Analgesics
Antiandrogens
Antihistamines
Azvudine
Bromhexine
Budesonide
Colchicine
Conv. Plasma
Curcumin
Famotidine
Favipiravir
Fluvoxamine
Hydroxychlor..
Ivermectin
Lifestyle
Melatonin
Metformin
Minerals
Molnupiravir
Monoclonals
Naso/orophar..
Nigella Sativa
Nitazoxanide
PPIs
Paxlovid
Quercetin
Remdesivir
Thermotherapy
Vitamins
More

Other
Feedback
Home
 
next
study
previous
study
c19early.org COVID-19 treatment researchSelect treatment..Select..
Melatonin Meta
Metformin Meta
Antihistamines Meta
Azvudine Meta Molnupiravir Meta
Bromhexine Meta
Budesonide Meta
Colchicine Meta Nigella Sativa Meta
Conv. Plasma Meta Nitazoxanide Meta
Curcumin Meta PPIs Meta
Famotidine Meta Paxlovid Meta
Favipiravir Meta Quercetin Meta
Fluvoxamine Meta Remdesivir Meta
Hydroxychlor.. Meta Thermotherapy Meta
Ivermectin Meta

 

The kinetics of SARS-CoV-2 infection based on a human challenge study

Iyaniwura et al., Proceedings of the National Academy of Sciences, doi:10.1073/pnas.2406303121, NCT04865237
Nov 2024  
  Post
  Facebook
Share
  Source   PDF  
Modeling study of the viral dynamics of SARS-CoV-2 infection using data from a human challenge study. There was a delay of 1-2 days between inoculation and the start of exponential viral growth. During the early stage of infection, viral RNA grew ~1.5 times faster than infectious virus, with a doubling time of ~2 hours for viral RNA and ~3 hours for infectious virus. Productively infected cells have an average lifespan of ~17 hours, spending ~6 hours in the eclipse phase and ~11 hours producing and secreting viruses before dying. Adaptive immune responses, both humoral and cellular, are estimated to be initiated around 7-11 days post-infection. The humoral response leads to a decline in infectious virus by neutralizing antibodies, while the cellular response increases the death rate of infected cells. These contribute to the multi-phasic viral decline observed. Viral rebound experienced by some participants in the later stages is consistent with a decline in the interferon response that puts cells into an antiviral refractory state. As infected cell levels fall, refractory cells transition back to susceptible target cells faster, enabling rebound.
Iyaniwura et al., 7 Nov 2024, peer-reviewed, 6 authors, trial NCT04865237 (history). Contact: asp@lanl.gov.
This PaperMiscellaneousAll
Abstract: RESEARCH ARTICLE SCIENCES | MEDICAL PHYSICS OPEN ACCESS The kinetics of SARS-­CoV-­2 infection based on a human challenge study Sarafa A. Iyaniwuraa,1 , Ruy M. Ribeiroa , Carolin Zitzmanna , Tin Phana , Ruian Kea , and Alan S. Perelsona,2 Affiliations are included on p. 9. Edited by Marcus Feldman, Stanford University, Stanford, CA; received March 28, 2024; accepted October 9, 2024 Studying the early events that occur after viral infection in humans is difficult unless one intentionally infects volunteers in a human challenge study. Here, we use data about severe acute respiratory syndrome coronavirus 2 (SARS-­CoV-­2) in such a study in combination with mathematical modeling to gain insights into the relationship between the amount of virus in the upper respiratory tract and the immune response it generates. We propose a set of dynamic models of increasing complexity to dissect the roles of target cell limitation, innate immunity, and adaptive immunity in determining the observed viral kinetics. We introduce an approach for modeling the effect of humoral immunity that describes a decline in infectious virus after immune activation. We fit our models to viral load and infectious titer data from all the untreated infected participants in the study simultaneously. We found that a power-­law with a power h < 1 describes the relationship between infectious virus and viral load. Viral replication at the early stage of infection is rapid, with a doubling time of ~2 h for viral RNA and ~3 h for infectious virus. We estimate that adaptive immunity is initiated ~7 to 10 d postinfection and appears to contribute to a multiphasic viral decline experienced by some participants; the viral rebound experienced by other participants is consistent with a decline in the interferon response. Altogether, we quantified the kinetics of SARS-­CoV-­2 infection, shedding light on the early dynamics of the virus and the potential role of innate and adaptive immunity in promoting viral decline during infection. Significance Studying the early dynamics of severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) infection in humans is difficult. Here, we take advantage of a detailed dataset from a human challenge study to fit dynamic models that include innate and adaptive immune responses to longitudinal changes in both infectious and total virus. We uncovered a nonlinear relationship between total virus and infectious virus. We found that viral replication, after a short delay, is rapid, with a doubling time of ~2 h for viral RNA and ~3 h for infectious virus. We also found that innate immunity wanes as virus is brought under control, which together with adaptive immunity, initiated ~7 to 10 d postinfection, contributes to a multiphasic viral decline experienced by some participants. SARS-­CoV-­2 | viral dynamics | human challenge study | infectious disease modeling | mathematical modeling Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide, with over 776 million reported cases and 7 million deaths as of August 14, 2024 (1). SARS-CoV-2 is a highly contagious virus that primarily infects cells in the respiratory tract and lungs and is the causal agent of COVID-19 (2–5) that was first detected in Wuhan, China, in December 2019 (6). During acute infection, SARS-CoV-2 viral load, measured by the qPCR in samples from nose (or throat) swabs, increases rapidly, reaches a peak, and then declines (7–9). However, qPCR..
{ 'indexed': { 'date-parts': [[2024, 11, 8]], 'date-time': '2024-11-08T05:23:57Z', 'timestamp': 1731043437073, 'version': '3.28.0'}, 'reference-count': 78, 'publisher': 'Proceedings of the National Academy of Sciences', 'issue': '46', 'license': [ { 'start': { 'date-parts': [[2024, 11, 7]], 'date-time': '2024-11-07T00:00:00Z', 'timestamp': 1730937600000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by-nc-nd/4.0/'}], 'funder': [ { 'DOI': '10.13039/100000002', 'name': 'HHS | NIH', 'doi-asserted-by': 'publisher', 'award': ['U54-HL143541'], 'id': [{'id': '10.13039/100000002', 'id-type': 'DOI', 'asserted-by': 'publisher'}]}, { 'DOI': '10.13039/100008902', 'name': 'DOE | NNSA | Los Alamos National Laboratory', 'doi-asserted-by': 'publisher', 'award': ['20200743ER'], 'id': [{'id': '10.13039/100008902', 'id-type': 'DOI', 'asserted-by': 'publisher'}]}, { 'DOI': '10.13039/100008902', 'name': 'DOE | NNSA | Los Alamos National Laboratory', 'doi-asserted-by': 'publisher', 'award': ['20200695ER'], 'id': [{'id': '10.13039/100008902', 'id-type': 'DOI', 'asserted-by': 'publisher'}]}, { 'DOI': '10.13039/100008902', 'name': 'DOE | NNSA | Los Alamos National Laboratory', 'doi-asserted-by': 'publisher', 'award': ['20210730ER'], 'id': [{'id': '10.13039/100008902', 'id-type': 'DOI', 'asserted-by': 'publisher'}]}], 'content-domain': {'domain': ['www.pnas.org'], 'crossmark-restriction': True}, 'published-print': {'date-parts': [[2024, 11, 12]]}, 'abstract': '<jats:p>\n' ' Studying the early events that occur after viral infection in humans is difficult ' 'unless one intentionally infects volunteers in a human challenge study. Here, we use data ' 'about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in such a study in ' 'combination with mathematical modeling to gain insights into the relationship between the ' 'amount of virus in the upper respiratory tract and the immune response it generates. We ' 'propose a set of dynamic models of increasing complexity to dissect the roles of target cell ' 'limitation, innate immunity, and adaptive immunity in determining the observed viral ' 'kinetics. We introduce an approach for modeling the effect of humoral immunity that describes ' 'a decline in infectious virus after immune activation. We fit our models to viral load and ' 'infectious titer data from all the untreated infected participants in the study ' 'simultaneously. We found that a power-law with a power\n' ' <jats:italic>h</jats:italic>\n' ' &lt; 1 describes the relationship between infectious virus and viral load. Viral ' 'replication at the early stage of infection is rapid, with a doubling time of ~2 h for viral ' 'RNA and ~3 h for infectious virus. We estimate that adaptive immunity is initiated ~7 to 10 d ' 'postinfection and appears to contribute to a multiphasic viral decline experienced by some ' 'participants; the viral rebound experienced by other participants is consistent with a ' 'decline in the interferon response. Altogether, we quantified the kinetics of SARS-CoV-2 ' 'infection, shedding light on the early dynamics of the virus and the potential role of innate ' 'and adaptive immunity in promoting viral decline during infection.\n' ' </jats:p>', 'DOI': '10.1073/pnas.2406303121', 'type': 'journal-article', 'created': {'date-parts': [[2024, 11, 7]], 'date-time': '2024-11-07T15:21:24Z', 'timestamp': 1730992884000}, 'update-policy': 'http://dx.doi.org/10.1073/pnas.cm10313', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'The kinetics of SARS-CoV-2 infection based on a human challenge study', 'prefix': '10.1073', 'volume': '121', 'author': [ { 'ORCID': 'http://orcid.org/0000-0002-8854-2335', 'authenticated-orcid': False, 'given': 'Sarafa A.', 'family': 'Iyaniwura', 'sequence': 'first', 'affiliation': [ { 'name': 'Theoretical Division, Theoretical Biology and Biophysics, Los ' 'Alamos National Laboratory, Los Alamos, NM 87545'}]}, { 'ORCID': 'http://orcid.org/0000-0002-3988-8241', 'authenticated-orcid': False, 'given': 'Ruy M.', 'family': 'Ribeiro', 'sequence': 'additional', 'affiliation': [ { 'name': 'Theoretical Division, Theoretical Biology and Biophysics, Los ' 'Alamos National Laboratory, Los Alamos, NM 87545'}]}, { 'ORCID': 'http://orcid.org/0000-0001-5188-0042', 'authenticated-orcid': False, 'given': 'Carolin', 'family': 'Zitzmann', 'sequence': 'additional', 'affiliation': [ { 'name': 'Theoretical Division, Theoretical Biology and Biophysics, Los ' 'Alamos National Laboratory, Los Alamos, NM 87545'}]}, { 'ORCID': 'http://orcid.org/0000-0001-9998-8263', 'authenticated-orcid': False, 'given': 'Tin', 'family': 'Phan', 'sequence': 'additional', 'affiliation': [ { 'name': 'Theoretical Division, Theoretical Biology and Biophysics, Los ' 'Alamos National Laboratory, Los Alamos, NM 87545'}]}, { 'ORCID': 'http://orcid.org/0000-0001-5307-8934', 'authenticated-orcid': False, 'given': 'Ruian', 'family': 'Ke', 'sequence': 'additional', 'affiliation': [ { 'name': 'Theoretical Division, Theoretical Biology and Biophysics, Los ' 'Alamos National Laboratory, Los Alamos, NM 87545'}]}, { 'ORCID': 'http://orcid.org/0000-0002-2455-0002', 'authenticated-orcid': False, 'given': 'Alan S.', 'family': 'Perelson', 'sequence': 'additional', 'affiliation': [ { 'name': 'Theoretical Division, Theoretical Biology and Biophysics, Los ' 'Alamos National Laboratory, Los Alamos, NM 87545'}]}], 'member': '341', 'published-online': {'date-parts': [[2024, 11, 7]]}, 'reference': [ { 'key': 'e_1_3_4_1_2', 'unstructured': 'World Health Organization (WHO) Number of COVID-19 deaths reported to ' 'WHO. WHO (2024). https://data.who.int/dashboards/covid19/cases?n=c. ' 'Accessed 14 March 2024.'}, {'key': 'e_1_3_4_2_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/jmv.25728'}, {'key': 'e_1_3_4_3_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.01623-05'}, {'key': 'e_1_3_4_4_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.abc6156'}, {'key': 'e_1_3_4_5_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41586-020-2196-x'}, { 'key': 'e_1_3_4_6_2', 'unstructured': 'World Health Organization (WHO) Timeline: WHO’s COVID-19 response. WHO ' '(2023). ' 'https://www.who.int/emergencies/diseases/novel-coronavirus-2019/interactive-timeline. ' 'Accessed 14 March 2024.'}, { 'key': 'e_1_3_4_7_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S2213-2600(22)00226-0'}, {'key': 'e_1_3_4_8_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41591-022-01780-9'}, { 'key': 'e_1_3_4_9_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pbio.3001333'}, {'key': 'e_1_3_4_10_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.2111477118'}, {'key': 'e_1_3_4_11_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41564-022-01105-z'}, { 'key': 'e_1_3_4_12_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pcbi.1009997'}, {'key': 'e_1_3_4_13_2', 'doi-asserted-by': 'publisher', 'DOI': '10.7554/eLife.69302'}, { 'key': 'e_1_3_4_14_2', 'doi-asserted-by': 'crossref', 'unstructured': 'J. Carruthers J. Xu T. Finnie I. Hall A within-host model of SARS-CoV-2 ' 'infection. medRxiv [Preprint] (2022). ' 'https://doi.org/10.1101/2022.04.22.22274137v1 (Accessed 18 January ' '2024).', 'DOI': '10.1101/2022.04.22.22274137'}, {'key': 'e_1_3_4_15_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1186/s12916-021-02220-0'}, { 'key': 'e_1_3_4_16_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.ppat.1010630'}, {'key': 'e_1_3_4_17_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/sciadv.abc7112'}, {'key': 'e_1_3_4_18_2', 'doi-asserted-by': 'publisher', 'DOI': '10.7554/eLife.63537'}, {'key': 'e_1_3_4_19_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.isci.2022.104448'}, {'key': 'e_1_3_4_20_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.2017962118'}, {'key': 'e_1_3_4_21_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/cpt.2160'}, {'key': 'e_1_3_4_22_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.mbs.2020.108438'}, { 'key': 'e_1_3_4_23_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pcbi.1008752'}, {'key': 'e_1_3_4_24_2', 'doi-asserted-by': 'publisher', 'DOI': '10.7554/eLife.75427'}, { 'key': 'e_1_3_4_25_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pcbi.1008785'}, {'key': 'e_1_3_4_26_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/jac/dkac048'}, { 'key': 'e_1_3_4_27_2', 'doi-asserted-by': 'crossref', 'unstructured': 'G. Lingas Modelling the association between neutralizing antibody levels ' 'and SARS-CoV-2 viral dynamics: Implications to define correlates of ' 'protection against infection. medRxiv [Preprint] (2023). ' 'https://doi.org/10.1101/2023.03.05.23286816.', 'DOI': '10.1101/2023.03.05.23286816'}, { 'key': 'e_1_3_4_28_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pcbi.1010721'}, {'key': 'e_1_3_4_29_2', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/v13081635'}, { 'key': 'e_1_3_4_30_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pmed.1003660'}, { 'key': 'e_1_3_4_31_2', 'unstructured': 'A. Rohatgi WebPlotDigitizer–Copyright 2010–2022 Ankit Rohatgi. ' 'Automeris.io (2022). https://apps.automeris.io/wpd/. Accessed 24 ' 'February 2023.'}, {'key': 'e_1_3_4_32_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/sciimmunol.adj9285'}, {'key': 'e_1_3_4_33_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1111/imr.12687'}, { 'key': 'e_1_3_4_34_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.282.5386.103'}, {'key': 'e_1_3_4_35_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/nri700'}, {'key': 'e_1_3_4_36_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1006/jtbi.1997.0548'}, {'key': 'e_1_3_4_37_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/psp4.12543'}, {'key': 'e_1_3_4_38_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.1125676'}, { 'key': 'e_1_3_4_39_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.ppat.1008737'}, { 'key': 'e_1_3_4_40_2', 'doi-asserted-by': 'crossref', 'unstructured': 'C. E. Samuel Antiviral actions of interferons. Clin. Microbiol. Rev. 14 ' '778–809 (2001).', 'DOI': '10.1128/CMR.14.4.778-809.2001'}, { 'key': 'e_1_3_4_41_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.ppat.1011680'}, { 'key': 'e_1_3_4_42_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0021-9258(18)33834-1'}, { 'key': 'e_1_3_4_43_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/978-1-4419-9863-7_946'}, { 'key': 'e_1_3_4_44_2', 'unstructured': 'S. A. S. Lixoft Monolix|Lixoft. Lixoft (2015). ' 'https://lixoft.com/products/monolix/. Accessed 20 January 2023.'}, { 'key': 'e_1_3_4_45_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/978-1-4757-2917-7_3'}, {'key': 'e_1_3_4_46_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.cell.2020.05.042'}, {'key': 'e_1_3_4_47_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1099/jgv.0.001453'}, { 'key': 'e_1_3_4_48_2', 'doi-asserted-by': 'crossref', 'unstructured': 'A. S. Perelson R. M. Ribeiro T. Phan An explanation for SARS-CoV-2 ' 'rebound after Paxlovid treatment. medRxiv [Preprint] (2023). ' 'https://www.medrxiv.org/content/ (Accessed 15 February 2024).', 'DOI': '10.1101/2023.05.30.23290747'}, { 'key': 'e_1_3_4_49_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.virol.2016.05.019'}, { 'key': 'e_1_3_4_50_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0021-9258(18)45454-3'}, {'key': 'e_1_3_4_51_2', 'doi-asserted-by': 'publisher', 'DOI': '10.7554/eLife.81849'}, { 'key': 'e_1_3_4_52_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pcbi.1011437'}, {'key': 'e_1_3_4_53_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.02078-09'}, {'key': 'e_1_3_4_54_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41586-024-07575-x'}, { 'key': 'e_1_3_4_55_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pcbi.1001058'}, {'key': 'e_1_3_4_56_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/jmv.25866'}, {'key': 'e_1_3_4_57_2', 'doi-asserted-by': 'publisher', 'DOI': '10.7554/eLife.60122'}, {'key': 'e_1_3_4_58_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.cell.2021.01.007'}, {'key': 'e_1_3_4_59_2', 'doi-asserted-by': 'publisher', 'DOI': '10.4049/jimmunol.1400844'}, {'key': 'e_1_3_4_60_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.tim.2017.02.003'}, {'key': 'e_1_3_4_61_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/nmicrobiol.2017.78'}, {'key': 'e_1_3_4_62_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.adg8488'}, { 'key': 'e_1_3_4_63_2', 'doi-asserted-by': 'crossref', 'unstructured': 'N. R. Cheemarla Dynamic innate immune response determines susceptibility ' 'to SARS-CoV-2 infection and early replication kinetics. J. Exp. Med. 218 ' 'e20210583 (2021).', 'DOI': '10.1084/jem.20210583'}, {'key': 'e_1_3_4_64_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s43856-022-00195-4'}, {'key': 'e_1_3_4_65_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/sciimmunol.abl4509'}, {'key': 'e_1_3_4_66_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41590-021-01122-w'}, {'key': 'e_1_3_4_67_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41564-022-01254-1'}, {'key': 'e_1_3_4_68_2', 'doi-asserted-by': 'publisher', 'DOI': '10.7326/M22-2381'}, { 'key': 'e_1_3_4_69_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.lanepe.2021.100164'}, {'key': 'e_1_3_4_70_2', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/v13081642'}, {'key': 'e_1_3_4_71_2', 'doi-asserted-by': 'publisher', 'DOI': '10.7326/M23-1756'}, {'key': 'e_1_3_4_72_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMc2205944'}, { 'key': 'e_1_3_4_73_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S1473-3099(23)00063-4'}, {'key': 'e_1_3_4_74_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jtbi.2023.111447'}, {'key': 'e_1_3_4_75_2', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/math10173154'}, {'key': 'e_1_3_4_76_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1006/jtbi.2000.1076'}, {'key': 'e_1_3_4_77_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41598-022-18683-x'}, {'key': 'e_1_3_4_78_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1137/090757009'}], 'container-title': 'Proceedings of the National Academy of Sciences', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://pnas.org/doi/pdf/10.1073/pnas.2406303121', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2024, 11, 7]], 'date-time': '2024-11-07T15:22:07Z', 'timestamp': 1730992927000}, 'score': 1, 'resource': {'primary': {'URL': 'https://pnas.org/doi/10.1073/pnas.2406303121'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2024, 11, 7]]}, 'references-count': 78, 'journal-issue': {'issue': '46', 'published-print': {'date-parts': [[2024, 11, 12]]}}, 'alternative-id': ['10.1073/pnas.2406303121'], 'URL': 'http://dx.doi.org/10.1073/pnas.2406303121', 'relation': {}, 'ISSN': ['0027-8424', '1091-6490'], 'subject': [], 'container-title-short': 'Proc. Natl. Acad. Sci. U.S.A.', 'published': {'date-parts': [[2024, 11, 7]]}, 'assertion': [ { 'value': '2024-03-28', 'order': 0, 'name': 'received', 'label': 'Received', 'group': {'name': 'publication_history', 'label': 'Publication History'}}, { 'value': '2024-10-09', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'publication_history', 'label': 'Publication History'}}, { 'value': '2024-11-07', 'order': 3, 'name': 'published', 'label': 'Published', 'group': {'name': 'publication_history', 'label': 'Publication History'}}]}
Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
  or use drag and drop   
Submit