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1.
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
2.
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
3.
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
4.
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
5.
Infect Control Hosp Epidemiol ; 43(8): 1051-1053, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1428663

ABSTRACT

Concerns persist regarding possible false-negative results that may compromise COVID-19 containment. Although obtaining a true false-negative rate is infeasible, using real-life observations, the data suggest a possible false-negative rate of ˜2.3%. Use of a sensitive, amplified RNA platform should reassure healthcare systems.


Subject(s)
COVID-19 , COVID-19/diagnosis , COVID-19 Testing , Clinical Laboratory Techniques/methods , Humans , Nasopharynx , SARS-CoV-2
6.
Lancet Microbe ; 1(6): e254-e262, 2020 10.
Article in English | MEDLINE | ID: covidwho-1428634

ABSTRACT

BACKGROUND: During the 2009 pandemic of an emerging influenza A virus (IAV; H1N1pdm09), data from several European countries indicated that the spread of the virus might have been interrupted by the annual autumn rhinovirus epidemic. We aimed to investigate viral interference between rhinovirus and IAV with use of clinical data and an experimental model. METHODS: We did a clinical data analysis and experimental infection study to investigate the co-occurrence of rhinovirus and IAV in respiratory specimens from adults (≥21 years) tested with a multiplex PCR panel at Yale-New Haven Hospital (CT, USA) over three consecutive winter seasons (Nov 1 to March 1, 2016-17, 2017-18, and 2018-19). We compared observed versus expected co-detections using data extracted from the Epic Systems electronic medical record system. To assess how rhinovirus infection affects subsequent IAV infection, we inoculated differentiated primary human airway epithelial cultures with rhinovirus (HRV-01A; multiplicity of infection [MOI] 0·1) or did mock infection. On day 3 post-infection, we inoculated the same cultures with IAV (H1N1 green fluorescent protein [GFP] reporter virus or H1N1pdm09; MOI 0·1). We used reverse transcription quantitative PCR or microscopy to quantify host cell mRNAs for interferon-stimulated genes (ISGs) on day 3 after rhinovirus or mock infection and IAV RNA on days 4, 5, or 6 after rhinovirus or mock infection. We also did sequential infection studies in the presence of BX795 (6 µM), to inhibit the interferon response. We compared ISG expression and IAV RNA and expression of GFP by IAV reporter virus. FINDINGS: Between July 1, 2016, and June 30, 2019, examination of 8284 respiratory samples positive for either rhinovirus (n=3821) or IAV (n=4463) by any test method was used to establish Nov 1 to March 1 as the period of peak virus co-circulation. After filtering for samples within this time frame meeting the inclusion criteria (n=13 707), there were 989 (7·2%) rhinovirus and 922 (6·7%) IAV detections, with a significantly lower than expected odds of co-detection (odds ratio 0·16, 95% CI 0·09-0·28). Rhinovirus infection of cell cultures induced ISG expression and protected against IAV infection 3 days later, resulting in an approximate 50 000-fold decrease in IAV H1N1pdm09 viral RNA on day 5 post-rhinovirus inoculation. Blocking the interferon response restored IAV replication following rhinovirus infection. INTERPRETATION: These findings show that one respiratory virus can block infection with another through stimulation of antiviral defences in the airway mucosa, supporting the idea that interference from rhinovirus disrupted the 2009 IAV pandemic in Europe. These results indicate that viral interference can potentially affect the course of an epidemic, and this possibility should be considered when designing interventions for seasonal influenza epidemics and the ongoing COVID-19 pandemic. FUNDING: National Institutes of Health, National Institute of General Medical Sciences, and the Yale Department of Laboratory Medicine.


Subject(s)
COVID-19 , Influenza A Virus, H1N1 Subtype , Influenza A virus , Data Analysis , Humans , Influenza A Virus, H1N1 Subtype/genetics , Influenza A virus/genetics , Interferons/metabolism , Pandemics , RNA, Viral/genetics , Rhinovirus/metabolism , United States
7.
Ann Emerg Med ; 79(2): 182-186, 2022 02.
Article in English | MEDLINE | ID: covidwho-1401173

ABSTRACT

STUDY OBJECTIVE: Our institution experienced a change in SARS-CoV-2 testing policy as well as substantial changes in local COVID-19 prevalence, allowing for a unique examination of the relationship between SARS-CoV-2 testing and emergency department (ED) length of stay. METHODS: This was an observational interrupted time series of all patients admitted to an academic health system between March 15, 2020, and September 30, 2020. Given testing limitations from March 15 to April 24, all patients receiving SARS-CoV-2 tests were symptomatic. On April 24, testing was expanded to all ED admissions. The primary and secondary outcomes were ED length of stay and number needed to test to obtain a positive, respectively. RESULTS: A total of 70,856 patients were cared for in the EDs during the 7-month period. The testing change increased admission length of stay by 1.89 hours (95% confidence interval 1.39 to 2.38). The number needed to test was 2.5 patients and was highest yield on April 1, 2020, when the state positivity rate was 39.7%; however, the number needed to test exceeded 170 patients by Sept 1, 2020, at which point the state positivity rate was 0.5%. CONCLUSION: Although universal SARS-CoV-2 testing of ED admissions may meaningfully support mitigation and containment efforts, the clinical cost of testing all admissions amid low community positivity is notable. In our system, universal ED SARS-CoV-2 testing was associated with a 24% increase in admission length of stay alongside the detection of only 1 positive case every other day. Given the known harms and risks of ED boarding and crowding, solutions must be developed to support regular operational flow while balancing infection prevention needs.


Subject(s)
COVID-19 Testing/methods , COVID-19/diagnosis , Emergency Service, Hospital/statistics & numerical data , Length of Stay/statistics & numerical data , COVID-19/epidemiology , Humans , Pandemics , SARS-CoV-2 , United States/epidemiology
8.
J Exp Med ; 218(8)2021 08 02.
Article in English | MEDLINE | ID: covidwho-1387679

ABSTRACT

Initial replication of SARS-CoV-2 in the upper respiratory tract is required to establish infection, and the replication level correlates with the likelihood of viral transmission. Here, we examined the role of host innate immune defenses in restricting early SARS-CoV-2 infection using transcriptomics and biomarker-based tracking in serial patient nasopharyngeal samples and experiments with airway epithelial organoids. SARS-CoV-2 initially replicated exponentially, with a doubling time of ∼6 h, and induced interferon-stimulated genes (ISGs) in the upper respiratory tract, which rose with viral replication and peaked just as viral load began to decline. Rhinovirus infection before SARS-CoV-2 exposure accelerated ISG responses and prevented SARS-CoV-2 replication. Conversely, blocking ISG induction during SARS-CoV-2 infection enhanced viral replication from a low infectious dose. These results show that the activity of ISG-mediated defenses at the time of SARS-CoV-2 exposure impacts infection progression and that the heterologous antiviral response induced by a different virus can protect against SARS-CoV-2.


Subject(s)
COVID-19/immunology , COVID-19/virology , Immunity, Innate/physiology , Nasopharynx/virology , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/genetics , Case-Control Studies , Chemokine CXCL10/metabolism , Disease Susceptibility/immunology , Female , Gene Expression Profiling , Host-Pathogen Interactions/physiology , Humans , Interferons/genetics , Interferons/immunology , Interferons/metabolism , Male , Middle Aged , Picornaviridae Infections/immunology , Picornaviridae Infections/virology , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Viral Load , Virus Replication
9.
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
10.
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
11.
J Clin Virol ; 130: 104567, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-688908

ABSTRACT

BACKGROUND: A major expansion in SARS CoV-2 testing is urgently needed. Saliva is an attractive option as an alternative for nasopharyngeal swabs (NPS), since saliva can be self-collected, is non-invasive, and sample quality is not dependent on the expertise of the collector. OBJECTIVE: To compare SARS CoV-2 positivity on paired NPS and saliva samples. STUDY DESIGN: NPS and paired saliva samples were prospectively collected from symptomatic outpatients suspected of having COVID-19 and were tested by real-time RT-PCR. RESULTS: In total, 35/124 (26.6 %) samples were RT-PCR positive, with 33/35 positive by NPS (sensitivity = 94.3 % (95 % CI 81.4%-99.0%)) and 30/35 by pure saliva (sensitivity = 85.7 % (95 % CI 70.6%-93.7%)), for an overall agreement of 117/124 (94.4 %). The median cycle threshold value was significantly lower for NPS than for saliva (p = 0.0331). A third or more of pure saliva samples from symptomatic patients were thick, stringy, and difficult to pipet. CONCLUSIONS: Real-time RT-PCR of pure saliva had an overall sensitivity for SARS CoV-2 RNA detection of 85.7 % when compared to simultaneously collected NPS. Our study highlighted the need to optimize collection and processing before saliva can be used for high volume testing.


Subject(s)
Coronavirus Infections/diagnosis , Molecular Diagnostic Techniques/standards , Pneumonia, Viral/diagnosis , RNA, Viral/analysis , Saliva/virology , Betacoronavirus , COVID-19 , COVID-19 Testing , COVID-19 Vaccines , Clinical Laboratory Techniques , Humans , Nasopharynx/virology , Outpatients , Pandemics , Prospective Studies , Real-Time Polymerase Chain Reaction , SARS-CoV-2 , Specimen Handling
12.
Nat Microbiol ; 5(10): 1299-1305, 2020 10.
Article in English | MEDLINE | ID: covidwho-638387

ABSTRACT

The recent spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exemplifies the critical need for accurate and rapid diagnostic assays to prompt clinical and public health interventions. Currently, several quantitative reverse transcription-PCR (RT-qPCR) assays are being used by clinical, research and public health laboratories. However, it is currently unclear whether results from different tests are comparable. Our goal was to make independent evaluations of primer-probe sets used in four common SARS-CoV-2 diagnostic assays. From our comparisons of RT-qPCR analytical efficiency and sensitivity, we show that all primer-probe sets can be used to detect SARS-CoV-2 at 500 viral RNA copies per reaction. The exception for this is the RdRp-SARSr (Charité) confirmatory primer-probe set which has low sensitivity, probably due to a mismatch to circulating SARS-CoV-2 in the reverse primer. We did not find evidence for background amplification with pre-COVID-19 samples or recent SARS-CoV-2 evolution decreasing sensitivity. Our recommendation for SARS-CoV-2 diagnostic testing is to select an assay with high sensitivity and that is regionally used, to ease comparability between outcomes.


Subject(s)
Betacoronavirus/genetics , Clinical Laboratory Techniques/methods , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , RNA, Viral/analysis , RNA, Viral/genetics , Reverse Transcriptase Polymerase Chain Reaction/methods , Betacoronavirus/isolation & purification , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques/statistics & numerical data , Coronavirus Infections/epidemiology , Genetic Variation , Genome, Viral , Humans , Molecular Probe Techniques/statistics & numerical data , Pandemics , Pneumonia, Viral/epidemiology , RNA/genetics , RNA Probes/genetics , Reverse Transcriptase Polymerase Chain Reaction/statistics & numerical data , SARS-CoV-2 , Sensitivity and Specificity
13.
Clin Lymphoma Myeloma Leuk ; 20(11): 720-723, 2020 11.
Article in English | MEDLINE | ID: covidwho-614242

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) has a high death rate in patients with comorbidities or in an immunocompromised state. We report a mild and attenuated SARS CoV-2 infection in a patient who is 17 months post stem cell transplantation and maintained on the JAK/STAT inhibitor ruxolitinib, a proposed novel therapy for SARS CoV-2 pneumonia.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/diagnosis , Graft vs Host Disease/drug therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Pneumonia, Viral/diagnosis , Pyrazoles/therapeutic use , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/virology , Graft vs Host Disease/etiology , Graft vs Host Disease/immunology , Humans , Immunocompromised Host , Lymphoma, T-Cell/immunology , Lymphoma, T-Cell/therapy , Male , Middle Aged , Nitriles , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Pyrimidines , SARS-CoV-2 , Severity of Illness Index , Transplantation, Homologous/adverse effects , Treatment Outcome
14.
Cell ; 181(5): 990-996.e5, 2020 05 28.
Article in English | MEDLINE | ID: covidwho-60444

ABSTRACT

The novel coronavirus SARS-CoV-2 was first detected in the Pacific Northwest region of the United States in January 2020, with subsequent COVID-19 outbreaks detected in all 50 states by early March. To uncover the sources of SARS-CoV-2 introductions and patterns of spread within the United States, we sequenced nine viral genomes from early reported COVID-19 patients in Connecticut. Our phylogenetic analysis places the majority of these genomes with viruses sequenced from Washington state. By coupling our genomic data with domestic and international travel patterns, we show that early SARS-CoV-2 transmission in Connecticut was likely driven by domestic introductions. Moreover, the risk of domestic importation to Connecticut exceeded that of international importation by mid-March regardless of our estimated effects of federal travel restrictions. This study provides evidence of widespread sustained transmission of SARS-CoV-2 within the United States and highlights the critical need for local surveillance.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/transmission , Pneumonia, Viral/transmission , Travel , Betacoronavirus/isolation & purification , COVID-19 , Connecticut/epidemiology , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Epidemiological Monitoring , Humans , Likelihood Functions , Pandemics , Phylogeny , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , SARS-CoV-2 , Travel/legislation & jurisprudence , United States/epidemiology , Washington/epidemiology
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