Author: alansilman

A study published a few days ago from the United States Centers for Disease Control (CDC), suggested that Covid-19 can more than double the risk of the new development of diabetes in children.  This study adds to the information from extensive research since the start of the pandemic that Covid-19 is bad news as far as diabetes is concerned.  We already knew that in people who have pre-existing diabetes, including those who are undiagnosed, Covid-19 infection makes their diabetes worse.

These data are the ‘other side of the coin’ from the much greater body of information emphasising that pre-existing diabetes increases the risk of severe Covid-19 including death.

In this blog post I consider the evidence that Covid-19 could actually cause diabetes, especially in children.  One consequence of this being true would be to add to the case for vaccinating children 

Two types of diabetes

• I am sure most readers will be aware that in simple terms diabetes is actually 2 separate disorders: unsurprisingly called Type 1 and Type 2

• Type 2 is much more common

• The major difference between the 2 types are shown below

• As Covid-19 infection is predominantly more of a problem in the elderly, inevitably  many of the studies up to now on Covid-19 and diabetes related to Type 2 diabetes
• These studies suggested that:
  • Patients with pre-existing diabetes who became ill with Covid-19 were more likely to lose control of their blood sugar and need to be hospitalised 
  • Mild to moderate Covid-19 infection could also unmask previously silent diabetes at an earlier age, ie such patients could well be diagnosed with diabetes in the future perhaps in response to another but non-Covid-19 infection
  • A severe infection with Covid-19 could cause such major changes to our metabolism  sufficient for  the new development of Type 2 diabetes that otherwise may not have ever happened 

Can Covid-19 cause Type 1 diabetes in children?

• The stimulus behind my writing this post was the concern that Covid-19 can lead to the more serious and life changing Type 1 diabetes in children
• Prior to the data this week, there was only anecdotal data from paediatric diabetic specialists reporting they were ‘seeing more new cases of diabetes’ in children since the pandemic started in 2020
• For example, a study from London reported an 80% increase in the number of new childhood cases

• Such findings were not universal and a group of German paediatricians reported no increase in the number of cases they were seeing
• Neither of these studies was a formal epidemiological study, until the much needed CDC study reported last week.

• The CDC statisticians compared the rates of new cases of diabetes in children aged under 18 between those with (blue bars) and without (orange bars) a diagnosis of Covid-19 
• Unlike much of Europe, there is no single health care database and thus data to answer this question came from two different providers of health care data –  ‘IQVIA’ and ‘Health Verity’- and combined they cover more than 0.5 million children
• The results are shown below

• The data from IQVIA showed a more than 2.5 times increased risk of diabetes
• The data from Health-Verity showed only a 30% increased risk of diabetes
  • In interpreting these results need to note that all the children in these datasets had had a clinical contact because of their Covid-19 and would not I believe have included children who were asymptomatic 
  • The ‘non-CoVid children’ were also identified differently in these two data sets and were in the Health-Verity dataset were sicker than the non-CoVid children in the IQVIA dataset for other reasons
• If the figures are accurate then it would suggest that around 1 in 300 children becoming ill with Covid-19 could go on to have diabetes, which could be 3 times that of uninfected children

How plausible is it that infection with Covid-19 could cause diabetes in childhood?

• The causes of diabetes in children are not fully known
• Perhaps surprisingly, genes are less important in Type 1  childhood diabetes than they are in Type 2, adult obesity related diabetes
• Type 1 diabetes is thought to be an ‘auto-immune’ disease in which the body produces antibodies that attack the specific, or ‘islet’, cells in the pancreas that make insulin.
• Patients with diabetes can have high levels of such ‘anti-islet’ antibodies in their blood
• The reasons why a virus could lead to the body’s immune system producing these unwelcome antibodies that attack our own organs is neatly shown in the diagram below:

• The body responds to infection with a virus by producing antibodies, (as in red arrow on this drawing), to the green bit on the surface of the virus.  These antibodies can then knock out the virus  
• Unfortunately  –  as shown by the blue arrow  – these antibodies that were produced to attack the virus, by a sad coincidence can also attack the pancreas
• In other words, an inadvertent consequence of the body’s response to a virus is to produce an antibody that attacks the body: a case of ‘friendly fire’, perhaps

Do other viruses lead to diabetes?

• Indeed, this has been a major theory for decades as to why diabetes develops in some children 
• Supporting this theory, there are  some anecdotal reports of children who had symptoms suggestive of being unwell with ‘flu-like symptoms suggestive of a viral illness shortly before they developed their diabetes
• In fairness, however, most cases of new onset childhood diabetes cannot be tracked to a recent viral infection
• In the table below, I list some of the viruses linked to the onset of diabetes

• Some of these viruses you will have heard of eg mumps
  • Rotaviruses are RNA viruses like Covid-19, but cause gastroenteritis by infecting the bowels
  • Enteroviruses are also RNA viruses which infect via the bowels
  • Some enteroviruses, including the Coxsackie virus, have been linked not only to the development of diabetes can affect the nervous system and also cause other severe diseases such as polio

Is there anything special about Covid-19 that might explain its link with diabetes?

• This is still a topic of continuing research and data are still being collected 
• One of the current theories about ‘Long CoVid’ has been that infection leads to the development of auto-immunity, ie the continuing symptoms with long covid are related to antibodies produced in response to the virus then attacking  other body systems. 
• At the moment, though, there is little data that Covid-19 produces antibodies against the islet cells
• Another compelling research idea, based on some laboratory data,  is that the virus itself, when severe, can infect the islets directly and destroy them

Conclusions

• The recent explosion of cases from Omicron, especially in children,  has perhaps highlighted the need to consider if there are long term consequences of an otherwise mild infection
• These recent US data do suggest that Covid-19 increases the risk of diabetes in children but do require confirmation
• We also need to know how severe the infection from  Covid-19 has to be to pose a risk of diabetes?
• Nonetheless a 1/300 risk, if that is what it is, is far from negligible 
• As the debate continues about the pros and cons of vaccinating children, the potential risk of diabetes does need to be included in the discussion 

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

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

Decline in vaccine immunity

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

How do boosters work

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

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

What worried the Israelis about declining immunity after the first booster

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

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

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

Is it too soon to start a 4^th dose?

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

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

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

What scientific data do we have at this stage?

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

Is there a fall in immunity following the boosters?

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

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

What about protection against severe disease?

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

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

What about a booster with a different vaccine?

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

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

My conclusions

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

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

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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

• 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 

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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

*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

• 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

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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!

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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

• 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!

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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

• 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

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!

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