Covid-19 vaccines

26 April 2020

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Clinical trials are now underway on a novel vaccine against COVID-19 developed by scientists at Oxford University. The vaccine has been developed at a rapid pace but the signs are looking good that it may prove effective in humans.

The new vaccine has been developed at the Jenner Institute for Vaccine Research at the University of Oxford. Dubbed ChAdOx1 nCoV-19, at its core is a chimpanzee adenovirus called ChAdOx1. This has been modified to remove an essential viral gene called E1. Without this, although the virus can successfully penetrate into human cells, it cannot produce new virus particles. This means that it cannot spread beyond the first cells it infects, making it very safe. And the use of a chimpanzee virus, which humans will not naturally have encountered, avoids problems of pre-existing immunity, which could occur if a human adenovirus were used. Human adenoviruses are common cause of the common cold, so many people already have antibodies against them.

To propagate their modified chimpanzee adenovirus, the Oxford team use cultured cells that have been specially engineered to produce the “missing” E1 gene product that their modified virus lacks. This is called a complementing cell line, and it will be critically important for the future mass production of the ChAdOx1 nCoV-19 viral vaccine.

Led by Prof Sarah Gilbert, the team at Oxford produced their candidate Covid-19 vaccine by adding to their ChAdOx1 chimpanzee virus the gene that the SARS-CoV-2 coronavirus uses to make its spike protein. The spike is the essential component that the virus uses to penetrate into our cells, so an immune response that targets this part of the virus should be capable of blocking infection.

In essence, the modified chimpanzee adenovirus is acting as a Trojan horse that delivers the coronavirus spike gene into our cells. As the chimpanzee adenovirus cannot replicate, the cells that take in the viral vaccine produce only the coronavirus spike protein, which they churn out in large amounts and display to the immune system.

The result is that immune cells are tricked into thinking that we have been infected with SARS-CoV-2 for real. The immune system mounts a response leading to the production of both antibodies, and a class of white blood cells called CD8 lymphocytes, that recognise the “Trojan” coronavirus infection. The antibodies will be able to recognise and neutralise the spikes on the outside of SARS-CoV-2 virus particles, preventing infection, while the CD8 cells are capable of identifying and destroying virus infected cells. Critically, the response also involves laying down an “immune memory” of the encounter that can be called up rapidly at a later date.

There are reasons to be optimistic about the Oxford University approach of using a chimpanzee adenovirus-based vaccine like this. Prior to the current COVID-19 outbreak, the team had already built up considerable expertise in the development of a vaccine against a close relative of SARS-CoV-2 called Middle East Respiratory Syndrome coronavirus (MERS-CoV). MERS-CoV emerged in 2012 in Saudi Arabia and is also a respiratory pathogen that passes from camels to humans. Although the mortality rate of MERS-CoV is higher than that of Covid-19, this virus has not evolved sufficiently to spread efficiently from human to human so, to date, a pandemic has been averted. Nonetheless the MERS virus remains a potential pandemic threat and this has been recognised by the WHO and the Coalition for Epidemic Preparedness Innovation (CEPI). 

The Oxford team have recently shown that a ChAdOx1 vector expressing the MERS-CoV spike protein provides strong protective immunity in experimental animals, and the virus has safely completed a Phase 1 clinical trial. The stage is therefore set for the establishment of clinical trials to determine the efficacy of both the MERS and COVID-19 vaccines.

To date, all signs are encouraging and the results of the efficacy trials will be eagerly anticipated. But many questions remain to be answered. Should the trial show that the vaccine can protect against COVID-19 in healthy volunteers, it will be important to determine whether similar protection can be obtained in high risk groups such as the elderly and those with co-morbidities such as diabetes and heart disease. Will all vaccinated people respond in the same way, and for how long will immunity last? And will some people at high risk owing to a suppressed immune system, like transplant recipients or some patients with HIV, respond effectively?

At present we do not know exactly what level and types of immune responses are necessary for protection against Covid-19 infection. Given our lack of knowledge, it will be important to determine whether the vaccine is capable of consistently inducing levels of protective immunity in vaccinees of different ages, sex and ethnicity. Finally we shouldn’t underestimate the logistical problems associated with large scale manufacture of an adenovirus-based vaccine. This is a complex vaccine to manufacture and relies on infection of complementing cell lines to produce large amounts of the vaccine virus, which then has to be purified, concentrated and assayed so that each vaccination dose has a precise quantity of intact adenovirus capable of  reliably inducing a protective immune response in a vaccinee. This is not a trivial task to do at a large scale and in a way that ensures consistency of the quality of each vaccine batch manufactured. These are not insurmountable problems, but it will take time and huge effort to get right.

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