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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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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

General Overview

All currently licensed vaccines stimulate the body to produce antibodies that help to prevent infections. In many cases, the levels of antibodies produced directly reflect the amount of protection the vaccine provides. Moreover, these antibody levels can serve as a marker for vaccine efficacy, i.e., a measurable factor that signifies that the vaccine is working.

Understanding how vaccines trigger production of protective antibodies, how these antibodies can be measured, and how they prevent infection, provides a rational basis for developing and evaluating vaccines.

Our research program aims to understand 1) how the envelope proteins on the surface of human immunodeficiency virus (HIV) and influenza viruses allow the viruses to infect cells; and 2) how antibodies to these proteins, which are generated during infection or induced by vaccines, interfere with virus infection.

The work is important because it will provide knowledge, skills, and expertise to CBER regulators that will increase their technical competency in 1) evaluating data used to support licensure of HIV and influenza vaccines; and 2) advising vaccine sponsors in various aspects of vaccine development.

This research program also provides added value to the scientific and vaccine developer communities through publication of research results in peer-reviewed scientific journals and development of methods that may help facilitate development of vaccines.

Scientific Overview

We are studying features of the HIV and influenza surface glycoproteins that influence virus infection, immunogenicity, and susceptibility to neutralizing antibodies. The laboratory uses cutting-edge biochemical, immunological, and genetic techniques and approaches to address these issues, with a heavy emphasis on the use and development of in vitro assays to detect virus infectivity and susceptibility to neutralizing antibodies.

HIV: We study the conserved regions of the envelope protein that regulate infection and serve as potential targets for broadly neutralizing antibodies that would effectively block infection of most HIV strains. This effort should aid the rational design and evaluation of vaccines for HIV/AIDS. Our lab (LIR) is the only one in CBER/OVRR that is studying HIV, and a large part of our regulatory load relates to vaccines for HIV/AIDS.

IInfluenza: We recently developed a novel, non-infectious, in vitro assay to detect neutralizing antibodies to influenza viruses for many subtypes, including pandemic H5N1 and H1N1 strains. This assay allows rapid evaluation of protective antibodies induced by vaccines or infection and can be performed in most labs without the need for high biocontainment facilities. Another technical advantage of this assay is that it facilitates the study of mutations that may render the virus less susceptible to neutralization by antibodies from previous infection or vaccination and does not depend on the need to isolate replicating virus.

We are now trying to validate this assay by comparing it to classic, live-virus assays that are used to evaluate sera from epidemiology and vaccine studies. Our findings indicate that this new assay will be a valuable complement to existing assays and has the major advantage of not requiring the use of live virus. We are the only lab at CBER using this assay, and have received many requests from outside researchers who have learned of this work through our peer-reviewed published articles.


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



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