A clinical trial for a coronavirus vaccine candidate developed by researchers at the University of Oxford will begin today in the U.K., the first trial of its kind in the country, said U.K. Health Secretary Matt Hancock in a recent press briefing. The U.K. government has pledged to support the trial with £20 million in government funding to support Oxford University’s ChAdOx1 nCoV-19 coronavirus vaccine program, and another £22.5 million to fund Phase II testing of a coronavirus vaccine in development by Imperial College London, which is projected to start human testing in June.The Imperial College London funding will also be used to help prepare for Phase III studies.
“We will throw everything we’ve got at developing a vaccine,” Hancock added. “The U.K. is at the forefront of the global effort … and for all of the efforts around the world, two of the leading vaccine developments are taking place here at home, at Oxford and Imperial.”
The start of human testing in the U.K. coincides with Germany’s regulator, the Paul-Ehrlich-Institut, giving German biotech BioNTech and partner Pfizer the green light to start the first coronavirus vaccine clinical trial in the country. “This is the fifth authorized clinical trial worldwide in which a preventive specific COVID-19 vaccine candidate is tested in humans,” the Federal Institute for Vaccines and Biomedicines said.
The Phase I/II study will evaluate the BNT162 vaccine program. Clinical trials are also expected to start in the United States upon regulatory approval, which is anticipated shortly, Pfizer said. The first part of the clinical study in Germany will test variants of the vaccine in 200 healthy volunteers aged 18–55 years. The second part of the study will be expanded to include volunteers who are at an increased risk of infection or increased risk of serious COVID-19 disease.
The Oxford vaccine project is headed by professors Sarah Gilbert, PhD, group head, Andrew Pollard, PhD, professor, pediatric infection and immunity, and Teresa Lambe, PhD, senior scientist, together with Sandy Douglas, DPhil, MRCP, DipPharmMed, group head and Adrian Hill, PhD, professor of human genetics. The team started work on designing a coronavirus vaccine on January 10, 2020. Their vaccine candidate is based on a nonreplicating chimpanzee adenovirus vector, ChAdOx1, which was originally developed at the Jenner Institute. Engineered to encode the SARS-CoV-2 spike protein, the ChAdOx1 nCoV-19 construct is designed to trigger production of the viral protein which then primes the immune system to recognize SARS-CoV-2 infection. The Phase I ChAdOx1 nCoV-19 trial will be carried out through a collaboration between the Oxford Vaccine Group’s clinical teams and the University’s Jenner Institute, and include 510 volunteers aged 18–55 years.
“Although it seems like a very long time since the work started, in reality, it is less than four months since we first heard of an outbreak of severe pneumonia cases, and began to plan a response,” the team said in a statement. “This week we will start the process of vaccine evaluation in our first human studies and are currently focusing all efforts on preparing for the start of the trials … Our brilliant team has been working tirelessly to get to this point using our skills and experience in vaccine development and testing, and will do the best job possible in moving quickly whilst at all times prioritizing the safety of the trial participants.”
Gilbert and team had previously developed a vaccine for Middle East respiratory syndrome (MERS), which showed promise in early clinical trials. “The Oxford team had exceptional experience of a rapid vaccine response, such as to the Ebola outbreak in West Africa in 2014, said Hill, who is director of the Jenner Institute at the University of Oxford. “This is an even greater challenge. Vaccines are being designed from scratch and progressed at an unprecedented rate. The upcoming trial will be critical for assessing the feasibility of vaccination against COVID-19 and could lead to early deployment.”
While early clinic evaluation gets under way, ChAdOx1 nCoV-19 vaccine manufacture is already being scaled up in preparation for larger trials. “The scale of this epidemic poses a huge challenge for vaccine manufacturing,” said Douglas, who is leading the vaccine manufacturing scale-up work. “We need to follow rigorous safety standards and that takes time. By starting work on large-scale manufacturing immediately, we hope to accelerate the availability of high quality, safe vaccine.”
Vaccine development usually takes more than five years, and even the high-speed 12–18 months development timeline projected for the Oxford ChAdOx1 nCoV-19 vaccine must encompass preclinical and clinical evaluation, and manufacturing process development. Squeezing development into this expedited projected timeframe has been possible by bypassing potential hurdles. Adapting an existing vaccine platform for the new pathogen shortens initial development timelines, while carrying out manufacturing scale-up in parallel with early trials process can also shorten timescales. Regulatory review in emergency situations will be prioritized to reduce delays.
If development of the ChAdOx1 nCoV-19 vaccine continues to plan, then Phase II studies following on from successful Phase I evaluation will extend the age range of trial participants to 55–70 years, then to the over 70s, before progressing to Phase III evaluation in 5,000 volunteers aged 18 years and over. It’s feasible that efficacy data from the Phase III trial could be generated by autumn 2020, in parallel with the achievement of large-scale manufacturing capacity, the team suggested. However, they noted that these “best-case timeframes are highly ambitious and subject to change.”
Imperial College London’s self-amplifying RNA vaccine, developed by a team led by Robin Shattock, PhD, at the department of infectious diseases, is designed to trigger muscle cells to produce the SARS-Co-2 spike protein that will stimulate the immune system to generate neutralizing antibodies against the virus. Tests in animals have been underway since February, and clinical trials could start in the summer, the team projects.
Imperial College London announced that it will also act as one of the key sites for Oxford’s ChAdOx1 nCoV-19 vaccine, and is recruiting volunteers. David Owen, MD, PHD, head of clinical studies at NIHR Imperial Clinical Research Facility, said the university is “delighted” to support the Oxford team delivering the trial.Commenting on the U.K. government funding, Shattock said, “This investment will help us accelerate our clinical program moving from starting human safety trials in June through to testing whether the vaccine can prevent infection in the wider community. We are working as fast as we can to determine the vaccine’s efficacy and to get to a position where millions or billions of the vaccine can be manufactured rapidly.” Shattock had previously indicated that the vaccine could be available during 2021, “if all goes well.”
In Germany, BioNTech and Pfizer are planning on carrying out clinical evaluation of the first four vaccine candidates to come out of their global “Lightspeed” COVID-19 vaccine development program. Each candidate represents a different mRNA format and target antigen. Two of the four vaccine candidates are nucleoside modified mRNA (modRNA) vaccines, a third is a uridine containing mRNA (uRNA), and the fourth vaccine candidate utilizes self-amplifying mRNA (saRNA). Each mRNA format is combined with a lipid nanoparticle (LNP) formulation. Two of the candidates incorporate the larger spike sequence, and the other two encode the smaller optimized receptor-binding domain (RBD) from the spike protein. The RBD-based candidates contain the piece of the spike that is thought to be most important for eliciting antibodies that can inactivate the virus.
The first Phase I/II dose-ranging study in Germany will evaluate the effects of repeat immunization for three of the four vaccine candidates that utilize uRNA or modRNA. “We are pleased to have completed preclinical studies in Germany and to have received this important regulatory approval to initiate this first-in-human trial,” stated Ugur Sahin, CEO and co-founder of BioNTech. “The speed with which we were able to move from the start of the program to regulatory approval to initiate this first-in-human trial speaks to the high level of engagement from everyone involved.”