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  1. Biologics Research Projects

Virus Entry and Its Inhibition by Antibodies: Studies to Aid the Development and Evaluation of Vaccines that Protect against Viral Infectious Diseases

Carol D. Weiss, M.D., Ph.D.

Office of Vaccines Research and Review
Division of Viral Products
Laboratory of Immunoregulation

[email protected]

Biosketch

Dr. Weiss is Chief of the Lab of Immunoregulation in the Division of Viral Products, in the Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, at the U.S. Food and Drug Administration. Her review portfolio includes vaccines to protect against HIV, influenza, and coronaviruses. Her research program focuses on basic and applied research relating to how viruses enter cells, how antibodies block this process, and the qualities of vaccines needed to induce neutralizing antibodies that protect against viral diseases and infections. She is board-certified in Internal Medicine and received her M.D. from the University of Chicago and Ph.D. from the University of California, San Francisco.

General Overview

All currently licensed vaccines cause the immune system to produce antibodies that help fight off infection and prevent disease. The quality and quantity of these antibodies can directly affect the degree of protection. Therefore, antibodies often serve as a "marker" for the effectiveness of vaccines, and antibody assessments are used to evaluate new vaccines. Protective antibodies are only produced, however, when the immune system sees viral proteins (antigens) in the right forms.

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, contributes to a scientific basis for developing and evaluating new vaccines that protect against diseases caused by viruses. Our research program uses cells in culture, animal models, and clinical serum samples to investigate the following dimensions of viral infections and immune responses to them:

  1. How the proteins on the surface of viruses, including human immunodeficiency virus (HIV), influenza, and coronaviruses, allow the viruses to infect cells;
  2. How antibodies to these viral surface proteins, which are produced in response to either infection or vaccines, interfere with virus infection and thus protect against disease;
  3. How different forms of these viral proteins affect production of protective antibodies; and
  4. What level (titer) of antibodies (if any) correlate with protection in clinical studies and animal models.

Undertaking this research gives CBER regulators the knowledge, skills, and expertise to assure technical competency for:

  1. Evaluating data used to support approval of vaccines that protect against diseases caused by viruses;
  2. Advising vaccine stakeholders on aspects of vaccine manufacture and development; and
  3. Contributing to the foundation of knowledge that supports the development of new, safe and effective vaccines that protect against illnesses caused by viruses.

Scientific Overview

We are studying how viruses initiate infection and how antibodies protect against infection and disease. Proteins on the surface of enveloped viruses allow viruses to attach to and fuse with cells to initiate infection. Antibodies produced by the immune system after vaccination or infection can bind to viral surface proteins and prevent virus attachment to or fusion with cells, but many viruses quickly mutate to evade neutralization by antibodies. Identifying vulnerable neutralizing sites on viral proteins that cannot readily tolerate mutations and designing vaccines that can elicit broadly potent antibodies to those sites remain important public health goals.

Our research aims to elucidate molecular details of how the envelope proteins of HIV, influenza, and coronaviruses catalyze virus entry and how antibodies neutralize these viruses. This work involves dissecting steps in the viral entry process and the associated structural changes in the envelope proteins that expose conserved sites that are vulnerable to neutralization by broadly potent antibodies. This work helps us evaluate whether viral proteins in vaccines (antigens) have the right form and structure for eliciting antibodies that can neutralize the many strains of a virus.

We use several strategies, including genetics and molecular biology, to identify amino acids and regions of the envelope proteins that are critical for virus entry and neutralization. We are studying (1) mutations that allow a virus to evade neutralization by antibodies or virus entry inhibitors and (2) how those mutations affect virus entry. This information is used to design and evaluate vaccine antigens and immunization strategies in animal models to further help us understand how 1) the protein structure that is recognized by the immune system (antigenicity) and 2) immunization regimens influence the elicitation of neutralizing antibodies (immunogenicity). Antibodies generated in these studies are further used by us and others to evaluate the structure and stability of vaccine antigens. These antibodies also serve as reagents for developing new measures of vaccine potency.

Methods and concepts currently being pursued to develop vaccines that can elicit neutralizing antibodies capable of providing protection against diverse strains of virus are similar. For influenza, however, developing new universal vaccines that protect against many strains of influenza is further complicated by a host's prior immunity to influenza. Immunity to past influenza strains can affect the induction of antibodies to new strains. Therefore, we are also studying how past influenza infections and vaccinations influence induction of new influenza antibodies and the effectiveness of new seasonal influenza vaccines. This work involves analyses of serum samples from clinical vaccine trials and experimental vaccines in animal models.

Important Links

Publications

  1. J Virol 2022 Jan;96(1):e0111021
    Key substitutions in the spike protein of SARS-CoV-2 variants can predict resistance to monoclonal antibodies, but other substitutions can modify the effects.
    Lusvarghi S, Wang W, Herrup R, Neerukonda SN, Vassell R, Bentley L, Eakin AE, Erlandson KJ, Weiss CD
  2. Viruses 2021 Dec 11;13(12):2485
    SARS-CoV-2 delta variant displays moderate resistance to neutralizing antibodies and spike protein properties of higher soluble ACE2 sensitivity, enhanced cleavage and fusogenic activity.
    Neerukonda SN, Vassell R, Lusvarghi S, Wang R, Echegaray F, Bentley L, Eakin AE, Erlandson KJ, Katzelnick LC, Weiss CD, Wang W
  3. Lett Appl Microbiol 2021 Sep;73(3):294-9
    Comparison of hemagglutination inhibition and hemagglutinin pseudovirus neutralization titers in relation to protection against influenza in a mouse model.
    Huang Y, Lin Z, Wang W, Weiss C, Xie H, Forshee RA
  4. PLoS One 2021 Mar 10;16(3):e0248348
    Establishment of a well-characterized SARS-CoV-2 lentiviral pseudovirus neutralization assay using 293T cells with stable expression of ACE2 and TMPRSS2.
    Neerukonda SN, Vassell R, Herrup R, Liu S, Wang T, Takeda K, Yang Y, Lin TL, Wang W, Weiss CD
  5. Clin Infect Dis 2021 Dec 1;73(11):e4312-20
    Comparison of A(H3N2) neutralizing antibody responses elicited by 2018-2019 season quadrivalent influenza vaccines derived from eggs, cells, and recombinant hemagglutinin.
    Wang W, Alvarado-Facundo E, Vassell R, Collins L, Colombo RE, Ganesan A, Geaney C, Hrncir D, Lalani T, Markelz AE, Maves RC, McClenathan B, Mende K, Richard SA, Schofield C, Seshadri S, Spooner C, Utz GC, Warkentien TE, Levine M, Coles CL, Burgess TH, Eichelberger M, Weiss CD
  6. Vaccines 2020 Jul 12;8(3):E382
    Neutralizing antibodies targeting the conserved stem region of influenza hemagglutinin.
    Nath Neerukonda S, Vassell R, Weiss CD
  7. Clin Infect Dis 2020 Dec 15;71(12):3096-3102
    Neutralizing and neuraminidase antibodies correlate with protection against influenza during a late season A/H3N2 outbreak among unvaccinated military recruits.
    Weiss CD, Wang W, Lu Y, Billings M, Eick-Cost A, Couzens L, Sanchez JL, Hawksworth AW, Seguin P, Myers CA, Forshee R, Eichelberger MC, Cooper MJ
  8. PLoS One 2019 Sep 12;14(9):e0222436
    Generation of a protective murine monoclonal antibody against the stem of influenza hemagglutinins from group 1 viruses and identification of resistance mutations against it.
    Wang W, Vassell R, Song HS, Chen Q, Keller PW, Verma S, Alvarado-Facundo E, Wan H, Schmeisser F, Meseda CA, Weir JP, Weiss CD
  9. J Virol 2019 Jun;93(11):e00142-19
    Mutations that increase the stability of the post-fusion gp41 conformation of the HIV-1 envelope glycoprotein are selected by both an X4 and R5 HIV-1 virus to escape fusion inhibitors corresponding to heptad repeat 1 of gp41, but the gp120 adaptive mutations differ between the two viruses.
    Zhuang M, Vassell R, Yuan C, Keller PW, Ling H, Wang W, Weiss CD
  10. Clin Infect Dis 2019 May 30;68(12):2067-78
    Neutralizing antibody responses to homologous and heterologous H1 and H3 influenza A strains after vaccination with inactivated trivalent influenza vaccine vary with age and prior year vaccination.
    Wang W, Chen Q, Ford-Siltz LA, Katzelnick LC, Parra GI, Song HS, Vassell R, Weiss CD
  11. J Virol 2018 Aug;92(16):e00583-18
    HIV-1 gp41 residues modulate CD4-induced conformational changes in the envelope glycoprotein and evolution of a relaxed conformation of gp120.
    Keller PW, Morrison O, Vassell R, Weiss CD
  12. J Virol 2018 Jun;92(12):e00247-18
    Conformational stability of the hemagglutinin of H5N1 influenza A viruses influences susceptibility to broadly neutralizing stem antibodies.
    Wang W, Song HS, Keller PW, Alvarado-Facundo E, Vassell R, Weiss CD
  13. Sci Rep 2018 Mar 29;8(1):5364
    Immunogenicity and protection against influenza H7N3 in mice by modified vaccinia virus Ankara vectors expressing influenza virus hemagglutinin or neuraminidase.
    Meseda CA, Atukorale V, Soto J, Eichelberger MC, Gao J, Wang W, Weiss CD, Weir JP
  14. 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
  15. 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
  16. 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
  17. 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
  18. J Virol 2015 Oct;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
  19. 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
  20. 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
  21. 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

 

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