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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Safety and Efficacy of Immune Globulins and Alpha-1 Proteinase Inhibitors

Principal Investigator: Dorothy Scott, MD
Office / Division / Lab: OBRR / DH / LPD


General Overview

An animal model to test treatments of severe smallpox vaccine complications.

The US is stockpiling smallpox vaccine as a precaution against an outbreak of this potentially fatal infection. This vaccine is made from a live but attenuated (weakened) virus called vaccinia, which is related to the actual smallpox virus.

While offering protection to many people, this vaccine virus can trigger a life-threatening infection called progressive vaccinia (PV) in people who have an immune deficiency disease. PV is fatal in about half of the individuals who develop it. People at risk for PV are those with cancer, HIV/AIDS, certain genetic deficiencies that make them more susceptible to infections, or who have undergone treatments that require suppressing their immune system with drugs. Some people with these risk factors receive the vaccine by mistake; or they "catch" vaccinia from someone else who received the vaccine. Our laboratory is working to improve treatments by giving vaccinia to immune-deficient mice, which develop a very similar disease. We will use this model to test new treatments that will help to ensure that the US is prepared if widespread smallpox vaccination is required in the future.


Developing a test to identify plasma that contains high concentrations of anti-influenza antibodies

Vaccination is the most effective way to prevent infection by influenza viruses. However, historical evidence from the 1918 flu outbreak and more recent data from animal studies suggest that antibodies against flu (FluIG) might also be effective in preventing or treating influenza. Such antibodies can be purified from plasma of donors who were infected or received a flu vaccine, and there is interest among researchers in testing their effectiveness in treating patients with severe influenza.

Our laboratory is working to identify antibodies in plasma that prevent flu from attaching to the cells it infects and to develop strategies that prevent virus-cell attachment. This could help to speed production of FluIG in the future and potentially provide another therapy for flu prevention or treatment.


Developing and improving treatments to prevent lung or liver failure in A1Pl deficiency

A1Pl is an enzyme that acts as a brake on the potentially destructive activities of certain other enzymes that the immune system releases during responses to infection and other threats. People with A1PI deficiency are at risk for severe lung infections and lung damage, as well as liver disease and liver failure. A1PI products treat lung disease in these patients; but these treatments do not prevent liver disease, which is caused by clumping of defective A1PI in liver cells. We are using atomic force microscopy to determine the structure of A1PI clumps. This technique is an extremely sensitive way to obtain information about molecules by using a mechanical probe that moves along the surface of a molecule and "feels" its shape. This new knowledge will help us to develop treatments that prevent A1Pl clump formation and liver disease.

In spite of A1PI treatment, lung disease may progress, albeit more slowly. Moreover, researchers have not yet determined exactly how A1PI protects lung tissue. However, our laboratory has shown that early during an infection in patients without lung disease, immune system cells called macrophages produce A1PI. We found that A1PI released by macrophages does not have the same activity as the A1Pl found in plasma. We are using human lung samples and macrophages in cell culture to clarify the function of macrophage-produced A1PI. This information should be helpful in determining whether higher doses of A1PI or inhalation of A1Pl are likely to benefit patients. This work might also contribute to better understanding and treatment of other lung diseases such as cystic fibrosis and emphysema.


Scientific Overview

Animal model for testing treatments for progressive vaccina

In the event of a smallpox outbreak there would likely be widespread vaccination against this virus. After vaccination, however, immune-deficient people, including those with HIV, immunosuppressive therapy, and with primary immune deficiencies would be at risk for developing progressive vaccinia (PV). Even among people with PV who are treated with licensed vaccinia immune globulin (VIG), mortality estimates are 50%.

In the absence of widespread vaccination, there are few cases of PV and therefore few opportunities for clinical trials designed to investigate the safety and efficacy of a new treatment for this problem. Therefore, FDA approval of new treatments must be based on results of studies in animal models. Therefore, we characterized a scarification model in SCID mice that has a similar clinical course to that of humans: an indolent but fatal infection characterized by an expanding lesion and secondary virus spread, which is partially responsive to treatment with VIG. This model has the potential for advancing national preparedness through testing proposed treatments.


Testing plasma levels of influenza immune globulin

When influenza vaccine is unavailable or the infection is severe, antiviral treatment must be instituted. For example, hyperimmune plasma was used to treat influenza in 1918, and more recent animal studies suggest the effectiveness of influenza immune globulin (FluIG). Producing purified FluIG from the plasma of convalescent or vaccinated donors could require screening of hundreds to thousands of donations for high levels of neutralizing antibodies. However, a streamlined test would speed development and manufacture. Our goal is to develop a simple, rapid, and robust method to detect antibody-mediated inhibition of influenza A hemagglutinin (HA) binding to corresponding glycan receptors. We have piloted a surface plasmon-resonance (SPR) assay that sensitively and specifically detects binding between influenza H5 HA and glycan receptors, as well as binding inhibition by monoclonal antibody. We are assessing the robustness, plasma interference, reagent selection, and polyclonal antibody binding inhibition. These methods could be adapted to detect antibodies against other strains of influenza.


Alpha 1 Proteinase Inhibitor (A1Pl) Studies

Patients with A1PI deficiency can have severe complications from respiratory infection, suggesting that A1PI affects inflammatory responses to lung pathogens. However, A1PI treatment does not abrogate pulmonary disease progression. We studied lung samples and secretions from non-A1PI-deficient patients and found that A1PI is abundantly expressed by lung-resident macrophages during severe lower respiratory infection and in late-stage cystic fibrosis. Surprisingly, this A1PI does not have the enzymatic activity observed in plasma A1PI, nor is it bound by elastase, suggesting that plasma A1Pl has a different function from A1PI in the lungs. Our laboratory is currently studying the function of pulmonary macrophage-secreted A1PI, which should inform dosing, route, and potency testing for A1PI treatments, and development of new therapies.

People with A1PI deficiency can also develop liver failure from polymerization of defective A1PI (PiZ) in liver cells. Understanding the structure of A1PI polymers should provide knowledge to advance development of treatment for this condition. In collaboration with the University of Texas at San Antonio, we are using atomic force microscopy (AFM) to obtain nanometer-scale, topographical resolution to analyze this molecule. We generated a variety of polymers in vitro from normal A1PI and purified PiZ-variant polymers from the liver of a transgenic mouse expressing the human PiZ variant of A1PI. We obtained preliminary AFM images that identify and distinguish distinct polymers, and are now analyzing them. In the future we will improve purification methods and purify polymers from liver explants of A1PI-deficient patients receiving liver transplants.


Publications

Influenza Other Respir Viruses 2013 Jan;7(1):46-54
Mucosal antibody responses are directed by viral burden in children with acute influenza infection.
He Y, Abid A, Fisher R, Eller N, Mikolajczyk M, Welliver RC Sr, Bonner AB, Scott DE, Reed JL

PLoS One 2012;7(11):e51078
Cytosolic, Autocrine Alpha-1 Proteinase Inhibitor (A1PI) Inhibits Caspase-1 and Blocks IL-1beta Dependent Cytokine Release in Monocytes.
Wang Y, He Y, Abraham B, Rouhani FN, Brantly ML, Scott DE, Reed JL

Transfusion 2012 Oct;52(10):2113-21
Immune globulins and thrombotic adverse events as recorded in a large administrative database in 2008 through 2010.
Daniel GW, Menis M, Sridhar G, Scott D, Wallace AE, Ovanesov MV, Golding B, Anderson SA, Epstein J, Martin D, Ball R, Izurieta HS

Virol J 2012 Sep 24;9:217
Epitope mapping by random peptide phage display reveals essential residues for vaccinia extracellular enveloped virion spread.
He Y, Wang Y, Struble EB, Zhang P, Chowdhury S, Reed JL, Kennedy M, Scott DE, Fisher RW

Clin Infect Dis 2012 Mar;54(6):832-40
Eczema vaccinatum.
Reed JL, Scott DE, Bray M

IEEE Trans Nanotechnol 2012 Jan;11(1):88-96
Pandemic Influenza Detection by Electrically Active Magnetic Nanoparticles and Surface Plasmon Resonance
Kamikawa TL, Mikolajczyk MG, Kennedy M, Zhong LL, Zhang P, Setterington EB, Scott DE, Alocilja EC

Arch Virol 2011 Oct;156(10):1877-81
Infection of cynomolgus macaques with a recombinant monkeypox virus encoding green fluorescent protein.
Goff A, Mucker E, Raymond J, Fisher R, Bray M, Hensley L, Paragas J

Virol J 2011 Sep 20;8:441
Polyclonal antibody cocktails generated using DNA vaccine technology protect in murine models of orthopoxvirus disease.
Golden JW, Zaitseva M, Kapnick S, Fisher RW, Mikolajczyk MG, Ballantyne J, Golding H, Hooper JW

Vox Sang 2011 Jul;101(1):83-9
An international collaborative study to establish the WHO 1st international standard for alpha-1-antitrypsin.
Thelwell C, Marszal E, Rigsby P, Longstaff C

PLoS Pathog 2011 Jun;7(6):e1002081
Cross-neutralizing antibodies to pandemic 2009 H1N1 and recent seasonal H1N1 influenza A strains influenced by a mutation in hemagglutinin subunit 2.
Wang W, Anderson CM, De Feo CJ, Zhuang M, Yang H, Vassell R, Xie H, Ye Z, Scott D, Weiss CD

Clin Vaccine Immunol 2011 Jan;18(1):67-74
Postexposure prevention of progressive vaccinia in SCID mice treated with vaccinia immune globulin.
Fisher RW, Reed JL, Snoy PJ, Mikolajczyk MG, Bray M, Scott DE, Kennedy MC

Biosens Bioelectron 2010 Dec 15;26(4):1346-52
Nanoparticle-based biosensor for the detection of emerging pandemic influenza strains.
Kamikawa TL, Mikolajczyk MG, Kennedy M, Zhang P, Wang W, Scott DE, Alocilja EC

Biologicals 2010 Sep;38(5):602-11
Meeting report on protein particles and immunogenicity of therapeutic proteins: filling in the gaps in risk evaluation and mitigation.
Carpenter J, Cherney B, Lubinecki A, Ma S, Marszal E, Mire-Sluis A, Nikolai T, Novak J, Ragheb J, Simak J

Transfusion 2009 Jun;49(6):1050-8
Investigation of whether the acute hemolysis associated with Rh(D) immune globulin intravenous (human) administration for treatment of immune thrombocytopenic purpura is consistent with the acute hemolytic transfusion reaction model.
Gaines AR, Lee-Stroka H, Byrne K, Scott DE, Uhl L, Lazarus E, Stroncek DF

J Infect Dis 2009 Apr 15;199(8):1128-1138
Innate Immune Signals Modulate Antiviral and Polyreactive Antibody Responses during Severe Respiratory Syncytial Virus Infection.
Reed JL, Welliver TP, Sims GP, McKinney L, Velozo L, Avendano L, Hintz K, Luma J, Coyle AJ, Welliver Sr RC

J Infect Dis 2008 Dec 15;198(12):1783-93
Macrophage Impairment Underlies Airway Occlusion in Primary Respiratory Syncytial Virus Bronchiolitis.
Reed JL, Brewah YA, Delaney T, Welliver T, Burwell T, Benjamin E, Kuta E, Kozhich A, McKinney L, Suzich J, Kiener PA, Avendano L, Velozo L, Humbles A, Welliver Sr RC, Coyle AJ

Clin Infect Dis 2008 May 15;46(10):1555-61
Severe eczema vaccinatum in a household contact of a smallpox vaccinee
Vora S, Damon I, Fulginiti V, Weber SG, Kahana M, Stein SL, Gerber SI, Garcia-Houchins S, Lederman E, Hruby D, Collins L, Scott D, Thompson K, Barson JV, Regnery R, Hughes C, Daum RS, Li Y, Zhao H, Smith S, Braden Z, Karem K, Olson V, Davidson W, Trindade G, Bolken T, Jordan R, Tien D, Marcinak J

J Virol 2007 Jul;81(14):7449-62
Temporal analysis of Andes virus and Sin Nombre virus infections of Syrian hamsters.
Wahl-Jensen V, Chapman J, Asher L, Fisher R, Zimmerman M, Larsen T, Hooper JW

Cancer Res 2007 May 15;67(10):5059
Regulatory B cells inhibit antitumor immunity.
Inoue S, Scott D, Golding B, Leitner WW

J Infect Dis 2006 Sep 15;194(6):781-9
Measles-virus-neutralizing antibodies in intravenous immunoglobulins.
Audet S, Virata-Theimer ML, Beeler JA, Scott DE, Frazier DJ, Mikolajczyk MG, Eller N, Chen FM, Yu MY

Cancer Res 2006 Aug 1;66(15):7741-7
Inhibitory effects of B cells on antitumor immunity.
Inoue S, Leitner WW, Golding B, Scott D

Curr Opin Biotechnol 2005 Oct;16(5):561-7
The clearance of viruses and transmissible spongiform encephalopathy agents from biologicals.
Farshid M, Taffs RE, Scott D, Asher DM, Brorson K

Nat Med 2005 Jul;11(7):740-7
Smallpox vaccine-induced antibodies are necessary and sufficient for protection against monkeypox virus.
Edghill-Smith Y, Golding H, Manischewitz J, King LR, Scott D, Bray M, Nalca A, Hooper JW, Whitehouse CA, Schmitz JE, Reimann KA, Franchini G

J Virol 2005 Jun;79(11):6791-800
Identification of a Linear Peptide Recognized by Monoclonal Antibody 2D7 Capable of Generating CCR5-Specific Antibodies with Human Immunodeficiency Virus-Neutralizing Activity.
Khurana S, Kennedy M, King LR, Golding H

Vaccine 2005 Feb 25;23(14):1730-8
Programming of CTL with heat-killed Brucella abortus and antigen allows soluble antigen alone to generate effective secondary CTL.
Inoue S, Golding B, Scott D

Clin Diagn Lab Immunol 2004 Nov;11(6):1158-64
Characterization of Antibodies to Capsular Polysaccharide Antigens of Haemophilus influenzae Type b and Streptococcus pneumoniae in Human Immune Globulin Intravenous Preparations.
Mikolajczyk MG, Concepcion NF, Wang T, Frazier D, Golding B, Frasch CE, Scott DE

J Med Primatol 2004 Aug;33(4):167-74
Systemic and mucosal immunity in rhesus macaques immunized with HIV-1 peptide and gp120 conjugated to Brucella abortus.
Eller N, Golding H, Inoue S, Beining P, Inman J, Matthews N, Scott DE, Golding B

Vox Sang 2004 Feb;86(2):125-9
Intravenous immunoglobulin products contain neutralizing antibodies to vaccinia.
Goldsmith JC, Eller N, Mikolajczyk M, Manischewitz J, Golding H, Scott DE

 

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