COVID-19 Challenge Trials Struggle to Infect Participants Amid High Immunity Levels
Efforts to test vaccines and treatments via controlled infections face hurdles as participants show robust resistance to ancestral virus strains. Natural immunity was strong among the unvaccinated.
In a series of COVID-19 'challenge' trials, researchers at institutions like the University of Oxford and Imperial College London encountered significant difficulties in infecting participants with SARS-CoV-2. The initial trials, which began in 2021, aimed to deliberately infect individuals to quickly evaluate the effectiveness of vaccines and treatments.
Initially targeting people without prior exposure to the virus, the studies used minimal doses of an ancestral strain. Despite increasing the virus dose up to 10,000 times, the trials largely failed to achieve sustained infections due to high levels of pre-existing immunity among participants.
Out of the 36 participants in the study, none of them developed sustained infection despite being inoculated with increasing doses of the SARS-CoV-2 virus. However, 14% of the participants experienced transient infection, which means they showed short-lived detection of the virus by PCR but did not have evidence of persistent viral replication. These findings suggest that the participants' natural immunity played a significant role in preventing sustained infection upon re-exposure to the virus.
With over 99% of the UK population and 59% of the global population reported to be seropositive to SARS-CoV-2, through vaccination or natural infection, a CHIM that can be used for therapeutics or vaccine development will need to reflect the dynamic range of immune protection from hybrid immunity (immunity arising from a combination of SARS-CoV-2 infection and vaccination) in the real-world population. Typically, CHIMs in individuals with pre-existing immunity require higher doses of the infectious challenge than needed in naive volunteers.
Later trials included individuals who had recovered from natural infections or had been vaccinated. Nearly 40% of participants contracted an Omicron variant after the study, highlighting the gap between the challenge strains used and circulating variants.
Natural immunity to COVID-19 fared well overall according to the study.
The study found that natural immunity alone, without vaccination, provided potent protective immunity against COVID-19 in seropositive individuals. Despite not being able to induce sustained infection in any volunteers with previous infection, the research demonstrated that those individuals had robust immune responses that protected them from developing severe or sustained infection upon re-exposure to the virus.
The findings suggest that current challenge trial methods may need significant adjustments. Researchers are considering higher doses of the virus, multiple dosing strategies, and selecting participants with lower immunity levels to more accurately represent community virus transmissions. Additionally, a new challenge trial focusing on the BA.5 Omicron subvariant is being planned, alongside innovative approaches to test vaccines that could prevent transmission.
These developments underscore the complexities and ethical considerations in using human challenge trials for pandemic research, despite their potential to expedite vaccine and treatment testing.