COVID Vaccination: How effective is the single dose?

Like me, many of you will have spent hours of some much-needed and precious time off over Christmas doing compulsory training modules before we could deliver the covid vaccines. I was hunched over a laptop ticking boxes instead of playing Monopoly (that seemed a better game choice than Pandemic) with the family. Most of this training was the irrelevant, pointless box-ticking that anyone who works in the NHS is sadly used to. But one crucial learning point was that the second dose of the Pfizer vaccine must be given 3 weeks after the first in line with the evidence and the license. Then on December 30th across the UK, the guidance changed completely, to prioritise giving a single dose to more people and to delay the second dose of both vaccines until 12 weeks. 

We and our patients were left perplexed and confused. OK, we get we need to vaccinate as many people as quickly as possible, but how do we know that a single dose will be effective before the proposed 12-week booster? 

To answer this question the NEJM has now published the full data from the original research study on the Pfizer-BioNTech vaccine and made it freely available NEJM 2020;383:2603, similarly the Oxford-AZ vaccine study is available Lancet Dec 2020 and the UK Joint Committee on Vaccination and Immunisation has published a JCVI statement 31/12/20 on why this decision was made. From these papers we can conclude:

• All patients in the Pfizer-BioNTech study received a second dose after 21 days, and this two-dose regimen was 95% effective against Covid-19. For those GPs sticking to the original plan and giving a second dose at 21 days, they can be confident that their patients will be 95% protected. 

• For the Pfizer-BioNTech vaccine there is no direct evidence for a delayed second dose regimen as the study did not compare different schedules. But there is direct evidence for the Oxford-AZ vaccine that a second dose at 8 to 12 weeks gives a better immune response compared to a second dose at 4 weeks.

• The Pfizer-BioNTech vaccine starts to become more effective than placebo 10 days after the first dose. In the interval between the first and second dose, the overall reported efficacy was only 52%. However, virtually all of the covid-19 cases occurring in vaccinated patients happened in the first 10 days, before you would expect to see an immune response i.e. before the vaccine was effective. Looking at the study data there is a striking divergence in the incidence graphs between the vaccine and placebo from 10 days.

• If the Pfizer-BioNTech data is just examined from day 14 after the first dose and before the second dose protection rises to 90%. This is only marginally below the 95% efficacy seen after two doses and suggests excellent protection after a single dose. However, this is based on a sub-set of data, the confidence interval is wide (95% CI 52% to 97%) and there is a lack of evidence (rather than evidence of lack) that this immunity is sustained after 21 days.

• The Oxford-AZ vaccine trial did include different dose intervals and found that a longer gap of 8 to 12 weeks led to a greater immune response compared to second dose at 4 weeks.

• The JCVI quote short term efficacy from the Pfizer-BioNTech of around 90% from two weeks after the first dose, and 70% for the Oxford-AZ vaccine with high protection from severe disease and a likely protective immunity of 12 weeks.

• The second dose is considered important to provide longer-lasting protection, and with most vaccines, an extended interval between the first and booster doses leads to a better immune response. There is direct evidence that this is the case with the Oxford-AZ vaccine.

• The JCVI have performed modelling which shows that given the current high rates of Covid-19, vaccinating a greater number with a single dose will prevent more deaths and hospitalisations than vaccinating a smaller number with two doses. Their modelling data suggest that in patients aged over 80 the NNT is only 250 to save one life after the first dose. 

• It is important to remember that the Pzizer-BioNTech study excluded a very important group of patients who are at high risk of serious Covid-19: those who are immune-suppressed and on immune suppressive therapy. 

• Whilst the results of these studies are unreservedly positive and represent a huge scientific triumph, significant unanswered questions remain:

o Does the vaccine prevent asymptomatic transmission?

o How long will immunity last?

o Will long term side effects emerge?

o How effective will it be in people who are immune-suppressed?

So, in conclusion, the crucial messages for our patients are:

• It takes 2 weeks to have an effective immune response after a single dose of the vaccine

• Patients can be confident that both vaccines give effective protection against covid-19 and severe disease from two weeks after a single dose, but it is not 100% so care and caution will still be needed especially for patients who are immune-suppressed

• Those who receive the Pfizer-BioNTech vaccine seem to have 90% protection two weeks after the first dose, but we don’t know how long it lasts

• Those who receive the Oxford-AZ vaccine seem to have 70% protection after the first dose, but we know that this will last for at least 12 weeks until the second dose 

• The 12-week booster is crucial for more enduring protection

Good luck delivering the vaccines in the weeks ahead!

Simon