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Article ; Online: A large scale Plasmodium vivax- Saimiri boliviensis trophozoite-schizont transition proteome.

Anderson, D C / Lapp, Stacey A / Barnwell, John W / Galinski, Mary R

PloS one

2017 Volume 12, Issue 8, Page(s) e0182561

Abstract: Plasmodium vivax is a complex protozoan parasite with over 6,500 genes and stage-specific differential expression. Much of the unique biology of this pathogen remains unknown, including how it modifies and restructures the host reticulocyte. Using a ... ...

Abstract	Plasmodium vivax is a complex protozoan parasite with over 6,500 genes and stage-specific differential expression. Much of the unique biology of this pathogen remains unknown, including how it modifies and restructures the host reticulocyte. Using a recently published P. vivax reference genome, we report the proteome from two biological replicates of infected Saimiri boliviensis host reticulocytes undergoing transition from the late trophozoite to early schizont stages. Using five database search engines, we identified a total of 2000 P. vivax and 3487 S. boliviensis proteins, making this the most comprehensive P. vivax proteome to date. PlasmoDB GO-term enrichment analysis of proteins identified at least twice by a search engine highlighted core metabolic processes and molecular functions such as glycolysis, translation and protein folding, cell components such as ribosomes, proteasomes and the Golgi apparatus, and a number of vesicle and trafficking related clusters. Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8 enriched functional annotation clusters of S. boliviensis proteins highlighted vesicle and trafficking-related clusters, elements of the cytoskeleton, oxidative processes and response to oxidative stress, macromolecular complexes such as the proteasome and ribosome, metabolism, translation, and cell death. Host and parasite proteins potentially involved in cell adhesion were also identified. Over 25% of the P. vivax proteins have no functional annotation; this group includes 45 VIR members of the large PIR family. A number of host and pathogen proteins contained highly oxidized or nitrated residues, extending prior trophozoite-enriched stage observations from S. boliviensis infections, and supporting the possibility of oxidative stress in relation to the disease. This proteome significantly expands the size and complexity of the known P. vivax and Saimiri host iRBC proteomes, and provides in-depth data that will be valuable for ongoing research on this parasite's biology and pathogenesis.
MeSH term(s)	Animals ; Plasmodium vivax/metabolism ; Proteome ; Protozoan Proteins/metabolism ; Trophozoites/metabolism
Chemical Substances	Proteome ; Protozoan Proteins
Language	English
Publishing date	2017-08-22
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0182561
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Article ; Online: Malaria disrupts the rhesus macaque gut microbiome.

Farinella, Danielle N / Kaur, Sukhpreet / Tran, ViLinh / Cabrera-Mora, Monica / Joyner, Chester J / Lapp, Stacey A / Pakala, Suman B / Nural, Mustafa V / DeBarry, Jeremy D / Kissinger, Jessica C / Jones, Dean P / Moreno, Alberto / Galinski, Mary R / Cordy, Regina Joice

Frontiers in cellular and infection microbiology

2023 Volume 12, Page(s) 1058926

Abstract: Previous studies have suggested that a relationship exists between severity and transmissibility of malaria and variations in the gut microbiome, yet only limited information exists on the temporal dynamics of the gut microbial community during a ... ...

Abstract	Previous studies have suggested that a relationship exists between severity and transmissibility of malaria and variations in the gut microbiome, yet only limited information exists on the temporal dynamics of the gut microbial community during a malarial infection. Here, using a rhesus macaque model of relapsing malaria, we investigate how malaria affects the gut microbiome. In this study, we performed 16S sequencing on DNA isolated from rectal swabs of rhesus macaques over the course of an experimental malarial infection with
MeSH term(s)	Animals ; Humans ; Macaca mulatta/genetics ; Macaca mulatta/metabolism ; Gastrointestinal Microbiome ; Malaria/parasitology ; Malaria, Vivax/parasitology ; Plasmodium cynomolgi/genetics ; Plasmodium cynomolgi/metabolism ; Bacteria/genetics ; RNA, Ribosomal, 16S/genetics
Chemical Substances	RNA, Ribosomal, 16S
Language	English
Publishing date	2023-01-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2022.1058926
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Article ; Online: Limited induction of SARS-CoV-2-specific T cell responses in children with multisystem inflammatory syndrome compared with COVID-19.

Singh, Vidisha / Obregon-Perko, Veronica / Lapp, Stacey A / Horner, Anna Marie / Brooks, Alyssa / Macoy, Lisa / Hussaini, Laila / Lu, Austin / Gibson, Theda / Silvestri, Guido / Grifoni, Alba / Weiskopf, Daniela / Sette, Alessandro / Anderson, Evan J / Rostad, Christina A / Chahroudi, Ann

JCI insight

2022 Volume 7, Issue 4

Abstract: Why multisystem inflammatory syndrome in children (MIS-C) develops after SARS-CoV-2 infection in a subset of children is unknown. We hypothesized that aberrant virus-specific T cell responses contribute to MIS-C pathogenesis. We quantified SARS-CoV-2- ... ...

Abstract	Why multisystem inflammatory syndrome in children (MIS-C) develops after SARS-CoV-2 infection in a subset of children is unknown. We hypothesized that aberrant virus-specific T cell responses contribute to MIS-C pathogenesis. We quantified SARS-CoV-2-reactive T cells, serologic responses against major viral proteins, and cytokine responses from plasma and peripheral blood mononuclear cells in children with convalescent COVID-19, in children with acute MIS-C, and in healthy controls. Children with MIS-C had significantly lower virus-specific CD4+ and CD8+ T cell responses to major SARS-CoV-2 antigens compared with children convalescing from COVID-19. Furthermore, T cell responses in participants with MIS-C were similar to or lower than those in healthy controls. Serologic responses against spike receptor binding domain (RBD), full-length spike, and nucleocapsid were similar among convalescent COVID-19 and MIS-C, suggesting functional B cell responses. Cytokine profiling demonstrated predominant Th1 polarization of CD4+ T cells from children with convalescent COVID-19 and MIS-C, although cytokine production was reduced in MIS-C. Our findings support a role for constrained induction of anti-SARS-CoV-2-specific T cells in the pathogenesis of MIS-C.
MeSH term(s)	Adolescent ; COVID-19/complications ; COVID-19/immunology ; Child ; Child, Preschool ; Female ; Humans ; Male ; SARS-CoV-2/immunology ; Systemic Inflammatory Response Syndrome/immunology ; T-Lymphocytes/immunology
Language	English
Publishing date	2022-02-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.155145
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Article ; Online: Original antigenic sin responses to Betacoronavirus spike proteins are observed in a mouse model, but are not apparent in children following SARS-CoV-2 infection.

Lapp, Stacey A / Edara, Venkata Viswanadh / Lu, Austin / Lai, Lilin / Hussaini, Laila / Chahroudi, Ann / Anderson, Larry J / Suthar, Mehul S / Anderson, Evan J / Rostad, Christina A

PloS one

2021 Volume 16, Issue 8, Page(s) e0256482

Abstract: Background: The effects of pre-existing endemic human coronavirus (HCoV) immunity on SARS-CoV-2 serologic and clinical responses are incompletely understood.: Objectives: We sought to determine the effects of prior exposure to HCoV Betacoronavirus ... ...

Abstract	Background: The effects of pre-existing endemic human coronavirus (HCoV) immunity on SARS-CoV-2 serologic and clinical responses are incompletely understood. Objectives: We sought to determine the effects of prior exposure to HCoV Betacoronavirus HKU1 spike protein on serologic responses to SARS-CoV-2 spike protein after intramuscular administration in mice. We also sought to understand the baseline seroprevalence of HKU1 spike antibodies in healthy children and to measure their correlation with SARS-CoV-2 binding and neutralizing antibodies in children hospitalized with acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome (MIS-C). Methods: Groups of 5 mice were injected intramuscularly with two doses of alum-adjuvanted HKU1 spike followed by SARS-CoV-2 spike; or the reciprocal regimen of SARS-Cov-2 spike followed by HKU1 spike. Sera collected 21 days following each injection was analyzed for IgG antibodies to HKU1 spike, SARS-CoV-2 spike, and SARS-CoV-2 neutralization. Sera from children hospitalized with acute COVID-19, MIS-C or healthy controls (n = 14 per group) were analyzed for these same antibodies. Results: Mice primed with SARS-CoV-2 spike and boosted with HKU1 spike developed high titers of SARS-CoV-2 binding and neutralizing antibodies; however, mice primed with HKU1 spike and boosted with SARS-CoV-2 spike were unable to mount neutralizing antibodies to SARS-CoV-2. HKU1 spike antibodies were detected in all children with acute COVID-19, MIS-C, and healthy controls. Although children with MIS-C had significantly higher HKU1 spike titers than healthy children (GMT 37239 vs. 7551, P = 0.012), these titers correlated positively with both SARS-CoV-2 binding (r = 0.7577, P<0.001) and neutralizing (r = 0.6201, P = 0.001) antibodies. Conclusions: Prior murine exposure to HKU1 spike protein completely impeded the development of neutralizing antibodies to SARS-CoV-2, consistent with original antigenic sin. In contrast, the presence of HKU1 spike IgG antibodies in children with acute COVID-19 or MIS-C was not associated with diminished neutralizing antibody responses to SARS-CoV-2.
MeSH term(s)	Adolescent ; Animals ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/immunology ; Antigen-Antibody Reactions ; Betacoronavirus/metabolism ; COVID-19/immunology ; COVID-19/pathology ; COVID-19/virology ; Child ; Female ; Humans ; Immunoglobulin G/blood ; Immunoglobulin G/immunology ; Male ; Mice ; Mice, Inbred BALB C ; SARS-CoV-2/isolation & purification ; SARS-CoV-2/metabolism ; Spike Glycoprotein, Coronavirus/immunology
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Immunoglobulin G ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2021-08-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0256482
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Article ; Online: Cerebrospinal fluid cytokine, chemokine, and SARS-CoV-2 antibody profiles in children with neuropsychiatric symptoms associated with COVID-19.

Ngo, Binh / Lapp, Stacey A / Siegel, Benjamin / Patel, Vikash / Hussaini, Laila / Bora, Sonali / Philbrook, Bryan / Weinschenk, Kristin / Wright, Laura / Anderson, Evan J / Rostad, Christina A / Gombolay, Grace Y

Multiple sclerosis and related disorders

2021 Volume 55, Page(s) 103169

Abstract: Background: Neuropsychiatric symptoms and CSF cytokine, chemokine, and SARS-COV-2 antibody profiles are unknown in pediatric patients with COVID-19 or multisystem inflammatory syndrome (MIS-C), (NP-COVID-19).: Methods: Children at a single pediatric ... ...

Abstract	Background: Neuropsychiatric symptoms and CSF cytokine, chemokine, and SARS-COV-2 antibody profiles are unknown in pediatric patients with COVID-19 or multisystem inflammatory syndrome (MIS-C), (NP-COVID-19). Methods: Children at a single pediatric institution quaternary referral center with laboratory-confirmed COVID-19 or MIS-C and neuropsychiatric symptoms were included in this retrospective case series. Clinical symptoms, ancillary testing data, treatments and outcomes are described. Multiplexed electrochemiluminescence assays for cytokines, chemokines and SARS-CoV-2 antibodies were tested in the CSF NP-COVID-19 patients compared to five controls and were analyzed using the Student's t-test. Results: Three of five NP-COVID-19 patients had psychiatric symptoms, and two patients had encephalopathy and seizures. All patients had full or near resolution of neuropsychiatric symptoms by discharge. One patient received intravenous steroids for treatment for psychiatric symptoms; 3/5 other patients received immunotherapy for MIS-C, including IVIG, high-dose steroids, anakinra, and tocilizumab. Pro-inflammatory chemokines, including MIG, MPC, MIP-1β, and TARC were significantly elevated in NP-COVID-19 patients compared to controls. Two of five patients had elevated CSF neurofilament light chain. CSF SARS-CoV-2 antibody titers to the full-length spike, receptor binding domain and N-terminal domain were significantly elevated. SARS-CoV-2 antibody titers strongly correlated with pro-inflammatory chemokines/cytokines, including IL-1β, IL-2, IL-8, TNF-α, and IFN-γ (P≤0.05 for all). Conclusions: A spectrum of neuropsychiatric clinical manifestations can occur in children with SARS-CoV-2 infection. CSF pro-inflammatory chemokines and SARS-CoV-2 antibodies may serve as biomarkers of SARS-CoV-2 mediated NP-COVID-19. Additional study is required to understand the pathophysiologic mechanisms of neuroinflammation in children with COVID-19 and MIS-C.
MeSH term(s)	COVID-19/complications ; Chemokines ; Child ; Cytokines ; Humans ; Retrospective Studies ; SARS-CoV-2 ; Systemic Inflammatory Response Syndrome
Chemical Substances	Chemokines ; Cytokines
Language	English
Publishing date	2021-07-24
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2645330-7
ISSN	2211-0356 ; 2211-0348
ISSN (online)	2211-0356
ISSN	2211-0348
DOI	10.1016/j.msard.2021.103169
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Article ; Online: The development and kinetics of functional antibody-dependent cell-mediated cytotoxicity (ADCC) to SARS-CoV-2 spike protein.

Chen, Xuemin / Rostad, Christina A / Anderson, Larry J / Sun, He-Ying / Lapp, Stacey A / Stephens, Kathy / Hussaini, Laila / Gibson, Theda / Rouphael, Nadine / Anderson, Evan J

Virology

2021 Volume 559, Page(s) 1–9

Abstract: Since the COVID-19 pandemic, functional non-neutralizing antibody responses to SARS-CoV-2, including antibody-dependent cell-mediated cytotoxicity (ADCC), are poorly understood. We developed an ADCC assay utilizing a stably transfected, dual-reporter ... ...

Abstract	Since the COVID-19 pandemic, functional non-neutralizing antibody responses to SARS-CoV-2, including antibody-dependent cell-mediated cytotoxicity (ADCC), are poorly understood. We developed an ADCC assay utilizing a stably transfected, dual-reporter target cell line with inducible expression of a SARS-CoV-2 spike protein on the cell surface. Using this assay, we analyzed 61 convalescent serum samples from adults with PCR-confirmed COVID-19 and 15 samples from healthy uninfected controls. We found that 56 of 61 convalescent serum samples induced ADCC killing of SARS-CoV-2 S target cells, whereas none of the 15 healthy controls had detectable ADCC. We then found a modest decline in ADCC titer over a median 3-month follow-up in 21 patients who had serial samples available for analysis. We confirmed that the antibody-dependent target cell lysis was mediated primarily via the NK FcγRIIIa receptor (CD16). This ADCC assay had high sensitivity and specificity for detecting serologic immune responses to SARS-CoV-2.
MeSH term(s)	Adult ; Aged ; Antibodies, Neutralizing/blood ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/blood ; Antibodies, Viral/immunology ; Antibody-Dependent Cell Cytotoxicity ; COVID-19/immunology ; Cell Line ; Cytotoxicity Tests, Immunologic ; Female ; Humans ; Killer Cells, Natural/immunology ; Kinetics ; Male ; Middle Aged ; Receptors, IgG/immunology ; SARS-CoV-2/immunology ; Sensitivity and Specificity ; Spike Glycoprotein, Coronavirus/immunology ; Young Adult
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; FCGR3A protein, human ; Receptors, IgG ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2021-03-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2021.03.009
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Article ; Online: SARS-CoV-2 immune repertoire in MIS-C and pediatric COVID-19.

Ravichandran, Supriya / Tang, Juanjie / Grubbs, Gabrielle / Lee, Youri / Pourhashemi, Sara / Hussaini, Laila / Lapp, Stacey A / Jerris, Robert C / Singh, Vidisha / Chahroudi, Ann / Anderson, Evan J / Rostad, Christina A / Khurana, Surender

Nature immunology

2021 Volume 22, Issue 11, Page(s) 1452–1464

Abstract: There is limited understanding of the viral antibody fingerprint following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children. Herein, SARS-CoV-2 proteome-wide immunoprofiling of children with mild/moderate or severe ... ...

Abstract	There is limited understanding of the viral antibody fingerprint following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children. Herein, SARS-CoV-2 proteome-wide immunoprofiling of children with mild/moderate or severe coronavirus disease 2019 (COVID-19) versus multisystem inflammatory syndrome in children versus hospitalized control patients revealed differential cytokine responses, IgM/IgG/IgA epitope diversity, antibody binding and avidity. Apart from spike and nucleocapsid, IgG/IgA recognized epitopes in nonstructural protein (NSP) 2, NSP3, NSP12-NSP14 and open reading frame (ORF) 3a-ORF9. Peptides representing epitopes in NSP12, ORF3a and ORF8 demonstrated SARS-CoV-2 serodiagnosis. Antibody-binding kinetics with 24 SARS-CoV-2 proteins revealed antibody parameters that distinguish children with mild/moderate versus severe COVID-19 or multisystem inflammatory syndrome in children. Antibody avidity to prefusion spike correlated with decreased illness severity and served as a clinical disease indicator. The fusion peptide and heptad repeat 2 region induced SARS-CoV-2-neutralizing antibodies in rabbits. Thus, we identified SARS-CoV-2 antibody signatures in children associated with disease severity and delineate promising serodiagnostic and virus neutralization targets. These findings might guide the design of serodiagnostic assays, prognostic algorithms, therapeutics and vaccines in this important but understudied population.
MeSH term(s)	Adolescent ; Antibodies, Neutralizing/metabolism ; Antibodies, Viral/metabolism ; COVID-19/complications ; COVID-19/diagnosis ; COVID-19/immunology ; COVID-19 Serological Testing/methods ; Child ; Child, Preschool ; Disease Progression ; Epitopes/metabolism ; Female ; Hospitalization ; Humans ; Immunity, Humoral ; Immunoglobulin A/metabolism ; Immunoglobulin G/metabolism ; Immunoglobulin M/metabolism ; Male ; Prognosis ; Proteome ; SARS-CoV-2/immunology ; Severity of Illness Index ; Systemic Inflammatory Response Syndrome/diagnosis ; Systemic Inflammatory Response Syndrome/immunology
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Epitopes ; Immunoglobulin A ; Immunoglobulin G ; Immunoglobulin M ; Proteome
Language	English
Publishing date	2021-10-05
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-021-01051-8
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Article ; Online: Immune responses and therapeutic challenges in paediatric patients with new-onset acute myeloid leukaemia and concomitant COVID-19.

Patel, Pratik A / Lapp, Stacey A / Grubbs, Gabrielle / Edara, Venkata V / Rostad, Christina A / Stokes, Claire L / Pauly, Melinda G / Anderson, Evan J / Piantadosi, Anne / Suthar, Mehul S / Khurana, Surender / Sabnis, Himalee S

British journal of haematology

2021 Volume 194, Issue 3, Page(s) 549–553

MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/therapeutic use ; Adolescent ; Alanine/analogs & derivatives ; Alanine/therapeutic use ; Antimalarials/therapeutic use ; Antineoplastic Agents/therapeutic use ; Antiviral Agents/therapeutic use ; COVID-19/complications ; COVID-19/diagnosis ; COVID-19/drug therapy ; COVID-19/immunology ; Disease Management ; Humans ; Hydroxychloroquine/therapeutic use ; Hydroxyurea/therapeutic use ; Leukemia, Myeloid, Acute/complications ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/immunology ; Male ; SARS-CoV-2/drug effects ; SARS-CoV-2/immunology ; SARS-CoV-2/isolation & purification ; Young Adult
Chemical Substances	Antimalarials ; Antineoplastic Agents ; Antiviral Agents ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; Hydroxychloroquine (4QWG6N8QKH) ; Alanine (OF5P57N2ZX) ; Hydroxyurea (X6Q56QN5QC)
Language	English
Publishing date	2021-06-07
Publishing country	England
Document type	Case Reports ; Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.17517
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Article ; Online: Altered amino acid profile in patients with SARS-CoV-2 infection.

Rees, Chris A / Rostad, Christina A / Mantus, Grace / Anderson, Evan J / Chahroudi, Ann / Jaggi, Preeti / Wrammert, Jens / Ochoa, Juan B / Ochoa, Augusto / Basu, Rajit K / Heilman, Stacy / Harris, Frank / Lapp, Stacey A / Hussaini, Laila / Vos, Miriam B / Brown, Lou Ann / Morris, Claudia R

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 25

Abstract: Low plasma arginine bioavailability has been implicated in endothelial dysfunction and immune dysregulation. The role of arginine in COVID-19 is unknown, but could contribute to cellular damage if low. Our objective was to determine arginine ... ...

Abstract	Low plasma arginine bioavailability has been implicated in endothelial dysfunction and immune dysregulation. The role of arginine in COVID-19 is unknown, but could contribute to cellular damage if low. Our objective was to determine arginine bioavailability in adults and children with COVID-19 vs. healthy controls. We hypothesized that arginine bioavailability would be low in patients with COVID-19 and multisystem inflammatory syndrome in children (MIS-C). We conducted a prospective observational study of three patient cohorts; arginine bioavailability was determined in asymptomatic healthy controls, adults hospitalized with COVID-19, and hospitalized children/adolescents <21 y old with COVID-19, MIS-C, or asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection identified on admission screen. Mean patient plasma amino acids were compared to controls using the Student's
MeSH term(s)	Adult ; Amino Acids/blood ; COVID-19/blood ; COVID-19/therapy ; Female ; Hospitalization ; Humans ; Male ; Middle Aged ; Retrospective Studies ; SARS-CoV-2/metabolism
Chemical Substances	Amino Acids
Language	English
Publishing date	2021-06-24
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Observational Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2101708118
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Article ; Online: An RSV live-attenuated vaccine candidate lacking G protein mucin domains is attenuated, immunogenic, and effective in preventing RSV in BALB/c mice.

The Journal of infectious diseases

2022

Abstract: Background: RSV is a leading viral respiratory pathogen in infants. The objective of this study was to generate RSV live-attenuated vaccine (LAV) candidates by removing the G-protein mucin domains to attenuate viral replication while retaining ... ...

Abstract	Background: RSV is a leading viral respiratory pathogen in infants. The objective of this study was to generate RSV live-attenuated vaccine (LAV) candidates by removing the G-protein mucin domains to attenuate viral replication while retaining immunogenicity through de-shielding of surface epitopes. Methods: Two LAV candidates were generated from recombinant RSV A2-line19F by deletion of the G-protein mucin domains (A2-line19F-G155) or deletion of the G-protein mucin and transmembrane domains (A2-line19F-G155S). Vaccine attenuation was measured in BALB/c mouse lungs by fluorescent focus unit (FFU) assays and RT-PCR. Immunogenicity was determined by measuring serum binding and neutralizing antibodies in mice following prime/boost on days 28 and 59. Efficacy was determined by measuring RSV lung viral loads on day 4 post-challenge. Results: Both LAVs were undetectable in mouse lungs by FFU assay and elicited similar neutralizing antibody titers compared to A2-line19F on days 28 and 59. Following RSV challenge, vaccinated mice showed no detectable RSV in the lungs by FFU assay and a significant reduction in RSV RNA in the lungs by RT-PCR of 560-fold for A2-line19F-G155 and 604-fold for A2-line19F-G155S compared to RSV-challenged, unvaccinated mice. Conclusions: Removal of the G-protein mucin domains produced RSV LAV candidates that were highly attenuated with retained immunogenicity.
Language	English
Publishing date	2022-10-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiac382
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