11. Januar 2021

Will the UK government's COVID-19 dosing regime gamble pay off?

Briefing

It's a sign of the times that the dosing regime of a medicinal product should cause as much controversy as the COVID-19 vaccines' have.

With case numbers close to overwhelming the NHS, the Joint Committee on Vaccination and Immunisation has recommended prioritising vaccination of more people with the first dose above offering the second dose, despite the vaccines being tested in a two-dose regime and uncertainty about level and longevity of protection after the first dose. It's a gamble we all want to win – but no one knows the odds.

How is the UK's COVID-19 vaccine roll-out at odds with existing guidance?

Information issued by the MHRA in connection with conditional authorisation of the vaccines currently available in the UK – the Pfizer/BioNTech, AstraZeneca and Moderna vaccines – specifies that patients are given two doses of the vaccine. The interval between doses should be at least 21 days for the Pfizer/BioNTech vaccine, between four and 12 weeks for the AstraZeneca vaccine, and exactly 28 days for the Moderna vaccine.

However, the most recent recommendation of the Joint Committee on Vaccination and Immunisation (JCVI) is to administer the second dose of Pfizer/BioNTech and AstraZeneca vaccines up to 12 weeks after the first (it was issued before the Moderna vaccine was authorised). JCVI's rationale for this recommendation was that "protection is obtained around two weeks after the first vaccine dose" and it's preferable to maximise public health benefits.

This decision appears to be supported in data for the AstraZeneca vaccine. According to the information published by the MHRA, the interval between first and second dose in clinical trials of this vaccine ranged between four and 26 weeks:

"Exploratory analyses showed that increased immunogenicity was associated with a longer dose interval. Efficacy is currently demonstrated with more certainty for dose intervals from 8 to 12 weeks. Data for intervals longer than 12 weeks are limited."

However, the same cannot be said for the Pfizer/BioNTech vaccine. The equivalent document published for the Pfizer BioNTech vaccine states that: "The efficacy analyses included participants that received their second vaccination within 19 to 42 days after their first vaccination." This vaccine hasn't been tested where the dose interval was greater. The information for the Moderna vaccine is even more specific: "For optimal protection, two doses should be administered one month apart."

The two unknown factors for those receiving the Pfizer/BioNTech and Moderna (if that is recommended) vaccines at an interval greater than the six weeks maximum period tested in the clinical trial are:

What measure of immunity is received after a single dose and how long does it last?
What is the measure of immunity after a second dose administered after a much greater time interval than was tested?

No one can definitively answer either of these questions without clinical data.

Is the EU following the UK's lead on COVID-19 vaccinations?

Meanwhile, in the EU, the European Medicines Agency (EMA) commented that the maximum interval of 42 days between the first and the second dose of the Pfizer-BioNtech vaccine should be respected to obtain full protection, adding that, "any change to this would require a variation to the marketing authorisation as well as more clinical data to support such a change, otherwise it would be considered as 'off label use'."

However, this isn't to say that the EU is not keen to accelerate the vaccination process: the EMA approved extraction of six doses from each vial of Pfizer/BioNTech vaccine, if a special type of syringe (low-dead volume) is used. This will allow vaccination of six people in one go, rather than the five-person limit currently practised in the UK and across Europe.

The French public health authorities have also announced they will extend the period for administration of Pfizer/BioNTech vaccine from previously recommended three weeks (21 days) to six weeks. While this is an extension of the dose interval, the French recommendation stays within the period supported by clinical data (42 days) and the EMA.

Is it legal for the UK government to ignore clinical trial data?

The UK government's decision to extend the dose interval for the Pfizer/BioNTech vaccine without the support of data from clinical trials is unusual, although within their power. There are inherent risks associated with 'off-label' use – as use according to the JVCI's recommendation could be viewed – including the potential for lower immunity levels both between doses and after the second dose.

This could mean a greater proportion of those being vaccinated falling ill with COVID-19 than would have been the case if the learnings from clinical studies were followed. Furthermore, it will be difficult to hold the manufacturer responsible for additional cases arising in vaccinated individuals during the extended dosing period.

It's possible that the level of immunity provided by the Pfizer/BioNTech vaccine doesn't diminish substantially after six weeks. If so, the JVCI will have "placed a good bet" and the British public will be the winners. The JVCI published a report setting out the reasons for their recommendation; the main thrust of their argument is that the first dose provides a high level of protection that the JCVI expects will last for a longer period of time.

Given the significant difference in reported efficacy of different vaccines – 95% for Pfizer/BioNTech compared to 70.4% for AstraZeneca – the JVCI also could argue that if immunity levels of the Pfizer/BioNTech vaccine after a single dose and/or a second dose administered after six weeks is reduced, the level of reduction brings it in line with the protection offered by the AstraZeneca vaccine. They could therefore claim that it's an acceptable level of risk. However, there is no data in the public domain to support this view.

The UK's dosing regime – an educated bet?

The decisions about authorisation of a medicinal product are always about balancing the expected benefits against possible risks. Governmental intervention in the dosing regime has altered this balance as assessed by the MHRA before granting the conditional authorisation in an unknown way.

With UK daily case numbers in tens of thousands, these are not normal times and the risk/benefit-related decisions in these circumstances are unusually hard. This is just one of the many such decisions, but at this stage, it's no more than a (possibly educated) bet.