Evidence suggesting an initial half dose of the vaccine being developed by drugs firm AstraZeneca and the University of Oxford is more effective than a full dose is counterintuitive, and even took the researchers by surprise.
Why would less be better than more when it comes to triggering an immune response?
Andrew Pollard, the director of the Oxford Vaccine Group, described the findings from the Phase 3 clinical trial as “intriguing”.
They showed that the vaccine had an efficacy of 62 percent among the people given two full doses a month apart.
But this rose to 90 percent for another group who received a half-dose first and then a full dose after a month.
“I think all of us expected that the two high doses would be the best response,” said Pollard, who noted researchers had only seen the details of the results over the weekend and would now start digging into the data.
“We think that by giving a smaller first dose, that we’re priming the immune system differently. We’re setting it up better to respond,” he told a press briefing.
Sarah Gilbert, professor at Oxford’s Nuffield Department of Medicine, said the better result with a smaller initial dose could be because this better “mimics what happens in a real infection”.
Essentially a vaccine uses a safe method to trick the immune system into believing it is dealing with a dangerous infection, triggering an immune response and an immune memory that can activate if the body comes across the real pathogen.
“It could be that by giving a small amount of the vaccine to start with and following up with a big amount, that’s a better way of kicking the immune system into action and giving us the strongest immune response,” Gilbert told reporters.
‘Trojan Horse’
The Astra/Oxford vaccine employs what is known as a “viral vector”, using engineered viruses to deliver genetic cargo into cells, giving them instructions on how to fight SARS-CoV-2.
The strategy uses the transporting virus as a “Trojan Horse”, said Colin Butter, Associate Professor at the University of Lincoln.
It is “complex and usually achieved experimentally: a luxury not available in the present situation”.
The technology itself may be the reason why an initial half-dose could work better, according to several scientists commenting on the results, with the immune system acting against the virus being used as a delivery vehicle.
“It may seem confusing that a higher initial dose gives a less favourable response, but this may just be due to a residual response in some patients to the disabled ‘vehicle’,” a snippet of chimpanzee virus used to deliver the vaccine “payload”, said Stephen Griffin, Associate Professor in the School of Medicine, University of Leeds.
But he said this could be “easily fixed” by using the adjusted dose.
Pollard said researchers would be looking to find out if the issue was the quantity or quality of the immune response.
He added that while with almost all single dose vaccines the higher the dose you give the better, methods based on priming the immune system first – and then later giving a booster – can work differently.
This is particularly the case with babies and infants, where you might have different numbers of priming doses, he said.
“I think the difference is that we’re not that used to dealing with infections like this coronavirus, which adult humans have never seen before,” Pollard said.
AZD1222 clinical trials now resumed globally
Clinical trials for the AstraZeneca Oxford coronavirus vaccine, AZD1222, have resumed across the world with regulators in the US, UK, Brazil, South Africa and Japan confirming that it was safe to do so.
The Food and Drug Administration (FDA) today authorised the restart in the US, following the resumption of trials in other countries in recent weeks. The FDA reviewed all safety data from trials globally and concluded it was safe to resume the trial.
As part of the standard review process for trial safety events, a voluntary pause to vaccination across all global trials was triggered on 6 September to allow the examination of safety data by independent monitoring committees. The recommendations from these reviews have been supported by international regulators, who also confirmed that the trials were safe to resume.
Pascal Soriot, Chief Executive Officer, said: “The restart of clinical trials across the world is great news as it allows us to continue our efforts to develop this vaccine to help defeat this terrible pandemic. We should be reassured by the care taken by independent regulators to protect the public and ensure the vaccine is safe before it is approved for use.”
It is not unusual that in large scale vaccine trials, some participants will become unwell, and every case has to be evaluated to ensure the careful assessment of safety.
Results from the late-stage trials are anticipated later this year, depending on the rate of infection within the communities where the clinical trials are being conducted. Data readouts will be submitted to regulators and published in peer-reviewed scientific journals. Rolling reviews of the vaccine programme have already begun in countries where this regulatory pathway has been established, providing regulators access to data as soon as they become available.
While trials are ongoing, AstraZeneca and Oxford University will continue to provide information to regulators, study investigators and participants according to clinical trial and regulatory standards.1-5
AZD1222
AZD1222 was co-invented by the University of Oxford and its spin-out company, Vaccitech. It uses a replication-deficient chimpanzee viral vector based on a weakened version of a common cold virus (adenovirus) that causes infections in chimpanzees and contains the genetic material of the SARS-CoV-2 virus spike protein. After vaccination, the surface spike protein is produced, priming the immune system to attack the SARS-CoV-2 virus if it later infects the body.
AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas – Oncology, Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.
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References
1. Declaration of Helsinki: Medical Research Involving Human Subjects. Available at https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/ [Last accessed October 2020].
2. Fleming T, et al, Maintaining confidentiality of interim data to enhance trial integrity and credibility. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2703711/ [Last accessed October 2020].
3. European Medicines Agency: Guideline for good clinical practice E6(R2). Available at https://www.ema.europa.eu/en/ich-e6-r2-good-clinical-practice [Last accessed October 2020].
4. Health Insurance Portability and Accountability Act (HIPAA): Protecting Personal Health Information in Research: Understanding the HIPAA Privacy Rule. Available at https://privacyruleandresearch.nih.gov/pdf/HIPAA_Booklet_4-14-2003.pdf [Last accessed October 2020].
5. General Data Protection Regulation: Article 5, Principles relating to processing of personal data. Available at: https://gdpr-info.eu/art-5-gdpr/ [Last accessed October 2020].
