DOCSLIB.ORG

Original Antigenic Sin Priming of Influenza Virus Hemagglutinin Stalk Antibodies

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Original Antigenic Sin Priming of Influenza Virus Hemagglutinin Stalk Antibodies Original antigenic sin priming of influenza virus hemagglutinin stalk antibodies Claudia P. Arevaloa, Valerie Le Sageb, Marcus J. Boltona, Theresa Eilolaa, Jennifer E. Jonesb, Karen A. Kormuthb, Eric Nturibib, Angel Balmasedac, Aubree Gordond, Seema S. Lakdawalab,e, and Scott E. Hensleya,1 aDepartment of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; bDepartment of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219; cCentro Nacional de Diagnóstico y Referencia, Ministry of Health, Managua, Nicaragua 16064; dDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109; and eCenter for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219 Edited by Michael B.A. Oldstone, Scripps Research Institute, La Jolla, CA, and approved May 27, 2020 (received for review November 18, 2019) Immunity to influenza viruses can be long-lived, but reinfections but there are more conserved epitopes in the HA stalk domain. with antigenically distinct viral strains and subtypes are common. Antibodies that recognize the HA stalk of group 1 or group 2 Reinfections can boost antibody responses against viral strains viruses have been well characterized, but antibodies that recog- first encountered in childhood through a process termed “original nize the HA stalk of both group 1 and group 2 viruses are rare antigenic sin.” It is unknown how initial childhood exposures af- (15, 16). Interestingly, childhood influenza A virus exposures are fect the induction of antibodies against the hemagglutinin (HA) associated with heterosubtypic protection against distinct stalk domain of influenza viruses. This is an important consider- emerging influenza virus subtypes later in life (13). For example, ation since broadly reactive HA stalk antibodies can protect early childhood exposures to H1N1 and H2N2 (both group 1 against infection, and universal vaccine platforms are being de- viruses) are associated with protection from H5N1 (also a group veloped to induce these antibodies. Here we show that experi- 1 virus), whereas childhood exposures to H3N2 (a group 2 virus) mentally infected ferrets and naturally infected humans establish strong “immunological imprints” against HA stalk antigens first are associated with protection from H7N9 (a group 2 virus) (13). encountered during primary influenza virus infections. We found This apparent cross-subtype protection is possibly mediated by that HA stalk antibodies are surprisingly boosted upon subsequent antibodies targeting conserved epitopes in the HA stalk; how- infections with antigenically distinct influenza A virus subtypes. ever, it is unclear how initial childhood influenza exposures af- MICROBIOLOGY Paradoxically, these heterosubtypic-boosted HA stalk antibodies fect the development of HA stalk antibody responses. do not bind efficiently to the boosting influenza virus strain. Our Here, we set out to determine how initial childhood influenza results demonstrate that an individual’s HA stalk antibody re- virus infections impact antibody responses against subsequent sponse is dependent on the specific subtype of influenza virus that heterosubtypic influenza virus infections. We first examined they first encounter early in life. We propose that humans are antibody responses elicited in ferrets sequentially exposed to susceptible to heterosubtypic influenza virus infections later in life different influenza virus subtypes. We then examined anti- since these viruses boost HA stalk antibodies that do not bind bodies elicited in children who had different prior influenza efficiently to the boosting antigen. virus exposures. influenza virus | hemagglutinin | original antigenic sin Significance ost humans are infected with influenza viruses early in life Humans are typically infected with influenza viruses in child- M(1) and then subsequently reinfected with antigenically hood and then continuously exposed to antigenically distinct distinct viral strains every 5 to 10 y (2). In a classic essay pub- influenza virus strains throughout life. Antibody responses lished in 1960, Thomas Francis Jr. reported that humans typi- elicited by initial influenza virus infections can be boosted cally have high antibody titers against influenza viruses that they upon subsequent exposures with antigenically drifted in- first encountered in childhood and that these antibodies are fluenza virus strains. Here, we examined how initial influenza boosted upon subsequent exposures to antigenically drifted in- virus infections affect antibody responses against subsequent fluenza virus strains (3). Francis coined the term “original anti- infections with an unrelated influenza virus subtype. We show genic sin” to describe this phenomenon. In 1966, Robert that heterosubtypic infections in ferrets and humans boost Webster and Stephen Fazekas de St. Groth demonstrated that hemagglutinin stalk antibodies that paradoxically do not bind original antigenic sin can be recapitulated in rabbits and ferrets effectively to the boosting influenza virus strain. We propose that are sequentially infected with different H1N1 strains (4, 5). that hemagglutinin stalk antibody repertoires are shaped by Recent human (6–9) and animal (9–12) serological studies have the specific subtype of influenza virus that an individual en- confirmed and extended these findings. Most studies of original counters early in life, and that this affects susceptibility to antigenic sin have analyzed immune responses elicited by se- heterosubtypic infections later in life. quential exposures with drifted versions of the same influenza virus subtype. Much less is known about how prior exposures Author contributions: C.P.A., S.S.L., and S.E.H. designed research; C.P.A., V.L.S., M.J.B., T.E., J.E.J., K.A.K., and E.N. performed research; A.B. and A.G. contributed new re- affect immune responses against heterosubtypic influenza virus agents/analytic tools; C.P.A., S.S.L., and S.E.H. analyzed data; and C.P.A. and S.E.H. infections. This is relevant since three different influenza A virus wrote the paper. subtypes (H1N1, H2N2, and H3N2) have circulated in humans Competing interest statement: S.E.H. reports receiving consulting fees from Sanofi Pas- over the past century, and most humans alive today have been teur, Lumen, Novavax, and Merck for work unrelated to this manuscript. infected with more than one of these subtypes at some point in This article is a PNAS Direct Submission. their lives (13). Published under the PNAS license. Different influenza A virus subtypes can be broadly split into 1To whom correspondence may be addressed. Email: [email protected]. two phylogenetic groups (“group 1” and “group 2”) based on This article contains supporting information online at https://www.pnas.org/lookup/suppl/ conservation in the hemagglutinin (HA) protein (14). The doi:10.1073/pnas.1920321117/-/DCSupplemental. globular head of HA differs substantially among these viruses, www.pnas.org/cgi/doi/10.1073/pnas.1920321117 PNAS Latest Articles | 1of7 Downloaded by guest on September 23, 2021 Results that recognized H3 antigens (Fig. 1 D–F). Similarly, animals HA Stalk Antibodies Elicited by Initial Influenza Virus Infections in initially infected with H3N2 produced H3-reactive antibodies Ferrets Are Boosted upon Subsequent Heterosubtypic Infections. To (Fig. 1D) that targeted both the H3 head (Fig. 1E) and H3 stalk better understand how initial influenza virus exposures shape (Fig. 1F), but did not produce antibodies that recognized H1 antibody responses against subsequent infections with distinct antigens (Fig. 1 A–C). For H1N1 and H3N2 primary infections, influenza virus subtypes, we completed a series of infection ex- total HA antibodies (Fig. 1 A and D) and HA stalk antibodies periments in ferrets that had never previously encountered in- (Fig. 1 C and F) remained at similar levels between 28 and 84 d fluenza virus. We infected ferrets with H1N1 (A/California/07/ after infection, while HA head antibodies peaked 14 d after in- 2009) and then reinfected the same ferrets 84 d later with H3N2 fection and then gradually declined over time (Fig. 1 B and E). (A/Perth/16/2009). We infected other ferrets with H3N2 and Animals initially infected with H1N1 and then subsequently then reinfected them with H1N1 84 d later. As controls, we in- infected with H3N2 mounted H3 antibody responses that were fected two additional groups of ferrets with either H1N1 or similar to those elicited by primary H3N2 infections (Fig. 1 D–F). H3N2 (both influenza A viruses) and then reinfected with in- Surprisingly, we found that secondary infections with H3N2 fluenza B virus (B/Brisbane/60/2008). We quantified total serum boosted H1 stalk-reactive antibodies in animals that were ini- HA antibody levels using ELISAs coated with full-length HA tially infected with H1N1 (4.2 μg/mL before and 81.0 μg/mL 14 d proteins, serum HA head-specific antibodies by hemagglutina- after secondary H3N2 infection; P = 0.0013 comparing titers; tion inhibition (HAI) assays, and serum HA stalk-reactive anti- Fig. 1C). We found similar results when the order of H1N1 and bodies using ELISAs coated with “headless” HA proteins. H3N2 infections was reversed. Animals initially infected with As expected, animals initially infected with H1N1 produced H3N2 and subsequently infected with H1N1 mounted H1 anti- H1-reactive antibodies (Fig. 1A) that targeted both the H1 head body responses
Load more

Recommended publications
  • A Conserved Influenza a Virus Nucleoprotein Code Controls Specific
    ARTICLE Received 8 Mar 2016 | Accepted 10 Aug 2016 | Published 21 Sep 2016 DOI: 10.1038/ncomms12861 OPEN A conserved influenza A virus nucleoprotein code controls specific viral genome packaging E´tori Aguiar Moreira1,2,3, Anna Weber1, Hardin Bolte1,2,3, Larissa Kolesnikova4, Sebastian Giese1, Seema Lakdawala5, Martin Beer6, Gert Zimmer7, Adolfo Garcı´a-Sastre8,9,10, Martin Schwemmle1 & Mindaugas Juozapaitis1 Packaging of the eight genomic RNA segments of influenza A viruses (IAV) into viral particles is coordinated by segment-specific packaging sequences. How the packaging signals regulate the specific incorporation of each RNA segment into virions and whether other viral or host factors are involved in this process is unknown. Here, we show that distinct amino acids of the viral nucleoprotein (NP) are required for packaging of specific RNA segments. This was determined by studying the NP of a bat influenza A-like virus, HL17NL10, in the context of a conventional IAV (SC35M). Replacement of conserved SC35M NP residues by those of HL17NL10 NP resulted in RNA packaging defective IAV. Surprisingly, substitution of these conserved SC35M amino acids with HL17NL10 NP residues led to IAV with altered packaging efficiencies for specific subsets of RNA segments. This suggests that NP harbours an amino acid code that dictates genome packaging into infectious virions. 1 Institute of Virology, University Medical Center Freiburg, 79104 Freiburg, Germany. 2 Spemann Graduate School of Biology and Medicine, University of Freiburg, 79104 Freiburg, Germany. 3 Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany. 4 Institute of Virology, Philipps-Universita¨t Marburg, 35043 Marburg, Germany. 5 Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15217, USA.
    [Show full text]
  • Priming of Virus-Immune Memory T Cells in Newborn Mice DAVID H
    INFECTION AND IMMUNITY, Jan. 1984, p. 202-205 Vol. 43, No. 1 0019-9567/84/010202-04$02.00/0 Copyright (© 1984, American Society for Microbiology Priming of Virus-Immune Memory T Cells in Newborn Mice DAVID H. SCHWARTZ, JULIA L. HURWITZ,* NEIL S. GREENSPAN,t AND PETER C. DOHERTYt The Wistar Institute ofAnatomy and Biology, Philadelphia, Pennsylvania 19104 Received 6 May 1983/Accepted 27 September 1983 Neonatal BALB/c mice can be primed at birth by intravenous inoculation of a small dose of A/Puerto Rico/8/34 (H1N1) (PR8) influenza virus, UV-inactivated PR8 virus, or PR8 virus complexed with monoclonal antibody to give a secondary cytotoxic T lymphocyte response when restimulated in vitro as adults. The frequency of responding T cells after secondary stimulation in vitro is approximately 40% of that found for adult mice primed intraperitoneally with a large dose of PR8 virus. The majority of the T cells generated from mice primed at birth or as adults are cross-reactive for H-2-compatible targets infected with the PR8 (H1N1) or A/Hong Kong/X31 (H3N2) viruses. Splenocytes from neonates receiving UV-inactivated vaccinia virus at birth give an augmented secondary cytotoxic T lymphocyte response when restimulated 8 days later in adoptive irradiated adult hosts. We found no indications of specific immunological unrespon- siveness in mice exposed to either virus. We have analyzed previously the development of virus- cells per ml for 1 h at 37°C. Graded numbers of effector specific T cell competence in neonatal mice and have spleen cells and 2 x 105 syngeneic virus-infected, irradiated reported the presence of vaccinia virus-specific cytotoxic T stimulator cells were distributed in 100-.pl portions to the 60 lymphocyte (CTL) precursors in the thymus of 0- to 3-day- inside wells of 96-well, V-bottom plates.
    [Show full text]
  • Priming with Inflammatory Cytokines Is Not a Prerequisite to Increase
    Lange-Consiglio et al. Stem Cell Research & Therapy (2020) 11:99 https://doi.org/10.1186/s13287-020-01611-z RESEARCH Open Access Priming with inflammatory cytokines is not a prerequisite to increase immune- suppressive effects and responsiveness of equine amniotic mesenchymal stromal cells Anna Lange-Consiglio1* , Pietro Romele2, Marta Magatti2, Antonietta Silini2, Antonella Idda1, Nicola Antonio Martino3, Fausto Cremonesi1 and Ornella Parolini2,4 Abstract Background: Equine amniotic mesenchymal stromal cells (AMSCs) and their conditioned medium (CM) were evaluated for their ability to inhibit in vitro proliferation of peripheral blood mononuclear cells (PBMCs) with and without priming. Additionally, AMSC immunogenicity was assessed by expression of MHCI and MHCII and their ability to counteract the in vitro inflammatory process. Methods: Horse PBMC proliferation was induced with phytohemagglutinin. AMSC priming was performed with 10 ng/ml of TNF-α, 100 ng/ml of IFN-γ, and a combination of 5 ng/ml of TNF-α and 50 ng/ml of IFN-γ. The CM generated from naïve unprimed and primed AMSCs was also tested to evaluate its effects on equine endometrial cells in an in vitro inflammatory model induced by LPS. Immunogenicity marker expression (MHCI and II) was evaluated by qRT-PCR and by flow cytometry. Results: Priming does not increase MHCI and II expression. Furthermore, the inhibition of PBMC proliferation was comparable between naïve and conditioned cells, with the exception of AMSCs primed with both TNF-α and IFN-γ that had a reduced capacity to inhibit T cell proliferation. However, AMSC viability was lower after priming than under other experimental conditions.
    [Show full text]
  • Dissecting Human Antibody Responses Against Influenza a Viruses and Antigenic Changes That Facilitate Immune Escape
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2018 Dissecting Human Antibody Responses Against Influenza A Viruses And Antigenic Changes That Facilitate Immune Escape Seth J. Zost University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Allergy and Immunology Commons, Immunology and Infectious Disease Commons, Medical Immunology Commons, and the Virology Commons Recommended Citation Zost, Seth J., "Dissecting Human Antibody Responses Against Influenza A Viruses And Antigenic Changes That Facilitate Immune Escape" (2018). Publicly Accessible Penn Dissertations. 3211. https://repository.upenn.edu/edissertations/3211 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/3211 For more information, please contact [email protected]. Dissecting Human Antibody Responses Against Influenza A Viruses And Antigenic Changes That Facilitate Immune Escape Abstract Influenza A viruses pose a serious threat to public health, and seasonal circulation of influenza viruses causes substantial morbidity and mortality. Influenza viruses continuously acquire substitutions in the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). These substitutions prevent the binding of pre-existing antibodies, allowing the virus to escape population immunity in a process known as antigenic drift. Due to antigenic drift, individuals can be repeatedly infected by antigenically distinct influenza strains over the course of their life. Antigenic drift undermines the effectiveness of our seasonal influenza accinesv and our vaccine strains must be updated on an annual basis due to antigenic changes. In order to understand antigenic drift it is essential to know the sites of antibody binding as well as the substitutions that facilitate viral escape from immunity.
    [Show full text]
  • Rapid Induction of Antigen-Specific CD4+ T Cells Guides Coordinated Humoral and Cellular Immune Responses to SARS-Cov-2 Mrna Vaccination
    bioRxiv preprint doi: https://doi.org/10.1101/2021.04.21.440862; this version posted April 22, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Rapid induction of antigen-specific CD4+ T cells guides coordinated humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination Authors: Mark M. Painter1,2, †, Divij Mathew1,2, †, Rishi R. Goel1,2, †, Sokratis A. Apostolidis1,2,3, †, Ajinkya Pattekar2, Oliva Kuthuru1, Amy E. Baxter1, Ramin S. Herati4, Derek A. Oldridge1,5, Sigrid Gouma6, Philip Hicks6, Sarah Dysinger6, Kendall A. Lundgreen6, Leticia Kuri-Cervantes1,6, Sharon Adamski2, Amanda Hicks2, Scott Korte2, Josephine R. Giles1,7,8, Madison E. Weirick6, Christopher M. McAllister6, Jeanette Dougherty1, Sherea Long1, Kurt D’Andrea1, Jacob T. Hamilton2,6, Michael R. Betts1,6, Paul Bates6, Scott E. Hensley6, Alba Grifoni9, Daniela Weiskopf9, Alessandro Sette9, Allison R. Greenplate1,2, E. John Wherry1,2,7,8,* Affiliations 1 Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 2 Immune Health™, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 3 Division of Rheumatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 4 NYU Langone Vaccine Center, Department of Medicine, New York University School of Medicine, New York, NY 5 Department
    [Show full text]
  • Safety and Immunogenicity of a Baculovirus- Expressed Hemagglutinin Influenza Vaccine a Randomized Controlled Trial
    PRELIMINARY COMMUNICATION Safety and Immunogenicity of a Baculovirus- Expressed Hemagglutinin Influenza Vaccine A Randomized Controlled Trial John J. Treanor, MD Context A high priority in vaccine research is the development of influenza vaccines Gilbert M. Schiff, MD that do not use embryonated eggs as the substrate for vaccine production. Frederick G. Hayden, MD Objective To determine the dose-related safety, immunogenicity, and protective ef- ficacy of an experimental trivalent influenza virus hemagglutinin (rHA0) vaccine pro- Rebecca C. Brady, MD duced in insect cells using recombinant baculoviruses. C. Mhorag Hay, MD Design, Setting, and Participants Randomized, double-blind, placebo-controlled Anthony L. Meyer, BS clinical trial at 3 US academic medical centers during the 2004-2005 influenza season Jeanne Holden-Wiltse, MPH among 460 healthy adults without high-risk indications for influenza vaccine. Hua Liang, PhD Interventions Participants were randomly assigned to receive a single injection of saline placebo (n=154); 75 µg of an rHA0 vaccine containing 15 µg of hemagglutinin Adam Gilbert, PhD from influenza A/New Caledonia/20/99(H1N1) and influenza B/Jiangsu/10/03 virus Manon Cox, PhD and 45 µg of hemagglutinin from influenza A/Wyoming/3/03(H3N2) virus (n=153); or 135 µg of rHA0 containing 45 µg of hemagglutinin each from all 3 components LL CURRENTLY LICENSED IN- (n=153). Serum samples were taken before and 30 days following immunization. fluenza vaccines in the United Main Outcome Measures Primary safety end points were the rates and severity of States are produced in em- solicited and unsolicited adverse events. Primary immunogenicity end points were the bryonated hen’s eggs.
    [Show full text]
  • Immunology 101
    Immunology 101 Justin Kline, M.D. Assistant Professor of Medicine Section of Hematology/Oncology Committee on Immunology University of Chicago Medicine Disclosures • I served as a consultant on Advisory Boards for Merck and Seattle Genetics. • I will discuss non-FDA-approved therapies for cancer 2 Outline • Innate and adaptive immune systems – brief intro • How immune responses against cancer are generated • Cancer antigens in the era of cancer exome sequencing • Dendritic cells • T cells • Cancer immune evasion • Cancer immunotherapies – brief intro 3 The immune system • Evolved to provide protection against invasive pathogens • Consists of a variety of cells and proteins whose purpose is to generate immune responses against micro-organisms • The immune system is “educated” to attack foreign invaders, but at the same time, leave healthy, self-tissues unharmed • The immune system can sometimes recognize and kill cancer cells • 2 main branches • Innate immune system – Initial responders • Adaptive immune system – Tailored attack 4 The immune system – a division of labor Innate immune system • Initial recognition of non-self (i.e. infection, cancer) • Comprised of cells (granulocytes, monocytes, dendritic cells and NK cells) and proteins (complement) • Recognizes non-self via receptors that “see” microbial structures (cell wall components, DNA, RNA) • Pattern recognition receptors (PRRs) • Necessary for priming adaptive immune responses 5 The immune system – a division of labor Adaptive immune system • Provides nearly unlimited diversity of receptors to protect the host from infection • B cells and T cells • Have unique receptors generated during development • B cells produce antibodies which help fight infection • T cells patrol for infected or cancerous cells • Recognize “foreign” or abnormal proteins on the cell surface • 100,000,000 unique T cells are present in all of us • Retains “memory” against infections and in some cases, cancer.
    [Show full text]
  • Biosafety Recommendations for Work with Influenza Viruses Containing a Hemagglutinin from the A/Goose/Guangdong/1/96 Lineage
    Morbidity and Mortality Weekly Report Recommendations and Reports / Vol. 62 / No. 6 June 28, 2013 Biosafety Recommendations for Work with Influenza Viruses Containing a Hemagglutinin from the A/goose/Guangdong/1/96 Lineage U.S. Department of Health and Human Services Centers for Disease Control and Prevention Recommendations and Reports CONTENTS Introduction ............................................................................................................2 Background .............................................................................................................2 Guidelines for Working with Influenza Viruses Containing an HA from the A/goose/Guangdong/1/96 Lineage ..................................3 Conclusion ...............................................................................................................6 References ...............................................................................................................7 Front cover photo: Transmission electron micrograph of avian influenza A H5N1 viruses (gold) grown in Madin-Darby canine kidney (MDCK) cells (green). The MMWR series of publications is published by the Office of Surveillance, Epidemiology, and Laboratory Services, Centers for Disease Control and Prevention (CDC), U.S. Department of Health and Human Services, Atlanta, GA 30333. Suggested Citation: Centers for Disease Control and Prevention. [Title]. MMWR 2013;62(No. RR-#):[inclusive page numbers]. Centers for Disease Control and Prevention Thomas R. Frieden, MD, MPH, Director
    [Show full text]
  • Autocatalytic Activation of Influenza Hemagglutinin
    University of Pennsylvania ScholarlyCommons Department of Chemical & Biomolecular Departmental Papers (CBE) Engineering December 2006 Autocatalytic Activation of Influenza Hemagglutinin Jeong H. Lee University of Pennsylvania Mark Goulian University of Pennsylvania Eric T. Boder University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/cbe_papers Recommended Citation Lee, J. H., Goulian, M., & Boder, E. T. (2006). Autocatalytic Activation of Influenza Hemagglutinin. Retrieved from https://repository.upenn.edu/cbe_papers/83 Postprint version. Published in Journal of Molecular Biology, Volume 364, Issue 3, December 2006, pages 275-282. Publisher URL: http://dx.doi.org/10.1016/j.jmb.2006.09.015 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/cbe_papers/83 For more information, please contact [email protected]. Autocatalytic Activation of Influenza Hemagglutinin Abstract Enveloped viruses contain surface proteins that mediate fusion between the viral and target cell membranes following an activating stimulus. Acidic pH induces the influenza virus fusion protein hemagglutinin (HA) via irreversible refolding of a trimeric conformational state leading to exposure of hydrophobic fusion peptides on each trimer subunit. Herein, we show that cells expressing fowl plague virus HA demonstrate discrete switching behavior with respect to the HA conformational change. Partially activated states do not exist at the scale of the cell, activation of HA leads to aggregation of cell surface trimers, and newly synthesized HA refold spontaneously in the presence of previously activated HA. These observations imply a feedback mechanism involving self-catalyzed refolding of HA and thus suggest a mechanism similar to the autocatalytic refolding and aggregation of prions.
    [Show full text]
  • ACRONYM & GLOSSARY LIST - Revised 9/2008
    Survey & Certification Emergency Preparedness Initiative – All Hazards EMERGENCY PREPAREDNESS ACRONYM & GLOSSARY LIST - Revised 9/2008 ACRONYMS AAL Authorized Access List AAR After-Action Report ACE Army Corps of Engineers ACIP Advisory Committee on Immunization Practices ACL Access Control List ACLS Advanced Cardiac Life Support ACF Administration for Children and Families (HHS) ACS Alternate Care Site ADP Automated Data Processing AFE Annual Frequency Estimate AHRQ Agency for Healthcare Research and Quality (HHS) AIE Annual Impact Estimate AIS Automated Information System AISSP Automated Information Systems Security Program AMSC American Satellite Communications ANG Air National Guard ANSI American National Standards Institute AO Accrediting Organization AoA Administration on Aging (HHS) APE Assistant Secretary for Planning and Evaluation (HHS) APF Authorized Program Facility APHL Association of Public Health Laboratories ARC American Red Cross ARES Amateur Radio Emergency Service ARF Agency Request Form ARO Annualized Rate of Occurrence ASAM Assistant Secretary for Administration & Management (HHS) ASC Ambulatory Surgical Center ASC Accredited Standards Committee ASH Assistant Secretary for Health (HHS) ASL Assistant Secretary for Legislation (HHS) ASPA Assistant Secretary for Public Affairs (HHS) ASPE Assistant Secretary for Planning & Evaluation (HHS) ASPR Assistant Secretary for Preparedness & Response (HHS) ASRT Assistant Secretary for Resources & Technology (HHS) ATSDR Agency for Toxic Substances & Disease Registry (HHS) BARDA
    [Show full text]
  • Original Antigenic Sin: a Comprehensive Review
    Journal of Autoimmunity 83 (2017) 12e21 Contents lists available at ScienceDirect Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm Review article Original antigenic sin: A comprehensive review Anup Vatti a, Diana M. Monsalve b, Yovana Pacheco b, Christopher Chang a, * Juan-Manuel Anaya b, M. Eric Gershwin a, a University of California at Davis, Division of Rheumatology, Allergy and Clinical Immunology, Suite 6501, 451 Health Sciences Drive, Davis, CA, 95616, USA b Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 No. 63-C-69, Bogota, Colombia article info abstract Article history: The concept of “original antigenic sin” was first proposed by Thomas Francis, Jr. in 1960. This phe- Received 27 March 2017 nomenon has the potential to rewrite what we understand about how the immune system responds to Received in revised form infections and its mechanistic implications on how vaccines should be designed. Antigenic sin has been 24 April 2017 demonstrated to occur in several infectious diseases in both animals and humans, including human Accepted 25 April 2017 influenza infection and dengue fever. The basis of “original antigenic sin” requires immunological Available online 5 May 2017 memory, and our immune system ability to autocorrect. In the context of viral infections, it is expected that if we are exposed to a native strain of a pathogen, we should be able to mount a secondary immune Keywords: “ ” Vaccination response on subsequent exposure to the same pathogen. Original antigenic sin will not contradict this Bocavirus well-established immunological process, as long as the subsequent infectious antigen is identical to the Dengue original one.
    [Show full text]
  • Vaccine Immunology Claire-Anne Siegrist
    2 Vaccine Immunology Claire-Anne Siegrist To generate vaccine-mediated protection is a complex chal- non–antigen-specifc responses possibly leading to allergy, lenge. Currently available vaccines have largely been devel- autoimmunity, or even premature death—are being raised. oped empirically, with little or no understanding of how they Certain “off-targets effects” of vaccines have also been recog- activate the immune system. Their early protective effcacy is nized and call for studies to quantify their impact and identify primarily conferred by the induction of antigen-specifc anti- the mechanisms at play. The objective of this chapter is to bodies (Box 2.1). However, there is more to antibody- extract from the complex and rapidly evolving feld of immu- mediated protection than the peak of vaccine-induced nology the main concepts that are useful to better address antibody titers. The quality of such antibodies (e.g., their these important questions. avidity, specifcity, or neutralizing capacity) has been identi- fed as a determining factor in effcacy. Long-term protection HOW DO VACCINES MEDIATE PROTECTION? requires the persistence of vaccine antibodies above protective thresholds and/or the maintenance of immune memory cells Vaccines protect by inducing effector mechanisms (cells or capable of rapid and effective reactivation with subsequent molecules) capable of rapidly controlling replicating patho- microbial exposure. The determinants of immune memory gens or inactivating their toxic components. Vaccine-induced induction, as well as the relative contribution of persisting immune effectors (Table 2.1) are essentially antibodies— antibodies and of immune memory to protection against spe- produced by B lymphocytes—capable of binding specifcally cifc diseases, are essential parameters of long-term vaccine to a toxin or a pathogen.2 Other potential effectors are cyto- effcacy.
    [Show full text]