Booster Jabs for Covid-19: What we know and what we don’t?

Two weeks ago the committee advising the UK government on vaccine policy recommended a booster (3^rd) dose of a Covid-19 vaccine from September this year with a roll out to protect the whole currently vaccinated population 

By contrast, last week the similar committees advising the USA government stated there was no evidence to support a third dose currently!

Who is right and what is the current level of knowledge about booster doses?

How do booster doses work?

• Covid-19 vaccines work by stimulating our bodies to produce an effective immune response when faced with the virus
• This response has both immediate and long term, but more hidden, benefits 
• The immediate benefit is the production of antibodies to the Covid-19 virus that can be detected in our bloodstream shortly after we have been vaccinated 
• The longer term, more hidden benefit is the instructions the vaccine gives to the body’s immune system to respond very quickly when an infection strikes us – if you like, it’s like building an immunity production line that just needs to be switched on when the infection happens.  This is called ‘immune memory’ 
• Not only do we want this ‘production line’ to go into action, but also that it produces a sufficiently large amount of  immunity 
• Indeed an effective booster dose of a vaccine not only gets the immunity production line ready for action, but using the same analogy enhances its output when infection strikes
• This is nicely shown in the picture below

One or 2 doses of Covid-19 vaccines? 

• It is now ‘old news’ but the vaccines that are in widespread use (Pfizer, AstraZeneca, Moderna) have all been shown to be much more effective after two doses. After two doses:
  • The clinical data show much greater protection against getting infected and getting seriously ill 
  • The laboratory studies using sophisticated tests have shown that all elements of our immune response (both antibodies and T cells) are much much (deliberately repeating the word!) stronger after two doses
• Interval between doses
  • Again old news but there does need to be a minimum gap to achieve maximum memory and for Pfizer and Moderna, 3 weeks seems to do the trick
  • The AstraZeneca situation is more complex because of the way they ran their initial trials and it seemed that a 3 month gap produced the best protection – which was plausible – the challenge was the longer wait in the middle of a pandemic to be fully protected 

Why the need for a third dose?

• Current information is that two doses of the vaccines are effective, both in laboratory and in clinical terms, for at least 6 months 
• The immediate benefit  of the the immune response, as judged by the measurement of our antibodies, probably declines with time.  
• The problem is that as the vaccines are still quite new we do not actually know how much that decline might be a problem
• This is because we don’t know whether the effective immune memory (the ‘production line’) would take over if we became infected 
• Basically we have no robust data on how effective is the memory part of the immune system beyond 6 months
• This could be tested in two ways: 

Clinical data 

• The best test would be to determine how many people who have had 2 jabs develop any/serious infection for the longer term period beyond six 6 months following their second dose.
  • These data will be coming out soon from countries such as England and Scotland and will be compared to those who had not been doubly vaccinated. There are a number of biases in these analyses and they do not take account of any differences in how much exposure to infection people between the vaccinated and non-vaccinated groups

Laboratory data

• The second helpful study would be intensive laboratory testing of double jabbed individuals after 6 months to see how their immune system would respond in a ‘test tube’ challenge to being infected
  • These experiments could compare the results in samples from people who had  two with those who had three vaccine doses 
• We do not have such data at the moment (but they should be coming!)

What about the new variants?

• One of the main arguments behind a third dose booster is that such a vaccine could be more useful against the new variants
• Remember all the vaccines had been designed to combat the original Wuhan variant
• Indeed an opinion piece (ie not research based) published by Iranian scientists argued that just giving the same vaccine repeatedly could be more harmful and rather than increase immunity might reduce the development of an effective immune response when a vaccine against new variants is available

• I do not know in all honesty how likely this is
• At the moment though all the push in the UK for a third dose is still based on using the original  vaccines
• The argument being that the current vaccines do work against the new variants* and we do not have a new variant-proof vaccine 

*A study published last year seemed to suggest that the AstraZeneca vaccine was not effective against the Beta (South African) variant, this study has not been replicated and had many problems in the design, so to me that question is still open

What vaccine will be used for any third dose?

• In brief there are no data suggesting what is the ideal vaccine for any third dose
• This is especially true as we do not have any specific vaccines that are targeted at the new variants
• Many studies of having two different vaccines for the first two doses have shown no problems and indeed possibly an even stronger response using a different vaccine second time round
• Vaccine availability, at the moment, more than anything else will be the driver for third dose vaccine choice, although those with a particularly bad reaction to one of their previous vaccine doses may be offered (or would actively seek!) an alternative  

Special considerations for people with weakened immunity

• There are several groups with weakened immune systems, either because of diseases like cancer or because of the treatments they are on
• They have a double challenge:
  • an infection with Covid-19 is much more dangerous
  • vaccines may be less likely to be as effective as in people who normal immune systems
• Thus
  • Because of the first reason they need to be a priority for vaccination
  • Because of the second, they are more likely to need a booster
• There was an interesting case of such a person reported in the medical literature recently
  • This person had 4 Pfizer jabs shown by the red blobs (BNT162b2 is posh name for the Pfizer vaccine)
  • Look at the blue line, which is the amount of the main antibody needed to give protection and you can see it was really only after the 4^th dose that the antibody level was sufficient to give immunity

• It is observations like this, albeit single case reports, that has pushed the Israeli government to go for a third Pfizer dose in such individuals

Is there any argument against a 3^rd dose?

• At the moment we do not have the type of data epidemiologists would want, either on the necessity for a third dose or its timing
• It could be argued that if not harmful, why wait until proof is obtained, which could be too late to prevent future waves of the infection
• The ‘original antigenic sin’ argument mentioned above would argue of a potential hazard of using a moderately ineffective vaccine which might make it harder to protect in the future against new variants
• From a local health service viewpoint, resources (staff etc) devoted to giving a third jab cannot be utilised for other pressing health issues
• From an international perspective, the rampant infection and low vaccine provision in many low and middle income countries may argue against a third dose in rich countries being a priority

And my conclusion?

• Sorry but still sitting on the fence on this one!
• I am sure a third dose (and maybe more) will be needed at some stage but not necessarily as early as 6 months
• A third dose ideally needs to be designed to be of value for the major variants currently responsible for the majority of cases 
• A piloted roll out with careful laboratory data collection on how effective a 3^rd dose would be after 6 months would be is sensible
• I would strongly support the Israeli approach of a third dose after 6 months of the current vaccines to those with a vulnerable immune system

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