A systematic review and meta-analysis of cross-reactivity of antibodies induced by H7 influenza vaccine

Inoculation with vaccine is the major intervention currently used to prevent influenza infections. However, it will be a challenge to produce and implement a new vaccine when a novel highly pathogenic influenza virus emerges in humans as significant infections. H7 subtype influenza viruses have similar epitopes on hemagglutinin, which can induce cross-reactive antibodies. In this study, a meta-analysis of the cross-reactivity of antibodies induced by one H7 subtype influenza vaccine against other H7 subtypes was performed. Database search was conducted in PubMed, Cochrane Library, EMBASE, MEDLINE, Chinese Biological Medicine Database (CBM), and Wanfang. A total of 9 articles comprising 811 human subjects were included in this meta-analysis. All assessed H7 influenza vaccines induced vaccine strain-specific protective antibodies [seroconversion rate (SCR) = 0.74, 95% CI (0.65, 0.82); seroprotection rate (SPR) = 0.81, 95% CI (0.78, 0.83)]. All H7 influenza virus monovalent vaccines exhibited cross-reactivity tested by hemagglutinin inhibition test (HI), microneutralization test (MN) and immunosorbent assay (ELISA) to other H7 subtype viruses. H7N1, H7N3, H7N7, and H7N9 vaccines elicited cross-reactive antibodies against other H7 subtype influenza viruses [SCR = 0.66, 95% CI (0.50, 0.82); SPR = 0.79, 95% CI (0.67, 0.91)]. The pooled SCR (95%CI) of cross-reactivity of H7N1 and H7N3 vaccines were 0.88 (0.85, 0.91) and 0.40 (0.26, 0.54), respectively. The consolidated SPR (95%CI) of H7N1 and H7N7 vaccines were 0.89 (0.86, 0.92) and 0.93 (0.81, 1.06). All H7 vaccines induced cross-reactive antibodies against H7N9 viruses [SCR = 0.69, 95% CI (0.52, 0.86); SPR = 0.85, 95% CI (0.76, 0.94)]. H7 vaccines can be used to limit influenza infection when a new highly pathogenic H7 virus appears

Immunogenicity of H5N1 influenza vaccines in elderly adults: a systematic review and meta-analysis

Several different vaccines have been produced for human use to prevent the highly pathogenic H5N1 influenza. Some studies reported that the clinical effectiveness of influenza vaccines in older adults may be lower than in younger adults. In this study, a meta-analysis of the immunogenicity of H5N1 influenza vaccines in elderly adults was performed. Database search was conducted in EMBASE, PubMed, the Cochrane Library, Chinese VIP, Wanfang and CBM. A total of 3951 elderly adults from 10 articles were included in the meta-analysis. Compared to a single dose, two doses of H5N1 vaccines resulted in the higher seroconversion and seroprotection. For all groups treated with adjuvanted vaccines, there were significant increases (1.55- to 2.16-fold) in the seroconversion rates (SCRs) and seroprotection rates (SPRs) after two immunizations. Oil-in-water emulsion (OE)-adjuvanted 7.5 μg vaccine caused higher antibody responses than 3.75 μg of vaccine (SCR: risk ratio (RR) = 1.26 (1.19, 1.33); SPR: RR = 1.25 (1.14, 1.36)). Elderly adults exhibited slightly lower antibody responses only when given 7.5 μg of OE-adjuvanted vaccine (SCR: RR = 1.06 (1.01, 1.11)) than younger adults. After treatment with the 7.5 μg of OE-adjuvanted vaccines, the most commonly reported adverse events were injection site pain, swelling and erythema, with the incidence of 32%, 3% and 2%, respectively, and no serious adverse events were found. These data demonstrate that two doses of 7.5 µg of OE-adjuvanted H5N1 vaccine are well tolerated and induce a robust antibody response in elderly adults

IL-15 enhances cross-reactive antibody recall responses to seasonal H3 influenza viruses in vitro [version 1; referees: 2 approved]

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 CpG2006 ODN in the presence of IL-15. H3 stalk-reactive antibodies were detected in  CpG2006 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 CpG2006 ODN can be enhanced by IL-15

IL-31 plays dual roles in lung inflammation in an OVA-induced murine asthma model

Interleukin 31 (IL-31) is a four-helix cytokine made predominantly by Th2 CD4+ T cells. It was initially identified as being associated with the promotion of atopic dermatitis, where increased levels of IL-31 levels have been found and IL-31 induced the expression of proinflammatory cytokines and chemokines in a human bronchial epithelial cell line. However, subsequent study has shown that IL-31RA knockout mice developed exacerbated type 2 inflammation in the lung following infection with Schistosoma mansoni eggs. In this study, we investigated the dynamic expression of IL-31 and IL-31RA during eight consecutive ovalbumin (OVA) challenges and measured the chemokines from lung alveolar epithelial cells induced by IL-31. In addition, we examined the effect deletion of IL-31RA has on lung inflammation and the differentiation of CD4+ T cells. Our results demonstrate that the expression of IL-31 and IL-31RA was elevated after each weekly OVA challenge, although slightly less of both observed after the first week of OVA challenge. IL-31 also promoted the expression of inflammatory chemokines CCL5, CCL6, CCL11, CCL16, CCL22, CCL28, CX3CL1, CXCL3, CXCL14 and CXCL16 in alveolar epithelial cells. Migration of macrophages and T cells was enhanced by culture supernatants of IL-31-stimulated alveolar epithelial cells. Lastly, and in contrast to the IL-31 results, mice deficient in IL-31RA developed exacerbated lung inflammation, increased IL-4-positive cell infiltrates and elevated Th2 cytokine responses in draining lymph nodes. The proliferation of IL-31RA−/− CD4+ T cells was enhanced in vitro after anti-CD3/anti-CD28 antibody stimulation. These data indicate that IL-31/IL-31RA may play dual roles, first as an early inflammatory mediator promoting the secretion of chemokines to recruit inflammatory cells, and subsequently as a late inflammatory suppressor, limiting Th2 cytokine responses in allergic asthma

Anamnestic broadly reactive antibodies induced by H7N9 virus more efficiently bind to seasonal H3N2 strains

The very first influenza virus exposure in a human during infancy is known to imprint the host immune system. However, it is unclear how the memory B cells that first target virus epitopes affect antibody response to the stalk of hemagglutinin (HA) domain of influenza virus. Our study is designed to measure the cross-reactivity of antibodies induced by inactivated H7N9 virus using isolated human peripheral blood B cells. Most of the participants displayed higher levels of plasma IgG against the seasonal strains A/Vic11 and A/Cali09 than those binding to historical outbreak A/HK68 and A/PR8. H3 stalk-binding antibodies were detected in plasma at a 1:5000 dilution in 12 of 13 donors, H1 stalk-binding antibodies in all donors, indicating the existence of H3 and H1 stalk-reactive memory B cells. A moderate to high level of broadly cross-reactive antibodies was induced in memory B cells from all donors after in vitro stimulation of B cells with H7N9 virus. H3 stalk-binding antibodies were also detected in most subjects, with cross-reactivity to H1 and H7 stalk domains. The stalk-reactive antibodies bound to five H3 strains spanning 45 years and different H1, H2, H3, H5, H6, H7, H9 and B strains. Interestingly, H1- and H3-reactive IgG were much higher than H7-binding antibodies after 6 days of H7N9 stimulation. Our results demonstrate that HA stalk-reactive antibodies induced by H7N9 viruses more efficiently bound to yearly circulating both H3N2 and H1N1 strains than the boosting strain, indicating that HA stalk immunological imprint can be extended across currently circulating strains or vaccines

Dataset 1: Anti-H3 Stalk Reactive Antibodies in Human Plasma

Plasma was obtained from 13 donors, 12 of which had been previously vaccinated within the past 5 years with trivalent or quadrivalent seasonal influenza vaccines. Plasma baseline anti-influenza IgG was measured by mPlex-Flu assay. (A) Levels of IgG against distinct H3N2 strains. Each column depicts mean fluorescence intensity (MFI), representing an individual donor. (B) Levels of H3 stalk-reactive IgG. Each symbol and line represents one donor. (C) IgG-binding to chimeric cH5/1 and cH5/3 proteins. This analysis was performed at a 1:5000 dilution

Dataset 2: Secretion of H3 clade cross-reactive antibodies by B cells stimulated with inactivated A/Vic11

Purified B cells were obtained by negative selection and stimulated with CpG ODN alone or together with A/Vic11 or A/SH13 for 6 days. (A) ASCs for H3 HA were examined by ELISpot assay. H3-binding antibodies in supernatants of activated B cells were monitored using beads bound with HA from H3N2 strains. (B) A/Vic11-specific IgG. Each symbol represents an individual donor. One-way AVONA was used to evaluate the difference among different groups (* P<0.05; ** P<0.01). (B) Results were verified by ELISpot after stimulation with A/Vic11. The values represent the number of anti-HA IgG specific antibody-secreting cells in 1.25 x 10^5 stimulated B cells/donor. (C) Correlation between anti-A/Vic11 IgG levels in plasma and secretion of A/Vic11-specific IgG by activated B cells. (D) Antibodies binding to H3 clades. (E) Comparison of A/Vic11-specific IgG and A/Swi13-reactive IgG

Dataset 6: Stalk-reactive antibody responses to H3 viruses enhanced by Il-15

Purified B cells were costimulated with CpG₂₀₀₆, A/Victoria/361/2011 viruses and IL-15. Stalk-reactive IgG in supernatants was detected at day 6. Chimeric molecules cH5/3, cH4/7 and cH5/1 were used for assessing antibodies against H3 stalk, H7 stalk and H1 stalk, respectively. Each symbol and line represents an individual donor. (A) H3 stalk-reactive antibodies. (B) H7 Stalk-reactive antibodies. (C) H1 stalk-reactive antibodies

Dataset 3: Influenza viruses induce cross-reactive antibody responses in vitro

B cells were obtained by negative selection, and then stimulated with CpG ODN 2006 or together with A/Vic11 for 6 days. Cross-reactive antibodies binding to H1, H2, H5, H6, H7 and B influenza subtypes in B cell culture were measured by mPlex-Flu assay. (A) Fold change in cross-reactive antibodies. All values of IgG levels (MFI) were subtracted those of medium before calculating fold change. Only those values of IgG induced by CpG plus A/Vic11 viruses, which were greater than 100, were selected to calculate fold change. Each symbol represents the median of fold change in levels of IgG induced by CpG plus H3 to IgG stimulated by CpG 2006 ODN alone. (B) Correlation between influenza specific antibodies and HA antigenic sequence

Dataset 4 - Induction of HA stalk-reactive antibodies by H3 viruses

B cells from healthy donors were stimulated with CpG 2006 ODN alone or together with inactivated A/Vic11 viruses, A/SH13 (H7N9), and A/Hong Kong/33982/2009 (A/HK09) (H9N2) and pandemic H1N1 viruses. The levels of IgG against H3 HA, H5 head and chimeric molecules cH5/3 are shown for individual honors. (A) Nine of 13 donors displayed increases in stalk-reactive IgG after A/Vic11 stimulation. (B, C) A correlation model assuming different coefficients for different H3N2 strains-specific antibodies was fitted to evaluate the relationship between HA stalk-reactive and strain-specific IgG