Category: Covid-19

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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The last week has seen headlines across the world concerning both the supply and uptake of vaccines.  The AstraZeneca vaccine has been the subject of twin concerns: not enough is being produced and – in some countries – hesitancy in accepting this (or indeed any other) vaccine.  Aside from worries about exceptionally rare health hazards, the hesitancy in large part reflects anxieties about the high prevalence of short term side effects and questions about the benefits in the face of new variants.  In this post I look into the very near future and review how some exciting new approaches to vaccines could address many of the issues of supply, side effects and indeed efficacy.

What are the plusses and minuses of vaccines given by injection?

• The short answer is that by injecting into muscle – with its good blood supply – the vaccine can rapidly be recognised by the immune system which can then start producing its response
• Vaccines given by mouth or inhaled have to combat the body’s immediate defence mechanisms which are designed to protect us against the effects of infecting organisms in  what we eat or breath in – which then turn against the vaccines 

There are a lot of minuses with injectable vaccines summarised in the Table below:

Before Covid-19 what vaccines were given without injection?

1. By Mouth

2. By inhalation

What about oral vaccines for Covid-19?  

• The second was announced yesterday between an Israeli Biotech company (Oramed) and the Indian pharmaceutical company (Premas) to develop a capsule for oral immunization against Covid-19 
• Despite the press release, given the above it was not a world first!

• What do we know about this vaccine
  • So far only tested in animals
  • In a single dose gave excellent antibody response
  • Active against multiple parts of the CoVid-19 virus (not just the spike protein) and could protect against mutations
  • A clinical study of 35 people completed recruitment in December and we await the results (though I gather that the antibody response may not be as good as the T cell response) 
  • My guess is though that the results are looking sufficiently good hence the announcement of the Israel/India tie up two days ago

My conclusion about oral vaccines?

• Theoretically it should be possible to achieve sufficient immunity with an oral capsule.  
• We should have a first  answer about how effective this will be in real life in say a couple of months and could possibly be available by the end of the year 

What about inhaled vaccines for Covid-a9?

• Like with the oral vaccines there are two approaches that are being tried
• The first is a version of the AstraZeneca vaccine and works in the same way (spike protein bolted onto a harmless virus)
• This has only been tried in Macaque monkeys so far but did prove to produce a strong immune response
• Infected  monkeys also had a rapid loss of the virus 
• Testing in humans is awaited  

• The second is a different type of vaccine to all the other Covid-19 vaccines 
• It is based on a weakened form of the Covid-19 virus, indeed like many conventional vaccines for non-Covid disorders 
• Because of this  it will create an immune response against all the bits of the virus and thus be more resilient to new variants

My conclusion?

• The inhaled version of the AstraZeneca approach looks OK so far and should be safe
• Obviously early days but using a weakened form of the virus seems to me to be a risk that it could mutate.

Making your own vaccine at home!

• Is this Star Wars or a genuine possibility?
• The essence is to use 3D printing (also called additive manufacture)
• For those of you not familiar with this amazing technological advance very briefly the steps are:
  • Develop a computer programme to build anything you want from basic ingredients
  • Allow the programme to access those ingredients and then the technology will physically make the desired object
  • The software can be downloaded and the object ‘printed’ locally
• Although it is mainly used to build inanimate objects such as car parts, it has been used to create artificial bits of human tissue like skin, bone etc
• The big advantage of the system is that the clever bit (the software) can be remote and provided you have the ingredients locally you can then make whatever you want where you want
• The guy in the picture printed his own virus!

• In theory therefore adopting the same approach one can 3D print a vaccine 
• This is most useful for mRNA vaccines (like Pfizer’s) and a company CureVac is working on this

• If it works then it could be of enormous benefit for vaccine supply and distribution especially to poorer parts of the world

My conclusion?

• I won’t dismiss the concept
• Certainly 3D printing is being used to produce vaccine administration systems (like very fine needles) which could reduce the amount of vaccine required 

Final words

• The pace of even more novel vaccine development globally has been breath-taking over the past 12 months. 
• We will need such advances to enhance vaccine production, vaccine acceptance and resilience to mutations

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My headline conclusion from yesterday’s post was that, compared to the general population, there was no increased risk of pulmonary embolism following the AstraZeneca vaccine: indeed, the published general population rate was about 6 times that following the AstraZeneca vaccine. More than one reader has commented that far from showing that the vaccine increased the risk of embolism, the reverse seemed to be the case and that the vaccine gave substantial protection against this disorder.  I do not believe protection is a logical conclusion and in this post I will explain why the data are problematic. 

Is there any plausibility that vaccines are protective?

• The short answer – it does not make sense that vaccines provide short term protection against the occurrence of embolism  
  • Vaccines do not have any anticoagulant properties that would provide the protection
  • Vaccines do not have anything that would protect the walls of veins from clots
• If the above are true, then what are the explanations for what would appear to be a false suggestion of a level of protection?
• Thinking about the calculation I posted; there are number of possible sources of error inherent in the available data

1. Was the quoted background population rate of pulmonary embolism inaccurate?

• I quoted the figure of 8/10,000 (800/million) provided in a  UK official guidance document on the prevention of this disorder*
• The accuracy of this  figure is reinforced by other data I have examined**
• Thus the estimate is as good as we can have

*https://www.nice.org.uk/guidance/ta287/documents/pulmonary-embolism-acute-treatment-vte-prevention-rivaroxaban-appendix-b-final-scope **https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718593/ 

2. What is the correct time interval following vaccination that should be considered relevant in counting a pulmonary embolism?

• I made a guess at one month, to allow time for a clot to have developed in the legs and then pass to the lungs
• From the publicly available data on AstraZeneca’s embolism cases though we don’t know the interval between vaccine and diagnosis
• If all occurred within a week then the apparent reduction in incidence is only 1.5 times, compared to 6 times, background risk by allowing 4 weeks for cases to be included

3. Could there be under-reporting of the  number of cases of pulmonary embolism following vaccination?

• The short answer is yes, but we ‘don’t know what we don’t know’
• I would have expected that something serious like pulmonary embolism occurring within a short time after vaccination would have been reported
• We might expect because of the publicity more cases will be reported in the future

4. Is like being compared with like?

• The regulators like the European Medicines Agency will have done a similar task to my own calculation
• Essentially two separate rates are being compared though the data are gathered in very different ways

• Perhaps the biggest difference is how pulmonary embolism is diagnosed
  • The general population cases will include the hospital cases that will have been picked up incidentally, for example as an unexpected finding on an X-ray 
  • By contrast, cases of pulmonary embolism following vaccines, would not have been detected if they had been mild, with only minor symptoms
• As mentioned yesterday many cases of pulmonary embolism occur as a complication of surgery and it is not easily possible to identify the rate of ‘underlying natural cases’
• Probably not a major issue, but any analysis needs to take account of age, gender and other factors such as ethnicity which might affect the overall rates 

Conclusion

• I do not think it is likely that any of the vaccines protect against pulmonary embolism – though calculations based on the limited available data could give that misleading impression
• There are many ways in which feeding the limitations of the available data into these calculations could distort the results 
• These comments only refer to the data on pulmonary embolism and do not address the other concern about thrombosis in the veins in the brain
• None of the above explain what appears to be lower rates of embolism from the Pfizer vaccine 

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News internationally has been dominated in the past two days by a string of European countries pausing their use of the AstraZeneca vaccine, due to reports of a possible increased risk of blood clots.  European regulators are not concerned, citing that the rates of these disorders just reflect the background population rates.  I have taken a deeper look at the figures and the issue is perhaps more complex than we are led to believe. 

What are the new data that have filled the news?

• The new data come from reports received both from companies and national drug safety agencies* on the numbers of cases with one of the above disorders
• What especially precipitated the current concern seems to have been:
  • 7 reported cases of ‘cavernous sinus thrombosis’ in 1.5 million Germans given the AstraZeneca vaccine
  • 4 cases in Norway of clotting problems, although 3 of these were too little clotting due to thrombocytopenia
• In response to this news AstraZeneca said they were aware from their data of about 40 cases of clotting problems:
  • 15 deep vein thromboses
  • 22 pulmonary embolisms
  • (they haven’t publicly mentioned thrombocytopenia)

*I did discuss in a previous post how these data are obtained
https://makingsenseofcovid19withs.com/2020/12/04/how-will-we-know-about-long-term-side-effects-of-vaccines-learnings-from-thalidomide-swine-flu-and-donald-rumsfeld/

What information regulators need to collect when checking such reports

• Before reaching any conclusions on the numbers, the quality of the diagnoses in the cases reported have to be checked
• These case reports to regulators come from many sources and diagnostic accuracy cannot be assumed 
• Companies and regulators would thus seek the following confirmatory information from relevant health records 

• Information on the risk factors in the table above may be used to identify specific subgroups for whom a warning may be required

What did I find in the UK?

• I have reviewed the data published on the MHRA ( the UK regulator) website for reports of all clotting events up to the end of February
• I cannot find exactly how many doses of AstraZeneca vaccine had been administered  by the end of February but
  •  There had been 1.5 million doses by early February
  •  I therefore have guessed 3 million by end of February 
• I searched through the list of the 200,000 reported side effects to the AstraZeneca vaccine published on 9 March (most were trivial like arm soreness) for any mention of thrombosis or pulmonary embolism – 
• This is what I found

• There are also rarer reports on clots at other sites in the body
• I suspect AstraZeneca’s figure publicised yesterday of just 40 cases in total worldwide is an under-estimate
• I cannot emphasise enough times that these cases may, or may not be, related to the vaccine
• A rate of 4/million for pulmonary embolus is also a very low risk 

What about data from other vaccines? 

• I searched the same UK database for reports of the same disorders from the Pfizer vaccine
  • Similar data from other countries on their licensed vaccines are likely to become available 
• When the UK database was updated my estimate is that there had been  3 times the number of Pfizer doses given compared to AstraZeneca 
• The table below therefore adds the column for the Pfizer vaccine 

• I could find no reports of pulmonary embolism from the Pfizer vaccine
• Whatever the inaccuracies, the rates of all these reports are much greater for AstraZeneca than for Pfizer 
•  Combining all reports that mentioned a clotting problem, the rate/million vaccinated (orange bars) was five times that for AstraZeneca than for Pfizer vaccine
• I have also displayed the key results on a graph

What about the background population risk of these events

• As readers of my previous blogposts on the topic of vaccine safety may remember we have to compare the rates of reports of disorders, such as clotting, to the occurrence of these in the general population
• I must emphasise that accurate data on the occurrence of these conditions in the general population is not easy to find 
• There are no population registers, as there are for some disorders such as cancers
• So we are reliant for serious clotting problem such as pulmonary embolism  on the number of cases recorded from hospital databases
• The number of such cases from hospitals with DVT or pulmonary emboli can be misleading as a source of the underlying population rate:
• Why: because 60% of these disorders are  the result of being in hospital – especially following an operation!
• For what it is worth, given this bias, I have taken one report suggesting that 800/million in the UK are diagnosed with a pulmonary embolism each year*
• I have therefore attempted to do my own calculation on the true background population rate of pulmonary embolism 
• I am assuming that pulmonary embolism is likely to be reported as a possible side effect of vaccination within 4 weeks of the vaccine  
• So I have estimated the background monthly incidence of new cases 
• This is my calculation:

• This rate of 25/million is around 6.5 times the rate of embolism even in the AstraZeneca vaccinated cases 
• This might suggest that the AstraZeneca vaccine might even by protective. I think that is very unlikely and that we need to very cautious in interpreting such data
• I have given further commentary on this is a new post published today (17 March): https://makingsenseofcovid19withs.com/2021/03/17/could-vaccines-actually-protect-against-pulmonary-embolus/

*https://www.nice.org.uk/guidance/ta287/documents/pulmonary-embolism-acute-treatment-vte-prevention-rivaroxaban-appendix-b-final-scope2

Are patients with Covid-19 infection at risk of clots?

• If we are interested in the risks of clots following the vaccine we should also look at the risk of clots following the infection!
• We have known for some time that patients admitted to hospital with severe Covid-19 are at risk of having blood clots
• Indeed clots are one of the major reasons for serious complications following Covid-19
• Perhaps 30% of Covid-19 patients admitted to hospital either have direct evidence of a clot or their blood tests suggest they are at risk
• I can only find a very few reports of severe clotting problems from mild Covid-19, but in those patients too the consequences can be substantial

Is it biologically likely that the vaccine could cause blood clots?

• The story linking AstraZeneca vaccine would be compelling if there was a biological explanation
• There are coherent pathways of how natural Covid-19 infection can lead to clotting
  • These are mainly as a consequence of the body’s overactive immune response to the virus  damaging the walls of blood vessels
  • Other suggestions are that there is an increase of clotting proteins in the blood
• I guess it is just possible that in some people there is an overactive immune response to the vaccine which could have the same effect
• This is pure conjecture (!) but some people do have very severe responses to the vaccines and just possibly a small subset of these have the same potential for damage to the walls of blood vessels to increase the risk of clotting

Conclusion

• Honestly this is a difficult one!
• I accept, though allowing for all the possible inaccuracies, that the rate of events such as pulmonary embolism following the AstraZeneca vaccine is much lower than the expected rate in the general population 
• The data though, again with all their inaccuracies, suggest that rates of all these events of concern are greater with the AstraZeneca vaccine than with Pfizer- for reasons that are not easily explained
• It may be that with closer examination of the cases who have reported these problems will identify a group of people who may be at particular high risk of clotting and possibly should not have the AstraZeneca vaccine.  We should keep an open mind on this
• Let me finish by emphasising that the risks of having a serious clotting  problem are much higher from a bad attack of Covid-19 than from the vaccine

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