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

ABSTRACT: We have previously shown that broadly neutralizing antibodies reactive to the conserved stem region of the influenza virus hemagglutinin (HA) were generated in people infected with the 2009 pandemic H1N1 strain. Such antibodies are rarely seen in humans following infection or vaccination with seasonal influenza virus strains. However, the important question remained whether the inactivated 2009 pandemic H1N1 vaccine, like the infection, could also induce these broadly neutralizing antibodies. To address this question, we analyzed B-cell responses in 24 healthy adults immunized with the pandemic vaccine in 2009. In all cases, we found a rapid, predominantly IgG-producing vaccine-specific plasmablast response. Strikingly, the majority (25 of 28) of HA-specific monoclonal antibodies generated from the vaccine-specific plasmablasts neutralized more than one influenza strain and exhibited high levels of somatic hypermutation, suggesting they were derived from recall of B-cell memory. Indeed, memory B cells that recognized the 2009 pandemic H1N1 HA were detectable before vaccination not only in this cohort but also in samples obtained before the emergence of the pandemic strain. Three antibodies demonstrated extremely broad cross-reactivity and were found to bind the HA stem. Furthermore, one stem-reactive antibody recognized not only H1 and H5, but also H3 influenza viruses. This exceptional cross-reactivity indicates that antibodies capable of neutralizing most influenza subtypes might indeed be elicited by vaccination. The challenge now is to improve upon this result and design influenza vaccines that can elicit these broadly cross-reactive antibodies at sufficiently high levels to provide heterosubtypic protection.

SUBMITTER: Li GM

PROVIDER: S-EPMC3384143 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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

Li Gui-Mei GM Chiu Christopher C Wrammert Jens J McCausland Megan M Andrews Sarah F SF Zheng Nai-Ying NY Lee Jane-Hwei JH Huang Min M Qu Xinyan X Edupuganti Srilatha S Mulligan Mark M Das Suman R SR Yewdell Jonathan W JW Mehta Aneesh K AK Wilson Patrick C PC Ahmed Rafi R

Proceedings of the National Academy of Sciences of the United States of America 20120521 23

We have previously shown that broadly neutralizing antibodies reactive to the conserved stem region of the influenza virus hemagglutinin (HA) were generated in people infected with the 2009 pandemic H1N1 strain. Such antibodies are rarely seen in humans following infection or vaccination with seasonal influenza virus strains. However, the important question remained whether the inactivated 2009 pandemic H1N1 vaccine, like the infection, could also induce these broadly neutralizing antibodies. To ...[more]

PMID: 22615367

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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.

Project description:Broadly cross-reactive antibodies (Abs) that recognize conserved epitopes within the influenza virus hemagglutinin (HA) stalk domain are of particular interest for their potential use as therapeutic and prophylactic agents against multiple influenza virus subtypes, including zoonotic virus strains. Here, we characterized four human HA stalk-reactive monoclonal antibodies (MAbs) for their binding breadth and affinity, in vitro neutralization capacity, and in vivo protective potential against an highly pathogenic avian influenza virus. The monoclonal antibodies were isolated from individuals shortly following infection with (70-1F02 and 1009-3B05) or vaccination against (05-2G02 and 09-3A01) A(H1N1)pdm09. Three of the MAbs bound HAs from multiple strains of group 1 viruses, and one MAb, 05-2G02, bound to both group 1 and group 2 influenza A virus HAs. All four antibodies prophylactically protected mice against a lethal challenge with the highly pathogenic A/Vietnam/1203/04 (H5N1) strain. Two MAbs, 70-1F02 and 09-3A01, were further tested for their therapeutic efficacy against the same strain and showed good efficacy in this setting as well. One MAb, 70-1F02, cocrystallized with H5 HA and showed heavy-chain-only interactions similar to those seen with the previously described CR6261 anti-stalk antibody. Finally, we show that antibodies that compete with these MAbs are prevalent in serum from an individual recently infected with the A(H1N1)pdm09 virus. The antibodies described here can be developed into broad-spectrum antiviral therapeutics that could be used to combat infections by zoonotic or emerging pandemic influenza viruses.IMPORTANCE The rise in zoonotic infections of humans by emerging influenza viruses is a worldwide public health concern. The majority of recent zoonotic human influenza cases were caused by H7N9 and H5Nx viruses and were associated with high morbidity and mortality. In addition, seasonal influenza viruses are estimated to cause up to 650,000 deaths annually worldwide. Currently available antiviral treatment options include only neuraminidase inhibitors, but some influenza viruses are naturally resistant to these drugs, and others quickly develop resistance-conferring mutations. Alternative therapeutics are urgently needed. Broadly protective antibodies that target the conserved "stalk" domain of the hemagglutinin represent potential potent antiviral prophylactic and therapeutic agents that can assist pandemic preparedness. Here, we describe four human monoclonal antibodies that target conserved regions of influenza HA and characterize their binding spectrum as well as their protective capacity in prophylactic and therapeutic settings against a lethal challenge with a zoonotic influenza virus.

Dataset Information

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

Publications

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

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