Evaluating Viral Antigens and Antibody Neutralization for HIV/AIDS, Smallpox, and Influenza
Principal Investigator: Carol D. Weiss, MD, PhD
Office / Division / Lab: OVRR / DVP / LI
All currently licensed vaccines cause the immune system to produce antibodies to help the body fight off infection and disease. The quality and quantity of these antibodies can directly affect the degree of protection. Antibodies can therefore serve as a "marker" for the effectiveness of vaccines and are used to evaluate new vaccines. However, such protective antibodies are produced only when the immune system sees certain forms of the viral proteins (antigens) with the right structure.
Information about the quality and quantity of antibodies that block (neutralize) virus entry into cells, as well as quality and quantity of viral antigens in vaccines that affect production of such protective antibodies, improves the scientific basis for developing and evaluating new viral vaccines. Our research program uses cells in culture and mouse models to investigate the following dimensions of this process:
- how the proteins on the surface of viruses, including human immunodeficiency virus (HIV) and influenza viruses, allow the viruses to infect cells
- how antibodies to these proteins, which are produced in response to either infection or vaccines, interfere with virus infection and thus protect against disease
- how different forms of these viral proteins affect production of protective antibodies.
Undertaking this research gives CBER regulators the knowledge, skills, and expertise to assure technical competency for
- evaluating data used to support approval of viral vaccines and
- advising vaccine stakeholders on aspects of vaccine manufacture and development.
Scientific regulation greatly benefits from review by regulators who are actively engaged in cutting-edge research and recognized as scientific peers in the research community. By developing laboratory methods and publishing research results in peer-reviewed scientific journals, the FDA contributes to the scientific community while facilitating the development of safe and effective vaccines.
Our research program studies how viruses initiate infection and how antibodies protect against infection and disease. Glycoproteins on the surface of enveloped viruses undergo structural changes that allow viruses to attach to and fuse with target cells to initiate an infection. Antibodies produced by the immune system after vaccination or infection can bind to viral surface glycoproteins and prevent the attachment or fusion processes, but molecular details of virus entry and neutralization are not well understood. Such information would aid development and evaluation of new viral vaccines that can elicit broadly potent neutralizing antibodies.
Projects in this research program aim to elucidate molecular details of how envelope glycoproteins mediate virus entry and how antibodies neutralize viruses to prevent infection and disease. This work involves dissecting steps in the viral entry process and the structural changes in the envelope glycoproteins associated with those steps. We are identifying the target sites and forms of the envelope glycoproteins that antibodies or other entry inhibitors bind to in order to prevent virus entry. Information from these studies is used to evaluate whether envelope glycoprotein antigens in vaccines have appropriate structural forms to elicit neutralizing antibodies.
We use several strategies to identify residues and regions of the envelope glycoproteins that are critical for virus entry and neutralization. We use genetics and molecular biology to generate and analyze mutations in the envelope glycoproteins that allow the virus to evade neutralization by antibodies or other entry inhibitors. We further study the effect of these mutations on virus entry and susceptibility to neutralization using cell culture methods. Information from these studies is used to generate recombinant envelope glycoproteins that are evaluated in animal models to study relationships between the structural features of the envelope glycoprotein that can be recognized by antibodies (antigenicity) and the ability of those recombinant proteins to induce the immune system to produce neutralizing antibodies (immunogenicity). Antibodies generated in these studies are additionally used to evaluate vaccine stability and antigenic structure, as well as to develop new potency assays for vaccines.
We are also studying human immune responses to influenza in order to address specific issues for influenza vaccines. We are analyzing
- the extent to which natural infection and influenza vaccines causes the immune system to produce broadly potent (cross-neutralizing) neutralizing antibodies capable of protecting against many influenza strains and
- the extent to which drifted and divergent strains can be neutralized by sera generated by prior seasonal or novel vaccines.
These studies involve analyzing sera from clinical samples and animal models to identify sites on the surface envelope protein (hemagglutinin) that are vulnerable inhibition by antibodies. This information guides strategies for developing and evaluating novel"universal" influenza vaccines that can elicit antibodies that neutralize many influenza A strains. These studies involve the development of assays and reagents that can help identify cross-neutralizing antibodies to highly-conserved parts of the influenza hemagglutinin. Such antibodies will also be used to develop new potency assays for influenza vaccines.
PLoS One 2017 Apr 19;12(4):e0175733
Determination of influenza B identity and potency in quadrivalent inactivated influenza vaccines using lineage-specific monoclonal antibodies.
Verma S, Soto J, Vasudevan A, Schmeisser F, Alvarado-Facundo E, Wang W, Weiss CD, Weir JP
Open Forum Infect Dis 2017 Feb 12;4(2):ofx023
Surveillance study of influenza occurrence and immunity in a Wisconsin cohort during the 2009 pandemic.
Lo CY, Strobl SL, Dunham K, Wang W, Stewart L, Misplon JA, Garcia M, Gao J, Ozawa T, Price GE, Navidad J, Gradus S, Bhattacharyya S, Viboud C, Eichelberger MC, Weiss CD, Gorski J, Epstein SL
J Infect Dis 2016 Feb 1;213(3):403-6
Sera from middle-aged adults vaccinated annually with seasonal influenza vaccines cross-neutralize some potential pandemic influenza viruses.
Wang W, Facundo EA, Chen Q, Anderson CM, Scott D, Vassell R, Weiss CD
PLoS One 2016 Feb 10;11(2):e0149149
Glycosylation of residue 141 of subtype H7 influenza A hemagglutinin (HA) affects HA-pseudovirus infectivity and sensitivity to site A neutralizing antibodies.
Alvarado-Facundo E, Vassell R, Schmeisser F, Weir JP, Weiss CD, Wang W
J Virol 2015 Oct 15;89(20):10602-11
Intermonomer interactions in hemagglutinin subunits HA1 and HA2 affecting hemagglutinin stability and influenza virus infectivity.
Wang W, DeFeo CJ, Alvarado E, Vassell R, Weiss CD
PLoS One 2015 Jun 18;10(6):e0128562
Immunogens modeling a fusion-intermediate conformation of gp41 elicit antibodies to the membrane proximal xxternal region of the HIV envelope glycoprotein.
Vassell R, He Y, Vennakalanti P, Dey AK, Zhuang M, Wang W, Sun Y, Biron-Sorek Z, Srivastava IK, LaBranche CC, Montefiori DC, Barnett SW, Weiss CD
J Virol 2015 Feb;89(4):1975-85
Influenza M2 protein ion channel activity helps maintain the pandemic 2009 H1N1 hemagglutinin fusion competence during transport to the cell surface.
Alvarado-Facundo E, Gao Y, Ribas-Aparicio RM, Jimenez-Alberto A, Weiss CD, Wang W
PLoS One 2015 Jan 28;10(1):e0117108
Antibodies to antigenic site A of influenza H7 hemagglutinin provide protection against H7N9 challenge.
Schmeisser F, Vasudevan A, Verma S, Wang W, Alvarado E, Weiss C, Atukorale V, Meseda C, Weir JP
Retrovirology 2014 Oct 2;11(1):86
HIV entry kinetics does not correlate with resistance to N-peptide fusion inhibitors or thermodynamic stability of the gp41 six-helix bundle.
De Feo CJ, Wang W, Hsieh ML, Zhuang M, Vassell R, Weiss CD
PLoS One 2013 Jul 23;8(7):e70005
Analysis of adaptation mutants in the hemagglutinin of the influenza A(H1N1)pdm09 virus.
Jimenez-Alberto A, Alvarado-Facundo E, Ribas-Aparicio RM, Castelan-Vega JA
Influenza Other Respir Viruses 2013 May;7(3):480-90
Neutralizing and protective epitopes of the 2009 pandemic influenza H1N1 hemagglutinin.
Schmeisser F, Friedman R, Besho J, Lugovtsev V, Soto J, Wang W, Weiss C, Williams O, Xie H, Ye Z, Weir JP
Viruses 2012 Dec;4(12):3859-911
Escape from human immunodeficiency virus type 1 (HIV-1) entry inhibitors.
De Feo CJ, Weiss CD
J Biol Chem 2012 Mar 9;287(11):8297-309
Trimeric, coiled-coil extension on peptide fusion inhibitor of HIV-1 influences selection of resistance pathways.
Zhuang M, Wang W, De Feo CJ, Vassell R, Weiss CD
J Virol 2011 Dec;85(24):12929-38
Selection with a peptide fusion inhibitor corresponding to the first heptad repeat of human immunodeficiency virus type 1 (HIV-1) gp41 identifies two genetic pathways conferring cross-resistance to peptide fusion inhibitors corresponding to the first and second heptad repeat (HR1 and HR2) of gp41.
Wang W, De Feo CJ, Zhuang M, Vassell R, Weiss CD
J Virol 2011 Dec;85(24):12929-38
Selection with a peptide fusion inhibitor corresponding to the first heptad repeat of HIV-1 gp41 identifies two genetic pathways conferring cross-resistance to peptide fusion inhibitors corresponding to the first and second heptad repeats (HR1 and HR2) of gp41.
Wang W, De Feo CJ, Zhuang M, Vassell R, Weiss CD
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
Virology 2010 Nov 25;407(2):374-80
A mutation in the receptor binding site enhances infectivity of 2009 H1N1 influenza hemagglutinin pseudotypes without changing antigenicity.
Wang W, Castelán-Vega JA, Jiménez-Alberto A, Vassell R, Ye Z, Weiss CD
J Virol Methods 2010 May;165(2):305-10
Characterization of lentiviral pseudotypes with influenza H5N1 hemagglutinin and their performance in neutralization assays.
Wang W, Xie H, Ye Z, Vassell R, Weiss CD
Vaccine 2010 Jan 8;28(3):699-706
Recombinant A27 protein synergizes with modified vaccinia Ankara in conferring protection against a lethal vaccinia virus challenge.
He Y, Meseda CA, Vassell RA, Merchlinsky M, Weir JP, Weiss CD
J Virol Methods 2008 Nov;153(2):111-9
Establishment of retroviral pseudotypes with influenza hemagglutinins from H1, H3, and H5 subtypes for sensitive and specific detection of neutralizing antibodies.
Wang W, Butler EN, Veguilla V, Vassell R, Thomas JT, Moos M, Ye Z, Hancock K, Weiss CD
J Infect Dis 2007 Oct 1;196(7):1026-32
Antibodies to the A27 Protein of Vaccinia Virus Neutralize and Protect against Infection but Represent a Minor Component of Dryvax Vaccine-Induced Immunity.
He Y, Manischewitz J, Meseda CA, Merchlinsky M, Vassell RA, Sirota L, Berkower I, Golding H, Weiss CD
Virology 2005 Dec 5;343(1):128-40
Identification and preliminary characterization of vaccinia virus (Dryvax) antigens recognized by vaccinia immune globulin.
Jones-Trower A, Garcia A, Meseda CA, He Y, Weiss C, Kumar A, Weir JP, Merchlinsky M
J Virol 2005 Apr;79(8):4774-81
Human Immunodeficiency Virus (HIV) gp41 Escape Mutants: Cross-Resistance to Peptide Inhibitors of HIV Fusion and Altered Receptor Activation of gp120.
Desmezieres E, Gupta N, Vassell R, He Y, Peden K, Sirota L, Yang Z, Wingfield P, Weiss CD