Principal Investigator: Carol D. Weiss, MD, PhD
Office / Division / Lab: OVRR / DVP / LI

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General Overview

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:

1. how the proteins on the surface of viruses, including human immunodeficiency virus (HIV) and influenza viruses, allow the viruses to infect cells
2. how antibodies to these 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.

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

1. evaluating data used to support approval of viral vaccines and
2. 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.

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Scientific Overview

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

1. 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
2. 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.

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Publications

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

Clin Infect Dis 2020 Sep 8 [Epub ahead of print]
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

Vaccines 2020 Jul 12;8(3):E382
Neutralizing antibodies targeting the conserved stem region of influenza hemagglutinin.
Nath Neerukonda S, Vassell R, Weiss CD

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

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

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

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

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

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

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

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 15;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