A 4th vaccine dose: is now the right time to consider?

The announcement this week that Israel was starting on a programme of providing a 4^th dose of vaccine to those over 60 has stimulated a debate as to whether the booster now being rolled out will be enough to contain the pandemic of Omicron, or indeed other variants that may follow.  What is the evidence that other countries need to plan to start such a ‘second booster’ programme?

 Before discussing the specifics of a 4th dose for Covid it is useful to consider why and how boosters are needed

Decline in vaccine immunity

• Every viral infection, and every vaccine to counter such infections, behave differently – so lessons from say flu or measles cannot be easily extrapolated to Covid-19 and that is before any issue of new variants
• We do know that antibody levels produced in the early weeks after any vaccine will decline but as stated before this might not matter as:
  • Vaccines also work by giving the body’s immune system instructions to rapidly produce more antibodies when faced with an infection
  • Vaccines also give the body instructions, in response to an infection, to produce very specific T cells that will destroy the virus

How do boosters work

• We also know that boosters work by both:
  • Giving a short-term boost to raise the  immediate antibody response higher than the level achieved after the previous doses (see diagram below)
  • Also ensuring a better memory for the above two responses

• If you want an analogy, think about memorising a poem or the words of a song
  • You may remember the words if you have to repeat them within  a short interval after learning
  • With time it is harder to recall them but a refresher lesson can, like a booster, both bring the memory back quicker and also help in searing the words in your long-term memory (I quite like this analogy!) 

What worried the Israelis about declining immunity after the first booster

• Israel was the first country to introduce a booster programme in July 2021 and by the end of September had extended this to all aged over 12 years
• Despite this programme, and with the rise of Omicron, cases of Covid-19 have risen sharply in the last 2 weeks, which in percentage terms is one of the steepest rises globally  in countries with reliable data   

• The case for a 4th dose is reinforced by laboratory data suggesting a decline in immunity following a booster
• Here are data last week from a study recruiting Japanese health workers who had had 3 vaccine doses:  
  • The study measured their level of antibodies at the following time points
    • Before any vaccine (white blobs)
    • 1 week after first two doses (black blobs)
    • 1, 4, 12 and 26 weeks after a booster dose (coloured blobs)
  • The results are shown in the figure below each ‘blob’ represents one health worker

• One week after the booster (turquoise blobs),  antibody levels increased almost 50 times compared to the level after before the booster (black blobs)
• Antibody levels then began to drop, such that after 26 weeks (6 months) the levels are now only similar (orange blobs) to those seen after two doses 
• The obvious conclusion might be that protection following the booster, especially against Omicron, will not last – hence justifying the need for the 4^th jab

Is it too soon to start a 4^th dose?

• As the Israeli ‘Top Covid Expert’ in her press briefing admitted, “we don’t yet have the clinical, peer-reviewed data showing the effectiveness of the fourth shot”
• But she continued that the dangers from delaying outweighed the risk that the 4th dose might prove to be of little benefit
• Thus, if there are no downsides to giving a 4^th dose, why not ‘go for it’ now
• Firstly, in support of that suggestion, there is no evidence that side effects will be worse 4th time round
  • Side effects from the 3^rd dose booster  were no greater than after the first 2 doses
  • Interestingly, those who were boosted with the Moderna vaccine received half the vaccine dose as that administered in the first two doses
  • Side effects are dose-related and the reduction in the dose for the Moderna booster did not adversely affect the antibody response
• Secondly it would defy biological logic that immunity could be worse with more doses of vaccine

So why not have a 4^th (or even a 5^th) dose?

• There is a health economic argument which is that it is unethical to spend scarce health care resources (cash and people) on an activity that does not produce an appropriate level of return – for example sufficient reduction in number of people admitted to hospital relative to the costs of the programme 
• There is also the wider ethical argument about limited global supplies of vaccine being more appropriately directed towards low and middle income countries 

What scientific data do we have at this stage?

• A very reasonable starting point is to understand what is the purpose of boosters and thus it is useful to consider two separate roles:
• How many doses of vaccines will be needed to reach the targeted level of protection (so called primary protection) – hence most Covid-19 vaccines (apart from the Johnson and Johnson) went for 2 doses spaced a few weeks apart
• Having achieved sufficient immunity, this may not be sustained and does fall over time: what is needed to bring the immunity back to that level or even beyond it?

Is there a fall in immunity following the boosters?

• Below are data last week from England assessing the decline in the success of vaccines against the development of symptomatic Covid-19 infection with both Delta and Omicron 
• The data below are for people who had Pfizer* for their first 2 doses:
  • The figures in the left hand black box show, without a booster, the decline in benefit against symptomatic infection which by 25 weeks is 60% for Delta (black squares) and under 20% for Omicron (grey circles)

• The figures in the blue box show that 4 weeks after a Pfizer booster, protection against symptomatic infection from Omicron increases to around 65% but then falls steadily to below 50% after 10 weeks
• The figures in the red box show that 5-9 weeks after a Moderna booster protection against symptomatic infection from Omicron is slightly higher at around 65% than after a Pfizer booster ( there are no 10 week plus data for Moderna)
• The effectiveness is much higher from both Pfizer and Moderna booster against symptomatic infection from Delta than Omicron

What about protection against severe disease?

• It is still early days as fortunately there have been too few severe cases: this is probably related in part to Omicron now being thought not to affect the lungs to anything like the same extent as Delta
• Indeed in Israel the rise in all cases (see the graph at the top of this post) has not been accompanied by a parallel rise in severe cases, as judged by admission to hospital, although there is a small upward trend in the past 4 weeks

• The UK data do show a 90% protection from a booster against admission to hospital with Omicron (but note there is a delay of around 2 weeks from onset of infection to admission and as Omicron has only recently taken over as the predominant variant, it is too soon to know what will happen over time)
• However, the sustained protection against Delta, as shown in the figure above, suggests there may not be too much cause for concern that there will be a greater decline with Omicron 

What about a booster with a different vaccine?

• One argument against the Israeli selection of the same vaccine (Pfizer or Moderna) for the 4^th booster is that better protection may be obtained by  using a different type of vaccine – either:
  • one which is more designed to cope with the mutations from Omicron
  • or a different type of vaccine: some data suggested that initial vaccine doses with AstraZeneca* followed by a Pfizer booster produce a better immune response
• As I have said before in this blog, we do not yet have another vaccine targeted against other variants ready to go into people’s arms at scale: indeed one logistic issue I have seen raised is that it would be a challenge to turn off the production of the old vaccines to produce any new one 

*There has been a substantial reluctance to use AstraZeneca vaccine since the reports of the very rare blood clotting affecting the brain   

My conclusions

• No one can be certain about what is going to happen in the future ,but it is probable that the current policy for most countries of a single booster* is sufficient for the present to prevent the overwhelming majority of severe cases
• Health care providers in high income countries need to think very carefully if a 4^th shot is going to do more to improve the health of the population compared to other ways that those same resources could be put to use

*I have not consider in this post the very different situation for people who have weakened immunity because of other disorders or treatments they are on 

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