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1.
Virus Evol ; 8(1): veab098, 2022.
Article in English | MEDLINE | ID: covidwho-1915850

ABSTRACT

Genomic sequencing is crucial to understanding the epidemiology and evolution of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Often, genomic studies rely on remnant diagnostic material, typically nasopharyngeal (NP) swabs, as input into whole-genome SARS-CoV-2 next-generation sequencing pipelines. Saliva has proven to be a safe and stable specimen for the detection of SARS-CoV-2 RNA via traditional diagnostic assays; however, saliva is not commonly used for SARS-CoV-2 sequencing. Using the ARTIC Network amplicon-generation approach with sequencing on the Oxford Nanopore MinION, we demonstrate that sequencing SARS-CoV-2 from saliva produces genomes comparable to those from NP swabs, and that RNA extraction is necessary to generate complete genomes from saliva. In this study, we show that saliva is a useful specimen type for genomic studies of SARS-CoV-2.

2.
Commun Biol ; 5(1): 439, 2022 05 11.
Article in English | MEDLINE | ID: covidwho-1839575

ABSTRACT

SARS-CoV-2 variants shaped the second year of the COVID-19 pandemic and the discourse around effective control measures. Evaluating the threat posed by a new variant is essential for adapting response efforts when community transmission is detected. In this study, we compare the dynamics of two variants, Alpha and Iota, by integrating genomic surveillance data to estimate the effective reproduction number (Rt) of the variants. We use Connecticut, United States, in which Alpha and Iota co-circulated in 2021. We find that the Rt of these variants were up to 50% larger than that of other variants. We then use phylogeography to show that while both variants were introduced into Connecticut at comparable frequencies, clades that resulted from introductions of Alpha were larger than those resulting from Iota introductions. By monitoring the dynamics of individual variants throughout our study period, we demonstrate the importance of routine surveillance in the response to COVID-19.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/epidemiology , Genomics , Humans , Pandemics , SARS-CoV-2/genetics , United States/epidemiology
3.
Med (N Y) ; 3(5): 325-334.e4, 2022 05 13.
Article in English | MEDLINE | ID: covidwho-1773641

ABSTRACT

Background: The SARS-CoV-2 Omicron variant became a global concern due to its rapid spread and displacement of the dominant Delta variant. We hypothesized that part of Omicron's rapid rise was based on its increased ability to cause infections in persons that are vaccinated compared to Delta. Methods: We analyzed nasal swab PCR tests for samples collected between December 12 and 16, 2021, in Connecticut when the proportion of Delta and Omicron variants was relatively equal. We used the spike gene target failure (SGTF) to classify probable Delta and Omicron infections. We fitted an exponential curve to the estimated infections to determine the doubling times for each variant. We compared the test positivity rates for each variant by vaccination status, number of doses, and vaccine manufacturer. Generalized linear models were used to assess factors associated with odds of infection with each variant among persons testing positive for SARS-CoV-2. Findings: For infections with high virus copies (Ct < 30) among vaccinated persons, we found higher odds that they were infected with Omicron compared to Delta, and that the odds increased with increased number of vaccine doses. Compared to unvaccinated persons, we found significant reduction in Delta positivity rates after two (43.4%-49.1%) and three vaccine doses (81.1%), while we only found a significant reduction in Omicron positivity rates after three doses (62.3%). Conclusion: The rapid rise in Omicron infections was likely driven by Omicron's escape from vaccine-induced immunity. Funding: This work was supported by the Centers for Disease Control and Prevention (CDC).


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/epidemiology , COVID-19 Vaccines , Hospitalization , Humans , SARS-CoV-2/genetics
4.
Cell Rep Med ; 3(4): 100583, 2022 04 19.
Article in English | MEDLINE | ID: covidwho-1735052

ABSTRACT

The SARS-CoV-2 Delta variant rose to dominance in mid-2021, likely propelled by an estimated 40%-80% increased transmissibility over Alpha. To investigate if this ostensible difference in transmissibility is uniform across populations, we partner with public health programs from all six states in New England in the United States. We compare logistic growth rates during each variant's respective emergence period, finding that Delta emerged 1.37-2.63 times faster than Alpha (range across states). We compute variant-specific effective reproductive numbers, estimating that Delta is 63%-167% more transmissible than Alpha (range across states). Finally, we estimate that Delta infections generate on average 6.2 (95% CI 3.1-10.9) times more viral RNA copies per milliliter than Alpha infections during their respective emergence. Overall, our evidence suggests that Delta's enhanced transmissibility can be attributed to its innate ability to increase infectiousness, but its epidemiological dynamics may vary depending on underlying population attributes and sequencing data availability.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/epidemiology , Humans , New England/epidemiology , Public Health , SARS-CoV-2/genetics
5.
Nat Med ; 28(3): 481-485, 2022 03.
Article in English | MEDLINE | ID: covidwho-1636460

ABSTRACT

The recent emergence of the SARS-CoV-2 Omicron variant is raising concerns because of its increased transmissibility and its numerous spike mutations, which have the potential to evade neutralizing antibodies elicited by COVID-19 vaccines. Here we evaluated the effects of a heterologous BNT162b2 mRNA vaccine booster on the humoral immunity of participants who had received a two-dose regimen of CoronaVac, an inactivated vaccine used globally. We found that a heterologous CoronaVac prime vaccination of two doses followed by a BNT162b2 booster induces elevated virus-specific antibody levels and potent neutralization activity against the ancestral virus and the Delta variant, resembling the titers obtained after two doses of mRNA vaccines. Although neutralization of Omicron was undetectable in participants who had received a two-dose regimen of CoronaVac, the BNT162b2 booster resulted in a 1.4-fold increase in neutralization activity against Omicron compared with the two-dose mRNA vaccine. Despite this increase, neutralizing antibody titers were reduced by 7.1-fold and 3.6-fold for Omicron compared with the ancestral strain and the Delta variant, respectively. These findings have immediate implications for multiple countries that previously used a CoronaVac regimen and reinforce the idea that the Omicron variant is associated with immune escape from vaccines or infection-induced immunity, highlighting the global need for vaccine boosters to combat the impact of emerging variants.


Subject(s)
COVID-19 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , SARS-CoV-2/genetics , Vaccination , Vaccines, Synthetic
6.
Transpl Infect Dis ; 24(2): e13782, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1583252

ABSTRACT

BACKGROUND: Solid organ transplant recipients are at increased risk of COVID-19-associated morbidity and mortality. AIMS: We describe a nosocomial outbreak investigation on an immunocompromised inpatient unit. METHODS: Patients positive for SARS-CoV-2 were identified. An epidemiologic investigation was assisted with whole genome sequencing of positive samples. RESULTS: Two patients were identified as potential index cases; one presented with diarrhea and was initially not isolated, and the other developed hypoxemia on hospital day 18 before testing positive. Following identification of a SARS-CoV-2 cluster, the unit was closed and all patients and staff received surveillance testing revealing eight additional positive patients and staff members. Whole genome sequencing confirmed an outbreak. Enhanced infection prevention practices mitigated further spread. Asymptomatic patients with COVID-19 were successfully treated with bamlanivimab. DISCUSSION: Preventing SARS-CoV-2 outbreaks in transplant units poses unique challenges as patients may have atypical presentations of COVID-19. Immunocompromised patients who test positive for SARS-CoV-2 while asymptomatic may benefit from monoclonal antibody therapy to prevent disease progression. All hospital staff members working with immunocompromised patients should be promptly encouraged to follow infection prevention behaviors and receive SARS-CoV-2 vaccination. CONCLUSION: SARS-CoV-2 outbreaks on immunocompromised units can be mitigated through prompt identification of cases and robust infection prevention practices.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines , Disease Outbreaks , Humans , Vaccination
8.
Open forum infectious diseases ; 8(Suppl 1):S284-S284, 2021.
Article in English | EuropePMC | ID: covidwho-1565017

ABSTRACT

Background Quickly detecting and isolating individuals positive for SARS-CoV-2 is essential for limiting virus spread. Policy makers rely on the number of active cases to make decisions, and individuals use this information to evaluate risk should they return to public spaces. Robust testing strategies have been plagued with limited authorized diagnostic assays and high test prices, with large-scale implementation hampered by worldwide supply chain issues. Methods Having identified its potential early in the pandemic, we simplified saliva-based COVID-19 diagnostic testing by (1) not requiring collection tubes with preservatives, (2) replacing nucleic acid extraction with a simple enzymatic and heating step, and (3) testing specimens for SARS-CoV-2 in dualplex RT-qPCR. Moreover, we validated this approach (“SalivaDirect”) with reagents and instruments from multiple vendors to circumvent supply chain disruptions. Results SalivaDirect’s simplified protocol does not compromise on sensitivity. In our hospital cohort, we found a high positive agreement (94%) between saliva tested with SalivaDirect and nasopharyngeal swabs tested with a commercial RT-qPCR kit. With the National Basketball Association we tested 3,779 saliva specimens from healthy individuals and detected low rates of invalid (0.3%) and false-positive (< 0.05%) results. Using comparative assays and sample types, we also demonstrated SalivaDirect to efficiently detect SARS-CoV-2 in asymptomatic individuals. SalivaDirect is a simplified method for SARS-CoV-2 detection (A) Schematic overview of SalivaDirect workflow depicting the main steps of mixing saliva with proteinase K, heat inactivation, and dualplex qRT-PCR testing. Figure created with Biorender.com. (B) SARS-CoV-2 is stable in saliva for at least 7 days at 4C, room temperature (RT;19C), and 30C without addition of stabilizing buffers. Spiked-in saliva samples of low virus concentrations (12, 25, and 50 SARS-CoV-2 copies/mL) were kept at the indicated temperature for 7 days and then tested with SalivaDirect. N1 cycle threshold (Ct) values were lower when kept for 7 days at 30C as compared to fresh specimens (Kruskal-Wallis;p = 0.03). Horizontal bars indicate the median. (C) Comparing Ct values for saliva treated with proteinase K and heat as compared to nucleic extraction yields higher N1 Ct values without extraction (Wilcoxon;p < 0.01). (D) Testing extracted nucleic acid from saliva with the N1 primer-probe set (singleplex) as compared to a multiplex assay showed stronger N1 detection in multiplex (Wilcoxon;p < 0.01). The dotted line in (B)–(D) indicates the limit of detection. Conclusion Saliva is a valid alternative to swabs for SARS-CoV-2 screening. Importantly, SalivaDirect enables labs to utilize existing infrastructure, improving test implementation time and requiring limited investment to scale-up to meet mass testing needs. With the safe and reliable self-collection of saliva, our vision is to help provide accessible and equitable testing solutions, especially in low-resource and remote settings. Disclosures Anne Wyllie, PhD, Global Diagnostic Systems (Consultant)Pfizer (Advisor or Review Panel member, Research Grant or Support)PPS Health (Consultant)Tempus Labs, Inc (Research Grant or Support) Nathan D. Grubaugh, PhD, Tempus Labs (Consultant)

10.
J Exp Med ; 219(1)2022 01 03.
Article in English | MEDLINE | ID: covidwho-1510855

ABSTRACT

As SARS-CoV-2 continues to cause morbidity and mortality around the world, there is an urgent need for the development of effective medical countermeasures. Here, we assessed the antiviral capacity of a minimal RIG-I agonist, stem-loop RNA 14 (SLR14), in viral control, disease prevention, post-infection therapy, and cross-variant protection in mouse models of SARS-CoV-2 infection. A single dose of SLR14 prevented viral infection in the lower respiratory tract and development of severe disease in a type I interferon (IFN-I)-dependent manner. SLR14 demonstrated remarkable prophylactic protective capacity against lethal SARS-CoV-2 infection and retained considerable efficacy as a therapeutic agent. In immunodeficient mice carrying chronic SARS-CoV-2 infection, SLR14 elicited near-sterilizing innate immunity in the absence of the adaptive immune system. In the context of infection with variants of concern (VOCs), SLR14 conferred broad protection against emerging VOCs. These findings demonstrate the therapeutic potential of SLR14 as a host-directed, broad-spectrum antiviral for early post-exposure treatment and treatment of chronically infected immunosuppressed patients.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , RNA/metabolism , SARS-CoV-2/drug effects , Animals , COVID-19/metabolism , Disease Models, Animal , Immunity, Innate/drug effects , Interferon Type I/metabolism , Mice , Mice, Inbred BALB C
11.
Nature ; 600(7889): 523-529, 2021 12.
Article in English | MEDLINE | ID: covidwho-1462014

ABSTRACT

The emergence of SARS-CoV-2 variants with mutations in major neutralizing antibody-binding sites can affect humoral immunity induced by infection or vaccination1-6. Here we analysed the development of anti-SARS-CoV-2 antibody and T cell responses in individuals who were previously infected (recovered) or uninfected (naive) and received mRNA vaccines to SARS-CoV-2. While individuals who were previously infected sustained higher antibody titres than individuals who were uninfected post-vaccination, the latter reached comparable levels of neutralization responses to the ancestral strain after the second vaccine dose. T cell activation markers measured upon spike or nucleocapsid peptide in vitro stimulation showed a progressive increase after vaccination. Comprehensive analysis of plasma neutralization using 16 authentic isolates of distinct locally circulating SARS-CoV-2 variants revealed a range of reduction in the neutralization capacity associated with specific mutations in the spike gene: lineages with E484K and N501Y/T (for example, B.1.351 and P.1) had the greatest reduction, followed by lineages with L452R (for example, B.1.617.2). While both groups retained neutralization capacity against all variants, plasma from individuals who were previously infected and vaccinated displayed overall better neutralization capacity than plasma from individuals who were uninfected and also received two vaccine doses, pointing to vaccine boosters as a relevant future strategy to alleviate the effect of emerging variants on antibody neutralizing activity.


Subject(s)
Antibodies, Viral/immunology , COVID-19/epidemiology , COVID-19/virology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Vaccines, Synthetic/immunology , mRNA Vaccines/immunology , 2019-nCoV Vaccine mRNA-1273/immunology , Adult , Aged , Antibodies, Neutralizing/immunology , BNT162 Vaccine/immunology , Female , Health Personnel/statistics & numerical data , Humans , Immunity, Humoral , Male , Middle Aged , Mutation , Retrospective Studies , SARS-CoV-2/classification , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
12.
PLoS Biol ; 19(5): e3001236, 2021 05.
Article in English | MEDLINE | ID: covidwho-1220158

ABSTRACT

With the emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants that may increase transmissibility and/or cause escape from immune responses, there is an urgent need for the targeted surveillance of circulating lineages. It was found that the B.1.1.7 (also 501Y.V1) variant, first detected in the United Kingdom, could be serendipitously detected by the Thermo Fisher TaqPath COVID-19 PCR assay because a key deletion in these viruses, spike Δ69-70, would cause a "spike gene target failure" (SGTF) result. However, a SGTF result is not definitive for B.1.1.7, and this assay cannot detect other variants of concern (VOC) that lack spike Δ69-70, such as B.1.351 (also 501Y.V2), detected in South Africa, and P.1 (also 501Y.V3), recently detected in Brazil. We identified a deletion in the ORF1a gene (ORF1a Δ3675-3677) in all 3 variants, which has not yet been widely detected in other SARS-CoV-2 lineages. Using ORF1a Δ3675-3677 as the primary target and spike Δ69-70 to differentiate, we designed and validated an open-source PCR assay to detect SARS-CoV-2 VOC. Our assay can be rapidly deployed in laboratories around the world to enhance surveillance for the local emergence and spread of B.1.1.7, B.1.351, and P.1.


Subject(s)
COVID-19/virology , SARS-CoV-2/genetics , COVID-19/diagnosis , COVID-19/genetics , DNA Primers , Humans , Multiplex Polymerase Chain Reaction/methods , Mutation , Polyproteins/genetics , Viral Proteins/genetics
13.
Cell ; 184(10): 2595-2604.e13, 2021 05 13.
Article in English | MEDLINE | ID: covidwho-1163482

ABSTRACT

The emergence and spread of SARS-CoV-2 lineage B.1.1.7, first detected in the United Kingdom, has become a global public health concern because of its increased transmissibility. Over 2,500 COVID-19 cases associated with this variant have been detected in the United States (US) since December 2020, but the extent of establishment is relatively unknown. Using travel, genomic, and diagnostic data, we highlight that the primary ports of entry for B.1.1.7 in the US were in New York, California, and Florida. Furthermore, we found evidence for many independent B.1.1.7 establishments starting in early December 2020, followed by interstate spread by the end of the month. Finally, we project that B.1.1.7 will be the dominant lineage in many states by mid- to late March. Thus, genomic surveillance for B.1.1.7 and other variants urgently needs to be enhanced to better inform the public health response.


Subject(s)
COVID-19 Testing , COVID-19 , Models, Biological , SARS-CoV-2 , COVID-19/genetics , COVID-19/mortality , COVID-19/transmission , Female , Humans , Male , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , United States/epidemiology
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