had a detectable H5-HA binding Abs and the GMT was 37.24 1.69 on Day 0, other 11 had a very low, even undetectable titer. While after vaccination, a 2.5-fold increase of H5-HA binding Ab titer was found in 11 donors and the GMT was 160.32 1.56 (P < 0.05, Fig. 1E). Since Br59-HA has great antigenic variability with CA04HA in the head region, with the amino acid identity in the stem domain being high as 89.5%, we speculated the cross-reactivity of the Abs might target HA stem, a highly conserved domain in HA (Table S1). As stem-reactive Abs were present at an extremely lower level and any biological interference caused by agents from sera disturbing the cross-binding Abs remained uncertain, we enriched the immunoglobulins (Igs) in the 17 paired sera by Protein A and measured their neutralizing activity with pseudovirus particles (pps) bearing a chimeric HA (cH5/1 SZ) as described in the Materials and Methods. The neutralizing Ab titer was defined as the reciprocal of the serum dilution causing a 90% reduction of relative luciferase unite (RLU) compared to the control. Seven of them showed neutralizing activity, four had a titer of more than 8 after immunization, and one with a titer of 2 and two had a titer of 2 preand post-immunization (Fig. 2A). The correlation analysis 144 r itte107 b A fo70 se40 a e r c ind20 l o F r e itt b 15 A f o sea 10 e r c n i ld 5 o F2.5 0 Ab binding to Br59-HA (H1) Ab binding to CA04-HA (H1) between Br59-HA bi (...truncated)


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Xiaopeng Zhao, Kun Qin, Jinlei Guo, Donghong Wang, Zi Li, Wenfei Zhu, Liqi Liu, Dayan Wang, Yuelong Shu, Jianfang Zhou. Hemagglutinin stem reactive antibody response in individuals immunized with a seasonal influenza trivalent vaccine, Protein & Cell, 2015, pp. 453-457, Volume 6, Issue 6, DOI: 10.1007/s13238-015-0160-6