How vaccines are delivered – expert questions – expert answers.

Vaccines– Dosing Schedules

By Nicola Oliver and Josephine Robertson

COVID-19 Actuaries Response Group – Learn. Share. Educate. Influence.


Around the globe we have been keenly watching and waiting for the development, production, and delivery of vaccines. Now that vaccines are here, this bulletin looks at the regulatory process, medical guidelines, and the delivery approach.

Where local guidelines fall outside of those stipulated by the manufacturer, there is a potential threat to vaccine effectiveness as well as a possibly increased chance that novel and significant mutational strains appear. The difficult challenge of vaccine hesitancy and real-world effectiveness is also discussed.

Vaccinations: approval and delivery

The regulatory process

All vaccines in the UK have to undergo an approval process and subsequent development of guidelines to assist clinicians in implementing a vaccination programme. This is much the same for all new medicines seeking marketing authorisation. The Medicines and Healthcare products Regulatory Agency (MHRA) is responsible for regulating all medicines and medical devices in the UK by ensuring they work and are acceptably safe.

The approval of vaccines to protect against COVID-19 has taken place at an accelerated rate through the granting of ‘temporary authorisation’ (as opposed to marketing authorisation), following changes that were made to the Human Medicines Regulations 2012 to allow the MHRA to grant temporary authorisation of a COVID-19 vaccine without needing to wait for the European Medicines Agency (EMA). A rolling review of data from the clinical trials assisted in speeding up this process, which will continue, as well as external testing and scrutiny by the National Institute for Biological Standards and Control (NIBSC)[1].

Guidelines for administration

The Green Book,[2] ‘Immunisation against infectious disease’, sets out the immunisation programme in the UK. For each vaccine, the guide clearly sets out dosage and schedule, administration method, contraindications, and precautions.

Green book dosing schedules

In December 2020, an additional chapter, 14a,[3] was added to the green book to include information and guidance on the Pfizer BioNTech COVID-19 mRNA Vaccine BNT162b2 and the AstraZeneca COVID-19 vaccine.

Green book recommendations

The Pfizer vaccine should be administered in 2 doses, a minimum of 21 days apart.

The AstraZeneca vaccine should be administered in 2 doses, a minimum of 28 days apart.

If the course is interrupted or delayed, it should be resumed using the same vaccine, but the first dose should not be repeated. There is no evidence on the interchangeability of the COVID-19 vaccines although studies are underway. Therefore, every effort should be made to determine which vaccine the individual received and to complete with the same vaccine.

The green book states:

‘Operationally, it is recommended that the second dose of both vaccines should be routinely scheduled between four and 12 weeks after the first dose. This will allow more people to benefit from the protection provided from the first dose during the roll out phase. Longer term protection will then be provided by the second dose. If an interval longer than the recommended interval is left between doses, the second dose should still be given (preferably using the same vaccine as was given for the first dose if possible). The course does not need to be restarted.’

Manufacturer’s guidelines for the Pfizer vaccine

After the first dose of the vaccine, you should receive a second dose of the same vaccine 21 days later to complete the vaccination course.

The manufacturer’s instructions noted that

“There are no data available on the interchangeability of Comirnaty with other COVID-19 vaccines to complete the vaccination course. Individuals who have received 1 dose of Comirnaty should receive a second dose of Comirnaty to complete the vaccination course”.

Manufacturer’s guidelines for the AstraZeneca vaccine

The COVID-19 Vaccine AstraZeneca vaccination course consists of two separate doses, the second dose should be administered between 4 and 12 weeks after the first dose.

The manufacturer recommends that individuals who receive a first dose of COVID-19 Vaccine AstraZeneca complete the vaccination course with the same vaccine.


The vaccine developed by Moderna has also received regulatory approval in the UK, but has not yet been detailed in the green book. The manufacturers guidelines recommend 2 doses with a 28-day interval, with the second dose being the same type of vaccine.

Subsequent UK dosing guidelines

Additional guidance[4] was issued by the NHS on the 30 December and distributed to the chief executives of all NHS trusts, primary care networks and GP practices. This confirmed the move to extend the dosing schedule of the second dose, as did a statement[5] issued by the Joint Committee on Vaccination and Immunisation (JCVI). Further correspondence issued by the UK Chief Medical Officers[6] set out that for operational reasons, a 12-week delay should be the standard rather than the maximum.

The British Society of Immunology[7] recognizes that a pragmatic approach in the short-term is required, and that whilst they would prefer the original dosing schedules to be used, they accept the rationale for the change in schedule. They do, however, call on the government to implement the following:

  • A programme of immune monitoring to assess how altering the dosing schedule impacts efficacy of both the Pfizer/BioNTech and Oxford/AstraZeneca vaccines, with rapid modification of dosing schedules as appropriate.
  • A high-profile, multifaceted engagement programme to build public understanding and confidence in COVID-19 vaccination.
  • Strong and clear messaging to the public that the highest level of protection is only gained through two doses of the vaccine.
  • The JCVI to make the full evidence for decisions around COVID-19 vaccines available immediately upon announcements being made to aid public understanding.

Questions raised by the interval extension

The decision to extend the time between the first and the second dose raises some questions:

  1. Is this within the manufacturer’s guidelines?
  2. Will the extended gap provide a fertile environment for the development of new viral mutations?
  3. Will the potential for onward transmission increase?

We consider these questions below.

Is this within the manufacturer’s guidelines?

The dosing schedule for the AstraZeneca vaccine recommends a second dose between 4 and 12 weeks after the first dose. Therefore, the current UK strategy of administering the second dose no sooner that 12 weeks after the first, falls outside of the manufacturer’s guidelines therefore rendering it ‘off label use’ and subsequently lowering the liability for the vaccine maker.

The dosing schedule for the Pfizer vaccine recommends a second dose 21 days following the first. In order to maximise the number of eligible people who receive the vaccine, the UK has recommended that the second dose be given no sooner than 12 weeks following the first. This falls outside of the manufacturer’s guidelines and presents some concerns.

BioNTech has said that its trials, run with US pharmaceutical group Pfizer, were largely based on two doses administered roughly three weeks apart and that this remains the recommended advice. 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.

The European Medicines Agency said on January 18 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. In a statement, a spokesman said, ‘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’.”[8] Off label use entails lower liabilities on vaccine makers.

On 4 January 2021, the FDA issued a statement similarly themed saying, ‘suggesting changes to the FDA-authorized dosing or schedules of these vaccines is premature and not rooted solidly in the available evidence.’[9]

Will the extended gap provide a fertile environment for the development of new viral mutations?

The SARS-CoV-2 virus has, like all viruses, mutated many thousands of times already. On 22 January, NERVTAG released a paper stating that there is evidence from analysis of Pillar 2 testing data linked to COVID-19 deaths that infection with variant of concern (VOC) B1.1.7 is associated with an increased case fatality rate compared to infection with non-VOC viruses.[10]

Although we might expect the evolutionary mechanism here to make ‘successful’ viruses more transmissible and less fatal, this is less likely with a longer period from infection to host death and the evolution of a more deadly strain cannot be ruled out. Allowing the virus to continue to circulate at high rates within a large population provides more opportunity for mutation.

There is a particular concern that ‘partial immunity’ produced through an extended delay between dose one and dose two may provide a fertile environment for the development of additional mutations that could be more transmissible and evade antibody responses induced by vaccines.

Generating a pool of hosts with just the right amount of neutralising antibody to apply selection pressure is a concept that can be likened to the process of antibiotic resistance. (Purely as an analogy, given that the mechanisms are quite different) Taking a partial course of antibiotics allows for selective pressure to produce a resistant bacterium, thus rendering the antibiotic ineffective.

Will the potential for onward transmission increase?

It is hoped that the immune response elicited following administration of the vaccine will include the development of neutralising antibodies (i.e., the antibodies which defend cells from a pathogen or infectious particle by neutralizing its effect). This reduces the likelihood of onward transmission. Non-neutralizing antibodies, or binding antibodies, bind specifically to the pathogen, but do not interfere with their infectivity.

Analysis published in 2015 suggests that vaccines that do not prevent transmission can create conditions that promote the emergence of pathogen strains that cause more severe disease in unvaccinated hosts. [11] Coupled with the ‘partial resistance’ induced by an extended delay between vaccine doses one and two outside the manufacturer’s guidelines, this threatens vaccine effectiveness and increases the potential for development of novel and significant mutational strains.

Vaccination rates – take-up, hesitancy and behaviour?

It is fair to say the whole process has been happening at pace. Could the speed of development, manufacture and variation at the delivery stage influence the take-up rate and so success in creating relief against the pandemic? To appreciate this, we can look at elements of vaccination take-up rates.

Vaccinations are for most, something that occurs in childhood with any decision taken by parents. For others, it is a generally accepted annual process to reduce the risk of severe flu symptoms [12]. Getting a vaccination is seen as beneficial for many reasons:

  1. reducing the risk to the individual of catching an infectious disease
  2. reducing the risk to the individual of severe symptoms and sequalae of an infectious disease
  3. reducing the risk of spreading to others in the community, and
  4. reducing health system pressures so other services can be provided to the individual and the community.

There are some who cannot receive vaccinations, some who may choose not to or choose to delay their choice. Those who cannot receive vaccinations for medical reasons are protected by the benefits of herd immunity (via c) to d) above). Fortunately, the COVID-19 vaccinations have few contraindications so this group may be small[13]. Those who are reluctant or refuse a vaccination despite its availability are referred to as ‘vaccine hesitant’[14].

So how many need to be vaccinated to achieve herd immunity for the few who cannot receive a vaccine? For COVID-19, unfortunately, this is a flawed question. Vaccine efficacy so far points to benefit b) but we do not yet have evidence that the vaccine provides benefit a) or c)[15]. As mentioned above, vaccination may provide a degree of unfounded confidence by those vaccinated but non-pharmaceutical interventions (“hands, face, space”) will still be required to keep R down.

To derive benefits b) and d), a higher level of vaccination take-up is better.  What causes people to be hesitant is varied and complex[16] but one study of COVID-19 vaccination indicates the following key issues[17]:

  • the potential collective benefit (benefits c and d)
  • the likelihood of COVID-19 infection (benefit a)
  • the effectiveness of a vaccine (benefits a, b, c and d)
  • its side effects (vaccine safety)
  • the speed of vaccine development (vaccine safety)

The vaccination development, manufacturing and delivery are elements that can be undertaken at pace but getting the vaccine into an arm still requires a specific ‘yes’ decision by each recipient.

A study in December 2020 provided insight into the general acceptability of vaccines in Great Britain[18] (Figure 8.) However, a poll at a certain point in time does not represent the fluidity of vaccine hesitancy.  As events occur, more information for or against key issues affecting decision-making will surface. This includes news items such as early signs of real-world effectiveness from Israel[19].

Vaccine hesitancy does not necessarily mean refusal and an individual’s choice may be revisited with time. Assuming high take-up rates initially may be optimistic. There may still be logistic challenges and tailored public health messaging may be required. Even if we could see good vaccination take-up rates (with benefits b) and d) emerging[20]) non-pharmaceutical interventions would continue to be necessary to achieve benefits a) and c).

This bulletin provides an overview of the regulatory process, medical guidelines, and delivery approach and so provides additional information on vaccine safety. The other key issues that could affect take-up rates and therefore the success in easing pandemic pressures will feature in future bulletins including more on vaccine hesitancy, logistics, and the need for real-world evaluation.





















About henry tapper

Founder of the Pension PlayPen,, partner of Stella, father of Olly . I am the Pension Plowman
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1 Response to How vaccines are delivered – expert questions – expert answers.

  1. Tim Simpson says:

    Hello Henry, Thank you for this which sets the situation out in details that the non-scientific [me] can easily understand. It also comes in the wake of an internicene dispute between a Professor of the JCVI [Newspapers Monday 25th Jan] and the BMA regarding the extended duration between jabs i.e. the JCVI are disregarding the manufacturers guidance because of ‘rock-solid evidence’ that to abide by it is now deemed unnecessary; the BMA disagree to the chagrin of the JCVI. Given the Government’s unfortunate mistakes so far, it begs the question [possibly as the BMA see it] that if the JCVI are mistaken, then it’s only the old, obese and sick who will suffer and die. This Old Cynic wonders, now that the target number of vaccinations has been fixed at 15m, if the above is only to enable that achievement and see what ‘rock-solid evidence’ is available then. If they are correct then hurrah, if not…?
    Kind regards,
    Tim Simpson

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