Jeffrey R. Currier

Walter Reed Army Institute of Research

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Heather Friberg

Walter Reed Army Institute of Research

Nelson L. Michael

Walter Reed Army Institute of Research

Gregory D. Gromowski

Walter Reed Army Institute of Research

Richard G. Jarman

Walter Reed Army Institute of Research

Adam T. Waickman

SUNY Upstate Medical University

Stephen J. Thomas

SUNY Upstate Medical University

Merlin L. Robb

Henry M. Jackson Foundation

Kayvon Modjarrad

Walter Reed Army Institute of Research

Alan L. Rothman

Providence College

Mary Marovich

National Institutes of Health

Cooperative Institutions

Walter Reed Army Institute of Research

293

Henry M. Jackson Foundation

202

National Institutes of Health

109

National Institute of Allergy and Infectious Diseases

Jackson Foundation

Armed Forces Research Institute of Medical Science

Uniformed Services University of the Health Sciences

Johns Hopkins University

SUNY Upstate Medical University

United States Army

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Analysis of cell-associated DENV RNA by oligo(dT) primed 5’ capture scRNAseq

Scientific Reports (2020)

Mark A. Sanborn Tao Li Kaitlin Victor Hayden Siegfried Christian Fung

Abstract Dengue is one of the most widespread vector-borne viral diseases in the world. However, the size, heterogeneity, and temporal dynamics of the cell-associated viral reservoir during acute dengue virus (DENV) infection remains unclear. In this study, we analyzed cells infected in vitro with DENV and PBMC from an individual experiencing a natural DENV infection utilizing 5’ capture single cell RNA sequencing (scRNAseq). Both positive- and negative-sense DENV RNA was detected in reactions containing either an oligo(dT) primer alone, or in reactions supplemented with a DENV-specific primer. The addition of a DENV-specific primer did not increase the total amount of DENV RNA captured or the fraction of cells identified as containing DENV RNA. However, inclusion of a DENV-specific cDNA primer did increase the viral genome coverage immediately 5’ to the primer binding site. Furthermore, while the majority of intracellular DENV sequence captured in this analysis mapped to the 5’ end of the viral genome, distinct patterns of enhanced coverage within the DENV polyprotein coding region were observed. The 5’ capture scRNAseq analysis of PBMC not only recapitulated previously published reports by detecting virally infected memory and naïve B cells, but also identified cell-associated genomic variants not observed in contemporaneous serum samples. These results demonstrate that oligo(dT) primed 5’ capture scRNAseq can detect DENV RNA and quantify virus-infected cells in physiologically relevant conditions, and provides insight into viral sequence variability within infected cells.

Primer (cosmetics)

10.1038/s41598-020-65939-5

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Citations (16)

A SARS-CoV-2 spike ferritin nanoparticle vaccine protects hamsters against Alpha and Beta virus variant challenge

npj Vaccines (2021)

Kathryn McGuckin Wuertz Erica K. Barkei Wei‐Hung Chen Elizabeth J. Martinez Inès Lakhal-Naouar

Abstract The emergence of SARS-CoV-2 variants of concern (VOC) requires adequate coverage of vaccine protection. We evaluated whether a SARS-CoV-2 spike ferritin nanoparticle vaccine (SpFN), adjuvanted with the Army Liposomal Formulation QS21 (ALFQ), conferred protection against the Alpha (B.1.1.7), and Beta (B.1.351) VOCs in Syrian golden hamsters. SpFN-ALFQ was administered as either single or double-vaccination (0 and 4 week) regimens, using a high (10 μg) or low (0.2 μg) dose. Animals were intranasally challenged at week 11. Binding antibody responses were comparable between high- and low-dose groups. Neutralizing antibody titers were equivalent against WA1, B.1.1.7, and B.1.351 variants following two high dose vaccinations. Dose-dependent SpFN-ALFQ vaccination protected against SARS-CoV-2-induced disease and viral replication following intranasal B.1.1.7 or B.1.351 challenge, as evidenced by reduced weight loss, lung pathology, and lung and nasal turbinate viral burden. These data support the development of SpFN-ALFQ as a broadly protective, next-generation SARS-CoV-2 vaccine.

Alpha (finance)

Antibody titer

10.1038/s41541-021-00392-7

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Citations (60)

Molecular defects in TCRBV genes preclude thymic selection and limit the expressed TCR repertoire.

The Journal of Immunology (1996)

Jeffrey R. Currier Maryam Yassai M.A. Robinson Jack Gorski

A prerequisite for the assembly of a functional TCR is the rearrangement of gene segments to result in in-frame transcripts that can vary in length across the CDR3 region. Selection for in-frame 3-bp spaced rearrangements is observed for functional TCRB genes in thymocyte DNA and mRNA transcripts from PBMC. Previous analyses of the expressed human TCRBV gene repertoire have suggested that BV10S1 and BV19S1 gene segments may be expressed at very low levels or not at all in some individuals. CDR3 size analysis for BV10 and BV19 transcripts and thymic DNA rearrangements revealed no such selection of in-frame 3-bp spaced rearrangements. Comparison of the BV19 leader intron sequence with consensus 5'-splice signal sequences suggested that the mature mRNA for this gene would contain the unspliced leader intron. Sequencing of BV19 transcripts from PBMC confirmed that the intron was not spliced, resulting in a predicted translation product that terminates prematurely. Both genomic DNA and mRNA were analyzed for the BV10 gene. The leader sequence contained a single extra base, which would result in a shift in the V region reading frame upon conventional mRNA splicing. This gene is predicted to be nonfunctional due to the presence of a stop codon in the V gene segment just after the splice signal. A splice variant that uses an alternative 3'-splice site further downstream in the V region was also detected. This variant is predicted to be nonfunctional due to the presence of an in-frame stop codon in the V region. These processing defects are sufficient to abrogate positive selection. Therefore, the conclusions drawn from previous studies of the expressed T cell repertoire in normal and disease states based on the presumed functional status of these two genes need to be reassessed.

Gene rearrangement

Stop codon

splice

10.4049/jimmunol.157.1.170

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Citations (29)

Longitudinal Analysis of Memory B and T Cell Responses to Dengue Virus in a 5-Year Prospective Cohort Study in Thailand

Frontiers in Immunology (2019)

Luis A. Sánchez-Vargas Sonia Kounlavouth Madison L. Smith Kathryn B. Anderson Anon Srikiatkhachorn

Prior exposure to dengue virus (DENV) has a profound impact on the outcome of infection, which varies according to the interval between infections. Antibodies secreted by B cells and cytokines secreted by T cells are thought to contribute both to protective immunity against DENV and the pathogenesis of dengue disease. We analyzed peripheral blood mononuclear cells (PBMC) collected from Thai children over a 5-year prospective cohort study to define the dynamics of DENV-specific memory B and T cell responses and the impact of symptomatic or subclinical DENV infections. To measure B cell responses, PBMC were stimulated with IL-2 plus R848 and culture supernatants were tested for DENV-binding antibodies by ELISA. To measure T cell responses, PBMC were stimulated in dual-color ELISPOT assays with overlapping peptide pools of structural and non-structural proteins from the four DENV types. B cell responses were low to one or more DENV types prior to symptomatic infection and increased with reactivity to all four types after infection. Subjects who had a subclinical infection or who did not experience a DENV infection during the study period showed strong memory B cell responses to all four DENV types. T cell responses to DENV peptides demonstrated a cytokine hierarchy of IFN-γ > IL-2 > IFN-γ/IL-2. T cell responses were low or absent prior to secondary infections. The trends in T cell responses to DENV peptides over 3 year post-infection were highly variable, but subjects who had experienced a secondary DENV1 infection showed higher cytokine responses compared to subjects who had experienced a secondary DENV2 or subclinical infection. The longitudinal nature of our study demonstrates persistent memory B cell responses over years and a lasting but variable impact of secondary DENV infection on DENV-specific T cell responses.

ELISPOT

Subclinical infection

10.3389/fimmu.2019.01359

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Citations (14)

Efficacy and breadth of adjuvanted SARS-CoV-2 receptor-binding domain nanoparticle vaccine in macaques

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Hannah A. D. King Michael Joyce Ines Elakhal Naouar Aslaa Ahmed Camila Macedo Cincotta

ABSTRACT Emergence of novel variants of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) underscores the need for next-generation vaccines able to elicit broad and durable immunity. Here we report the evaluation of a ferritin nanoparticle vaccine displaying the receptor-binding domain of the SARS-CoV-2 spike protein (RFN) adjuvanted with Army Liposomal Formulation QS-21 (ALFQ). RFN vaccination of macaques using a two-dose regimen resulted in robust, predominantly Th1 CD4+ T cell responses and reciprocal peak mean neutralizing antibody titers of 14,000-21,000. Rapid control of viral replication was achieved in the upper and lower airways of animals after high-dose SARS-CoV-2 respiratory challenge, with undetectable replication within four days in 7 of 8 animals receiving 50 µg RFN. Cross-neutralization activity against SARS-CoV-2 variant B.1.351 decreased only ∼2-fold relative to USA-WA1. In addition, neutralizing, effector antibody and cellular responses targeted the heterotypic SARS-CoV-1, highlighting the broad immunogenicity of RFN-ALFQ for SARS-like betacoronavirus vaccine development. Significance Statement The emergence of SARS-CoV-2 variants of concern (VOC) that reduce the efficacy of current COVID-19 vaccines is a major threat to pandemic control. We evaluate a SARS-CoV-2 Spike receptor-binding domain ferritin nanoparticle protein vaccine (RFN) in a nonhuman primate challenge model that addresses the need for a next-generation, efficacious vaccine with increased pan-SARS breadth of coverage. RFN, adjuvanted with a liposomal-QS21 formulation (ALFQ), elicits humoral and cellular immune responses exceeding those of current vaccines in terms of breadth and potency and protects against high-dose respiratory tract challenge. Neutralization activity against the B.1.351 VOC within two-fold of wild-type virus and against SARS-CoV-1 indicate exceptional breadth. Our results support consideration of RFN for SARS-like betacoronavirus vaccine development.

Coronavirus

10.1101/2021.04.09.439166

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Citations (11)

A SARS-CoV-2 Spike Ferritin Nanoparticle Vaccine Is Protective and Promotes a Strong Immunological Response in the Cynomolgus Macaque Coronavirus Disease 2019 (COVID-19) Model

Vaccines (2022)

Sara C. Johnston Keersten M. Ricks Inès Lakhal-Naouar Alexandra Jay Caroline Subra

The COVID-19 pandemic has had a staggering impact on social, economic, and public health systems worldwide. Vaccine development and mobilization against SARS-CoV-2 (the etiologic agent of COVID-19) has been rapid. However, novel strategies are still necessary to slow the pandemic, and this includes new approaches to vaccine development and/or delivery that will improve vaccination compliance and demonstrate efficacy against emerging variants. Here, we report on the immunogenicity and efficacy of a SARS-CoV-2 vaccine comprising stabilized, pre-fusion spike protein trimers displayed on a ferritin nanoparticle (SpFN) adjuvanted with either conventional aluminum hydroxide or the Army Liposomal Formulation QS-21 (ALFQ) in a cynomolgus macaque COVID-19 model. Vaccination resulted in robust cell-mediated and humoral responses and a significant reduction in lung lesions following SARS-CoV-2 infection. The strength of the immune response suggests that dose sparing through reduced or single dosing in primates may be possible with this vaccine. Overall, the data support further evaluation of SpFN as a SARS-CoV-2 protein-based vaccine candidate with attention to fractional dosing and schedule optimization.

Pandemic

Coronavirus

Vaccine efficacy

10.3390/vaccines10050717

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Citations (23)

A panel of MHC class I restricted viral peptides for use as a quality control for vaccine trial ELISPOT assays

Journal of Immunological Methods (2002)

Jeffrey R. Currier Ellen Kuta Ellen Turk Lyndsay B Earhart Larry D. Loomis-Price

ELISPOT

CTL*

10.1016/s0022-1759(01)00535-x

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Citations (326)

Temporally integrated single cell RNA sequencing analysis of PBMC from experimental and natural primary human DENV-1 infections

PLoS Pathogens (2021)

Adam T. Waickman Heather Friberg Gregory D. Gromowski Wiriya Rutvisuttinunt Tao Li

Dengue human infection studies present an opportunity to address many longstanding questions in the field of flavivirus biology. However, limited data are available on how the immunological and transcriptional response elicited by an attenuated challenge virus compares to that associated with a wild-type DENV infection. To determine the kinetic transcriptional signature associated with experimental primary DENV-1 infection and to assess how closely this profile correlates with the transcriptional signature accompanying natural primary DENV-1 infection, we utilized scRNAseq to analyze PBMC from individuals enrolled in a DENV-1 human challenge study and from individuals experiencing a natural primary DENV-1 infection. While both experimental and natural primary DENV-1 infection resulted in overlapping patterns of inflammatory gene upregulation, natural primary DENV-1 infection was accompanied with a more pronounced suppression in gene products associated with protein translation and mitochondrial function, principally in monocytes. This suggests that the immune response elicited by experimental and natural primary DENV infection are similar, but that natural primary DENV-1 infection has a more pronounced impact on basic cellular processes to induce a multi-layered anti-viral state.

Flavivirus

10.1371/journal.ppat.1009240

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Citations (29)

Contributions of CD4+, CD8+, and CD4+CD8+ T cells to skewing within the peripheral T cell receptor β chain repertoire of healthy macaques

Human Immunology (1999)

Jeffrey R. Currier Kimberly Stevenson Patricia Kehn K L Zheng Vanessa M. Hirsch

Cd4 t cell

10.1016/s0198-8859(98)00109-8

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Citations (26)

Characterization of the T cell response from non-exposed individuals to Plasmodium falciparum blood-stage antigens

Jeffrey R. Currier

10.14264/366294

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Citations (0)