Carol D. Weiss

United States Food and Drug Administration

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Russell Vassell

Center for Biologics Evaluation and Research

Sabrina Lusvarghi

United States Food and Drug Administration

Sabari Nath Neerukonda

Center for Biologics Evaluation and Research

Emilie Goguet

Uniformed Services University of the Health Sciences

Timothy Burgess

Uniformed Services University of the Health Sciences

Edward Mitre

Uniformed Services University of the Health Sciences

Simon Pollett

Uniformed Services University of the Health Sciences

Eric D. Laing

Uniformed Services University of the Health Sciences

Christopher C. Broder

Uniformed Services University of the Health Sciences

David R. Tribble

Uniformed Services University of the Health Sciences

Cooperative Institutions

United States Food and Drug Administration

114

National Institutes of Health

112

Center for Biologics Evaluation and Research

Uniformed Services University of the Health Sciences

Henry M. Jackson Foundation

National Institute of Allergy and Infectious Diseases

Naval Medical Research Command

Johns Hopkins University

Unifor

Molecular Partners (Switzerland)

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Immunogenicity and Protection Against Influenza H7N3 in Mice by Modified Vaccinia Virus Ankara Vectors Expressing Influenza Virus Hemagglutinin or Neuraminidase

Scientific Reports (2018)

Clement A. Meseda Vajini Atukorale Jackeline Soto Maryna C. Eichelberger Jin Gao

Abstract Influenza subtypes such as H7 have pandemic potential since they are able to infect humans with severe consequences, as evidenced by the ongoing H7N9 infections in China that began in 2013. The diversity of H7 viruses calls for a broadly cross-protective vaccine for protection. We describe the construction of recombinant modified vaccinia virus Ankara (MVA) vectors expressing the hemagglutinin (HA) or neuraminidase (NA) from three H7 viruses representing both Eurasian and North American H7 lineages – A/mallard/Netherlands/12/2000 (H7N3), A/Canada/rv444/2004 (H7N3), and A/Shanghai/02/2013 (H7N9). These vectors were evaluated for immunogenicity and protective efficacy against H7N3 virus in a murine model of intranasal challenge. High levels of H7-, N3-, and N9-specific antibodies, including neutralizing antibodies, were induced by the MVA-HA and MVA-NA vectors. Mice vaccinated with MVA vectors expressing any of the H7 antigens were protected, suggesting cross-protection among H7 viruses. In addition, MVA vectors expressing N3 but not N9 elicited protection against H7N3 virus challenge. Similar outcomes were obtained when immune sera from MVA vector-immunized mice were passively transferred to naïve mice prior to challenge with the H7N3 virus. The results support the further development of an MVA vector platform as a candidate vaccine for influenza strains with pandemic potential.

H5N1 genetic structure

Pandemic

10.1038/s41598-018-23712-9

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Citations (17)

Neutralizing and Neuraminidase Antibodies Correlate With Protection Against Influenza During a Late Season A/H3N2 Outbreak Among Unvaccinated Military Recruits

Clinical Infectious Diseases (2019)

Carol D. Weiss Wei Wang Yun Lu Monisha Billings Angelia A Eick-Cost

Abstract Background Antibodies that inhibit hemagglutination have long been considered a correlate of protection against influenza, but these antibodies are only a subset of potentially protective antibodies. Neutralizing and neuraminidase antibodies may also contribute to protection, but data on their associations with protection are limited. Methods We measured preoutbreak hemagglutinin pseudovirus neutralization (PVN) and neuraminidase inhibition (NAI) antibody titers in unvaccinated military recruits who experienced an H3N2 influenza outbreak during training. We conducted a case-control study to investigate the association between titers and protection against influenza illness or H3N2-associated pneumonia using logistic regression. Results With every 2-fold increase in PVN titer, the odds of medically attended polymerase chain reaction–confirmed H3N2 infection (H3N2+) decreased by 41% (odds ratio [OR], 0.59; 95% confidence interval [CI], .45 to .77; P < .001). Among those who were H3N2+, the odds for pneumonia decreased by 52% (OR, 0.48; CI, .25 to .91; P = .0249). With every 2-fold increase in NAI titer, the odds of medically attended H3N2 infection decreased by 32% (OR, 0.68; 95% CI, .53 to .87; P = .0028), but there was no association between NAI titers and H3N2-associated pneumonia. There was also no synergistic effect of PVN and NAI antibodies. Conclusions PVN and NAI titers were independently associated with reduced risk of influenza illness. NAI titers associated with protection had greater breadth of reactivity to drifted strains than PVN titers. These findings show that PVN and NAI titers are valuable biomarkers for assessing the odds of influenza infection.

Antibody titer

10.1093/cid/ciz1198

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Citations (36)

Establishment of a well-characterized SARS-CoV-2 lentiviral pseudovirus neutralization assay using 293T cells with stable expression of ACE2 and TMPRSS2

PLoS ONE (2021)

Sabari Nath Neerukonda Russell Vassell Rachel Herrup Shufeng Liu Tony T. Wang

Pseudoviruses are useful surrogates for highly pathogenic viruses because of their safety, genetic stability, and scalability for screening assays. Many different pseudovirus platforms exist, each with different advantages and limitations. Here we report our efforts to optimize and characterize an HIV-based lentiviral pseudovirus assay for screening neutralizing antibodies for SARS-CoV-2 using a stable 293T cell line expressing human angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). We assessed different target cells, established conditions that generate readouts over at least a two-log range, and confirmed consistent neutralization titers over a range of pseudovirus input. Using reference sera and plasma panels, we evaluated assay precision and showed that our neutralization titers correlate well with results reported in other assays. Overall, our lentiviral assay is relatively simple, scalable, and suitable for a variety of SARS-CoV-2 entry and neutralization screening assays.

TMPRSS2

HEK 293 cells

10.1371/journal.pone.0248348

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Citations (124)

D-dimer and CoV-2 spike-immune complexes contribute to the production of PGE2 and proinflammatory cytokines in monocytes

PLoS Pathogens (2022)

Yun-Jong Park David Acosta Russell Vassell Juanjie Tang Surender Khurana

An overreactive inflammatory response and coagulopathy are observed in patients with severe form of COVID-19. Since increased levels of D-dimer (DD) are associated with coagulopathy in COVID-19, we explored whether DD contributes to the aberrant cytokine responses. Here we show that treatment of healthy human monocytes with DD induced a dose dependent increase in production of pyrogenic mediator, Prostaglandin E2 (PGE2) and inflammatory cytokines, IL-6 and IL-8. The DD-induced PGE2 and inflammatory cytokines were enhanced significantly by co-treatment with immune complexes (IC) of SARS CoV-2 recombinant S protein or of pseudovirus containing SARS CoV-2 S protein (PVCoV-2) coated with spike-specific chimeric monoclonal antibody (MAb) containing mouse variable and human Fc regions. The production of PGE2 and cytokines in monocytes activated with DD and ICs was sensitive to the inhibitors of β2 integrin and FcγRIIa, and to the inhibitors of calcium signaling, Mitogen-Activated Protein Kinase (MAPK) pathway, and tyrosine-protein kinase. Importantly, strong increase in PGE2 and in IL-6/IL-8/IL-1β cytokines was observed in monocytes activated with DD in the presence of IC of PVCoV-2 coated with plasma from hospitalized COVID-19 patients but not from healthy donors. The IC of PVCoV-2 with convalescent plasma induced much lower levels of PGE2 and cytokines compared with plasma from hospitalized COVID-19 patients. PGE2 and IL-6/IL-8 cytokines produced in monocytes activated with plasma-containing IC, correlated well with the levels of spike binding antibodies and not with neutralizing antibody titers. Our study suggests that a combination of high levels of DD and high titers of spike-binding antibodies that can form IC with SARS CoV-2 viral particles might accelerate the inflammatory status of lung infiltrating monocytes leading to increased lung pathology in patients with severe form of COVID-19.

Proinflammatory cytokine

Monocyte

10.1371/journal.ppat.1010468

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Citations (12)

Ensovibep, a novel trispecific DARPin candidate that protects against SARS-CoV-2 variants

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Sylvia Rothenberger Daniel L. Hurdiss Marcel Walser Francesca Malvezzi Jennifer Mayor

Abstract SARS-CoV-2 has infected millions of people globally and continues to undergo evolution. Emerging variants can be partially resistant to vaccine induced immunity and therapeutic antibodies, emphasizing the urgent need for accessible, broad-spectrum therapeutics. Here, we report a comprehensive study of ensovibep, the first trispecific clinical DARPin candidate, that can simultaneously engage all three units of the spike protein trimer to potently inhibit ACE2 interaction, as revealed by structural analyses. The cooperative binding of the individual modules enables ensovibep to retain inhibitory potency against all frequent SARS-CoV-2 variants, including Omicron BA.1 and BA.2, as of February 2022. Moreover, viral passaging experiments show that ensovibep, when used as a single agent, can prevent development of escape mutations comparably to a cocktail of monoclonal antibodies (mAb). Finally, we demonstrate that the very high in vitro antiviral potency also translates into significant therapeutic protection and reduction of pathogenesis in Roborovski dwarf hamsters infected with either the SARS-CoV-2 wild-type or the Alpha variant. In this model, ensovibep prevents fatality and provides substantial protection equivalent to the standard of care mAb cocktail. These results support further clinical evaluation and indicate that ensovibep could be a valuable alternative to mAb cocktails and other treatments for COVID-19.

10.1101/2021.02.03.429164

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Citations (16)

Characterization of lentiviral pseudotypes with influenza H5N1 hemagglutinin and their performance in neutralization assays

Journal of Virological Methods (2010)

Wei Wang Hang Xie Zhiping Ye Russell Vassell Carol D. Weiss

Infectivity

Hemagglutination assay

10.1016/j.jviromet.2010.02.009

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Citations (42)

Novel resistance mechanism of HIV-1 To peptide fusion inhibitors

Retrovirology (2006)

Nidhi Gupta Russell Vassell Wei Wang Yong He Carol D. Weiss

HIV fusion is mediated by conformational changes in HIV envelope glycoprotein (Env) that involves assembly of two heptad repeats (N- and C-HR) in the gp41 ectodomain to form a six-helix bundle (6HB). Peptides corresponding to the N- and C-HR of gp41, termed as fusion inhibitors, are potent inhibitors of HIV infection. However, HIV rapidly develops resistance to such fusion inhibitors. To better understand mechanisms of resistance that will aid development of new fusion inhibitors, we generated an escape mutant virus to an N peptide inhibitor (N44). This virus, however, was also equally resistant to T20 and other C peptides. This cross-resistance to fusion inhibitors was surprising because T20 binds the N-HR, while N44 binds the C-HR. We show that two point mutations, one each in the N-HR and C-HR were responsible for the resistance, but structural modeling of these mutations indicate that the mutations would not directly impair peptide binding. Further mechanistic studies of the resistant Env demonstrated that the mutations conferred increased infection kinetics, greater sensitivity to sCD4, enhanced syncytia formation, and enhanced exposure to CD4-induced epitopes. In summary these findings indicate a novel resistance mechanism involving improved receptor usage and faster entry kinetics. This indirect method of resistance is distinctively different from previous reports of escape from C peptide inhibitors that involve reduced peptide-binding affinity for the endogenous heptad repeat.

Ectodomain

Heptad repeat

Enfuvirtide

Entry inhibitor

Receptor–ligand kinetics

10.1186/1742-4690-3-s1-s86

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HIV-1 gp41 Residues Modulate CD4-Induced Conformational Changes in the Envelope Glycoprotein and Evolution of a Relaxed Conformation of gp120

Journal of Virology (2018)

Paul W. Keller Orrianne Morrison Russell Vassell Carol D. Weiss

Binding of the HIV envelope glycoprotein (Env) to cellular CD4 and chemokine receptors triggers conformational changes in Env that mediate virus entry, but premature triggering of Env conformational changes leads to virus inactivation. Currently, we have a limited understanding of the network of residues that regulate Env conformational changes. Here, we identify residues in HR1 of gp41 that modulate conformational changes in response to gp120 binding to CD4 and show that the mutations in HR1 and HR2 that confer resistance to fusion inhibitors are associated with gp120 mutations in different regions of Env that confer a more open conformation. These findings contribute to our understanding of the regulation of Env conformational changes and efforts to design new entry inhibitors and stable Env vaccine immunogens.

Conformational change

Envelope (radar)

10.1128/jvi.00583-18

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Citations (20)

Comparative Analysis of SARS-CoV-2 Antigenicity across Assays and in Human and Animal Model Sera

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Barbara Mühlemann Samuel Wilks Lauren Baracco Meriem Bekliz Juan Manuel Carreño

Abstract The antigenic evolution of SARS-CoV-2 requires ongoing monitoring to judge the immune escape of newly arising variants. A surveillance system necessitates an understanding of differences in neutralization titers measured in different assays and using human and animal sera. We compared 18 datasets generated using human, hamster, and mouse sera, and six different neutralization assays. Titer magnitude was lowest in human, intermediate in hamster, and highest in mouse sera. Fold change, immunodominance patterns and antigenic maps were similar among sera. Most assays yielded similar results, except for differences in fold change in cytopathic effect assays. Not enough data was available for conclusively judging mouse sera, but hamster sera were a consistent surrogate for human first-infection sera.

Antigenicity

2019-20 coronavirus outbreak

10.1101/2023.09.27.559689

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Citations (3)

Human Immunodeficiency Virus (HIV) gp41 Escape Mutants: Cross-Resistance to Peptide Inhibitors of HIV Fusion and Altered Receptor Activation of gp120

Journal of Virology (2005)

Emmanuel Desmézières Nidhi Gupta Russell Vassell Yong He Keith Peden

Human immunodeficiency virus (HIV) infects cells by fusing with cellular membranes. Fusion occurs when the envelope glycoprotein (Env) undergoes conformational changes while binding to cellular receptors. Fusogenic changes involve assembly of two heptad repeats in the ectodomain of the gp41 transmembrane subunit to form a six-helix bundle (6HB), consisting of a trimeric N heptad repeat (N-HR) coiled-coil core with three antiparallel C heptad repeats (C-HRs) that pack in the coiled-coil grooves. Peptides corresponding to the N-and C-HRs (N and C peptides, respectively) interfere with formation of the 6HB in a dominant-negative manner and are emerging as a new class of antiretroviral therapeutics for treating HIV infection. We generated an escape mutant virus with resistance to an N peptide and show that early resistance involved two mutations, one each in the N- and C-HRs. The mutations conferred resistance not only to the selecting N peptide but also to C peptides, as well as other types of N-peptide inhibitors. Moreover, the N-HR mutation altered sensitivity to soluble CD4. Biophysical studies suggest that the 6HB with the resistance mutations is more stable than the wild-type 6HB and the 6HB formed by inhibitor binding to either wild-type or mutant C-HR. These findings provide new insights into potential mechanisms of resistance to HIV peptide fusion inhibitors and dominant-negative inhibitors in general. The results are discussed in the context of current models of Env-mediated membrane fusion.

Heptad repeat

Ectodomain

Enfuvirtide

Coiled coil

V3 loop

10.1128/jvi.79.8.4774-4781.2005

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Citations (28)