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Use of Hemagglutinin Stem Probes Demonstrate Prevalence of Broadly Reactive Group 1 Influenza Antibodies in Human Sera.

ABSTRACT: A better understanding of the seroprevalence and specificity of influenza HA stem-directed broadly neutralizing antibodies (bNAbs) in the human population could significantly inform influenza vaccine design efforts. Here, we utilized probes comprising headless, HA stabilized stem (SS) to determine the prevalence, binding and neutralization breadth of antibodies directed to HA stem-epitope in a cross-sectional analysis of the general population. Five group-1 HA SS probes, representing five subtypes, were chosen for this analyses. Eighty-four percent of samples analyzed had specific reactivity to at least one probe, with approximately 60% of the samples reactive to H1 probes, and up to 45% reactive to each of the non-circulating subtypes. Thirty percent of analyzed sera had cross-reactivity to at least four of five probes and this reactivity could be blocked by competing with F10 bNAb. Binding cross-reactivity in sera samples significantly correlated with frequency of H1+H5+ cross-reactive B cells. Interestingly, only 33% of the cross-reactive sera neutralized both H1N1 and H5N1 pseudoviruses. Cross-reactive and neutralizing antibodies were more prevalent in individuals >50 years of age. Our data demonstrate the need to use multiple HA-stem probes to assess for broadly reactive antibodies. Further, a universal vaccine could be designed to boost pre-existing B-cells expressing stem-directed bNAbs.

SUBMITTER: Yassine HM

PROVIDER: S-EPMC5988737 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Use of Hemagglutinin Stem Probes Demonstrate Prevalence of Broadly Reactive Group 1 Influenza Antibodies in Human Sera.

Yassine Hadi M HM McTamney Patrick M PM Boyington Jeffery C JC Ruckwardt Tracy J TJ Crank Michelle C MC Smatti Maria K MK Ledgerwood Julie E JE Graham Barney S BS

Scientific reports 20180605 1

A better understanding of the seroprevalence and specificity of influenza HA stem-directed broadly neutralizing antibodies (bNAbs) in the human population could significantly inform influenza vaccine design efforts. Here, we utilized probes comprising headless, HA stabilized stem (SS) to determine the prevalence, binding and neutralization breadth of antibodies directed to HA stem-epitope in a cross-sectional analysis of the general population. Five group-1 HA SS probes, representing five subtyp ...[more]

PMID: 29872070

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Project description:Human influenza virus infections with avian subtype H7N9 viruses are a major public health concern and have encouraged the development of effective H7 prepandemic vaccines. In this study, baseline and postvaccination serum samples of individuals aged 18 years and older who received a recombinant H7 hemagglutinin vaccine with and without an oil-in-water emulsion (SE) adjuvant were analyzed using a panel of serological assays. While only a small proportion of individuals seroconverted to H7N9 as measured by the conventional hemagglutination inhibition assay, our data show strong induction of anti-H7 hemagglutinin antibodies as measured by an enzyme-linked immunosorbent assay (ELISA). In addition, cross-reactive antibodies against phylogenetically distant group 2 hemagglutinins were induced, presumably targeting the conserved stalk domain of the hemagglutinin. Further analysis confirmed an induction of stalk-specific antibodies, suggesting that epitopes outside the classical antigenic sites are targeted by this vaccine in the context of preexisting immunity to related H3 hemagglutinin. Antibodies induced by H7 vaccination also showed functional activity in antibody-dependent cell-mediated cytotoxicity reporter assays and microneutralization assays. Additionally, our data show that sera from hemagglutination inhibition seroconverters conferred protection in a passive serum transfer experiment against lethal H7N9 virus challenge in mice. Interestingly, sera from hemagglutination inhibition nonseroconverters also conferred partial protection in the lethal animal challenge model. In conclusion, while recombinant H7 vaccination fails to induce measurable levels of hemagglutination-inhibiting antibodies in most subjects, this vaccination regime induces homosubtypic and heterosubtypic cross-reactive binding antibodies that are functional and partly protective in a murine passive transfer challenge model. IMPORTANCE Zoonotic infections with high case fatality rates caused by avian H7N9 influenza viruses have been reported since early 2013 in China. Since then, the fifth wave of the H7N9 epidemic emerged in China, resulting in higher numbers of laboratory-confirmed cases than in previous years. Recently, H7N9 has started to antigenically drift and split into two new lineages, the Pearl River Delta and Yangtze River Delta clades, which do not match stockpiled H7 vaccines well. Humans are immunologically naive to these subtypes, and an H7N9 strain that acquires the capability of efficient human-to-human transmission poses a credible pandemic threat. Other characteristics of H7N9 are raising concerns as well, like its ability to bind to receptors in the human upper respiratory tract, the recent emergence of highly pathogenic variants, and the ability to quickly gain resistance to neuraminidase inhibitors. Therefore, developing and testing H7N9 vaccines constitutes a priority for pandemic preparedness.

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Dataset Information

Use of Hemagglutinin Stem Probes Demonstrate Prevalence of Broadly Reactive Group 1 Influenza Antibodies in Human Sera.

Publications

Use of Hemagglutinin Stem Probes Demonstrate Prevalence of Broadly Reactive Group 1 Influenza Antibodies in Human Sera.

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