In the UK we have already started to roll out the Pfizer and Astra-Zeneca / Oxford vaccines whilst in the USA the Pfizer and Moderna ones are currently being used. (Links are to their published clinical data). The EU has so far approved only the Pfizer vaccine. India is rolling out the Astra-Zeneca vaccine with a local manufacturer having been licensed to make it themselves and for other non-Western countries.The UK Government medical advisors have made a pragmatic decision to delay the second doses of COVID19 vaccines to up to twelve weeks. It is believed that this is better for the whole population. The aim is to get at least some efficacy in twice the number of people sooner.This decision has been criticised by some. Some GPs objected to the extra admin involved in delaying appointments already made and felt that not delivering on their promises to individual patients who had received their first dose was questionable ethically.A number of UK experts also expressed some concerns whilst welcoming the vaccine program and in some cases understanding the desire to get as many people some protection as soon as possible.The choice of three weeks gap by Pfizer in their clinical trial does seem to be somewhat arbitrary. Moderna chose a four week gap in their study and AstraZeneca / Oxford team chose up to twelve weeks.Pfizer has stated that their clinical data only examined the two dose schedule. They are quoted in a Bloomberg piece as follows:

“Data from the Phase 3 study demonstrated that, although partial protection from the vaccine appears to begin as early as 12 days after the first dose, two doses of the vaccine are required to provide the maximum protection against the disease, a vaccine efficacy of 95%,” read more

Fauci, the USA top infectious disease expert was quoted in the same piece as stating that a similar approach to spreading out the doses was “under consideration” in the USA.What is best for the country? Maximum protection for half the number of individuals or possibly slightly less protection for twice the number? What will prevent most hospitalisations and deaths?It seems that the experts advising the UK government are aware of the data from all three publications and believe that fundamentally these vaccines all work in a similar way – introducing the genetic code into human cells to make Coronavirus spike protein in order to then prompt the immune system to react (both B and T lymphocytes). Presumably they believe that the fact one of the vaccines uses an adenovirus to effectively protect the genetic code is not that important when it comes to a similar common endpoint.Their thought seems to be that if the Oxford vaccine can work with a longer gap between doses than surely the other vaccines can too. Indeed that makes sense in terms of how other vaccines work too. There is precedence for other vaccines given with an increased gap actually being more effective in some cases.

The Joint Vaccine Committee Statement

“Short term vaccine efficacy from the first dose of the Pfizer-BioNTech vaccine is calculated at around 90%, short term vaccine efficacy from the first dose of the AstraZeneca vaccine is calculated at around 70% (efficacy estimates are not directly comparable between the two vaccines)
Given the high level of protection afforded by the first dose, models suggest that initially vaccinating a greater number of people with a single dose will prevent more deaths and hospitalisations than vaccinating a smaller number of people with two doses
The second dose is still important to provide longer lasting delivered at an interval of 12 weeks from the first dose . . .
When considering vaccination schedules JCVI often considers first principles, and regularly advises schedules which differ from the marketing authorisation. In every case, the advice of JCVI is aimed at maximising protection in the population . . .With most vaccines an extended interval between the prime and booster doses leads to a better immune response to the booster dose. There is evidence that a longer interval between the first and second doses promotes a stronger immune response with the AstraZeneca vaccine. There is currently no strong evidence to expect that the immune response from the Pfizer-BioNTech vaccine would differ substantially from the AstraZeneca and Moderna vaccines. The rate of vaccine delivery in the UK is currently limited by vaccine supply rather than by workforce capacity.”Read more

Jonathan Van-Tam, the UK’s Deputy Chief Medical office wrote on 2 January:

Last week, the UK became the first country in the world to authorise the Oxford/AstraZeneca vaccine and this week we’ll be the first to start using it to inoculate people against Covid-19 – having already given more than a million people an initial first dose of the Pfizer/BioNTech vaccine . . .
The independent Joint Committee on Vaccination and Immunisation (JCVI) has advised that at this stage of the pandemic, the priority should be to deliver first vaccine doses to as many people on the Phase 1 priority list in the shortest possible timeframe . . . It means across the UK, the NHS will now prioritise giving the first dose of the vaccine to those in the most high-risk groups, with a second dose due to be administered within 12 weeks of the first . . . which allows us to save more lives.
Their analysis shows the Pfizer/BioNTech vaccine is 89 per cent effective against preventing Covid-19 in the period from 15 to 21 days after the first dose.
Science experts know that if you have protection as high as 89 per cent on Day 21, it is not really possible that this would have declined by much after just 84 days, or 12 weeks. If a vaccine is that good, antibody levels simply don’t drop away that fast.
The evidence clearly shows vaccinated individuals get almost complete protection after the first dose.
Simply put, every time we vaccinate someone a second time, we are not vaccinating someone else for the first time.
It means we are missing an opportunity to greatly reduce the chances of the most vulnerable people getting severely ill from Covid-19.
If a family has two elderly grandparents and there are two vaccines available, it is better to give both 89 per cent protection than to give one 95 per cent protection with two quick doses, and the other grandparent no protection at all.
The virus is unfortunately spreading fast, and this is a race against time. My mum, as well as you or your older loved ones, may be affected by this decision, but it is still the right thing to do for the nation as a whole.
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An NHS respiratory consultant further explained on his Facebook page

This is good news in a number of ways. The most important practical thing is that there are only a limited number of vaccines available to give, so from the start of December whenever anyone got a vaccination, their second dose had to be put aside to give to them a month later. Now we can use those ‘second doses’ to vaccinate more people for the first time – more people vaccinated at all is a good thing.
Vaccines work by generating an immune response to a foreign antigen, in this case COVID proteins (either generated by transcribing injected mRNA, or spliced onto some simian adenovirus), leading to production of antibodies (easy to measure) and memory T cells (hard to measure).
After the first vaccine shot there are detectable antibodies at 28 days . . .comparable to the figures found in people who have had COVID. 28 days after the second shot there are more detectable antibodies. . . the response actually goes up the longer the interval between the vaccinations: 22k at < 6 week interval; 24k 6-8 weeks; 34k 9-11 weeks; and 63k when the interval is ≥ 12 weeks. There’s a rationale for this – the complete immune response is probably not complete until 6 weeks post vaccination; the simian adenovirus vector generates an immune response too, but it wanes so leaving the second vaccination longer means less simian adenovirus antibody, so more exposure to the vaccine, and a bigger COVID antibody response.
Longer dosing schedules lead to improved responses in other forms of vaccine too. . . flu and ebola vaccinations generate better antibody responses when given at longer intervals, using a variety of vaccination mechanisms, not just adenovirus vectoring. So although we only have the longer dose interval data for the Oxford/AZ vaccine, not the Pfizer vaccine, there isn’t a very good rationale for why the response would be any different . . .The upshot of all this is, if you’ve had your first vaccine and have just found out that your second vaccine due next week has been postponed, it’s good news for someone else who is going to get that vaccine instead, and good news for you that you’ll probably be better protected from the booster by having it 8 to 12 weeks later, not 4 . .Read More

https://twitter.com/sandyddouglas/status/1344949258483621888In the official regulatory information about the Astra-Zeneca / Oxford vaccine it states:

Following vaccination with COVID-19 Vaccine AstraZeneca, in participants who were seronegative at baseline, seroconversion (as measured by a ≥4 fold increase from baseline in S binding antibodies) was demonstrated in ≥98% of participants at 28 days after the first dose and >99% at 28 days after the second. Higher S binding antibodies were observed with increasing dose interval.Read More

To translate that into normal English, a fantastically high proportion people (close to 100%) made antibodies to the spike protein of the COVID19 virus after just one dose. This of course doesn’t mean that every single one of those people would be entirely immune to the virus, but having antibodies is likely to mean that if they do catch COVID19 it would hopefully be less likely for them to present with severe illness.There was some increase in the amount of those binding antibodies after the second dose, but in patients who had a longer gap between the doses (some had as much as twelve weeks) this increase was greater not less.The Oxford / AstraZeneca vaccine was the first to start major clinical trials and as such needed to make tweaks to their plans whilst the study was ongoing. This is common practice, but it was good to hear them being honest about it

“The timing of priming and booster vaccine administration varied between studies. As protocol amendments to add a booster dose took place when the trials were underway, and owing to the time taken to manufacture and release a new batch of vaccine, doses could not be administered at a 4-week interval.” AstraZeneca / Oxford publication

Crucially these logistical challenges actually demonstrated not only that lengthening the gap is not a problem but even suggested that this likely leads to an increase in efficacy.Encouragingly a similarly large early response (97.8%) after just one vaccine dose was also seen in patients over 65 who often have weaker immune systems. As I have mentioned before, this very high response rate surely implies it is likely that many people with blood cancer will get an immune response (even if it is lower than 98%).Immunologists know that when you have a large response to a vaccine and antibodies are created in abundance they do not just disappear overnight.Pfizer Trial shows efficacy after first dose

The graph, particularly the zoomed in section clearly shows a plateauing of the red line around the day 12 post first dose mark and the line remains remarkably flat with no evidence of a further change in the curve in the weeks following the second dose. This strongly suggests efficacy from the first dose.Indeed the figures below the graph tell a similar story. If we look at the COVID19 cases which are not included in the Pfizer primary endpoint because they occur earlier than seven days after the second dose we see the following. 41 cases in vaccinated patients and 103 in the placebo patients. This still represents an effective vaccine with the reported reduction in risk of 52.4% for even very early cases and 90% for the period when you would not anticipate the effect of the second dose to have arisen.Advocates of using the vaccine exactly as in the study will quote the 52.4% effectiveness for one dose figure. But as that would include people who were already incubating COVID19 on the day of vaccination it seems much more reasonable to use the 90% figure excluding those very early figures. This argument is explained further in the Appendix to the vaccination committee’s statement.Clearly this is not evidence that the second dose is a waste of time. Most experts believe the second dose will prolong the period that the vaccine will be effective.Moderna Trial shows efficacy after first dose

In the Moderna paper the crucial table is above which shows that before the second dose is given there is already a big gap between the two lines in terms of cases. And if we work on the assumption that the second dose will take around two weeks to work, you can reasonably pool the top three lines of the table beneath the graph. If we assume that until two weeks after the second dose we are relying on the first dose then the placebo group had 65 cases and the vaccinated group had just 7 still giving an approximately 90% risk reduction. This is also discussed further in the UK vaccine committee’s statement Appendix.It seems reasonable to assume that with such a dramatic reduction in risk it is most likely that protection would continue to act for at least several more weeks. It is worth noting that the Moderna had a cut off of 29 days and did not include data on patients re-vaccinated after that date.As I will explain further in a different article there was also some evidence of a reduction in asymptomatic spread seen in the Moderna study after only one dose.

Conclusion

There is good evidence that delaying the second dose is unlikely to significantly reduce the efficacy of the vaccine and may even increase it.
The vaccination committees conclusion that this decision is likely to save lives seems reasonable.