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.
Single dose efficacy of the AstraZeneca 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%.
Single dose efficacy of the Moderna vaccine
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%.
Evidence of protection against serious COVID-19 disease
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.
Duration of single dose protection
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:
- Evidence of efficacy emerged 22 days after the first dose and persisted for at least 12 weeks until the second dose was given.
- Efficacy of the vaccine (as measured at least 15 days after the second dose) increased as the interval between doses increased. For example, in the 59% of the sample who received their second dose 4–8 weeks after the first, VE was estimated at 56% compared with a VE of 70% in the 22% who received the second dose between 9 to 12 weeks. The highest efficacy (VE 78%) was seen in the 16% who received the second dose more than 12 weeks after the first.
Evidence from mathematical modelling
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.
Deviating from the dosing schedules used in clinical trials
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.
Potential impacts of changes to the dosing schedule
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.