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Covid-19

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

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

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

What is the UK government narrative?

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

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

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

What is the alternative narrative?

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

What are the facts?

1. Covid-19 is probably endemic

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

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

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

3. The vaccines are doing their job

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

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

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

4. How much does vaccine immunity wanes

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

5. Does it matter that the numbers are increasing?

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

. Finally, what about mutations?

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

Conclusion

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

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Covid-19

Can a booster following Pfizer and AstraZeneca vaccines stop transmission?

The UK, following other countries, is now giving a 3rd 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
As many readers know, all these types of data have a range of accuracy
to allow for the uncertainties in the calculations.  These are shown as the lightly coloured broader bands, in red for AstraZeneca and blue for Pfizer
  • 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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Covid-19

CoVid-19: natural occurrence or lab leak?

https://www.nationalgeographic.com/science/article/why-its-so-tricky-to-trace-the-origin-of-covid-19

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
Source: https://www.euroimmunblog.com/mers-outbreak-in-the-asian-pacific-region/
 

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
Categories
Covid-19

Even if we were all vaccinated, Covid-19 would still be a problem

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
Andrew Marr is a well known BBC presenter in the UK
  • 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! 

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Booster Jabs for Covid-19: What we know and what we don’t?

Two weeks ago the committee advising the UK government on vaccine policy recommended a booster (3rd) dose of a Covid-19 vaccine from September this year with a roll out to protect the whole currently vaccinated population 

By contrast, last week the similar committees advising the USA government stated there was no evidence to support a third dose currently!

Who is right and what is the current level of knowledge about booster doses?

How do booster doses work?

  • Covid-19 vaccines work by stimulating our bodies to produce an effective immune response when faced with the virus
  • This response has both immediate and long term, but more hidden, benefits 
  • The immediate benefit is the production of antibodies to the Covid-19 virus that can be detected in our bloodstream shortly after we have been vaccinated 
  • The longer term, more hidden benefit is the instructions the vaccine gives to the body’s immune system to respond very quickly when an infection strikes us – if you like, it’s like building an immunity production line that just needs to be switched on when the infection happens.  This is called ‘immune memory’ 
  • Not only do we want this ‘production line’ to go into action, but also that it produces a sufficiently large amount of  immunity 
  • Indeed an effective booster dose of a vaccine not only gets the immunity production line ready for action, but using the same analogy enhances its output when infection strikes
  • This is nicely shown in the picture below
https://www.science.org.au/education/immunisation-climate-change-genetic-modification/science-immunisation/3-who-benefits

One or 2 doses of Covid-19 vaccines? 

  • It is now ‘old news’ but the vaccines that are in widespread use (Pfizer, AstraZeneca, Moderna) have all been shown to be much more effective after two doses. After two doses:
    • The clinical data show much greater protection against getting infected and getting seriously ill 
    • The laboratory studies using sophisticated tests have shown that all elements of our immune response (both antibodies and T cells) are much much (deliberately repeating the word!) stronger after two doses
  • Interval between doses
    • Again old news but there does need to be a minimum gap to achieve maximum memory and for Pfizer and Moderna, 3 weeks seems to do the trick
    • The AstraZeneca situation is more complex because of the way they ran their initial trials and it seemed that a 3 month gap produced the best protection – which was plausible – the challenge was the longer wait in the middle of a pandemic to be fully protected 

Why the need for a third dose?

  • Current information is that two doses of the vaccines are effective, both in laboratory and in clinical terms, for at least 6 months 
  • The immediate benefit  of the the immune response, as judged by the measurement of our antibodies, probably declines with time.  
  • The problem is that as the vaccines are still quite new we do not actually know how much that decline might be a problem
  • This is because we don’t know whether the effective immune memory (the ‘production line’) would take over if we became infected 
  • Basically we have no robust data on how effective is the memory part of the immune system beyond 6 months
  • This could be tested in two ways: 

Clinical data 

  • The best test would be to determine how many people who have had 2 jabs develop any/serious infection for the longer term period beyond six 6 months following their second dose.
    • These data will be coming out soon from countries such as England and Scotland and will be compared to those who had not been doubly vaccinated. There are a number of biases in these analyses and they do not take account of any differences in how much exposure to infection people between the vaccinated and non-vaccinated groups

Laboratory data

  • The second helpful study would be intensive laboratory testing of double jabbed individuals after 6 months to see how their immune system would respond in a ‘test tube’ challenge to being infected
    • These experiments could compare the results in samples from people who had  two with those who had three vaccine doses 
  • We do not have such data at the moment (but they should be coming!)

What about the new variants?

  • One of the main arguments behind a third dose booster is that such a vaccine could be more useful against the new variants
  • Remember all the vaccines had been designed to combat the original Wuhan variant
  • Indeed an opinion piece (ie not research based) published by Iranian scientists argued that just giving the same vaccine repeatedly could be more harmful and rather than increase immunity might reduce the development of an effective immune response when a vaccine against new variants is available
  • I do not know in all honesty how likely this is
  • At the moment though all the push in the UK for a third dose is still based on using the original  vaccines
  • The argument being that the current vaccines do work against the new variants* and we do not have a new variant-proof vaccine 

*A study published last year seemed to suggest that the AstraZeneca vaccine was not effective against the Beta (South African) variant, this study has not been replicated and had many problems in the design, so to me that question is still open

What vaccine will be used for any third dose?

  • In brief there are no data suggesting what is the ideal vaccine for any third dose
  • This is especially true as we do not have any specific vaccines that are targeted at the new variants
  • Many studies of having two different vaccines for the first two doses have shown no problems and indeed possibly an even stronger response using a different vaccine second time round
  • Vaccine availability, at the moment, more than anything else will be the driver for third dose vaccine choice, although those with a particularly bad reaction to one of their previous vaccine doses may be offered (or would actively seek!) an alternative  

Special considerations for people with weakened immunity

  • There are several groups with weakened immune systems, either because of diseases like cancer or because of the treatments they are on
  • They have a double challenge:
    • an infection with Covid-19 is much more dangerous
    • vaccines may be less likely to be as effective as in people who normal immune systems
  • Thus
    • Because of the first reason they need to be a priority for vaccination
    • Because of the second, they are more likely to need a booster
  • There was an interesting case of such a person reported in the medical literature recently
    • This person had 4 Pfizer jabs shown by the red blobs (BNT162b2 is posh name for the Pfizer vaccine)
    • Look at the blue line, which is the amount of the main antibody needed to give protection and you can see it was really only after the 4th dose that the antibody level was sufficient to give immunity
https://ard.bmj.com/content/early/2021/06/23/annrheumdis-2021-220834.long
  • It is observations like this, albeit single case reports, that has pushed the Israeli government to go for a third Pfizer dose in such individuals

Is there any argument against a 3rd dose?

  • At the moment we do not have the type of data epidemiologists would want, either on the necessity for a third dose or its timing
  • It could be argued that if not harmful, why wait until proof is obtained, which could be too late to prevent future waves of the infection
  • The ‘original antigenic sin’ argument mentioned above would argue of a potential hazard of using a moderately ineffective vaccine which might make it harder to protect in the future against new variants
  • From a local health service viewpoint, resources (staff etc) devoted to giving a third jab cannot be utilised for other pressing health issues
  • From an international perspective, the rampant infection and low vaccine provision in many low and middle income countries may argue against a third dose in rich countries being a priority

And my conclusion?

  • Sorry but still sitting on the fence on this one!
  • I am sure a third dose (and maybe more) will be needed at some stage but not necessarily as early as 6 months
  • A third dose ideally needs to be designed to be of value for the major variants currently responsible for the majority of cases 
  • A piloted roll out with careful laboratory data collection on how effective a 3rd dose would be after 6 months would be is sensible
  • I would strongly support the Israeli approach of a third dose after 6 months of the current vaccines to those with a vulnerable immune system

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Double vaccinated with Pfizer or AstraZeneca: but how protected am I against new variants?

The initial euphoria following the roll out of vaccines is currently tempered by concerns that their effectiveness is less certain against new variants of the virus.  We now have data from both Pfizer and AstraZeneca vaccines but providing an answer to the question above is quite complex but hopefully this post will help!

New variants for old

  • The vaccines were developed based on the original ‘Wuhan’ strain of the virus and the first clinical trials, proving their success, were in populations exposed to that variant
  • It is obviously relevant to know if those early clinical trial results now also apply to the main current variants, especially the Delta (India) one

A quick comment on the new variants

  • Current focus is on the Delta variant, but there are a number of other variants that are beginning to emerge
  • The data are based on detailed DNA analysis of positive swabs
  • In the main the impact of the variants influences is on how infectious (transmissible) they are, rather than the severity of infection
  • The main reason I give this list with all the newer variants is not to generate anxiety but rather to emphasise that this growing number is an inevitable consequence of the evolution of new mutations during a pandemic
  • There are bound to be other named variants to come – so don’t even bother trying to memorise this list!
  • Although nothing in this pandemic is certain, our knowledge of how effective the vaccines are against the Alpha and Delta strains can probably also be applied to these newer variants 

Five questions to be asked

As someone who has been double vaccinated (with the AstraZeneca vaccine) I assess my risk by considering the following 5 questions:

  1. What is the rate of infection in the population I am exposed to?
  2. How transmissible are the current variants?
  3. How protected is the rest of the population I am exposed to?
  4. Will my vaccine stop me getting infected?
  5. If I do get infected, will my vaccine stop me getting seriously ill?

The answers are of course interconnected but I will deal with them in turn.

1.) What is the rate of infection in the population I am exposed to?

  • It is stating the obvious, but worth repeating, that if the infection rate is very low in my area, then it is less of a worry if my vaccine does not give perfect (100%) protection
  • In this map from last week in England, there was at least a 6-fold variation in the rate of infection between different regions 
To explain: a prevalence of 0.006 is the same as 0.6% of the population is infected
  • I’ve tried to illustrate the impact of this 6 fold variation in relation to my vaccine status in the diagram below, assuming that my vaccine gave me 90% protection. 
  • In an area with a high rate of infection there will be far more cases of infection in both vaccinated and unvaccinated people than in areas with low infection rates
  • The consequence is that the rate of infection in my area is (obviously)  important to my risk of being infected

2) How transmissible are the current variants?

  • Infection rates within a population do not stay static and thus I don’t only need to know what is the current rate of infection, but also is it changing?
  • The figure below comes from English data published this week
  • The top (very light!) grey/purple curve is the curve for Delta and that shows how much more transmissible this variant is than all the other variants analysed

  • Again, even if the vaccines were equally effective against all variants, looking to the short-term future, more vaccinated people will get infected in areas where the Delta variant predominates 

3) How protected is the rest of the population I am exposed to?

  • The hope from the start of the vaccination programme was that not only would I be protected by my own vaccine but also that people around me would have been vaccinated and they would be less likely to get infected and pass that benefit on to me (herd immunity)
  • To be honest it is still not clear how far this is the case.  As discussed below, the vaccines are not perfect against being infected
  • There are good data from populations looking at the trends in the numbers with infection as the vaccination rate increased:
    • For example, data from Israel and the elderly in the UK support that idea that high levels of vaccine uptake might also protect unvaccinated people in those populations
    • Such trends though do not prove cause and effect
  • My conclusion is that even if the vaccines were equally effective against all variants, although I would feel more protected if those around me were also vaccinated, I cannot quantify the change in the level of personal benefit that would bring

4) Will my vaccine stop me getting infected with the new variants?

  • We knew from the early clinical trials (i.e. before the new variants) that the vaccines did stop many people getting infected, but that this was not 100% 
  • Thus these clinical trials suggested that the short term protection was less than perfect for all the vaccines
  • The level of protection was also less with the AstraZeneca than with the Pfizer or Moderna vaccines 
  • We now have data, not from clinical trials but from much larger national population databases, on the effectiveness of the vaccines against the new variants
  • Both England and Scotland have provided such data on this issue
  • They linked:
    • Results from the national testing services which collected information on who tested positive and whether they had symptoms.  These data also gave information on which variant
    • The vaccine status, including data and number of doses and which vaccine 
  • By analysing the data from all the positive tests, they have been able to answer the following question: 
    • How much lower was the rate of infection with symptoms in people who had been vaccinated compared to people who had not been vaccinated?
    • And in particular
      • Was there any difference between AstraZeneca and Pfizer vaccines in this effect?
      • Was there any difference in the effectiveness of the vaccines between the Alpha and Delta variants?
  • This is what they found: 
  • To explain this graph, look at the orange bars (Pfizer vaccine)
    • After two doses of the vaccine, compared to people who had not been vaccinated, the rate of having a symptomatic infection was 
      • 0.06 (or if you like 6%) for the Alpha variant
      • 0.12 (12%) for the Delta variant
  • The figures for the AstraZeneca vaccine were
    • 0.26 (26%) for the Alpha variant
    • 0.33 (33%) for the Delta variant
  • The data from Scotland were similar – for the Delta variant
    • Rates of infection after the Pfizer vaccine rates were 17% of those in unvaccinated people
    •  Rates of infection after the AstraZeneca vaccine rates were 39% of those in unvaccinated people 
  • Actually, these are not that different from the vaccines’ success against the original variant: the Pfizer vaccine has a substantial effect on reducing rate of having an infection the AstraZeneca has a lower effect
  • But this data is less important to me than the risk of becoming seriously ill- next question

5) If I do get infected, will my vaccine stop me getting seriously ill with the new variants?

  • The data came from linking everyone who tested positive and self-reported symptoms with the national hospital record systems 
  • The question then is how far did the vaccines protect against having such a serious infection that they needed to be admitted to hospital
  • However (and this is good news) their first result was that , despite high numbers of people being infected, the absolute numbers of people admitted to hospital were very low and hence the reported effects of vaccination on this may not be very accurate
  • Below are the data from England
  • Again look at the orange bars (Pfizer vaccine)
    • After two doses of the vaccine compared to people who had not been vaccinated the rate of being hospitalised was 
      • 0.88 (or if you like 88%) for the Alpha variant
      • 0.34(34%) for the Delta variant
  • The figures for the AstraZeneca vaccine were
    • 0.53 (53%) for the Alpha variant
    • 0.25 (25%) for the Delta variant
  • These results seem very strange!
    • They suggest that protection against hospitalisation was stronger against the Delta variant than the Alpha variant
    • They suggest that protection against hospitalisation was stronger following the AstraZeneca than the Pfizer vaccine
    • But remember these are based on small numbers 

Combining the answers to questions (4) and (5) together

  • My main question is: will my vaccine stop me getting infected so badly, I need to be admitted to hospital
  • The level of protection will thus be based on how much less likely is it that:
    • I will get any symptomatic infection – and –
    • If I have a symptomatic infection, I will need to be hospitalised
  • The calculation is quite complex and I have shown the details in the box below
  • In summary, these data show that the Pfizer vaccine is 95% effective and the AstraZeneca vaccine is 92% effective against the Delta variant

And the take home message:

  • Apologies, it is a complex question that defies a simple answer!
  • The main messages are
    • Both Pfizer and AstraZeneca (and probably Moderna) vaccines are as effective against the Delta variant as they were against other variants
    • But high rates of infection with the Delta variant, because of its greater infectivity, will mean I am a little less protected than I was when other variants predominate 

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Will my vaccine protect me against the Indian Variant?

First data from Pfizer vaccine.

The Indian Variant (now referred to as ‘Delta’) is recognised as being highly transmissible and, as a consequence, it is now the predominant variant in the UK and elsewhere.  The question in many people’s minds is whether, despite the rising number of cases, those who have been fully vaccinated will still be protected against this variant.  A laboratory study published this weekend in the Lancet suggested that vaccines may be less effective.  This has important consequences both for individuals and communities as to how careful, despite vaccination, we need to be in returning to ‘normal’ life. 

A second concern raised by this study is that the level of protection against this variant after one dose could be much less than against other variants. As vaccine roll out to younger generations is proceeding apace, how much more careful should they be with this variant? Are greater warnings needed not to relax their guard until after their second dose? 

In this post I will try and explain the issues and what the new data tell us

Why we need to understand the background to these variants in relation to current vaccines? 

  • In order to understand why there is now a concern about vaccines and variants, we need to trace the rise and fall of the key variants 
  • The variants of the virus all differ in the shape of its spike protein
  • Importantly they vary in the specific part of the spike protein that allows the virus to enter our cells
  • The Indian variant is the most different in this respect from the Wuhan original virus 
  • Vaccines were developed to produce an antibody response to the spike protein and were designed specifically based on the detailed genetic code for the protein for the Wuhan variant – which was shared worldwide early on in the pandemic by the Chinese
  • The hope from the vaccine developers, even though they could not know what mutations might arise, was that the spike protein of any emergent variants would not be so different that the ‘Wuhan designed vaccine’ would not still work
  • However, the Indian variant is the most different in that part of the spike protein that attaches to the cells in the body, so it is less of a given how much vaccines would work against it

What does ‘how much vaccines work’ mean? 

  • The vaccines all aim that the body produces antibodies against the spike protein of any of the variants
  • These antibodies can knock out (posh term ‘neutralise’) the virus  
  • This is not an all or nothing response with any of the vaccines:
    • All the vaccines should produce some neutralising response
    • The level of this response may vary between the different variants of the virus, as explained above
    • But the vaccines are designed to be very powerful, so just because there is a lower neutralising response against some variants, this does not mean that this would not be  sufficient to stop infection
  • Also importantly individuals will vary in their antibody response because of:
    • Age
    • Gender
    • Health issues including obesity
    • Other factors that are not known 
  • Plus the antibody response may wane over time
  • (not discussed in this post is that – as regular readers will recall – vaccines also work by boosting our T cells to fight infection as well as antibodies – but they are much harder to study!)

What do these new Lancet data tell us:

The study addressed the following questions:

Who did they study?

  • 250 health worker volunteers in London
  • All had had 2 doses of the Pfizer vaccine
  • Their mean age was 42, with just one quarter aged over 52

What did they test?

  • The serum from these volunteers was tested for the level of ‘neutralising antibodies’ (ie antibodies that should stop the infection) at 25 days after the first and 25 and 100 days after the second vaccine dose
  • Antibodies were tested in each serum sample to see if they would neutralise against the following strains of the virus:

1.  Wuhan 

2.  D614G

3.  UK (Alpha)

4.  South African (Beta)

5.  Indian (Delta)

(the Brazilian (Gamma) strain was not tested)

  • They also analysed the antibody responses to compare the results by age, between men and woman  and by body weight 

What did they find?

  • The good news was that only 3% of the participants had no antibodies against the Indian strain
  • Indeed, that percentage was less than the 5% who had no antibodies against the South African strain
  • But, the ability of the antibodies to neutralise the virus  was different when compared between the strains
  • The researchers helpfully presented their data, not just in the levels of antibodies, but more importantly in simple terms ‘how much less good was each sample at neutralising one of the variants compared to the Wuhan’
  • As an analogy think of taking an antibiotic for a throat infection caused by one of 2 bacteria, ‘A’ and ‘B’.  The antibiotic might have some benefit against both types of bacteria but on average be only half as effective against ‘B’ than ‘A’.
  • The researchers in the Lancet study, rather than presenting such a result as ‘half as effective”, preferred to say ‘twice (twofold) as ineffective’ (hope that’s not too confusing!)
  • So here are the data:
  • Thus these vaccinated volunteers had weaker responses to all the strains but they were particularly weaker (nearly 6 times) against the Indian variant
  • But they were also 5 times weaker against the South African variant

Were the results from all people the same?

  • As you would expect, the answer is no
    • Many of the volunteers actually had a good neutralising response to the Indian variant
    • Others had a very weak response
    • On average their response was much lower than against the other variants
  • The older the person, the weaker the response – and that was true against all the variants
  • The more obese the person was, the weaker the response – and again that was also true for all the variants
  • All variants showed a weaker response 100 days after the second dose compared to 25 days

What about vaccine effectiveness after one dose

  • Here the results were more worrying
  • Remember that the first trials of all the vaccines, especially the Pfizer vaccine, showed a good response after one dose
  • Indeed that was the behind the UK government’s decision to increase the delay between doses to 12 weeks – ‘Given the availability and resources to administer the vaccine better to cover twice the number of people with one dose
  • Now look at this figure which I have adapted from the Lancet article: 
  • The black diamonds show the average level of antibodies after 1 and 2 doses
  • As examples I have used red arrows to point to the average values against the Indian variant
  • The top purple line I have drawn shows the ideal level of response, the bottom purple line the lowest level of antibodies that can neutralise the virus: the aim should be to lie between the two lines
  • After two doses, most of the samples were above the minimum in their response –   but lower against  the Indian and South African variants
  • With the Wuhan, D416G and UK variants, one dose of vaccine does provide protection for more than half the volunteers
  • That is not true for the Indian variant, with more than half the volunteers being below the minimal level of response (lower red arrow)

How bad news is all this?

  • As always, need to be cautious!
  • Laboratory samples of antibodies may not reflect what happens in real life in the body when we are exposed to the virus:
    • Antibody levels may increase and could be high enough to neutralise any of the variants
    • T cells may also be active enough 
  • In theory therefore two doses of Pfizer vaccine could still provide sufficient protection against the Indian variant 
  • This may be less likely for older and/or obese people
  • Time will tell the answers to the above – but my guess is that the results of this lab-based study may turn out to be pessimistic 
  • One thing is clear which is that one dose – of what is the most effective vaccine (Pfizer) – does not protect against the Indian variant
  • We need to ensure that younger people, now entering vaccine programmes should not relax their guard until after a second dose!
  • Indeed given these results there is less defence for having a long interval between doses of the Pfizer vaccine 

AstraZeneca or Moderna Vaccine?

These results refer to the data from Pfizer, but it has to be assumed that the conclusions apply to the other vaccines as well

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Our poo – the best early warning system against future waves of Covid-19

Amongst the unsung research heroes for tackling this pandemic have been waste water engineers and geographers.  Examining sewage for traces of the virus has been a truly worldwide effort that is now a key component for managing the pandemic. In this post I address the background and the questions raised by this development. 

How is sewage testing used?

  • Sewage testing looks for evidence that there are cases of Covid-19 infection amongst a community of people 
  • There is a statistically close relationship between the amount of viral fragments found in a sample of sewage and the number of cases in that area
  • In the study below from Canada, the orange bars represent the amount of virus traces in sewage and the blue line the average number of cases
  • Sewage testing can then reveal which areas or communities have high, low  or even absent levels of infection 
  • The street diagram below from Boston in USA shows a map of the sewage pipelines, where the cases occurred and which manholes (the blue circles) should be entered for testing
  • Similarly, sewage testing can also reveal how infection rates in an area change over time
  • In this series of diagrams from Spain, the maps show the changing sewage patterns over the early months of the pandemic and hence where the most cases then emerged

What are the pros and cons of using sewage compared to looking at data from the number of positive swab tests in an area?

  • Sewage testing of course cannot be used for diagnosing individuals or for individual tracing of cases
  • It is however probably superior for  charting infection rates in different areas and communities than local swab test results
  • This is for a number of reasons:
    • The number of people with a positive swab test depends on how many people turn up for testing
    • Thus unless everyone is swabbed there are biases
    • Sewage testing by its nature covers the whole  of that area
    • It is also far cheaper 

What size of population can be tested?

  • The simple answer depends on where in the sewage system the samples are collected
  • Thus, sample collection close  or ‘high up’ in the system has been used in schools and university campuses
  • By contrast sample collection further away can be used in streets/districts and whole towns

If the sewage in my area/community tests negative does that mean there is no infection?

  • There are no guarantees and not every individual, with a current or recent infection, who has provided samples for the laboratory, will pass viral fragments in their stool
  • It is reasonable though to conclude where no viral traces are found in a sewage sample from your area that the likelihood of a significantly risky rate of infection in the community contributing  that sewage is very low
  • More importantly, given the uncertainties in interpreting the swab test data from any small area, I would be more reassured by the absence of virus in the sewage than there were no swab positive cases in my area 

Are the data of the level of viral traces from sewage publicly available?

  • They should and could easily be made as available to the public , in the same way as the number of people with a positive swab test
  • In some countries, such as Netherlands and Australia, these data are on publicly accessible websites
  • This is not yet true for the UK

Will testing sewage be capable of picking up on new variants?

  • Absolutely, the technique is focused on a detailed genetic analysis of the material
  • It is thus probably the most efficient strategy for identifying and then monitoring the spread of new variants
  • Indeed, in one sample of sewage tested in Bristol, they identified 118 different genetic variants

Can you catch Covid-19 from handling sewage?

  • That’s the interesting thing – this appears very unlikely – not that anyone is recommending handling sewage!
  • The viral content in sewage is genetic traces, in the form of RNA and not whole viruses, ie unlikely to be capable of infecting people
  • For the record there have been some laboratory studies which have cultured the virus from sewage but most have been unable to do this

Could this technique provide ‘early warning’ of other serious viral infections?

  • Yes, now the sample gathering processes and testing techniques have been upscaled, it is easy
  • This is now being done in some countries – alooking for early evidence of other viruses such as norovirus (which causes major outbreaks of gastro-enteritis on cruises)

How sensitive is the testing?

  • Difficult to be completely certain, but sewage can show viral traces even if only a tiny proportion of people were infected 
  • One expert suggested that viral RNA could be detected in a sewage system even if there was only one person affected in a system that was ‘served’ by 10,000 people

How quickly would sewage show traces of infection from someone who is infected?

  • This is the interesting result!
  • It seems that sewage is likely to be positive some days before any symptoms develop
  • There are many examples suggesting that the delay between sewage in an area being positive and there being a report of a clinical case is around  5 days
  • Even more fascinating are the data from Italy suggesting that viral RNA was detected in the waste from Milan 64 days before the first clinical case was detected in that city

How long after people had been infected would traces of the virus still be present in sewage?

  • People who had been infected could continue to shed bits of virus material in their stool possibly be for weeks
  • This is not surprising, as we know from PCR tests that viral RNA can still be cultured from swabs long after the infection is passed and the person is neither ill nor infectious

Is there a place not just for testing sewage but testing stool samples from individuals (to replace swab testing)? 

  • In theory stool testing from individuals would pick up that they had viral fragments
  • But the test would not distinguish between active or old infection
  • At an individual level, stools could also be falsely negative when an infection was present so not appropriate for diagnosis or contact tracing for example 
  • There are also considerable and obvious logistic issues in the individual collection, processing and analysis

Conclusion

Worldwide there is now the technology, at an affordable cost, that by the simple act of regular testing of sewage, we now have an early warning system that can monitor how the virus is, and is not, spreading, and with that have the data to help in advising communities about the success of all their policies they’ve introduced to limit the spread of infection

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Indian variant, vaccines and immune escape: what do we know?

Hitting the headlines this week is news about yet another mutant strain, particularly newsworthy because of the accelerating tragedy of the pandemic in India.  This variant is now present in 40 countries. What do we know about this strain, its impact and in particular any possibility that the success of the vaccines could be imperilled?

Is this strain different from other ‘Variants of Concern’?

  • As before, the bit of the virus we are interested in is the spike protein
  • That’s the bit that allows the virus to enter cells and that’s the bit that the vaccines are designed to attack
  • Previous research had shown there were a couple of genetic differences between the ‘natural’ virus (referred to as the Wuhan strain for obvious reasons) and the  other worrying variants such as ‘South Africa’ and ‘Brazil’
  • The ‘Indian’ variant has lots of differences, as shown in the picture below by the code numbers shown in red (Amazing that such a tiny part of such a tiny organism can be so complicated!)
  • Obviously just because there are so many differences, doesn’t mean that any or all of them matter

Any reason that this multi-mutant has arisen?

  • Viruses do mutate all the time 
  • The more the virus reproduces, the more likely it is each time that a mutant can arise
  • In areas with high infection rates such as India, especially with people being quite sick, there are even more reproductions
  • Interestingly some biologists have suggested that often viruses have the ability to weed out mutants that stray from their origins, but Covid-19 is not that careful
  • What we don’t know is how much these new variants would have arisen naturally in any population and how many are brought in
  • The Indian variant may have started life as an import of the UK variant

Is the Indian variant more transmissible?

  • It is quite remarkable how quickly this variant has taken over and seems to be the predominant one across that country 
  • Shown by the arrows:  Kerala in the south, Maharashta in the west, Delhi in the north and West Bengal in the east
  • There has certainly been a phenomenal rise in the number of cases, which can only realistically be explained by the newer variants having a much greater ability to transmit
  • Data emerging from the UK, would also suggest that this variant, like the UK (‘Kent’) variant before, is more transmissible than previous variants

Are cases of the new variant more severe?

  • The brief answer is we don’t know 
  • Laboratory studies on human tissues  suggest that this particular strain is more likely to enter cells lining the lungs
  • Studies on hamsters deliberately infected with different strains showed that the Indian strain produced more severe infection – but not substantially so
  • BUT:
    • Laboratory studies on tissues do not necessarily replicate what happens in whole animals
    • Studies on hamsters may have no relevance for humans (though to be fair it is not unreasonable to do these studies, as it is not ethical to deliberately infect volunteers for the same purposes) 
    • It is not obvious anyway why infection with these strains should be more serious, as opposed to being more transmissible

Will immunity from previous infection protect from the new variant?

  • You may have read the term ‘escape mutant’, which would imply that a previous Covid-19 infection would not protect someone from getting an infection with the new strain
  • There was evidence that prior infection did not protect against the Brazilian variant
  • A study from Germany this week studied the serum from people with a previous infection
    • The study was done entirely based on testing samples in the lab
    • They ‘infected’ these sera with small amounts of either the Indian or the old variant
    • They wanted to see if there was any difference how the existing antibodies in these serum samples would neutralise the infection between these 2 variants
    • They found that these existing antibodies were only 50% as effective against the new variant compared to the old one
    • BUT: 50% might still be enough
    • AND (as above) laboratory studies are not real life

Will the vaccines still protect against the Indian variant?

  • Not surprisingly, we don’t have too much data as yet!
  • There have been some studies on both the Pfizer and the AstraZeneca vaccines
  • For the Pfizer vaccine, I am aware of 2 studies but with quite different results :
    • A study from Cambridge:
      • They tested  serum after one dose of vaccine
      • The sera studied had 80% of the ability to neutralise the spike protein derived from the Indian variant compared to the standard variant
    • A study from Germany:
      • They tested serum after two doses of vaccine
      • The sera studied had only 33% ability to neutralise the spike protein derived from the Indian variant compared to the standard variant
  • For the AstraZeneca vaccine I am also aware of just two reports (which don’t really count as formal research!)
    • The first was anecdotal reports that some health care professionals in Delhi, despite being vaccinated, developed Covid-19 
    • The second was only in the form of a Tweet- reassuring but hardly peer -reviewed – what has the research world come to in only releasing research in Tweets!!!

  • The fact that some of the lab studies suggest that vaccines are less effective against the Indian variant doesn’t mean that they not sufficiently effective – the vaccines have spare capacity in the level of antibodies they produce
  • As regular readers of the blog will know, we also have another part of our immune system – T cells – and even if the antibody response to the new variant is not as strong, our T cells may do the trick (the research to show this is trickier)
  • There is also the reassurance that the vaccines from other laboratory studies are likely to be sufficiently effective against other highly transmissible variants, such as the ‘South African’ one.
  • Finally, given what I have said above, the Indian variant I am sure will be followed by others as the virus continues to mutate and transmit especially in those who are unvaccinated

For further reading and the studies mentioned see: https://www.nature.com/articles/d41586-021-01274-7?utm_source=Nature+Briefing&utm_campaign=9a8cc368a5-briefing-dy-20210511&utm_medium=email&utm_term=0_c9dfd39373-9a8cc368a5-45876838

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Categories
Covid-19

High vaccine uptake can control pandemic even with lifting social distancing

That vaccines can protect against Covid-19, in its severe forms, is well established from clinical trials.  Questions remained as to whether (i) when applied to the wider population, these benefits would hold, (ii) vaccines could reduce transmission and asymptomatic infection and (iii) in the ‘real world’ these benefits would be achieved after allowing a return to ‘normal life’.  Data published this weekend in the Lancet from Israel suggests that, at least for the Pfizer vaccine,  the concerns raised by these questions can be discounted

What did we know before this study?

  • In clinical trials two doses of the vaccines achieved a reduction in the risk of contracting severe Covid-19 by over 90% in the 1-2 month period after vaccination
  • There were more modest reductions in the risk of asymptomatic infections, suggesting that the vaccines may be less successful at stopping transmission

What did we want to know?

  • Whether the reduction in severe infections was sustained for longer periods – it was always considered this was likely, but the clinical trials were too short to address this
  • Whether if enough people were vaccinated, the cumulative effect would be to reduce transmission within a community – leading to eventually a greater reduction in asymptomatic cases 
  • Whether premature lifting of social measures, despite high vaccination rates, would increase transmission and ensure the persistence of a ‘pool’ of infected cases within the community

How the Israeli experience can address these unknowns

  • As has been well publicised, Israel has been the leader internationally in the speed of vaccinating its adult population.
  • Only the Pfizer vaccine has been used in Israel and at the recommended 3 week interval
  • There had been a steady roll out of the vaccine programme since the beginning of December
  • By 3 April, 60% of all adults had had two doses, including 90% of those over 65  
  • Israeli public health officials, as part of the ‘deal’ for Pfizer to provide Israel with enough vaccine to cover the country rapidly, agreed to collect data on all the cases of Covid-19 that arose since the start of the vaccine programme
  • The epidemiologists in Israel have therefore been able to compare the risks of developing Covid-19 infection between people who had, and had not, been vaccinated

How did the Israelis do their analysis?

(You can skip this part if you want and go to the results below!)

  • The analysis was quite complex but let me explain what they did
  • The population data were obtained from the 2020 census and thus all adults were included in the analysis
  • Data were gathered on all cases recorded in Israel from 24 January until 3 April 2021
  • Cases of Covid-19 were identified both from the widely and freely available laboratory testing in that country as well as those who were admitted to hospitals
  • It was thus possible to analyse separately the benefits of vaccination on reducing the risk of :
    • Cases with no symptoms (just from testing)
    • Cases with  symptoms but who had not gone to hospital
    • Cases in hospital
    • Cases classified as severe (life threatening)
  • People who had only had one dose of the vaccine, and those whose second dose was less than one week before the end of the surveillance period, were excluded
  • The research thus compared the reduction in the risk of infection between 
    • people who had been vaccinated, at least 7 days after their second dose 
    • people either (i) who remained unvaccinated or (ii) in those who were vaccinated – in the period before their second dose (+7 days)
    • To explain (ii) above consider the diagram below
  • Suppose an individual had completed the course of vaccine on 19th February, so by 26th February they would be considered fully vaccinated 
  • If they had developed Covid-19 in the 30 days up to26th February (the orange period) this case would be counted as having occurred in a non-vaccinated person
  • If they had developed Covid-19 in the 36 days after 26th February up to April 3rd (the blue period) this case would be counted as having occurred in a vaccinated person
  • This person therefore contributed 30 unvaccinated and 36 vaccinated days to the overall analysis
  • The rates of infection could then be compared between the total of ‘unvaccinated days’ and ‘vaccinated days’ in the whole population 

What did they find?

  • The headline result was that the rate of infection in vaccinated people (expressed as cases per 100,000 vaccinated days) was much lower than in people who had not been vaccinated
  • This was as true for very severe cases as for those which had been detected by testing but had not had symptoms
  • The data can also be expressed as the reduction in risk following vaccination: ie how much less in percentage terms were the rates of infection between days after compared to before vaccine (or in those who had had not had any dose)
  • This is what they found:
  • There was an over 90% reduction in all cases, whatever their severity

How do these figures relate to the relaxation of lockdown measures?

  • The helpful diagram below shows on the same chart the path of relaxation of lockdown measures and the rate of cases as reported by the laboratory
  • Israel was going through a serious second wave at the end of the year when the vaccine programme began
  • This was then accompanied by a stringent lockdown as well as the rapid rolling out of the vaccine programme
  • There was a progressive reopening of Israeli society during February, but despite that  the number of cases has continued to fall
  • Given the reduction shown above in the number of cases in the days following  vaccination, it is reasonable to conclude that:
    • Re-opening society clearly did not reduce the impact of the vaccine programme on the number of cases
    • The reduction in the numbers of all cases (ie including asymptomatic cases) suggests that transmission has also fallen again despite relaxation of lockdown and hence widespread vaccination is also leading to an interruption of transmission hastening the end of the pandemic.

Any cautions?

  • The predominant variant in Israel in this period has been the UK variant, so if another variant took hold the results may not be as positive
  • The data only refer to the Pfizer vaccine and for example other vaccines such as AstraZeneca may not achieve the same results
  • As mentioned above it is still early days and we only have 5 months of data; waning immunity following vaccination is still a possibility  
  • Israel is a very mixed society with a large number of ultra-Orthodox who have been at particular risk of infection
    • Indeed there were differences in vaccine rates between ultra-Orthodox and other population groups with only 40% of the former being vaccinated compared to 80% of the remaining Jewish population  
  • It remains therefore to be seen if sub-groups such as the ultra-orthodox will continue to harbour the infection 

Conclusions

  • I believe these data do add importantly to our view about the potential of a successful vaccine programme being capable of ending this pandemic whilst allowing a return to normal life within a reasonable period of time
  • Whether this can be replicated in other countries  remains to be tested in time

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