Categories
Covid-19

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 4th 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
*The levels on the vertical axis are shown on a logarithmic scale (which as you can see is able to show on the same graph differences in level 100,000 fold – so small intervals on the graph can represent a big change in the level)
  • 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 4th jab

Is it too soon to start a 4th 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 4th 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 3rd 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 4th (or even a 5th) 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 data for people who had AstraZeneca for their first 2 doses are similar
  • 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 4th 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 4th 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 

If you would like to receive email notifications of new posts on this blog just click this link and enter your email at the bottom of the home page: https://makingsenseofcovid19withs.com

Categories
Covid-19

Are self-testing rapid antigen (lateral flow) tests for Covid-19 accurate enough

The dramatic rise in the number of cases of the Omicron Covid-19 variant has led to an increased use of self-testing kits for the virus.  The results from these tests are used to guide personal behaviour.  Many people are confused about how their own results should be interpreted and acted on, with varying guidelines and differences in expert opinions on what to do following a positive test.  I hope this blogpost answers these questions and helps families and groups make informed decisions.  Please share and do send me your feedback through the Comments section below together with any questions 

What is the purpose of these tests?

  • This might seem a somewhat obvious question, as both lateral flow (LFT) and PCR tests are designed to diagnose Covid-19 infection
  • But, as is well known, the purpose of diagnosing Covid-19 is not primarily to guide  what treatment people should have: the more practical role is deciding if someone is infectious and hence could pass the virus on to other people
  • Thus, the accuracy of these tests is more important in determining whether someone is infectious*  than whether they are just infected with Covid-19
  • This is important as one can be infectious without being  ill and be ill without being infectious  

*A comment on words: the terms contagious and infectious I have seen interchangeably in articles on Covid-19, some argue that the Latin origin of the former strictly speaking means transfer of infection by touch which is not predominantly the case with Covid-19 

What is the time course of Covid-19 infection? 

  • I am sure most readers will be familiar with these details, but a refresher can often help!
  • In the above chart, assuming that the  contact with an infectious person is at ‘Day 0’, then there is a short period of time – called the ‘latent period’ – during which  the virus gets established  
    • This is probably around 2-3 days
    • This may be a little shorter with Omicron, but is at least a day and probably longer
  • This is then followed by a period called the ‘incubation period’ – where the virus start multiplying and invading cells in the body
    • At the beginning of this period everyone is asymptomatic
    • Typically around 3 to 7 days, symptomatic infection can start
  • The light blue bar shows that you can be asymptomatic for up to 10 days before first symptoms occur, but if symptoms are going to happen then they will normally have developed within 7 days 
  • Conversely, as shown in the red bar, symptoms can continue beyond the 10th day – ‘long Covid’ being used if symptoms persist for more than 28 days   
  • Now look at the diagram below in terms of when people are infectious
  • People typically start being infectious during the period of incubation, whether or not they are going to get  symptoms
  • But 90% of people stop being infectious after a week
  • As the red bar shows it is exceptionally rare to be infectious after 10 days – including people who still have symptoms

Is there a totally foolproof  way of determining if someone is still infectious?

  • LFT and PCR both assess if someone is still infectious but they are both only indirect tests
  • The only true way of determining if someone is still infectious is to culture (ie attempt to grow) the live virus from a swab
  • If the virus grows in the laboratory, we assume that it could grow ‘in life’ and spread to another person
  • Such tests are not done routinely because of their costs, time to complete and complexity
  • It is also not a definite that even if you can culture a virus from a nose swab, that there is enough virus present to pass on the infection
  • Summary: despite PCR and LFT both being indirect ways of measuring infectivity, they are  entirely appropriate, especially as public health tools, for large scale testing

What is the difference between a PCR and LFT?

  • (For those who are interested, I have given some more technical detail about these tests in an Appendix at the end of this post)
  • Both tests use the same sample from a nose swab 
  • The PCR test aims to discover the presence of evidence of Covid-19 RNA in the sample
  • The LFT test aims to discover the  presence of proteins made by Covid-19 virus in the sample
  • Why this difference is important is shown in the chart below:
  • The PCR test becomes positive very soon after the latent period but remains positive sometimes for a week or even longer after people stop being infectious
  • The LFT needs the infection to be established and the virus to be producing enough proteins before that test becomes positive
  • With this background, I will attempt to answer the key questions about these tests in terms of their performance to accurately detect if someone is infectious
  1. Do these tests work differently depending on the variant?
    • The short answer is no
    • Most of the research about these tests does not come from Omicron, but the conclusions should  apply to this variant for both PCR and  LFT 
  2. Is it possible to be infectious but be negative on both PCR and LFT?
    • The answer is yes and possibly as high as 5% of infected people could be negative on both PCR/LFT
    • There are a number of ‘technical reasons’ for a false negative given all the steps where there could be a problem (see below)
    • As one example, there are many LFT kits on the market which when they have been tested on the same swab, do not always give the same result
    • But in general, it is very unlikely (less than 5%) that someone is shedding virus that could infect another person and yet has a negative PCR 

3. How often is someone negative on LFT and positive on PCR?

  • This is the question that most worries people:  indeed, it is well recognised that an LFT may be negative when a PCR would be positive 
  • From the previous diagram above there are two main periods of times when this occurs:
    • At the end of the incubation period, and especially if people do not have symptoms
    • After  around 7-10 days, when the PCR continues to be positive but the virus has stopped producing new proteins in the nose
  • There have been a very large number of studies to answer how often a PCR is positive and the LFT is negative with very differing results 
  • The answer is indeed not simple as it depends on:
    • Whether symptoms are present or not: LFT is much more likely to be negative if there are no symptoms 
    • The time since the onset of infection: LFT is much more likely to be positive in the first five days of symptoms 
    • The threshold for a PCR positive
      • The result from an LFT is just either negative or positive.    
      • By contrast, PCR is very sensitive and can pick up very tiny concentrations of virus RNA even if only a very small amount is present in the swab.  
      • In the lab the PCR process can be tweaked to increase the amount of RNA.  
      • The likelihood that viral RNA is  detected by the PCR test can then depend on how much tweaking (so-called ‘amplification’) is needed to get enough RNA for a positive result (this is the nature of the science behind PCR, see Appendix)
      • LFT is less likely to be positive the more the PCR test needs to be amplified 
  • I have summarised the results from a publication that looked at 48 studies in the chart below
  • The percent refers to what proportion of the samples that were positive for PCR were detected as positive on LFT
Taylor et al, Cochrane Database System Rev 2021 (3) CD013705
  • Thus, for people with symptoms and a positive PCR (the first left hand blue column), around 70% would have a positive LFT, compared to under 60% without symptoms
  • Similarly, in those with a positive PCR,  LFT is more likely to be positive in the first week of infection than in the second week 
  • Thirdly LFT is much more likely to be positive if the PCR is positive without the need for lots of amplification 
  • A completely separate point relates to the fact above that the PCR test can be positive long after someone stopped being infectious 
    • This is especially a problem for interpreting the result of a ‘routine’ LFT in someone without symptoms for say a work or social engagement
    • A PCR done at the same time could be positive and the LFT negative
    • The problem is we cannot know with an asymptomatic person like this, we cannot know whether their PCR positive means an old or a new infection
    • If the latter is the case, then the negative LFT, is giving a ‘correct result’ about not  being  infectious

Conclusions 

  • Apologies if I have made a simple question seem very complex!
  • Given the impossibility of population wide PCR testing, LFT are a very reasonable substitute but the interpretation of a negative result needs to take account of the timing since the possible contact and the onset of any symptoms
  • LFT needs to detect people who are infectious so failure to detect people who are positive on PCR after the infectious phase has passed is not a concern – although the timing may not be known
  • If a very sensitive approach is used for the PCR to pick up tiny amounts of virus RNA, then such people, although positive, may not pass on the infection and hence a negative LFT may also not be a problem
  • For sure after a definite contact with an infected person, compared with LFT, PCR is more likely to be positive sooner and before symptoms develop
  • Maybe the bottom line is there is no perfect test of infectivity and to control the spread of a highly infectious variant such as Omicron, that widespread LFT testing is no substitute for mitigation measures (mask wearing etc)  

Appendix

How does a PCR test work?

  • The Covid-19 PCR test aims to discover the presence of evidence of RNA from the virus in a swab from the nose or mouth
  • PCR stands for polymerase chain reaction and is a laboratory method for making very large amounts of DNA or RNA from tiny samples (we use the term ‘amplification’ to describe this)
  • Thus ‘in the test tube’ what started off as a very small quantity of RNA is increased to produce a much larger amount
  • This process is used in police investigations to identify suspects from minute samples dissolved from blood stains – as you will know from any detective TV drama!
  • For Covid-19 the PCR technology can also  identify very specific strains – which is how Omicron was identified in the first place
  • The other aspect of the PCR test to be aware of is that the lab can also measure how easy it is to find RNA ie how much ‘amplification’ is needed.  The more amplification, needed to get enough RNA the lower the amount of virus genetic material in the original sample

How does the rapid antigen (lateral flow) test work?

  • The LFT test aims to discover the  presence of proteins made by the virus, also from nose and throat swabs
  • (We now know that Covid-19 is much more likely to grow in the nose, that a throat swab is not really necessary) 
  • The presence of the virus protein is detected by seeing if a sample of nose fluid reacts with a specific laboratory-made antibody
  • The test works by the absorbent paper strip inside the plastic cover being impregnated at the ‘T’ level with this antibody 
  • If the sample has such proteins, the antibodies on the strip react with them, produces a reaction and a line appears as on the right below
  • Whether or not there are  viral proteins in the sample, the sample drops will also dissolve the antibodies at the T mark, and then the drops spread to the C mark
  • The antibodies react with a dye at the C mark to produce the red line as shown
  • A positive LFT will produce both a line at T and at C, indeed if there is no line at either, the test has not worked or been done properly 

If you would like to receive email notifications of new posts on this blog just click this link and enter your email at the bottom of the home page: https://makingsenseofcovid19withs.com

Categories
Covid-19

Omicron and hospitalisation: new data on the protection from vaccines

Released yesterday (22nd December) are data from a study which has examined the rate of hospitalisation following infection with Omicron addressing the questions (i) does it differ from the rate following Delta infection and (ii) what is the influence of vaccination on this rate

The study

In this very rapidly produced report* (data was collected as late as 21st), researchers at Imperial College have undertaken a preliminary analysis using nationally available data for England

*https://www.imperial.ac.uk/media/imperial-college/medicine/mrc-gida/2021-12-22-COVID19-Report-50.pdf

What data did they use?

  • Linked 3 national datasets which were:
  1. All patients with a positive PCR positive, up to December 14th, for one of the two variants identified: either Delta or Omicron
  2. All admission to NHS hospital (up to 21st December) with CoVid
  3. National Covid-19 immunisation database of CoVid vaccine status

What analysis did they do?

  • Compared hospitalisation rates in patients who were diagnosed with an infection between those with Delta and those with Omicron
  • Separate analysis by vaccine status: both by number of doses (1, 2 and 2+booster) and whether the vaccine for the first two doses was Pfizer/Moderna or AstraZeneca
  • The analysis took account of  age, gender, ethnicity and socio-economic status that might have influenced hospital admission 

What did they find: overall hospitalisation

  • The study identified around 55,000 patients with a positive PCR for Omicron, of whom approximately just over 200 were admitted to hospital: a rate of 4/1000
  • This rate of admission was about 10% lower than the rate of admissions following Delta infection after allowing for all the factors mentioned above

What did they find: hospitalisation by vaccine status?

  • I have extracted the data by vaccine status following (i) 2 doses and (ii) 2 doses plus Pfizer booster and did this for both if the first two doses were AstraZeneca and if the first 2 doses were Pfizer or Moderna
  • The data below show the percentage reduction of being admitted to hospital with (i) Delta or (ii) Omicron by vaccine status compared with the risk of being admitted in the unvaccinated 
  • Let me explain: 
    • The first blue bar on the left, shows a rate of 62%.  This means that 2 doses of the AstraZeneca vaccine reduces the risk of admission to hospital following an infection with Delta by 62% compared to those people who had had no vaccine at all
    • The first orange bar on the left, shows a rate of 69%.  This means that 2 doses of the AstraZeneca vaccine reduces the risk of admission to hospital following an infection with Omicron  by 69% compared to those people who had had no vaccine at all
  • Thus the chart thus shows that  people who had had AstraZeneca  for their first two doses had a greater protection against admission to hospital with Omicron than with Delta.  
  • People who had had Pfizer/Moderna for their first two doses had more protection against both variants than the data from AsttraZeneca
  • By contrast with the AstraZeneca data there was only a slightly greater protection against admission to hospital with Omicron than with Delta 
  • The second chart below compares the hospital admission rates between these two variants in people who had also had a booster: again giving data separately for those whose first two doses were (i) AstraZeneca and (ii) Pfizer/Moderna
  • The results are broadly similar
    • There is no evidence that hospitalisation risk was higher with Omicron infection than with Delta
    • The opposite seems more the case: with a greater protection against admission following Omicron (78%) compared to Delta (64%) in those who had had AstraZeneca and a Pfizer booster
    • By contrast the rate of hospitalisation following Delta or Omicron are very similar in those who had had Pfizer/Moderna and a Pfizer booster
    • These data suggest that first two doses AstraZeneca plus booster possibly give a greater protection 

Data warning

  • These are very preliminary data and a longer time is needed to obtain more precise results
  • The numbers of people admitted to hospital following Omicron who had had 3 doses of any of these vaccine schedules is still low (around 30) which is good news; but means that the results, say from the comparison between the vaccines, may not hold up with larger numbers 

My headline conclusions

  • Firstly, admission to hospital following Omicron infection is very low.  This is likely to be explained in large part by most people in the population having protection from being vaccinated (and that many of those infected with Omicron are young) 
  • My second conclusion is that there is no evidence that hospitalisations were higher following Omicron than with Delta, if anything at this stage may be slightly less likely
  • This is important as there has been a lot of laboratory data suggesting that the mutations in Omicron could mean that the antibodies we had from the vaccines were both reduced in amount and could be less effective, compared to Delta.  This does not appear to be the case
  • It would be a wrong conclusion that there is no worry that Omicron infection will lead to hospitalisation in those who are vaccinated but more that the risk for individuals is the same independent of whether we are infected with Delta or Omicron 
  • The unexpected finding, which might not persist with larger numbers, is the apparent greater protection when first two doses of vaccine are with the AstraZeneca vaccine
  • The vaccine data have been confusing as most studies show a greater and more sustained benefit of Pfizer or Moderna after 2 doses compared to AstraZeneca
  • It is possible that the combination of 2 doses of AstraZeneca followed by a Pfizer  booster might give some additional benefit  over 3 doses of Pfizer, and this might just be more obvious with Omicron – we shall have to see
  • Overall, these data have to be reassuring given all the concerns from the laboratory data but they of course do not take away from the much greater infectivity of Omicron over Delta .

If you would like to receive email notifications of new posts on this blog just click this link and enter your email at the bottom of the home page: https://makingsenseofcovid19withs.com

Categories
Covid-19

Omicron: emerging data on transmission, severity and protection from vaccines

Since the start of the Omicron story, there has been an unprecedented focus by national authorities on collecting the data to answer the key questions. English data are now available and although there is much to be learnt and the analyses are very preliminary, there is information emerging about this variant

How quickly is Omicron spreading?

  • As widely reported in the media, although the absolute number of known cases is low (as I write this perhaps under 2000 in the UK) the rate of increase is very high
  • Case numbers are doubling perhaps every 3-5 days
  • These are the official data released yesterday from England of the total number of cases for every variant since the start of the pandemic*
    • Each curve shows the growth in the total number of cases by the time (in days) since each variant had been first identified.
    • Just look at the green line: Omicron and the light purple line: Delta (which I have arrowed)
    • The Omicron curve is the steepest
    • From the steepness of this slope, ie the rate of increase of Omicron cases, statisticians are therefore predicting a rapid rise in the total number which could reach half a million within a month or so
You will note that the Y axis (number of cases) is on a logarithmic scale to show the steepness of the increase.

*Note data emerging in past 2 hours suggest that the numbers might already be at the 2000

  • The reason for this is that Omicron is more transmissible than even Delta: it was highly suspected this would be the case given the mutations
  • One estimate is that this increase is around 3 times
  • I have tried to illustrate this in my diagram below
  • Imagine there are two people in your household: one with Delta and the other with Omicron.  
  • The data from household contacts shows that you are 3.2 times more likely to catch infection from the Omicron than the Delta member
  • It is for this reason that we are confident that Omicron will overtake Delta as the origin of the majority of new cases, perhaps as soon as the end of this year

Is infection with Omicron more severe?

  • Thus far the data are reassuring
  • I am not aware that any of the first 600 English cases infected with Omicron have been admitted to ICU but this will change
  • However, most cases of Omicron as shown in the Figure below are in those under 50, with only a tiny number over 70.  This could of course (see below) be related to the success of boosters in protecting this age group
  • The numbers are increasing daily so the figures may be out of date very quickly
Public Health England: Technical briefing documents on novel SARS-CoV-2 variants
  • The data from South Africa are also reassuring.  The Omicron cases in South Africa are predominantly in younger people, but again thus far the cases are mild
  • Indeed, the Omicron cases in South Africa in patients in hospital are all incidental, ie the patients were in hospital for another reason and the Omicron infection was picked up on routine Covid-19 testing

What do we know about re-infection risk?

  • People who have had a previous infection will have some immunity from that, in addition to any provided from their vaccines
  • We know that this immunity does not completely prevent a second infection with any of the variants and also wanes with time – hence everyone is recommended for vaccines whether or not they have had a previous infection
  • It is of interest though to know if the risk of re-infection is higher with Omicron
  • This is a very challenging question to answer but there are preliminary data from England looking at how often a new case of Omicron is a re-infection compared with a new case of Delta
  • The current estimate is, for those with a previous definite infection, the likelihood of contacting a second infection due to Omicron is 5 times higher than that due to Delta
  • On the one hand this is not surprising, given what we know about the difference between Omicron and Delta, but there are a number of issues in the way this increased rate was calculated and this figure could well be an overestimate 

What do we know about the effectiveness of current vaccines against Omicron?

  • I make no apologies for emphasising that, although we have some data, these are very preliminary and the way the data have been derived could lead to the results looking worse
  • The English data have looked at 56000 recent Delta cases with symptoms and compared their vaccine history with nearly 600 Omicron cases also with symptoms
  • The results looked separately at the rate of cases (i) 6 months after 2 doses of vaccine and (ii) 2 weeks after a booster
  • All boosters were with Pfizer but there was a separate analysis depending on whether the first 2 doses were AstraZeneca or Pfizer
  • Here are the results of the percentage effectiveness for those who had AstraZeneca for their first 2 doses:
  • The blue bars show the results for Delta and confirm that, as  we knew, the protection had waned by 6 months to around 40%.  In addition, there was very little protection against Omicron
  • After the booster, there was a very good protection against Omicron of around 70%, but less than the 95% against Delta
  • Here are the results of the percentage effectiveness for those who had Pfizer for their first 2 doses
  • The protection after 2 doses of Pfizer was higher than for AZ against both Delta and Omicron, although for the latter was under 40%
  • The data after a booster were the same as for AstraZeneca
  • Note that these are the results from all symptomatic cases, most of whom were mild
  • The rate of protection following a booster against severe cases could be higher
  • How long the protection following a booster will last is of course unknown

Conclusion

  • It is still early days and there is much we need to find out
  • The data I have presented come with a number of ‘health warnings’ which epidemiologists have been keen to emphasise
  • The conclusions may well change with more data and more sophisticated analysis
  • When I look to see what I posted a year ago about the then new variants, I considered many of the same questions, although we did not have the vaccine coverage we have now

If you would like to receive email notifications of new posts on this blog just click this link and enter your email at the bottom of the home page: https://makingsenseofcovid19withs.com

Categories
Covid-19

Will vaccines protect against Omicron: what, when and how we will know?

The big question worldwide is ‘will current vaccines be effective against Omicron?’  In the absence of any real hard information, news media are reporting on every expert utterance and each new case.  In this post I will try and provide a foundation for how to interpret the emerging information.  

Let us be clear on the important questions!

Given where we were a week ago (what a long time ago that seems!) this is what we knew – that:

  • Delta variant predominated
  • Delta is highly transmissible and responsible for the recent surge in Europe
  • Vaccines reduced Delta transmission by a reasonable amount but the likelihood of severe infection by a very substantial amount
  • These vaccine successes were enhanced in those who had had a third dose

To me, the important questions about Omicron are therefore:

  • Is Omicron more transmissible than Delta in individuals who have been vaccinated – and if so, by how much?
  • Is infection with Omicron more severe than with Delta in individuals who have been vaccinated – and if so, by how much?
  • For each of the above questions, we would want the answers broken down by:
    • Which vaccine
    • One, two or three doses

What do we have at the moment: expert opinion

  • In the absence of any real evidence, media are seeking out expert opinion
  • In fairness, the opinions are not based on just hunches but based on scientific assessment, in this case, of the relationship between the mutations described and what we know about the virus and the body’s immune response to the current vaccines 
  • The problem is experts’ opinion is just that, and given all the uncertainties, they won’t agree: for example this is the bosses of the 2 mRNA vaccines who said different things yesterday!
  • (I know from my own experience with the media on complex issues such as this, you won’t get quoted unless you come off the fence!)

What do we have at the moment: anecdotes

  • Epidemiologists use the term ‘anecdote’ to cover for example information that comes from just one or maybe a group of patients, but without any statistical underpinning
  • We cannot know what these limited reports mean in terms of our big questions
  • Under this category for example would be these recent reports about Omicron that there were 
    • “9 cases of infection from a single source in Scotland” 
    • “Some cases in South Africa have had 3 doses of the vaccine”  
    • “Most cases in Southern Africa have been mild or asymptomatic”  
    • “No cases of severe infection have been reported amongst the 44 known cases (to yesterday) in Europe”

  • Undoubtedly there will be a case soon in Europe of a triply vaccinated person who becomes hospitalised because of Omicron, and this will be headlines around the world
  • As an epidemiologist, I find both these ‘worrying’ and ‘reassuring’ stories to be of some interest, but they do not and cannot answer my key questions above

What we will get soon: lab studies

  • Laboratories are working round the clock testing the response to Omicron in people who have been vaccinated
  • The results should come in about 2 weeks
  • We should expect, because of the complexity of the experiments, that not all labs will produce the same results!
  • Below I show in simple terms one of the main approaches
  1. Scientists produce a virus which is harmless but is ‘engineered’ to have the same spike mutations

2. They will then take blood samples from people who have been vaccinated with different doses or none, and mix the new Omicron lookalike virus with these blood samples.

3. They will then measure how much response there is in terms of both antibodies and T cells, and if they are strong enough to fight the infection

  • Whilst these results will be very useful, especially if they show that, say after 3 doses of vaccine, the cells produce enough antibodies and T cells to combat the virus 
  • The problem is that what happens in the test tube does not necessarily correspond to what happens in real life

What we will get: real world epidemiological data

  • The proof of the pudding in terms of my key questions above will come from collecting real data from patients
  • Many countries including Israel, UK and Netherlands can link individuals’ vaccine details with national data that provide subsequent rates of (i) any infection (from the national testing) and (ii) being admitted to hospital with Covid-19    
  • Epidemiologists will need to examine these data on rates of infection, relative to how many doses of vaccine, and compare these results between infections from Delta and from Omicron
  • The data will only be useful when enough cases have emerged from Omicron in the different vaccine groups
  • Paradoxically if there are very few triply vaccinated individuals who become hospitalised in the next few weeks, especially as Omicron may take time to become (if that is the likely outcome) the predominant strain, we might take reassurance from the low numbers but they won’t be able to provide a robust statistical answer to my questions 

Conclusion

  • Scientists have set this Omicron ‘hare’ running and for very good reasons
  • If the resultant publicity then leads to greater uptake of boosters and mask wearing, then all to the good for managing the consequences of infection with Delta
  • Just be cautious in how you interpret all the material that is emerging on a daily basis!

If you would like to receive email notifications of new posts on this blog just click this link and enter your email at the bottom of the home page: https://makingsenseofcovid19withs.com

Categories
Covid-19

The new variant: how much of a concern?

Worldwide, media ran the story this morning of a new variant of the Covid-19 virus from South Africa which is causing anxiety and leading to travel restrictions.  We may remember  previous headlines about the India-Delta variant as well as other variants that hit the news: Brazil – Gamma, South Africa – Beta, that also led to travel bans from those counties.

What is this variant:

  • This new variant was identified this week by South African scientists
  • It is currently referred to as B.1.1.529 but I think will be given the Greek letter ‘Nu’*
  • It has  32 mutations in the all-important spike protein, as compared with the original Covid-19 strain (Wuhan) strain

*Since posting this blog WHO decided this evening to call the variant after the Greek letter Omicron rather than Nu (which was the next letter in the Greek alphabet)

Useful also to remember

  • This new variant was only picked up because of the very sophisticated DNA testing by South African virologists when they were investigating a sharp rise in cases in a province in South Africa 
  • We don’t know whether in other parts of the world, without such sophisticated laboratory systems, there are other variants, or indeed this one, which might also be becoming rampant 

Will this variant spread to Europe?

  • The first handful of cases were confined to countries in Africa but over the past 24 hours there have been cases in Hong Kong, Israel and now Belgium
  • Unless countries that are islands stop all inward movement , we have to expect cases in Europe 
  • Indeed this has just come up on my screen as I am typing this post:

What mutations does the Delta Strain have?

  • The Delta strain has  between 15 and 17 mutations  on its spike protein which make it different from the Wuhan strain
  • These differences make it easier for the virus to enter the cells and reproduce
  • This leads to a shorter incubation period 
  • And also increases the transmissibility of the virus
  • The Delta mutations did not mean this strain caused more severe disease
  • Though the fact that it resulted in a higher total number of cases – then there was be a proportionate increase in the total number within a population requiring hospitalisation
  • More importantly the vaccines worked against Delta, reducing substantially the risk of severe infection

Are the mutations on the Omicron strain more significant?

  • Firstly, because there are more mutations, the spike protein will have a different shape which the body’s immunity defences will have to respond to
  • The picture below on the left shows the whole virus with its spikes in red
  • The picture on the right is a detailed view of one spike and shows how the spike protein can be a very complicated shape and the greater the number of mutations the greater the change in shape
https://theconversation.com/new-coronavirus-variant-what-is-the-spike-protein-and-why-are-mutations-on-it-important-152463
  • Scientists say these mutations make the spike protein quite different to the shape of the Wuhan spike protein in 4 distinct ways
  • These mutations are predicted to make it easier for the virus to enter cells, in the same way that the original South African (Beta variant) did
  • The Beta strain was also predicted to cause more severe disease
  • Of greater concern though were concerns that the Beta strain could ‘escape’ the protection from the current vaccines
  • In fact the Beta strain never took a hold and whilst vaccines may not have been so successful against Beta, the lack of increased transmission ensured that Beta strain did not become a public health problem

What is the concern with this variant Omicron?.

  • The theoretical concern is that this variant could be both more transmissible and (relatively) more resistant to the vaccines, ie equivalent to the combined effects of the Beta and Delta strains
  • Vaccine resistance has been seen in South African patients with Omicron who have had vaccines, including Pfizer and AstraZeneca, but we don’t know if any of these people had severe disease
  • We should also remember that the level of immunity from the current vaccines, especially after a booster, is very high, with some spare capacity which experts believe could cope even with some quite different spike proteins.
  • For the moment we just don’t know if this new variant poses in practice an increased risk of 
    • Greater transmissibility
    • Greater severity
    • Vaccine resistance
  • These consequences are related to some extent

Conclusion

  • Is the media hype justified or have we been here before?
  • The changes in the spike protein are substantial but the theoretical risks above may not prove to be real
  • Whilst not being complacent, and we need to keep a watching brief, the anxiety may be misplaced
  • The key thing is to look out for any data on vaccine resistance, and development of severe disease in fully vaccinated (plus booster) individuals.  My guess and hope is that when these data emerge, they should be reassuring 

If you would like to receive email notifications of new posts on this blog just click this link and enter your email at the bottom of the home page: https://makingsenseofcovid19withs.com

Categories
Covid-19

Rising cases in Europe: what is going on and why

The news from Europe in recent days has been dominated by the almost exponential rise in the number of Covid-19 cases across several Western European countries.  What is the size of this problem and more importantly why is it happening? Is it too simplistic to focus on vaccination rates?

What is the data on cases

  • In the graph below I have extrapolated from Oxford University’s Covid-19 data website (Our World in Data) trends in the fortnightly rate of cases over the past 2 months in some selected countries
  • There is no doubt that especially in the past month there has been a phenomenal rise in the rate of cases (ie allowing for the population size) in Austria, Netherlands, Belgium and, though not at the same speed of rise, Germany
  • Data in recent days suggest possible rises in Southern European countries
  • The exception is the UK which has rates that are remarkably steady but, by comparison with countries outside Europe (and indeed over the 24 months of the pandemic) high

What about the rates of severe cases?

  • Much of the growth in the number of cases could be explained by 2 issues that would not be so worrying:
    • Greater publicity leading to increased testing of the population thereby identifying more milder/asymptomatic cases
    • Greater numbers of infections in younger people, given their greater social mixing at school and higher education, and whose infection is less severe 
  • However, the increases in the number of cases above are mirrored by an increase in the number of deaths
  • Again, the figures in the  graph below take account of different population size in each of these countries
  • For completion I show similar data for hospitalisation 

*Data from hospitalisations in Germany at a national level are not available (to me anyway!)

Is it all vaccination rates?

  • Regular readers of this blog and other media sources will be aware that vaccines are great at preventing severe infection but less good at preventing all transmission
  • In all these countries the severe cases are indeed concentrated in those who have not been vaccinated 
  • Thus differences in vaccine uptake might explain some of different trends in these countries: but what do the data actually show?
  • The answer in regards to the question above is very little: vaccine rates are not that different between countries
  • Other data I have seen suggest that in comparison with the UK, the rate of fully vaccinated people is only 4% less in Austria and 1% less in Germany
  • The conclusion is not that vaccination rates need to be higher in these countries (which they do) but rather that differences in vaccine rates do not explain why these sudden rises are happening now

Are there different strains at play?

  • Throughout this pandemic the concern has been that different strains of the virus, resulting from mutations, could explain higher rates of cases
  • Indeed the Delta variant, with its much higher rate of transmission, has explained the second and especially the third wave of cases seen in many countries
  • It has also been, what was an unexpected observation, that there have been no major new strains emerging during 2021 since and the Delta does still predominate in all the European countries
  • A variant of Delta, called AY4.2, is becoming more common (around 15% of cases) and might be more transmissible, but at the moment this is not thought to explain these recent trends
  • It is also reassuring and needs repeating (!) that contrary to initial worries, the vaccines used today are still based on the original Wuhan strain of the virus and yet still protect against both Delta and the AY4.2 variant

What about mask wearing?

  • Of all the mitigation measures, mask wearing is the most effective at reducing transmission 
  • Could differences in mask wearing explain the trends?
  • We know that research suggests infected people are less likely to have been wearing masks than their contacts who remain well 
  • It is difficult though to obtain data that are meaningful about who wears a mask and in what circumstances. 
  • There are some survey data on mask wearing behaviour from different European countries which are interesting
https://www.statista.com/statistics/1114375/wearing-a-face-mask-outside-in-european-countries/
  • Without doubt the population from Southern European countries are more likely to wear masks but Netherlands and Germany have higher rates than UK (I don’t have Austrian data)
  • I don’t think mask wearing explains all the trends but these data are supportive of that hypothesis and logically that could be the case

Conclusion

  • For sure the trends in some European countries are worrying but also unexplained
  • I suspect there are worse data to come both in terms of more deaths and hospitalisations, as well as rises in other countries
  • Vaccines, and especially boosters will help prevent these rises translating into public health and health service crises
  • Covid-19 is re-writing the rule book on how epidemic viruses behave!

If you would like to receive email notifications of new posts on this blog just click this link and enter your email at the bottom of the home page: https://makingsenseofcovid19withs.com

Categories
Covid-19

Another game changer – or not? 

Could a 5 day course of pills from your local pharmacist make Covid-19 a minor illness?

In the past month, the  drug companies Merck and Pfizer have both issued a press release about a new anti-Covid-19 pill.  These suggested that for newly diagnosed patients with Covid-19, a short course of these pills can substantially reduce – and in the case of the Pfizer pill almost take away  – the risk of needing to be admitted to hospital.  How justified are these claims and can they take the ‘sting out of the tail’ of this pandemic?

(Note to readers: as there is more detail in this post than some of you want, to make it easier you can skip the sections in italics!)

Tamiflu and the 2009 Swine Flu pandemic

  • Lest you feel this is the stuff of science fiction there is the example of Tamiflu and the swine flu epidemic in 2009.
  • Tamiflu a pill that could be taken at first symptoms of the H1N1 virus (behind swine flu)
  • At the time this epidemic caused a similar level of public anxiety as CoVid-19
  • Potentially it was suggested Tamiflu could prevent hundred of thousands of deaths in the UK alone
  • It was developed to be a drug which potentially could be obtained without a prescription to enable rapid take-up during such a large-scale epidemic 

 

  • Encouraged by scare stories in the media, the UK government stockpiled £500 million of the drug, subsequently to find that that by the time it was administered  it had very little clinical benefit in terms of reducing recovery time
  • And that money spent was probably wasted 

What about Covid-19?

  • In this blog in July 2020, I stated the obvious (so you don’t need to be impressed!) 
  • A successful anti-viral drug could stop the virus producing many copies of itself and hence stop people who had contracted the infection becoming unwell in any meaningful way
  • This is what antibiotics do to combat infections caused by bacteria;  but unlike antibiotics which work against many different bacteria, each virus needs is own antivirus drug
  • There was not a specific anti-Covid-19 drug, so early on in the pandemic doctors tried many anti-viral drugs which had been successful against other viral infections such as HIV
  • The most promising drug was remdesivir, which had been partially successful against other coronaviruses such as SARS, however in clinical trials the impact on Covid-19 was only modest
  • Remdesivir also needs to be given by injection into a vein.  What was needed, and should be possible, was a drug in pill form and easily obtained from your local pharmacist
  • The ‘game changer’ could be that once infection had been diagnosed, say by a lateral flow test, the patient could buy a short course of the pills from their pharmacist
  • We now have two pills that can be potentially taken in this way

The Merck pill: Molnupiravir

  • This is not a new drug but had been shown to work against lots of other viruses, especially coronaviruses
  • The US Biotech Company ‘Ridgeback Therapeutics’ found the drug stopped the Covid-19 virus producing sufficient copies of itself, when tested in ferrets
  • Merck then thought to test this in humans
  • It seems to work in quite a clever way: basically the copies of the Covid-19 virus produced when exposed to Molnupiravir are so changed that the virus can’t further reproduce

What are the new clinical data from Molnupiravir?

  • The data have only been presented in the company’s press release and not in a scientific publication (this is the new normal in this pandemic!)
  • The pill was tested on the following patients:
    • Adults aged 18 and over
    • ‘mild to moderate’ Covid-19 for less than 5 days
    • Had one feature that made them at risk of developing severe illness
  • The trial in the press release compared 5 days of 2 capsules a day with a placebo
  • The trial had originally planned to continue to May 2022, but an early analysis of the results showed that Molnupiravir was clearly effective – so the trial stopped recruitment
  • By 28 days after the start of treatment, 7% of patients on molnupiravir needed to be hospitalised, compared to 14% on placebo
  • More impressive still,  there were 8 (2%) deaths in the placebo group and none in the Molnupiravir group
  • There was no increase in the number of side effects between the 2 groups
  • The data have been scrutinised by drug regulators in the USA, UK and Europe.  In the UK, the  MHRA were sufficiently impressed to have approved the use of the drug
  • Consequently the UK government has bought 500,000 doses 

The Pfizer drug: Paxlovid

  • This is not a single drug but a combination of 2 drugs
    • The first is an antiviral drug that specifically targets Covid-19
    • The second is the well-known anti-HIV drug: Ritonavir, which works by slowing down the body’s mechanism to break down the antiviral – this keeps the circulating  level of active antiviral higher (clever I think!)

What are the clinical data from Paxlovid?

  • Again the data have only been presented in the company’s press release and not in a scientific publication
  • The trial was a bit like Merck’s trial and compared 390 patients who were at ‘high risk’ of getting serious illness to a similar number who were given placebo
  • Again 5 days of two capsules a day were used
  • The results were even more impressive:
    • Less than 1% of Paxlovid patients needed hospitalisation compared to 7% on placebo. 
    • There were no deaths in the Paxlovid group and 7 in the placebo group
  • The drug regulator in the USA, the FDA, on the basis of these results, advised stopping the trial as the data were overwhelming.  The FDA are likely to give emergency use authorization very soon

But there are an important number of unknowns about both these drugs

  1. Which group of patents would benefit from these drugs? Conversely which groups would not benefit: ie including both
    1. those who would not need the drugs as they would not be at risk of developing serious problems?
    2. those for whom these drugs would be given too late and other treatments should not be delayed?
  2. Most importantly until we have seen all the data, it is not clear who these groups are
  3. Indeed, studies by Merck suggest that their drug is not useful once the infection is severe – that is perhaps not unreasonable though, if it is given past the time the virus has done its damage
  4. Also, although the patients in the Merck trial had to have “1 characteristic or underlying medical condition associated with an increased risk of severe illness from COVID-19” until the data are published we don’t know whether these patients were typical of patients with mild Covid-19 
  5. How is mild or moderate disease defined and what criteria were used to conclude someone is at risk?
  6. For example in the Merck trial the 14% risk of hospitalisation and 2% death rate in the placebo group are much higher than the current situation in newly diagnosed patients in USA/UK/Europe

b) What about side effects?

  • Reassuringly the total number of adverse events was low for both the Pfizer and the Merck drugs
  • We haven’t seen the details of the side effects in these trials, just the total number of side effects combined
    • The trials were too small to know whether there are any individual major side effects we should worry about
    • If either drug was going to be used very widely we would need this information
  • BUT: this is all normal process in drug licensing, and at this stage in drug development we won’t have all these answers, but emphasises the need for longer term studies on patients treated with these drugs as they become licensed 

c) Could Covid-19 become resistant to these agents?

  • Theoretically the answer must be yes
  • Molnupiravir  works by disrupting the DNA of the virus, it is possible that whilst this could encourage the development of mutations that are less dangerous, equally these mutations could strengthen the virus –  but that seems unlikely 
  • Resistance is also possible against the Pfizer drug: the history of anti-HIV therapy is sadly associated with the development of drug-resistant strains
  • Although such resistance is possible, the duration of treatment is quite short which is helpful
  • On the plus side, because these drugs do not target the spike protein, which has been the main source of new variants, eg Delta, drug resistance is less likely.  Indeed these drugs could be very useful if other new, and  potentially vaccine-resistant, variants become widespread

Drugs versus vaccines

  • This to me is an interesting question especially as, in practice, the real benefit of vaccines has been to protect against severe infection rather than against contracting the infection
  • Indeed, the vaccine data suggest they can give about 90% protection against being hospitalised – ie the same benefit as claimed from the new Pfizer drug (and higher than the Merck drug)
  • Neither of the companies’ press releases specify if the patients in these trials had been double vaccinated
  • Thus a key question is whether these drugs offer any additional protection over the vaccines
  • Although a reasonable answer is that
    • These drugs act in a different way and can add a second line of defence for people who get sick despite being vaccinated
    • Given waning immunity, these drugs may be particularly useful in people for example who have not had a booster or for whom the immune response from the course of the vaccine is weak 

Conclusion

  • Yet again the media and pharmaceutical industry  are talking about ‘game changers’ in our fight against Covid-19 
  • I do acknowledge that these drugs, given to the right people at the right time in their infection, could provide major protection against severe illness – we just don’t know who these people are
  • More data are needed on both short and long term side effects

If you would like to receive email notifications of new posts on this blog just click this link and enter your email at the bottom of the home page: https://makingsenseofcovid19withs.com

Categories
Covid-19

What we need to know about flu and its vaccines 

When the Covid-19 pandemic started, earliest thoughts were that Covid-19 could be considered like a version of flu, indeed much emphasis was given to the fact that the number of hospitalisations and deaths during a ‘bad flu season’, especially in the most vulnerable,  were known to be substantial.  Many authorities were slow to accept Covid-a9 was different!

Further, most of the early thoughts about transmission, and its prevention, were based on knowledge and evidence from research on flu.  Clearly Covid-19 is a much more serious disorder than flu, both in public health and individual clinical outcomes, but this winter there is current emphasis on a successful flu vaccination programme. 

In this post I consider what we know about flu and its vaccines and why these issues are especially important in relation to controlling the impact of Covid-19 

Flu and Influenza viral infections: ‘flu’

  • For the sake of simplicity, I am going to separate out ‘flu’ the illness from the viral  infection ‘influenza’
  • We all diagnose ourselves as having flu based on the combination of having a fever, muscle aches and pains and feeling lousy
  • Like Covid-19, flu can cause severe complications such as pneumonia or heart failure but these are really restricted to those with underlying health problems  
  • There is no diagnostic test but doctors and patients feel more confident about ‘flu’ being the cause of our symptoms when many others have a similar pattern
  • Many viruses can cause these kinds of symptoms and indeed other infections such as a bacterial sore throat or glandular fever can mimic what we call flu
  • It is easy to forget that in the pre-Covid-19 era, there was very limited data about the viral background to people with clinical symptoms.  There were no equivalents of lateral flow or PCR testing available for widespread use
  • We don’t know how common asymptomatic infection was because this was not, and is not, routinely tested in flu
    • Flu does appear to have a very short incubation period of around 2 days and in that period people can pass the infection on but not be ill
    • How likely it is that people get infected and don’t have symptoms at all is not known and this will also vary each year, depending on the strain

Viral influenza

  • The presumption is that many people with ‘flu’ symptoms have an infection with one of the specific influenza viruses
  • There are 2 main types, amazingly called Influenza A and Influenza B!  (Actually there is Influenza C, which is rare, and Influenza D, which is only an animal infection)
  • The clinical infections caused by Influenza A and Influenza B are very similar 
  • There are also many different sub-types of both Influenza A and Influenza B 
  • The Influenza A sub-types are determined by the presence on the virus surface of two different types of proteins: ‘H’ and ‘N’
  • You may remember that the Covid-19 virus has the one very important spike protein on its surface, sso the Influenza A virus has 2 important spikes
https://www.scientificanimations.com/3d-view-structure-swine-flu-h1n1-virus/
T
  • This is the complicated bit!
    • There are 18 different varieties of H spikes (H1-H18) and 11 different varieties of N spikes (N1-11) so in theory there are 198 (18*11) different combinations 
    • The two most common combinations are H1N1 and H3N2 and it is against these the vaccines are designed to protect us
    • Although infection with one type may give protection against one of the others, this is not often very strong and cannot be relied upon
  • And even more complicated!
    • Each year different genetic mutations appear within each subtype such that for example a H1N1 circulating in one year may be quite different to a H1N1 three years later.  
    • To consider how this compares with the coronaviruses. 
      • Covid-19 is one subtype of coronavirus, equivalent to an Influenza A HN subgroup. So an infection with one coronavirus eg SARS does not give immunity against other coronaviruses eg Covid-19
      • But Covid-19 has developed many different variants, such as Delta, each with some differences on the spike protein.  Unlike Influenza A though, there is some protection carried through from one Covid-19 strain to another. We do not probably have this carry over protection with influenza variants
  • Influenza B also has subtypes (to be strict they are called lineages ie from their origins) and these two lineages (called ‘Victoria’ and ‘Yamagata’) also have different genetic strains which change each year
  • So that is why we need a new vaccine each year, because the virus strains can be so different with the result that our past exposures may give us little or no immunity 

What is in a flu vaccine ?

  • The challenge with developing flu vaccines is based on the complexity and changing nature of the circulating strains
  • We never know from one season to another how much immunity is carried forward
  • Each year a bunch of experts from the World Health Organisation try and predict what strains the vaccines  will need to protect against
  • The emerging vaccine actually normally has 4 separate vaccines  – two active against the presumed likely Influenza A strains of H1N1 and H3N2 and two active against the likely Influenza B strains of Victoria and Yamagata
  • Interestingly the strains of interest are conveniently named after the place where the current strain emerged.
  • So the 2021/22 vaccine contains vaccines against the following
*It is a coincidence that this year’s vaccine has a ‘Victoria’ origin for both Influenza A and B!

Are the flu vaccines like the Covid-19 vaccines?

  • The Covid-19 vaccines such as Pfizer and AstraZeneca are manufactured by very different approaches to the flu vaccines which are developed using traditional vaccine manufacturing methods
  • The flu vaccines are principally of 2 types
    • live but very weakened forms of the 4 viruses, which can be given as a nasal spray
    • an inactivated form of the 4 viruses, some of which are grown on eggs, which require an injection
  • Adults are always given the injectable forms.  
  • There is always a debate as to which is better both in terms of side effects and effectiveness

Who should get flu vaccines?

  • An interesting question in these Covid-19 times!
  • Typically, national programmes target those above a certain age, such as 50, or those who are clinically vulnerable as the infection is much less likely to be serious in younger healthy adults 
  • Key workers such as health care professionals are also targeted 
  • Widespread use of flu vaccines to both infants and school age children is recommended, both to preserve schooling and also to help in reducing the spread of flu in the population.
  • The fact that protecting children against flu, despite it being a mild disease for that group, is widely accepted – which is interesting given the great ongoing debate about protecting children with Covid-19 where similar arguments apply!

How effective are flu vaccines?

  • With Covid-19 we have been wanting 90% or greater protection and the bar has been set high for being successful
  • Interestingly, seasonal flu vaccines are much less protective BUT:
    • No-one tests flu vaccines for protection against having asymptomatic infection, so the effectiveness is only based on people reporting being unwell
    • Given what was said above, if someone develops a ‘flu-like’ illness despite being vaccinated it doesn’t mean that the vaccines didn’t work against the strains they were designed to protect 
  • Below are data about the modest vaccine effectiveness from the last 15 years of flu vaccines in the USA  – but other countries will have similar results 
  • The reasons why the vaccines are not as effective as we would like will depend on:
    • The effectiveness of the vaccines in providing immunity against the specific strains that have been targeted
    • Whether the circulating strains are different from the ones that have been targeted 
    •  What natural immunity from previous flu vaccines and illnesses may be carried forward
  • Why are we not given two flu vaccines if one is not that effective?
  • The short answer is a second shot has not been shown to give additional benefit
    • The studies that have been done have been on at-risk groups such as people with cancer or on dialysis, so maybe people who are otherwise well might also benefit from two shots
    • There is a health economic argument against two shots for healthy people for a disorder that otherwise is very self-limiting 

Conclusion about flu in the era of Covid-19

  • Below is a headline from 2018 from the UK: flu is not an insignificant public health problem
  • Much of the original thinking about tackling Covid-19 came from what we knew was important for managing flu
  • This includes issues such as the benefits of masks, hand washing, ventilation etc
  • In 2018 and 2019, there were just under 30,000 deaths from flu and its complication in the UK
  • Up to now we did not have the tools to test for viral infections such as flu, so the true size of the problem was unknown
  • In most western countries handwashing or mask wearing, whilst effective against flu were never taken up as important public health measures 
  • What the Covid-19 pandemic has achieved maybe is to our taking flu more seriously because of the risk of spreading to the most vulnerable and also none of us like being laid low year after year!

If you would like to receive email notifications of new posts on this blog just click this link and enter your email at the bottom of the home page: https://makingsenseofcovid19withs.com

Categories
Covid-19

Persistent high case numbers in the UK but does the Government’s ‘carry on as normal’ approach make sense?

https://coronavirus.data.gov.uk/details/cases

New cases of Covid-19 are now around  50,000 per day, with deaths and hospitalisations seemingly rising.  Yet the government response is to focus on the successful roll out of their vaccine programme, and not to be unduly concerned. This ‘passive’ response is being widely criticised in the media and by some experts.  In this post I consider how far the available data justify this ‘ vaccine only’ strategy.  (For the non-UK readers, I hope that many of the issues I raise are relevant to other countries with population-wide vaccine programmes)

What is the UK government narrative?

It may not have been enunciated as such, but this is my take on their view!

  • Covid-19 is now endemic within the population (rather than epidemic*), ie has moved from being an unusual one-off event to being a permanent state – at least for as long as anyone can forecast) – and its eradication is not likely  
  • Vaccines have been phenomenally successful at protecting against the adverse health consequences from being  infected 
  • Booster vaccines extend this protection
  • If the most vulnerable are vaccinated to the highest reasonable extent, ie by boosters at appropriate intervals, then the risk to individuals is as low as it can be and the burden on the health care system is acceptable
  • Whilst the overall number of cases was important as a measure of public health success at controlling the epidemic in March 2020, it is less relevant today – because of the success of vaccines 
  • We  accept that vaccines cannot eliminate transmission; but the recent overall rise in cases is predominantly explained by cases amongst the unvaccinated, especially teenage children 
  • This rise was entirely expected following the relaxation of mitigation measures in July and the return to schools and colleges last month 
  • Although not stated as such, the narrative above could also be summarised as “the new normal is that this flu-like illness will be around at some level continuously – but  given that this ‘flu’ has a successful vaccine to prevent the overwhelming majority of sufferers becoming seriously ill, no further public health interventions are needed.“

*What’s in a word? Pandemic is used when an infection covers several countries and populations, so the world has a pandemic whilst our individual countries suffer an epidemic  

What is the alternative narrative?

  • Cases are soaring out of control and are much higher than in other Western European countries who were more cautious in relaxing mitigation regulations 
  • With increasing number of cases, even if the percentage risk of a bad infection is the same, there will be numerically more deaths and those with serious complications
  • The reliance on vaccines may be over-optimistic if immunity is waning
  • The higher the number of people infected, the greater the chance that more vaccine-resistant mutations could become established
  • Public health measures should not only focus on preventing serious consequences but also stopping people getting ill at all; and even trying to stop transmission.

What are the facts?

1. Covid-19 is probably endemic

  • Even very high vaccination rates in some countries such as Singapore, they  are still seeing significant number of new cases
  • Indeed several national examples of infection rates disappearing almost to nothing then to reappear
  • Most experts accepted that Covid-19 was going to move to becoming endemic although this can only be proven in the future!

2. It is unvaccinated teenagers contributing the majority of the new cases

  • The UK government is correct that most cases are amongst the non-vaccinated, with teenagers being the group at greatest risk
  • The data from last week illustrate this clearly 
https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/coronaviruscovid19infectionsurveypilot/22october2021#percentage-of-people-who-had-covid-19-in-england-wales-northern-ireland-and-scotland
  • Most of the teenagers being infected had not been vaccinated: of 220,000 total cases in those under 18 in the most recent data; around 190,000 had had no vaccine

3. The vaccines are doing their job

  • It is well known that being double vaccinated gives excellent protection, greatly both reducing hospitalisations and deaths 
  • Some recent data last month published in the British Medical Journal* showed that
    • 97% of the 40,000 people admitted to hospital in 2021 (to the end of July) had not been double vaccinated
    • 99.5% of the 52,000 people who died within 28 days of  a positive test in the same time period had not been double vaccinated

*https://www.bmj.com/content/374/bmj.n2306

  • But these results can be easily misinterpreted, as double vaccination took some time to roll out
    •  ie the fact that there were only 3% of hospitalisations and 0.5% of deaths in people who had been double vaccinated reflects in part the low numbers that received their second dose by July
  • There is no dispute that vaccines are very protective, but that is not the main question we have as individuals.  Put crudely, “I am not interested that my risk is lower than if I had not been vaccinated, I want to know what my absolute risk is from getting really ill if I become infected
  • We now have these data from linking vaccine, testing and hospital datasets in the UK
  • The chart below shows the rate per 100,00 of ending up being admitted to hospital if you test positive (the black bars) 
  • As an example, this shows that this month even in the over 80s, less than 60/100,000 people who have been double vaccinated and who become infected are admitted, ie less than 1/1000
  • For the risk of dying following an infection the figures are equally reassuring 
  • Thus even in the 70-79 age group, less than 1/5000 double vaccinated, but infected, people will die (within 28 days of a positive test)
  • At first sight the data would support the government narrative that relying on vaccines at both an individual and societal level would appear to make sense

4. How much does vaccine immunity wanes

  • The above data assume that vaccines continue to be as effective over time – but we know that immunity wanes  
  • How much this waning protects against the most severe forms of infection is still not clear but rather than wait, UK and other countries have started a booster programme
  • The national data from Israel, and the recent clinical trial data from Pfizer,  would suggest that with a booster the protection against severe infection is maintained 
  • ‘We can only know what we know’ and cannot predict beyond the data we have; but a booster can restore or even raise the level of protection

5. Does it matter that the numbers are increasing?

  • It is mathematically obvious that as the number of cases increases, then transmission will increase
  • This is not necessarily linear and at any point the number of cases could soar
  • Thus, with increasing number of cases, the chances of any of us being in close contact with an infected person rise: so even if the percent protection from our vaccine against contracting  infection is the same, we are at greater risk of catching the infection (this is blindingly obvious but not often stated!)
  • So as a vaccinated person, as the number of cases rises, then my individual chance of contracting Covid-19 will rise and hence my individual risk of getting a severe outcome will also rise
  • But given the data above, even if my risk of catching Covid-19 infection increases 10-fold from the current rates – which is highly unlikely – then my absolute risk, as a double vaccinated person, of dying or getting a severe infection is still very small 

. Finally, what about mutations?

  • It is true that the higher the number of cases, the greater the risk of new mutations 
  • There are thus new mutations emerging all the time, with the most recent being a Delta-related variant: although these cause much excitement in the media they do not at the moment raise specific risks for vaccine success (so called ‘escape variants’)

Conclusion

  • It would be an act of folly to totally ignore the rising number of cases of Covid-19 in the UK
  • Given the relaxation by both government and the population of their vigilance and acts of mitigation, such as enforced mask wearing, it was obvious that transmission would increase and the numbers of cases grow
  • Thus far though, the data would support the success of the vaccine programme  as dramatically reducing the impact of the virus on individually affected people
  • The continuing emphasis on the vaccine programme, including boosters, should prevent any looming catastrophe from the current increased number of cases
  • Of course, there is a compelling case that say encouraging mask wearing might be a no-brainer at one level, to reduce transmission as far as possible and avoid even mild infection with the potential for longer-term symptoms

If you would like to receive email notifications of new posts on this blog just click this link and enter your email at the bottom of the home page: https://makingsenseofcovid19withs.com