Category: Covid-19

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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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. 

• 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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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

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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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 19^th February, so by 26^th February they would be considered fully vaccinated 
• If they had developed Covid-19 in the 30 days up to26^th 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 26^th February up to April 3^rd (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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One of the tragic aspects of the news about the escalating pandemic in India is the relatively high proportion of children and young people, not just in the number of cases overall, but also – unexpectedly given Western experience – amongst those with serious infection.  This raises the issue as to the possibility of children being more vulnerable to new variants  and hence whether Western countries need to give greater attention to vaccinating children.  In this post I consider the most recent information and indeed expert opinion on this issue.

Size of the Covid-19 health burden in children 

• That children also develop Covid-19 in large numbers is not debated
• The rate of childhood infections is to a great extent related to social mixing at schools and similar institutions 
• Probably, given exposure to a similar level of the source, children become infected at the same rate as adults
• Our safeguard from becoming seriously ill with an infection depends on the effectiveness of the ‘first strike immune system’ (referred to as the ‘innate’ immunity we all have in the lining of our noses and throats that protects us against invading bacteria and viruses)
• Research published this month showed that the innate system is stronger in children and this might explain the lower risk 

Serious infection in children

• Despite the above, children can still become seriously ill
• There have, for example, been over 250 child deaths from Covid-19 in the USA
• The latest data show that 3% of all cases of Covid-19 hospitalised in the USA are in children 
• It is also established that some groups of children are at particular risk of having bad infection and dying

• The other health concern is the very strange and rare disorder called ‘multisystem inflammatory syndrome in children’ (MIS-C)
• Indeed, there have been 3000 cases of MIS-C up to April this year in the USA
• This severe and previously much less known disorder is difficult to treat and possibly 70% require admission to intensive care, although with adequate treatment mortality rate is only around 2%

What is the state of vaccine testing in  children? 

• Given concerns about the potential hazard of cerebral venous thrombosis from the AstraZeneca vaccine, this is not I believe being tested further in children 
• Currently vaccines from Moderna and Johnson & Johnson are being tested and results awaited
• Data have been published from Pfizer 
  • 2000 adolescents aged 12-15 involved in clinical trial
  • 18 cases of infection occurred in those that had placebo
  • No cases of infection in those who had the active vaccine
  • There were no serious reports of side effects
• Pfizer want the authorities to license the vaccine for this age group and the result of this application is awaited
• But  the trial was not large enough, nor could it easily be so, to confirm the necessary safety from serious but uncommon side effects
• Similarly, given that the cases in the placebo arm were mild or asymptomatic, we do not know how many thousands of children would need to be vaccinated to prevent one serious infection

The ethical arguments for and against vaccinating children

• One powerful argument in favour is that even the relatively small number of Covid-19 deaths and cases of MIS-C still represents a substantial public health problem
  • Measles vaccine was introduced in the USA at a time when there were 300 deaths a year in children – not too dissimilar from Covid-19 
• As shown above, there are certain especially disadvantaged groups of children at high risk 
• In addition, child death rates from Covid-19 are higher in those from certain minority groups – representing an equality issue
• High vaccine uptake will help ensure full time schooling is more likely and “sellable” to parents
• The two main arguments against are (i) the low actual risk from the virus, and (ii) the potential of harm from the vaccine
• Ethically speaking, in  a world where there are vaccine shortages in low-income countries, is there not a responsibility to give vaccines as a priority to adults in those countries?

Herd immunity

• The main epidemiological question is whether vaccinating children increases the likelihood of herd immunity reducing the risk of infection in adults
• This raises the ethical question as to  the acceptability of widespread childhood vaccination which is mainly aimed to protects adults – whether or not children will benefit themselves 
• Put simply – “will the virus disappear more quickly if children are vaccinated?” or indeed the converse “will the virus still be around if we don’t vaccinate children?”, as outlined in a recent New York Times leader

• There is no proof of this however
• Indeed, data from Israel would seem (thus far) to suggest that herd immunity – as exemplified by the number of new cases dwindling to almost none – might be accomplished without vaccinating children 
• A related biological argument is that if children are not vaccinated, is there a risk that new variants will arise in children that will then spread to vaccinated adults, whose vaccine status is not sufficient to protect them against such variants 
  • Whilst such an argument is superficially persuasive, there are no data (as yet) to support it
  • Many expert virologists have struggled to find evidence that this has happened with other viral infections and vaccines 
• The second question which is the converse of the above is whether we don’t need to vaccinate children as they benefit from the herd immunity provided from high rates of vaccinated adults 
• Data (also from Israel) this month would support this: population surveillance of new cases suggest that the increasing rates of vaccination in adults have seen a parallel reduction in cases of infection both in adults and in children 

• In other words the lower rates of infection in children may be explained by the protection from high rates of vaccine uptake in adults
  • But it is only recently that lockdown has been relaxed in Israel  and children have returned to school – so if there had been a surge, it would not have been picked up by this research study
• Similar data from the USA have shown that a reduction in the number of cases in adults, which is thought to be partially explained by vaccine uptake in adults, is also mirrored by a similar reduction of cases in children 

And my conclusion?

• This is really difficult, for the reasons I have stated 
• So, it is not surprising there is not a clear cut conclusion to be drawn at this stage
• The vaccines are probably as safe as is reasonable, so that supports childhood vaccines
• Children may indeed be protected by high rates of vaccination in adults 
• It is much less obvious that high rates of vaccination in children will protect adults 

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As vaccination progresses in most countries, there is still the concern that although the vaccines protect against severe infection, they are less successful in preventing transmission, especially with the so-called “variants of concern”.  Yet experts are even this week arguing as to what is the most important route for catching the virus.  Public confidence and adherence to appropriate social distancing need them to be singing (but not too loudly!) from the same song sheet. (And that song might just involve cucumbers – see the end of this post!)

Aerosol or droplets as main route of infection?

• Readers I am sure will remember the discussion about whether Covid-19 is transmitted by large droplets or can be carried much further in the air as an aerosol 
• Handwashing and social distancing to a metre are considered sufficiently protective against droplet transmission 
• Indeed by 2 metres droplet transmission is unlikely 
• Hence at the beginning of the pandemic the World Health Organisation (WHO) at their infamous press conference argued against the value of face masks

• WHO suggested that aerosol transmission was not an important route as Covid-19 was not airborne 
• That opinion delayed widespread mask wearing and did not discourage social distancing beyond that short distance

• Much of the data for airborne transmission came from experiments in the laboratory trying to recreate what happens in life
• The argument was that the virus can transmit via the airborne route in the laboratory does not tell us how important that route of infection are in explaining who gets and who does not get infected 
• But if airborne infection is the most likely route then too rapid a reduction in social distancing and mask wearing regulations could contribute to further surges in infection

World Health Organisation: are they wrong again?

• At the end of March this year a review of the available data, funded by WHO, suggested that airborne transmission could  not be proven 

• In that paper, which was widely publicised before peer review, Heneghan (from the Centre for Evidence Based Medicine at Oxford) and colleagues reviewed 90 research articles which had attempted to discover if Covid-19 could be airborne
• They applied their own stringent criteria to assess the quality of those research  studies
• They rejected a firm conclusion because the quality of the research was not considered high enough
• As an epidemiologist I am (of course!) in favour of research being high quality, but such reports need to be careful in dismissing something as important for public health as this issue
• Indeed in the past 24 hours, the initial peer reviewers’ comments have just been posted and are not looking too good!

What is the evidence in favour of airborne transmission?

• Given the publicity for that WHO report there has been an rapid riposte.
• In an authoritative paper published in the Lancet a week ago, another colleague from Oxford, Trish Greenhalgh, gave 10 pieces of evidence which I believe would stand up in a court of law as proving more likely than not that airborne transmission was the key route of transmission
• These were her points:

1. Superspreading events such as on cruise ships and choirs can only be explained by that route
2. Transmission of infection between people isolating in their rooms, across corridors for example in those quarantined in hotels 
3. Perhaps as many as 1 in 3 of cases are transmitted from asymptomatic  people who are not coughing or sneezing, and not passing out large droplets 
4. Transmission of SARS-CoV-2 is far higher indoors than outdoors and is substantially reduced by indoor ventilation
5. Hospital and care home acquired infections have occurred  despite very  strict precautions against droplet spread and the limited effectiveness of much  personal protective equipment (PPE) – which is designed to protect against droplet but not aerosol exposure
6. Laboratory studies have shown that the Covid-19 virus can survive in the air and be infectious for up to 3 hours
7. The Covid-19 virus has been found in air filters and building ducts in hospitals with COVID-19 patients
8. Studies of infected caged animals which were connected to separately caged uninfected animals via an air duct and then caught the infection 
9. The data from contact tracing and interviews of infected people found no other convincing route of infection other than airborne
10. Finally, although Heneghan and colleagues might argue against the quality of the research proving airborne transmission, the opposite has not been proven – that airborne transmission does not occur  

The conclusion in that Lancet article is worth repeating here:

And the role of cucumbers:

• No this is not April 1^st!
• Research published this week looked at how long the virus survived on various fresh fruit and veg food items that were unlikely to be cooked 
• They inoculated test areas of the surface of these foods with the virus and measured the concentration of the virus on the surface at various subsequent time points
• Concentrations in terms of the number virus particles fell from the thousands over the next few hours

• As shown in the diagram, the virus had gone from apples and tomatoes within 16 hours but was still present on cucumbers at 72 hours
• Of course there are no data to suggest that cucumbers are in any way a likely source of infection, though interestingly the pH of the surface of cucumbers is more friendly to viral survival
• And remember you saw this important result on this blog first! 

Take home message

I mention the cucumber study not because it is of major importance to the spread of infection. Rather to illustrate my main point that, especially in this pandemic, it is so important to judge all the research ‘in the round’

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Vaccine roll out success, coupled with adherence to behavioural rules, has led to substantial declines of infections in the UK and Israel.  Increasing vaccine coverage in North America and Europe is seen also as the route back to normality.  Yet infectious disease epidemiologists are still worried about a third wave causing large numbers of severe cases.  Are they right to be worried?

Let’s start with the current success

• Excluding countries in the Far East and Australasia, globally most other countries have had substantial second peaks of infection
• I have plotted below the rates/million total population (including children) of new diagnosed infections in Israel and UK 

• The UK – with one of the most stringent and (probably) adhered to lockdown measures since the start of January – has seen a substantial fall in the rate of new cases.  Given that only around 10% of the population has had a second jab, then the decline in new cases is predominantly explained by the measures enforced
• Israel has a second jab rate of around 60% and epidemiological studies, examining the vaccination records of those who have become ill, by contrast, do point to vaccine roll out being the major explanation for the decline
• Indeed Israel began easing its lockdown rules in mid-February without seeing, so far, any rise in the rate of infection 

So what’s the worry?

• Worth repeating (and I have!), though obvious – if we all stayed at home then the infection would die out.  So whether the rates of new infection are going to remain controlled as lockdown is released depends on a number of factors
• I have illustrated these in the diagram below and will consider them all in turn

• The general point is that we need to consider a range of factors in order to achieve the elimination of the threat of Covid-19 

Vaccine effectiveness

• In terms of transmission we want the vaccines to stop people being able to pass on the infection those around them
• We know that the vaccines stop people getting ill, but it is still uncertain by how much the vaccines stop people transmitting the infection
• Here are some estimates from two epidemiology groups from the UK: Imperial College London and Warwick University
• ‘All infections’ includes those with and without symptoms 

• The rates of infection are following the second jab and assume no waning in immunity over time
• The assumption about waning immunity is probably reasonable over a short time frame, i.e. protection at least until the end of this year
• These figures are from the rolled out vaccination programmes rather than the earlier clinical trials and are estimates of the effects across all adult age groups 
• Pfizer probably stops 90% of transmissions and AstraZeneca around 60%
• A 60% reduction in transmission though is really good if the population rates of infection are low.  Conversely if the population rates of infection are high then, even with a 90% reduction, there is still scope for high numbers of new infections to be passed from vaccinated people

Vaccine coverage

• Thus far in Israel, UK and USA, the vaccine coverage has been higher than the pessimists feared
• Concerns about hazards and the roll out to younger populations less at-risk from severe infection might see a decline in take up, although restrictions on travel etc for those without a vaccine might encourage greater take up
• Based on different sources of data here are the projections (OK they are guesses!) of vaccine take up in the UK:

• Although these figures seem ‘very good’, as with the effectiveness data above, in periods of high infection even 10% of people who are not vaccinated could contribute to a large number of people being susceptible to infection

Speed of vaccine roll out

• Again obvious, but the longer it takes to vaccinate the population the greater the number of people who can transmit the infection
• This is because as mentioned above  vaccinated people, even with a pessimistic (AstraZeneca) protection, are 60% less likely to transmit the infection
• An interesting ethical issue is that younger people have more social contacts and currently in many countries contribute proportionately more cases of infection than older people
• Thus it could be argued that to prevent transmission alone, it might make some sense to focus vaccine efforts on those who are younger 
• Anecdotally this may be what is happening  in some countries in Eastern Europe

Seasonality

• As is well known, influenza pandemics tend to occur in winter
• Whether this is because in the summer there is reduced viral survival with the greater  sunlight and/or humidity, or we spend less time outdoors, is unknown
• The concern from some epidemiologists is that the decline observed now in countries such as the UK may represent a seasonal decline and that come winter there will be a bounce back 
• This is the effect of season from the Warwick and Imperial guesses

• These are not large differences but could tip the balance
• This underlines the importance of achieving high vaccine coverage before the autumn

Impact of new variants

• It is now well known that the current major variant in UK, USA, Israel and indeed the rest of Europe is the so-called English variant
• This variant does spread more easily
• The South African variant also spreads even more easily, but it seems that high rates of the English variant seem to reduce the South African (or indeed the Brazilian) variants from taking a major hold
• The epidemiologists have in their scenario planning assumed that no new nastier variant will take hold – this is probably reasonable but cannot be relied on absolutely

Social Behaviours 

• Clearly a return to normal social interchange increases the chances of transmission
• It was believed at the start of the pandemic that the natural R value, i.e. the average number of cases caused by one person passing it on to others, is around 2.5
• Countries with their various lockdowns are achieving rates of say between 0.8 and 1.5
• R values have to be considered against how many cases there are of course, but the worry is that releasing the brakes given all the other issues mentioned above could lead to a greater number of new transmissions.

Putting it altogether

• Complicated isn’t it!!
• This is just one model from Warwick attempting to predict the number of cases hospitalised in a third wave this summer: 

• To be honest they’ve brought so much together in that graph that I’m not going to even try and explain it all ! But there is an important message here
• The red line has allowed for all the things I have mentioned above (they call it the ‘central assumption’)
• An increase in R because of any of the issues mentioned would have major effects on the numbers of severe cases (in this graph shown as the how many beds in hospitals in the UK are occupied by Covid-19 patients) 
• We can’t easily change the effectiveness of the vaccines (they are pretty good), the seasonal impact or the possibility of new variants
• By contrast, we can ensure maximum and speedy vaccine coverage
• More importantly, it will be necessary to keep tabs on all the above, to ensure that any return to ‘normality’ is carefully monitored

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In my post earlier today, I stated that “it is possible that the risks of cerebral venous sinus thrombosis in younger women are greater than the risks from Covid-19 infection”.  This afternoon, the regulator in the UK announced the results of their detailed calculation addressing this question.  

This is the result of their calculation and I have adapted their slide for this post

• This is how they did their calculation
• First they obtained the current rate of new Covid-19 infections in the population.
• They then identified how likely it was that someone with a new infection would be admitted to an intensive care unit (ICU)
• They analysed these data by age
• They then calculated how many people per 100,000 in each 10 year age group would be admitted to an ICU in a 16 week period  at that rate of infection
• These rates (the blue boxes) were very low for those age under 30 at less than 1/100,000,  but were much higher for those aged 60-69 at 14/100,000
• They then calculated what the rates of serious harms would be in those who were vaccinated based on the numbers and ages of the cases reported to date
• They then estimated how many people per 100,000 who had been vaccinated with one dose would have a serious clotting problem
• They estimated these rates separately for each 10 year age group would
• The rates of vaccine problems were highest – at 1/100,000 in those under 30 and lowest at 0.2/100,000 in those 60-69
• Putting all this together the conclusion is that
  • In those aged 20-29, the risks from the virus and those from the vaccine were similar
  • In those aged 60-69, the risks from the virus were 70 times (ie 14.1 divided by 0.2) higher than those from the vaccine
• In most other European countries the rate of infection is much higher than in the UK
• The higher the rate of infection and the more the number of people get infected then more get admitted to ICU, whereas the risks from the vaccine remain the same
• The consequence is that as the incidence of infection rises, (it is obvious really), the benefits from the vaccine relative to the harms becomes more favourable 

My conclusion:

• Given the low rates of current infection in the UK it makes sense to use alternative vaccines in those aged under 30
• The European Medicines Agency has not issued the same advice, they may do so of course in the near future, but with the higher infection rates in EU countries, the benefits from the vaccine are still present for all age groups 

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In my post on March 16, I considered the evolving information on rare blood clotting events in relation to the AstraZeneca vaccine.  I concluded that the risk of pulmonary embolism, although higher with the AstraZeneca than the Pfizer vaccine, was no higher than that in the general population.  Attention recently has focused on the rarer brain clotting disorder: cerebral venous sinus thrombosis. More cases of this disorder have been reported in the past few weeks and in this post I review the new data and discuss the link to the AstraZeneca vaccine and the nature of any risk.

How many cases of cerebral venous sinus thrombosis (CVST) have there been following vaccination?

• Obviously the numbers are changing and different reports give different numbers
• Credible rates of CVST in UK and the rest of Europe are as follows:
  • 62 cases have been reported in the European Union from around 9 million vaccinated
  • Half of these were reported in Germany from around 3.4 million vaccinated
  • 79 cases have been reported in the UK from around 20 million vaccinated
• The numbers of cases are higher in younger people (aged under 50)
• Approximately a third of those with CVST have died
• I have not been able to find any reports of this disorder following the Pfizer or Moderna vaccines 

What is the exact nature of this brain disorder?

• The disorder reported in people following the AstraZeneca vaccine is an unusual one – it is actually combination of two separate disorders

• The second abnormality seen in the CVST patients following vaccination is the development of antibodies against their own platelets
  • There are a number of other causes of having low platelets, for example it can be a complication of some prescribed drugs
  • We need enough platelets to help us clot normally and stop bleeding
  • Having a low platelet count is actually quite common and indeed it is known that many cases are due to people developing antibodies against their own platelets – although this is normally an easily treated disorder
  • What is weird about the loss of platelets in the post-vaccine patients is that, instead of increasing the risk of bleeding, it increases the risk of clotting

How common is this combination in the general population?

The combination of a low platelet count and CVST is so rare we do not know how common this combination is in the general population

If we look at the two parts separately:

1. CVST

• CVST is very rare and accurate figures of the incidence are difficult to obtain
  • My reading suggests that a rate of 2-4/million per year is a reasonable estimate
  • Most cases of CVST in the population are due to infection

2. Low platelet count and increased risk of clotting:

• The overall incidence of a low platelet count with thrombosis (which has been reported in many different blood vessels – both arteries and veins)  is also around 2/million/year
  • It is mainly seen in people aged under 45
  • Most cases have occurred as a strange reaction to the anticoagulant injection heparin
  • In such cases, there is also both a low platelet count and a blood clot – the latter can be in either an artery or a vein
• The combination seems very rare
• This headline from an article published in January last year showed the disorder is so unusual that the existence of a single case is enough for it to warrant publication in the medical press

Do these data prove that there is a link?

• Proving cause and effect is almost impossible with such a rare disorder
• It is also difficult to compare the numbers in the short period after being vaccinated with general population rates that are calculated over a year
• I think that the chances of these cases being random is small and that the points below all point to the link being causal:
  • the number of cases
  • the timing in relation to the vaccine
  • the immune nature of the likely cause
• Unlike the situation I discussed a few weeks ago in relation to pulmonary embolism, where the data did not prove the rate of that disorder post-vaccine was greater than the underlying risk, my take on CVST is that all cases need to be considered as a consequence of the AstraZeneca vaccine 

What then is the risk of CVST in people who have had the vaccine?

• The question then is not “is there an increased risk of CVST compared to ‘normal’?” but rather
  • “what is the size of the risk?”
  • “does this risk vary in particular sub-groups of the population?”
• From the available information, which is limited, the German data suggests an incidence of around 1/100,000 vaccinated 
• The UK data suggests a lower rate of around 1/250,000
• BUT although I have not seen a detailed breakdown by age and gender, about 2/3 of the cases of CVST are reported to be in women and more in those under the age of 55
• Given that most of the vaccine programmes have been focussed above the age of 50, the overall rates of CVST in younger women could be even higher

Could this problem have been identified earlier?

• I cannot see how this could have been foreseen
• I am not aware of any other vaccines that have been linked to this complication
• Even if the incidence is as frequent as 1/100,000, then the clinical trials of the vaccines, which studied around 30,000 subjects, would have been too small to detect any cases

How does this risk compare with risks of other rare severe medical events?

• In thinking about a risk that say lies between 1/100,000 and 1/250,000, a frame of reference is the risk of other severe medical events in previously healthy people 
• I have taken two comparisons:
  • Deaths in pregnancy and childbirth
  • Deaths and severe complications from having an anaesthetic in people with no prior health problems 
• The results are shown below:

• The results show that for these two comparators, which most would consider non-risky (getting pregnant or having an elective operation), the rates of CVST – even taking the most pessimistic (German) data – are lower

What can happen now?

• More intensive analysis of the cases of CVST that have happened will quantify a more accurate risk in the different age and gender groups 
• The risk of dying or having a serious complication from contracting Covid-19 in younger people is small (and indeed women do not have as many  serious complications as men) 
• Thus it is possible that the risks of CVST in younger women are greater than the risks from Covid-19 infection 
• My view is that regulators should be open and accept:
  • that it is highly probable there is a link
  • the issue has only come to light because of the many millions who have been vaccinated
  • the absolute risk to those most at risk of the serious consequences from Covid-19 is far greater than the risk of CVST from the AstraZeneca vaccine; the same may not be true for younger people
• I have to accept that regulators’ views on ‘who to vaccinate and with what’ may need to change to allow public confidence 

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STOP PRESS:

• Since posting this at 12:30 UK time today, the UK regulator has just announced that people aged under 30 will be offered another vaccine to the AstraZeneca
• I provide details of the data behind this decision in a new post https://makingsenseofcovid19withs.com/2021/04/07/new-calculation-risks-from-astrazeneca-vaccine-exceed-benefits-in-people-under-30/

• This is a sensible move both from an epidemiological perspective and reducing vaccine hesitancy in those at lower risk from the effects of Covid-19.

Two recent  studies, one from the UK and the other  from Denmark, have addressed the question as to how likely is it that having been infected with Covid-19 once, you can catch it again.  The hope is that a previous infection would give sufficient immunity to protect against a second infection.  How far is this the case?

What did we know before these studies?

• If infected with Covid-19, most people will develop some immunity 
• The level of the immunity has been measured by the level of antibodies produced
• Immunity might be less strong:
  • In those who had a very mild infection
  • (Rarely) in those who had a very severe infection (which paradoxically dampens the effectiveness of the immune system)
• But we know the level of antibodies:
  • Is not the same in everyone who has been infected and is lower, for example, in older people
  • Does tend to fall over time following the infection and may even disappear within 6 months 
•  But we also know that when faced with another infection
  • Previous low levels of antibodies (even if they’ve fallen to zero) can rise again in response to a new infection
  • Antibodies are not the only defence we have: there are our T cells as well
  • As explained before in this blog*, when faced with a second infection, our T cells can also be woken up and attack and destroy the virus

What we didn’t know?

• Despite the data about antibodies, we didn’t know for certain if they would be enough
• Indeed, even if our level of antibody response after a first infection was not that high, the only important statistic is how much less likely is it that they would prevent us getting a second infection 

What about the new variants? 

• We do know, for example, that the Brazilian variant is not such a great respecter of antibodies from a previous infection as we would like.
• The new UK (Kent) variant though, which is the main variant in much of the world currently, should be covered by previous antibodies; although the UK variant passes more easily from person to person than the original strains
• Thus, there is no reason to believe that there would be any difference in the protection resulting from a previous infection – whether this was the original or the new UK strain

Why answering the question about re-infection is not that easy?

• The obvious question is (as my title suggests): “I have had Covid-19 once, how likely will I get it again?”
• It is obvious that the answer is that reinfection:
  • is not “impossible” 
  • and must be related to how many people around you have the infection
  • and how careful you are
  • and if you’ve had the vaccine
  • and how successful the vaccine is
• The question we now have some answer to is:

• The answer has therefore required some careful monitoring of large populations to make those comparisons; in the UK we have ad the Siren study

• Let me help in interpreting this graph!
  • Look at the dashed line, this is what happened to those workers who had not had any infection first time round
  • By the end of the next 6 months, around 5% of them had evidence of a new infection
  • Now look at the continuous line, which is what happened to the workers who had a previous infection
  • By the end of the next 6 months only around 1% of them had evidence of a new infection
  • This is a reduction of 80%
• Of course, we don’t know if the two groups had the same exposure to new infections they were all continuing their roles  in the NHS
  • Perhaps those with a previous infection were more careful, hence their lower rate
  • Equally, they may have been less careful, thinking that they were less at risk because of their immunity
• The conclusion was that previous infection did not take away the risk of a second infection completely but did reduce it (as expected) by a large amount up to 6 months later

The Danish Study

• This was a very similar study 
• The headline result was identical: an 80% reduction in the risk of a second infection 

• The study also showed that the relative size of this  reduction did not go down with time:

• The result thus suggests our immunity can burst back into action
• What was a bit worrying, but not entirely unexpected, was the protection from a previous infection was less in those aged over 65
  • The elderly with a previous infection had a much lower rate of protection  against a second infection compared to those younger age groups  

What does 80% protection mean?

• It is probably worth saying that the absolute risk of having a second infection will still depend on how common the infection is in the general population 
• Look at this diagram below, which shows how likely it is someone with a previous infection will get an infection in a second (or say third) wave*
• The different sizes of the pies illustrate the overall number of cases occurring depending on how widespread the infection is
• The orange slice shows that the number of people with a second infection will vary depending on how widespread the virus is
• Although the absolute numbers in the orange slice vary accordingly, their proportion remains the same

What’s the impact of vaccination on interpreting these results?

• Firstly, across all ages a previous infection does not give complete protection against a second infection
• Next, that is more true for people aged over 65, reinforcing the need to have the jab even if you have had a previous infection
• We know that vaccines work, giving at least 80% protection in those over 65, much higher in those who are younger.
• I conclude that vaccines do then give a higher level of protection than natural infection
• What we don’t know is whether a previous infection plus being vaccinated gives more protection than just being vaccinated – I suspect not, but let’s see as the results come in over the next few months 

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