LONDON – Researchers at the Jenner Institute in Oxford have given an inside view of how they are accelerating clinical development of a COVID-19 vaccine and at the same time putting in place commercial manufacturing for when phase III efficacy data are available, expected in August or September.

Alongside expediting internal research, the Jenner has pulled together a consortium of companies in India, China, Europe and the U.S., to scale up the bioprocess for the product, ChAdOx1, and transfer it to commercial manufacturing facilities whilst the clinical trials are taking place. A total of 510 healthy volunteers have been recruited for phase I, with the first subject due to be dosed next week.

Sarah Gilbert, professor of vaccinology at Oxford University, said she is “80% confident” ChAdOx1, which uses a chimpanzee-derived adenoviral vector to deliver the genetic code for the spike protein through which the virus infects host cells, will be effective. If so, it would then be made available for emergency use.

“The aim is to have at least a million doses by about September, once you know the vaccine efficacy results, and then move even faster from there," said Adrian Hill, director of the Jenner.

If the product is not effective, “the money is wasted,” Hill said. But if it does work, the stage will be set to start larger-scale manufacturing. "It's pretty clear the world is going to need hundreds of millions of doses, ideally by the end of this year, to end this pandemic, to lead us out of lockdown,” he said. The intention is to apply for approval for emergency use, pending a full commercial license.

What gives the researchers confidence to do clinical and manufacturing development in parallel is their previous experience of using the chimpanzee adenoviral vector in the development of Lassa Fever, Nipah virus infection, MERS and SARS vaccines. The vector has been used in 12 clinical trials with more than 330 people vaccinated to date. A further 6,000 individuals have been vaccinated with a similar vector.

“I’ve worked with this technology a lot,” Gilbert said. “We know a lot about it; we see safety and a strong immune response,” she said. “Regulators and ethical bodies are familiar with it, so we can go faster.”

The Jenner group worked with contract manufacturers on those earlier studies, building expertise in the technology. “We are the only group using a chimpanzee adenoviral vector, which is relatively easy to manufacture and gives a higher yield; it’s five times better than other adenoviral vectors,” Hill said.

Fast off the mark

The team was fast off the mark because the underlying technology platform was designed as the basis for developing a vaccine against “Disease X.”

“That is the name given to the unknown disease that was going to come and cause a pandemic. We’ve been putting plans into place to be able to go quickly,” Gilbert said.

When news of the COVID-19 outbreak first emerged in January, Gilbert decided that even if it was not going to spark a pandemic, it would be a good demonstration project to test the technology.

“We were following the progress of the outbreak and, from February to March, as things got worse, we changed gear and accelerated our plans,” said Gilbert.

The Jenner has a GMP-grade facility for manufacturing clinical trial supplies. “Once we got the viral genome, we were straight into production in a human cell line,” said Catherine Green, associate professor and head of the clinical biomanufacturing facility.

The first batches will have completed quality assurance and be ready for phase I in the next few days.

In preparation for phase I, the 510 healthy volunteers have been screened and are ready to be recruited into the study. Andrew Pollard, chief investigator, said that screening was a “huge logistical challenge” in the context of social distancing measures currently in place to limit transmission of the virus.

Unusually, the phase I is designed to generate both safety and efficacy data, with a control group receiving placebo. “We can see if the coronavirus vaccine prevents people from developing disease over the months ahead,” Pollard said.

In phase II, the vaccine will be tested in older adults who are more at risk of suffering severe infections, and the numbers in the younger age groups will be expanded. “All three phases will be recruited in the next few months – that normally takes five years,” said Pollard. “There are no changes in overall procedures, but there is urgency to move faster.”

As Pollard acknowledged, it is possible the trial is confounded as the rate of transmission of COVID-19 slows down. The idea of carrying out a challenge trial has been discussed, but Pollard said that would not be feasible until there is an effective therapy for use in case a volunteer developed the infection.

The team also is building on experience gained during the 2013 – 2015 Ebola epidemic, when four vaccines, including the chimpanzee adenovirus-based cAd3-ZEBOV, were tested at the Jenner in phase I trials. One of the gaps that work exposed was that it was not possible to compare the immunogenicity of vaccine candidates in advance of efficacy trials.

To avoid a similar situation in this case, Teresa Lambe, associate professor at the Jenner, has since January been working to develop assays for assessing antibody and T-cell responses. The work sets the scene for comparing the level of immune response seen in phase I studies of the many different COVID-19 vaccines that are in development, giving a sense of which are likely to be most effective in providing immunity.

“We are working through the World Health Organization assays and standards committee, and would be keen to work with other vaccines developers so we can compare immune responses,” Lambe said.

Caution is needed

They may have cause for optimism, but soon after the Jenner group gave the online briefing describing how they are accelerating their program, the U.K. government chief scientist Patrick Vallance, former chief scientist at Glaxosmithkline plc, urged caution. “The reality is a single project does not have a very high probability of success,” Vallance said in the government’s daily televised briefing on the pandemic and its response.

At the briefing, the government announced the formation of a national task force to coordinate public and private work to accelerate development and manufacturing of COVID-19 vaccines. Members of the task force, to be led by Vallance, include the research charity Wellcome Trust and Astrazeneca plc.

No Comments