LONDON - The world’s first COVID-19 human challenge trial is due to start in London next year, after the government announced £33.6 million (US$42.5 million) funding for the project.

In the initial phase, the aim is to establish the dose of SARS-CoV-2 needed to cause infection and to characterize the immune response to virus. That will lead on to tests of individual COVID-19 vaccines, in which volunteers will be challenged with the effective dose of SARS-CoV-2 one month after inoculation.

Of the funding, £10 million will go to human challenge specialist Open Orphan plc, to pay for manufacture of the SARS-CoV-2 virus, and for the work to characterize the immune response to infection to create the challenge model that can be used to assess efficacy of vaccines.

The government also has reserved three slots with Dublin-based Open Orphan to test COVID-19 vaccines in 2021, at a cost of £2.5 million per slot. Open Orphan will do the research in collaboration with U.K. experts led by Imperial College London.

To develop the challenge model, up to 90 volunteers, ages 18 to 30, will be infected with SARS-CoV-2 using a nasal spray, at a biosecure facility at the Royal Free Hospital, London. The dosing study will establish the level at which the virus infects the upper respiratory tract, with volunteers remaining in isolation for up to two weeks and being monitored 24 hours a day.

The study will look at the biochemical and immunological response, to set a base for the vaccine challenge studies. There is “enormous power” to look at the earliest stages of infection, before any symptoms are displayed, said Peter Openshaw, professor of experimental medicine at Imperial College. “You can find things you can’t get from studies in the community; you get immunological data you can’t get otherwise.”

With levels of COVID-19 on the rise worldwide after a summer lull, it now seems likely that one or more of the most advanced COVID-19 vaccines could complete development and be approved before the challenge model is ready, around May next year.

However, the model will make it possible to directly compare vaccines against each other, and to weed out products at the earlier stages of development, before they are moved into expensive phase III trials. Openshaw said that with 250 vaccines coming through the pipeline worldwide, a valid challenge model will test the strength of the innovative technologies on which many are based, and “greatly accelerate” development.

“The evolving vaccines landscape may be a very dynamic one. We need a way of comparing head-to-head, to see what [a vaccine] does to the immune system and how it protects against infection,” said Openshaw.

Open Orphan’s subsidiary, Hvivo, has a long history of making respiratory viruses for challenge studies. The SARS-CoV-2 virus to be used to develop the model will be a full strength strain based on samples from a network of 200 hospitals around the U.K. that was set up in the wake of the 2009 flu pandemic to be ready to identify and collect clinical samples.

“Keep in mind, the ultimate aim. It needs to be a model that is very useful for testing vaccines, so the virus has to be representative of what is circulating,” said Andrew Catchpole, scientific director of Hvivo. “It is not attenuated in any way.”

Matching the virulence of the manufactured virus to the wild type also means that data from challenge studies will read across to data collected in the community, Catchpole noted.

The virus is now being manufactured at Great Ormond Street Children’s Hospital, which has two decades of experience in making cell and gene therapies for clinical trials.

All the volunteers will be thoroughly screened beforehand to eliminate people with risk factors such as diabetes and hypertension.

Subjects will be routinely treated with Gilead Sciences Inc.’s antiviral, Veklury (remdesivir), as rescue remedy once they are infected.

“We are trying to reduce risk as much as possible. The plan is to treat [volunteers] as soon there is a confirmed viral infection, using remdesivir,” said Chris Chiu, consultant in infectious diseases at Imperial College, who is principal investigator for the study.

“Our number one priority is the safety of volunteers. My team has been safely running human challenge studies with other respiratory viruses for over 10 years,” Chiu said.

Data from the World Health Organization-sponsored Solidarity trial that reported last week cast doubt on the effectiveness of remdesivir, showing there was no impact on mortality or length of hospital stay. However, Chiu said, “This is a very different scenario because our volunteers won’t be sick.” Based on nonhuman primate data, remdesivir is expected to limit the spread of the virus into the lower respiratory tract, preventing more severe symptoms, he said.

Protocol design, approvals up next

It is not known at this stage which vaccines will be assessed first. “The challenge model is being set up without preconception about any particular vaccine being tested,” Catchpole said. It will fall to the U.K. vaccines taskforce, which has agreed advance purchase deals for a number of different products, to decide.

The final protocol for the challenge study is being drawn up and regulatory and ethical approval must then be given before it can start.

Among the aspects for the ethics committee to consider will be how much volunteers are paid. Catchpole said this is finely calibrated to ensure the financial returns do not incentivize volunteers. “It’s about compensating them for their time, not to get them to take a risk,” he said.

The imperative to keep the risk as low as possible means people in black, Asian and other ethnic groups that have been shown to be at greater risk of severe COVID-19 infection, will not initially be involved in the study. Chiu said it is hoped to widen inclusion criteria once the lowest infective dose of the virus is established.

As things stand, it is not intended to recruit older people, despite them being at greater risk and therefore more in need of the protective effects of a vaccine.

“Challenge studies don’t replace all the ways of testing vaccines. It’s a fast track way of seeing if a vaccine has potential. It won’t replace the need to test vaccines in more vulnerable groups,” said Chiu.

In addition, testing in young volunteers is the best way to gauge how good a vaccine is, Chiu noted. “We know from almost every vaccine in existence that young healthy adults make the best immune response. If you’re not seeing an immune response in healthy volunteers, it won’t work in older people,” he said.

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