How COVID-19 challenge trials will be shaped by emerging data
The CRO behind the first COVID-19 human challenge trials plans to adapt its inclusion criteria and endpoints as the risks of SARS-CoV-2 infection become better understood.
Critics worry that lingering uncertainty about the virus’ effects means human challenge trials are still too dangerous, and that the exclusion criteria used to reduce the studies’ safety risks will limit the utility of their results.
Yet the intentional infection strategy is increasingly being seen as a way to make evidence-based comparisons across vaccines, particularly as the availability of first-generation of products makes it more difficult to recruit participants for placebo-controlled trials of next-generation candidates.
“A number of questions about vaccines will be answered with more confidence more quickly by permitting them than not,” Arthur Caplan, head of the Division of Medical Ethics at New York University School of Medicine, told BioCentury. “Challenge trials are advantageous because they may speed the comparative assessment of vaccines.”
The hVIVO subsidiary of Open Orphan plc (LSE:ORPH) announced Tuesday contract of about £10 million ($12.9 million) with the U.K. government to manufacture viral stocks and perform first-in-human characterization studies to determine the appropriate SARS-CoV-2 dose for future vaccine studies. The characterization studies, which are awaiting regulatory and ethical review and are expected to finish in 2021, will be conducted together with The Royal Free Hospital in London.
The U.K. government also paid hVIVO an additional £7.5 million ($9.7 million) to reserve three slots to test vaccine candidates using the human challenge model; these studies are expected to start in 2021, most likely after at least one first-generation candidate is already authorized for emergency use.
hVIVO has eight human viral challenge models in its portfolio, including influenza, respiratory syncytial virus (RSV) and human rhinovirus.
CSO Andrew Catchpole told BioCentury the models are typically used after Phase I studies to decide which candidate to advance to larger trials. For COVID-19, it will also be important to use them for late-stage vaccines to enable comparisons to newer candidates, he said.
According to Catchpole, hVIVO determined it was an appropriate time to initiate a human challenge model because there was enough known about which strains of virus are predominant in the population, and about what broad categories of people are at higher risk for severe disease.
He said the company is “continuously trawling data” on COVID-19 risk, and updating its inclusion criteria as new insights emerge, including research on genetic predisposition to severe disease.
The infection characterization study is recruiting patients aged 18-30, and excludes people with respiratory issues such as asthma patients, or smokers.
Preliminary data from COVID-19 vaccine trials suggests immunity may vary widely between younger and older adults, which could limit the predictive power of challenge studies in the former.
But Catchpole said data from younger people could be used to identify immune correlates of protection, which could then be used to assess vaccine efficacy in older adults.
He said the age range for human challenge trial participants could expand as the virus’ effects on different age groups become better understood, adding that the company’s influenza challenge trials recruit patients up to age 64, and its RSV trials recruit those as old as 74.
Determining how to incorporate ethnicity in the study’s inclusion criteria is “much harder,” as data are still emerging, Catchpole said.
“We expect the very first volunteers are likely to be Caucasian, but as soon as we’re able to, we of course want to widen this trial to include as many ethnic groups as possible,” when the company believes it has enough data to determine those participants aren’t at higher risk, he said.
hVIVO is also reducing risk by adapting its typical respiratory virus challenge procedures to the threats posed by COVID-19.
For example, the company is using a containment facility under negative air pressure to reduce the risk of viral particles infecting individuals outside the study, and including additional safety monitoring procedures including X-rays to assess lung function.
Another key difference from past studies is that the company will administer antivirals to all participants regardless of symptoms because of the high likelihood that the young trial participants will be asymptomatic, and emerging evidence that COVID-19 can cause “silent” tissue damage in seemingly healthy individuals.
Participants will be tested for SARS-CoV-2 infection via nasal swab tests twice per day, and treated with an antiviral therapy as soon as infection is confirmed. Those who do not test positive during the expected time window will also be treated, likely four or five days after exposure, Catchpole said.
The plan is to treat participants with Veklury remdesivir from Gilead Sciences Inc. (NASDAQ:GILD); however, Catchpole said that could change if more effective antiviral therapy becomes available, including mAbs, which are expected to be authorized soon.
Instantly treating participants means the human challenge trials will be able to determine whether vaccines reduce viral load and transmission capability, but not the incidence or severity of symptoms.
“We’re not setting up an illness model per se , we’re setting up an infection model. We’re actually designing the trial to minimize the risk of even seeing any clinical symptoms at all,” said Catchpole. “When we start to see data, and hopefully get good confidence that this is well tolerated, we might be able to remove or delay the treatment with antivirals, which will enable us to have a wider range of endpoints.”
Washington Editor Steve Usdin contributed reporting to this article.