On December 31, 2020 the four UK Chief Medical Officers (CMOs) published a statement announcing changes to the dosing schedule for the second dose of the Pfizer/BioNTech and University of Oxford/AstraZeneca vaccines. It stated that the interval between the first and second dose should be extended from 3–4 weeks to up to 12 weeks. This rapid response examines the evidence behind this decision.
Each of the three vaccines currently authorised for use in the UK require two doses to produce maximum protection, with the first dose inducing an initial immune response that is both strengthened and prolonged using a second (booster) dose. The authorisations were made based on evidence from large-scale clinical trials in which the vaccines were given as two doses separated by an interval of 3–4 weeks. The first vaccine to be authorised (on 2 December 2020) was the Pfizer/BioNTech vaccine. The first doses of this vaccine were given by the NHS on 8 December 2020, with the second dose scheduled 3 weeks later. On 30 December 2020, the Medicines and Healthcare products Regulatory Agency (MHRA) announced that it had authorised use of a second (AstraZeneca) vaccine with a dosing schedule for the second dose of 4–12 weeks after the first.
On 31 December 2020, the four Chief Medical Officers of the UK nations wrote to the medical profession to explain the dosing schedule of the AstraZeneca vaccine and announcing changes to the dosing schedule of the Pfizer/BioNTech vaccine. The letter explained that; against a backdrop of limited vaccine supply, rising cases of the UK COVID-19 variant and seasonal pressure on the NHS; the dosing schedule had been changed to extend the interval between doses to up to 12 weeks to prioritise giving as many people as possible protection from a single dose. It noted that the second dose was likely to be very important for the duration of protection but the increase of vaccine efficacy arising from it was likely to be “modest”. This was based on an analysis by the Joint Committee on Vaccination and Immunisation (JCVI) of data that suggested that a single dose of either vaccine would “provide substantial protection within 2–3 weeks of vaccination for clinical disease, and in particular severe COVID disease”.
This rapid response examines how dosing schedules are determined and evaluated in clinical trials, the manufacture and delivery of vaccines, how vaccine efficacy is assessed, the efficacy of a single dose of vaccines, the duration of the immune response and potential issues and impacts arising from changes to the dosing schedule.
Clinical trials of vaccines are conducted in phases. Phase 1 trials typically involve tens or hundreds of people, and are principally designed to assess vaccine safety, although data on immune responses may also be collected. Variables such optimum vaccine preparation, dose and dosing schedule are then assessed in Phase 2 trials that typically involve hundreds or thousands of people in multiple trials running in parallel. By the end of Phase 2 trials, researchers should have a good idea of the optimum composition, dose and dosing schedule of the vaccine and this information will be used to inform the design of Phase 3 clinical trials. The aim of Phase 3 trials is to provide regulatory bodies with sufficient data on efficacy and safety to assess whether to authorise use of the vaccine.
The terms of authorisation for a vaccine include details of the population that are eligible to receive it (for example excluding its use in pregnant women or children) and details on how the vaccine is to be used, including its dosing schedule. The MHRA stipulated that the second dose of the Pfizer/BioNTech vaccine should be given at least 21 days after the first dose, so the changes to the dosing schedule comply with the terms of authorisation. Other regulators have adopted a different approach. For example, the US Food and Drink Administration (FDA) published a statement in January 2021 on changes to the dosing schedules for COVID-19 vaccines. Included in the statement was the following: “We have been following the discussions and news reports about reducing the number of doses, extending the length of time between doses, changing the dose (half-dose), or mixing and matching vaccines in order to immunize more people against COVID-19. These are all reasonable questions to consider and evaluate in clinical trials. However, at this time, suggesting changes to the FDA-authorized dosing or schedules of these vaccines is premature and not rooted solidly in the available evidence.” For further information see the POST Rapid Response on “Regulatory approval of COVID-19 vaccines in the UK”.
The UK Government established the UK Vaccine Taskforce (VTF) in April 2020 to ensure that the UK public had access to vaccines against COVID-19. It has secured 367 million doses of vaccine from seven different developers to date, but obtaining sufficient supplies of these vaccines has been the rate-limiting step in the UK vaccine delivery plan. These supply issues partly reflect the massive global demand for vaccines but are also a function of the fact that vaccines must be manufactured and packaged in licenced facilities, in batches that undergo rigorous quality control checks, and must be distributed through a refrigerated distribution chain and delivered by trained healthcare professionals. The VTF has worked to ease supply side issues, for example by securing access to a Fill-Finish (where vaccines are filled and sealed into vials) facility in North Wales. For further information see the POST Rapid Response on “Manufacturing COVID-19 vaccines”.
To date, the NHS has delivered more than 18 million first doses and over 600,000 second doses of vaccine. The initial priority in the UK vaccine delivery plan was to ensure that all people in the top four JCVI priority groups had received a first dose of the vaccine. These groups include:
Delivery of doses of the vaccine is through a combination of vaccine centres (large-scale venues), NHS hospital hubs, and existing primary care (GPs) and community networks augmented where necessary by a small number of mobile units operating in rural settings.
In a clinical trial for a vaccine, tens of thousands of volunteers are randomly allocated to one of two equal-sized groups, one of which receives the vaccine and the other a placebo. The efficacy of the vaccine can be assessed by comparing the COVID-19 infection rates in the two groups. If the vaccine is having a protective effect, the infection rate in the vaccine group (Iv) should be significantly lower than that in the placebo group (Ip). VE can be estimated by dividing the difference between the infection rates (Ip minus Iv) by the infection rate found in the placebo group (Ip) and expressing it as a percentage.
Vaccines may take a week or more to elicit a strong immune response and until that response has been induced, the infection rate in the vaccine group may not be much lower than that in the placebo group. This means that estimates of VE made before the immune response has been induced will tend to under-estimate vaccine efficacy. Ideally, estimates of the efficacy of a single dose of vaccine would be made at the end of a clinical trial involving large numbers in both the control and vaccine groups, and conducted over an appropriate period (12 weeks in this case). In practice, the clinical trials data available for assessing the efficacy of a single dose of the authorised vaccines are more limited as the clinical trials were designed to assess a two-dose regimen. The following sections describe the data available for such assessments and estimates for single dose VE for each of the three vaccines authorised for use in the UK. For further information on how the COVID-19 vaccines have performed outside of trials see “The performance of COVID-19 vaccines in clinical trials and in real world conditions”.
The clinical trial of the Pfizer/BioNTech vaccine recruited more than 43,400 volunteers aged 16 years and over. Half (21,720) were randomly assigned to the vaccine group and half (21,728) to the placebo (sterile saline) group. Each group received 2 doses, with the second dose being given 21 days after the first. The main data collected were adverse events (to assess safety) and laboratory-confirmed cases of COVID-19 (to assess efficacy). Overall, the vaccine was assessed as being both safe and efficacious, with an estimated VE of 95% at least 7 days after the second dose.
The clinical trial data included an estimated single dose VE of 52.4% in the period between the first (day 1) and second (day 21) dose. These data were considered by the JCVI. It noted that the lines (see Figure below; red line for placebo and blue line for vaccine group) plotting the cumulative cases of COVID-19 in each group did not start to diverge until around 12 days after the first dose. JCVI considered that this delay in divergence reflected the time taken to generate a vaccine-induced response. It suggested that VE estimates based on data from 14 days onwards would give a truer idea of the single dose efficacy of the vaccine and made two such estimates:
Further data are available from a retrospective study of more than 500,000 people receiving a single dose of the Pfizer/BioNTech in Israel. The study did not contain a control (placebo) group but rather the initial paper estimated overall vaccine effectiveness as 51% by comparing the cumulative case rates from days 1 to 12 (before the vaccine took effect) with those from days 13 to 24 (once the vaccine had induced immune responses). However, a reanalysis of these data produced estimates of case incidence for each day (1–24) of the trial and used these to estimate vaccine efficacy for each day between days 13–24. These estimates suggested that vaccine efficacy started to rise after day 14, reaching a peak level of 91% by day 21. The authors noted that the “early results coming from Israel support the UK policy of extending the gap between doses by showing that a single dose can give a high level of protection”. Overall, the JCVI analysis and reanalysis of the Israel data suggest that the Pfizer BioNTech vaccine is more protective (VE ~90%) for up to four weeks after the first dose than originally reported (~50%).
Early data from Public Health England’s (PHE’s) SIREN study (where healthcare workers are tested for COVID-19 every 2 weeks) found that one dose of the Pfizer/BioNTech vaccine reduced the risk of workers aged under 65 years catching the infection by more than 70% after the first dose. This increased to 85% after the second dose.
The continuous assessment of routine data by PHE also found that one dose is 57% effective against symptomatic COVID-19 disease in people aged over 80 years (3–4 weeks after vaccination), rising to 85% after the second dose. Overall hospitalisations and deaths will be reduced by over 75% in those who have received a dose of the vaccine.
The clinical trial assessing the safety and efficacy of the AstraZeneca vaccine is more complex, consisting of data from four trials being conducted in the UK, Brazil and South Africa. Overall, these pooled data suggested that the vaccine efficacy of two doses lies between 62.1% (for people receiving two standard doses) to 90% (for a smaller group of people receiving a half dose followed by a standard dose), with an average efficacy of around 70% across both groups. Data on the efficacy of a single dose of the vaccine is available from an exploratory analysis of a subset of the participants in the trials whose second dose was delayed. Although the time period between doses varied in this analysis, most (62%) of the group received the second dose at least 6 weeks after the first. This analysis found 12 cases of COVID-19 among 7,998 people receiving a single dose of the vaccine compared with 44 cases in those receiving a single dose of placebo, giving an estimated single dose VE of 73%.
In January 2021, the MHRA announced authorisation for a third vaccine. The Moderna vaccine is another two-dose vaccine with the second dose being given 28 days after the first. Its safety and efficacy were assessed in clinical trials involving 28,000 participants. Overall efficacy was estimated at 94.1% 14 days after the second dose was received. Efficacy after the first dose was assessed in a separate analysis of around 2,000 people with a median follow–up time of 28 days (range 1 to 108 days). In this analysis, seven cases of COVID-19 were seen among the 996 participants in the vaccine group compared with 39 cases among the 1,079 people in the placebo group. These figures give an estimated VE of 80.2% for a single dose. Of the seven COVID-19 cases in the vaccine group, five occurred in the first 14 days, before a full immune response was induced. Discounting these cases gives a single dose VE of 92.1%.
All three clinical trials reported preliminary data on protection against serious COVID-19 disease. The AstraZeneca trial found 10 cases of severe COVID disease that emerged after the first dose of the vaccine and before the second dose was given 3 weeks later. Of these severe cases, nine were among the placebo group and one was in the vaccine group. The authors of the clinical trial report suggest that this “provides preliminary evidence of vaccine-mediated protection against severe disease”. The Pfizer/BioNTEch trial identified 12 cases of hospitalised COVID-19 in a subset of the trial participants receiving a single dose. Two of the cases were in the vaccine group but occurred before an immune response was likely to have been induced (one case on the same day that the first dose was given, the other 10 days later). The remaining 10 cases were found in the control group. The authors of the clinical trial report suggested that this showed “complete protection against hospitalisation for COVID-19”. Thirty participants in the Moderna trial had developed severe COVID-19 disease up to 14 days after the second dose, with one fatality. All 30 of these were in the placebo group.
In addition to these data from clinical trials, recent data from the real-world deployment of vaccines in Scotland compared the health outcomes of people who had received their first dose of vaccine against COVID-19 with those who had not. It found that 4 weeks after receiving a vaccine, the risk of hospitalisation was greatly reduced (by 85% for the Pfizer/BioNTech vaccine and by 94% for the AstraZeneca vaccine) in the vaccinated population compared with the unvaccinated population.
There is very little information available on the duration of single dose efficacy from the clinical trials data for the Moderna or Pfizer/BioNTech vaccines. As noted in the FDA statement, in “the phase 3 trials, 98% of participants in the Pfizer-BioNTech trial and 92% of participants in the Moderna trial received two doses of the vaccine at either a three- or four-week interval, respectively. Those participants who did not receive two vaccine doses at either a three-or four-week interval were generally only followed for a short period of time, such that we cannot conclude anything definitive about the depth or duration of protection after a single dose of vaccine from the single dose percentages reported by the companies”.
Preliminary analyses of data from subsets of participants in the AstraZeneca trial whose second dose was delayed due to logistical difficulties suggest that:
In January 2021, the JCVI published further research in support of its advice. This research is based on mathematical modelling and took several factors into account: the supply of available vaccine, the risk between different age groups (oldest groups are at highest risk), the uptake of the vaccine, and the relative efficacy of a single dose compared with a double dose. The modelling concluded that, when vaccine supply is limited, prioritising the first dose would avert the maximum number of deaths and hospitalisations. It suggested the optimum approach would be to provide one dose for all age groups over 70 years. Once this has been achieved (or vaccine supply increases) the priority switches to providing a second dose to all those over 80 years. And once this has been achieved, the priority switches back to providing a first dose to successively lower age groups.
In an ideal world, once a vaccine is authorised, it is used in strict accordance with the dosing schedule considered by regulators during the authorisation process. These changes to the dosing schedule represent a move away from this convention and reaction to it has been mixed. The British Society for Immunology’s statement on COVID-19 vaccine dosing schedules noted that “although we would prefer the original dosing schedules tested in the trials to be used clinically, we recognise that a pragmatic approach in the short-term is needed, and accept the rationale for the change in dosing schedule for the Oxford/AstraZeneca and for the Pfizer/BioNTech vaccine that has been recommended by… JCVI”. However, it called for the Government to ensure that a robust programme of immune monitoring was in place to assess the impact of changes to the dosing schedule on vaccine efficacy with rapid modification of dosing as appropriate. One such programme is the Public Health England SIREN study that regularly monitors over 20,000 frontline and non-clinical health workers for COVID-19 status and antibody responses.
The World Health Organization’s (WHO) interim guidance recommended a dosing interval of 21–28 days for the Pfizer/BioNTech vaccine and 28 days for the Moderna vaccine. In both cases the WHO recommends that if the second dose is inadvertently delayed beyond 28 days it should be given as soon as possible thereafter. However, the WHO interim guidance for the AstraZeneca vaccine was published in February 2021, after the dosing schedule changes were implemented. It recommended a dosing interval of 8–12 weeks for this vaccine, which would be compatible with the revised UK dosing schedule.
In the US, the FDA has licenced both the Pfizer BioNTech and Moderna vaccines with a dosing interval of 3 weeks and one month respectively. In its January 2021 statement on dosing intervals the FDA noted that “until vaccine manufacturers have data and science supporting a change, we continue to strongly recommend that health care providers follow the FDA-authorized dosing schedule for each COVID-19 vaccine”. The AstraZeneca vaccine is not authorised for use in the US.
The British Medical Association (BMA) published a statement shortly after the four CMOs’ letter to the medical profession expressing a number of concerns over the schedule changes. A prime concern was that rescheduling second dose appointments “will have a terrible impact on the emotional wellbeing of their most vulnerable, at-risk patients”. It called the decision “unreasonable and totally unfair” and noted that the rescheduling would also cause “huge logistical problems” for practices and vaccination centres. Nevertheless, on 11 January 2021, NHS England wrote to all vaccination sites with an instruction that “all appointments to receive the second dose must be rescheduled, with recipients to be booked in for a second dose in the 12th week”.
The BSI statement noted that it did not “not expect any specific safety issues to arise for the individual due to delaying the second dose, other than an increased potential risk of disease during the extended period due to lowered protection”. It also stated that most immunologists would agree that delaying a second ‘booster’ dose of a protein antigen vaccine… by eight weeks would be unlikely to have a negative effect on the overall immune response post-boost”. There is no evidence yet to support other hypothetical impacts such as concerns about partial protection providing an environment for the emergence of variants that can escape immune response or affect transmission rates. Emerging evidence on the impacts of vaccines on transmission is summarised in the POST Rapid Response “The performance of COVID-19 vaccines in clinical trials and in real world conditions”.
Another potential concern over changes to the dosing schedule is its potential to affect public confidence in COVID-19 vaccination. This could happen, for example, if the extending interval protected against severe COVID-19 disease but resulted in an increase in milder cases among those receiving the first dose of a vaccine. The BSI has called for a high-profile public engagement programme to build public understanding of, and confidence in, COVID-19 vaccination as well as clear messaging on the importance of receiving a second dose for maximum protection.
As the UK COVID-19 immunisation programme reaches all adults, the Government has announced an update to its policy on using a COVID-19 vaccine in children. So, how does COVID-19 affect children? What will the impact of vaccinating children be on preventing disease and minimising associated risks? And what do we know about public attitudes to using COVID-19 vaccines in children?
What are the different mechanisms by which the novel SARS-CoV-2 coronavirus is transmitted from one person to another, how has the scientific thinking changed, and how can transmission be reduced?
The COVID-19 vaccination programme launched in January 2021. All adults over 18 have now been offered the vaccine, although it was reported that 1.3 million people who had been offered a vaccine had not received it. Some people are vaccine hesitant whilst others experience barriers to accessing vaccines. Targeted interventions have been promoted locally and nationally to improve vaccine uptake.
