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1.
Elife ; 112022 08 02.
Article in English | MEDLINE | ID: covidwho-1969731

ABSTRACT

Tracking the emergence and spread of SARS-CoV-2 lineages using phylogenetics has proven critical to inform the timing and stringency of COVID-19 public health interventions. We investigated the effectiveness of international travel restrictions at reducing SARS-CoV-2 importations and transmission in Canada in the first two waves of 2020 and early 2021. Maximum likelihood phylogenetic trees were used to infer viruses' geographic origins, enabling identification of 2263 (95% confidence interval: 2159-2366) introductions, including 680 (658-703) Canadian sublineages, which are international introductions resulting in sampled Canadian descendants, and 1582 (1501-1663) singletons, introductions with no sampled descendants. Of the sublineages seeded during the first wave, 49% (46-52%) originated from the USA and were primarily introduced into Quebec (39%) and Ontario (36%), while in the second wave, the USA was still the predominant source (43%), alongside a larger contribution from India (16%) and the UK (7%). Following implementation of restrictions on the entry of foreign nationals on 21 March 2020, importations declined from 58.5 (50.4-66.5) sublineages per week to 10.3-fold (8.3-15.0) lower within 4 weeks. Despite the drastic reduction in viral importations following travel restrictions, newly seeded sublineages in summer and fall 2020 contributed to the persistence of COVID-19 cases in the second wave, highlighting the importance of sustained interventions to reduce transmission. Importations rebounded further in November, bringing newly emergent variants of concern (VOCs). By the end of February 2021, there had been an estimated 30 (19-41) B.1.1.7 sublineages imported into Canada, which increasingly displaced previously circulating sublineages by the end of the second wave.Although viral importations are nearly inevitable when global prevalence is high, with fewer importations there are fewer opportunities for novel variants to spark outbreaks or outcompete previously circulating lineages.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/epidemiology , Genomics/methods , Humans , Ontario , Phylogeny , SARS-CoV-2/genetics
2.
Science ; : abp8715, 2022 Jul 26.
Article in English | MEDLINE | ID: covidwho-1962061

ABSTRACT

Understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 is critical to preventing zoonotic outbreaks before they become the next pandemic. The Huanan Seafood Wholesale Market in Wuhan, China, was identified as a likely source of cases in early reports but later this conclusion became controversial. We show the earliest known COVID-19 cases from December 2019, including those without reported direct links, were geographically centered on this market. We report that live SARS-CoV-2 susceptible mammals were sold at the market in late 2019 and, within the market, SARS-CoV-2-positive environmental samples were spatially associated with vendors selling live mammals. While there is insufficient evidence to define upstream events, and exact circumstances remain obscure, our analyses indicate that the emergence of SARS-CoV-2 occurred via the live wildlife trade in China, and show that the Huanan market was the epicenter of the COVID-19 pandemic.

3.
Science ; : eabp8337, 2022 Jul 26.
Article in English | MEDLINE | ID: covidwho-1962060

ABSTRACT

Understanding the circumstances that lead to pandemics is important for their prevention. Here, we analyze the genomic diversity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) early in the coronavirus disease 2019 (COVID-19) pandemic. We show that SARS-CoV-2 genomic diversity before February 2020 likely comprised only two distinct viral lineages, denoted A and B. Phylodynamic rooting methods, coupled with epidemic simulations, reveal that these lineages were the result of at least two separate cross-species transmission events into humans. The first zoonotic transmission likely involved lineage B viruses around 18 November 2019 (23 October-8 December), while the separate introduction of lineage A likely occurred within weeks of this event. These findings indicate that it is unlikely that SARS-CoV-2 circulated widely in humans prior to November 2019 and define the narrow window between when SARS-CoV-2 first jumped into humans and when the first cases of COVID-19 were reported. As with other coronaviruses, SARS-CoV-2 emergence likely resulted from multiple zoonotic events.

4.
Nat Commun ; 13(1): 2891, 2022 05 24.
Article in English | MEDLINE | ID: covidwho-1860373

ABSTRACT

Aging is associated with a reduced magnitude of primary immune responses to vaccination. mRNA-based SARS-CoV-2 vaccines have shown efficacy in older adults but virus variant escape is still unclear. Here we analyze humoral and cellular immunity against an early-pandemic viral isolate and compare that to the P.1 (Gamma) and B.1.617.2 (Delta) variants in two cohorts (<50 and >55 age) of mRNA vaccine recipients. We further measure neutralizing antibody titers for B.1.617.1 (Kappa) and B.1.595, with the latter SARS-CoV-2 isolate bearing the spike mutation E484Q. Robust humoral immunity is measured following second vaccination, and older vaccinees manifest cellular immunity comparable to the adult group against early-pandemic SARS-CoV-2 and more recent variants. More specifically, the older cohort has lower neutralizing capacity at 7-14 days following the second dose but equilibrates with the younger cohort after 2-3 months. While long-term vaccination responses remain to be determined, our results implicate vaccine-induced protection in older adults against SARS-CoV-2 variants and inform thinking about boost vaccination.


Subject(s)
COVID-19 , SARS-CoV-2 , Aged , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Immunity, Humoral , RNA, Messenger/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Vaccination , Vaccines, Synthetic , mRNA Vaccines
5.
PNAS Nexus ; 1(1): pgac028, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1806566

ABSTRACT

Saliva specimens have drawn interest for diagnosing respiratory viral infections due to their ease of collection and decreased risk to healthcare providers. However, rapid and sensitive immunoassays have not yet been satisfactorily demonstrated for such specimens due to their viscosity and low viral loads. Using paper microfluidic chips and a smartphone-based fluorescence microscope, we developed a highly sensitive, low-cost immunofluorescence particulometric SARS-CoV-2 assay from clinical saline gargle samples. We demonstrated the limit of detection of 10 ag/µL. With easy-to-collect saline gargle samples, our clinical sensitivity, specificity, and accuracy were 100%, 86%, and 93%, respectively, for n = 27 human subjects with n = 13 RT-qPCR positives.

6.
Biosens Bioelectron ; 207: 114192, 2022 Jul 01.
Article in English | MEDLINE | ID: covidwho-1739563

ABSTRACT

Respiratory viruses, especially coronaviruses, have resulted in worldwide pandemics in the past couple of decades. Saliva-based paper microfluidic assays represent an opportunity for noninvasive and rapid screening, yet both the sample matrix and test method come with unique challenges. In this work, we demonstrated the rapid and sensitive detection of SARS-CoV-2 from saliva samples, which could be simpler and more comfortable for patients than existing methods. Furthermore, we systematically investigated the components of saliva samples that affected assay performance. Using only a smartphone, an antibody-conjugated particle suspension, and a paper microfluidic chip, we made the assay user-friendly with minimal processing. Unlike the previously established flow rate assays that depended solely on the flow rate or distance, this unique assay analyzes the flow profile to determine infection status. Particle-target immunoagglutination changed the surface tension and subsequently the capillary flow velocity profile. A smartphone camera automatically measured the flow profile using a Python script, which was not affected by ambient light variations. The limit of detection (LOD) was 1 fg/µL SARS-CoV-2 from 1% saliva samples and 10 fg/µL from simulated saline gargle samples (15% saliva and 0.9% saline). This method was highly specific as demonstrated using influenza A/H1N1. The sample-to-answer assay time was <15 min, including <1-min capillary flow time. The overall accuracy was 89% with relatively clean clinical saline gargle samples. Despite some limitations with turbid clinical samples, this method presents a potential solution for rapid mass testing techniques during any infectious disease outbreak as soon as the antibodies become available.


Subject(s)
Biosensing Techniques , COVID-19 , Influenza A Virus, H1N1 Subtype , COVID-19/diagnosis , Humans , Microfluidics , SARS-CoV-2 , Smartphone
7.
Science ; 374(6572): 1202-1204, 2021 Dec 03.
Article in English | MEDLINE | ID: covidwho-1583228

ABSTRACT

Elucidating the origin of the pandemic requires understanding of the Wuhan outbreak.


Subject(s)
COVID-19/epidemiology , Disease Outbreaks , China/epidemiology , Humans , Pandemics
8.
Nat Med ; 27(11): 2002-2011, 2021 11.
Article in English | MEDLINE | ID: covidwho-1447313

ABSTRACT

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have shown high efficacy, but immunocompromised participants were excluded from controlled clinical trials. In this study, we compared immune responses to the BNT162b2 mRNA Coronavirus Disease 2019 vaccine in patients with solid tumors (n = 53) who were on active cytotoxic anti-cancer therapy to a control cohort of participants without cancer (n = 50). Neutralizing antibodies were detected in 67% of patients with cancer after the first immunization, followed by a threefold increase in median titers after the second dose. Similar patterns were observed for spike protein-specific serum antibodies and T cells, but the magnitude of each of these responses was diminished relative to the control cohort. In most patients with cancer, we detected spike receptor-binding domain and other S1-specific memory B cell subsets as potential predictors of anamnestic responses to additional immunizations. We therefore initiated a phase 1 trial for 20 cancer cohort participants of a third vaccine dose of BNT162b2 ( NCT04936997 ); primary outcomes were immune responses, with a secondary outcome of safety. At 1 week after a third immunization, 16 participants demonstrated a median threefold increase in neutralizing antibody responses, but no improvement was observed in T cell responses. Adverse events were mild. These results suggest that a third dose of BNT162b2 is safe, improves humoral immunity against SARS-CoV-2 and could be immunologically beneficial for patients with cancer on active chemotherapy.


Subject(s)
/administration & dosage , COVID-19/prevention & control , Neoplasms/therapy , Adult , Aged , Antibodies, Viral/blood , Antibodies, Viral/metabolism , Arizona , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Cohort Studies , Dose-Response Relationship, Drug , Female , Humans , Immunity, Humoral/drug effects , Immunity, Humoral/physiology , Male , Middle Aged , Neoplasms/immunology , Neoplasms/pathology , RNA, Messenger/immunology , RNA, Viral/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Young Adult
9.
Cell ; 184(19): 4848-4856, 2021 09 16.
Article in English | MEDLINE | ID: covidwho-1363914

ABSTRACT

Since the first reports of a novel severe acute respiratory syndrome (SARS)-like coronavirus in December 2019 in Wuhan, China, there has been intense interest in understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in the human population. Recent debate has coalesced around two competing ideas: a "laboratory escape" scenario and zoonotic emergence. Here, we critically review the current scientific evidence that may help clarify the origin of SARS-CoV-2.


Subject(s)
SARS-CoV-2/physiology , Animals , Biological Evolution , COVID-19/virology , Humans , Laboratories , SARS-CoV-2/genetics , Zoonoses/virology
11.
Science ; 372(6540): 412-417, 2021 04 23.
Article in English | MEDLINE | ID: covidwho-1199748

ABSTRACT

Understanding when severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged is critical to evaluating our current approach to monitoring novel zoonotic pathogens and understanding the failure of early containment and mitigation efforts for COVID-19. We used a coalescent framework to combine retrospective molecular clock inference with forward epidemiological simulations to determine how long SARS-CoV-2 could have circulated before the time of the most recent common ancestor of all sequenced SARS-CoV-2 genomes. Our results define the period between mid-October and mid-November 2019 as the plausible interval when the first case of SARS-CoV-2 emerged in Hubei province, China. By characterizing the likely dynamics of the virus before it was discovered, we show that more than two-thirds of SARS-CoV-2-like zoonotic events would be self-limited, dying out without igniting a pandemic. Our findings highlight the shortcomings of zoonosis surveillance approaches for detecting highly contagious pathogens with moderate mortality rates.


Subject(s)
COVID-19/epidemiology , COVID-19/virology , Genome, Viral , Pandemics , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Animals , COVID-19/transmission , China/epidemiology , Computer Simulation , Evolution, Molecular , Genetic Fitness , Humans , Models, Theoretical , Phylogeny , Retrospective Studies , Viral Zoonoses
12.
Cell ; 184(10): 2587-2594.e7, 2021 05 13.
Article in English | MEDLINE | ID: covidwho-1157175

ABSTRACT

The highly transmissible B.1.1.7 variant of SARS-CoV-2, first identified in the United Kingdom, has gained a foothold across the world. Using S gene target failure (SGTF) and SARS-CoV-2 genomic sequencing, we investigated the prevalence and dynamics of this variant in the United States (US), tracking it back to its early emergence. We found that, while the fraction of B.1.1.7 varied by state, the variant increased at a logistic rate with a roughly weekly doubling rate and an increased transmission of 40%-50%. We revealed several independent introductions of B.1.1.7 into the US as early as late November 2020, with community transmission spreading it to most states within months. We show that the US is on a similar trajectory as other countries where B.1.1.7 became dominant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality.


Subject(s)
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
13.
bioRxiv ; 2020 Nov 24.
Article in English | MEDLINE | ID: covidwho-955722

ABSTRACT

Understanding when SARS-CoV-2 emerged is critical to evaluating our current approach to monitoring novel zoonotic pathogens and understanding the failure of early containment and mitigation efforts for COVID-19. We employed a coalescent framework to combine retrospective molecular clock inference with forward epidemiological simulations to determine how long SARS-CoV-2 could have circulated prior to the time of the most recent common ancestor. Our results define the period between mid-October and mid-November 2019 as the plausible interval when the first case of SARS-CoV-2 emerged in Hubei province. By characterizing the likely dynamics of the virus before it was discovered, we show that over two-thirds of SARS-CoV-2-like zoonotic events would be self-limited, dying out without igniting a pandemic. Our findings highlight the shortcomings of zoonosis surveillance approaches for detecting highly contagious pathogens with moderate mortality rates.

14.
Nat Commun ; 11(1): 5110, 2020 10 09.
Article in English | MEDLINE | ID: covidwho-841957

ABSTRACT

Spatiotemporal bias in genome sampling can severely confound discrete trait phylogeographic inference. This has impeded our ability to accurately track the spread of SARS-CoV-2, the virus responsible for the COVID-19 pandemic, despite the availability of unprecedented numbers of SARS-CoV-2 genomes. Here, we present an approach to integrate individual travel history data in Bayesian phylogeographic inference and apply it to the early spread of SARS-CoV-2. We demonstrate that including travel history data yields i) more realistic hypotheses of virus spread and ii) higher posterior predictive accuracy compared to including only sampling location. We further explore methods to ameliorate the impact of sampling bias by augmenting the phylogeographic analysis with lineages from undersampled locations. Our reconstructions reinforce specific transmission hypotheses suggested by the inclusion of travel history data, but also suggest alternative routes of virus migration that are plausible within the epidemiological context but are not apparent with current sampling efforts.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , Travel , Bayes Theorem , Betacoronavirus/classification , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/virology , Genome, Viral/genetics , Humans , Pandemics , Phylogeny , Phylogeography , Pneumonia, Viral/virology , SARS-CoV-2 , Travel/statistics & numerical data
15.
Science ; 370(6516): 564-570, 2020 10 30.
Article in English | MEDLINE | ID: covidwho-760215

ABSTRACT

Accurate understanding of the global spread of emerging viruses is critical for public health responses and for anticipating and preventing future outbreaks. Here we elucidate when, where, and how the earliest sustained severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission networks became established in Europe and North America. Our results suggest that rapid early interventions successfully prevented early introductions of the virus from taking hold in Germany and the United States. Other, later introductions of the virus from China to both Italy and Washington state, United States, founded the earliest sustained European and North America transmission networks. Our analyses demonstrate the effectiveness of public health measures in preventing onward transmission and show that intensive testing and contact tracing could have prevented SARS-CoV-2 outbreaks from becoming established in these regions.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Phylogeny , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , Air Travel , COVID-19 , China/epidemiology , Computer Simulation , Contact Tracing , Coronavirus Infections/prevention & control , Evolution, Molecular , Genome, Viral , Germany/epidemiology , Humans , Italy/epidemiology , Mass Screening , Mutation , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , SARS-CoV-2 , Washington/epidemiology
16.
mBio ; 11(5)2020 09 04.
Article in English | MEDLINE | ID: covidwho-744826

ABSTRACT

In December of 2019, a novel coronavirus, SARS-CoV-2, emerged in the city of Wuhan, China, causing severe morbidity and mortality. Since then, the virus has swept across the globe, causing millions of confirmed infections and hundreds of thousands of deaths. To better understand the nature of the pandemic and the introduction and spread of the virus in Arizona, we sequenced viral genomes from clinical samples tested at the TGen North Clinical Laboratory, the Arizona Department of Health Services, and those collected as part of community surveillance projects at Arizona State University and the University of Arizona. Phylogenetic analysis of 84 genomes from across Arizona revealed a minimum of 11 distinct introductions inferred to have occurred during February and March. We show that >80% of our sequences descend from strains that were initially circulating widely in Europe but have since dominated the outbreak in the United States. In addition, we show that the first reported case of community transmission in Arizona descended from the Washington state outbreak that was discovered in late February. Notably, none of the observed transmission clusters are epidemiologically linked to the original travel-related case in the state, suggesting successful early isolation and quarantine. Finally, we use molecular clock analyses to demonstrate a lack of identifiable, widespread cryptic transmission in Arizona prior to the middle of February 2020.IMPORTANCE As the COVID-19 pandemic swept across the United States, there was great differential impact on local and regional communities. One of the earliest and hardest hit regions was in New York, while at the same time Arizona (for example) had low incidence. That situation has changed dramatically, with Arizona now having the highest rate of disease increase in the country. Understanding the roots of the pandemic during the initial months is essential as the pandemic continues and reaches new heights. Genomic analysis and phylogenetic modeling of SARS-COV-2 in Arizona can help to reconstruct population composition and predict the earliest undetected introductions. This foundational work represents the basis for future analysis and understanding as the pandemic continues.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , Arizona/epidemiology , Betacoronavirus/classification , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/virology , Evolution, Molecular , Genome, Viral/genetics , Humans , Incidence , Mutation , Pandemics , Phylogeny , Pneumonia, Viral/virology , SARS-CoV-2 , Viral Proteins/genetics
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