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Article ; Online: RSV neutralizing antibodies in dried blood.

Terstappen, Jonne / Delemarre, Eveline M / Versnel, Anouk / White, Joleen T / Derrien-Colemyn, Alexandrine / Ruckwardt, Tracy J / Bont, Louis J / Mazur, Natalie I

The Journal of infectious diseases

2023

Abstract: Background: The key correlate of protection of respiratory syncytial virus (RSV) vaccines and monoclonal antibodies (mAb) is virus neutralization, measured using sera obtained through venipuncture. Dried blood obtained with a finger prick can simplify ... ...

Abstract	Background: The key correlate of protection of respiratory syncytial virus (RSV) vaccines and monoclonal antibodies (mAb) is virus neutralization, measured using sera obtained through venipuncture. Dried blood obtained with a finger prick can simplify acquisition, processing, storage, and transport in trials, and thereby reduce costs. In this study we validate an assay to measure RSV neutralization in dried capillary blood. Methods: Functional antibodies were compared between matched serum and dried blood samples from a phase I trial with RSM01, an investigational anti-RSV Prefusion F mAb. Hep-2 cells were infected with a serial dilution of sample-virus mixture using RSV-A2-mKate to determine half-maximal inhibitory concentration. Stability of dried blood was evaluated over time and during temperature stress. Results: Functional antibodies in dried blood were highly correlated with serum (R2 = 0.98, p < 0.0001). The precision of the assay for dried blood was similar to serum. The function of mAb remained stable for 9 months at room temperature and frozen dried blood samples. Interpretation: We demonstrated the feasibility of measuring RSV neutralization using dried blood as a patient-centered solution that may replace serology testing in trials against RSV or other viruses, such as influenza and SARS-CoV-2.
Language	English
Publishing date	2023-11-30
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/jiad543
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Article ; Online: Vaccination with prefusion-stabilized respiratory syncytial virus fusion protein elicits antibodies targeting a membrane-proximal epitope.

McCool, Ryan S / Musayev, Maryam / Bush, Sabrina M / Derrien-Colemyn, Alexandrine / Acreman, Cory M / Wrapp, Daniel / Ruckwardt, Tracy J / Graham, Barney S / Mascola, John R / McLellan, Jason S

Journal of virology

2023 Volume 97, Issue 10, Page(s) e0092923

Abstract: Importance: Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants, infecting all children by age 5. RSV also causes substantial morbidity and mortality in older adults, and a vaccine for older adults based on a ...

Abstract	Importance: Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants, infecting all children by age 5. RSV also causes substantial morbidity and mortality in older adults, and a vaccine for older adults based on a prefusion-stabilized form of the viral F glycoprotein was recently approved by the FDA. Here, we investigate a set of antibodies that belong to the same public clonotype and were isolated from individuals vaccinated with a prefusion-stabilized RSV F protein. Our results reveal that these antibodies are highly potent and recognize a previously uncharacterized antigenic site on the prefusion F protein. Vaccination with prefusion RSV F proteins appears to boost the elicitation of these neutralizing antibodies, which are not commonly elicited by natural infection.
MeSH term(s)	Humans ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/immunology ; Epitopes, B-Lymphocyte/chemistry ; Epitopes, B-Lymphocyte/immunology ; Respiratory Syncytial Virus Infections/immunology ; Respiratory Syncytial Virus Infections/prevention & control ; Respiratory Syncytial Virus Vaccines/immunology ; Respiratory Syncytial Virus, Human/immunology ; Vaccination ; Viral Fusion Proteins/chemistry ; Viral Fusion Proteins/immunology ; Viral Fusion Proteins/metabolism
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Epitopes, B-Lymphocyte ; Respiratory Syncytial Virus Vaccines ; Viral Fusion Proteins
Language	English
Publishing date	2023-09-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Intramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.00929-23
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Article ; Online: Level of maternal respiratory syncytial virus (RSV) F antibodies in hospitalized children and correlates of protection.

Taleb, Sara A / Al-Ansari, Khalid / Nasrallah, Gheyath K / Elrayess, Mohamed A / Al-Thani, Asmaa A / Derrien-Colemyn, Alexandrine / Ruckwardt, Tracy J / Graham, Barney S / Yassine, Hadi M

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases

2021 Volume 109, Page(s) 56–62

Abstract: Background: Respiratory syncytial virus (RSV) is a major cause of lower respiratory infection among children and no vaccine is available. The stabilized form of the fusion (F) protein - pre-F - is a leading vaccine candidate to target different ... ...

Abstract	Background: Respiratory syncytial virus (RSV) is a major cause of lower respiratory infection among children and no vaccine is available. The stabilized form of the fusion (F) protein - pre-F - is a leading vaccine candidate to target different populations, including pregnant women. This study aimed to determine the magnitude and nature of RSV-directed maternal antibodies (matAbs) in hospitalized children with RSV infection. Methods: Sixty-five paired blood samples were collected from RSV-infected children aged <6 months and their corresponding mothers. All pairs were screened for levels of pre-F and post-F antibodies using ELISA. The neutralizing antibodies (NAbs) in both groups were measured in vitro against mKate RSV-A2 using H28 cells. Results: It was found that 14% of matAbs (log Conclusions: The maintenance of neutralizing activity in infants relative to maternal titers was greater than the maintenance of antibody binding based on ELISA, suggesting that higher-potency antibodies may have a longer half-life than weakly neutralizing antibodies.
MeSH term(s)	Antibodies, Neutralizing ; Antibodies, Viral ; Child ; Child, Hospitalized ; Female ; Humans ; Pregnancy ; Respiratory Syncytial Virus Infections/prevention & control ; Respiratory Syncytial Virus Vaccines ; Respiratory Syncytial Virus, Human ; Viral Fusion Proteins
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Respiratory Syncytial Virus Vaccines ; Viral Fusion Proteins
Language	English
Publishing date	2021-06-10
Publishing country	Canada
Document type	Journal Article
ZDB-ID	1331197-9
ISSN	1878-3511 ; 1201-9712
ISSN (online)	1878-3511
ISSN	1201-9712
DOI	10.1016/j.ijid.2021.06.015
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Article ; Online: Erratum for Vanderheiden et al., "CCR2 Signaling Restricts SARS-CoV-2 Infection".

Vanderheiden, Abigail / Thomas, Jeronay / Soung, Allison L / Davis-Gardner, Meredith E / Floyd, Katharine / Jin, Fengzhi / Cowan, David A / Pellegrini, Kathryn / Creanga, Adrian / Pegu, Amarendra / Derrien-Colemyn, Alexandrine / Shi, Pei-Yong / Grakoui, Arash / Klein, Robyn S / Bosinger, Steven E / Kohlmeier, Jacob E / Menachery, Vineet D / Suthar, Mehul S

mBio

2022 Volume 13, Issue 3, Page(s) e0025922

Language	English
Publishing date	2022-04-14
Publishing country	United States
Document type	Journal Article ; Published Erratum
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mbio.00259-22
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Article ; Online: Divergent age-related humoral correlates of protection against respiratory syncytial virus infection in older and young adults: a pilot, controlled, human infection challenge model.

The lancet. Healthy longevity

2022 Volume 3, Issue 6, Page(s) e405–e416

Abstract: Background: Respiratory viral infections are typically more severe in older adults. Older adults are more vulnerable to infection and do not respond effectively to vaccines due to a combination of immunosenescence, so-called inflamm-ageing, and ... ...

Abstract	Background: Respiratory viral infections are typically more severe in older adults. Older adults are more vulnerable to infection and do not respond effectively to vaccines due to a combination of immunosenescence, so-called inflamm-ageing, and accumulation of comorbidities. Although age-related changes in immune responses have been described, the causes of this enhanced respiratory disease in older adults remain poorly understood. We therefore performed volunteer challenge with respiratory syncytial virus (RSV) in groups of younger and older adult volunteers. The aim of this study was to establish the safety and tolerability of this model and define age-related clinical, virological, and immunological outcomes. Methods: In this human infection challenge pilot study, adults aged 18-55 years and 60-75 years were assessed for enrolment using protocol-defined inclusion and exclusion criteria. Symptoms were documented by self-completed diaries and viral load determined by quantitative PCR of nasal lavage. Peripheral blood B cell frequencies were measured by enzyme-linked immunospot and antibodies against pre-fusion and post-fusion, NP, and G proteins in the blood and upper respiratory tract were measured. The study was registered with ClinicalTrials.gov, NCT03728413. Findings: 381 adults aged 60-75 years (older cohort) and 19 adults aged 18-55 years (young cohort) were assessed for enrolment using protocol-defined inclusion and exclusion criteria between Nov 12, 2018, and Feb 26, 2020. 12 healthy volunteers aged 60-75 years and 21 aged 18-55 years were inoculated intranasally with RSV Memphis-37. Nine (67%) of the 12 older volunteers became infected, developing mild-to-moderate upper respiratory tract symptoms that resolved without serious adverse events or sequelae. Viral load peaked on day 6 post-inoculation and symptoms peaked between days 6 and 8. Increases in circulating IgG-positive and IgA-positive antigen-specific plasmablasts, serum neutralising antibodies, and pre-F specific IgG were similar younger and older adults. However, in contrast to young participants, secretory IgA titres in older volunteers failed to increase during infection and, unlike serum IgG, did not correlate with protection. Interpretation: Better understanding of age-related differences in clinical outcomes and immune correlates of protection can overcome reduction in vaccine efficacy with advancing age. We identify correlates of protection in older adults, revealing previously unrecognised factors which might have implications for targeted vaccine discovery and drug development in this vulnerable group. Funding: Medical Research Council and GlaxoSmithKline EMINENT Consortium.
MeSH term(s)	Aged ; Antibodies, Viral ; Humans ; Immunoglobulin G ; Pilot Projects ; Respiratory Syncytial Virus Infections/prevention & control ; Respiratory Syncytial Virus, Human ; Young Adult
Chemical Substances	Antibodies, Viral ; Immunoglobulin G
Language	English
Publishing date	2022-06-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2666-7568
ISSN (online)	2666-7568
DOI	10.1016/S2666-7568(22)00103-9
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Article: Infection and vaccine-induced neutralizing antibody responses to the SARS-CoV-2 B.1.617.1 variant.

Edara, Venkata-Viswanadh / Lai, Lilin / Sahoo, Malaya K / Floyd, Katharine / Sibai, Mamdouh / Solis, Daniel / Flowers, Maria W / Hussaini, Laila / Ciric, Caroline Rose / Bechnack, Sarah / Stephens, Kathy / Mokhtari, Elham Bayat / Mudvari, Prakriti / Creanga, Adrian / Pegu, Amarendra / Derrien-Colemyn, Alexandrine / Henry, Amy R / Gagne, Matthew / Graham, Barney S /

Wrammert, Jens / Douek, Daniel C / Boritz, Eli / Pinsky, Benjamin A / Suthar, Mehul S

bioRxiv : the preprint server for biology

2021

Abstract: SARS-CoV-2 has caused a devastating global pandemic. The recent emergence of SARS-CoV-2 variants that are less sensitive to neutralization by convalescent sera or vaccine-induced neutralizing antibody responses has raised concerns. A second wave of SARS- ... ...

Abstract	SARS-CoV-2 has caused a devastating global pandemic. The recent emergence of SARS-CoV-2 variants that are less sensitive to neutralization by convalescent sera or vaccine-induced neutralizing antibody responses has raised concerns. A second wave of SARS-CoV-2 infections in India is leading to the expansion of SARS-CoV-2 variants. The B.1.617.1 variant has rapidly spread throughout India and to several countries throughout the world. In this study, using a live virus assay, we describe the neutralizing antibody response to the B.1.617.1 variant in serum from infected and vaccinated individuals. We found that the B.1.617.1 variant is 6.8-fold more resistant to neutralization by sera from COVID-19 convalescent and Moderna and Pfizer vaccinated individuals. Despite this, a majority of the sera from convalescent individuals and all sera from vaccinated individuals were still able to neutralize the B.1.617.1 variant. This suggests that protective immunity by the mRNA vaccines tested here are likely retained against the B.1.617.1 variant. As the B.1.617.1 variant continues to evolve, it will be important to monitor how additional mutations within the spike impact antibody resistance, viral transmission and vaccine efficacy.
Language	English
Publishing date	2021-05-10
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.05.09.443299
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Article: CCR2-dependent monocyte-derived cells restrict SARS-CoV-2 infection.

bioRxiv : the preprint server for biology

2021

Abstract: SARS-CoV-2 has caused a historic pandemic of respiratory disease (COVID-19) and current evidence suggests severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection ... ...

Abstract	SARS-CoV-2 has caused a historic pandemic of respiratory disease (COVID-19) and current evidence suggests severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Here we characterize a mouse model of SARS-CoV-2 infection and find that early CCR2-dependent infiltration of monocytes restricts viral burden in the lung. We find that a recently developed mouse-adapted MA-SARS-CoV-2 strain, as well as the emerging B. 1.351 variant, trigger an inflammatory response in the lung characterized by expression of pro-inflammatory cytokines and interferon-stimulated genes. scRNA-seq analysis of lung homogenates identified a hyper-inflammatory monocyte profile. Using intravital antibody labeling, we demonstrate that MA-SARS-CoV-2 infection leads to increases in circulating monocytes and an influx of CD45+ cells into the lung parenchyma that is dominated by monocyte-derived cells. We utilize this model to demonstrate that mechanistically, CCR2 signaling promotes infiltration of classical monocytes into the lung and expansion of monocyte-derived cells. Parenchymal monocyte-derived cells appear to play a protective role against MA-SARS-CoV-2, as mice lacking CCR2 showed higher viral loads in the lungs, increased lung viral dissemination, and elevated inflammatory cytokine responses. These studies have identified a CCR2-monocyte axis that is critical for promoting viral control and restricting inflammation within the respiratory tract during SARS-CoV-2 infection.
Language	English
Publishing date	2021-05-04
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.05.03.442538
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Article ; Online: Selective Insulin-like Growth Factor Resistance Associated with Heart Hemorrhages and Poor Prognosis in a Novel Preclinical Model of the Hematopoietic Acute Radiation Syndrome.

Kenchegowda, Doreswamy / Legesse, Betre / Hritzo, Bernadette / Olsen, Cara / Aghdam, Saeed / Kaur, Amandeep / Culp, William / Derrien-Colemyn, Alexandrine / Severson, Grant / Moroni, Maria

Radiation research

2018 Volume 190, Issue 2, Page(s) 164–175

Abstract: Although bone marrow aplasia has been considered for the past decades as the major contributor of radiation-induced blood disorders, cytopenias alone are insufficient to explain differences in the prevalence of bleeding. In this study, the minipig was ... ...

Abstract	Although bone marrow aplasia has been considered for the past decades as the major contributor of radiation-induced blood disorders, cytopenias alone are insufficient to explain differences in the prevalence of bleeding. In this study, the minipig was used as a novel preclinical model of hematopoietic acute radiation syndrome to assess if factors other than platelet counts correlated with bleeding and survival. We sought to determine whether radiation affected the insulin-like growth factor-1 (IGF-1) pathway, a growth hormone with cardiovascular and radioprotective features. Gottingen and Sinclair minipigs were exposed to ionizing radiation at hematopoietic doses. The smaller Gottingen minipig strain was more sensitive to radiation; differences in IGF-1 levels were minimal, suggesting that increased sensitivity could depend on weak response to the hormone. Radiation caused IGF-1 selective resistance by inhibiting the anti-inflammatory anti-oxidative stress IRS/PI3K/Akt but not the pro-inflammatory MAPK kinase pathway, shifting IGF-1 signaling towards a pro-oxidant, pro-inflammatory environment. Selective IGF-1 resistance associated with hemorrhages in the heart, poor prognosis, increase in C-reactive protein and NADPH oxidase 2, uncoupling of endothelial nitric oxide synthase, inhibition of nitric oxide (NO) synthesis and imbalance between the vasodilator NO and the vasoconstrictor endothelin-1 molecules. Selective IGF-1 resistance is a novel mechanism of radiation injury, associated with a vicious cycle amplifying reactive oxygen species-induced damage, inflammation and endothelial dysfunction. In the presence of thrombocytopenia, selective inhibition of IGF-1 cardioprotective function may contribute to the development of hemostatic disorders. This finding may be particularly relevant for individuals with low IGF-1 activity, such as the elderly or those with cardiometabolic dysfunctions.
MeSH term(s)	Acute Radiation Syndrome/diagnosis ; Acute Radiation Syndrome/metabolism ; Acute Radiation Syndrome/pathology ; Angiotensin II/metabolism ; Animals ; Biopterins/analogs & derivatives ; Biopterins/metabolism ; C-Reactive Protein/metabolism ; Disease Models, Animal ; Heart/radiation effects ; Hematopoietic System/radiation effects ; Hemorrhage/diagnosis ; Hemorrhage/etiology ; Hemorrhage/metabolism ; Hemorrhage/pathology ; Insulin-Like Growth Factor I/metabolism ; Male ; Nitric Oxide Synthase Type III/metabolism ; Prognosis ; Radiation Tolerance ; Signal Transduction/radiation effects ; Swine ; Swine, Miniature
Chemical Substances	Angiotensin II (11128-99-7) ; Biopterins ; Insulin-Like Growth Factor I (67763-96-6) ; C-Reactive Protein (9007-41-4) ; Nitric Oxide Synthase Type III (EC 1.14.13.39) ; sapropterin (EGX657432I)
Language	English
Publishing date	2018-05-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80322-4
ISSN	1938-5404 ; 0033-7587
ISSN (online)	1938-5404
ISSN	0033-7587
DOI	10.1667/RR14993.1
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Article ; Online: Infection and Vaccine-Induced Neutralizing-Antibody Responses to the SARS-CoV-2 B.1.617 Variants.

Edara, Venkata-Viswanadh / Pinsky, Benjamin A / Suthar, Mehul S / Lai, Lilin / Davis-Gardner, Meredith E / Floyd, Katharine / Flowers, Maria W / Wrammert, Jens / Hussaini, Laila / Ciric, Caroline Rose / Bechnak, Sarah / Stephens, Kathy / Graham, Barney S / Bayat Mokhtari, Elham / Mudvari, Prakriti / Boritz, Eli / Creanga, Adrian / Pegu, Amarendra / Derrien-Colemyn, Alexandrine /

Henry, Amy R / Gagne, Matthew / Douek, Daniel C / Sahoo, Malaya K / Sibai, Mamdouh / Solis, Daniel / Webby, Richard J / Jeevan, Trushar / Fabrizio, Thomas P

The New England journal of medicine

2021 Volume 385, Issue 7, Page(s) 664–666

MeSH term(s)	Antibodies, Neutralizing/blood ; Antibodies, Viral/blood ; COVID-19/immunology ; COVID-19/prevention & control ; COVID-19 Vaccines/immunology ; Humans ; Immunogenicity, Vaccine ; SARS-CoV-2/immunology
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; COVID-19 Vaccines ; mRNA-1273 vaccine (EPK39PL4R4) ; BNT162 vaccine (N38TVC63NU)
Language	English
Publishing date	2021-07-07
Publishing country	United States
Document type	Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	207154-x
ISSN	1533-4406 ; 0028-4793
ISSN (online)	1533-4406
ISSN	0028-4793
DOI	10.1056/NEJMc2107799
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Article ; Online: CCR2-dependent monocyte-derived cells restrict SARS-CoV-2 infection

bioRxiv

Abstract	SARS-CoV-2 has caused a historic pandemic of respiratory disease (COVID-19) and current evidence suggests severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Here we characterize a mouse model of SARS-CoV-2 infection and find that early CCR2-dependent infiltration of monocytes restricts viral burden in the lung. We find that a recently developed mouse-adapted MA-SARS-CoV-2 strain, as well as the emerging B.1.351 variant, trigger an inflammatory response in the lung characterized by expression of pro-inflammatory cytokines and interferon-stimulated genes. scRNA-seq analysis of lung homogenates identified a hyper-inflammatory monocyte profile. Using intravital antibody labeling, we demonstrate that MA-SARS-CoV-2 infection leads to increases in circulating monocytes and an influx of CD45+ cells into the lung parenchyma that is dominated by monocyte-derived cells. We utilize this model to demonstrate that mechanistically, CCR2 signaling promotes infiltration of classical monocytes into the lung and expansion of monocyte-derived cells. Parenchymal monocyte-derived cells appear to play a protective role against MA-SARS-CoV-2, as mice lacking CCR2 showed higher viral loads in the lungs, increased lung viral dissemination, and elevated inflammatory cytokine responses. These studies have identified a CCR2-monocyte axis that is critical for promoting viral control and restricting inflammation within the respiratory tract during SARS-CoV-2 infection.
Keywords	covid19
Language	English
Publishing date	2021-05-04
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.05.03.442538
Database	COVID19

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