Safety, tolerability, viral kinetics, and immune correlates of protection in healthy, seropositive UK adults inoculated with SARS-CoV-2: a single-centre, open-label, phase 1 controlled human infection study
Susan Jackson, Julia L. Marshall, Andrew Mawer, Raquel Lopez‐Ramon, Stephanie A. Harris, Iman Satti, Eileen Hughes, Hannah Preston-Jones, Ingrid Cabrera Puig, Stéphanie Longet, Tom Tipton, Stephen M. Laidlaw, Rebecca Powell Doherty, Hazel Morrison, Robert A. Mitchell, Rachel Tanner, Alberta Ateere, Elena Stylianou, Meng-San Wu, Timothy Peter Jones, Judith Breuer, Garth Rapeport, Vanessa M. Ferreira, Fergus Gleeson, Andrew J. Pollard, Miles W. Carroll, Andrew Catchpole, Christopher Chiu, Helen McShane, Maricel Alparaque, Liisa Anid, Eleanor Barnes, Rachel Benamore, Neha Bharti, Bhumika Patel, Adrian Burns, Nicholas Byard, Oliver Conway, Cushla Cooper, Charlotte Crowther, Susanna J Dunachie, Trudi Johnstone, Jyolsna Jose, Michael Luciw, Yama Mujadidi, Aiseosa Nehiweze, Sibongile Nyamunda, Maria Orobiyi-Rieba, Bindu Parvelikudy, Abigail Platt, Dzikamayi Pswarayi, Jack Quaddy, Binnie Elizabeth Samuel, Alessandro Sette, Victoria Sodipo, Preethu Srijith, Helen Stone, Cheryl Turner, Mary Ann Valmores, Alexandru Voaides, Gavindren Vuddamalay
Abstract
Background A SARS-CoV-2 controlled human infection model (CHIM) has been successfully established in seronegative individuals using a dose of 1×10 1 50% tissue culture infectious dose (TCID 50 ) pre-alpha SARS-CoV-2 virus. Given the increasing prevalence of seropositivity to SARS-CoV-2, a CHIM that could be used for vaccine development will need to induce infection in those with pre-existing immunity. Our aim was to find a dose of pre-alpha SARS-CoV-2 virus that induced infection in previously infected individuals. Methods Healthy, UK volunteers aged 18–30 years, with proven (quantitative RT-PCR or lateral flow antigen test) previous SARS-CoV-2 infection (with or without vaccination) were inoculated intranasally in a stepwise dose escalation CHIM with either 1×10 1 , 1×10 2 , 1×10³, 1×10 4 , or 1×10 5 TCID 50 SARS-CoV-2/human/GBR/484861/2020, the same virus used in the seronegative CHIM. Post-inoculation, volunteers were quarantined in functionally negative pressure rooms (Oxford, UK) for 14 days and until 12-hourly combined oropharyngeal–nasal swabs were negative for viable virus by focus-forming assay. Outpatient follow-up continued for 12 months post-enrolment, with additional visits for those who developed community-acquired SARS-CoV-2 infection. The primary objective was to identify a safe, well tolerated dose that induced infection (defined as two consecutive SARS-CoV-2 positive PCRs starting 24 h after inoculation) in 50% of seropositive volunteers. This study is registered with ClinicalTrials.gov (NCT04864548); enrolment and follow-up to 12 months post-enrolment are complete. Findings Recruitment commenced on May 6, 2021, with the last volunteer enrolled into the dose escalation cohort on Nov 24, 2022. 36 volunteers were enrolled, with four to eight volunteers inoculated in each dosing group from 1×10 1 to 1×10 5 TCID 50 SARS-CoV-2. All volunteers have completed quarantine, with follow-up to 12 months complete. Despite dose escalation to 1×10 5 TCID 50 , we were unable to induce sustained infection in any volunteers. Five (14%) of 36 volunteers were considered to have transient infection, based on the kinetic of their PCR-positive swabs. Transiently infected volunteers had significantly lower baseline mucosal and systemic SARS-CoV-2-specific antibody titres and significantly lower peripheral IFNγ responses against a CD8 + T-cell SARS-CoV-2 peptide pool than uninfected volunteers. 14 (39%) of 36 volunteers subsequently developed breakthrough infection with the omicron variant after discharge from quarantine. Most adverse events reported by volunteers in quarantine were mild, with fatigue (16 [44%]) and stuffy nose (16 [44%]) being the most common. There were no serious adverse events. Interpretation Our study demonstrates potent protective immunity induced by homologous vaccination and homologous or heterologous previous SARS-CoV-2 infection. The community breakthrough infections seen with the omicron variant supports the use of newer variants to establish a model with sufficient rate of infection for use in vaccine and therapeutic development. Funding Wellcome Trust and Department for Health and Social Care.