Category: Covid-19

Covid-19 infections are on the increase, many people are now getting their second or third Covid infection but now with Omicron BA.5* as the main culprit.  Why is this happening, and why is there so little apparent protection through immunity either from previous infections and or from the vaccines? 

*In this blog I mainly focus on BA.5 variant where there is separate information.  Much of the available laboratory and epidemiological data do combine the results from BA.4 with BA.5, as they are very similar in their effects.  Hence some places I will refer to BA.5 and other places BA.4/BA.5

How much more infectious is Omicron BA.5?

• We are used to new strains of Covid-19 virus emerging during the 2.5 years of the pandemic and rapidly becoming the predominant strain
• The reasons why this happens relate, firstly, to the new strains evolving to overcome the immunity mounted to older strains and, secondly, in some instances the new strains being naturally more infectious
• You may recall the ‘R’ number being the infectiousness score of a virus
• Indeed we were worried by the R for the original Wuhan strain creeping above 1.0 as it would represent a growing epidemic as from this slide from the BBC back in May 2020 – an R of 1.1 was ‘bad news’:

• As a comparison the R value for BA.5 is above 3!!

BA.4/BA.5 are now the predominant strains in many countries

• The  figures below are from the USA (but other countries are the same!) and show that BA.4/BA.5 from being barely registrable on 7^th May (blue arrow) by 9^th July BA.5 accounted for 70% of all new cases (red arrow)

Could we face other, even more infectious, strains?

• Coming to terms with BA.5 is challenging enough but are there still other new strains to come?
• This of course would always be expected in a pandemic

• Indeed this week a new strain from India (unhelpfully given the nickname “Centaurus” and currently referred  to as BA.2.5!) is increasing there and has been found in the UK, Germany and Netherlands
• The worry is that this new strain could bypass our immune system (see below) like BA.5 
• For now I will focus on BA.5

How different is BA.5?

• Well here is the interesting thing!
• Genetically it is very similar to the other Omicron variants from BA.1 onwards that had been responsible for all the cases since the beginning of the year
• When I say the genetics are similar, I mean that the detailed DNA of the virus and its all-important spike protein are similar to other Omicron variants and, indeed, quite different from the earlier variants
• In the picture below, the relationship between the structure of all the major variants of Covid-19 since the start of the pandemic is shown

• Essentially how close to each other the different variants are positioned on this drawing is an indication of their genetic similarity
• It is easy to see that BA.4 and BA.5 are positioned very close to the other Omicron (BA) variants and some way from older variants like Delta 
• But this is not the whole story!
  • Although BA.5 is similar genetically, the same cannot be said for the body’s immune response 
  • In practice the body’s immune system ‘sees’ BA.5 as no more similar to the other Omicron variants than it does to the original Wuhan variant
• Look at this picture where a laboratory examined the immune patterns of the different Covid-19 variants

• In simple terms the closer two variants are placed in the diagram, the more likely the body’s immunity to an infection from them is similar

• What this picture clearly shows is that (to me surprisingly!) BA.4 and BA.5 are very different from the other Omicron variants in this respect
• As a consequence, the immunity from a prior infection say with the first Omicron variant BA.1 (we may have caught in January this year) would provide less protection  against BA.4 or BA.5 than it would do against the original Wuhan variant!
• Why is this so: basically BA.4 and BA.5 have a few extra crucial mutations –  not only in the spike protein – but in other key bits of the virus that allow the virus to stick to our cells and multiply 
• Thus BA.5 can easily evade the immunity we have established with previous infections both from other Omicron as well as non-Omicron variants

Do these theoretical differences transfer into what is happening ‘on the ground’?

• The above all refer to research from the laboratory; do these worrying trends reflect what is happening in terms of reinfection rates? 
• Thus one measure of how successful BA.5 is at evading our immune response from previous infections is to look at the risk of second infection
• Here are some data from France showing the risk of a second infection following a first infection with different variants within each particular wave (typically over the 2.5 years of the pandemic each wave lasts around 6 months)

• At the start of the pandemic with the Wuhan variant, reinfections during that first wave were very rare – so rare that there were headlines if there was a second case in the same person!
• With Omicron in the current wave, second infections, and maybe third or more, are increasingly common.  Given the above information about the differences between the Omicron variants, this is perhaps not surprising 

What about vaccines? 

• It is well known a full course of vaccines, including boosters, protect against getting serious infection and this applies to all the known variants including BA.4/BA.5
• Similarly the vaccines do not protect against getting any infection, and that is as true, or more true, for BA.4/BA.5 than older variants
• Hence, we would not expect the current vaccines to prevent mild infections with BA.5
• There are new vaccines, designed to be more active against Omicron, which are being trialled, but my guess is they may still not be much use against BA.5

The big question is about severity

• Does it matter if our immunity to BA.5 is weak, if the infection from it is less severe and/or that our vaccines will still protect us from any severe consequences?
• As overwhelmingly most of the population at risk of severe infection from BA.5 (ie age over 60) have been vaccinated, it is very difficult to know what the severity would be if they had not been vaccinated 
• There have been recent rises in the absolute numbers of cases admitted to hospitals in many countries, who have tested positive for BA.5
• These rises are driven by the growth in the overall number of cases and not by any difference in the severity of infection caused by BA.5 compared to other Omicron variants
  • ie if the hospitalisation rate during the current BA.5 wave is say 1/1000 cases
  • in a region with 1 million cases there would be 1000 hospital admissions
  • in a region with 100,000 cases, there would be 100 hospital admissions

But what about long Covid?

• What causes and drives ‘long Covid’ is still a mystery
• There is no evidence that any particular variant is associated with a greater risk of long Covid than any other variant, and that is just as true with BA.5
• But recent data from the USA suggests that the likelihood of having long lasting symptoms following an infection with Covid, increases with each infection

• This study published last week does have some weaknesses and it may be that by chance alone, the more bouts of infection, the greater the chance that one will have longer lasting symptoms
• Many people will though now be having  a second or even a third infection from BA.5, because it is so much more infectious – and this theoretically increases the likelihood of long Covid
• It does not seem likely that BA.5 on its own poses a greater risk of long Covid

Conclusion

• It is certainly the case that BA.5 has shown we are going to have to live with the risk of having repeated minor infections with Covid-19 and there is no obvious end in sight
• Existing vaccines and even previous infections do not offer the protection against mild infection with all its consequences including the risk of long Covid
• Mask wearing, which was compulsory in many situations and now only advisory, absolutely cannot be off the agenda

And finally..

The author of this blog succumbed to my first infection a month ago, nasty but fortunately short-lived but may have coloured my views a little!

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The media have been full of headlines about a tiny number of cases of the viral disease monkeypox.  What do we know about it, why has there been a recent surge and, given the experience with Covid-19, should we be getting concerned?

What is monkeypox infection like?

• Monkeypox is a viral infection that causes flu-like symptoms
• It also causes swelling of the lymph nodes
• It has a characteristic blistering rash especially on the hands, feet and face
• Most people recover within 2 weeks

Is there more than one kind of monkeypox?

• Like Covid-19, there is more than one genetic strain
• There appear to be 2 major strains, one predominant in Western Africa in countries such as Ghana and Nigeria, and the other in Central Africa in countries like Democratic Republic of Congo
• The Western Africa strain has a very low mortality – even in poor rural populations – of around 1%, whereas mortality is much higher – 10% – from the Central Africa strain
• Fortunately the strain identified as causing cases in Europe and America is the milder West African strain

Why have public health experts got excited recently?

• Basically up to the last week or so, cases of monkeypox were only seen in Africans or in people from Africa who had spread the infection elsewhere
• The recent concern is that the new cases in Europe, Australia and North America do not seem to have had any African contact 
• Obviously, the number is growing but around 200 cases have now been diagnosed in the past week outside Africa which is more than the entire total of non-African cases diagnosed since 1970
• Why this should be so is unknown

How does monkeypox spread? 

• Monkeypox spreads differently from Covid-19 
• Basically it requires much closer contact 
• Also – unlike Covid-19 –  asymptomatic spread, ie catching the disease from someone without symptoms at the time of contact, is (or was) very unusual

Anything unusual about the new cases in Europe?

• As mentioned above, the lack of contact with an affected African individual is very unusual 
• Secondly, and at this stage only based on individual reports, there does appear to be asymptomatic spread, which could be worrying
• Thirdly, the recent cases have been proportionately greater in gay and bisexual men aged 30-50
• Whether this suggests that it is transmitted by sexual intercourse is unknown, but monkeypox had not been thought to be a sexually transmitted infection

What do we know about the monkeypox virus?

What about the connection with smallpox?

• This is probably the good news bit!
• Smallpox and monkeypox viruses are closely related
• Smallpox was only transmissible from person to person and hence a widespread international vaccination campaign led to the complete eradication of smallpox
• The last case of smallpox in the world was in Somalia in 1977
• Thus for decades there have been no new cases of smallpox and there is no need for anyone now to be vaccinated it
• Studies from Africa show that smallpox vaccine provides 85% protection against monkeypox which is good news for older generations who have received this vaccine
• Interestingly smallpox vaccines are used as a treatment for new cases of monkeypox, as well as for protecting close contacts
• There are also specific monkeypox vaccines that have been developed for use in Africa, which seem to be very effective with low risk of side effects

The outstanding questions:

• If this virus is now spreading from asymptomatic cases, that will make quarantining and containing spread more difficult.
• Whilst older people will have been vaccinated against smallpox, and hopefully protected against monkeypox, if any kind of outbreak takes hold it could it spread quite quickly amongst generations who were not vaccinated 
• Remember it is a mild disease, but I’m not sure that any country would wish to see an outbreak, or any individual developing an infection, even with ‘only’ a 1-2 week duration of being unwell, given what we have all gone through with Covid-19!

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As the original Omicron variant continues to mutate, its greater ability to transmit has been offset in terms of the public health risk by (i) the milder illness it causes and (ii) the protection against severe disease from both natural infection and the current vaccine regimes.  However, should we now be worried about the new variants now spreading from South Africa to Europe and North America?

A bit about the original Omicron 

• The original Omicron variant when originally identified was not thought to have significant subvariants 
• Then in South Africa, in late 2021, 3 sub-variants of Omicron were identified, and are now referred to as BA.1, BA.2 and BA.3
  • These 3 had many different genetic mutations from the original Omicron, but also differed from each other
  • All these subvariants were associated with mild infection, although some of the protection against serious infection will be a consequence of immunity from either, or both of, vaccines and natural infection
• One or more of these variants rapidly predominated in Europe
• Indeed in the UK, during the 2021/22 winter peak of Omicron, around 95% of new cases reported were from BA.2
• There have been many reports now of people having a repeat attack from one of these original Omicron variants, but these have also been mild
• As a consequence, and despite the greater transmissibility of Omicrons BA.1-3, the milder disease consequent on our natural and vaccine immunity led to the lifting of behaviour rules and also a reduction in self testing which has had a knock-on effect on our not knowing the exact numbers of cases

What are Omicron BA.4 and BA.5?

• These are two quite different subvariants of the original Omicron BA.1-3
• Both were first identified in South Africa this year in two provinces: BA.4 in Limpopo in the far north and BA.5 in KwaZulu-Natal in the south east. 
• These two subvariants have some of the same mutations as the original Delta variant
• They also have different mutations on the spike protein to other Omicron subvariants,  which makes them more sticky onto human cells and hence more likely to lead to infection
• Thus, not surprisingly, there has been a massive increase in the proportion of cases in South Africa due to these subvariants over a very short time
• As shown in the picture below, almost all cases in South Africa now are either BA.4 or 5

Have these variants spread to other countries?

• Indeed yes and they are already contributing to a growing proportion of cases in the few countries that have been able to test for these

• Thus they probably amount to 15% of all cases in the UK (both variants combined)

Do we need to worry about these subvariants?

• Obviously, the big question!
• Compared to the original Omicron subvariants, BA.4 and 5 are probably more transmissible so the absolute number of new cases is likely to increase (compared to what the numbers would have been if BA.1-3 were predominant)
• Indeed, the number of notified cases in South Africa has risen from around 1000/day in mid-April to over 10,000/day by the end of last week, a tenfold rise in less than 4 weeks
• As a consequence of the numbers alone, this has had a knock-on effect on the numbers being admitted to hospital; and indeed the challenge of increasing sickness amongst South African health workers with the new sub variants
• As with the original Omicron subvariants, the disease though is predominantly mild

What about protection from vaccines and previous infections with the older Omicron subvariants?

• That at the moment is the big unknown
• Experts are asking if this surge in cases in South Africa means that these new subvariants can evade our acquired immunity?
• Alternatively is any protection from the vaccines/previous infections waning? Hence the increase in cases from these subvariants just represents that phenomenon and would have happened with any circulating variant.
• This is where a research paper published this week might provide some insights to address this issue:
• This is what the research did

Their conclusions as summarised below was interesting and perhaps sobering!

• In brief the ability of this virus to mutate means that herd immunity is not an achievable outcome 
• Just giving boosters of the existing vaccines derived from the original Wuhan variant may not be of much benefit

But to some extent this is the situation with seasonal flu – except that Covid-19 mutations seem to be occurring in a 6-month cycle (see this picture from this week’s Nature)

And finally are there new more effective vaccines coming on stream?

• Before the BA.4/5 issue, both Moderna and Pfizer were already  modifying their mRNA vaccines to be effective against Omicron BA.1-3
• They have promised results by June 30^th
• I wonder if the BA.4/5 story means that the virus is mutating so quickly that major beneficial changes cannot be achieved with these new Omicron-derived vaccines
• The virus can mutate more quickly than vaccines can be developed to stop transmission

Conclusion

• Covid-19 is clearly here to stay and will continue to mutate
• The good news is that whilst repeat infections are likely, and may be impossible to prevent, the dire consequences of 2020 should not recur

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Despite the worldwide relaxation in Covid-19 mitigation and the awful situation in Ukraine displacing other news, that does not mean that Covid-19 has gone away.  What do the latest data show?

We cannot rely on the numbers of self-reported cases

• Regular readers of this blog will know that the number of self-reported or health care professional-reported cases cannot be relied on as a source of the true underlying trends
• Such information can only be gained from epidemiological studies of random samples of the whole population. In the UK, we have been fortunate to have 2 such studies: 
  • REACT which which has nearly 100,000 people sending in swabs every month in England
  • The Office of National Statistics (ONS) Covid-19 Infection survey which has 180,000 people sending in swabs every fortnight from all 4 countries in the UK
  • These studies therefore pick up anyone who is positive, whether or not they have symptoms and whether or not they did – or did not – report (for example) the results of a home lateral flow test
  • These studies can usefully estimate the total number of Covid-19 cases there are likely to be in the whole country
• This is the most recent data:

• Thank goodness we have stopped seeing these meaningless reports in the media of the number of reported cases
• I am sure that the same under-reporting is a worldwide phenomenon, we are just fortunate in having UK funding of these population studies*

*Although the Research Lead for the REACT study told me on Friday that government funding is ceasing for that study at the end of the month as they believe it is all over!

What do these epidemiological studies show?

• In England there has been very little change in the rate of new cases since the beginning of the year
  • Monthly rates hover around 4% or 1 in 25 of the population
  • If anything, last week saw a small rise

• In Scotland the recent rise is more pronounced and is unlikely to be due to the normal ‘up and down’ in such data

• A similar recent rise has been seen in Northern Ireland, with 1 in 17 of the population being positive 
• These differences between the UK constituent nations are also mirrored by different trends in different parts of England

• Thus for example the Southeast has had no fall
• The current higher rates in London and the Southeast might reflect their greater social mixing and work patterns
• There have also been differences between age groups in the trends: 

• The take home message is that since the start of the year there has been a decline in rates, especially in children, but conversely a slight rise in those over 50
• Childhood rates had been very high and they are now, as expected, approaching those in the rest of their households
• The slight rise in the older age groups might reflect the expected greater mixing following the relaxation in mitigation measures

Do we know anything about hospitalisation rates?

• Trends in hospitalisation rates based on the national reporting systems should be a reasonable indicator  of the underlying trend in the number of new severe cases 
• As is well-known, hospitalisations have been falling since the beginning  of the year due to a combination of the success of vaccines and the dominance of the milder variant Omicron
• Indeed declines in the number of people being admitted with Covid-19 have been observed in all the major European countries 
• However in the last couple of weeks there has been a worrying slight increase in the number of cases admitted in the UK, but not in other major European countries 

• By contrast, in the past week across Europe there seems to be quite a marked increase in the number of reported cases
• It will be interesting to see if these rates translate into more hospitalised cases over the next two weeks 

Is Omicron still the main variant?

• Indeed Omicron accounts for 99% of all UK cases 
• The interesting thing though is the proportionate increase in the sub-variant BA.2*
• This variant is even more transmissible than ‘regular’ Omicron but does not differ in severity
• The figure below shows the estimated percentage of all new cases in England due to BA.2:
  • The green blobs – show the daily laboratory  reports of the proportion of samples that are BA.2 positive
  • Because the numbers tested each day are quite small, the statisticians allow for this by giving a range – the green vertical lines
  • No BA.2 cases were identified before mid-January, whereas by 20th February the proportion of BA.2 was approaching 50%

*Despite its name BA.2 is not an advert for the world’s favourite airline!

• It seems that the vaccine protection against BA.2 is the same as against other Omicron variants. 
• Whether previous infection with the latter protects against further infection with BA.2 is not known, but certainly there are many reports of people having a second Omicron infection 

Conclusion

• Just because Covid-19 is not in the news, it has not gone away and might be increasing
• No new variants of concern have arisen and the latest variant BA.2, although responsible for keeping the virus spreading within the community, is not causing any specific new medical concerns 
• It is obvious that the overall risk of a significant infection to any fully vaccinated individual is based on the combined effects of the local infection rates and the severity risk of the predominant current variant(s)
• There is no evidence of the risk declining and possibly a small increase in risk, but mainly of mild infection
• Thus, despite Covid-19 not being in the news, no reason to change whatever feels individually comfortable in mask wearing etc

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I was looking at the data on the rate of new cases in different countries.  This showed the Faeroe Islands – a group of islands to the north of Great Britain – currently have the highest rates of infection in the world. On 25^th January they reported 913 new cases, equivalent to almost 2% of the population, just in 1 day

• To see how these rates are so much higher than elsewhere, look at this graph:

• The key question is what is the variant underlying these phenomenal rate rises and does it pose a risk for the rest of Europe and indeed the world?

What variants are infecting Denmark?

• The key variant is the so-called BA.2, which has mutated from the original Omicron variant, (correctly referred to as BA.1)

• Over a very small number of weeks BA.2 has become the most common variant in that country
• Below is a screenshot (apologies for poor quality) of the graph from the main Danish lab showing the takeover by BA.2

• It thus seems highly likely that BA.2 is more infectious, explaining the growth in the number of cases
• My suspicion is that, given the close links with Denmark, the surge in the Faeroe Islands is also due to BA.2

Is there any difference in the infection caused by BA.2?

• The variant is even more infectious but not more severe than BA.1 Omicron 
• There hasn’t been a surge in the number of deaths from Covid-19 in Denmark 
• Although there has been an increase in the number admitted to hospital, this is only to the extent that is expected from the increase in the number of cases
• Further weeks of observation on this new variant are needed to confirm these reassuring observations 

What about other countries?

• This is the strange thing!
• In England, which has one of the best developed PCR laboratory services, there have only been 400 cases of BA.2 identified up to last week despite the first case being identified as long ago as December 6^th
• I cannot find any data about BA.2 in France, which also is in the middle of a major surge
• The first handful of cases of BA.2 have now been identified in the USA
• Why I think this is very strange:
  • Given the data from Denmark, a bit like the situation when Omicron (BA.1) arrived, we might have expected a very rapid takeover by the new BA.2 variant in all countries
  • This takeover has not happened yet in any other country, suggesting that outside Denmark, the cases of BA.2 were not so much more infectious than BA.1 – which has its own very high transmission rate

What about vaccination rates?

• As frequently described in this blog, vaccines offer little protection against transmission of asymptomatic infection, but do offer some
• For what it’s worth, Denmark (and the Faeroe Islands) have very high population rates of vaccination (2 doses) compared with the rest of the EU and the UK

• Experts do not believe that the vaccines are any more, or any less, effective against BA.2 Omicron than they are against BA.1 Omicron 

A final comment on how is BA.2 identified?

• First identified in the UK by the national genetic screening of samples sent for PCR testing
• Initially considered just one of several sub-variants that typically will have arisen by chance from Omicron and possibly of little significance 
• BA.2 has several different mutations compared to the original Omicron (called BA.1)

• One of these differences is that the BA.1 variant of Omicron has a gene missing in its spike protein (the so-called  ‘S-gene dropout’)  – this  dropout is not seen in the BA.2 spike protein  
• S-gene dropout is easy to detect in a laboratory, and is widely used to decide if Omicron is present
• The worry is that the laboratories round the world have been relying on this approach to diagnose Omicron: this strategy would therefore miss detecting BA.2 Omicron

Conclusion

• Is the BA.2 surge in Denmark a worry for the rest of Europe and the world is not easily answered
• The infection the variant causes is no more severe and perhaps if it infects more of the population more quickly, then maybe such countries will achieve the benefit of population-wide natural immunity 
• We also don’t know, but need to know, if this variant might lead to an increased likelihood of re-infection: ie for people who have had BA1; is there a greater chance of being reinfected with BA2 than a second dose of BA1?
• The WHO has labelled BA.2 as a Variant of Interest as opposed to a Variant of Concern.  
• This seems sensible, we have no need to panic but we need to keep a close eye on the rates of new cases especially if cases continue at their current high rates

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In the UK, with the pressure on hospital beds from Omicron being containable, the government announced last week a relaxation in the rules brought in to minimise transmission of infection.  In this post I consider why the data might not support this decision

What is happening to infection rates in UK, Europe and North America?

• There is no shortage of data on reported infection rates in every country
• In this graph I show the rates of infection since the start of the Omicron wave in 5 selected countries 

• The broadest conclusion is that over the past 2 weeks, rates have certainly not fallen, and in France indeed are rising
• Many other European countries are also showing even more substantial rises
• in total, cases in the past week are 15% up from the previous week across the whole of Europe

• We need to be careful, though, as these data are of ‘confirmed cases’:
  • If the number of people seeking to be tested falls, for reasons perhaps related to the logistics of obtaining a test – 
  • Then (everything else being equal) these published numbers of confirmed infections may underestimate the true number of cases
  • The opposite may occur, of course, if tests are easier to obtain
• As an example, though, the UK government on 11^th January removed the requirement to have a PCR test if you were asymptomatic despite having a positive lateral flow test
  • Whilst this was not unreasonable given the demand for PCR tests, it inevitably could have resulted in the initial fall in the number of PCR positive cases
  • I have shown, that after January 11 (red arrow on the graph above), there was a fall for a week but that this fall has now levelled off 
  • Given the upward/flat trend in other European countries, I question how accurate are the UK figures, reported daily in the media.
    
• Thanks to KS for also reminding me that another inaccuracy in the daily data from England is that the number of cases reported excludes anyone who has been registered as having an infection in the past: reinfection

Can we know the true rates of new infections? 

• A simple question but a bit complicated to answer (typical epidemiologist!)
• Fortunately, in the UK, there is the Office of National Statistics (ONS) weekly survey of a random population sample, using PCR tests on everyone in the sample – whether they have symptoms
• The most recent results, published 3 days ago, provide the best guide to the numbers of people who are positive on the day of testing in the 4 UK countries
• The graph below shows the data for England from December 1^st to January 15^th, ie in the period since cases of Omicron started to be seen in the data

• The data showed that on 15th January, it was estimated that 5% of the population were infected: 1 in 20
• Remember also a positive PCR does not absolutely indicate a current infection
  • PCR may take a few days to become positive
  • The PCR can then be positive for 2 weeks or longer 
  • Thus ONS in their data assume that across the total number of people who  are PCR positive today, the “average” date they caught their infection is probably about 2 weeks ago
  • Thus, their most accurate assessment of the rate of new infections is on January 1^st, which if sustained suggests that each week, at the start of the year, which is consistent with 5% of the population were developing a new infection
• Now look back at the first graph, which shows the flattening trend over the past couple of weeks
• Inevitably sophisticated data sets such as the ONS survey are playing ‘catch up’
• Over the next couple of weeks there may be an important downward trend in new infections, but we cannot be certain yet
• Conclusion: Difficult to be accurate but even if the weekly rate of new cases is now not quite as high as 5% of the population, it is unlikely to be much lower and the infection must be considered as still unacceptably widespread in the population

Should boosters not have impacted on these trends?

• An obvious question, but why haven’t the rates dropped since the booster programmes have now been rolled out in many countries?
• We know that the main effect of the boosters is to reduce severity of the infection

• Indeed, the report this weekend from the USA showed that triple-vaccinated people had one third of the rate of symptomatic Omicron, (including those with just mild symptoms) compared to doubly vaccinated, which is great news
• But current vaccines do not have a major effect of preventing transmission
• The consequence is that being in a room of triple-vaccinated people does not preclude a significant risk of contracting the infection 

Is there a rationale for relaxing measures aimed at reducing transmission?

• A summary of the above is therefore that there is still lots of Omicron around which can continue to infect fully vaccinated people
• The data are still being collected on the chance of catching Omicron twice, but it won’t be negligible 
• For sure, Omicron is milder, especially in fully vaccinated people, and there is a line of argument that says transmission of an infection of that (low) level of severity need not be a public health concern
• But if we can reduce transmission even of this milder but highly infectious illness, without societal cost, why not?
• There is a Latin expression which underpins much of medical guidance: primum non nocere (first do no harm)  
• I mention that because wearing masks on public transport and other places, at a time when there is a background infection rate of 1 in 20, would seem to be a no-brainer
• For statistically inclined readers, rate of 1 in 20 does not mean that if you are in a gathering of 19 people, you are protected!  In fact, with that background rate, in any gathering of just 10 people, there is a 40% chance that at least one person will be infected

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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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