As the rate of daily COVID-19 cases within the UK rapidly rises, the race to find a safe and effective vaccine has never been so critical. Oxford University is one of the many establishments working at unprecedented speeds at the forefront of this search and are currently running Phase III human trials for their ChAdOx1 vaccine.
Under normal circumstances, the development of a vaccine is often a long and complex process, usually spanning years or even a decade. This process includes multiple assessments to determine the efficacy and safety of the vaccine, in addition to any necessary modifications that need to be made to the vaccine or study design. It is important to acknowledge that these stages cannot be looked over, due to the escalated pressure of the global threat, but are indeed just as crucial.
On the 6th of September 2020, the Oxford/AstraZeneca study had come to a pause, which triggered a disconcerting response from the general public. The voluntary pause was prompted to allow an independent safety review committee to review the safety data of the trial. Although there is speculation that a trial participant had experienced an adverse reaction to the vaccine, details of the events that elicited a safety review have been kept confidential as well as any medical information regarding the illness of the participant.
The public’s interest in clinical trials has never been greater, with high hopes and expectations resting in the hands of researchers. News of the halt, undoubtedly, sparked worry amongst the public; questioning the safety of the vaccine. However, study pauses, such as this one, are often routine action within trials and represent how rigorous the development process actually is.
Upon independent review, the trial resumed in the UK on the 12th of September, following the recommendations received by the independent safety review committee and the MHRA. Before the pause, the trial had entered its third phase at the end of July. Trials began in April 2020 where 1077 healthy volunteers were recruited across multiple sites located around England to receive either the candidate vaccine (ChAdOx1 nCoV-19) or the ‘control’ licensed vaccine (MenACWY).
Participants were blinded to which one they had received and were asked to record any symptoms they experienced for the 7 days following the administration of the vaccine and if they felt unwell in the following 3 weeks. Induced immune responses to the vaccines were monitored through testing neutralising antibody and T cell responses from blood samples taken from participants during follow-up visits.
Whilst Phase II of the study focused on expanding the age ranges of the participants to assess any differences in the immune responses between children and older people, Phase III assesses how well the vaccine works in a large population over the age of 18. This part of the trial has been extended internationally, to Brazil, South Africa and the USA, which of course were also paused when the safety data were being reviewed. Phase III trials will now also begin in the city of Pune starting next week.
In order to assess the efficacy of the vaccine, the number of infections in the control group will be compared to the number of infections in the vaccinated group. Assessing the efficacy of the ChAdOx1 nCoV-19 vaccine could take a long time due to low transmission rates. This is why the study has prioritised frontline healthcare workers and key workers across multiple locations in which the transmission rates vary, to increase the chances of attaining an efficacy endpoint as soon as possible.
The ChAdOx1 vaccine technology has previously been used to develop candidate vaccines against pathogens such as Zika, Middle East Respiratory Syndrome (MERS) and the Flu and was being used to prepare pandemic procedures for ‘Disease X’. Therefore, when the virus had surfaced in China last year, the teams moved swiftly to commence the development of a new vaccine as soon as the genetic sequence of the virus was available.
The particular piece of genetic material used in the ChAdOx1 vaccine encodes for a ‘spike protein’ (S-protein) found on the surface of the virus. The spike protein is responsible for 2 primary tasks which play a vital role in host infection. The spike protein acts as the mediator between the host cell receptors and the virus, after which the protein assists the fusion between the host cell membrane and virus membrane, facilitating the virus’ entry into the cell.
Spike proteins are produced in the cytoplasm, which means that it does not affect the cell’s own DNA (genetic material). Once produced, the body’s immune system can recognise the protein as a foreign virus and initiate a neutralising antibody response, consequently providing protection from the whole virus in the future.
The Oxford vaccine is a chimpanzee adenovirus vector modified so that it is unable to grow in humans and therefore unable to cause disease. It is a weakened and harmless adenovirus that usually causes the common cold in chimpanzees. This vector is ideal as it is safer to administrate to the elderly, children and those with pre-existing conditions. Through genetic sequencing the ChAdOx1 viral vector is engineered to match the spike protein found on SARS-CoV-2.
Administration of the vaccine should induce an appropriate immune response which primes the immune system to be able to fight against the coronavirus if that person becomes infected. If this vaccine proves to be successful, Oxford University is prepared to produce and scale up distribution, in agreement with AstraZeneca.
Their aim is to work with the British government to ensure that the vaccine is made fairly available as soon as possible in sufficient quantities to the entire UK population. As per agreement with AstraZeneca, countries who are facing the worst effects of the coronavirus will be priority when making the vaccine available, granting them early access.
As always, with any treatment, there are many factors that influence effectiveness. It is unlikely that one vaccine will have the same effect for the entire population, which is why it is crucial that vaccine development projects around the world work together to produce multiple vaccines appropriate for all.