Influenza virus hemagglutinin stalk-based antibodies and vaccines.

doi:10.1016/J.COVIRO.2013.07.007

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Influenza virus hemagglutinin stalk-based antibodies and vaccines.

Journal Article•DOI•

Influenza virus hemagglutinin stalk-based antibodies and vaccines.

Florian Krammer¹, Peter Palese¹•Institutions (1)

Icahn School of Medicine at Mount Sinai¹

01 Oct 2013-Current Opinion in Virology (NIH Public Access)-Vol. 3, Iss: 5, pp 521-530

TL;DR: Broadly protective vaccine candidates based on the epitopes of these antibodies, for example, chimeric and headless hemagglutinin structures, are under development and show promising results in animals models, and could be developed into universal influenza virus vaccines that protect from infection with drifted seasonal as well as novel pandemic influenza virus strains therefore obviating the need for annual vaccination, and enhancing pandemic preparedness.

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About: This article is published in Current Opinion in Virology.The article was published on 2013-10-01 and is currently open access. It has received 301 citations till now. The article focuses on the topics: Influenza A virus & H5N1 genetic structure.

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Journal Article•DOI•

Advances in the development of influenza virus vaccines.

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Florian Krammer¹, Peter Palese¹•Institutions (1)

Icahn School of Medicine at Mount Sinai¹

01 Mar 2015-Nature Reviews Drug Discovery

TL;DR: Improvements have been made recently to enhance immune protection induced by seasonal and pandemic vaccines, and to speed up production in case of a pandemic.

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Abstract: Influenza virus infections are a major public health concern and cause significant morbidity and mortality worldwide. Current influenza virus vaccines are an effective countermeasure against infection but need to be reformulated almost every year owing to antigenic drift. Furthermore, these vaccines do not protect against novel pandemic strains, and the timely production of pandemic vaccines remains problematic because of the limitations of current technology. Several improvements have been made recently to enhance immune protection induced by seasonal and pandemic vaccines, and to speed up production in case of a pandemic. Importantly, vaccine constructs that induce broad or even universal influenza virus protection are currently in preclinical and clinical development.

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455 citations

Journal Article•DOI•

The human antibody response to influenza A virus infection and vaccination.

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Florian Krammer¹•Institutions (1)

Icahn School of Medicine at Mount Sinai¹

01 Jun 2019-Nature Reviews Immunology

TL;DR: The differences between natural infection and vaccination in terms of the antibody responses they induce and how these responses protect against future infection are reviewed.

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Abstract: The adaptive immune response to influenza virus infection is multifaceted and complex, involving antibody and cellular responses at both systemic and mucosal levels. Immune responses to natural infection with influenza virus in humans are relatively broad and long-lived, but influenza viruses can escape from these responses over time owing to their high mutation rates and antigenic flexibility. Vaccines are the best available countermeasure against infection, but vaccine effectiveness is low compared with other viral vaccines, and the induced immune response is narrow and short-lived. Furthermore, inactivated influenza virus vaccines focus on the induction of systemic IgG responses but do not effectively induce mucosal IgA responses. Here, I review the differences between natural infection and vaccination in terms of the antibody responses they induce and how these responses protect against future infection. A better understanding of how natural infection induces broad and long-lived immune responses will be key to developing next-generation influenza virus vaccines. Developing universal influenza virus vaccines will require understanding how broad and long-lived antibody responses to natural infection with influenza A virus are generated, a topic that has benefited greatly from technologies that enable the analysis of single human B cells.

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367 citations

Journal Article•DOI•

Immune history profoundly affects broadly protective B cell responses to influenza.

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Sarah F. Andrews¹, Yunping Huang¹, Kaval Kaur¹, Lyubov I. Popova¹, Irvin Y. Ho¹, Noel T. Pauli¹, Carole J. Henry Dunand¹, William Taylor¹, Samuel Lim¹, Min Huang¹, Xinyan Qu¹, Jane-Hwei Lee¹, Marlene Salgado-Ferrer¹, Florian Krammer², Peter Palese², Jens Wrammert³, Rafi Ahmed³, Patrick C. Wilson¹ - Show less +14 more•Institutions (3)

University of Chicago¹, Icahn School of Medicine at Mount Sinai², Emory University³

02 Dec 2015-Science Translational Medicine

TL;DR: An in-depth study of the B cell response to the pandemic 2009 H1N1 vaccine over consecutive years found that people with low titers of preexisting antibodies were more likely to generate a broadly reactive response that targets the more conserved hemagglutinin (HA) stalk region, whereas those with higher levels of preeXisting antibodies responded by targeting the more variable HA head.

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Abstract: Generating a broadly protective influenza vaccine is critical to global health. Understanding how immune memory influences influenza immunity is central to this goal. We undertook an in-depth study of the B cell response to the pandemic 2009 H1N1 vaccine over consecutive years. Analysis of monoclonal antibodies generated from vaccine-induced plasmablasts demonstrated that individuals with low preexisting serological titers to the vaccinating strain generated a broadly reactive, hemagglutinin (HA) stalk-biased response. Higher preexisting serum antibody levels correlated with a strain-specific HA head-dominated response. We demonstrate that this HA head immunodominance encompasses poor accessibility of the HA stalk epitopes. Further, we show polyreactivity of HA stalk-reactive antibodies that could cause counterselection of these cells. Thus, preexisting memory B cells against HA head epitopes predominate, inhibiting a broadly protective response against the HA stalk upon revaccination with similar strains. Consideration of influenza exposure history is critical for new vaccine strategies designed to elicit broadly neutralizing antibodies.

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334 citations

Cites background from "Influenza virus hemagglutinin stalk..."

...The discovery that divergent influenza strains can preferentially boost rare, broadly neutralizing memory B cells has led groups to design strategies for preferentially inducing these B cells (9, 10)....
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Journal Article•DOI•

mRNA as a Transformative Technology for Vaccine Development to Control Infectious Diseases.

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Giulietta Maruggi, Cuiling Zhang¹, Junwei Li¹, Jeffrey B. Ulmer, Dong Yu - Show less +1 more•Institutions (1)

Qingdao Agricultural University¹

10 Apr 2019-Molecular Therapy

TL;DR: The unique attributes of mRNA vaccine approaches are overviewed, the data of mRNA vaccines against infectious diseases are reviewed, the current challenges are discussed, and perspectives about the future of this promising technology are highlighted.

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260 citations

Journal Article•DOI•

Influenza vaccines: challenges and solutions.

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Katherine V. Houser¹, Kanta Subbarao¹•Institutions (1)

National Institutes of Health¹

11 Mar 2015-Cell Host & Microbe

TL;DR: This review focuses on how currently licensed influenza vaccines are generated in the U.S., why the biology of influenza poses vaccine challenges, and vaccine approaches on the horizon that address these challenges.

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240 citations

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References

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Journal Article•DOI•

Human Infection with a Novel Avian-Origin Influenza A (H7N9) Virus

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Rongbao Gao¹, Bin Cao², Yunwen Hu, Zijian Feng¹, Dayan Wang¹, Wanfu Hu³, Jian Chen³, Zhijun Jie, Haibo Qiu, Ke Xu¹, Xuewei Xu³, Hongzhou Lu, Wenfei Zhu¹, Zhancheng Gao⁴, Nijuan Xiang¹, Yinzhong Shen, Zebao He, Y. Gu, Zhiyong Zhang, Yi Yang, Xiang Zhao¹, Lei Zhou¹, Xiaodan Li¹, Shumei Zou¹, Ye Zhang¹, Xiyan Li¹, Lei Yang¹, Junfeng Guo¹, Jie Dong¹, Qun Li¹, Libo Dong¹, Yun Zhu¹, Tian Bai¹, Shiwen Wang¹, Pei Hao⁵, Weizhong Yang¹, Yanping Zhang¹, Jun Han¹, Hongjie Yu¹, Dexin Li¹, George F. Gao¹, Guizhen Wu¹, Yu Wang¹, Zhenghong Yuan, Yuelong Shu¹ - Show less +41 more•Institutions (5)

Chinese Center for Disease Control and Prevention¹, Beijing Chao-Yang Hospital², Centers for Disease Control and Prevention³, Peking University⁴, Chinese Academy of Sciences⁵

15 May 2013-The New England Journal of Medicine

TL;DR: Novel reassortant H7N9 viruses were associated with severe and fatal respiratory disease in three patients, and all three patients died.

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Abstract: Background Infection of poultry with influenza A subtype H7 viruses occurs worldwide, but the introduction of this subtype to humans in Asia has not been observed previously. In March 2013, three urban residents of Shanghai or Anhui, China, presented with rapidly progressing lower respiratory tract infections and were found to be infected with a novel reassortant avian-origin influenza A (H7N9) virus. Methods We obtained and analyzed clinical, epidemiologic, and virologic data from these patients. Respiratory specimens were tested for influenza and other respiratory viruses by means of real-time reverse-transcriptase–polymerase-chain-reaction assays, viral culturing, and sequence analyses. Results A novel reassortant avian-origin influenza A (H7N9) virus was isolated from respiratory specimens obtained from all three patients and was identified as H7N9. Sequencing analyses revealed that all the genes from these three viruses were of avian origin, with six internal genes from avian influenza A (H9N2) virus...

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2,113 citations

"Influenza virus hemagglutinin stalk..." refers background in this paper

...Human cases of avian H7N9 in China in early spring 2013 clearly demonstrated the threat by these zoonotic viruses [1]....
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Journal Article•DOI•

Antibody Recognition of a Highly Conserved Influenza Virus Epitope

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Damian C. Ekiert¹, Gira Bhabha¹, Marc-André Elsliger¹, Robert H. E. Friesen², Mandy Jongeneelen², Mark Throsby², Jaap Goudsmit², Ian A. Wilson¹ - Show less +4 more•Institutions (2)

Scripps Research Institute¹, Crucell²

10 Apr 2009-Science

TL;DR: TheCR6261 epitope identified here should accelerate the design and implementation of improved vaccines that can elicit CR6261-like antibodies, as well as antibody-based therapies for the treatment of influenza.

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Abstract: Influenza virus presents an important and persistent threat to public health worldwide, and current vaccines provide immunity to viral isolates similar to the vaccine strain. High-affinity antibodies against a conserved epitope could provide immunity to the diverse influenza subtypes and protection against future pandemic viruses. Cocrystal structures were determined at 2.2 and 2.7 angstrom resolutions for broadly neutralizing human antibody CR6261 Fab in complexes with the major surface antigen (hemagglutinin, HA) from viruses responsible for the 1918 H1N1 influenza pandemic and a recent lethal case of H5N1 avian influenza. In contrast to other structurally characterized influenza antibodies, CR6261 recognizes a highly conserved helical region in the membrane-proximal stem of HA1 and HA2. The antibody neutralizes the virus by blocking conformational rearrangements associated with membrane fusion. The CR6261 epitope identified here should accelerate the design and implementation of improved vaccines that can elicit CR6261-like antibodies, as well as antibody-based therapies for the treatment of influenza.

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1,325 citations

"Influenza virus hemagglutinin stalk..." refers background in this paper

...Many of these antibodies like F10, CR6261 and CR9114 are derived from the human germline VH1–69 [16,18,25]....
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...The vast majority of stalk reactive antibodies (including CR6261, F10, FI6 and C179) share a common footprint on the stalk domain [16–19,20 ]....
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...By binding to the stalk domain of the HA of incoming virions [34 ] many of these antibodies inhibit pH induced conformational changes of the HA in the endosome [16,22,26,27] (Figure 2)....
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...CR6261, F10, C179, KB2 or GG3) members of the group 1 HAs (H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, Figure 1e) [16–19,20 ,22,23]....
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...The footprint of many stalkreactive antibodies covers the protease cleavage site between HA1 and HA2 and antibody bound to the HA therefore prevents HA maturation [16,19,26]....
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Journal Article•DOI•

Structural and Functional Bases for Broad-Spectrum Neutralization of Avian and Human Influenza A Viruses

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Jianhua Sui¹, William C. Hwang², Sandra Elizabeth Pérez³, Ge Wei², Daniel Aird¹, Li-Mei Chen³, Eugenio Santelli², Boguslaw Stec², Greg Cadwell², Maryam Ali¹, Hongquan Wan³, Akikazu Murakami¹, Anuradha Yammanuru¹, Thomas Han¹, Nancy J. Cox³, Laurie A. Bankston², Ruben O. Donis³, Robert C. Liddington², Wayne A. Marasco¹ - Show less +15 more•Institutions (3)

Harvard University¹, Sanford-Burnham Institute for Medical Research², National Center for Immunization and Respiratory Diseases³

22 Feb 2009-Nature Structural & Molecular Biology

TL;DR: The crystal structure of one such nAb bound to H5 shows that it blocks infection by inserting its heavy chain into a conserved pocket in the stem region, thus preventing membrane fusion, and suggests that nAb-based immunotherapy is a promising strategy for broad-spectrum protection against seasonal and pandemic influenza viruses.

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Abstract: Influenza virus remains a serious health threat, owing to its ability to evade immune surveillance through rapid genetic drift and reassortment. Here we used a human non-immune antibody phage-display library and the H5 hemagglutinin ectodomain to select ten neutralizing antibodies (nAbs) that were effective against all group 1 influenza viruses tested, including H5N1 ‘bird flu’ and the H1N1 ‘Spanish flu’. The crystal structure of one such nAb bound to H5 shows that it blocks infection by inserting its heavy chain into a conserved pocket in the stem region, thus preventing membrane fusion. Nine of the nAbs employ the germline gene VH1-69, and all seem to use the same neutralizing mechanism. Our data further suggest that this region is recalcitrant to neutralization escape and that nAb-based immunotherapy is a promising strategy for broad-spectrum protection against seasonal and pandemic influenza viruses.

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1,192 citations

"Influenza virus hemagglutinin stalk..." refers background in this paper

...Many of these antibodies like F10, CR6261 and CR9114 are derived from the human germline VH1–69 [16,18,25]....
[...]
...The vast majority of stalk reactive antibodies (including CR6261, F10, FI6 and C179) share a common footprint on the stalk domain [16–19,20 ]....
[...]
...CR6261, F10, C179, KB2 or GG3) members of the group 1 HAs (H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, Figure 1e) [16–19,20 ,22,23]....
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...The epitope recognized by these antibodies is conformational [21] and involves HA1 as well as HA2 residues [16–19,20 ]....
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...The fact that some of these antibodies make contacts only with their heavy chains might reflect the library based approach through which they were obtained [16–18]....
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Journal Article•DOI•

A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins

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Davide Corti, Jarrod Voss¹, Steven J. Gamblin¹, Giosiana Codoni, Annalisa Macagno, David Jarrossay, Sebastien G. Vachieri¹, Debora Pinna, Andrea Minola, Fabrizia Vanzetta, Chiara Silacci, Blanca Fernandez-Rodriguez, Gloria Agatic, Siro Bianchi, Isabella Giacchetto-Sasselli, Lesley J. Calder¹, Federica Sallusto, Patrick J. Collins¹, Lesley F. Haire¹, Nigel J. Temperton², Johannes P. M. Langedijk, John J. Skehel¹, Antonio Lanzavecchia³ - Show less +19 more•Institutions (3)

National Institute for Medical Research¹, University of Kent², ETH Zurich³

12 Aug 2011-Science

TL;DR: An antibody able to broadly neutralize both group 1 and group 2 influenza A viruses—and its target epitope—are identified and may be used for passive protection and to inform vaccine design because of its broad specificity and neutralization potency.

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Abstract: The isolation of broadly neutralizing antibodies against influenza A viruses has been a long-sought goal for therapeutic approaches and vaccine design. Using a single-cell culture method for screening large numbers of human plasma cells, we isolated a neutralizing monoclonal antibody that recognized the hemagglutinin (HA) glycoprotein of all 16 subtypes and neutralized both group 1 and group 2 influenza A viruses. Passive transfer of this antibody conferred protection to mice and ferrets. Complexes with HAs from the group 1 H1 and the group 2 H3 subtypes analyzed by x-ray crystallography showed that the antibody bound to a conserved epitope in the F subdomain. This antibody may be used for passive protection and to inform vaccine design because of its broad specificity and neutralization potency.

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1,146 citations

"Influenza virus hemagglutinin stalk..." refers background in this paper

...The vast majority of stalk reactive antibodies (including CR6261, F10, FI6 and C179) share a common footprint on the stalk domain [16–19,20 ]....
[...]
...CR6261, F10, C179, KB2 or GG3) members of the group 1 HAs (H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, Figure 1e) [16–19,20 ,22,23]....
[...]
...The footprint of many stalkreactive antibodies covers the protease cleavage site between HA1 and HA2 and antibody bound to the HA therefore prevents HA maturation [16,19,26]....
[...]
...The epitope recognized by these antibodies is conformational [21] and involves HA1 as well as HA2 residues [16–19,20 ]....
[...]
...Two stalk-reactive antibodies, FI6 and 05-2G02, that cover both members of group 1 and group 2 HAs (H3, H4, H7, H10, H14, H15, Figure 1e) have been isolated as well [19,24 ]....
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Journal Article•DOI•

Rapid cloning of high-affinity human monoclonal antibodies against influenza virus

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Jens Wrammert¹, Kenneth J. Smith², Joseph I. Miller¹, William A. Langley¹, Kenneth E. Kokko¹, Christian P. Larsen¹, Nai-Ying Zheng², Israel Mays², Lori Garman², Christina Helms², Judith A. James³, Judith A. James², Gillian M. Air³, J. Donald Capra³, J. Donald Capra², Rafi Ahmed¹, Patrick C. Wilson³, Patrick C. Wilson² - Show less +14 more•Institutions (3)

Emory University¹, Oklahoma Medical Research Foundation², University of Oklahoma Health Sciences Center³

29 May 2008-Nature

TL;DR: The panel of influenza-virus-specific human mAbs allowed us to address the issue of original antigenic sin (OAS): the phenomenon where the induced antibody shows higher affinity to a previously encountered influenza virus strain compared with the virus strain present in the vaccine.

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Abstract: Pre-existing neutralizing antibody provides the first line of defence against pathogens in general. For influenza virus, annual vaccinations are given to maintain protective levels of antibody against the currently circulating strains. Here we report that after booster vaccination there was a rapid and robust influenza-specific IgG+ antibody-secreting plasma cell (ASC) response that peaked at approximately day 7 and accounted for up to 6% of peripheral blood B cells. These ASCs could be distinguished from influenza-specific IgG+ memory B cells that peaked 14-21 days after vaccination and averaged 1% of all B cells. Importantly, as much as 80% of ASCs purified at the peak of the response were influenza specific. This ASC response was characterized by a highly restricted B-cell receptor (BCR) repertoire that in some donors was dominated by only a few B-cell clones. This pauci-clonal response, however, showed extensive intraclonal diversification from accumulated somatic mutations. We used the immunoglobulin variable regions isolated from sorted single ASCs to produce over 50 human monoclonal antibodies (mAbs) that bound to the three influenza vaccine strains with high affinity. This strategy demonstrates that we can generate multiple high-affinity mAbs from humans within a month after vaccination. The panel of influenza-virus-specific human mAbs allowed us to address the issue of original antigenic sin (OAS): the phenomenon where the induced antibody shows higher affinity to a previously encountered influenza virus strain compared with the virus strain present in the vaccine. However, we found that most of the influenza-virus-specific mAbs showed the highest affinity for the current vaccine strain. Thus, OAS does not seem to be a common occurrence in normal, healthy adults receiving influenza vaccination.

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1,015 citations

"Influenza virus hemagglutinin stalk..." refers background in this paper

...Stalk-reactive antibodies are not [4-6], or very rarely [18,54], found in individuals vaccinated with seasonal inactivated influenza virus vaccines....
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...Antibodies against the stalk domain are generally not induced by vaccination with inactivated influenza virus vaccines and these types of antibodies are rare in humans [4,5]....
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...These antibodies are directed against the membrane distal part of the HA, the globular head domain (Figure 1A, B and D) [4-6], which has a high plasticity and is subject to constant antigenic drift driven by human herd immunity....
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