Scientists tried to give people COVID — and failed

Nature / by Ewen Callaway / May 1, 2024 at 4:29 AM

When Paul Zimmer-Harwood volunteered to be intentionally infected with SARS-CoV-2, he wasn’t sure what to expect. He was ready for a repeat of his first brush with COVID-19, through a naturally acquired infection that gave him influenza-like symptoms. But he hoped his immunity would help him feel well enough to use the indoor bicycle trainer that he had brought into quarantine.

It turned out that Zimmer-Harwood, a PhD student at University of Oxford, UK, had nothing to worry about. Neither he nor any of the 35 other people who participated in the ‘challenge’ trial actually got COVID-19.

The study’s results, published on 1 May in Lancet Microbe1, raise questions about the usefulness of COVID-19 challenge trials for testing vaccines, drugs and other therapeutics. “If you can’t get people infected, then you can’t test those things,” says Tom Peacock, a virologist at Imperial College London. Viral strains used in challenge trials take many months to produce, making it impossible to match emerging circulating variants that can overcome high levels of existing immunity in populations.

Researchers use challenge trials to understand infections and quickly test vaccines and therapies. In March 2021, after months of ethical debate, UK researchers launched the world’s first COVID-19 challenge trial. The study2 identified a minuscule dose of the SARS-CoV-2 strain that circulated in the early days of the pandemic that could infect about half of the participants, who had not previously been infected with the virus (at that time, vaccines weren’t yet widely available).

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doi: https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(24)00025-9/fulltext

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, MRCP ∗
Julia L Marshall, DPhil ∗
Andrew Mawer, BMBCh ∗
Raquel Lopez-Ramon, MSc
Stephanie A Harris, BSc
Iman Satti, PhD
et al.


Published:May 01, 2024
DOI:https://doi.org/10.1016/S2666-524724)00025-9

Summary

Background

A SARS-CoV-2 controlled human infection model (CHIM) has been successfully established in seronegative individuals using a dose of 1×101 50% tissue culture infectious dose (TCID50) 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 1×101, 1×102, 1×10³, 1×104, or 1×105 TCID50 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 1×101 to 1×105 TCID50 SARS-CoV-2. All volunteers have completed quarantine, with follow-up to 12 months complete. Despite dose escalation to 1×105 TCID50, 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.