Publications by authors named "Viviana Simon"

116 Publications

Variable cellular responses to SARS-CoV-2 in fully vaccinated patients with multiple myeloma.

Cancer Cell 2021 11 19;39(11):1442-1444. Epub 2021 Oct 19.

Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2021.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523488PMC
November 2021

Functionality of the putative surface glycoproteins of the Wuhan spiny eel influenza virus.

Nat Commun 2021 10 25;12(1):6161. Epub 2021 Oct 25.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

A panel of influenza virus-like sequences were recently documented in fish and amphibians. Of these, the Wuhan spiny eel influenza virus (WSEIV) was found to phylogenetically cluster with influenza B viruses as a sister clade. Influenza B viruses have been documented to circulate only in humans, with certain virus isolates found in harbor seals. It is therefore interesting that a similar virus was potentially found in fish. Here we characterize the putative hemagglutinin (HA) and neuraminidase (NA) surface glycoproteins of the WSEIV. Functionally, we show that the WSEIV NA-like protein has sialidase activity comparable to B/Malaysia/2506/2004 influenza B virus NA, making it a bona fide neuraminidase that is sensitive to NA inhibitors. We tested the functionality of the HA by addressing the receptor specificity, stability, preferential airway protease cleavage, and fusogenicity. We show highly specific binding to monosialic ganglioside 2 (GM2) and fusogenicity at a range of different pH conditions. In addition, we found limited antigenic conservation of the WSEIV HA and NA relative to the B/Malaysia/2506/2004 virus HA and NA. In summary, we perform a functional and antigenic characterization of the glycoproteins of WSEIV to assess if it is indeed a bona fide influenza virus potentially circulating in ray-finned fish.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-26409-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546056PMC
October 2021

Evidence for retained spike-binding and neutralizing activity against emerging SARS-CoV-2 variants in serum of COVID-19 mRNA vaccine recipients.

EBioMedicine 2021 Nov 20;73:103626. Epub 2021 Oct 20.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell Based Medicine Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Global Health and Emerging Pathogen Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Background: Highly efficacious vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed. However, the emergence of viral variants that are more infectious than the earlier SARS-CoV-2 strains is concerning. Several of these viral variants have the potential to partially escape neutralizing antibody responses, warranting continued immune-monitoring.

Methods: We used a panel of 30 post-mRNA vaccination sera to determine neutralization and RBD and spike binding activity against a number of emerging viral variants. The virus neutralization was determined using authentic SARS-CoV-2 clinical isolates in an assay format that mimics physiological conditions.

Findings: We tested seven currently circulating viral variants of concern/interest, including the three Iota sublineages, Alpha (E484K), Beta, Delta and Lambda in neutralization assays. We found only small decreases in neutralization against Iota and Delta. The reduction was stronger against a sub-variant of Lambda, followed by Beta and Alpha (E484K). Lambda is currently circulating in parts of Latin America and was detected in Germany, the US and Israel. Of note, reduction in a receptor binding domain and spike binding assay that also included Gamma, Kappa and A.23.1 was negligible.

Interpretation: Taken together, these findings suggest that mRNA SARS-CoV-2 vaccines may remain effective against these viral variants of concern/interest and that spike binding antibody tests likely retain specificity in the face of evolving SARS-CoV-2 diversity.

Funding: This work is part of the PARIS/SPARTA studies funded by the NIAID Collaborative Influenza Vaccine Innovation Centers (CIVIC) contract 75N93019C00051. In addition, this work was also partially funded by the Centers of Excellence for Influenza Research and Surveillance (CEIRS, contract # HHSN272201400008C), the JPB Foundation, the Open Philanthropy Project (research grant 2020-215611 (5384), by anonymous donors and by the Serological Sciences Network (SeroNet) in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024, Task Order No. 75N91020F00003.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2021.103626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527879PMC
November 2021

Human anti-neuraminidase antibodies reduce airborne transmission of clinical influenza virus isolates in the guinea pig model.

J Virol 2021 Oct 20:JVI0142121. Epub 2021 Oct 20.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

The public health burden caused by influenza virus infections is not adequately addressed with existing vaccines and antivirals. Identifying approaches that interfere with human-to-human transmission of influenza viruses remains a pressing need. The importance of neuraminidase (NA) activity for the replication and spread of influenza viruses led us to investigate whether broadly reactive human anti-NA monoclonal antibodies (mAbs) could affect airborne transmission of the virus using the guinea pig model. In that model, infection with recent influenza virus clinical isolates resulted in 100% transmission from inoculated donors to recipients in an airborne transmission setting. Anti-NA mAbs were administered either to the inoculated animals on days 1, 2, and 4 after infection or to the naïve contacts on days 2 and 4 after donor infection. Administration of NA-1G01, a broadly cross-reactive anti-NA mAb, to either the donor or recipient reduced transmission of the A/New York City/PV02669/2019 (H1N1) and A/New York City/PV01148/2018 (H3N2) viruses. Administration of 1000-3C05, an anti-N1 mAb, to either the donor or recipient reduced transmission of A/New York City/PV02669/2019 (H1N1) virus but did not reduce transmission of A/New York City/PV01148 (H3N2) virus. Conversely, 229-2C06, an anti-N2 mAb, reduced transmission of A/New York City/PV01148 (H3N2) but did not impact transmission of A/New York City/PV02669/2019 (H1N1) virus. Our work demonstrates that anti-NA mAbs could be further developed into prophylactic or therapeutic agents to prevent influenza virus transmission and thus control viral spread. The burden of influenza remains substantial despite unremitting efforts to reduce the magnitude of seasonal influenza epidemics and prepare for pandemics. While vaccination remains the mainstay of these efforts, current vaccines are designed to stimulate an immune response against the viral hemagglutinin. Interest in the role immunity against neuraminidase plays in influenza virus infection and transmission has recently surged. Human antibodies that bind broadly to neuraminidases of diverse influenza viruses and protect mice against lethal viral challenge have previously been characterized. Here, we show that three such antibodies inhibit the neuraminidase activity of recent isolates and reduce their airborne transmission in a guinea pig model. In addition to contributing to the accumulating support for incorporating neuraminidase as a vaccine antigen, these findings also demonstrate the potential of direct administration of anti-neuraminidase antibodies to individuals infected with influenza virus and to individuals for post-exposure prophylaxis to prevent the spread of influenza.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.01421-21DOI Listing
October 2021

Mosaic Hemagglutinin-Based Whole Inactivated Virus Vaccines Induce Broad Protection Against Influenza B Virus Challenge in Mice.

Front Immunol 2021 16;12:746447. Epub 2021 Sep 16.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Influenza viruses undergo antigenic changes in the immuno-dominant hemagglutinin (HA) head domain, necessitating annual re-formulation of and re-vaccination with seasonal influenza virus vaccines for continuing protection. We previously synthesized mosaic HA (mHA) proteins of influenza B viruses which redirect the immune response towards the immuno-subdominant conserved epitopes of the HA sequential immunization. As ~90% of current influenza virus vaccines are manufactured using the inactivated virus platform, we generated and sequentially vaccinated mice with inactivated influenza B viruses displaying either the homologous (same B HA backbones) or the heterologous (different B HA backbones) mosaic HAs. Both approaches induced long-lasting and cross-protective antibody responses showing strong antibody-dependent cellular cytotoxicity (ADCC) activity. We believe the B virus mHA vaccine candidates represent a major step towards a universal influenza B virus vaccine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.746447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481571PMC
September 2021

Longitudinal analysis of severe acute respiratory syndrome coronavirus 2 seroprevalence using multiple serology platforms.

iScience 2021 Sep 31;24(9):102937. Epub 2021 Jul 31.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological tests are based on the full-length spike (S), the receptor-binding domain (RBD), or the nucleoprotein (NP) as substrates. Here, we used samples from healthcare workers (HCWs) to perform a longitudinal analysis of the antibody responses using a research-grade RBD and spike-based enzyme-linked immunosorbent assay (ELISA), a commercial RBD and spike-based ELISA, and a commercial NP-based chemiluminescent microparticle immunoassay. Seroprevalence ranged around 28% early during the pandemic and a good correlation was observed between RBD and spike-based ELISAs. Modest correlations were observed between NP and both RBD and spike-based assays. The antibody levels in HCWs declined over time; however, the overall seroprevalence measured by RBD and spike-based assays remained unchanged, while the seroprevalence of NP-reactive antibodies significantly declined. Moreover, RBD and spike-based assays effectively detected seroconversion in vaccinees. Overall, our results consolidate the strength of different serological assays to assess the magnitude and duration of antibodies to SARS-CoV-2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2021.102937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324485PMC
September 2021

SARS-CoV-2 in Transit: Characterization of SARS-CoV-2 Genomes From Venezuelan Migrants in Colombia.

Int J Infect Dis 2021 Sep 29;110:410-416. Epub 2021 Jul 29.

Instituto de Investigaciones Biomédicas IDB/Emerging Pathogens Network-Incubadora Venezolana de la Ciencia, Cabudare, Venezuela; Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Objectives: To evaluate the genomic epidemiology of SARS-CoV-2 from Venezuelan migrants living in Colombia.

Methods: This study sequenced SARS-CoV-2 from 30 clinical specimens collected from Venezuelan migrants. Genomes were compared with the Wuhan reference genome to identify polymorphisms, reconstruct phylogenetic relationships and perform comparative genomic analyses. Geographic, sociodemographic and clinical data were also studied across genotypes.

Results: This study demonstrated the presence of six distinct SARS-CoV-2 lineages circulating among Venezuelan migrants, as well as a close relationship between SARS-CoV-2 genomic sequences obtained from individuals living in the Venezuelan-Colombian border regions of La Guajira (Colombia) and Zulia (Venezuela). Three clusters (C-1, C-2 and C-3) were well supported by phylogenomic inference, supporting the hypothesis of three potential transmission routes across the Colombian-Venezuelan border. These genomes included point mutations previously associated with increased infectivity. A mutation (L18F) in the N-terminal domain of the spike protein that has been associated with compromised binding of neutralizing antibodies was found in 2 of 30 (6.6%) genomes. A statistically significant association was identified with symptomatology for cluster C2.

Conclusion: The close phylogenetic relationships between SARS-CoV-2 genomes from Venezuelan migrants and from people living at the Venezuela-Colombian border support the importance of human movements for the spread of COVID-19 and for emerging virus variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijid.2021.07.069DOI Listing
September 2021

Highly variable SARS-CoV-2 spike antibody responses to two doses of COVID-19 RNA vaccination in patients with multiple myeloma.

Cancer Cell 2021 08 29;39(8):1028-1030. Epub 2021 Jun 29.

Department of Medicine, Hematology, and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2021.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238657PMC
August 2021

SARS-CoV-2 mRNA vaccination induces functionally diverse antibodies to NTD, RBD, and S2.

Cell 2021 07 8;184(15):3936-3948.e10. Epub 2021 Jun 8.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

In this study we profiled vaccine-induced polyclonal antibodies as well as plasmablast-derived mAbs from individuals who received SARS-CoV-2 spike mRNA vaccine. Polyclonal antibody responses in vaccinees were robust and comparable to or exceeded those seen after natural infection. However, the ratio of binding to neutralizing antibodies after vaccination was greater than that after natural infection and, at the monoclonal level, we found that the majority of vaccine-induced antibodies did not have neutralizing activity. We also found a co-dominance of mAbs targeting the NTD and RBD of SARS-CoV-2 spike and an original antigenic-sin like backboost to spikes of seasonal human coronaviruses OC43 and HKU1. Neutralizing activity of NTD mAbs but not RBD mAbs against a clinical viral isolate carrying E484K as well as extensive changes in the NTD was abolished, suggesting that a proportion of vaccine-induced RBD binding antibodies may provide substantial protection against viral variants carrying single E484K RBD mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2021.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185186PMC
July 2021

Molecular evidence of SARS-CoV-2 in New York before the first pandemic wave.

Nat Commun 2021 06 8;12(1):3463. Epub 2021 Jun 8.

Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Numerous reports document the spread of SARS-CoV-2, but there is limited information on its introduction before the identification of a local case. This may lead to incorrect assumptions when modeling viral origins and transmission. Here, we utilize a sample pooling strategy to screen for previously undetected SARS-CoV-2 in de-identified, respiratory pathogen-negative nasopharyngeal specimens from 3,040 patients across the Mount Sinai Health System in New York. The patients had been previously evaluated for respiratory symptoms or influenza-like illness during the first 10 weeks of 2020. We identify SARS-CoV-2 RNA from specimens collected as early as 25 January 2020, and complete SARS-CoV-2 genome sequences from multiple pools of samples collected between late February and early March, documenting an increase prior to the later surge. Our results provide evidence of sporadic SARS-CoV-2 infections a full month before both the first officially documented case and emergence of New York as a COVID-19 epicenter in March 2020.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23688-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187428PMC
June 2021

SARS-CoV-2 vaccines for all but a single dose for COVID-19 survivors.

EBioMedicine 2021 Jun 26;68:103401. Epub 2021 May 26.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, United States; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2021.103401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149267PMC
June 2021

Deciphering the introduction and transmission of SARS-CoV-2 in the Colombian Amazon Basin.

PLoS Negl Trop Dis 2021 04 15;15(4):e0009327. Epub 2021 Apr 15.

Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia.

Background: The SARS-CoV-2 pandemic has forced health authorities across the world to take important decisions to curtail its spread. Genomic epidemiology has emerged as a valuable tool to understand introductions and spread of the virus in a specific geographic location.

Methodology/principal Findings: Here, we report the sequences of 59 SARS-CoV-2 samples from inhabitants of the Colombian Amazonas department. The viral genomes were distributed in two robust clusters within the distinct GISAID clades GH and G. Spatial-temporal analyses revealed two independent introductions of SARS-CoV-2 in the region, one around April 1, 2020 associated with a local transmission, and one around April 2, 2020 associated with other South American genomes (Uruguay and Brazil). We also identified ten lineages circulating in the Amazonas department including the P.1 variant of concern (VOC).

Conclusions/significance: This study represents the first genomic epidemiology investigation of SARS-CoV-2 in one of the territories with the highest report of indigenous communities of the country. Such findings are essential to decipher viral transmission, inform on global spread and to direct implementation of infection prevention and control measures for these vulnerable populations, especially, due to the recent circulation of one of the variants of concern (P.1) associated with major transmissibility and possible reinfections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pntd.0009327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078805PMC
April 2021

The plasmablast response to SARS-CoV-2 mRNA vaccination is dominated by non-neutralizing antibodies and targets both the NTD and the RBD.

medRxiv 2021 May 1. Epub 2021 May 1.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

In this study we profiled vaccine-induced polyclonal antibodies as well as plasmablast derived mAbs from individuals who received SARS-CoV-2 spike mRNA vaccine. Polyclonal antibody responses in vaccinees were robust and comparable to or exceeded those seen after natural infection. However, the ratio of binding to neutralizing antibodies after vaccination was greater than that after natural infection and, at the monoclonal level, we found that the majority of vaccine-induced antibodies did not have neutralizing activity. We also found a co-dominance of mAbs targeting the NTD and RBD of SARS-CoV-2 spike and an original antigenic-sin like backboost to seasonal human coronaviruses OC43 and HKU1. Neutralizing activity of NTD mAbs but not RBD mAbs against a clinical viral isolate carrying E484K as well as extensive changes in the NTD was abolished, suggesting that a proportion of vaccine induced RBD binding antibodies may provide substantial protection against viral variants carrying single E484K RBD mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.03.07.21253098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987037PMC
May 2021

Influenza hemagglutinin-specific IgA Fc-effector functionality is restricted to stalk epitopes.

Proc Natl Acad Sci U S A 2021 02;118(8)

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;

In this study, we utilized a panel of human immunoglobulin (Ig) IgA monoclonal antibodies isolated from the plasmablasts of eight donors after 2014/2015 influenza virus vaccination (Fluarix) to study the binding and functional specificities of this isotype. In this cohort, isolated IgA monoclonal antibodies were primarily elicited against the hemagglutinin protein of the H1N1 component of the vaccine. To compare effector functionalities, an H1-specific subset of antibodies targeting distinct epitopes were expressed as monomeric, dimeric, or secretory IgA, as well as in an IgG1 backbone. When expressed with an IgG Fc domain, all antibodies elicited Fc-effector activity in a primary polymorphonuclear cell-based assay which differs from previous observations that found only stalk-specific antibodies activate the low-affinity FcγRIIIa. However, when expressed with IgA Fc domains, only antibodies targeting the stalk domain showed Fc-effector activity in line with these previous findings. To identify the cause of this discrepancy, we then confirmed that IgG signaling through the high-affinity FcγI receptor was not restricted to stalk epitopes. Since no corresponding high-affinity Fcα receptor exists, the IgA repertoire may therefore be limited to stalk-specific epitopes in the context of Fc receptor signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2018102118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923359PMC
February 2021

Identification and Characterization of Novel Antibody Epitopes on the N2 Neuraminidase.

mSphere 2021 02 10;6(1). Epub 2021 Feb 10.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA

The influenza virus neuraminidase (NA) is becoming a focus for novel vaccine designs. However, the epitopes of human anti-NA antibodies have been poorly defined. Using a panel of 10 anti-N2 monoclonal antibodies (MAbs) that bind the H3N2 virus A/Switzerland/9715293/2013, we generated five escape mutant viruses. These viruses contained mutations K199E/T, E258K, A272D, and S331N. We found that mutations at K199 and E258 had the largest impact on MAb binding, NA inhibition and neutralization activity. In addition, a natural isolate from the 2017-2018 season was found to contain the E258K mutation and was resistant to numerous antibodies tested. The mutation S331N, was identified in virus passaged in the presence of antibody; however, it had little impact on MAb activity and greatly decreased viral fitness. This information aids in identifying novel human MAb epitopes on the N2 and helps with the detection of antigenically drifted NAs. The influenza virus neuraminidase is an emerging target for universal influenza virus vaccines. However, in contrast to influenza virus hemagglutinin, we know little about antibody epitopes and antigenic sites on the neuraminidase. Characterizing and defining these sites is aiding vaccine development and helping to understand antigenic drift of NA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mSphere.00958-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8544889PMC
February 2021

The E484K mutation in the SARS-CoV-2 spike protein reduces but does not abolish neutralizing activity of human convalescent and post-vaccination sera.

medRxiv 2021 Jan 29. Epub 2021 Jan 29.

One year in the coronavirus disease 2019 (COVID-19) pandemic, the first vaccines are being rolled out under emergency use authorizations. It is of great concern that newly emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can escape antibody-mediated protection induced by previous infection or vaccination through mutations in the spike protein. The glutamate (E) to Lysine (K) substitution at position 484 (E484K) in the receptor binding domain (RBD) of the spike protein is present in the rapidly spreading variants of concern belonging to the B.1.351 and P.1 lineages. We performed in vitro microneutralization assays with both the USA-WA1/2020 virus and a recombinant (r)SARS-CoV-2 virus that is identical to USA-WA1/2020 except for the E484K mutation introduced in the spike RBD. We selected 34 sera from study participants based on their SARS-CoV-2 spike ELISA antibody titer (negative [N=4] versus weak [N=8], moderate [N=11] or strong positive [N=11]). In addition, we included sera from five individuals who received two doses of the Pfizer SARS-CoV-2 vaccine BNT162b2. Serum neutralization efficiency was lower against the E484K rSARS-CoV-2 (vaccination samples: 3.4 fold; convalescent low IgG: 2.4 fold, moderate IgG: 4.2 fold and high IgG: 2.6 fold) compared to USA-WA1/2020. For some of the convalescent donor sera with low or moderate IgG against the SARS-CoV-2 spike, the drop in neutralization efficiency resulted in neutralization ID50 values similar to negative control samples, with low or even absence of neutralization of the E484K rSARS-CoV-2. However, human sera with high neutralization titers against the USA-WA1/2020 strain were still able to neutralize the E484K rSARS-CoV-2. Therefore, it is important to aim for the highest titers possible induced by vaccination to enhance protection against newly emerging SARS-CoV-2 variants. Two vaccine doses may be needed for induction of high antibody titers against SARS-CoV-2. Postponing the second vaccination is suggested by some public health authorities in order to provide more individuals with a primer vaccination. Our data suggests that this may leave vaccinees less protected against newly emerging variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.01.26.21250543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852247PMC
January 2021

The N501Y mutation in SARS-CoV-2 spike leads to morbidity in obese and aged mice and is neutralized by convalescent and post-vaccination human sera.

medRxiv 2021 Jan 20. Epub 2021 Jan 20.

The current COVID-19 (coronavirus disease 19) pandemic, caused by SARS-CoV-2, disproportionally affects the elderly and people with comorbidities like obesity and associated type 2 diabetes mellitus. Small animal models are crucial for the successful development and validation of antiviral vaccines, therapies and to study the role that comorbidities have on the outcome of viral infections. The initially available SARS-CoV-2 isolates require adaptation in order to use the mouse angiotensin converting enzyme 2 (mACE-2) entry receptor and to productively infect the cells of the murine respiratory tract. We have "mouse-adapted" SARS-CoV-2 by serial passaging a clinical virus isolate in the lungs of mice. We then used low doses of this virus in mouse models for advanced age, diabetes and obesity. Similar to SARS-CoV-2 infection in humans, the outcome of infection with mouse-adapted SARS-CoV-2 resulted in enhanced morbidity in aged and diabetic obese mice. Mutations associated with mouse adaptation occurred in the S, M, N and ORF8 genes. Interestingly, one mutation in the receptor binding domain of the S protein results in the change of an asparagine to tyrosine residue at position 501 (N501Y). This mutation is also present in the newly emerging SARS-CoV-2 variant viruses reported in the U.K. (20B/501Y.V1, B1.1.7 lineage) that is epidemiologically associated with high human to human transmission. We show that human convalescent and post vaccination sera can neutralize the newly emerging N501Y virus variant with similar efficiency as that of the reference USA-WA1/2020 virus, suggesting that current SARS-CoV-2 vaccines will protect against the 20B/501Y.V1 strain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.01.19.21249592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836140PMC
January 2021

Immunological memory to SARS-CoV-2 assessed for up to eight months after infection.

bioRxiv 2020 Dec 18. Epub 2020 Dec 18.

Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA.

Understanding immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines, and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥ 6 months post-infection. IgG to the Spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4 T cells and CD8 T cells declined with a half-life of 3-5 months. By studying antibody, memory B cell, CD4 T cell, and CD8 T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.11.15.383323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805444PMC
December 2020

Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.

Science 2021 02 6;371(6529). Epub 2021 Jan 6.

Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA.

Understanding immune memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for improving diagnostics and vaccines and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥6 months after infection. Immunoglobulin G (IgG) to the spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month after symptom onset. SARS-CoV-2-specific CD4 T cells and CD8 T cells declined with a half-life of 3 to 5 months. By studying antibody, memory B cell, CD4 T cell, and CD8 T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.abf4063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919858PMC
February 2021

Real-Time Investigation of a Large Nosocomial Influenza A Outbreak Informed by Genomic Epidemiology.

Clin Infect Dis 2020 Nov 30. Epub 2020 Nov 30.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.

Background: Nosocomial respiratory virus outbreaks represent serious public health challenges. Rapid and precise identification of cases and tracing of transmission chains is critical to end outbreaks and to inform prevention measures.

Methods: We combined conventional surveillance with influenza A virus (IAV) genome sequencing to identify and contain a large IAV outbreak in a metropolitan healthcare system. A total of 381 individuals, including 91 inpatients and 290 health care workers (HCWs), were included in the investigation.

Results: During a 12-day period in early 2019, infection preventionists identified 89 HCWs and 18 inpatients as cases of influenza-like illness (ILI), using an amended definition without the requirement for fever. Sequencing of IAV genomes from available nasopharyngeal (NP) specimens identified 66 individuals infected with a nearly identical strain of influenza A H1N1pdm09 (43 HCWs, 17 inpatients, and 6 with unspecified affiliation). All HCWs infected with the outbreak strain had received the seasonal influenza virus vaccination. Characterization of five representative outbreak viral isolates did not show antigenic drift. In conjunction with IAV genome sequencing, mining of electronic records pinpointed the origin of the outbreak as a single patient and a few interactions in the emergency department that occurred one day prior to the index ILI cluster.

Conclusions: We used precision surveillance to delineate a large nosocomial IAV outbreak, mapping the source of the outbreak to a single patient rather than HCWs as initially assumed based on conventional epidemiology. These findings have important ramifications for more effective prevention strategies to curb nosocomial respiratory virus outbreaks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa1781DOI Listing
November 2020

SARS-CoV-2 spread across the Colombian-Venezuelan border.

Infect Genet Evol 2020 12 4;86:104616. Epub 2020 Nov 4.

Grupo de Investigaciones Microbiológicas-UR (GIMUR), Departamento de Biología, Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia.

Introduction: Venezuela and Colombia both adopted measures of containment early in response to the COVID-19 pandemic. However, Venezuela's ongoing humanitarian crisis has decimated its health care system, and forced millions of Venezuelans to flee through its porous border with Colombia. The extensive shared border, and illegal cross-border transit through improvised trails between the two countries are major challenges for public health authorities. We report the first SARS-CoV-2 genomes from Venezuela, and present a snapshot of the SARS-CoV-2 epidemiologic landscape in the Colombian-Venezuelan border region.

Methods: We sequenced and assembled viral genomes from total RNA extracted from nasopharyngeal (NP) clinical specimens using a custom reference-based analysis pipeline. Three assemblies obtained were subjected to typing using the Phylogenetic Assignment of Named Global Outbreak LINeages 'Pangolin' tool. A total of 376 publicly available SARS-CoV-2 genomes from South America were obtained from the GISAID database to perform comparative genomic analyses. Additionally, the Wuhan-1 strain was used as reference.

Results: We found that two of the SARS-CoV-2 genomes from Venezuela belonged to the B1 lineage, and the third to the B.1.13 lineage. We observed a point mutation in the Spike protein gene (D614G substitution), previously reported to be associated with increased infectivity, in all three Venezuelan genomes. Additionally, three mutations (R203K/G204R substitution) were present in the nucleocapsid (N) gene of one Venezuelan genome.

Conclusions: Genomic sequencing demonstrates similarity between SARS-CoV-2 lineages from Venezuela and viruses collected from patients in bordering areas in Colombia and from Brazil, consistent with cross-border transit despite administrative measures including lockdowns. The presence of mutations associated with increased infectivity in the 3 Venezuelan genomes we report and Colombian SARS-CoV-2 genomes from neighboring borders areas may pose additional challenges for control of SARS-CoV-2 spread in the complex epidemiological landscape in Latin American countries. Public health authorities should carefully follow the progress of the pandemic and its impact on displaced populations within the region.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.meegid.2020.104616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609240PMC
December 2020

Repeated cross-sectional sero-monitoring of SARS-CoV-2 in New York City.

Nature 2021 02 3;590(7844):146-150. Epub 2020 Nov 3.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first detected in China and has since caused a pandemic of coronavirus disease 2019 (COVID-19). The first case of COVID-19 in New York City was officially confirmed on 1 March 2020 followed by a severe local epidemic. Here, to understand seroprevalence dynamics, we conduct a retrospective, repeated cross-sectional analysis of anti-SARS-CoV-2 spike antibodies in weekly intervals from the beginning of February to July 2020 using more than 10,000 plasma samples from patients at Mount Sinai Hospital in New York City. We describe the dynamics of seroprevalence in an 'urgent care' group, which is enriched in cases of COVID-19 during the epidemic, and a 'routine care' group, which more closely represents the general population. Seroprevalence increased at different rates in both groups; seropositive samples were found as early as mid-February, and levelled out at slightly above 20% in both groups after the epidemic wave subsided by the end of May. From May to July, seroprevalence remained stable, suggesting lasting antibody levels in the population. Our data suggest that SARS-CoV-2 was introduced in New York City earlier than previously documented and describe the dynamics of seroconversion over the full course of the first wave of the pandemic in a major metropolitan area.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2912-6DOI Listing
February 2021

Robust neutralizing antibodies to SARS-CoV-2 infection persist for months.

Science 2020 12 28;370(6521):1227-1230. Epub 2020 Oct 28.

Clinical Microbiology Laboratory, Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic with millions infected and more than 1 million fatalities. Questions regarding the robustness, functionality, and longevity of the antibody response to the virus remain unanswered. Here, on the basis of a dataset of 30,082 individuals screened at Mount Sinai Health System in New York City, we report that the vast majority of infected individuals with mild-to-moderate COVID-19 experience robust immunoglobulin G antibody responses against the viral spike protein. We also show that titers are relatively stable for at least a period of about 5 months and that anti-spike binding titers significantly correlate with neutralization of authentic SARS-CoV-2. Our data suggest that more than 90% of seroconverters make detectable neutralizing antibody responses. These titers remain relatively stable for several months after infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.abd7728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810037PMC
December 2020

COVID-19: Staging of a New Disease.

Cancer Cell 2020 11 10;38(5):594-597. Epub 2020 Oct 10.

Department of Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Coronavirus disease 2019 (COVID-19), like cancer, is a complex disease with clinical phases of progression. Initially conceptualized as a respiratory disease, COVID-19 is increasingly recognized as a multi-organ and heterogeneous illness. Disease staging is a method for measuring the progression and severity of an illness using objective clinical and molecular criteria. Integral to cancer staging is "metastasis," defined as the spread of a disease-producing agent, including neoplastic cells and pathogens such as certain viruses, from the primary site to distinct anatomic locations. Staging provides valuable frameworks and benchmarks for clinical decision-making in patient management, improved prognostication, and evidence-based treatment selection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2020.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547574PMC
November 2020

Humoral response and PCR positivity in patients with COVID-19 in the New York City region, USA: an observational study.

Lancet Microbe 2020 Nov 25;1(7):e283-e289. Epub 2020 Sep 25.

Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. The proportion of infected individuals who seroconvert is still an open question. In addition, it has been shown in some individuals that viral genome can be detected up to 3 months after symptom resolution. We investigated both seroconversion and PCR positivity in a large cohort of convalescent serum donors in the New York City (NY, USA) region.

Methods: In this observational study, we ran an outreach programme in the New York City area. We recruited participants via the REDCap (Vanderbilt University, Nashville, TN, USA) online survey response. Individuals with confirmed or suspected SARS-CoV-2 infection were screened via PCR for presence of viral genome and via ELISA for presence of anti-SARS-CoV-2 spike antibodies. One-way ANOVA and Fisher's exact test were used to measure the association of age, gender, symptom duration, and days from symptom onset and resolution with positive antibody results.

Findings: Between March 26 and April 10, 2020, we measured SARS-CoV-2 antibody titres in 1343 people. Of the 624 participants with confirmed SARS-CoV-2 infection who had serologies done after 4 weeks, all but three seroconverted to the SARS-CoV-2 spike protein, whereas 269 (37%) of 719 participants with suspected SARS-CoV-2 infection seroconverted. PCR positivity was detected up to 28 days from symptom resolution.

Interpretation: Most patients with confirmed COVID-19 seroconvert, potentially providing immunity to reinfection. We also report that in a large proportion of individuals, viral genome can be detected via PCR in the upper respiratory tract for weeks after symptom resolution, but it is unclear whether this signal represents infectious virus. Analysis of our large cohort suggests that most patients with mild COVID-19 seroconvert 4 weeks after illness, and raises questions about the use of PCR to clear positive individuals.

Funding: None.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2666-5247(20)30120-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518831PMC
November 2020

Positive, again! What to make of "re-positive" SARS-CoV-2 molecular test results.

EBioMedicine 2020 Oct 22;60:103011. Epub 2020 Sep 22.

Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2020.103011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506438PMC
October 2020

Human Antibodies Targeting Influenza B Virus Neuraminidase Active Site Are Broadly Protective.

Immunity 2020 10 24;53(4):852-863.e7. Epub 2020 Sep 24.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; The Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Influenza B virus (IBV) infections can cause severe disease in children and the elderly. Commonly used antivirals have lower clinical effectiveness against IBV compared to influenza A viruses (IAV). Neuraminidase (NA), the second major surface protein on the influenza virus, is emerging as a target of broadly protective antibodies that recognize the NA active site of IAVs. However, similarly broadly protective antibodies against IBV NA have not been identified. Here, we isolated and characterized human monoclonal antibodies (mAbs) that target IBV NA from an IBV-infected patient. Two mAbs displayed broad and potent capacity to inhibit IBV NA enzymatic activity, neutralize the virus in vitro, and protect against lethal IBV infection in mice in prophylactic and therapeutic settings. These mAbs inserted long CDR-H3 loops into the NA active site, engaging residues highly conserved among IBV NAs. These mAbs provide a blueprint for the development of improved vaccines and therapeutics against IBVs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2020.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572813PMC
October 2020

A High-Throughput Assay for Circulating Antibodies Directed Against the S Protein of Severe Acute Respiratory Syndrome Coronavirus 2.

J Infect Dis 2020 10;222(10):1629-1634

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

More than 24 million infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were confirmed globally by September 2020. While polymerase chain reaction-based assays are used for diagnosis, there is a need for high-throughput, rapid serologic methods. A Luminex binding assay was developed and used to assess simultaneously the presence of coronavirus disease 2019 (COVID-19)-specific antibodies in human serum and plasma. Clear differentiation was achieved between specimens from infected and uninfected subjects, and a wide range of serum/plasma antibody levels was delineated in infected subjects. All 25 specimens from 18 patients with COVID-19 were positive in the assays with both the trimeric spike and the receptor-binding domain proteins. None of the 13 specimens from uninfected subjects displayed antibodies to either antigen. There was a highly statistically significant difference between the antibody levels of COVID-19-infected and -uninfected specimens (P < .0001). This high-throughput antibody assay is accurate, requires only 2.5 hours, and uses 5 ng of antigen per test.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiaa531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499578PMC
October 2020
-->