Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults
<p>Since its emergence in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused hundreds of millions of cases and continues to circulate globally. To establish a novel SARS-CoV-2 human challenge model that enables controlled investigation of pathogenesis, correlates of...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2022
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| _version_ | 1797106988711149568 |
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| author | Killingley, B Mann, AJ Kalinova, M Boyers, A Goonawardane, N Zhou, J Lindsell, K Hare, SS Brown, J Frise, R Smith, E Hopkins, C Noulin, N Löndt, B Wilkinson, T Harden, S McShane, H Baillet, M Gilbert, A Jacobs, M Charman, C Mande, P Nguyen-Van-Tam, JS Semple, MG Read, RC Ferguson, NM Openshaw, PJ Rapeport, G Barclay, WS Catchpole, AP Chiu, C |
| author_facet | Killingley, B Mann, AJ Kalinova, M Boyers, A Goonawardane, N Zhou, J Lindsell, K Hare, SS Brown, J Frise, R Smith, E Hopkins, C Noulin, N Löndt, B Wilkinson, T Harden, S McShane, H Baillet, M Gilbert, A Jacobs, M Charman, C Mande, P Nguyen-Van-Tam, JS Semple, MG Read, RC Ferguson, NM Openshaw, PJ Rapeport, G Barclay, WS Catchpole, AP Chiu, C |
| author_sort | Killingley, B |
| collection | OXFORD |
| description | <p>Since its emergence in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused hundreds of millions of cases and continues to circulate globally. To establish a novel SARS-CoV-2 human challenge model that enables controlled investigation of pathogenesis, correlates of protection and efficacy testing of forthcoming interventions, 36 volunteers aged 18–29 years without evidence of previous infection or vaccination were inoculated with 10 TCID<sub>50</sub> of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally in an open-label, non-randomized study (ClinicalTrials.gov identifier NCT04865237; funder, UK Vaccine Taskforce). After inoculation, participants were housed in a high-containment quarantine unit, with 24-hour close medical monitoring and full access to higher-level clinical care. The study’s primary objective was to identify an inoculum dose that induced well-tolerated infection in more than 50% of participants, with secondary objectives to assess virus and symptom kinetics during infection. All pre-specified primary and secondary objectives were met. Two participants were excluded from the per-protocol analysis owing to seroconversion between screening and inoculation, identified post hoc. Eighteen (~53%) participants became infected, with viral load (VL) rising steeply and peaking at ~5 days after inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log<sub>10</sub> copies per milliliter (median, 95% confidence interval (8.41, 9.53)). Viable virus was recoverable from the nose up to ~10 days after inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected participants, beginning 2–4 days after inoculation, whereas two (11%) participants remained asymptomatic (no reportable symptoms). Anosmia or dysosmia developed more slowly in 15 (83%) participants. No quantitative correlation was noted between VL and symptoms, with high VLs present even in asymptomatic infection. All infected individuals developed serum spike-specific IgG and neutralizing antibodies. Results from lateral flow tests were strongly associated with viable virus, and modeling showed that twice-weekly rapid antigen tests could diagnose infection before 70–80% of viable virus had been generated. Thus, with detailed characterization and safety analysis of this first SARS-CoV-2 human challenge study in young adults, viral kinetics over the course of primary infection with SARS-CoV-2 were established, with implications for public health recommendations and strategies to affect SARS-CoV-2 transmission. Future studies will identify the immune factors associated with protection in those participants who did not develop infection or symptoms and define the effect of prior immunity and viral variation on clinical outcome.</p> |
| first_indexed | 2024-03-07T07:08:43Z |
| format | Journal article |
| id | oxford-uuid:1494b243-139b-4c2b-9345-90e1b9b3dc25 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:08:43Z |
| publishDate | 2022 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:1494b243-139b-4c2b-9345-90e1b9b3dc252022-06-10T12:12:01ZSafety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adultsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:1494b243-139b-4c2b-9345-90e1b9b3dc25EnglishSymplectic ElementsSpringer Nature2022Killingley, BMann, AJKalinova, MBoyers, AGoonawardane, NZhou, JLindsell, KHare, SSBrown, JFrise, RSmith, EHopkins, CNoulin, NLöndt, BWilkinson, THarden, SMcShane, HBaillet, MGilbert, AJacobs, MCharman, CMande, PNguyen-Van-Tam, JSSemple, MGRead, RCFerguson, NMOpenshaw, PJRapeport, GBarclay, WSCatchpole, APChiu, C<p>Since its emergence in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused hundreds of millions of cases and continues to circulate globally. To establish a novel SARS-CoV-2 human challenge model that enables controlled investigation of pathogenesis, correlates of protection and efficacy testing of forthcoming interventions, 36 volunteers aged 18–29 years without evidence of previous infection or vaccination were inoculated with 10 TCID<sub>50</sub> of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally in an open-label, non-randomized study (ClinicalTrials.gov identifier NCT04865237; funder, UK Vaccine Taskforce). After inoculation, participants were housed in a high-containment quarantine unit, with 24-hour close medical monitoring and full access to higher-level clinical care. The study’s primary objective was to identify an inoculum dose that induced well-tolerated infection in more than 50% of participants, with secondary objectives to assess virus and symptom kinetics during infection. All pre-specified primary and secondary objectives were met. Two participants were excluded from the per-protocol analysis owing to seroconversion between screening and inoculation, identified post hoc. Eighteen (~53%) participants became infected, with viral load (VL) rising steeply and peaking at ~5 days after inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log<sub>10</sub> copies per milliliter (median, 95% confidence interval (8.41, 9.53)). Viable virus was recoverable from the nose up to ~10 days after inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected participants, beginning 2–4 days after inoculation, whereas two (11%) participants remained asymptomatic (no reportable symptoms). Anosmia or dysosmia developed more slowly in 15 (83%) participants. No quantitative correlation was noted between VL and symptoms, with high VLs present even in asymptomatic infection. All infected individuals developed serum spike-specific IgG and neutralizing antibodies. Results from lateral flow tests were strongly associated with viable virus, and modeling showed that twice-weekly rapid antigen tests could diagnose infection before 70–80% of viable virus had been generated. Thus, with detailed characterization and safety analysis of this first SARS-CoV-2 human challenge study in young adults, viral kinetics over the course of primary infection with SARS-CoV-2 were established, with implications for public health recommendations and strategies to affect SARS-CoV-2 transmission. Future studies will identify the immune factors associated with protection in those participants who did not develop infection or symptoms and define the effect of prior immunity and viral variation on clinical outcome.</p> |
| spellingShingle | Killingley, B Mann, AJ Kalinova, M Boyers, A Goonawardane, N Zhou, J Lindsell, K Hare, SS Brown, J Frise, R Smith, E Hopkins, C Noulin, N Löndt, B Wilkinson, T Harden, S McShane, H Baillet, M Gilbert, A Jacobs, M Charman, C Mande, P Nguyen-Van-Tam, JS Semple, MG Read, RC Ferguson, NM Openshaw, PJ Rapeport, G Barclay, WS Catchpole, AP Chiu, C Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults |
| title | Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults |
| title_full | Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults |
| title_fullStr | Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults |
| title_full_unstemmed | Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults |
| title_short | Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults |
| title_sort | safety tolerability and viral kinetics during sars cov 2 human challenge in young adults |
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