The UK’s healthcare regulator the Medicines and Healthcare products regulatory agency (MHRA) approved the world’s first Covid-19 vaccine for emergency use on 2 December; the product in question is Pfizer and BioNTech’s mRNA vaccine, BNT162b2. Within a week, the UK began rolling out the first dose of this vaccine in hospitals with the second dose scheduled three weeks later.

Less than a month later, on 30 December, the regulator emergency approved its second vaccine, AstraZeneca (AZ) and the University of Oxford’s adenovirus candidate. At the same time as the AZ/Oxford approval, the MHRA announced the dosing schedule for the two vaccines. The regulator recommended spacing out the two doses of the two vaccines by up to 12 weeks to optimise the UK’s Covid-19 vaccination programme, thereby significantly extending the previously recommended interval of three to four weeks for the Pfizer/BioNTech vaccine doses.  The regulator also called on existing appointments for the second dose of the Pfizer/BioNTech vaccine to be rescheduled.

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Since then, the MHRA has approved a third Covid-19 vaccine made by Moderna. It does not seem as if Moderna‘s mRNA Covid-19 vaccine will be subject to this 12 week dosing schedule, but this may change.

It is important to note that the MHRA’s decision comes in the context of an escalating Covid-19 epidemic in the UK. At the time of writing, it has been estimated by the Office for National Statistics that one in 50 people in the UK have Covid-19, which is higher than the April peak. There are real concerns that hospitals, particularly in London and the South East of England, are close to being overwhelmed.

In addition, the UK has seen a steady increase in cases since Christmas and the beginning of the 2021. This includes more than 3,000 deaths in the past week, bringing the total for the epidemic to more than 81,000 deaths. This means the UK has the fifth largest death rate in the world, according to the John Hopkins University Covid-19 dashboard. The UK only lags behind the US, Brazil, India and Mexico, but these countries have significantly larger populations.

JCVI explains Covid-19 vaccines dosing decision

The MHRA’s decision to change the dosage scheduling was not greeted with universal agreement. There were some concerns from the scientific community about the evidence this decision was based upon and whether extending the doses, particularly for the Pfizer/BioNTech vaccine, was in fact the best decision for public health.

One day after the MHRA announced the decision, in an attempt to allay some of these concerns, the Joint Committee on Vaccination and Immunisation (JCVI) published its reasoning for advising a dosage gap extension for the Covid-19 vaccines.

In a statement, the JCVI explained that “rapid delivery of vaccines is required to protect those most vulnerable” and that data suggests that the short-term efficacy of the two vaccines is high enough that “models suggest that initially vaccinating a greater number of people with a single dose will prevent more deaths and hospitalisations than vaccinating a smaller number of people with two doses”.

The JCVI notes that the efficacy between dose one and dose two of Pfizer/BioNTech’s vaccine is 52.4% and this increases to 89% between day 15 and 21. This Phase III study efficacy data is published in the New England Journal of Medicine. According to exploratory analysis published in The Lancet, vaccine efficacy of the AZ/Oxford vaccine from 22 days after the first dose was 73%.

The JCVI also noted that “with most vaccines an extended interval between the prime and booster doses leads to a better immune response to the booster dose.”

Therefore, JCVI concluded, particularly in the context of the Covid-19 crisis in the UK, that “an extended interval between vaccine doses together with initial prioritisation of the first vaccine dose would increase the flow of vaccine supply in the short term. This will allow for more first doses to be delivered to more people earlier”.

Experts defend the UK Covid-19 vaccines dosing schedule

In support of the MHRA and the JCVI, the four chief medical officers of the UK wrote and signed a letter laying out the scientific and public health rationale for the dosing schedule change. They noted: “We are confident that based on publicly available data as well as data available to the JCVI, the statutory independent body, that the first dose of either Pfizer or AZ vaccine provides substantial protection within 2-3 weeks of vaccination for clinical disease, and in particular severe Covid disease.”

Focusing on the data that JCVI cited from The Lancet and New England Journal of Medicine, University of East Anglia professor in medicine Paul Hunter noted: “In my view the evidence for delaying the second dose of vaccine to enable as many as people as possible to receive the first dose sooner is clear.  The evidence for this is clear from the published report of the Phase 3 trial of the Pfizer vaccine the rate of new cases occurring dropped markedly in the vaccine group compared to the control from 12 days after the first dose.

“The evidence for the beneficial effect of a single dose for the Oxford vaccine is somewhat less clear at least from publicly available data…Nevertheless, what data there is does support extending the time to second dose.”

Hunter added: “There is also evidence from animal experiments.  For example, Wu et al [published in Nature] recently showed with another adenoviral vector vaccine (not the Oxford AstraZeneca one) that a single dose in ferrets did provide protection up to at least eight weeks when the experiment was completed.”

“It is much better to vaccinate as many people as possible with one dose, than half that number of people with two doses in the next few months,” noted Wellcome Trust director Jeremey Farrar.  “It remains critical that groups most at risk, such as the elderly and frontline healthcare and essential workers, are prioritised to receive the first doses, but we must not delay getting the vaccine to everyone, in this country and around the world.  The dosing regimen announced today will allow a more rapid rollout.”

UK dosage schedule changes: concerns remain

Despite these attempts to explain the rationale and address concerns from the scientific community, apprehensions remain, particularly regarding the Pfizer/BioNTech vaccine. Two of the loudest voices against the decision come from Pfizer and BioNTech themselves.

In a joint statement published in the British Medical Journal, Pfizer and BioNTech said: “The safety and efficacy of the vaccine has not been evaluated on different dosing schedules as the majority of trial participants received the second dose within the window specified in the study design . . . There is no data to demonstrate that protection after the first dose is sustained after 21 days.”

The incomplete nature of the evidence is why the US Food and Drug Administration (FDA) has published a statement saying it will not be changing the dosing schedules for the Pfizer/BioNTech vaccine. The FDA has not yet approved the AZ/Oxford Covid-19 vaccine.

The World Health Organisation has also shared its concerns that there is not sufficient scientific evidence for a delay of more than six weeks for the Pfizer/BioNTech vaccine’s second dose. Dr Kate O’Brien, who is a member of the WHO’s strategic advisory group of experts on immunisation, told the Guardian: “I think we have to emphasise the need for additional evidence. …there is no entirety of the evidence that tells us the clear and full answer to these policy questions.”

Managing consultant at PharmaFlow and author of Taming the Pharma Monster Hedley Rees agrees that there is a lack of scientific data for these changes and notes that “the potential risk to patients is unquantified as the approach has not been tested in clinical trials”. As a result, he says Pfizer’s reaction is to be expected.

University of Leeds associate professor in the school of medicine Dr Stephen Griffin noted the differences between the two approved vaccines in the UK. He acknowledged that the data for the AZ/Oxford vaccine are more nuanced and broader as there were different dosing schedules studied in the clinical trials. However, he added: “It is a concern that aspects deemed favourable for one vaccine should now also be applied to the other.”

“Such changes would entail using the Pfizer vaccine ‘off-label’, and the company has understandably distanced itself from this notion,” Griffin added. “The UK is notably the only country currently considering this path. Given the tremendous effort and investment required to mount clinical trials on this scale, it feels unwise to alter the Pfizer protocol – put simply, if it ain’t broke, don’t fix it.”