Researchers deliberately infected participants with SARS-CoV-2 in ‘challenge’ trials – but high levels of immunity complicated efforts to test vaccines and treatments, frustrating the scientists and raising questions about the usefulness of such trials.
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.
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, accoridng to the journal Nature.
The study’s results, published in The Lancet Microbe, bring into question the point 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 study 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).
In parallel, a team led by Helen McShane, an infectious-disease researcher at Oxford, launched a second SARS-CoV-2 challenge study in people – including Zimmer-Harwood – who had recovered from naturally caught SARS-CoV-2 infections, caused by a range of variants. The trial later enrolled participants who had also been vaccinated.
Evolving strains
The first participants got the same tiny dose of the ‘ancestral’ SARS-CoV-2 strain as did those in the first trial. When nobody developed a sustained infection, the researchers increased the dose by more and more in subsequent groups of participants, until they reached a level 10 000 times the initial dose. A few volunteers developed short-lived infections, but these quickly vanished.
“We were quite surprised,” says Susan Jackson, a study clinician at Oxford and co-author of the latest study. “Moving forward, if you want a Covid challenge study, you’re going to have to find a dose that infects people.”
Despite their immunity to the ancestral strains, nearly 40% of the participants experienced an Omicron infection after being released from quarantine by December 2022, and one even got it twice.
An ongoing Covid-19 challenge trial at Imperial College London, in which participants have been exposed to the Delta SARS-CoV-2 variant, has also encountered problems with infecting participants reliably, says Christopher Chiu, an immunologist and infectious-disease physician at Imperial who is leading that trial and was involved in the other challenge trials.
Some participants have experienced infections, but probably not enough for a study testing whether a vaccine works, adds Chiu.
“We need a challenge strain that’s more representative of what’s circulating in the community,” says Anna Durbin, a vaccine scientist at Johns Hopkins University School of Medicine in Baltimore, who was a member of the board that oversaw the safety of the latest ‘reinfection’ trial.
Viral strains used in challenge trials are produced under stringent conditions, a process that can take six months or longer, say scientists, making it impossible to match circulating variants perfectly. McShane and Chiu are readying a challenge trial using the BA.5 Omicron subvariant that emerged in 2022.
Raising doses
Researchers are looking at other ways to give people Covid-19. Jackson says that an even higher SARS-CoV-2 dose might be needed – one similar to doses used in influenza challenge trials, in which participants have substantial immunity.
Another method could be giving participants multiple doses. Chiu says that his team is exploring the possibility of screening potential participants to identify those with low levels of immune protection against the BA.5 variant and any future challenge strains.
Chiu is leading a consortium that in March was awarded US$57m by the European Union and the Coalition for Epidemic Preparedness Innovations (CEPI), in Oslo, to use challenge trials to test inhaled and intranasal Covid-19 vaccines that might also block transmission.
He’s hopeful that such changes to trial protocols will do the trick. “What you really want is a model that replicates a genuine infection and ideally one that cause some symptoms,” he adds.
Study details
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 Marshall, Andrew Mawer, Raquel Lopez-Ramon, Stephanie Harris, Iman Satti et al.
Published in The Lancet Microbe on 1 May 2024
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.
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.
Nature article – Scientists tried to give people COVID — and failed (Open access)
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Infection from Covid gives same immunity as jabs – US meta-analysis
Decoding some of Covid’s mysteries, four years on
Why some people don’t get sick from Covid-19 – US study
Omicron infection improves immunity more than boosters – 2 US studies