As the definitive year of 2020 draws to a close, news of another vaccine candidate brings more much-needed hope that the curtailing of the COVID-19 pandemic is nigh. On November 23rd, a press release from the partnership between pharmaceutical firm AstraZeneca and the University of Oxford announced the anticipatory preliminary analysis of their ChAdOx1 nCoV-19 vaccine candidate. Strikingly, the accidental, yet fortuitous, discrepancy in dosing regimes in the phase III trial has spurred initial controversy over the reliability of the safety and efficacy claims being made. With the interim results from the phase III trial now published in The Lancet, we can perhaps come to appreciate this landmark scientific discovery, which may well have initiated one of the most paramount turning points in infectious disease history of our time.
The science of vaccines, simplified
Vaccines work by exposing our immune systems to a safe level of a pathogen’s antigen to stimulate the programming of T cells and the creation of antibodies. Let’s break that down:
- pathogens are disease-causing microorganisms, such as viruses, bacteria, fungi, and parasites;
- antigens are, usually, protruding proteins that surround the exterior surface of pathogens;
- T cells makeup part of the immune system and are responsible for recognising, responding to, and remembering antigens;
- antibodies are also part of the body’s natural immune response and their role is to attach to antigens which leads to pathogen elimination.
Each pathogen has a unique molecular makeup, ergo each antigen has a unique structure. The immune system has to learn how to recognise the antigen’s disease-specific shape and create a ‘bespoke’ antibody that will attach to it. the immune system can struggle to create the right antibody in time if the body is exposed to a novel pathogen that can cause severe disease such as the case of the SARS-CoV-19.
This is where vaccines step in. Vaccines harness the awesome powers of the body’s natural immune response by delivering a safer version of the antigen: one which stimulates a broad immune response without causing full-blown disease. Our immune system can then practice building the right tools to overcome disease when the threat of disease is not too severe., such as the aforementioned T cells and antibodies. This prior stimulation induced by vaccination means if a vaccinated person is exposed to the corresponding pathogen later on, the immune system already has the right T cells and antibodies ready to go.
The Trial and Tribulations
The AstraZeneca-Oxford vaccine candidate was developed using adenoviral vector technology, which researchers based at the Jenner Institute at the University of Oxford have been studying for over a decade. The scientists genetically modified a virus known as an adenovirus, which typically causes colds in chimpanzees. The genetic alteration made the adenoviral vector contain the coronavirus antigen—the infamous spike protein—and ensured that the vector would not replicate itself inside the body, avoiding the causation of disease.
Fast forward to the phase III clinical trial, the viral vector is administered in two doses given four weeks apart. Approximately 3,000 participants were accidentally given a half dose followed by a full dose four weeks later. Excitingly, 90% of this cohort appeared to be protected against COVID-19. Alternatively, efficacy dropped to 62% in the larger group where nearly 9000 volunteers were given the intended two full doses also four weeks apart. AstraZeneca-Oxford combined these efficacy rates, claiming the candidate has, on average, 70% efficacy at preventing Covid-19.
The researchers at the Jenner Institute are still trying to decipher what exactly happened to create such a large difference in efficacy. Many critics have postulated that the problem lies in the data set and/or the arguably problematic way in which the trial was conducted. Prof David Salisbury, immunisation expert and associate fellow of the global health program at the Chatham House think tank, said:
“You’ve taken two studies for which different doses were used and come up with a composite that doesn’t represent either of the doses. I think many people are having trouble with that.”
For example, it could simply be a matter of not enough data being collected. The restricted number of volunteers in the subgroup could make the differences calculated statistically insignificant and efficacy rates may even out as the sample size increases. Moreover, the accidental subgroup only contained participants under the age of 55, a subset of the population that is less vulnerable to COVID-19.
Though initially controversial and confusing, the discrepancies revealed in the first press release have pique considerable curiosity now that the interim results have been published. Richard Horton, editor-in-chief of The Lancet, shares:
“This study is the very first peer-reviewed evidence that this particular type of vaccine platform, the adenoviral vector, can actually stimulate an immune response that protects against getting severe COVID-19…although still lots of questions remain…I think it is worth just pausing to say this is a stunning achievement.”
The researchers working on the candidate argue that gauging the difference is likely to not be a matter of anomalies and are exploring the potential biological mechanisms underpinning efficacy rates. It is suggested that the lower first dose is either more effective at stimulating T cells or at establishing memory, which is triggered by a second dose boost. It is also possible that the mystifying effects are a combination of both hypotheses – only further study can tell.
What is special about the AstraZeneca-Oxford candidate?
Despite the discussed pitfalls of the trial, the promises that the AstraZeneca-Oxford coalition aims to offer cannot pass unnoticed. The research group has been working on adenoviral vectors for over a decade, previously focussing on infectious diseases that usually receive less attention and funding. With the onset of the pandemic, the Oxford researchers put all other vaccine projects on the back burner—or, rather, the refrigerator—and pivoted their work. With the garnered support and mobilization of funding, the researchers were able to deliver what seems to be a safe and effective vaccine candidate within 8 months.
From the outset, the partnership aimed to develop a low-cost, easily distributable vaccine: committed to ensuring the availability and accessibility of this preventative medicine in low-resource settings. The vaccine was carefully designed so that it would cost US$2-3 per dose and be easily distributed within existing, potentially limited, healthcare infrastructures.
Currently, not only do pharmaceutical giants Moderna and the Pfizer and BionNTech partnership all seek to gain profit from their candidates, but the RNA technology also necessitates being kept at −70 ºC until shortly before administration. This presents an expensive logistical nightmare for many healthcare administrators, particularly those in low and middle-income settings rendering the RNA vaccines out of reach to many. In light of this, the AstraZeneca-Oxford vaccine is a welcomed, equitable addition to the growing toolkit to overcome the virus.
The Wrap Up
Indeed, there are still some puzzle pieces about the trial that need to be put together. The loose strings left in the interim results don’t tell us, for example, how long protection lasts and if vaccinated persons are still contagious. And, yes, more data does need to be collected about the dosing discrepancy along with more robust knowledge of the evoked immune response.
Nevertheless, what a truly remarkable feat that exemplifies what can be achieved when funding agencies and scientists underpinned by bioethical framework combine efforts. 2020 was tumultuous, to say the least, but to close with what will most likely be one of the most definitive global health success stories of the 21st century is an incredible tenet of progress to have potentially witnessed: a testament to the tenacity of humans in the face of great challenge.