Author: alansilman

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• The numbers are increasing daily so the figures may be out of date very quickly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

What is the UK government narrative?

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

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

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

What is the alternative narrative?

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

What are the facts?

1. Covid-19 is probably endemic

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

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

• The UK government is correct that most cases are amongst the non-vaccinated, with teenagers being the group at greatest risk
• The data from last week illustrate this clearly 

• Most of the teenagers being infected had not been vaccinated: of 220,000 total cases in those under 18 in the most recent data; around 190,000 had had no vaccine

3. The vaccines are doing their job

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

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

• But these results can be easily misinterpreted, as double vaccination took some time to roll out
  •  ie the fact that there were only 3% of hospitalisations and 0.5% of deaths in people who had been double vaccinated reflects in part the low numbers that received their second dose by July
• There is no dispute that vaccines are very protective, but that is not the main question we have as individuals.  Put crudely, “I am not interested that my risk is lower than if I had not been vaccinated, I want to know what my absolute risk is from getting really ill if I become infected”
• We now have these data from linking vaccine, testing and hospital datasets in the UK
• The chart below shows the rate per 100,00 of ending up being admitted to hospital if you test positive (the black bars) 

• As an example, this shows that this month even in the over 80s, less than 60/100,000 people who have been double vaccinated and who become infected are admitted, ie less than 1/1000
• For the risk of dying following an infection the figures are equally reassuring 

• Thus even in the 70-79 age group, less than 1/5000 double vaccinated, but infected, people will die (within 28 days of a positive test)
• At first sight the data would support the government narrative that relying on vaccines at both an individual and societal level would appear to make sense

4. How much does vaccine immunity wanes

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

5. Does it matter that the numbers are increasing?

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

. Finally, what about mutations?

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

Conclusion

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

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The UK, following other countries, is now giving a 3^rd dose of vaccine.  Whilst the Pfizer, AstraZeneca  and other vaccines protect against severe infection, they only are able to reduce, but not eliminate, transmission.  Despite the success of the vaccine roll out, increasing numbers of fully (ie double) vaccinated people are becoming infected with the Delta variant. What was unknown until research just published this week is just how much protection do these vaccines provide against the transmission of Delta? This new research also addresses two additional questions: (i) are there any differences between the Pfizer and AstraZeneca vaccines and (ii) by how much does the ability to protect against transmission wane over time?

How can vaccines protect against transmission?

• In thinking about the protection from the vaccines, we need to distinguish between the following two scenarios:

• As you will see, these are not the same question and the answers are different (read on!)
• Vaccines may work in several ways to stop both types of transmission
• Amongst the theories are:
  • They can stop some people getting the infection at all, by attacking the virus before it can take hold
  • They don’t stop people becoming infected (ie they will still have a positive test), but stop  people getting symptoms and for example coughing out the virus
  • If people become infected despite being vaccinated, the amount of virus they shed (‘viral load’) is lower
  • If people become infected despite being vaccinated, the amount of time they shed virus is lower

These are the questions for which up to now the answers are unclear

• Vaccines stop us getting very ill, but by how much do they stop the virus being transmitted?
• If I have been double vaccinated, by how much will that stop me picking up the infection from being in contact with another infected person?
  • Will my risk be different if I had the Pfizer or the AstraZeneca vaccine? 
  • How much will that risk wane over the months since I have been vaccinated?
• There is a separate question which relates to the risk that unvaccinated people pose to me.
• Thus if I am in contact with an infected person, how much less is my risk of getting infected if that person had been vaccinated?
  • Will that risk be different if they had the Pfizer or the AstraZeneca vaccine?
  • How much will that risk wane over the months since they had been vaccinated

Sorry I don’t mean to make this seem complicated but it is important to be very precise about the question being addressed.  Hopefully the results below will help if you are confused! Feel free to skip down to my conclusions at the end of this post

The Oxford/NHS England Research

• The research comes from linking the NHS Test and Trace system with the national vaccine database and has emerged in a non peer-reviewed paper
• This is what the researchers did

• The NHS ‘Test and Trace’ system was used to identify all new cases – called an ‘index case’ (ie the person was not previously known to the system)  – who had tested positive from a PCR test
• The system (like many other national systems) then attempted to follow up any known contacts of the infected person
• Those contacts who agreed then had a PCR test
• The research also identified through the national vaccine database the double vaccination status of:
  • the index case
  • the contacts of the index case
• They separately identified from the vaccine database which vaccine had been used  (AstraZeneca or Pfizer – the data was gathered before Moderna was introduced) and what was the interval between the second dose of the vaccine and the PCR test

What did they find: the benefits of vaccine to the contacts?

• I have expressed the results comparing the risk of becoming infected when contacts had been vaccinated compared to those who had not (which I fixed at 100%).

• The results at first sight look impressive:
  • If a contact had the Pfizer vaccine they would have just 10% of the risk of catching an infection compared to the contacts who had not been vaccinated 
  • If a contact  had the AstraZeneca vaccine they would have  28% of the risk of catching an infection compared to contacts who had not been vaccinated
  • The protection from Pfizer was thus noticeably higher than from AstraZeneca  

• This protection contacts had from their vaccines becomes much less strong, the longer the interval since their second vaccine dose.  This is true for both Pfizer and AstraZeneca 
• Let me try and explain the graph below

• The dotted line “unvaccinated contact” gives the proportion of contacts who when tested had a positive PCR.  This was around 0.7 (or 70%).
  • This proportion seems very high, but the Test and Trace system typically follows up on close – mainly household – contacts.
  • It is also possible that those contacts who were closest  and/ or feeling unwell were more likely to turn up for testing
• The red line is the experience of those who had the  AstraZeneca vaccine 
  • This showed that the proportion of contacts tested with a positive PCR increases, the longer the interval since they had received their second dose
  • Thus by 14 weeks after the second AstraZeneca dose about 0.5 (50%) of contacts tested were positive on PCR
• The blue line is the experience of those who had the  Pfizer vaccine 
  • This showed that the proportion of contacts tested with a positive PCR increases, the longer the interval since they had received their second dose.
  • Thus by 14 weeks after the second Pfizer dose about 0.4 (40%) of contacts tested were positive on PCR

• What do these results mean?
  • The biggest challenge in interpreting  these results is that we only know about the contacts who came for testing
  • Those contacts that were tested were more likely to have symptoms and to have been in closer contact with the index case, hence the positive rates will be higher
  • Nonetheless the headline conclusion is that:
    • Vaccination gives a moderate degree of protection against getting infected when you are in close contact with an infected person
    • This protection is higher following Pfizer than AstraZeneca vaccine
    • The protection does wane quite quickly

What did they find about transmission from a vaccinated person?

• For this part of the research they focused their analysis on those who had been vaccinated and (despite their vaccine) still became infected 
• They were compared with those who had not been vaccinated and became infected
• They wanted to see if the close contacts of vaccinated people had a lower risk of being positive than the close contacts of people who were unvaccinated 
• This is what they found:

• Again, for comparison purposes I have set the risk of an unvaccinated person passing the infection on to contacts as 100 (%)
• As you can see:
  • if the infected person had had the Pfizer jab, they were had around 35% of the risk of that from unvaccinated people to pass on the infection  to a contact
  • if the infected person had had the AstraZeneca jab, they were had around 64% of the risk of that from unvaccinated people to pass on the infection  to a contact
• Maybe these results are not surprising, ie once a vaccinated person becomes infected then why wouldn’t they be able to pass the infection on to close contacts?
• The research also looked at how time since vaccination affected their risk of passing the infection on
• This is what they found:

• In some ways these data are similar to the analysis undertaken from the perspective of the vaccine status of the contact (see above).
• The bottom line is that if a vaccinated person gets an infection, then by 14 weeks after their second dose their risk of passing the infection to a close contact is almost the same as if they had not been vaccinated 

How reliable are these data?

• Being honest, these are very difficult questions to address and difficult studies to do
• The risks of any of us becoming infected depends on so many things – just look at the list below:

• The researchers attempted to address all these issues and try and identify the specific contribution of vaccine status
• But there are always remaining concerns that the results may not be that accurate – although these inaccuracies should be the same for both Pfizer and AstraZeneca

My conclusions

• We already knew that vaccines did not stop transmission and that doubly vaccinated people could still contract the infection from another infected person
• That this risk declines with time since vaccination is also not too much of a surprise, though the speed of the decline, in these data, is perhaps unexpected
• It also seemed reasonable that if, despite being vaccinated, a person contracted the infection, they would still be able to pass this on to others
• We might have hoped that the vaccination might have lowered the amount of virus they shed and reduced the risk to contacts, but this was not the case
• Whilst AstraZeneca vaccine has enormous benefits in cutting down on serious illness, we don’t know why it is less impressive than Pfizer in stopping transmission
• The key question  though is what do these data tell us about the role of boosters in cutting transmission? To be honest I am really not sure
• It is hoped that boosters might make it harder to transmit the virus and may increase the duration of protection against transmission.  We just don’t know yet
• Worth repeating at the end of this post –  these data do NOT change what we know about  the success of the vaccines at stopping serious disease which boosters should enhance 

One final thought about compulsory vaccination as a public health message!

There is much heated debate, and worry, that our being exposed to people who are unvaccinated puts us at greater risk.  These new data do not argue against the benefits of vaccination but perhaps limit by how much our own protection is enhanced.  To me I would rather the person sitting opposite to me on the train today had worn a mask (which as I wrote this he was not*) than was vaccinated!

*He did lend me his iPhone charger though!

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Three days ago, National Geographic website ran a story about the origins of the CoVid-19 pandemic, following on a US National Intelligence Council investigation published 2 weeks ago.  21 months into the global pandemic, it is still appropriate to address this question – and to me the answer is as elusive – and as fascinating – as ever

At the end of August the US Intelligence agencies released their conclusion about the origins of CoVid-19.  They considered 3 possible explanations:

1. The Chinese had engineered the virus as a biological weapon
2. There was bona fide research on coronaviruses taking place in the Wuhan laboratory, and the virus had escaped by accident 
3. The virus that infected humans had naturally crossed species from bat via another animal to human

• The first option was discounted by all the experts, but both traditional and social media will continue to propound that as a theory!
• However, the US experts could not agree, despite all the months of consideration, on which of the other two conclusions was most likely.  This is what the report said

• Knowing the answer is vitally important for the future of our species!  
  • If CoVid-19 was a zoonotic disease (ie defined simply as one that normally affects one species but can spread to another), then we could take steps to limit human contact with animals
  • If CoVid-19 had been the result of a laboratory accident, the world needs to tighten up even more on lab safety
• To be honest the majority opinion on the NIC was that, more likely than not, infection was natural, but this was not unanimous.  In this post, I consider some of the evidence in both directions in detail 

The evidence from previous CoVid virus epidemics of transmission between species

Firstly, it is not disputed from 2 previous C0Vid virus outbreaks that those epidemics were caused by natural infection spreading from a bat via an intermediate animal 

2002 SARS-CoV 

• This is now widely agreed to have spread from horseshoe bats to live palm civets (a wild cat) – sold in live animal markets in Guangdong- province in southeast China – and then to humans
• The evidence for this is based on research showing how genetically identical the civet virus was to the SARS virus in humans

• The virus isolated from a civet from that live animal market was 99.8% genetically identical to human SARS
• Further the virus was not present in other civets not found in the animal market
• How the virus got into the market civet was not known for sure but, in 2012, in bat caves in Yunnan, a province in southwest China, researchers found almost by accident the same genetic sequence in the bat virus as that found in both the wet market civet and in humans carrying SARS virus

2012 MERS-CoV

• The first case was a business man in Jeddah who died from respiratory failure
• Given what had been found with SARS, MERS  was also thought to have spread from bats to humans but there were two unknowns: the genetic details were not available, and no middle step had been identified
• The latter was resolved in 2013 when a camel owner went down with MERS and, on analysing the blood from his herd, there was again almost complete genetic similarity between the CoVid virus found in the camel and the infected human

What was found in the wet markets in Hunan province  in 2020?

• Some of this information was gathered by the team of World Health organisation (WHO) scientists who had been given some access to some of the Chinese laboratory data and other results.
• WHO discovered that in 2020, Chinese researchers took more than 2000 samples from a variety of  live and frozen animals from the market and also from wild animals near by
• The WHO report implied that all these samples were negative for CoVid-19
• However it is possible that by the time the sampling was done in 2020, there were no affected animals
• Then there is the pangolin story!

• Pangolins are supposed to be a protected species but are trafficked to make handbags etc
• Pangolins did carry CoVid-19 but the genetic similarity between pangolin and human virus was inconclusive – about 85-90% – and further pangolins were not sold in the Hunan market

What about the role of bats?

• For sure, many species of bats in China carry coronaviruses
• Chinese researchers found coronaviruses with genetic sequences close to the human CoVid-19 in caves in Yunnan
• Similarly coronaviruses with genetic sequences close to the human CoVid-19 have also been found in other countries including Thailand and Cambodia
• The problem is that the genetic similarity with the bat virus is not as high as found with bat virus in both SARS and MERS and, this genetic data is really not conclusive 

How to explain that a bat virus could suddenly infect humans?

• One missing piece of the jigsaw is why should a bat virus, which is harmless to bats, ‘out of the blue’ be able to infect humans?
• We know that the virus can only get into our cells by sticking to them and taking over the complex mechanisms to then enter cells: these bits of the virus were not though to be naturally present in the bat.
• How did this genetic change in the bat virus occur to make them more likely to infect us, some argued that would have required this to have been ‘manufactured’ in a lab
• However in 2020 detailed analysis of other coronaviruses isolated from bats and pangolins had demonstrated the some of these properties were available.
• Why this research is important is that it argues against one aspect of the laboratory error theory  
  • That theory was that the CoVid-19 virus emerged from the Wuhan laboratory’s genetic research
  • Further that without such research, the CoVid-19 virus would not have had the ability to enter and infect humans

And what is the evidence that CoVid-19 comes from a laboratory leak?

• Some of this was gathered by the team of World Health organisation (WHO) scientists who had been given some access to some of the Chinese laboratory data and other results.
• The first is the obvious coincidence is that the epidemic started in the area containing the world famous coronavirus research lab – but the answer is that the lab was there because it was close to the bat caves where they needed to be
• The Wuhan Institute  of Virology reported that their research showed no match between the bat coronaviruses they were investigating and the CoVid-19 strains, but these actual records were not available to the WHO team investigating the origins of the pandemic 
• There was a report in the Wall Street Journal in May this year suggesting that 3 lab workers in Wuhan had had a mysterious illness in November 2019
• There are no other sickness data from the workers in the laboratory in 2019 suggesting CoVid-19 infection, but one issue is whether “no data” means no data or no evidence
• There is however one fascinating piece of evidence was reported in in the National Geographic article this week!

• Between 2014 and 2019, the US National Institutes of Health had funded a collaborative research project between a research group in New York  based ‘EcoHealth Alliance’ and Wuhan
• This research involved engineering a natural bat coronavirus and adding a spike protein so it could more easily enter human cells
• This is the same spike protein that has caused all the damage to humans
• A virological expert approached by National Geographic however dismissed this as irrelevant, as the bat coronavirus in this experiment was not the same as CoVid-19

Have laboratory leaks caused virus infections before?

• The short answer is yes!
• Indeed, the National Geographic article reported lab workers in several Asian countries working on CoVid-19 who had becoming infected
• By way of personal interest, the last case of smallpox in the world happened tragically from a laboratory  error in Birmingham – and the junior doctor who cared for the woman who died became one of my closest research colleagues 

My conclusion on if we will we ever get the answer?

• It is plausible that CoVid-19 could have spread from bats to other animals and then to humans, but the genetic data – whilst strong – is not absolute
• Conversely, the data suggesting a lab leak is all circumstantial – but cannot be discounted 
• So I don’t see how this question – one of the most important to arise globally – can ever be properly answered

It was many experts’ original expectation that immunity acquired either from natural infection or vaccination, or both,  would result in a state of herd immunity: ie a sufficiently high proportion of the population would be resistant to becoming infected.  Thus, the virus would not have enough unprotected people it could spread infection to.  The pandemic would thus peter out.

For several reasons this is now proving unlikely and even if we were all vaccinated the Covid-19 virus could still be present and being passed from person to person.

In this post I consider what is behind this and what are the implications for individuals and societies.

What is the level of protection from current vaccines? 

• Well known, of course, but Covid-19 has a spectrum of severity
• Again, well known, the greatest achievement from vaccination is to reduce the risk of getting severe Covid-19  

Most recent data suggests that, even for the delta variant, vaccines reduce the risk of needing to go to hospital by 19/20 (95%)

Similarly the vaccines probably stop about 2/3 of people getting any detectable infection

How many are getting ill despite being double vaccinated?

• The above figures show that the vaccines do not prevent everyone who has been vaccinated from having a detectable infection, even if they do not become ill
• They also show that , albeit rarely, there will be some fully vaccinated people who do become seriously ill
• The reductions of 2/3 for any detectable infection and of 19/20 for serious infection are important to have in mind as we interpret the news about vaccinated people becoming ill 
• It is obvious that, everything else being equal, the bigger the number of people in a population who become ill, the bigger the subgroup of those who had been double vaccinated

• We might then conclude wrongly that the vaccine did not work as well in Green town
• That would be false because without vaccines the overall number would be much higher in Green town
• Indeed in the extreme case, if in Green town 100% had been vaccinated, every case of infection would be in those who had been double jabbed  
• It is not surprising that we will know fully vaccinated friends, relations and colleagues, even TV presenters  who became ill

• And that in places with a successful vaccine programme, like Israel, headline data might suggest, as below, that vaccines are not successful 

Why are the vaccines better at stopping serious infection than preventing all infections?

• The vaccines work by stopping the virus entering cells and this seems to be especially effective for lung cells, which is why vaccinated people are much less likely to get serious breathing difficulties

Why some vaccinated people are protected against being infected at all and others are not?

• There are a number of possible explanations which include:
  • The amount of virus individuals are exposed to: the more contacts, the closer the contacts and the higher the number of droplets – each would make it that bit harder for the vaccine 
  • Differences in the genes which fight infection: we all have systems to hold off infection and in some people these are more effective than in others
  • A stronger immune response to the vaccine:  we know that people do vary in the level of immunity resulting from the vaccine.  This is not always easy to test (it’s more complicated that can be assessed from a single  antibody level)

Was our original optimism about the vaccines misplaced?

• If the Covid-19 virus followed the rules, then we had anticipated that there would be enough people who were immune to infection, either because of natural infection, or as a result of immunisation
• Once that stage was reached the virus would have had no-one else it could infect and would then die out – this is behind the concept of ‘herd immunity’ 
• We did not know how high ‘enough’ would need to be, it was thought as the pandemic progresses this could be as low as 60%, the pessimists felt it could be closer to 90%
• What had not been anticipated was the virus’s ability, especially of the delta variant, to be sufficiently capable of evading the immune system in some people so that it can multiply and be passed to others – including  a vaccinated person – though they might be much less likely to become ill

So, does this mean the pandemic will never go away?

• Vaccines do stop an important proportion of infections and in time this should translate into the pandemic disappearing
• Remember the all-important R value!
  • It is still correct to say that if each new case infects on average less than one other person, the infection will die out
  • The lower the value of R is below 1, the quicker the pandemic will die out
• The delta variant is so transmissible that it makes it a real challenge to get R below 1

Trends in R values since the beginning of the pandemic

• The charts below show the calculated estimates of R over the  duration of the pandemic, in the UK and USA, since the start.
  • The data for August (shown in brown) is the best estimate based on the current data
  • The paler shading around the thicker lines shows that there is still a level of uncertainty as to what the exact values are 

• As can be seen despite the vaccine programmes it is a real struggle to get the R value below 1

If vaccines are not the complete answer, what can be done?

There are a few possible responses to this:

• We don’t worry about stopping all infections and just focus on stopping serious infections
  • This can be substantially achieved by current vaccines 
  • There is a continuing debate about a booster jab, but it should be useful in further reducing transmission
  • Ensure the most vulnerable limit their risk of contracting infection, especially in areas/times with high numbers infected 
• Keep on with some measures of mitigation – mask wearing is the most obvious as it:
  • does little harm to the economy or normal activity 
  • is also the best way to keep transmission low
• We could reduce transmission by achieving the highest possible rate of vaccination
• There is a real debate as to the role of vaccinating children to achieve this:
  • Children (especially teenage) are the greatest reservoir of infection that can be transmitted to others
  • It would be challenging to lower R without their vaccination
  • The net benefit to the children themselves from being vaccinated is probably close to zero 
  • It is a novel ethical question as to whether vaccinating children to protect adults is justifiable

My conclusion

• We can’t get rid of Covid-19 completely any time soon, we will have to live with a high prevalence of detectable infection but, for most vaccinated people, a low risk of being seriously ill
• Vaccines have made an enormous difference on the numbers getting seriously ill, but cannot stop the virus remaining a threat to some
• Achieving as high a vaccination rate as possible, including children, could speed up the time to elimination
• Now is not the time to throw away the masks!