65 results on '"Fauver JR"'
Search Results
2. Assessing de novo parasite genomes assembled using only Oxford Nanopore Technologies MinION data.
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Herzog KS, Wu R, Hawdon JM, Nejsum P, and Fauver JR
- Abstract
In this study, we assessed the quality of de novo genome assemblies for three species of parasitic nematodes ( Brugia malayi , Trichuris trichiura , and Ancylostoma caninum ) generated using only Oxford Nanopore Technologies MinION data. Assemblies were compared to current reference genomes and against additional assemblies that were supplemented with short-read Illumina data through polishing or hybrid assembly approaches. For each species, assemblies generated using only MinION data had similar or superior measures of contiguity, completeness, and gene content. In terms of gene composition, depending on the species, between 88.9 and 97.6% of complete coding sequences predicted in MinION data only assemblies were identical to those predicted in assemblies polished with Illumina data. Polishing MinION data only assemblies with Illumina data therefore improved gene-level accuracy to a degree. Furthermore, modified DNA extraction and library preparation protocols produced sufficient genomic DNA from B. malayi and T. trichiura to generate de novo assemblies from individual specimens., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)
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- 2024
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3. DengueSeq: a pan-serotype whole genome amplicon sequencing protocol for dengue virus.
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Vogels CBF, Hill V, Breban MI, Chaguza C, Paul LM, Sodeinde A, Taylor-Salmon E, Ott IM, Petrone ME, Dijk D, Jonges M, Welkers MRA, Locksmith T, Dong Y, Tarigopula N, Tekin O, Schmedes S, Bunch S, Cano N, Jaber R, Panzera C, Stryker I, Vergara J, Zimler R, Kopp E, Heberlein L, Herzog KS, Fauver JR, Morrison AM, Michael SF, and Grubaugh ND
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- Humans, Genotype, Dengue virology, Dengue diagnosis, High-Throughput Nucleotide Sequencing methods, RNA, Viral genetics, Dengue Virus genetics, Dengue Virus isolation & purification, Dengue Virus classification, Whole Genome Sequencing methods, Genome, Viral, Serogroup
- Abstract
Background: The increasing burden of dengue virus on public health due to more explosive and frequent outbreaks highlights the need for improved surveillance and control. Genomic surveillance of dengue virus not only provides important insights into the emergence and spread of genetically diverse serotypes and genotypes, but it is also critical to monitor the effectiveness of newly implemented control strategies. Here, we present DengueSeq, an amplicon sequencing protocol, which enables whole-genome sequencing of all four dengue virus serotypes., Results: We developed primer schemes for the four dengue virus serotypes, which can be combined into a pan-serotype approach. We validated both approaches using genetically diverse virus stocks and clinical specimens that contained a range of virus copies. High genome coverage (>95%) was achieved for all genotypes, except DENV2 (genotype VI) and DENV 4 (genotype IV) sylvatics, with similar performance of the serotype-specific and pan-serotype approaches. The limit of detection to reach 70% coverage was 10-100 RNA copies/μL for all four serotypes, which is similar to other commonly used primer schemes. DengueSeq facilitates the sequencing of samples without known serotypes, allows the detection of multiple serotypes in the same sample, and can be used with a variety of library prep kits and sequencing instruments., Conclusions: DengueSeq was systematically evaluated with virus stocks and clinical specimens spanning the genetic diversity within each of the four dengue virus serotypes. The primer schemes can be plugged into existing amplicon sequencing workflows to facilitate the global need for expanded dengue virus genomic surveillance., (© 2024. The Author(s).)
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- 2024
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4. Viral kinetics of sequential SARS-CoV-2 infections.
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Kissler SM, Hay JA, Fauver JR, Mack C, Tai CG, Anderson DJ, Ho DD, Grubaugh ND, and Grad YH
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- Humans, SARS-CoV-2, COVID-19 Testing, Research Design, Kinetics, COVID-19
- Abstract
The impact of a prior SARS-CoV-2 infection on the progression of subsequent infections has been unclear. Using a convenience sample of 94,812 longitudinal RT-qPCR measurements from anterior nares and oropharyngeal swabs, we identified 71 individuals with two well-sampled SARS-CoV-2 infections between March 11
th , 2020, and July 28th , 2022. We compared the SARS-CoV-2 viral kinetics of first vs. second infections in this group, adjusting for viral variant, vaccination status, and age. Relative to first infections, second infections usually featured a faster clearance time. Furthermore, a person's relative (rank-order) viral clearance time, compared to others infected with the same variant, was roughly conserved across first and second infections, so that individuals who had a relatively fast clearance time in their first infection also tended to have a relatively fast clearance time in their second infection (Spearman correlation coefficient: 0.30, 95% credible interval (0.12, 0.46)). These findings provide evidence that, like vaccination, immunity from a prior SARS-CoV-2 infection shortens the duration of subsequent acute SARS-CoV-2 infections principally by reducing viral clearance time. Additionally, there appears to be an inherent element of the immune response, or some other host factor, that shapes a person's relative ability to clear SARS-CoV-2 infection that persists across sequential infections., (© 2023. Springer Nature Limited.)- Published
- 2023
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5. Phylogeographic reconstruction of the emergence and spread of Powassan virus in the northeastern United States.
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Vogels CBF, Brackney DE, Dupuis AP 2nd, Robich RM, Fauver JR, Brito AF, Williams SC, Anderson JF, Lubelczyk CB, Lange RE, Prusinski MA, Kramer LD, Gangloff-Kaufmann JL, Goodman LB, Baele G, Smith RP, Armstrong PM, Ciota AT, Dellicour S, and Grubaugh ND
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- Animals, New England, Deer, Encephalitis Viruses, Tick-Borne, Ixodes
- Abstract
Powassan virus is an emerging tick-borne virus of concern for public health, but very little is known about its transmission patterns and ecology. Here, we expanded the genomic dataset by sequencing 279 Powassan viruses isolated from Ixodes scapularis ticks from the northeastern United States. Our phylogeographic reconstructions revealed that Powassan virus lineage II was likely introduced or emerged from a relict population in the Northeast between 1940 and 1975. Sequences strongly clustered by sampling location, suggesting a highly focal geographical distribution. Our analyses further indicated that Powassan virus lineage II emerged in the northeastern United States mostly following a south-to-north pattern, with a weighted lineage dispersal velocity of ~3 km/y. Since the emergence in the Northeast, we found an overall increase in the effective population size of Powassan virus lineage II, but with growth stagnating during recent years. The cascading effect of population expansion of white-tailed deer and I. scapularis populations likely facilitated the emergence of Powassan virus in the northeastern United States.
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- 2023
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6. Nonsystematic Reporting Biases of the SARS-CoV-2 Variant Mu Could Impact Our Understanding of the Epidemiological Dynamics of Emerging Variants.
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Petrone ME, Lucas C, Menasche B, Breban MI, Yildirim I, Campbell M, Omer SB, Holmes EC, Ko AI, Grubaugh ND, Iwasaki A, Wilen CB, Vogels CBF, and Fauver JR
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- Humans, SARS-CoV-2 genetics, Bias, Genomics, COVID-19 epidemiology, COVID-19 genetics
- Abstract
Developing a timely and effective response to emerging SARS-CoV-2 variants of concern (VOCs) is of paramount public health importance. Global health surveillance does not rely on genomic data alone to identify concerning variants when they emerge. Instead, methods that utilize genomic data to estimate the epidemiological dynamics of emerging lineages have the potential to serve as an early warning system. However, these methods assume that genomic data are uniformly reported across circulating lineages. In this study, we analyze differences in reporting delays among SARS-CoV-2 VOCs as a plausible explanation for the timing of the global response to the former VOC Mu. Mu likely emerged in South America in mid-2020, where its circulation was largely confined. In this study, we demonstrate that Mu was designated as a VOC ∼1 year after it emerged and find that the reporting of genomic data for Mu differed significantly than that of other VOCs within countries, states, and individual laboratories. Our findings suggest that nonsystematic biases in the reporting of genomic data may have delayed the global response to Mu. Until they are resolved, the surveillance gaps that affected the global response to Mu could impede the rapid and accurate assessment of future emerging variants., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)
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- 2023
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7. How the Commonwealth of the Northern Mariana Islands stalled COVID-19 for 22 months and managed its first significant community transmission.
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Davis D, Kern-Allely S, Muldoon L, Tudela JM, Tudela J, Raho R, Pangelinan HS, Palacios H, Tabaguel J, Hinson A, Lifoifoi G, Villagomez W, Fauver JR, Cash HL, Muña E, Casey ST, and Khan AS
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- Humans, Micronesia epidemiology, Pacific Islands, Vaccination, Vaccination Coverage, COVID-19
- Abstract
Objective: The Commonwealth of the Northern Mariana Islands (CNMI) is a remote Pacific island territory with a population of 47 329 that successfully prevented the significant introduction of coronavirus disease (COVID-19) until late 2021. This study documents how the response to the introduction of COVID-19 in CNMI in 2021 was conducted with limited resources without overwhelming local clinical capacity or compromising health service delivery for the population., Methods: Data from COVID-19 case investigations, contact tracing, the Commonwealth's immunization registry and whole genome sequencing were collated and analysed as part of this study., Results: Between 26 March 2020 and 31 December 2021, 3281 cases and 14 deaths due to COVID-19 were reported in CNMI (case fatality rate, 0.4%). While notification rates were highest among younger age groups, hospitalization and mortality rates were disproportionately greater among those aged > 50 years and among the unvaccinated. The first widespread community transmission in CNMI was detected in October 2021, with genomic epidemiology and contact tracing data indicating a single introduction event involving the AY.25 lineage and subsequent rapid community spread. Vaccination coverage was high before widespread transmission occurred in October 2021 and increased further over the study period., Discussion: Robust preparedness and strong leadership generated resilience within the public health sector such that COVID-19 did not overwhelm CNMI's health system as it did in other jurisdictions and countries around the world. At no point was hospital capacity exceeded, and all patients received adequate care without the need for health-care rationing., Competing Interests: The authors have no conflicts of interest to declare., ((c) 2023 The authors; licensee World Health Organization.)
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- 2023
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8. Nasal host response-based screening for undiagnosed respiratory viruses: a pathogen surveillance and detection study.
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Cheemarla NR, Hanron A, Fauver JR, Bishai J, Watkins TA, Brito AF, Zhao D, Alpert T, Vogels CBF, Ko AI, Schulz WL, Landry ML, Grubaugh ND, van Dijk D, and Foxman EF
- Subjects
- United States, Humans, SARS-CoV-2 genetics, Multiplex Polymerase Chain Reaction, RNA, COVID-19 diagnosis, COVID-19 epidemiology, Viruses genetics
- Abstract
Background: Symptomatic patients who test negative for common viruses are an important possible source of unrecognised or emerging pathogens, but metagenomic sequencing of all samples is inefficient because of the low likelihood of finding a pathogen in any given sample. We aimed to determine whether nasopharyngeal CXCL10 screening could be used as a strategy to enrich for samples containing undiagnosed viruses., Methods: In this pathogen surveillance and detection study, we measured CXCL10 concentrations from nasopharyngeal swabs from patients in the Yale New Haven health-care system, which had been tested at the Yale New Haven Hospital Clinical Virology Laboratory (New Haven, CT, USA). Patients who tested negative for a panel of respiratory viruses using multiplex PCR during Jan 23-29, 2017, or March 3-14, 2020, were included. We performed host and pathogen RNA sequencing (RNA-Seq) and analysis for viral reads on samples with CXCL10 higher than 1 ng/mL or CXCL10 testing and quantitative RT-PCR (RT-qPCR) for SARS-CoV-2. We used RNA-Seq and cytokine profiling to compare the host response to infection in samples that were virus positive (rhinovirus, seasonal coronavirus CoV-NL63, or SARS-CoV-2) and virus negative (controls)., Findings: During Jan 23-29, 2017, 359 samples were tested for ten viruses on the multiplex PCR respiratory virus panel (RVP). 251 (70%) were RVP negative. 60 (24%) of 251 samples had CXCL10 higher than 150 pg/mL and were identified for further analysis. 28 (47%) of 60 CXCL10-high samples were positive for seasonal coronaviruses. 223 (89%) of 251 samples were PCR negative for 15 viruses and, of these, CXCL10-based screening identified 32 (13%) samples for further analysis. Of these 32 samples, eight (25%) with CXCL10 concentrations higher than 1 ng/mL and sufficient RNA were selected for RNA-Seq. Microbial RNA analysis showed the presence of influenza C virus in one sample and revealed RNA reads from bacterial pathobionts in four (50%) of eight samples. Between March 3 and March 14, 2020, 375 (59%) of 641 samples tested negative for 15 viruses on the RVP. 32 (9%) of 375 samples had CXCL10 concentrations ranging from 100 pg/mL to 1000 pg/mL and four of those were positive for SARS-CoV-2. CXCL10 elevation was statistically significant, and a distinguishing feature was found in 28 (8%) of 375 SARS-CoV-2-negative samples versus all four SARS-CoV-2-positive samples (p=4·4 × 10
-5 ). Transcriptomic signatures showed an interferon response in virus-positive samples and an additional neutrophil-high hyperinflammatory signature in samples with high amounts of bacterial pathobionts. The CXCL10 cutoff for detecting a virus was 166·5 pg/mL for optimal sensitivity and 1091·0 pg/mL for specificity using a clinic-ready automated microfluidics-based immunoassay., Interpretation: These results confirm CXCL10 as a robust nasopharyngeal biomarker of viral respiratory infection and support host response-based screening followed by metagenomic sequencing of CXCL10-high samples as a practical approach to incorporate clinical samples into pathogen discovery and surveillance efforts., Funding: National Institutes of Health, the Hartwell Foundation, the Gruber Foundation, Fast Grants for COVID-19 research from the Mercatus Center, and the Huffman Family Donor Advised Fund., Competing Interests: Declaration of interests EFF is an inventor on a pending patent application (WO2019/217296 A1) and provisional patent application (63/293386). EFF and MLL are inventors on a pending patent application (WO2018/071498 A1). NDG is a paid consultant for Tempus Labs and the National Basketball Association for infectious disease genomics. WLS is a consultant for Hugo Health; cofounder of Refacto Health; and received funds from Merck, Regeneron, the Shenzen Center for Health Information, and the Beijing National Center for Cardiac Diseases. AIK received funding from Merck, Regeneron, and the Reckitt Global Hygiene Institute. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2023
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9. Quantifying the impact of immune history and variant on SARS-CoV-2 viral kinetics and infection rebound: A retrospective cohort study.
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Hay JA, Kissler SM, Fauver JR, Mack C, Tai CG, Samant RM, Connolly S, Anderson DJ, Khullar G, MacKay M, Patel M, Kelly S, Manhertz A, Eiter I, Salgado D, Baker T, Howard B, Dudley JT, Mason CE, Nair M, Huang Y, DiFiori J, Ho DD, Grubaugh ND, and Grad YH
- Subjects
- Humans, Aged, SARS-CoV-2 genetics, RNA, Viral, Retrospective Studies, Antibodies, Viral, COVID-19 epidemiology, Dermatitis
- Abstract
Background: The combined impact of immunity and SARS-CoV-2 variants on viral kinetics during infections has been unclear., Methods: We characterized 1,280 infections from the National Basketball Association occupational health cohort identified between June 2020 and January 2022 using serial RT-qPCR testing. Logistic regression and semi-mechanistic viral RNA kinetics models were used to quantify the effect of age, variant, symptom status, infection history, vaccination status and antibody titer to the founder SARS-CoV-2 strain on the duration of potential infectiousness and overall viral kinetics. The frequency of viral rebounds was quantified under multiple cycle threshold (Ct) value-based definitions., Results: Among individuals detected partway through their infection, 51.0% (95% credible interval [CrI]: 48.3-53.6%) remained potentially infectious (Ct <30) 5 days post detection, with small differences across variants and vaccination status. Only seven viral rebounds (0.7%; N=999) were observed, with rebound defined as 3+days with Ct <30 following an initial clearance of 3+days with Ct ≥30. High antibody titers against the founder SARS-CoV-2 strain predicted lower peak viral loads and shorter durations of infection. Among Omicron BA.1 infections, boosted individuals had lower pre-booster antibody titers and longer clearance times than non-boosted individuals., Conclusions: SARS-CoV-2 viral kinetics are partly determined by immunity and variant but dominated by individual-level variation. Since booster vaccination protects against infection, longer clearance times for BA.1-infected, boosted individuals may reflect a less effective immune response, more common in older individuals, that increases infection risk and reduces viral RNA clearance rate. The shifting landscape of viral kinetics underscores the need for continued monitoring to optimize isolation policies and to contextualize the health impacts of therapeutics and vaccines., Funding: Supported in part by CDC contract #200-2016-91779, a sponsored research agreement to Yale University from the National Basketball Association contract #21-003529, and the National Basketball Players Association., Competing Interests: JH, MN, YH, DH No competing interests declared, SK SMK has a consulting agreement with the NBA, JF, NG has a consulting agreement for Tempus and receives financial support from Tempus to develop SARS-CoV-2 diagnostic tests, CM, CT, RS, SC is an employee of IQVIA, Real World Solutions, DA is co-owner of Infection Control Education for Major Sports, GK, MM, MP, SK, AM, IE, DS, TB, BH, JD, CM is an employee of Tempus Labs, JD is an employee of the NBA, YG has a consulting agreement with the NBA, (© 2022, Hay, Kissler, Fauver et al.)
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- 2022
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10. Lineage abundance estimation for SARS-CoV-2 in wastewater using transcriptome quantification techniques.
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Baaijens JA, Zulli A, Ott IM, Nika I, van der Lugt MJ, Petrone ME, Alpert T, Fauver JR, Kalinich CC, Vogels CBF, Breban MI, Duvallet C, McElroy KA, Ghaeli N, Imakaev M, Mckenzie-Bennett MF, Robison K, Plocik A, Schilling R, Pierson M, Littlefield R, Spencer ML, Simen BB, Hanage WP, Grubaugh ND, Peccia J, and Baym M
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- Humans, Wastewater, RNA, Viral genetics, Transcriptome, SARS-CoV-2 genetics, COVID-19
- Abstract
Effectively monitoring the spread of SARS-CoV-2 mutants is essential to efforts to counter the ongoing pandemic. Predicting lineage abundance from wastewater, however, is technically challenging. We show that by sequencing SARS-CoV-2 RNA in wastewater and applying algorithms initially used for transcriptome quantification, we can estimate lineage abundance in wastewater samples. We find high variability in signal among individual samples, but the overall trends match those observed from sequencing clinical samples. Thus, while clinical sequencing remains a more sensitive technique for population surveillance, wastewater sequencing can be used to monitor trends in mutant prevalence in situations where clinical sequencing is unavailable., (© 2022. The Author(s).)
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- 2022
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11. Rapid emergence of SARS-CoV-2 Omicron variant is associated with an infection advantage over Delta in vaccinated persons.
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Chaguza C, Coppi A, Earnest R, Ferguson D, Kerantzas N, Warner F, Young HP, Breban MI, Billig K, Koch RT, Pham K, Kalinich CC, Ott IM, Fauver JR, Hahn AM, Tikhonova IR, Castaldi C, De Kumar B, Pettker CM, Warren JL, Weinberger DM, Landry ML, Peaper DR, Schulz W, Vogels CBF, and Grubaugh ND
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- COVID-19 Vaccines, Hospitalization, Humans, COVID-19 epidemiology, SARS-CoV-2 genetics
- 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)., Competing Interests: N.D.G. is a consultant for Tempus Labs and the National Basketball Association for work related to COVID-19 but is outside the submitted work. All other authors declare no competing interests., (© 2022 Elsevier Inc.)
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- 2022
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12. Combining genomic and epidemiological data to compare the transmissibility of SARS-CoV-2 variants Alpha and Iota.
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Petrone ME, Rothman JE, Breban MI, Ott IM, Russell A, Lasek-Nesselquist E, Badr H, Kelly K, Omerza G, Renzette N, Watkins AE, Kalinich CC, Alpert T, Brito AF, Earnest R, Tikhonova IR, Castaldi C, Kelly JP, Shudt M, Plitnick J, Schneider E, Murphy S, Neal C, Laszlo E, Altajar A, Pearson C, Muyombwe A, Downing R, Razeq J, Niccolai L, Wilson MS, Anderson ML, Wang J, Liu C, Hui P, Mane S, Taylor BP, Hanage WP, Landry ML, Peaper DR, Bilguvar K, Fauver JR, Vogels CBF, Gardner LM, Pitzer VE, St George K, Adams MD, and Grubaugh ND
- Subjects
- Genomics, Humans, Pandemics, United States epidemiology, COVID-19 epidemiology, SARS-CoV-2 genetics
- 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 (R
t ) 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., (© 2022. The Author(s).)- Published
- 2022
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13. Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection: A Case Series From a 12-Month Longitudinal Occupational Cohort.
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Mack CD, Tai C, Sikka R, Grad YH, Maragakis LL, Grubaugh ND, Anderson DJ, Ho D, Merson M, Samant RM, Fauver JR, Barrett J, Sims L, and DiFiori J
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- Humans, Reinfection, Research, COVID-19, SARS-CoV-2
- Abstract
Findings are described in 7 patients with severe acute respiratory syndrome coronavirus 2 reinfection from the National Basketball Association 2020-2021 occupational testing cohort, including clinical details, antibody test results, genomic sequencing, and longitudinal reverse-transcription polymerase chain reaction results. Reinfections were infrequent and varied in clinical presentation, viral dynamics, and immune response., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)
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- 2022
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14. Insights into the limited global spread of the immune evasive SARS-CoV-2 variant Mu.
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Petrone ME, Lucas C, Menasche B, Breban MI, Yildirim I, Campbell M, Omer SB, Ko AI, Grubaugh ND, Iwasak A, Wilen CB, Vogels CBF, and Fauver JR
- Abstract
SARS-CoV-2 'Variants of Concern' (VOCs) continue to reshape the trajectory of the COVID-19 pandemic. However, why some VOCs, like Omicron, become globally dominant while the spread of others is limited is not fully understood. To address this question, we investigated the VOC Mu, which was first identified in Colombia in late 2020. Our study demonstrates that, although Mu is less sensitive to neutralization compared to variants that preceded it, it did not spread significantly outside of South and Central America. Additionally, we find evidence that the response to Mu was impeded by reporting delays and gaps in the global genomic surveillance system. Our findings suggest that immune evasion alone was not sufficient to outcompete highly transmissible variants that were circulating concurrently with Mu. Insights into the complex relationship between genomic and epidemiological characteristics of previous variants should inform our response to variants that are likely to emerge in the future., Competing Interests: CONFLICTS OF INTEREST NDG and JRF are paid consultants for Tempus Labs, and NDG is a paid consultant for the National Basketball Association for work related to COVID-19 but is outside the submitted work. IY reported being a member of the mRNA-1273 Study Group and has received funding to her institution to conduct clinical research from Pfizer and Moderna outside the submitted work.
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- 2022
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15. Comparative transmissibility of SARS-CoV-2 variants Delta and Alpha in New England, USA.
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Earnest R, Uddin R, Matluk N, Renzette N, Turbett SE, Siddle KJ, Loreth C, Adams G, Tomkins-Tinch CH, Petrone ME, Rothman JE, Breban MI, Koch RT, Billig K, Fauver JR, Vogels CBF, Bilguvar K, De Kumar B, Landry ML, Peaper DR, Kelly K, Omerza G, Grieser H, Meak S, Martha J, Dewey HB, Kales S, Berenzy D, Carpenter-Azevedo K, King E, Huard RC, Novitsky V, Howison M, Darpolor J, Manne A, Kantor R, Smole SC, Brown CM, Fink T, Lang AS, Gallagher GR, Pitzer VE, Sabeti PC, Gabriel S, MacInnis BL, Tewhey R, Adams MD, Park DJ, Lemieux JE, and Grubaugh ND
- Subjects
- Humans, New England epidemiology, Public Health, COVID-19 epidemiology, SARS-CoV-2 genetics
- 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., Competing Interests: N.D.G. is a paid consultant for Tempus Labs and the National Basketball Association and has received speaking fees from Goldman Sachs. P.C.S. is a co-founder of, shareholder in, and scientific advisor to Sherlock Biosciences, Inc., as well as a board member of and shareholder in Danaher Corporation. The remaining authors declare no competing interests., (© 2022 The Authors.)
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- 2022
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16. Longitudinal Immune Profiling of a Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection in a Solid Organ Transplant Recipient.
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Klein J, Brito AF, Trubin P, Lu P, Wong P, Alpert T, Peña-Hernández MA, Haynes W, Kamath K, Liu F, Vogels CBF, Fauver JR, Lucas C, Oh J, Mao T, Silva J, Wyllie AL, Muenker MC, Casanovas-Massana A, Moore AJ, Petrone ME, Kalinich CC, Dela Cruz C, Farhadian S, Ring A, Shon J, Ko AI, Grubaugh ND, Israelow B, Iwasaki A, and Azar MM
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- Aged, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Humans, Male, Organ Transplantation, Phylogeny, SARS-CoV-2 genetics, COVID-19 immunology, Reinfection immunology, Reinfection virology, Transplant Recipients
- Abstract
Background: The underlying immunologic deficiencies enabling severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection are currently unknown. We describe deep longitudinal immune profiling of a transplant recipient hospitalized twice for coronavirus disease 2019 (COVID-19)., Methods: A 66-year-old male renal transplant recipient was hospitalized with COVID-19 March 2020 then readmitted to the hospital with COVID-19 233 days after initial diagnosis. Virologic and immunologic investigations were performed on samples from the primary and secondary infections., Results: Whole viral genome sequencing and phylogenetic analysis revealed that viruses causing both infections were caused by distinct genetic lineages without evidence of immune escape mutations. Longitudinal comparison of cellular and humoral responses during primary SARS-CoV-2 infection revealed that this patient responded to the primary infection with low neutralization titer anti-SARS-CoV-2 antibodies that were likely present at the time of reinfection., Conclusions: The development of neutralizing antibodies and humoral memory responses in this patient failed to confer protection against reinfection, suggesting that they were below a neutralizing titer threshold or that additional factors may be required for efficient prevention of SARS-CoV-2 reinfection. Development of poorly neutralizing antibodies may have been due to profound and relatively specific reduction in naive CD4 T-cell pools. Seropositivity alone may not be a perfect correlate of protection in immunocompromised patients., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
- Published
- 2022
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17. Sequencing SARS-CoV-2 genomes from saliva.
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Alpert T, Vogels CBF, Breban MI, Petrone ME, Wyllie AL, Grubaugh ND, and Fauver JR
- 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., (© The Author(s) 2022. Published by Oxford University Press.)
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- 2022
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18. Viral Dynamics of SARS-CoV-2 Variants in Vaccinated and Unvaccinated Persons.
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Kissler SM, Fauver JR, Mack C, Tai CG, Breban MI, Watkins AE, Samant RM, Anderson DJ, Metti J, Khullar G, Baits R, MacKay M, Salgado D, Baker T, Dudley JT, Mason CE, Ho DD, Grubaugh ND, and Grad YH
- Subjects
- Bayes Theorem, Humans, SARS-CoV-2 isolation & purification, Vaccination, COVID-19 virology, COVID-19 Vaccines, SARS-CoV-2 physiology, Viral Load
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- 2021
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19. COVID-19 Outcomes and Genomic Characterization of SARS-CoV-2 Isolated From Veterans in New England States: Retrospective Analysis.
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Lee M, Sallah YH, Petrone M, Ringer M, Cosentino D, Vogels CBF, Fauver JR, Alpert TD, Grubaugh ND, and Gupta S
- Abstract
Background: Clinical and virologic characteristics of COVID-19 infections in veterans in New England have not been described. The average US veteran is a male older than the general US population. SARS-CoV-2 infection is known to cause poorer outcomes among men and older adults, making the veteran population an especially vulnerable group for COVID-19., Objective: This study aims to evaluate clinical and virologic factors impacting COVID-19 outcomes., Methods: This retrospective chart review included 476 veterans in six New England states with confirmed SARS-CoV-2 infection between April and September 2020. Whole genome sequencing was performed on SARS-CoV-2 RNA isolated from these veterans, and the correlation of genomic data to clinical outcomes was evaluated. Clinical and demographic variables were collected by manual chart review and were correlated to the end points of peak disease severity (based on oxygenation requirements), hospitalization, and mortality using multivariate regression analyses., Results: Of 476 veterans, 274 had complete and accessible charts. Of the 274 veterans, 92.7% (n=254) were men and 83.2% (n=228) were White, and the mean age was 63 years. In the multivariate regression, significant predictors of hospitalization (C statistic 0.75) were age (odds ratio [OR] 1.05, 95% CI 1.03-1.08) and non-White race (OR 2.39, 95% CI 1.13-5.01). Peak severity (C statistic 0.70) also varied by age (OR 1.07, 95% CI 1.03-1.11) and O2 requirement on admission (OR 45.7, 95% CI 18.79-111). Mortality (C statistic 0.87) was predicted by age (OR 1.06, 95% CI 1.01-1.11), dementia (OR 3.44, 95% CI 1.07-11.1), and O2 requirement on admission (OR 6.74, 95% CI 1.74-26.1). Most (291/299, 97.3%) of our samples were dominated by the spike protein D614G substitution and were from SARS-CoV-2 B.1 lineage or one of 37 different B.1 sublineages, with none representing more than 8.7% (26/299) of the cases., Conclusions: In a cohort of veterans from the six New England states with a mean age of 63 years and a high comorbidity burden, age was the largest predictor of hospitalization, peak disease severity, and mortality. Non-White veterans were more likely to be hospitalized, and patients who required oxygen on admission were more likely to have severe disease and higher rates of mortality. Multiple SARS-CoV-2 lineages were distributed in patients in New England early in the COVID-19 era, mostly related to viruses from New York State with D614G mutation., Competing Interests: Conflicts of Interest: NDG is a paid consultant of Tempus Labs for infectious disease genomics., (©Megan Lee, Ya Haddy Sallah, Mary Petrone, Matthew Ringer, Danielle Cosentino, Chantal B F Vogels, Joseph R Fauver, Tara D Alpert, Nathan D Grubaugh, Shaili Gupta. Originally published in JMIRx Med (https://med.jmirx.org), 17.12.2021.)
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- 2021
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20. Impact of circulating SARS-CoV-2 variants on mRNA vaccine-induced immunity.
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Lucas C, Vogels CBF, Yildirim I, Rothman JE, Lu P, Monteiro V, Gehlhausen JR, Campbell M, Silva J, Tabachnikova A, Peña-Hernandez MA, Muenker MC, Breban MI, Fauver JR, Mohanty S, Huang J, Shaw AC, Ko AI, Omer SB, Grubaugh ND, and Iwasaki A
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- 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, Antibodies, Viral immunology, COVID-19 epidemiology, COVID-19 virology, SARS-CoV-2 immunology, T-Lymphocytes immunology, Vaccines, Synthetic immunology, mRNA Vaccines immunology
- Abstract
The emergence of SARS-CoV-2 variants with mutations in major neutralizing antibody-binding sites can affect humoral immunity induced by infection or vaccination
1-6 . 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., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2021
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21. Impact of extrinsic incubation temperature on natural selection during Zika virus infection of Aedes aegypti and Aedes albopictus.
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Murrieta RA, Garcia-Luna SM, Murrieta DJ, Halladay G, Young MC, Fauver JR, Gendernalik A, Weger-Lucarelli J, Rückert C, and Ebel GD
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- Aedes classification, Aedes genetics, Animals, Chlorocebus aethiops, Saliva virology, Vero Cells, Viral Load, Zika Virus Infection virology, Aedes virology, Genetic Fitness, Mosquito Vectors virology, Selection, Genetic, Temperature, Zika Virus growth & development, Zika Virus Infection transmission
- Abstract
Arthropod-borne viruses (arboviruses) require replication across a wide range of temperatures to perpetuate. While vertebrate hosts tend to maintain temperatures of approximately 37°C-40°C, arthropods are subject to ambient temperatures which can have a daily fluctuation of > 10°C. Temperatures impact vector competence, extrinsic incubation period, and mosquito survival unimodally, with optimal conditions occurring at some intermediate temperature. In addition, the mean and range of daily temperature fluctuations influence arbovirus perpetuation and vector competence. The impact of temperature on arbovirus genetic diversity during systemic mosquito infection, however, is poorly understood. Therefore, we determined how constant extrinsic incubation temperatures of 25°C, 28°C, 32°C, and 35°C control Zika virus (ZIKV) vector competence and population dynamics within Aedes aegypti and Aedes albopictus mosquitoes. We also examined fluctuating temperatures which better mimic field conditions in the tropics. We found that vector competence varied in a unimodal manner for constant temperatures peaking between 28°C and 32°C for both Aedes species. Transmission peaked at 10 days post-infection for Aedes aegypti and 14 days for Aedes albopictus. Conversely, fluctuating temperature decreased vector competence. Using RNA-seq to characterize ZIKV population structure, we identified that temperature alters the selective environment in unexpected ways. During mosquito infection, constant temperatures more often elicited positive selection whereas fluctuating temperatures led to strong purifying selection in both Aedes species. These findings demonstrate that temperature has multiple impacts on ZIKV biology, including major effects on the selective environment within mosquitoes., Competing Interests: The authors have declared that no competing interests exist.
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- 2021
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22. Tracing the Origin, Spread, and Molecular Evolution of Zika Virus in Puerto Rico, 2016-2017.
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Santiago GA, Kalinich CC, Cruz-López F, González GL, Flores B, Hentoff A, Charriez KN, Fauver JR, Adams LE, Sharp TM, Black A, Bedford T, Ellis E, Ellis B, Waterman SH, Paz-Bailey G, Grubaugh ND, and Muñoz-Jordán JL
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- Evolution, Molecular, Humans, Puerto Rico epidemiology, Epidemics, Zika Virus genetics, Zika Virus Infection epidemiology
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We reconstructed the 2016-2017 Zika virus epidemic in Puerto Rico by using complete genomes to uncover the epidemic's origin, spread, and evolutionary dynamics. Our study revealed that the epidemic was propelled by multiple introductions that spread across the island, intricate evolutionary patterns, and ≈10 months of cryptic transmission.
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- 2021
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23. Comparative transmissibility of SARS-CoV-2 variants Delta and Alpha in New England, USA.
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Earnest R, Uddin R, Matluk N, Renzette N, Siddle KJ, Loreth C, Adams G, Tomkins-Tinch CH, Petrone ME, Rothman JE, Breban MI, Koch RT, Billig K, Fauver JR, Vogels CBF, Turbett S, Bilguvar K, De Kumar B, Landry ML, Peaper DR, Kelly K, Omerza G, Grieser H, Meak S, Martha J, Dewey HH, Kales S, Berenzy D, Carpenter-Azevedo K, King E, Huard RC, Smole SC, Brown CM, Fink T, Lang AS, Gallagher GR, Sabeti PC, Gabriel S, MacInnis BL, Tewhey R, Adams MD, Park DJ, Lemieux JE, and Grubaugh ND
- Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant quickly rose to dominance in mid-2021, displacing other variants, including Alpha. Studies using data from the United Kingdom and India estimated that Delta was 40-80% more transmissible than Alpha, allowing Delta to become the globally dominant variant. However, it was unclear if the ostensible difference in relative transmissibility was due mostly to innate properties of Delta's infectiousness or differences in the study populations. To investigate, we formed a partnership with SARS-CoV-2 genomic surveillance programs from all six New England US states. By comparing logistic growth rates, we found that Delta emerged 37-163% faster than Alpha in early 2021 (37% Massachusetts, 75% New Hampshire, 95% Maine, 98% Rhode Island, 151% Connecticut, and 163% Vermont). We next computed variant-specific effective reproductive numbers and estimated that Delta was 58-120% more transmissible than Alpha across New England (58% New Hampshire, 68% Massachusetts, 76% Connecticut, 85% Rhode Island, 98% Maine, and 120% Vermont). Finally, using RT-PCR data, we estimated that Delta infections generate on average ∼6 times more viral RNA copies per mL than Alpha infections. Overall, our evidence indicates that Delta's enhanced transmissibility could be attributed to its innate ability to increase infectiousness, but its epidemiological dynamics may vary depending on the underlying immunity and behavior of distinct populations.
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- 2021
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24. Variant abundance estimation for SARS-CoV-2 in wastewater using RNA-Seq quantification.
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Baaijens JA, Zulli A, Ott IM, Petrone ME, Alpert T, Fauver JR, Kalinich CC, Vogels CBF, Breban MI, Duvallet C, McElroy K, Ghaeli N, Imakaev M, Mckenzie-Bennett M, Robison K, Plocik A, Schilling R, Pierson M, Littlefield R, Spencer M, Simen BB, Hanage WP, Grubaugh ND, Peccia J, and Baym M
- Abstract
Effectively monitoring the spread of SARS-CoV-2 variants is essential to efforts to counter the ongoing pandemic. Wastewater monitoring of SARS-CoV-2 RNA has proven an effective and efficient technique to approximate COVID-19 case rates in the population. Predicting variant abundances from wastewater, however, is technically challenging. Here we show that by sequencing SARS-CoV-2 RNA in wastewater and applying computational techniques initially used for RNA-Seq quantification, we can estimate the abundance of variants in wastewater samples. We show by sequencing samples from wastewater and clinical isolates in Connecticut U.S.A. between January and April 2021 that the temporal dynamics of variant strains broadly correspond. We further show that this technique can be used with other wastewater sequencing techniques by expanding to samples taken across the United States in a similar timeframe. We find high variability in signal among individual samples, and limited ability to detect the presence of variants with clinical frequencies <10%; nevertheless, the overall trends match what we observed from sequencing clinical samples. Thus, while clinical sequencing remains a more sensitive technique for population surveillance, wastewater sequencing can be used to monitor trends in variant prevalence in situations where clinical sequencing is unavailable or impractical.
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- 2021
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25. Viral dynamics of acute SARS-CoV-2 infection and applications to diagnostic and public health strategies.
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Kissler SM, Fauver JR, Mack C, Olesen SW, Tai C, Shiue KY, Kalinich CC, Jednak S, Ott IM, Vogels CBF, Wohlgemuth J, Weisberger J, DiFiori J, Anderson DJ, Mancell J, Ho DD, Grubaugh ND, and Grad YH
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- Adult, Athletes, Basketball, COVID-19 epidemiology, COVID-19 pathology, COVID-19 virology, Convalescence, Humans, Male, Prospective Studies, Public Health methods, SARS-CoV-2 growth & development, Severity of Illness Index, United States epidemiology, COVID-19 diagnosis, COVID-19 Nucleic Acid Testing statistics & numerical data, RNA, Viral genetics, SARS-CoV-2 genetics, Virus Replication genetics, Virus Shedding genetics
- Abstract
SARS-CoV-2 infections are characterized by viral proliferation and clearance phases and can be followed by low-level persistent viral RNA shedding. The dynamics of viral RNA concentration, particularly in the early stages of infection, can inform clinical measures and interventions such as test-based screening. We used prospective longitudinal quantitative reverse transcription PCR testing to measure the viral RNA trajectories for 68 individuals during the resumption of the 2019-2020 National Basketball Association season. For 46 individuals with acute infections, we inferred the peak viral concentration and the duration of the viral proliferation and clearance phases. According to our mathematical model, we found that viral RNA concentrations peaked an average of 3.3 days (95% credible interval [CI] 2.5, 4.2) after first possible detectability at a cycle threshold value of 22.3 (95% CI 20.5, 23.9). The viral clearance phase lasted longer for symptomatic individuals (10.9 days [95% CI 7.9, 14.4]) than for asymptomatic individuals (7.8 days [95% CI 6.1, 9.7]). A second test within 2 days after an initial positive PCR test substantially improves certainty about a patient's infection stage. The effective sensitivity of a test intended to identify infectious individuals declines substantially with test turnaround time. These findings indicate that SARS-CoV-2 viral concentrations peak rapidly regardless of symptoms. Sequential tests can help reveal a patient's progress through infection stages. Frequent, rapid-turnaround testing is needed to effectively screen individuals before they become infectious., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JW is an employee of Quest Diagnostics. JW is an employee of Bioreference Laboratories. NDG has a consulting agreement for Tempus and receives financial support from Tempus to develop SARS-CoV-2 diagnostic tests. SMK, SWO, and YHG have a consulting agreement with the NBA.
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- 2021
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26. Combining genomic and epidemiological data to compare the transmissibility of SARS-CoV-2 lineages.
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Petrone ME, Rothman JE, Breban MI, Ott IM, Russell A, Lasek-Nesselquist E, Kelly K, Omerza G, Renzette N, Watkins AE, Kalinich CC, Alpert T, Brito AF, Earnest R, Tikhonova IR, Castaldi C, Kelly JP, Shudt M, Plitnick J, Schneider E, Murphy S, Neal C, Laszlo E, Altajar A, Pearson C, Muyombwe A, Downing R, Razeq J, Niccolai L, Wilson MS, Anderson ML, Wang J, Liu C, Hui P, Mane S, Taylor BP, Hanage WP, Landry ML, Peaper DR, Bilguvar K, Fauver JR, Vogels CBF, Gardner LM, Pitzer VE, St George K, Adams MD, and Grubaugh ND
- Abstract
Emerging SARS-CoV-2 variants have shaped the second year of the COVID-19 pandemic and the public health discourse around effective control measures. Evaluating the public health threat posed by a new variant is essential for appropriately adapting response efforts when community transmission is detected. However, this assessment requires that a true comparison can be made between the new variant and its predecessors because factors other than the virus genotype may influence spread and transmission. In this study, we develop a framework that integrates genomic surveillance data to estimate the relative effective reproduction number (R
t ) of co-circulating lineages. We use Connecticut, a state in the northeastern United States in which the SARS-CoV-2 variants B.1.1.7 and B.1.526 co-circulated in early 2021, as a case study for implementing this framework. We find that the Rt of B.1.1.7 was 6-10% larger than that of B.1.526 in Connecticut in the midst of a COVID-19 vaccination campaign. To assess the generalizability of this framework, we apply it to genomic surveillance data from New York City and observe the same trend. Finally, we use discrete phylogeography to demonstrate that while both variants were introduced into Connecticut at comparable frequencies, clades that resulted from introductions of B.1.1.7 were larger than those resulting from B.1.526 introductions. Our framework, which uses open-source methods requiring minimal computational resources, may be used to monitor near real-time variant dynamics in a myriad of settings.- Published
- 2021
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27. Isolation and characterization of a novel bacteriophage WO from Allonemobius socius crickets in Missouri.
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Kupritz J, Martin J, Fischer K, Curtis KC, Fauver JR, Huang Y, Choi YJ, Beatty WL, Mitreva M, and Fischer PU
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- Animals, Bacteriophages classification, Bacteriophages isolation & purification, Capsid Proteins genetics, DNA, Bacterial chemistry, DNA, Bacterial metabolism, DNA, Viral chemistry, DNA, Viral metabolism, Female, Gryllidae virology, Membrane Proteins genetics, Missouri, Open Reading Frames genetics, Phylogeny, Whole Genome Sequencing, Wolbachia genetics, Wolbachia isolation & purification, Wolbachia virology, Bacteriophages genetics, Genome, Viral, Gryllidae microbiology
- Abstract
Wolbachia are endosymbionts of numerous arthropod and some nematode species, are important for their development and if present can cause distinct phenotypes of their hosts. Prophage DNA has been frequently detected in Wolbachia, but particles of Wolbachia bacteriophages (phage WO) have been only occasionally isolated. Here, we report the characterization and isolation of a phage WO of the southern ground cricket, Allonemobius socius, and provided the first whole-genome sequence of phage WO from this arthropod family outside of Asia. We screened A. socius abdomen DNA extracts from a cricket population in eastern Missouri by quantitative PCR for Wolbachia surface protein and phage WO capsid protein and found a prevalence of 55% and 50%, respectively, with many crickets positive for both. Immunohistochemistry using antibodies against Wolbachia surface protein showed many Wolbachia clusters in the reproductive system of female crickets. Whole-genome sequencing using Oxford Nanopore MinION and Illumina technology allowed for the assembly of a high-quality, 55 kb phage genome containing 63 open reading frames (ORF) encoding for phage WO structural proteins and host lysis and transcriptional manipulation. Taxonomically important regions of the assembled phage genome were validated by Sanger sequencing of PCR amplicons. Analysis of the nucleotides sequences of the ORFs encoding the large terminase subunit (ORF2) and minor capsid (ORF7) frequently used for phage WO phylogenetics showed highest homology to phage WOAu of Drosophila simulans (94.46% identity) and WOCin2USA1 of the cherry fruit fly, Rhagoletis cingulata (99.33% identity), respectively. Transmission electron microscopy examination of cricket ovaries showed a high density of phage particles within Wolbachia cells. Isolation of phage WO revealed particles characterized by 40-62 nm diameter heads and up to 190 nm long tails. This study provides the first detailed description and genomic characterization of phage WO from North America that is easily accessible in a widely distributed cricket species., Competing Interests: The authors have declared that no competing interests exist.
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- 2021
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28. Sequencing SARS-CoV-2 Genomes from Saliva.
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Alpert T, Vogels CBF, Breban MI, Petrone ME, Wyllie AL, Grubaugh ND, and Fauver JR
- Abstract
Genomic sequencing is crucial to understanding the epidemiology and evolution of SARS-CoV-2. Often, genomic studies rely on remnant diagnostic material, typically nasopharyngeal 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 nasopharyngeal 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.
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- 2021
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29. Early introductions and transmission of SARS-CoV-2 variant B.1.1.7 in the United States.
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Alpert T, Brito AF, Lasek-Nesselquist E, Rothman J, Valesano AL, MacKay MJ, Petrone ME, Breban MI, Watkins AE, Vogels CBF, Kalinich CC, Dellicour S, Russell A, Kelly JP, Shudt M, Plitnick J, Schneider E, Fitzsimmons WJ, Khullar G, Metti J, Dudley JT, Nash M, Beaubier N, Wang J, Liu C, Hui P, Muyombwe A, Downing R, Razeq J, Bart SM, Grills A, Morrison SM, Murphy S, Neal C, Laszlo E, Rennert H, Cushing M, Westblade L, Velu P, Craney A, Cong L, Peaper DR, Landry ML, Cook PW, Fauver JR, Mason CE, Lauring AS, St George K, MacCannell DR, and Grubaugh ND
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- Female, Humans, Male, United States epidemiology, COVID-19 genetics, COVID-19 mortality, COVID-19 transmission, COVID-19 Testing, Models, Biological, SARS-CoV-2 genetics, SARS-CoV-2 metabolism, SARS-CoV-2 pathogenicity
- 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., Competing Interests: Declarations of interests M.J.M., G.K., J.M., J.T.D., M.N., N.B., and C.E.M. work for Tempus Labs. K.S.G. receives research support from Thermo Fisher for the development of assays for the detection and characterization of viruses. The remaining authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2021
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30. Lying in wait: the resurgence of dengue virus after the Zika epidemic in Brazil.
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Brito AF, Machado LC, Oidtman RJ, Siconelli MJL, Tran QM, Fauver JR, Carvalho RDO, Dezordi FZ, Pereira MR, de Castro-Jorge LA, Minto ECM, Passos LMR, Kalinich CC, Petrone ME, Allen E, España GC, Huang AT, Cummings DAT, Baele G, Franca RFO, da Fonseca BAL, Perkins TA, Wallau GL, and Grubaugh ND
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- Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Viral immunology, Brazil epidemiology, Child, Child, Preschool, Dengue immunology, Dengue transmission, Dengue virology, Dengue Virus genetics, Dengue Virus isolation & purification, Epidemics prevention & control, Epidemiological Monitoring, Female, Genome, Viral genetics, Humans, Immunity, Heterologous, Incidence, Infant, Infant, Newborn, Male, Middle Aged, Molecular Typing, Mosquito Vectors virology, Phylogeography, Serotyping, Young Adult, Zika Virus immunology, Zika Virus Infection epidemiology, Dengue epidemiology, Dengue Virus immunology, Disease Susceptibility immunology, Epidemics statistics & numerical data, Zika Virus Infection immunology
- Abstract
After the Zika virus (ZIKV) epidemic in the Americas in 2016, both Zika and dengue incidence declined to record lows in many countries in 2017-2018, but in 2019 dengue resurged in Brazil, causing ~2.1 million cases. In this study we use epidemiological, climatological and genomic data to investigate dengue dynamics in recent years in Brazil. First, we estimate dengue virus force of infection (FOI) and model mosquito-borne transmission suitability since the early 2000s. Our estimates reveal that DENV transmission was low in 2017-2018, despite conditions being suitable for viral spread. Our study also shows a marked decline in dengue susceptibility between 2002 and 2019, which could explain the synchronous decline of dengue in the country, partially as a result of protective immunity from prior ZIKV and/or DENV infections. Furthermore, we performed phylogeographic analyses using 69 newly sequenced genomes of dengue virus serotype 1 and 2 from Brazil, and found that the outbreaks in 2018-2019 were caused by local DENV lineages that persisted for 5-10 years, circulating cryptically before and after the Zika epidemic. We hypothesize that DENV lineages may circulate at low transmission levels for many years, until local conditions are suitable for higher transmission, when they cause major outbreaks.
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- 2021
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31. Multiplex qPCR discriminates variants of concern to enhance global surveillance of SARS-CoV-2.
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Vogels CBF, Breban MI, Ott IM, Alpert T, Petrone ME, Watkins AE, Kalinich CC, Earnest R, Rothman JE, Goes de Jesus J, Morales Claro I, Magalhães Ferreira G, Crispim MAE, Singh L, Tegally H, Anyaneji UJ, Hodcroft EB, Mason CE, Khullar G, Metti J, Dudley JT, MacKay MJ, Nash M, Wang J, Liu C, Hui P, Murphy S, Neal C, Laszlo E, Landry ML, Muyombwe A, Downing R, Razeq J, de Oliveira T, Faria NR, Sabino EC, Neher RA, Fauver JR, and Grubaugh ND
- Subjects
- COVID-19 diagnosis, COVID-19 genetics, DNA Primers, Humans, Multiplex Polymerase Chain Reaction methods, Mutation, Polyproteins genetics, Viral Proteins genetics, COVID-19 virology, SARS-CoV-2 genetics
- 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., Competing Interests: The authors have declared that no competing interests exist.
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- 2021
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32. Case Study: Longitudinal immune profiling of a SARS-CoV-2 reinfection in a solid organ transplant recipient.
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Klein J, Brito AF, Trubin P, Lu P, Wong P, Alpert T, Peña-Hernández MA, Haynes W, Kamath K, Liu F, Vogels CBF, Fauver JR, Lucas C, Oh J, Mao T, Silva J, Wyllie AL, Muenker MC, Casanovas-Massana A, Moore AJ, Petrone ME, Kalinich CC, Cruz CD, Farhadian S, Ring A, Shon J, Ko AI, Grubaugh ND, Israelow B, Iwasaki A, and Azar MM
- Abstract
Prior to the emergence of antigenically distinct SARS-CoV-2 variants, reinfections were reported infrequently - presumably due to the generation of durable and protective immune responses. However, case reports also suggested that rare, repeated infections may occur as soon as 48 days following initial disease onset. The underlying immunologic deficiencies enabling SARS-CoV-2 reinfections are currently unknown. Here we describe a renal transplant recipient who developed recurrent, symptomatic SARS-CoV-2 infection - confirmed by whole virus genome sequencing - 7 months after primary infection. To elucidate the immunological mechanisms responsible for SARS-CoV-2 reinfection, we performed longitudinal profiling of cellular and humoral responses during both primary and recurrent SARS-CoV-2 infection. We found that the patient responded to the primary infection with transient, poor-quality adaptive immune responses. The patient's immune system was further compromised by intervening treatment for acute rejection of the renal allograft prior to reinfection. Importantly, we also identified the development of neutralizing antibodies and the formation of humoral memory responses prior to SARS-CoV-2 reinfection. However, these neutralizing antibodies failed to confer protection against reinfection, suggesting that additional factors are required for efficient prevention of SARS-CoV-2 reinfection. Further, we found no evidence supporting viral evasion of primary adaptive immune responses, suggesting that susceptibility to reinfection may be determined by host factors rather than pathogen adaptation in this patient. In summary, our study suggests that a low neutralizing antibody presence alone is not sufficient to confer resistance against reinfection. Thus, patients with solid organ transplantation, or patients who are otherwise immunosuppressed, who recover from infection with SARS-CoV-2 may not develop sufficient protective immunity and are at risk of reinfection.
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- 2021
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33. PCR assay to enhance global surveillance for SARS-CoV-2 variants of concern.
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Vogels CBF, Breban MI, Alpert T, Petrone ME, Watkins AE, Ott IM, de Jesus JG, Claro IM, Ferreira GM, Crispim MAE, Singh L, Tegally H, Anyaneji UJ, Hodcroft EB, Mason CE, Khullar G, Metti J, Dudley JT, MacKay MJ, Nash M, Wang J, Liu C, Hui P, Murphy S, Neal C, Laszlo E, Landry ML, Muyombwe A, Downing R, Razeq J, de Oliveira T, Faria NR, Sabino EC, Neher RA, Fauver JR, and Grubaugh ND
- Abstract
With the emergence of SARS-CoV-2 variants that may increase transmissibility and/or cause escape from immune responses
1-3 , 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 UK4,5 could be serendipitously detected by the ThermoFisher 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 that lack spike Δ69-70, such as B.1.351 (also 501Y.V2) detected in South Africa6 and P.1 (also 501Y.V3) recently detected in Brazil7 . We identified a deletion in the ORF1a gene (ORF1a Δ3675-3677) in all three 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 variants of concern8 . Our assay can be rapidly deployed in laboratories around the world to enhance surveillance for the local emergence spread of B.1.1.7, B.1.351, and P.1.- Published
- 2021
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34. SalivaDirect: A simplified and flexible platform to enhance SARS-CoV-2 testing capacity.
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Vogels CBF, Watkins AE, Harden CA, Brackney DE, Shafer J, Wang J, Caraballo C, Kalinich CC, Ott IM, Fauver JR, Kudo E, Lu P, Venkataraman A, Tokuyama M, Moore AJ, Muenker MC, Casanovas-Massana A, Fournier J, Bermejo S, Campbell M, Datta R, Nelson A, Dela Cruz CS, Ko AI, Iwasaki A, Krumholz HM, Matheus JD, Hui P, Liu C, Farhadian SF, Sikka R, Wyllie AL, and Grubaugh ND
- Subjects
- COVID-19 Testing, Humans, Laboratories, Saliva, COVID-19 diagnosis, SARS-CoV-2 genetics
- Abstract
Background: Scaling SARS-CoV-2 testing to meet demands of safe reopenings continues to be plagued by assay costs and supply chain shortages. In response, we developed SalivaDirect, which received Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration (FDA)., Methods: We simplified our saliva-based diagnostic test by (1) not requiring collection tubes with preservatives, (2) replacing nucleic acid extraction with a simple enzymatic and heating step, and (3) testing specimens with a dualplex qRT-PCR assay. Moreover, we validated SalivaDirect with reagents and instruments from multiple vendors to minimize supply chain issues., Findings: From our hospital cohort, we show a high positive agreement (94%) between saliva tested with SalivaDirect and nasopharyngeal swabs tested with a commercial qRT-PCR kit. In partnership with the National Basketball Association (NBA) and National Basketball Players Association (NBPA), we tested 3,779 saliva specimens from healthy individuals and detected low rates of invalid (0.3%) and false-positive (<0.05%) results., Conclusions: We demonstrate that saliva is a valid alternative to swabs for SARS-CoV-2 screening and that SalivaDirect can make large-scale testing more accessible and affordable. Uniquely, we can designate other laboratories to use our sensitive, flexible, and simplified platform under our EUA (https://publichealth.yale.edu/salivadirect/ )., Funding: This study was funded by the NBA and NBPA (N.D.G.), the Huffman Family Donor Advised Fund (N.D.G.), a Fast Grant from Emergent Ventures at the Mercatus Center at George Mason University (N.D.G.), the Yale Institute for Global Health (N.D.G.), and the Beatrice Kleinberg Neuwirth Fund (A.I.K.). C.B.F.V. is supported by NWO Rubicon 019.181EN.004., Competing Interests: A.L.W. has received research funding through grants from Pfizer to Yale and has received consulting fees for participation in advisory boards for Pfizer. N.D.G. and A.L.W. have received research funding from Tempus to Yale to develop future versions of SalivaDirect. The remaining authors declare no competing interests., (© 2020 Elsevier Inc.)
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- 2021
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35. Early introductions and community transmission of SARS-CoV-2 variant B.1.1.7 in the United States.
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Alpert T, Brito AF, Lasek-Nesselquist E, Rothman J, Valesano AL, MacKay MJ, Petrone ME, Breban MI, Watkins AE, Vogels CBF, Kalinich CC, Dellicour S, Russell A, Kelly JP, Shudt M, Plitnick J, Schneider E, Fitzsimmons WJ, Khullar G, Metti J, Dudley JT, Nash M, Beaubier N, Wang J, Liu C, Hui P, Muyombwe A, Downing R, Razeq J, Bart SM, Grills A, Morrison SM, Murphy S, Neal C, Laszlo E, Rennert H, Cushing M, Westblade L, Velu P, Craney A, Fauntleroy KA, Peaper DR, Landry ML, Cook PW, Fauver JR, Mason CE, Lauring AS, George KS, MacCannell DR, and Grubaugh ND
- 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 2500 COVID-19 cases associated with this variant have been detected in the US since December 2020, but the extent of establishment is relatively unknown. Using travel, genomic, and diagnostic data, we highlight the primary ports of entry for B.1.1.7 in the US and locations of possible underreporting of B.1.1.7 cases. 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., Competing Interests: Declarations of Interests M.J.M, G.K., J.M., J.T.D., M.N., N.B., and C.E.M. work for Tempus Labs. K.S.G. receives research support from Thermo Fisher for the development of assays for the detection and characterization of viruses. All other authors declare no competing interests.
- Published
- 2021
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36. Public health actions to control new SARS-CoV-2 variants.
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Grubaugh ND, Hodcroft EB, Fauver JR, Phelan AL, and Cevik M
- Subjects
- Age Factors, COVID-19 epidemiology, COVID-19 virology, Epidemiological Monitoring, Global Health, Humans, Mandatory Programs, Pandemics, SARS-CoV-2 physiology, Travel legislation & jurisprudence, United Kingdom epidemiology, Vulnerable Populations, COVID-19 prevention & control, COVID-19 transmission, Communicable Disease Control, SARS-CoV-2 genetics
- Abstract
Recent reports suggest that some SARS-CoV-2 genetic variants, such as B.1.1.7, might be more transmissible and are quickly spreading around the world. As the emergence of more transmissible variants could exacerbate the pandemic, we provide public health guidance for increased surveillance and measures to reduce community transmission., Competing Interests: Declarations of Interest The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2021
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37. Analytical sensitivity and efficiency comparisons of SARS-CoV-2 RT-qPCR primer-probe sets.
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Vogels CBF, Brito AF, Wyllie AL, Fauver JR, Ott IM, Kalinich CC, Petrone ME, Casanovas-Massana A, Catherine Muenker M, Moore AJ, Klein J, Lu P, Lu-Culligan A, Jiang X, Kim DJ, Kudo E, Mao T, Moriyama M, Oh JE, Park A, Silva J, Song E, Takahashi T, Taura M, Tokuyama M, Venkataraman A, Weizman OE, Wong P, Yang Y, Cheemarla NR, White EB, Lapidus S, Earnest R, Geng B, Vijayakumar P, Odio C, Fournier J, Bermejo S, Farhadian S, Dela Cruz CS, Iwasaki A, Ko AI, Landry ML, Foxman EF, and Grubaugh ND
- Subjects
- 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, 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
- 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.
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- 2020
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38. SARS-CoV-2 infection of the placenta.
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Hosier H, Farhadian SF, Morotti RA, Deshmukh U, Lu-Culligan A, Campbell KH, Yasumoto Y, Vogels CB, Casanovas-Massana A, Vijayakumar P, Geng B, Odio CD, Fournier J, Brito AF, Fauver JR, Liu F, Alpert T, Tal R, Szigeti-Buck K, Perincheri S, Larsen C, Gariepy AM, Aguilar G, Fardelmann KL, Harigopal M, Taylor HS, Pettker CM, Wyllie AL, Cruz CD, Ring AM, Grubaugh ND, Ko AI, Horvath TL, Iwasaki A, Reddy UM, and Lipkind HS
- Subjects
- Abortion, Therapeutic, Abruptio Placentae etiology, Abruptio Placentae pathology, Abruptio Placentae virology, Adult, COVID-19, Coronavirus Infections pathology, Coronavirus Infections virology, Female, Humans, Microscopy, Electron, Transmission, Pandemics, Phylogeny, Pneumonia, Viral pathology, Pneumonia, Viral virology, Pre-Eclampsia etiology, Pre-Eclampsia pathology, Pre-Eclampsia virology, Pregnancy, Pregnancy Complications, Infectious pathology, Pregnancy Trimester, Second, RNA, Viral genetics, RNA, Viral isolation & purification, SARS-CoV-2, Viral Load, Betacoronavirus genetics, Betacoronavirus isolation & purification, Betacoronavirus pathogenicity, Coronavirus Infections complications, Placenta pathology, Placenta virology, Pneumonia, Viral complications, Pregnancy Complications, Infectious etiology, Pregnancy Complications, Infectious virology
- Abstract
BACKGROUNDThe effects of the novel coronavirus disease 2019 (COVID-19) in pregnancy remain relatively unknown. We present a case of second trimester pregnancy with symptomatic COVID-19 complicated by severe preeclampsia and placental abruption.METHODSWe analyzed the placenta for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through molecular and immunohistochemical assays and by and electron microscopy and measured the maternal antibody response in the blood to this infection.RESULTSSARS-CoV-2 localized predominantly to syncytiotrophoblast cells at the materno-fetal interface of the placenta. Histological examination of the placenta revealed a dense macrophage infiltrate, but no evidence for the vasculopathy typically associated with preeclampsia.CONCLUSIONThis case demonstrates SARS-CoV-2 invasion of the placenta, highlighting the potential for severe morbidity among pregnant women with COVID-19.FUNDINGBeatrice Kleinberg Neuwirth Fund and Fast Grant Emergent Ventures funding from the Mercatus Center at George Mason University. The funding bodies did not have roles in the design of the study or data collection, analysis, and interpretation and played no role in writing the manuscript.
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- 2020
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39. Real-time public health communication of local SARS-CoV-2 genomic epidemiology.
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Kalinich CC, Jensen CG, Neugebauer P, Petrone ME, Peña-Hernández M, Ott IM, Wyllie AL, Alpert T, Vogels CBF, Fauver JR, Grubaugh ND, and Brito AF
- Subjects
- COVID-19, Genomics, Humans, Pandemics, Phylogeny, SARS-CoV-2, Betacoronavirus genetics, Coronavirus Infections epidemiology, Information Dissemination, Pneumonia, Viral epidemiology, Public Health
- Abstract
Genomic epidemiology can provide a unique, real-time understanding of SARS-CoV-2 transmission patterns. Yet the potential for genomic analyses to guide local policy and community-based behavioral decisions is limited because they are often oriented towards specially trained scientists and conducted on a national or global scale. Here, we propose a new paradigm: Phylogenetic analyses performed on a local level (municipal, county, or state), with results communicated in a clear, timely, and actionable manner to strengthen public health responses. We believe that presenting results rapidly, and tailored to a non-expert audience, can serve as a template for effective public health response to COVID-19 and other emerging viral diseases., Competing Interests: The authors have declared that no competing interests exist.
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- 2020
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40. Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19.
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Farhadian S, Glick LR, Vogels CBF, Thomas J, Chiarella J, Casanovas-Massana A, Zhou J, Odio C, Vijayakumar P, Geng B, Fournier J, Bermejo S, Fauver JR, Alpert T, Wyllie AL, Turcotte C, Steinle M, Paczkowski P, Dela Cruz C, Wilen C, Ko AI, MacKay S, Grubaugh ND, Spudich S, and Barakat LA
- Subjects
- Acute Disease, Aged, Biomarkers cerebrospinal fluid, COVID-19, Female, Humans, SARS-CoV-2, Seizures, Betacoronavirus, Coronavirus Infections, Cytokines cerebrospinal fluid, Encephalitis, Viral, Pandemics, Pneumonia, Viral
- Abstract
Background: COVID-19 is caused by the severe acute respiratory syndrome virus SARS-CoV-2. It is widely recognized as a respiratory pathogen, but neurologic complications can be the presenting manifestation in a subset of infected patients., Case Presentation: We describe a 78-year old immunocompromised woman who presented with altered mental status after witnessed seizure-like activity at home. She was found to have SARS-CoV-2 infection and associated neuroinflammation. In this case, we undertake the first detailed analysis of cerebrospinal fluid (CSF) cytokines during COVID-19 infection and find a unique pattern of inflammation in CSF, but no evidence of viral neuroinvasion., Conclusion: Our findings suggest that neurologic symptoms such as encephalopathy and seizures may be the initial presentation of COVID-19. Central nervous system inflammation may associate with neurologic manifestations of disease.
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- 2020
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41. Host response-based screening to identify undiagnosed cases of COVID-19 and expand testing capacity.
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Cheemarla NR, Brito AF, Fauver JR, Alpert T, Vogels CBF, Omer SB, Ko A, Grubaugh ND, Landry ML, and Foxman EF
- Abstract
The COVID-19 pandemic has created unprecedented challenges in diagnostic testing. At the beginning of the epidemic, a confluence of factors resulted in delayed deployment of PCR-based diagnostic tests, resulting in lack of testing of individuals with symptoms of the disease. Although these tests are now more widely available, it is estimated that a three- to ten-fold increase in testing capacity will be required to ensure adequate surveillance as communities reopen(1). In response to these challenges, we evaluated potential roles of host-response based screening in the diagnosis of COVID-19. Previous work from our group showed that the nasopharyngeal (NP) level of CXCL10, a protein produced as part of the host response to viral infection, is a sensitive predictor of respiratory virus infection across a wide spectrum of viruses(2). Here, we show that NP CXCL10 is elevated during SARS-CoV-2 infection and use a CXCL10-based screening strategy to identify four undiagnosed cases of COVID-19 in Connecticut in early March. In a second set of samples tested at the Yale New Haven Hospital, we show that NP CXCL10 had excellent performance as a rule-out test (NPV 0.99, 95% C.I. 0.985-0.997). Our results demonstrate how biomarker-based screening could be used to leverage existing PCR testing capacity to rapidly enable widespread testing for COVID-19.
- Published
- 2020
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42. Coast-to-Coast Spread of SARS-CoV-2 during the Early Epidemic in the United States.
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Fauver JR, Petrone ME, Hodcroft EB, Shioda K, Ehrlich HY, Watts AG, Vogels CBF, Brito AF, Alpert T, Muyombwe A, Razeq J, Downing R, Cheemarla NR, Wyllie AL, Kalinich CC, Ott IM, Quick J, Loman NJ, Neugebauer KM, Greninger AL, Jerome KR, Roychoudhury P, Xie H, Shrestha L, Huang ML, Pitzer VE, Iwasaki A, Omer SB, Khan K, Bogoch II, Martinello RA, Foxman EF, Landry ML, Neher RA, Ko AI, and Grubaugh ND
- Subjects
- 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, United States epidemiology, Washington epidemiology, Betacoronavirus genetics, Coronavirus Infections transmission, Pneumonia, Viral transmission, Travel legislation & jurisprudence
- 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., Competing Interests: Declaration of Interests A.L.W. is the principal investigator on a research grant from Pfizer to Yale University and has received consulting fees for participation in advisory boards for Pfizer., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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43. Genomic Epidemiology as a Public Health Tool to Combat Mosquito-Borne Virus Outbreaks.
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Pollett S, Fauver JR, Maljkovic Berry I, Melendrez M, Morrison A, Gillis LD, Johansson MA, Jarman RG, and Grubaugh ND
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- Animals, Chikungunya Fever epidemiology, Chikungunya Fever prevention & control, Chikungunya Fever virology, Chikungunya virus genetics, Dengue epidemiology, Dengue prevention & control, Dengue virology, Humans, Mosquito Vectors virology, Vector Borne Diseases epidemiology, Vector Borne Diseases virology, West Nile Fever epidemiology, West Nile Fever prevention & control, West Nile Fever virology, Yellow Fever epidemiology, Yellow Fever prevention & control, Yellow Fever virology, Zika Virus genetics, Zika Virus Infection epidemiology, Zika Virus Infection prevention & control, Zika Virus Infection virology, Culicidae virology, Disease Outbreaks prevention & control, Genomics, Mosquito Control, Public Health, Vector Borne Diseases prevention & control
- Abstract
Next-generation sequencing technologies, exponential increases in the availability of virus genomic data, and ongoing advances in phylogenomic methods have made genomic epidemiology an increasingly powerful tool for public health response to a range of mosquito-borne virus outbreaks. In this review, we offer a brief primer on the scope and methods of phylogenomic analyses that can answer key epidemiological questions during mosquito-borne virus public health emergencies. We then focus on case examples of outbreaks, including those caused by dengue, Zika, yellow fever, West Nile, and chikungunya viruses, to demonstrate the utility of genomic epidemiology to support the prevention and control of mosquito-borne virus threats. We extend these case studies with operational perspectives on how to best incorporate genomic epidemiology into structured surveillance and response programs for mosquito-borne virus control. Many tools for genomic epidemiology already exist, but so do technical and nontechnical challenges to advancing their use. Frameworks to support the rapid sharing of multidimensional data and increased cross-sector partnerships, networks, and collaborations can support advancement on all scales, from research and development to implementation by public health agencies., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
- Published
- 2020
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44. Coast-to-coast spread of SARS-CoV-2 in the United States revealed by genomic epidemiology.
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Fauver JR, Petrone ME, Hodcroft EB, Shioda K, Ehrlich HY, Watts AG, Vogels CBF, Brito AF, Alpert T, Muyombwe A, Razeq J, Downing R, Cheemarla NR, Wyllie AL, Kalinich CC, Ott I, Quick J, Loman NJ, Neugebauer KM, Greninger AL, Jerome KR, Roychoudhury P, Xie H, Shrestha L, Huang ML, Pitzer VE, Iwasaki A, Omer SB, Khan K, Bogoch II, Martinello RA, Foxman EF, Landry ML, Neher RA, Ko AI, and Grubaugh ND
- Abstract
Since its emergence and detection in Wuhan, China in late 2019, the novel coronavirus SARS-CoV-2 has spread to nearly every country around the world, resulting in hundreds of thousands of infections to date. The virus 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 U.S., 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 impacts of federal travel restrictions. This study provides evidence for widespread, sustained transmission of SARS-CoV-2 within the U.S. and highlights the critical need for local surveillance.
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- 2020
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45. De novo Assembly of the Brugia malayi Genome Using Long Reads from a Single MinION Flowcell.
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Fauver JR, Martin J, Weil GJ, Mitreva M, and Fischer PU
- Subjects
- Animals, Female, Genome, Mitochondrial genetics, Genome, Protozoan genetics, Sequence Analysis, DNA, Brugia malayi genetics
- Abstract
Filarial nematode infections cause a substantial global disease burden. Genomic studies of filarial worms can improve our understanding of their biology and epidemiology. However, genomic information from field isolates is limited and available reference genomes are often discontinuous. Single molecule sequencing technologies can reduce the cost of genome sequencing and long reads produced from these devices can improve the contiguity and completeness of genome assemblies. In addition, these new technologies can make generation and analysis of large numbers of field isolates feasible. In this study, we assessed the performance of the Oxford Nanopore Technologies MinION for sequencing and assembling the genome of Brugia malayi, a human parasite widely used in filariasis research. Using data from a single MinION flowcell, a 90.3 Mb nuclear genome was assembled into 202 contigs with an N50 of 2.4 Mb. This assembly covered 96.9% of the well-defined B. malayi reference genome with 99.2% identity. The complete mitochondrial genome was obtained with individual reads and the nearly complete genome of the endosymbiotic bacteria Wolbachia was assembled alongside the nuclear genome. Long-read data from the MinION produced an assembly that approached the quality of a well-established reference genome using comparably fewer resources.
- Published
- 2019
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46. Mapping of lymphatic filariasis in loiasis areas: A new strategy shows no evidence for Wuchereria bancrofti endemicity in Cameroon.
- Author
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Wanji S, Esum ME, Njouendou AJ, Mbeng AA, Chounna Ndongmo PW, Abong RA, Fru J, Fombad FF, Nchanji GT, Ngongeh G, Ngandjui NV, Enyong PI, Storey H, Curtis KC, Fischer K, Fauver JR, Lew D, Goss CW, and Fischer PU
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Algorithms, Animals, Antibodies, Protozoan blood, Antigens, Protozoan analysis, Cameroon epidemiology, Child, Cross-Sectional Studies, Diagnostic Tests, Routine methods, Female, Humans, Immunoassay methods, Male, Middle Aged, Prevalence, Real-Time Polymerase Chain Reaction, Rural Population, Young Adult, Elephantiasis, Filarial epidemiology, Endemic Diseases, Loiasis epidemiology, Topography, Medical, Wuchereria bancrofti isolation & purification
- Abstract
Background: Mapping of lymphatic filariasis (LF) caused by Wuchereria bancrofti largely relies on the detection of circulating antigen using ICT cards. Several studies have recently shown that this test can be cross-reactive with sera of subjects heavily infected with Loa loa and thus mapping results in loiasis endemic areas may be inaccurate., Methodology/principal Findings: In order to develop an LF mapping strategy for areas with high loiasis prevalence, we collected day blood samples from 5,001 subjects residing in 50 villages that make up 6 health districts throughout Cameroon. Antigen testing using Filarial Test Strip (FTS, a novel platform that uses the same reagents as ICT) revealed an overall positivity rate of 1.1% and L. loa microfilaria (Mf) rates of up to 46%. Among the subjects with 0 to 8,000 Mf/ml in day blood, only 0.4% were FTS positive, while 22.2% of subjects with >8,000 Mf/ml were FTS positive. A Mf density of >8,200 Mf/ml was determined as the cut point at which positive FTS results should be excluded from the analysis. No FTS positive samples were also positive for W. bancrofti antibodies as measured by two different point of care tests that use the Wb123 antigen not found in L. loa. Night blood examination of the FTS positive subjects showed a high prevalence of L. loa Mf with densities up to 12,710 Mf/ml. No W. bancrofti Mf were identified, as confirmed by qPCR. Our results show that high loads of L. loa Mf in day blood are a reliable indicator of FTS positivity, and Wb123 rapid test proved to be relatively specific., Conclusions/significance: Our study provides a simple day blood-based algorithm for LF mapping in loiasis areas. The results indicate that many districts that were formerly classified as endemic for LF in Cameroon are non-endemic and do not require mass drug administration for elimination of LF., Competing Interests: The authors have declared that no competing interests exist.
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- 2019
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47. A reverse-transcription/RNase H based protocol for depletion of mosquito ribosomal RNA facilitates viral intrahost evolution analysis, transcriptomics and pathogen discovery.
- Author
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Fauver JR, Akter S, Morales AIO, Black WC 4th, Rodriguez AD, Stenglein MD, Ebel GD, and Weger-Lucarelli J
- Subjects
- Aedes virology, Animals, Anopheles virology, Culex virology, Culicidae genetics, Flaviviridae classification, Flaviviridae isolation & purification, Gene Expression Profiling, Genome, Viral, Host Microbial Interactions genetics, Ribonuclease H genetics, Transcriptome, Culicidae virology, RNA, Ribosomal genetics, Reverse Transcription, Ribonuclease H metabolism, West Nile virus pathogenicity
- Abstract
Identifying novel viruses or assessing viral variation by NGS requires high sequencing coverage. More than 90% of total RNA is ribosomal (rRNA), making variant calling, virus discovery or transcriptomic profiling difficult. Current methods to increase informative reads suffer from drawbacks, either they cannot be used for some viruses, are optimized for a single species, or introduce bias. We describe a two-part approach combining reverse-transcription to create RNA/DNA hybrids which are then degraded with RNaseH/DNase sequentially that works for three medically relevant mosquito genera; Aedes, Anopheles, and Culex. We demonstrate depletion of rRNA from different samples, including whole mosquitoes and midgut contents from FTA cards. We describe novel insect-specific virus genomes from field collected mosquitoes. The protocol requires only common laboratory reagents and small oligonucleotides specific to rRNA. This approach can be adapted for other organisms, aiding virus diversity analyses, virus discovery and transcriptomics in both laboratory and field samples., (Copyright © 2018. Published by Elsevier Inc.)
- Published
- 2019
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48. Variation in competence for ZIKV transmission by Aedes aegypti and Aedes albopictus in Mexico.
- Author
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Garcia-Luna SM, Weger-Lucarelli J, Rückert C, Murrieta RA, Young MC, Byas AD, Fauver JR, Perera R, Flores-Suarez AE, Ponce-Garcia G, Rodriguez AD, Ebel GD, and Black WC 4th
- Subjects
- Aedes virology, Animals, Female, Humans, Male, Mexico, Mosquito Vectors virology, Zika Virus Infection virology, Aedes physiology, Mosquito Vectors physiology, Zika Virus physiology, Zika Virus Infection transmission
- Abstract
Background: ZIKV is a new addition to the arboviruses circulating in the New World, with more than 1 million cases since its introduction in 2015. A growing number of studies have reported vector competence (VC) of Aedes mosquitoes from several areas of the world for ZIKV transmission. Some studies have used New World mosquitoes from disparate regions and concluded that these have a variable but relatively low competence for the Asian lineage of ZIKV., Methodology/principal Findings: Ten Aedes aegypti (L) and three Ae. albopictus (Skuse) collections made in 2016 from throughout Mexico were analyzed for ZIKV (PRVABC59-Asian lineage) VC. Mexican Ae. aegypti had high rates of midgut infection (MIR), dissemination (DIR) and salivary gland infection (SGIR) but low to moderate transmission rates (TR). It is unclear whether this low TR was due to heritable salivary gland escape barriers or to underestimating the amount of virus in saliva due to the loss of virus during filtering and random losses on surfaces when working with small volumes. VC varied among collections, geographic regions and whether the collection was made north or south of the Neovolcanic axis (NVA). The four rates were consistently lower in northeastern Mexico, highest in collections along the Pacific coast and intermediate in the Yucatan. All rates were lowest north of the NVA. It was difficult to assess VC in Ae. albopictus because rates varied depending upon the number of generations in the laboratory., Conclusions/significance: Mexican Ae. aegypti and Ae. albopictus are competent vectors of ZIKV. There is however large variance in vector competence among geographic sites and regions. At 14 days post infection, TR varied from 8-51% in Ae. aegypti and from 2-26% in Ae. albopictus., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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49. Xenosurveillance reflects traditional sampling techniques for the identification of human pathogens: A comparative study in West Africa.
- Author
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Fauver JR, Weger-Lucarelli J, Fakoli LS 3rd, Bolay K, Bolay FK, Diclaro JW 2nd, Brackney DE, Foy BD, Stenglein MD, and Ebel GD
- Subjects
- Animals, Hepacivirus genetics, Hepacivirus pathogenicity, Hepatitis B epidemiology, Hepatitis B virology, Hepatitis B virus genetics, Hepatitis B virus isolation & purification, Hepatitis B virus pathogenicity, Hepatitis C epidemiology, Hepatitis C virology, High-Throughput Nucleotide Sequencing, Humans, Liberia epidemiology, Metagenomics, Mosquito Vectors virology, Sampling Studies, Virus Diseases virology, Viruses genetics, Viruses pathogenicity, Culicidae virology, Epidemiological Monitoring, Virus Diseases epidemiology, Viruses isolation & purification
- Abstract
Background: Novel surveillance strategies are needed to detect the rapid and continuous emergence of infectious disease agents. Ideally, new sampling strategies should be simple to implement, technologically uncomplicated, and applicable to areas where emergence events are known to occur. To this end, xenosurveillance is a technique that makes use of blood collected by hematophagous arthropods to monitor and identify vertebrate pathogens. Mosquitoes are largely ubiquitous animals that often exist in sizable populations. As well, many domestic or peridomestic species of mosquitoes will preferentially take blood-meals from humans, making them a unique and largely untapped reservoir to collect human blood., Methodology/principal Findings: We sought to take advantage of this phenomenon by systematically collecting blood-fed mosquitoes during a field trail in Northern Liberia to determine whether pathogen sequences from blood engorged mosquitoes accurately mirror those obtained directly from humans. Specifically, blood was collected from humans via finger-stick and by aspirating bloodfed mosquitoes from the inside of houses. Shotgun metagenomic sequencing of RNA and DNA derived from these specimens was performed to detect pathogen sequences. Samples obtained from xenosurveillance and from finger-stick blood collection produced a similar number and quality of reads aligning to two human viruses, GB virus C and hepatitis B virus., Conclusions/significance: This study represents the first systematic comparison between xenosurveillance and more traditional sampling methodologies, while also demonstrating the viability of xenosurveillance as a tool to sample human blood for circulating pathogens.
- Published
- 2018
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50. The Use of Xenosurveillance to Detect Human Bacteria, Parasites, and Viruses in Mosquito Bloodmeals.
- Author
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Fauver JR, Gendernalik A, Weger-Lucarelli J, Grubaugh ND, Brackney DE, Foy BD, and Ebel GD
- Subjects
- Animals, Bacillus anthracis immunology, Humans, Middle East Respiratory Syndrome Coronavirus immunology, Trypanosoma brucei gambiense immunology, Zika Virus Infection immunology, Anopheles microbiology, Anopheles parasitology, Anopheles virology, Antibodies, Bacterial blood, Antibodies, Protozoan blood, RNA, Viral blood
- Abstract
Infectious disease surveillance is hindered by several factors, including limited infrastructure and geographic isolation of many resource-poor regions. In addition, the complexities of sample acquisition, processing, and analysis, even in developed regions, can be rate limiting. Therefore, new strategies to survey human populations for emerging pathogens are necessary. Xenosurveillance is a method that utilizes mosquitoes as sampling devices to search for genetic signatures of pathogens in vertebrates. Previously we demonstrated that xenosurveillance can detect viral RNA in both laboratory and field settings. However, its ability to detect bacteria and parasites remains to be assessed. Accordingly, we fed Anopheles gambiae mosquitoes blood that contained Trypanosoma brucei gambiense and Bacillus anthracis . In addition, we determined whether two additional emerging viruses, Middle East Respiratory Syndrome Coronavirus and Zika virus could be detected by this method. Pathogen-specific real-time reverse transcription polymerase chain reaction was used to evaluate the sensitivity of xenosurveillance across multiple pathogen taxa and over time. We detected RNA from all pathogens at clinically relevant concentrations from mosquitoes processed up to 1 day postbloodfeeding. These results demonstrate that xenosurveillance may be used as a tool to expand surveillance for viral, parasitic, and bacterial pathogens in resource-limited areas.
- Published
- 2017
- Full Text
- View/download PDF
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