Vaccines: 1 or 2 doses and how far apart?

Plus does this shed light on the AstraZeneca vaccine dose mystery?

Today Astra Zeneca had their vaccine approved for use by the UK regulator, with the suggestion that their vaccine would be more successful if the second dose was given after a longer interval.

The AstraZeneca dose mystery

• The overall success rate for the AstraZeneca vaccine was 70% – lower than the 90+% achieved with the other two licensed vaccines (Pfizer and Moderna)
• Readers will though probably recall the unexplained finding in the group of around 25% of participants from the trial who – unplanned – received only half the expected amount of vaccine in their first dose  
• That group had a 90% reduction in the number of cases of infection
• In the remaining group – 75% of the participants – the reduction was only around 60%. 
• This difference did not make sense to many experts
• Newly  reported data might now give an explanation, which I discuss later in this post

Science behind 2 doses for any vaccine 

• The aim of any viral vaccine is to give the body’s immune system a memory so it will respond with antibodies when faced with the ‘real’ virus
• One measure of how the body will respond to the real virus is to measure the antibody response following a dose of a vaccine
• In animals and in humans the size of the response is increased by the number of doses of vaccine: more than 3 doses probably though has no further benefit
• There is however a minimum period between doses to allow the body’s response to develop fully, too short a gap and maximum effect is not achieved
• Mathematically for influenza at least, it has been shown that if a sufficient response can be achieved after one dose, then despite a two–dose regime being more effective, the one-dose approach may achieve a greater benefit in terms of herd immunity 

What is the recommendation for other viral vaccines in adults?

In the table below, I list the current recommendation about number of doses and the intervals for some common vaccines in adults

• Interesting to note that for some vaccines there is still a debate as to how many doses are needed
• The recommendations focus on the minimum gap and this is relevant: too short an interval and full protection is not achieved, but within reasonable limits a longer delay than the minimum is not a problem

Is there any evidence in Covid-19 vaccines that one dose is sufficient?

• The Pfizer and AstraZeneca trials only collected new cases that were diagnosed one week after the second dose 
• The only trial with data on the effectiveness from a single dose is from Moderna
• In their trial a small number of only around 2000 participants just had a single injection (half were given active vaccine, half placebo)
• Moderna were able then to compare the infection rates between these groups
• In that ‘mini’ trial a single dose of vaccine was 80 to 90% effective, but the numbers were too small for this to be more than a rough estimate
• We need more data, but Johnson and Johnson have a vaccine very similar to the AstraZeneca vaccine and have completed recruitment to a trial of just a single dose
• Their results will be emerging at the end of January

What are the current recommendations for the licensed vaccines?

• The current recommendations for the interval between doses as of 30^th December  are listed below

• The FDA has chosen the intervals between doses based on those that were actually used in the two trials – Pfizer and Moderna – at 3 and 4 weeks respectively and have suggested that these are the gaps that should be used.
  • That makes sense as both vaccines had over 90% success with those intervals so there is no reason to suggest a longer interval.  
  • The shorter the interval (above that minimum), the quicker immunity is achieved
• MHRA reported today on the AstraZeneca data and although they approved a minimum interval of 4 weeks they suggested a 12-week interval
  • MHRA looked at the data from those who received the full amount of vaccine at each dose
  • The results of clinical trials conducted by AZ that produced these data come from studies in different populations, including the UK, Brazil and South Africa. 
  • For a variety of logistic reasons, the gap between doses varied considerably in the trial volunteers
  • The interval ranged from 4 – 10 weeks and was higher (typically 7-9 weeks) in the UK volunteers compared to the Brazilian participants (typically 4-8 weeks) 
  • MHRA looked at the impact of the delay on the effectiveness of the vaccine, these data are not yet publicly available, but concluded that the longer delay the more effective the vaccine
  • Indeed, reports suggest that in those with a 12 week interval, the AstraZeneca vaccine provides an 80% success
  • Further it is suggested that the previously reported greater effectiveness  in those who had the lower amount of vaccine first time round might be explained by their longer time interval (typically 11-13 weeks)

How do I put this all together!

OK it’s all a bit confusing but this is my take:

• If a single dose was effective enough then given the logistics and costs of distributing vaccines, then there might be an arguable case for just using a single dose which would double the number of people vaccinated 
• The data supporting such a strategy come only from the very small number in the Moderna trial and we need to wait and see if they are supported by the results of the Johnson and Johnson trial
• In general, most vaccines require two doses but we should perhaps keep an open mind on this
• The AstraZeneca results however argue not only for two doses but that there is a necessary longer minimum interval
• There will be arguments, I am sure, about MHRA’s interpretation of the AstraZeneca results and their conclusion about 80% effectiveness
• It is however plausible that it was the longer gap between doses that explained the greater benefit in those who only had half the vaccine in their first dose
• Both individuals and society are keen to achieve maximum protection as rapidly as possible so a 3- month gap for the AstraZeneca vaccine might seem to be a disadvantage compared with the other vaccines 
• However, given the substantially lower cost and the easier logistics, the AstraZeneca vaccine can have a major part to play in the worldwide battle against Covid-19. Interestingly since I first posted this the UK government have announced a 12 week gap for the Pfizer vaccine, even for those who have had their first dose!
• Of course, on current data, protection is only assured after the second dose

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