Category: Covid-19

As vaccine rollout grows apace, the media are full of concerns that vaccines may not protect everyone, and may prove much less useful against new variants of the Covid-19 virus.  The EU announced this afternoon support for researching new vaccines. In this post, however, I want to give a fuller introduction to the less well-known aspect of our immunity: our T cells; and why these cells will do the necessary so that even current vaccines should be effective against the new variants.

A quick refresher on antibodies and Covid-19 

• Antibodies* are produced a few days after we become infected and neutralise the foreign proteins carried on the surface of the Covid-19 virus
• The most important of these proteins is the spike protein which is how the virus attaches itself to our cells
• Following naturally acquired Covid-19 infection, we produce antibodies; the worse the infection the more the antibodies, although those with a very severe infection may have their immune system ‘paralysed’
• After the infection has settled, antibodies wane and may disappear after a few months
• The current licensed vaccines act in different ways but all work by getting the body to produce large quantities of neutralising antibodies against this spike protein
• Either from a natural infection or vaccination (or both), the B cells that produce these antibodies have a memory (very useful!) so they can ramp up production of fresh antibodies when faced with a new infection

*And in case I forget to mention this later on, antibodies are produced by cells called B cells

• We do know
  • Up to now, a second natural infection is very uncommon, which is evidence that  natural immunity does provide future protection
  • The vaccines all produce very high levels of neutralising antibodies and in clinical trials these are sufficient to:
    • Virtually eliminate deaths or very serious complications if we do become infected
    • Substantially reduce the need to be hospitalised if we do become infected
    • Substantially reduce the overall number of people in the population who are infected, although without reducing the number with asymptomatic infections 

• We do not know for sure
  • How effective antibodies following vaccination are against new variants but:
    • It seems that sufficient neutralising antibodies are produced to stop serious consequences of infection
    • The well-publicised, small, and not peer-reviewed, study from South Africa also suggested the AstraZeneca vaccine may not prevent mild illness in young people
  • How long the antibody response could remain active for, without needing a third dose of vaccine

Let’s look at T cells!

• I like this picture which shows the  large T cell doing its stuff against the smaller Covid-19 virus (they are the blue cauliflower looking blobs!)

A simple guide to how do T cells work:

• T cells respond to getting a message that there is a foreign protein (such as from the virus)
• There are two types of T cells: ‘Helper’ and ‘Killer’

• What we know about how T cells work after natural infection and vaccines 
  • There has been a lot of research as to how long after an infection the T cell responses continue to work
    • My reading is that the T cell responses are less likely to wane than the antibody response 
    • Interestingly these T cell responses in some people may be present from contact in the past from other coronaviruses – in particular, from the 2003 SARS epidemic
  • In laboratory testing, all the vaccines produced very strong T cell responses
  • Although we need longer-term data, the T cell responses following vaccination last as long as, and possibly longer than, the antibody response.

Why T cell responses may be more resilient to new variants

• Firstly, the T cell system responds to many of the different bits of foreign proteins whereas the antibody is response is more focused
• Why is this important?
  • Scientists estimate that perhaps we will produce separate T cells against may be 15-20 different bits of the spike protein 
  • Given this number of different T cells, they can then fight the virus on all these different fronts – making it much harder for any new variant to completely escape 
  • This is all hypothetical, are there real-life data?
• Secondly, there was an interesting paper published last week from looking at results of vaccines

• They studied people who had been vaccinated 
  • They research looked in detail at how their T cells responded
  • They found that the response by T cells to the spike protein generated from the vaccines was much  broader than that resulting from natural infection
  • They concluded from their results, that these T cell responses would still be active against the spike protein seen in the South African or related variants
• My conclusion: OK I’ll be cautious – laboratory data is not the same as evidence from real live patients; but in theory our T cell responses to vaccines should be good enough to protect against new variants
• Trying to put this all together my take is as follows:
  • T cells work once the virus seriously invades cells.
  • T cell response following vaccines might therefore not be expected to stop the early stages of infection from new (or indeed old) variants
  • However, T cell response following vaccines could be sufficient to stop the infection being severe from any of the known variants

One final piece of exciting news on the horizon 

• As mentioned, all the information above relates to the spike protein, this is because
  • all the licensed vaccines are directed against the spike protein
  • this is where the mutations are in the new variants 
• New vaccines are now being developed (by biotech companies such as Grimstone) to produce T cell responses against a broader range of proteins

• Thus whatever mutations may appear in the spike protein, such new T cell based vaccines will have loads of other targets to attack the virus with
• What I liked was the reported comment from Gritstone’s CEO, that they were happy to do this development but hoping that this might not be necessary because our T cell responses to the current vaccines would be enough!

(Acknowledgment: much of the material in this blog is based on the excellent piece in Nature by Heidi Ledford: https://www.nature.com/articles/d41586-021-00367-7 )

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The clinical trials of all currently used vaccines studied relatively small numbers of people. As volunteers they were also healthier and younger than the general population.  Now, after millions of doses of the Pfizer and AstraZeneca vaccines have been given in the UK, we have much more data which apply especially to older people and other groups vulnerable to the consequences of Covid-19.  I think we all need this information both for our own reassurance and to counter concerns of others.

Source of the new data

• In my previous blog* (posted on my birthday 4^th December!) I outlined the different sources of data on side effects from vaccines following their introduction
• The most rapid source of data is based on individuals and their health care professionals reporting to a centralised database a suspected side effect

*https://makingsenseofcovid19withs.com/2020/12/04/how-will-we-know-about-long-term-side-effects-of-vaccines-learnings-from-thalidomide-swine-flu-and-donald-rumsfeld/

Expected side effects

• We already knew from the clinical trials that there were a number of very common, short-lived, side effects and a high proportion of these 23,000 reports were for these same symptoms

• From the MHRA reports can be added other common short-lived side effects: 
  • Numbness/pins and needles in the arm and/or hand
  • Rapid heart rate/palpitations
  • Diarrhoea
  • Shaking
• The occurrence of all these common side effects could be considered ‘good news’!
• Remember the vaccines involve injecting into muscle a relatively large quantity of foreign material 
  • We want there to be an immediate response from the body’s first line, general immune defence mechanisms
  • These are referred to as our innate immunity, are nothing to do with antibodies and are not specific to any vaccine or indeed any infection

Anaphylaxis/severe allergic events: the concern This has been the major concern for many people who have had severe allergic reactions to vaccines, other medicines as well as other chemicals

• The concern has been more about what else is in the vaccine as opposed to the actual active bit
• None of the vaccines contain egg albumen
• The Pfizer (and Moderna) vaccines do contain polyethylene glycol (PEG), a chemical which is also widely used in food preparation
• PEG enhances the immune response to the active component in mRNA vaccines 
• Allergy to PEG does occur but is rare and people who have experienced this in the past are advised to avoid the Pfizer vaccine.  
• The AstraZeneca vaccine does not contain PEG but does contain a similar compound, Polysorbate 80, which is probably less allergenic than PEG
• National authorities only recommend not being vaccinated if there has been an issue with a constituent like PEG
• Allergies to other chemicals/foods/drugs are not a contra-indication to being vaccinated 

Anaphylaxis and severe allergic events: the data

• Obviously we don’t know how many people have refused vaccines because of concerns, whether appropriate or not, because of past allergy history
• There have been only a tiny number of cases of anaphylaxis reported in the UK
• All these patients recovered

*In the UK because of the issue with PEG, people who are vaccinated with the Pfizer vaccine are asked to wait for 15 minutes before leaving.  The risk from polysorbate is considered much lower

Conclusion: Severe allergy to vaccines is only an exceptionally rare complication

Severe neurological complications

• There was widespread publicity in September to a case of the rare spinal disease, transverse myelitis, in a participant in the AstraZeneca trial
• This led to a pausing of the trial in UK and (for a much longer period) in the USA) 

• The good news  from the MHRA data is the extreme rarity of any serious neurological complication
• Just one case of transverse myelitis each in the Pfizer and AstraZeneca vaccines
• And of course those cases may be completely unrelated to the vaccine 

• There have also been no other reports of other serious, possibly immune-related neurological disorders such as multiple sclerosis 
• Conclusion: The worries about severe neurological complications are at this stage unfounded

Any unexpected side effects?

• The only side effect reported in any significant number is Bell’s palsy (see picture at the top of this post)
  • This disorder is a paralysis of the facial muscles on one side
  • Can be a complication of a viral infection 
  • It does get better and most people are fully recovered by 6 months
  • Is treated with steroids
•  In the UK dataset  there have been:
  • 69 cases following Pfizer (13/million)
  • 6 cases following AstraZeneca (4/million)
  • But around 200/million people per year in the general population get this condition
• Conclusion: Despite the publicity the number of these cases is no higher than the general population incidence 

Why I find these data important

• I have been giving a number of online talks to community groups about Covid-19 in general and, more recently, vaccines in particular.  Two weeks ago I came across my first ‘anti-vaxxer’ who asked:

“How could I guarantee the vaccines were 100% safe (especially for a young non-vulnerable person such as myself?)”

• I think my answer was a bit weak as I emphasised the much greater and known problems from Covid-19 itself
• If I was asked this now my answer would be:

“I am confident that there is  a much bigger risk of having an accident in the car on the way to vaccination than any serious health risk from the jab itself”!

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This week has seen research supporting the idea that having the two doses from different vaccines would be more effective than two doses of the same vaccine.  This idea is being taken seriously and thus this week there were announcements of two trials:

• In the UK with AstraZeneca and Pfizer vaccines as the different doses
• In Azerbaijan & UAE using AstraZeneca and Sputnik vaccines as the different doses. 

In this post I discuss the background and what may be the potential benefits of such ‘vaccine mixing’.

The case for these 2 combinations are different

1. Pfizer/AstraZeneca

Rationale for a Pfizer/AstraZeneca 2-dose vaccine regime

• Pfizer and AstraZeneca  vaccines are both designed to produce the spike protein that when injected leads to immunity to the real virus
• The spike protein produced by these 2 vaccines should be identical as the genetic instructions were based on the same genetic code, they just work in different ways
• Theoretically then the body’s immune response to either of these vaccines should be similar.
• Readers may recall that we have two immune responses to vaccines:  
  • Antibodies 
  • T cells*
• These 2 immunity weapons both need to work to get full protection
• It was thus interesting that a (not peer reviewed) paper published  a week ago showed that there may be differences between these two types response  between the 2 vaccine:
  • Pfizer is better at antibodies
  • AstraZeneca is better at T cells

• Thus having these 2 different vaccines can have a theoretical advantage
• A second consideration relates to side effects:
  • Side effects from the second dose of the Pfizer vaccine were reported this week to be worse than after the first dose
  • Switching vaccine to the AstraZeneca could possibly protect against this 
• There are also logistical  justifications for testing this mixing:
  • Given the complexity of how they are made, production of these vaccines is a precarious process and even with all the quality controls in place, something could go wrong, limiting the availability of the product
  • AstraZeneca vaccine is far cheaper to produce and distribute 
• So knowing that one of these vaccines can substitute for the other can be very helpful

Rationale for  AstraZeneca/Sputnik two dose regime

First let me introduce you to the Sputnik vaccine!

• When Russia announced the launch of their ‘Sputnik’ vaccine in August 2020, Western media were concerned that the necessary clinical trials had not been completed prior to its wider use.  

• Thus it might seem strange that, only a few months later, formal clinical trials are going to start in collaboration with AstraZeneca  
• Whatever the views about the political situation in Russia, this is an interesting vaccine!
• Basically, it is the same type of vaccine as the AstraZeneca one: so-called ‘viral vector’ vaccines, and also planned to be given in 2 doses 
  • The  term ‘vector’ means that the active bit of the vaccine – the genetic instructions to make the spike protein – is carried on a harmless virus 
  • The harmless virus in Sputnik is one that affects humans whereas that in AstraZeneca is a monkey virus – though this difference probably doesn’t matter
  • However, whilst the AstraZeneca vaccine uses the same monkey virus in both doses, the two doses of the Sputnik vaccine uses two slightly different human viruses 

Is the Sputnik vaccine successful?

• Results from the Sputnik vaccine were published in full in the Lancet this week
• Note that the first reports of the success from the other vaccines have come from a press release or an early version of the results not checked by peer review 
• The results of this clinical trial of Sputnik with placebo, comparing 2 doses 3 weeks apart with a placebo, were impressive

• The number of cases in each age groups was too small for very accurate analysis, but there was no indication that Sputnik is less effective in people aged over 60 
• They didn’t collect any data on asymptomatic cases so we can’t comment on whether Sputnik reduces transmission
• Conclusion: The results from Sputnik, albeit in very different populations, are at least as impressive as the AstraZeneca vaccine 

Back to the rationale for mixing these vaccines 

• There is a plausible biological pathway for understanding why a pairing of the two vaccines  may be better than just two doses of the AstraZeneca vaccine 

• With the Sputnik vaccine, using a  different carrier at each dose reduces this risk
• This is a theoretical advantage of the Sputnik over the AstraZeneca vaccine
• And therefore this is also a theoretical advantage for combining the AstraZeneca and the Sputnik vaccines 

Challenges of doing ‘mixing’ studies

• It is not that simple to know how best to study the benefits of mixing compared to sticking with one vaccine 
• Given what we know already about these vaccines, it would be almost impossible to prove that a mixing regimes (mixed) was better than 2 doses of the same vaccine (same)
• This is because all the individual vaccines:
  • Lead to a very large  reduction in the number of cases.  
  • The numbers that therefore in any trials that would need to be studied to show that ‘mixed’ was better than ‘same’ would be enormous!
• My guess is that studies are more likely just to analyse the laboratory results of these different regimes, in the hope that if the lab outcomes were the same then the clinical benefits should follow – though this is not necessarily true

What about new variants of the virus?

• All these vaccines were designed to work against the initial variants which may be an issue
• However, the AstraZeneca but especially the Pfizer and Moderna vaccines can be very easily modified to work better against the new variants, so for some people their second dose (booster dose) could be in theory ‘a different vaccine’.
• More importantly, if one vaccine is easier to produce in a new-variant-proof version, then this could well be the vaccine of choice for the second dose, independent of the vaccine in the first dose

Conclusions

• This is a unique situation in public health; for most viral vaccines we are not faced with this choice or this dilemma
• Thus far, the vaccines licensed for use all work extremely well in leading to enormous drops in the number of people becoming seriously ill, so there is not an immediate powerful case for mixing 
• There is a scientific logic though for looking at mixing vaccines as being beneficial
• It is indeed possible that new variants will mean that booster doses (second or even third!) might well come from a different vaccine
• At the very least, studying  mixing of vaccines is sensible, if only to prove their success rates are just as good

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What’s the same, what’s new and what we still don’t know

Yesterday (2^nd February) the Lancet released a non-peer-reviewed publication on further analysis evaluating the results from the use of the AstraZeneca vaccine. I believe some of the media coverage was misleading! 

Data were provided which address 3 specific questions: 

• What is the level of protection after one dose of the vaccine? 
• What is the evidence to support the (UK) recommended  interval of 3 months between doses?
• How effective is the vaccine at preventing transmission of the infection?

In this post I briefly summarise what we knew before these results, consider what has changed and what we still need to know or have confirmed.

(Readers may be aware that yesterday also saw the publication of a paper from the Russian ‘Sputnik’ vaccine team. Their results are very relevant given the close similarity between the AstraZeneca and the Russian vaccines. I will discuss these in further post later this week!)

What do we mean by protection?

It is really important to be clear what is meant by the term ‘protection’ and how we interpret expressions such as ‘60% protection’.  I have defined this before, but it is worth repeating here.

• Firstly, vaccines report their success at reducing outcomes of varying impact 

• Secondly, any percentage for any of these outcomes refers to a comparison with an identical group of people  who were not vaccinated
• This can only come from a clinical trial where there was such a comparison group
• Thus, a vaccine that has 60% protection against being admitted to hospital means that in the clinical trial there were 60% fewer admissions in the groups who had been vaccinated compared to those who had the dummy vaccine
• Further, it is hard to assess the significance of  some of the percentages reported as they are based on small numbers of cases 

What did we know before the recent results?

The authors repeated yesterday the results that had already been published at the time of licensing the vaccine and discussed in previous posts.  These all refer to the protection analysed 14 days after the second dose:  in brief these were:

We also already knew, again as I discussed in a previous post

• The vaccine gives good antibody protection after one dose, but this wanes after about a month
• A second dose maintains that initial protection
• The greater the interval between doses, the greater the protection in terms of people reporting symptoms, reaching 80% with a 12-week gap

The new data

What is the level of protection after one dose of the vaccine? 

• In this new analysis the researchers  took advantage of the fact that:
  • Some of the people in their trial had a 3 month interval between doses
  • Some people dropped out after one dose
• They compared the number of cases occurring in the active vaccine and the placebo groups, in the period from 3 weeks to 3 months after the first dose
• Each group had about 9250 volunteers
• For simplicity I have shown the values as the number of cases rather than rates/1000 people

• Let me explain this graph: 
• Looking at the first two bars on the left
  • In those who had the active vaccine there were 17 cases with symptoms 
  • In those who had the placebo there were 71 cases with symptoms 
  • This means a 76% reduction of symptomatic cases in that 3 week to 3 month interval
• The second two bars show there was no reduction in asymptomatic cases
• The third set of two bars show that by combining both symptomatic and asymptomatic cases, the overall reduction was 67%

Summary

• There is indeed protection against developing infection with symptoms in the period between 3 weeks and 3 months after the first dose.
• This is important!  These data show that whilst waiting for a second dose there is good protection against being ill, they do not show that a second dose is not needed.
• Remember that without a second dose the level of antibodies does fall and hence it is unlikely that this level of protection would be maintained

What is the evidence to support the (UK) recommended  interval of 3 months between doses?

• Here a very different question is being addressed:

“In those who had two doses, how much does the interval between doses affect the level of protection for the period starting 14 days after the second dose?”

• The volunteers were followed up, depending on when they were recruited, for up to 6 months after the second dose
• This is what the data showed:

• Again let me explain: 
  • from the left-hand  bar: if the interval between first and second dose was between 3 to 6 weeks, then the people who had the active vaccine had 54% fewer cases with symptoms than those who had the dummy vaccine 
  • from the right-hand bar: If the interval between first and second dose was longer than 11 weeks then the people who had the active vaccine had 82% fewer cases with symptoms

Summary:

• The longer the delay the greater the protection after the second dose.
• This is the same as the conclusion from the earlier study, the difference being that they now have up to 6 months of follow up data compared to only around 2 months in  the first report.
• This reinforces the message that for this vaccine a 3 month delay is if anything beneficial  

How effective is the vaccine at preventing transmission of the infection?

• This third question is really relevant to considering the issue of herd immunity.  
• We want the vaccine to reduce the number of people who can spread the infection, which means reducing both those with and without symptoms.
• The data from people who just had one dose of the vaccine (the middle two bars in the first graph of this blogpost) showed no reduction in the number of people who have asymptomatic infection
• I have also looked at the data for people who have had two doses 
• Looking at who developed an asymptomatic infection, the numbers were identical: 41 who had the active vaccine and 42 who had the placebo 
• We also need to consider the combined number of both symptomatic and asymptomatic cases

Summary: 

• Overall there is a large reduction in the combined number of symptomatic and asymptomatic cases
• The virus  of course can be transmitted by both symptomatic and asymptomatic cases
• Whilst the vaccine reduces the number who can transmit the virus after becoming ill, it does not reduce the number who do so with a ‘silent infection’
• I think the media reports may have been misleading here

We also still don’t know:

• As per my post last week – whether these results apply to the over 65’s: they may, we don’t know
• We also don’t know how these results will apply to the new variants of the virus, as the data were gathered before these variants were widespread 
• Half the participants were actually in South Africa or Brazil, but whether the cases that developed in the participants came from the new variants was not investigated

Conclusions

• My views on the AstraZeneca vaccine have not really been changed by these new data
• It is good that the first dose gives some protection whilst people wait for their second dose 
• It is also reassuring that the data support the suggested interval in the UK of 3 months between doses 
• The results do not detract from the positive fact that there were no severe cases in the active vaccine group 
• However as there were only 3 such cases in the placebo group, there are only limited conclusions that can be drawn from that comparison 
• This headline from AstraZeneca’s press release may need to be interpreted with these data in mind
• And “yes” I would still have this vaccine!

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It’s been a very busy day keeping track of all the news emerging this afternoon, UK time, on the different vaccines! In this second but short post today, I provide an update on the European decision on the AstraZeneca vaccine and give very brief comments on the Janssen and Novovax vaccines.

EU decision on AstraZeneca Vaccine

• The AstraZeneca vaccine is now licensed for use throughout the EU despite the German worries
• In terms of interval between doses the license says: “The second dose should be administered between 4 and 12 weeks (28 to 84 days) after the first dose” 
• In terms of age, whereas the EU has enabled its use in adults aged over 55, its wording is “Currently available clinical trial data do not allow an estimate of vaccine efficacy in subjects over 55 years of age“

Comment

• In terms of my post earlier today, I believe the EU is right not to have actually restricted use to adults under 55
• Interestingly, the EU has not highlighted the data suggesting that a longer interval than 3 weeks between doses is preferable
• The EU’s lack of specific endorsement for those over 55 was perhaps expected given their regulatory viewpoint
• However, I do not change the conclusions in my earlier post today about the likely benefit for the elderly of this vaccine, especially given the new data from Janssen (see below)

Janssen one dose vaccine

• Last week* I had already indicated that the results from the Janssen (Johnson & Johnson) vaccine would be published at the end of this month
• (One of the problems in this pandemic is that the results of important research are first announced by press release and only later are the detailed results made available to the scientific community to make a detailed assessment)
• The press release suggests a very good result clinically after one dose, with a two thirds reduction in the number of cases.
• The press release quotes that the vaccine was as effective in those aged over 60

Comment

• These results are exciting at this stage
• I am unable to provide any detailed assessment of the potential role of this single shot vaccine until the detailed results are available to allow a propter scrutiny
• I would also make the observation that the results of their preliminary laboratory assessment were only published last week. This shows the speed with which companies are very keen to publicise their clinical findings as quickly as possible!
• There is also a relevance of these findings for the AstraZeneca vaccine, as the J&J vaccine is using an almost identical technology (with both being different to the Pfizer and Moderna RNA approaches)
• Thus the observation that the J&J vaccine is effective in older people, would increase my expectation that further data from the AstraZeneca vaccine on older people may be similarly effective

*https://makingsenseofcovid19withs.com/2021/01/19/could-one-dose-of-vaccine-be-sufficient-some-interesting-new-data/

Novovax

• This is a very different approach to vaccine design *
• Again we only have a press release and although the results are impressive, we do need to wait for further information to be made available
• One data item I did pick up was that there was only one case of very severe infection in the whole trial (which was in the placebo arm) so it is difficult to infer too much at this stage on this aspect of protection

*For those who are interested in how this vaccine works see my post from early November https://makingsenseofcovid19withs.com/2020/11/22/two-new-approaches-to-a-covid-19-vaccine-how-do-they-fit-in/

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Yesterday Germany did not recommend the use of the AstraZeneca vaccine for people aged over 65.  The EU is going to announce their ruling today (29^th January).  Given that the over 65’s are the most vulnerable, and the first target for vaccination in most countries, this is a disturbing conclusion.  

Its potential impact is all the greater as the production of AstraZeneca vaccine is planned to be the largest in the world, in part because of its low price and the fact that AstraZeneca have agreed to deliver it at cost.  In this post I consider what conclusions can be drawn on the success of the different vaccines in older people.

The challenges of the clinical trials

• All the vaccines being licensed for widespread use require proof of both safety and benefit 
• That proof is based on a comparison in large trials between the active vaccine and a placebo
• Companies doing these trials have to plan to study enough people, and to have long enough follow up to produce meaningful results
• There ae complex statistical calculations when planning a trial to ensure that enough people are recruited to provide accurate estimates of how well the vaccines work
• Given the urgency of the situation regarding the development of Covid-19 vaccines, all companies wanted to get their trials completed as quickly as possible
• All companies realised they needed to recruit across broad sections of the population but that the overall number might not be sufficient to provide accurate answers for each sub-group.
• With all these trials, the “headline result” is the outcome in all the trial participants
• Subgroup analyses are then done say by age, but accepting that within each of these subgroups there may not have been sufficient numbers recruited to answer the detailed questions 
• Even ignoring  age (see below) we can’t know from the trials for example how the vaccine works in people of different ethnicities, with different levels of obesity etc
• The aim is that once the vaccines are licensed, ‘authorities’ will be able to collect data on much larger groups of individuals in all kinds of subgroups, to provide more detailed answers
• The challenge for regulators is that they have to deal with the data they have and make assumptions about how far the data from say age subgroups is sufficient to allow a wider license  

What were the data from older age groups  in the clinical trials?

• Let me be absolutely up front and say that the numbers in older age groups recruited to the AstraZeneca trials were much lower than for the Pfizer or Moderna trials

• AstraZeneca’s initial programme was to focus on the under 55s. It was the first company to start Phase 3 trials and as is common practice, early studies on vaccines often start with recruiting younger, healthier volunteers 
• We should also note that as people age, they accumulate other health problems and it is typically only the fitter older people who are both allowed to, and actually volunteer to participating in clinical trials.
• Thus, the older people who do participate may not be representative of the general population of older people
• Nonetheless AstraZeneca had far few older people than the other companies on whom to study the effects of their vaccine 

What did the data show on the success of the vaccines in older people?

• AstraZeneca said in their publication of the trial results “vaccine efficacy could not be assessed but will be determined if sufficient data are available in the future”
• The data from Pfizer showed the following:

• Two obvious points:
  • The number of cases of Covid-19 that happened in the placebo group was very small, especially in those over 74, thus we cannot have very accurate estimates of benefit in that group  
  • On the data that do exist, the vaccine was obviously very successful in reducing cases in the over 65s
• Although the data are not repeated here, the level of protection was similar in those over 65 to the over 90% protection seen in the much larger groups of participants below that age

• The data from Moderna showed the following:

• Conclusions are very much the same as with the Pfizer vaccine.  The rate of reduction of cases (86%) was just a little lower than the 95% seen in the younger participants 

Are there other data to suggest the AstraZeneca vaccine is successful in older people?

• Before embarking on the large scale clinical trials, AstraZeneca and the other companies undertook studies on the level of immunity following vaccine 
• These were complex laboratory studies to see if the vaccine would produce the necessary  high levels of immunity in the blood samples tested
• The blood results were very reassuringly positive, which is why the companies then tested whether this would be translated into reducing the number of cases as discussed above
• I have gone back to the blood results data from the AstraZeneca vaccine early studies to see if there was any influence of age on the level of the immunity achieved.
• These are the data on the antibody response, looking only at antibodies that would ‘neutralise’ the virus
• This is what I found:

• There was no reduction in the level of the antibody response in those aged 70 and over
• I then looked at the other part of our immune response to vaccines: – the T cell response – which might be more important – and this is what I found:

• Again no evidence of a reduction in this component of our vaccine produced immunity
• Thus for the AstraZeneca vaccine the immune response was not reduced by age in the people they studied

Conclusions

• German (and may be European) regulators are right in saying that the data are too limited to say that the AstraZeneca vaccine is successful in preventing clinical infection in people over 65
• As I have shown in this blog previously, the AstraZeneca vaccine, given in 2 doses 12 weeks apart, achieves an 80% reduction in clinical cases in people under 65
• All the 3 licensed vaccines – by targeting the spike protein – are working in the same way
• The Pfizer and Moderna vaccines work equally well in preventing clinical infection in people above and below age 65, but the numbers were still too small to be confident about the accuracy of the estimates
• The AstraZeneca vaccine produces a substantially more than adequate immune response in laboratory testing which was very similar in all age groups
• Taking all this into account, I believe the UK regulator, under its emergency powers, was right to conclude that on balance the AstraZeneca vaccine was likely to be effective in those over 65
• Obviously we will get more data as the vaccines are rolled out for general use, although these data are much harder to interpret when not in a randomised trial 
• And yes, I would be happy to have the AstraZeneca vaccine (I am older than 65!)

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Most readers of this blog have focused on vaccines for themselves and their elderly relatives: widespread vaccination for children seems a long way off.  New data are very clear: children contract and transmit the infection, if anything, more easily than adults. In this post I summarise the recent data from both sides of the Atlantic on the occurrence and severity of Covid-19 in children, and consider the impact of the ‘adult first’ policy on ending the pandemic.   

How common is Covid-19 in children?

• It is now widely acknowledged that children are as frequently infected with Covid-19 as adults
• These recent data from a large true random population sample in the UK show that children have slightly higher rates of infection than adults

• Of course, infection rates in any age group are related to the likelihood of being in contact with an infected person, and children are likely via schools to  have more social contacts
• One way of investigating this is to compare the risks between children and adults of catching the infection from an infected member in their household
• A recent study did just that and this is what they found:

• As the graph shows, child contacts are just as likely to be infected as adult contacts

What about children transmitting infection to adults?

• A study published last week from Wuhan examined the pattern of transmission in over 57000 households with an infection

• Children, as expected, were much less likely to have symptoms
• They were however 60% more likely to pass on infection than adults aged over 60
• Of course, there are many reasons for this, which might include a reduced level of preventive behaviours (such as social distancing) in young people without symptoms

How severe is Covid-19 in children? 

• As is well known children are much less likely to get ill with Covid-19 
• But clearly some do get very sick – recent data from the USA showed by end of 2020
  • 154 had died
  • 7500 had been hospitalised 
• In the UK over 2000 children have been admitted to hospital since the start of the second wave in September 

• It is also worthwhile making the point that if we had had the same number of admissions to hospital with another viral infection, such as measles, that would be considered a mini public health crisis and trigger a drive to make sure children are protected 

What is the story about vaccines in children?

• The 3 currently licensed vaccines did not include children in their clinical trials
• As a result, regulators in both the UK and USA only licensed the vaccines for use in adults, they cannot go beyond the available data 

• Regulators have a duty of care and need to be assured of safety – and all medicines, especially those targeted at widespread use, need to provide that assurance
• The immune response to vaccines in childhood and adolescence may not be identical to that in adults and, at the very least, there need to be careful dosage calculations
• It is of interest that both in the USA and in Europe, drug companies have a legal duty to test vaccines in children (but not necessarily at the time of testing in adults)   

Why vaccinating children might be important to end the pandemic?

• The vaccines are the way out to end the pandemic and thus far they are successful in reducing the numbers of people getting sick
• As I mentioned in a previous blog, and is mentioned by politicians who are urging caution, the data we currently have do not show that vaccines prevent people contracting the virus and transmitting the infection to others
• In simple terms:
  • Person A has been vaccinated 
  • Person A is then in contact with infected Person B and catches the virus but doesn’t become sick because he has been vaccinated
  • Person A can then pass the infection on to others
• This means it is going to be very hard to achieve herd immunity without very high proportions of the population being vaccinated.  Protecting adults is not going to be sufficient
• The good news is that this week is that all 3 vaccine companies have started trials, but it may take much longer to get the results than anticipated
• There may also be reluctance to be recruited into a study in which they may end up being vaccinated with a placebo.
• If that worry translates into participants being cautious about social interactions and with schools still being closed, will we get a result that is applicable to the real world?

Conclusions

• All commentators on the pandemic would recommend having the most vulnerable and those responsible for their health and care being a priority for vaccination
• But hopefully the numbers filling our hospitals will decline and the priority will be to protect all of the community 
• This underscores the need for clinical trials of vaccines in children, which probably need to be demonstrably even safer than in adults
• We also need research to understand what information parents in particular would require  to feel confident to allow their children to be vaccinated – given their admittedly low (but not nil) risk of a serious outcome
• Please feel free to share any comments from your own family!

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Media yesterday reported on research published last week in the New England Journal of Medicine. That study looked at the immune response to one versus two doses of vaccine and suggested that we might only need one dose to get immunity to the virus.  In this post I critically review these data and examine how they change what we currently know. 

Confusion alert!

This post is not about how long should the delay be between two doses, which has been the subject of much debate.  The question I address is will one dose of a new vaccine be sufficient?

What are the recent Johnson and Johnson (J&J) data?

• (You may also read stuff about this as a vaccine produced by Janssen: the latter is a Belgian- owned subsidiary of J&J)
• J&J have produced a vaccine very similar to the AstraZeneca vaccine: ie a harmless adenovirus onto which is bolted the genetic instructions to make the Covid-19 spike protein
• From the start of their clinical research programme, J&J have included a comparison of one dose versus two doses, which the other vaccine developers have not done
• Whether one dose will provide a sufficient level of protection for the public is being studied in a large-scale (Phase 3) trial comparing the numbers of cases of infection between the two groups – that is between one or two doses.
• Results from this trial may come out in the next two weeks
• On January 14th J&J provided the results from a small preliminary (Phase 1/2) study comparing the antibody response between one or two doses 

• These data are only from people aged under 55.  I understand the Phase 3 trial will include people aged up to 75
• They studied 2 dose levels of the vaccine: ‘high’ and ‘low’ (a bit like AstraZeneca, see below)
• They then compared people who had had one dose followed by a placebo  with those who had two doses of the active vaccine – for each of these two levels
• The results of the antibody response are shown below at 4 weeks after the second vaccine dose:

• To explain the labels in this chart: – as example ‘Low 1 dose’ means people in that group had two ‘jabs’: the first was the low dose of the active vaccine, the second was a placebo )
• The antibody units are a measure of how much antibody was produced, which in all 4 groups were almost zero before the first dose
• The graph clearly shows that there is a substantial increase in the level of antibodies from the zero baseline in all the four groups (from left to right)
  • 1^st jab low dose, 2^nd jab placebo
  • 1^st jab low dose, 2^nd jab low dose
  • 1^st jab high dose, 2^nd jab placebo
  • 1^st jab high dose, 2^nd jab high dose
• For the two groups whose second ‘jab’ contained just a placebo their levels of antibodies were not as high as the groups that had two jabs with the active vaccine.  
• The research then compared the antibody response at 8 weeks with that at 4 weeks and this is what they found:

• Firstly, and interestingly, the level of antibodies increased between 4 weeks versus 8 weeks after the first dose in the two groups that only had one ‘jab’ with the active vaccine,
• Secondly, (though as expected) the antibody levels were even  higher in people who had had two jabs with the active vaccine 
• I need to emphasise that:
  • These results are of antibody levels and may not be carried through into reduction in the number of infections 
  • The results are only from those aged under 55
• I thus await their the results of their much larger Phase 3  clinical trial with interest to answer the points above
• However these data raise the possibility that one dose of this vaccine may be sufficient to achieve herd immunity in the population more quickly

Recap about the data from AstraZeneca vaccine and one dose

• Given that the J&J vaccine is the same type as the AstraZeneca vaccine, how do the results on antibody response from the two vaccines compare? 
• Regular readers of this blog may recall that I presented this data in my post on 5^th January (see https://makingsenseofcovid19withs.com/2021/01/05/how-much-protection-is-there-after-one-dose-of-vaccine/)
• I am reproducing the AstraZeneca figure from that post  here as it is relevant in interpreting these new data from J&J
• AstraZeneca studied the level of immunity in people from 3 age groups, with two older age groups comprising half who had had one jab, and other half who had two jabs
• In this graph day ‘0 is the day of the first jab, day ’28’ is the day of the second jab (in those groups who had a second jab)

• After one dose of the AstraZeneca vaccine there were good levels of antibody response after 28 days*
• The antibody level in those two groups who just had one dose of vaccine (dotted lines) did then fall after 28 days, whilst for those who had a second dose of vaccine at 28 days, their antibody levels stayed high
• Thus despite the J&J and the AZ vaccines being of the same type, their results on the strength of the antibody response after one dose varied
• Although both vaccines give a good response after one dose but they were quite different in how long this is sustained

*we can’t compare the actual units between the AZ and J&J data because of differences in the way they measured antibody levels

Recap about about the data from Pfizer vaccine and one dose

• For completeness I will also recap about the data from one dose of the Pfizer vaccine 
• Pfizer only tested a two-dose regime, with the two doses 3 weeks apart
• They did, however, look separately at the number of cases of infection that developed in each of the two groups (active and placebo) in the interval between the first and second doses
• I have not shown you these data before, but they were used by the UK’s ‘Joint Committee on Vaccine and Immunization’  in deciding to accept that a longer delay between doses would still give worthwhile protection from the first dose
• I have now drawn a graph based on these data

• The two bars on the left show that there were about 50% fewer cases in the three-week period between doses in the active vaccine group (the first blue bar) than there were in the placebo group (the first orange bar)
• The numbers of cases in those 3 weeks were quite small so the infections rates may prove to be not very accurate
• The bars after two doses show what has already been widely publicised:  a 95% reduction in cases after two doses of active vaccine compared to two doses of placebo
• Given the design of the trial, we have no data on whether the 50% reduction in the number of cases after one dose would have persisted beyond the 3 weeks
• (At the risk of being repetitive!) at this moment we only know that one dose of the Pfizer vaccine gives some protection for at least 3 weeks.
• This may, and very well might, last the 12 week interval now operating between doses in the UK schedule but protection should not be assumed until after the second dose

Conclusion

• I hope I haven’t confused you more, but it was quite a challenge to interpret these data
• The first fact is that one dose of these 3 vaccines does produce a ‘good’ levels of antibodies
• Whether these levels  are ‘good enough’ is not known: there is likely to be a reduction in the number of people being ill but this will be less than that following two doses.  How much less and to what extent is an issue that remains to be determined
• There is also still another question mark:
  • We don’t know if the length of time any immunity lasts is meaningfully different following one or two doses of vaccine
• The only safe bet is that there will be further posts!

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