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1.
Cell Host & Microbe ; 2022.
Article in English | ScienceDirect | ID: covidwho-1632076

ABSTRACT

Summary SARS-CoV-2 lineages have diverged into highly prevalent variants termed Variants of Concern (VOCs). Here, we characterized emerging SARS-CoV-2 spike polymorphisms in vitro and in vivo to understand their impact on transmissibility, virus pathogenicity and fitness. We demonstrate that the substitution S:655Y, represented in the Gamma and Omicron VOCs, enhances viral replication and spike protein cleavage. The S:655Y substitution was transmitted more efficiently than its ancestor S:655H in the hamster infection model and was able to outcompete S:655H in the hamster model and in a human primary airway system. Finally, we analyzed a set of emerging SARS-CoV-2 variants to investigate how different sets of mutations may impact spike processing. All VOCs tested exhibited increased spike cleavage and fusogenic capacity. Taken together, our study demonstrates that the spike mutations present in VOCs that become epidemiologically prevalent in humans, are linked to an increase in spike processing and virus transmission.

2.
Nature ; 2021 Dec 31.
Article in English | MEDLINE | ID: covidwho-1616995

ABSTRACT

The Omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially identified in November of 2021 in South Africa and Botswana as well as in a sample from a traveler from South Africa in Hong Kong1,2. Since then, B.1.1.529 has been detected globally. This variant seems to be at least equally infectious than B.1.617.2 (Delta), has already caused super spreader events3 and has outcompeted Delta within weeks in several countries and metropolitan areas. B.1.1.529 hosts an unprecedented number of mutations in its spike gene and early reports have provided evidence for extensive immune escape and reduced vaccine effectiveness2,4-6. Here, we investigated the neutralizing and binding activity of sera from convalescent, mRNA double vaccinated, mRNA boosted, convalescent double vaccinated, and convalescent boosted individuals against wild type, B.1.351 and B.1.1.529 SARS-CoV-2 isolates. Neutralizing activity of sera from convalescent and double vaccinated participants was undetectable to very low against B.1.1.529 while neutralizing activity of sera from individuals who had been exposed to spike three or four times was maintained, albeit at significantly reduced levels. Binding to the B.1.1.529 receptor binding domain (RBD) and N-terminal domain (NTD) was reduced in convalescent not vaccinated individuals, but was mostly retained in vaccinated individuals.

3.
Front Immunol ; 12: 759688, 2021.
Article in English | MEDLINE | ID: covidwho-1605844

ABSTRACT

Antibodies (Abs) are essential for the host immune response against SARS-CoV-2, and all the vaccines developed so far have been designed to induce Abs targeting the SARS-CoV-2 spike. Many studies have examined Ab responses in the blood from vaccinated and infected individuals. However, since SARS-CoV-2 is a respiratory virus, it is also critical to understand the mucosal Ab responses at the sites of initial virus exposure. Here, we examined plasma versus saliva Ab responses in vaccinated and convalescent patients. Although saliva levels were significantly lower, a strong correlation was observed between plasma and saliva total Ig levels against all SARS-CoV-2 antigens tested. Virus-specific IgG1 responses predominated in both saliva and plasma, while a lower prevalence of IgM and IgA1 Abs was observed in saliva. Antiviral activities of plasma Abs were also studied. Neutralization titers against the initial WA1 (D614G), B.1.1.7 (alpha) and B.1.617.2 (delta) strains were similar but lower against the B.1.351 (beta) strain. Spike-specific antibody-dependent cellular phagocytosis (ADCP) activities were also detected and the levels correlated with spike-binding Ig titers. Interestingly, while neutralization and ADCP potencies of vaccinated and convalescent groups were comparable, enhanced complement deposition to spike-specific Abs was noted in vaccinated versus convalescent groups and corresponded with higher levels of IgG1 plus IgG3 among the vaccinated individuals. Altogether, this study demonstrates the detection of Ab responses after vaccination or infection in plasma and saliva that correlate significantly, although Ig isotypic differences were noted. The induced plasma Abs displayed Fab-mediated and Fc-dependent functions with comparable neutralization and ADCP potencies, but a greater capacity to activate complement was elicited upon vaccination.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Saliva/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , Aged , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Antibody Formation/immunology , COVID-19/blood , COVID-19/virology , Female , Humans , Immunoglobulin G/immunology , Male , Middle Aged , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Saliva/virology , Vaccination
4.
J Med Virol ; 2021 Dec 07.
Article in English | MEDLINE | ID: covidwho-1589045

ABSTRACT

The COVID-19 pandemic sparked rapid development of SARS-CoV-2 diagnostics. However, emerging variants pose the risk for target dropout and false-negative results secondary to primer/probe binding site (PBS) mismatches. The Agena MassARRAY® SARS-CoV-2 Panel combines RT-PCR and MALDI-TOF mass-spectrometry to probe for five targets across N and ORF1ab genes, which provides a robust platform to accommodate PBS mismatches in divergent viruses. Herein, we utilize a deidentified dataset of 1,262 SARS-CoV-2-positive specimens from Mount Sinai Health System (New York City) from December 2020 through April 2021 to evaluate target results and corresponding sequencing data. Overall, the level of PBS mismatches was greater in specimens with target dropout. Of specimens with N3 target dropout, 57% harbored an A28095T substitution that is highly-specific for the alpha (B.1.1.7) variant of concern. These data highlight the benefit of redundancy in target design and the potential for target performance to illuminate the dynamics of circulating SARS-CoV-2 variants. This article is protected by copyright. All rights reserved.

5.
Preprint | EuropePMC | ID: ppcovidwho-296962

ABSTRACT

Mucosal immune responses are critical to prevent respiratory infections but it is unclear to what extent antigen specific mucosal secretory IgA (SIgA) antibodies are induced by mRNA vaccination in humans. We analyzed, therefore, paired serum and saliva samples from study participants with and without COVID-19 at multiple timepoints before and after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination. Our results suggest that the level of mucosal SIgA responses induced by mRNA vaccination depend on pre-existing immunity. Indeed, vaccination induced only a weak mucosal SIgA response in individuals without pre-existing mucosal antibody responses to SARS-CoV-2 while SIgA induction after vaccination was efficient in COVID-19 survivors. Our data indicate that vaccinated seropositive individuals were able to swiftly induce relatively high anti-spike SIgA responses by boosting pre-existing mucosal immunity. In contrast, seronegative individuals did not have pre-existing anti-SARS-CoV-2 or cross-reacting anti-HCoV SIgA antibodies prior to vaccination, and, thus, little or no anti-SARS-CoV-2 SIgA antibodies were induced by vaccination in these individuals.

6.
Preprint | EuropePMC | ID: ppcovidwho-296852

ABSTRACT

Early, high-resolution metrics are needed to ascertain the immune response to vaccinations. The T cell receptor (TCR), a heterodimer of one α and one β chain, is a promising target, with the complete TCR repertoire reflecting the T cells present in an individual. To this end, we developed Tseek, an unbiased and accurate method for profiling the TCR repertoire by sequencing the TCR α and β chains and developing a suite of tools for repertoire analysis. An added advantage is the ability to non-invasively analyze T cells in peripheral blood mononuclear cells (PBMCs). Tseek and the analytical suite were used to explore the T cell response to both the COVID-19 mRNA vaccine (n=9) and the seasonal inactivated Influenza vaccine (n=5) at several time points. Neutralizing antibody titers were also measured in the covid vaccine samples. The COVID-19 vaccine elicited a broad T cell response involving multiple expanded clones, whereas the Influenza vaccine elicited a narrower response involving fewer clones. Many distinct T cell clones responded at each time point, over a month, providing temporal details lacking in the antibody measurements, especially before the antibodies are detectable. In individuals recovered from a SARS-CoV-2 infection, the first vaccine dose elicited a robust T cell response, while the second dose elicited a comparatively weaker response, indicating a saturation of the response. The physical symptoms experienced by the recipients immediately following the vaccinations were not indicative of the TCR/antibody responses, while a weak TCR response seemed to presage a weak antibody response. We also found that the TCR repertoire acts as an individual fingerprint: donors of blood samples taken years apart could be identified solely based upon their TCR repertoire, hinting at other surprising uses the TCR repertoire may have. These results demonstrate the promise of TCR repertoire sequencing as an early and sensitive measure of the adaptive immune response to vaccination, which can help improve immunogen selection and optimize vaccine dosage and spacing between doses.

7.
Preprint | EuropePMC | ID: ppcovidwho-296713

ABSTRACT

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to circulate, multiple variants of concern (VOC) have emerged. New variants pose challenges for diagnostic platforms since sequence diversity can alter primer/probe binding sites (PBS), causing false-negative results. The Agena MassARRAY ® SARS-CoV-2 Panel utilizes reverse-transcription polymerase chain reaction and mass-spectrometry to detect five multiplex targets across N and ORF1ab genes. Herein, we utilize a dataset of 256 SARS-CoV-2-positive specimens collected between April 11, 2021-August 28, 2021 to evaluate target performance with paired sequencing data. During this timeframe, two targets in the N gene (N2, N3) were subject to the greatest sequence diversity. In specimens with N3 dropout, 69% harbored the Alpha-specific A28095U polymorphism that introduces a 3’-mismatch to the N3 forward PBS and increases risk of target dropout relative to specimens with 28095A (relative risk (RR): 20.02;p<0.0001;95% Confidence Interval (CI): 11.36-35.72). Furthermore, among specimens with N2 dropout, 90% harbored the Delta-specific G28916U polymorphism that creates a 3’-mismatch to the N2 probe PBS and increases target dropout risk (RR: 11.92;p<0.0001;95% CI: 8.17-14.06). These findings highlight the robust capability of Agena MassARRAY ® SARS-CoV-2 Panel target results to reveal circulating virus diversity and underscore the power of multi-target design to capture VOC.

8.
Preprint in English | Other preprints | ID: ppcovidwho-294083

ABSTRACT

Summary 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.

12.
EBioMedicine ; 73: 103626, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1471943

ABSTRACT

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.

13.
iScience ; 24(9): 102937, 2021 Sep 24.
Article in English | MEDLINE | ID: covidwho-1461106

ABSTRACT

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.

14.
Int J Infect Dis ; 110: 410-416, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1330878

ABSTRACT

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.


Subject(s)
COVID-19 , Transients and Migrants , Colombia/epidemiology , Humans , Phylogeny , SARS-CoV-2
15.
Science ; 371(6529)2021 02 05.
Article in English | MEDLINE | ID: covidwho-1309798

ABSTRACT

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.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , Immunologic Memory , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cross-Sectional Studies , Female , Humans , Longitudinal Studies , Male , Middle Aged , Spike Glycoprotein, Coronavirus/immunology , United States , Young Adult
17.
Nat Commun ; 12(1): 3463, 2021 06 08.
Article in English | MEDLINE | ID: covidwho-1261999

ABSTRACT

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.


Subject(s)
COVID-19/epidemiology , Pandemics , SARS-CoV-2/physiology , Humans , Nasopharynx/virology , New York/epidemiology , Phylogeny , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification
18.
Cell ; 184(15): 3936-3948.e10, 2021 07 22.
Article in English | MEDLINE | ID: covidwho-1260677

ABSTRACT

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.


Subject(s)
Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , RNA, Messenger/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Vaccination , Amino Acid Substitution , Angiotensin-Converting Enzyme 2/immunology , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/isolation & purification , Antibodies, Neutralizing/immunology , Antibody Formation/immunology , Binding, Competitive , Humans , Immunoglobulin G/metabolism , Mutation/genetics , Protein Domains , Somatic Hypermutation, Immunoglobulin/genetics
20.
J Med Virol ; 93(2): 1158-1163, 2021 02.
Article in English | MEDLINE | ID: covidwho-1196437

ABSTRACT

We performed phylogenomic analysis of severe acute respiratory syndrome coronavirus-2 from 88 infected individuals across different regions of Colombia. Eleven different lineages were detected, suggesting multiple introduction events. Pangolin lineages B.1 and B.1.5 were the most frequent, with B.1 being associated with prior travel to high-risk areas.


Subject(s)
COVID-19/virology , Genetic Variation , Genome, Viral , Phylogeny , SARS-CoV-2/genetics , Adult , COVID-19/epidemiology , COVID-19/transmission , Colombia/epidemiology , Female , Geography , Humans , Male , Middle Aged , RNA, Viral/genetics , Travel
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