Category: Vaccines

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Covid-19 Immunity Risk transmission Vaccines

South African and UK: two Covid-19 variants – two countries in crisis ?

The UK and South Africa are two countries where the transmission of the virus has escalated. Last week a highly transmissible new strain was identified as the source in the UK. Three days ago, the explanation of a marked upswing in cases in South Africa was also shown to be related to a new genetic variant of the Covid-19 virus. Indeed, in an unpleasant twist, two cases of this variant were also yesterday reported to the UK. The outbreak caused by these new variants will be much more challenging to control, both within these countries and beyond.

(I hadn’t intended blogging again before the holiday, but these new data are sufficiently concerning I thought readers would want some of this background!)

Some comments on terms!

  1. Mutation – a change in one of the genes of the virus as it multiplies
  2. Variant – as a consequence of one or more mutations, a different version of the virus appears with slightly different genes from the initial version
  3. Strain – often refers to when a particular variant becomes an important cause of some or all of the cases in a particular outbreak

Thus the new UK strain has some 23 separate mutations and this variant has become the dominant strain causing infection in much of this country

What do we know about the new South African strain?

  • South Africa has seen a marked  increase recently in the number of new cases of Covid-19 
  • Around 90% of new cases in that country are due to a new strain, based on a number of mutations
  • As well as the 2 UK cases, the South African variant has now been found in Australia and Switzerland
  • No doubt as other countries undertake the necessary complex genetic analysis this strain will also be identified in many other countries

Concern in younger people

  • At the beginning of the epidemic less than 0.5% of cases in South Africa were in people under 30 (which may be related to who was being tested)
  • In some South African provinces the peak age is now in the 15-19 year age group
https://www.plenglish.com/index.php?o=rn&id=62600&SEO=south-africa-affected-by-second-wave-of-covid-19
  • As with the new UK strain, the new South African one multiplies much more quickly than the previous common strains
  • The problem is that those infected with these strains then produce much larger amounts of virus.
  • Thus, the concern is young people infected with these strains have higher levels of virus than they did with the previous strain: the latter of which only rarely led to a severe illness.
  • The greater viral load with the new strain could make them sicker
  • Indeed, there are a few unconfirmed reports from South Africa, of young people with no pre-existing illnesses who became seriously ill with this strain
  • It is too early to know how big these numbers are

How close are the South African and UK strains?

  • Both strains are quite different variants
  • Both however contain a number of mutations in the spike protein region, thought to be responsible for the increase in transmission
  • Thus both the South African and the new UK strain carry the same ‘N501Y’ mutation in the spike protein
  • It is likely that that these two variants have arisen spontaneously in different countries, but by chance both of them are particularly highly transmissible
  • We may see other countries reporting on other highly transmissible strains

For the UK variant, is there any new analysis of its impact?

  • In my post last week I thought it was highly likely that the UK strain would result in an increase in R
  • The graph below, from an epidemiology modelling unit in Oxford shows that the transmission rate, R, is now well over 1.0
 
http://epidemicforecasting.org/country-rt-estimates?region=GB
  • It is fairly definite that the increase in R is because of the UK’s new strain (now called B117 or VUI-202012/0)
  • What is interesting is that South Africa and the UK are two countries which, despite all the current lockdowns and mitigations, have two of the highest estimated R values in the world
    • UK R=1.26
    • South Africa R=1.33
  • As a comparison the estimates for other high prevalence countries are lower
    • USA R= 1.03
    • France R = 1.06
    • Italy R = 0.88

Conclusions about these new strains remain the same

  • New strains occurring during a pandemic are not unusual
  • The fact that these strains are more likely to transmit infection does not mean that the infection is more serious, but this will need to be monitored
  • Most experts also still expect the new vaccines to be effective, as the antibodies generated by these vaccines should still ‘work’ against even the mutant forms of the spike protein
  • As I mentioned last week, if necessary new vaccines can be made very easily against a new strain
  • Indeed, one sensible suggestion this week was that even if the vaccines turn out to be less effective against any new strain, that wouldn’t necessarily be a big problem
  • Given what is known about the effectiveness and safety of existing vaccines, it may be possible for regulators to approve slightly modified new vaccines without the need for additional lengthy trials

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Covid-19 Vaccines

Oxford AZ results: how do they change where we are on vaccines?

Little did I think when I posted last night on the differences between the DNA and RNA vaccines* (and in a parallel post I tried to explain these differences in scientific terms)**, that first thing this morning (UK time) Astra Zeneca (AZ) would announce in a press release the results of their DNA vaccine!  In this post I briefly answer the questions that their new data raise.

*https://makingsenseofcovid19withs.com/2020/11/22/two-new-approaches-to-a-covid-19-vaccine-how-do-they-fit-in/

**https://makingsenseofcovid19withs.com/2020/11/22/how-do-dna-and-rna-vaccines-work/

What are the headline results from the AZ Trial?

  • The AZ trial actually combined the results of several smaller trials which were all embedded within an umbrella of the single large investigation
  • These smaller trials (consider them ‘sub-studies’) used different dosage regimes:
    • Size of dose of the vaccine injected
    • Difference in the interval between doses 
    • Differences in the age of the participants
  • Although the numbers in some of these sub-studies are quite small, AZ decided the time had come that enough cases (131) had emerged that they could produce some preliminary results
  • The limited results presented were as follows:
    • In the total population whose results were analysed, the vaccine was 70% effective
    • The interest in the media this morning was that there was a difference when the study participants were divided into two groups:
      • 2,471 had a half the amount of the vaccine in their first dose and the full amount in the second dose – that regime had a 90% effectiveness
      • 8,895 had the full amount in both doses – that regime had a 62% effectiveness
  • The press release also said there were no severe cases of infection in those who had the active vaccine.  However, we are not given how many severe cases of infection occurred in the placebo group; so not easy to reach a conclusion on severity.

Which of these figures should we take?

  • At one level, AZ are proposing that the 90% effectiveness is proof of the success of the half/full dose regime
  • I would urge caution here for a number of reasons
    • The numbers are still quite small and indeed, even if the results from the half/full dose regime are better, we need much larger numbers to get more precise estimates of this percent benefit (we also need larger numbers for the other vaccines as well to get more precise estimates of these)
    • My understanding of the reason for having a half dose starter was not that the investigators thought this would be more effective but rather:
      • It might be less likely to give side effects
      • It would use less virus and hence be cheaper, and the  vaccine produced could be given to a larger number of people 
    • Thus, taking a formal statistical view there is always a worry when a result comes up from a ‘sub-group’ analysis which was not expected and is then presented as the headline result.  The approach in ‘normal’ times would be to check this unexpected result in new data
  • What is clear in the past from a number of trials of influenza vaccine, is that in a pandemic using half the expected effective dose can give the same level of protection as the full dose
  • So my conclusion is to note the 90% effectiveness in the half/full dose but, at this stage, take a cautious approach and use the 70% overall effect as being the key result to take forward

Does this mean the AZ vaccine is less effective than Pfizer or Moderna?

  • Firstly a 70% effectiveness, if that is how the AZ vaccine turns out, is still a success – would all conventional vaccines had that success!
  • Please read my posts yesterday on DNA and RNA vaccines where I show that the approach is different and that theoretically RNA vaccines (eg Pfizer and Moderna) might indeed be more effective
  • Against this, AZ vaccine follows perhaps a more tested approach, and will be much cheaper to produce and distribute
  • Thus in a world when only the AZ vaccine existed, I would consider that – unless contradicted as more data emerged –  this vaccine would be approved for widespread use

What about how easy will it be to achieve herd immunity with a vaccine with 70% effectiveness compared to one that is 95% effective?

  • Regular readers of this blog will know that I had anticipated this question emerging when the AZ data came out. The analysis I undertook therefore on this topic in my post you might find interesting to reread:

https://makingsenseofcovid19withs.com/2020/11/13/what-percent-of-the-population-needs-to-be-vaccinated-to-end-the-pandemic/

  • Some of you will remember this figure which showed the data where I tried to address how differences in vaccine effectiveness influence herd immunity (the yellow bars can now be read as the overall AZ vaccine result)

Conclusion

  • The results from the AZ DNA vaccine are good news of course
  • It would be wrong at this stage to say that this approach to making a Covid-19 vaccine is equally as effective as an RNA approach
  • More follow up data will provide a more definitive answer as to the relative benefits of the two approaches
  • With the limited evidence thus far available, and taking account of the different technologies, it is not a surprise that RNA vaccines might be more effective
  • All countries will now have a choice in terms of vaccine procurement but if (unlikely I know) that everything else (costs/availability/logistics) being equal it would make sense based on my previous post that the higher the effectiveness, the attainment of herd immunity will be so much easier- especially in the face of challenges in achieving high take up 

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Covid-19 Vaccines

How do DNA and RNA vaccines work?

In a post just published I described the different approaches to making vaccines against Covid-19.  For many of the readers of this blog I appreciate that the concepts RNA and DNA vaccines may be difficult to understand. I have attempted in this post to give, hopefully, an easy to follow introduction to the science behind these different approaches. 

How DNA and RNA make proteins, such as the spike protein   

  • Think of a protein as a string of beads, with the each individual bead being one of a chemical called amino acids
  • There are 20 different amino acids and all proteins are made of long strings of these in different orders
    • Insulin is a simple protein which has two strings of around 20-30 amino acids
    • The spike protein in Covid-19 virus has 1190 amino acids!
  • The clever thing is how all our cells are able to produce individual proteins with exactly the right sequence of amino acids
  • This is how it happens:
  • Imagine you have a box of 20 different colours of beads then the issue is where are the instructions to put the different beads in the right order
  • This is where DNA and RNA come in, they provide these instructions

How do the DNA and RNA instructions work?

  • In 1953, in the greatest of all scientific discoveries, Watson and Crick solved this question
  • Each of our genes is made up of its own string of DNA, that contains instructions for making proteins, each protein having its own set of DNA instructions
  • A gene thus needs to be long enough to match the protein it is going to produce (genes are actually even longer than that but that is another topic!) 
  • Genes however do not have 20 different building blocks to match the 20 amino acids, they just have 4 chemicals (called nucleotides)
  • Scientists refer to them by the first letter of their chemical name (‘A’, ‘C’, ‘G’ and ‘T’) (many geneticists do like their G&T’s!).  I am going to use the four primary colours to represent these 4 chemicals
  • The instructions for each of the 20 amino acids is represented in DNA by a unique sequence of 3 of these 4 chemical.
  • As examples:
    • one amino acid may be formed by the sequence ‘Green/Green/Blue’
    • another amino acid may be formed by the sequence ‘Red/Yellow/Green’
  • As you can imagine, some genes can be very long and the number of the individual nucleotides can be several thousands
  • Thus the entire DNA string can be very long and could easily get damaged so to make it stronger
    • The complete DNA sequence is not actually in the form of a long string but in a tightly bound spiral or helix 
    • Watson and Crick showed was that the stability of DNA was also increased by DNA being two spirals bound to each other (became known as the ‘double helix’)
  • The tight binding was a result of the pairing of these 4 chemicals, so ‘Blue’ always paired with ‘Green’ and ‘Yellow with Red’ (actually ‘A’ with ‘T’ and ‘C’ with ‘G”)

The tight binding was achieved by chemical bridges between these pairs 

  • So using my colour analogy the sequence:

red-blue-red-yellow-blue-red-green on one spiral

would be bound on the other spiral to the sequence

yellow-green-yellow-red-green-yellow-blue

  • Because of these bridges DNA is very stable and can last for ever – scientists have extracted DNA from Egyptian mummies!
  • But because DNA is in this very stable form, it cannot produce proteins on its own and this is where RNA comes in 
  • What happens is that when DNA wants to start producing a protein, its two spirals separate and the individual spirals hang around waiting for an messenger
  • That messenger is RNA which starts forming the ‘lost second spiral but in this case the RNA is not bound to the DNA and, when it is fully formed, it breaks free
  • I like this picture which shows how the RNA molecule is produced from DNA
  • Then the RNA can do its main work to produce a protein, by using the same 3 letter codes to build up the protein, one amino acid at a time, until the protein is fully formed
  • Thus giving a vaccine which is just RNA will start producing the spike protein exactly as it should be!
  • By contrast a DNA vaccine could make an error (or two) in making the RNA.

You can now read the post about two new vaccines with a professional eye!

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Covid-19 Vaccines

Two new approaches to a Covid-19 vaccine: how do they fit in?

In a frenetic two weeks, when results of one successful approach to making a vaccine based on RNA dominated the media, comes news of two other different pathways, each with their own promise. That is on top of the Oxford vaccine that was ‘first off the blocks’ with results due ‘anytime’.  In this post I take stock of where we are and provide what I hope is a really simple guide to these different approaches and what each could bring. 

The starting point: the common enemy – the Spike Protein

  • From the beginning of the Covid-19 outbreak, it was discovered that this virus has a number of proteins
  • Importantly it is covered in spikes which allow the virus to enter our lungs and other organs and start spreading
https://coronavirusexplained.ukri.org/en/article/cad0010/
  • If we could target the spike protein we could get rid of the virus from the body
  • The way to do this was to use a vaccine that would lead the body to develop antibodies against the spike protein, and when people who had been vaccinated came into contact with the virus the antibodies targeting the spike protein would emerge and do their stuff

What were the choices?

There are 5 different ways that success could be achieved: each one aiming to be a safe and effective way of leading to antibodies. They are using a vaccine that delivers one of the following: 

  1. A weak form of the virus
  • This is the traditional approach to making a vaccine and is now being tried for Covid-19 
  • The aim is to produce a safe vaccine from either a dead form of that virus, or a live virus that is sufficiently similar to produce the necessary antibodies, but not dangerous enough to produce a Covid-19 like infection
  • Takes a lot of testing to produce the right final product
  • Not always effective
  • Worries about safety and whether any weak form of the virus would be harmful to some people
  • Nonetheless tried and tested  approach and could be quite cheap to produce 

2. DNA from the virus for the body to start making its own spike protein

(In a post published alongside this one I have provided an easy to follow guide to how DNA and RNA vaccines work to produce the spike protein, which you may find helpful to understand the science behind these different approaches)

  • This is the basis of the Oxford/Astra Zeneca vaccine
  • In a very novel approach, only really tried with Ebola, the developers added the DNA sequence that is needed to produce the Covid-19 spike protein to a harmless virus
  • Thus, when this harmless virus was injected into the body, it would produce the spike protein, but not other parts of the Covid-19 virus
  • We know that the approach is successful in producing antibodies against the spike protein, we are waiting to see how successful it is in preventing infections with Covid-19
  • Even the harmless virus with the new bit of DNA could be excreted by those who are vaccinated, but worries about whether this is going to be harmful seem to be unfounded from what we know  

3.  RNA from the virus for the body to start making its own spike protein

  • This is the basis of the Pfizer and Moderna vaccines
  • This is an even more novel approach 
  • The vaccine does not involve a virus at all, but just the RNA from the virus sequence that is needed to produce the Covid-19 spike protein
  • We now know this is very successful in the short term at preventing infection
  • Because it bypasses the DNA stage of protein production, it removes one risk that the instructions for making the protein literally* “get lost in translation”
  • Also, because no virus is involved at all, it should be very safe
  • RNA is however unstable and that is why the Pfizer vaccine needs to be kept deep frozen.  Moderna have found a way to keep it just cold for a short while though
  • At the moment RNA vaccines are expensive to produce

4.  The actual (or a version of the) spike protein

  • An obvious question is why bother going down the DNA or RNA route, why not just make the spike protein artificially and give that as a vaccine?
  • The answer is that this is possible (the company Novavax issued a press release earlier this month)
  • A vaccine using this approach is in advanced development and the US government have given Novavax $2 billionto produce it
  • One problem is that the protein on its own will probably not produce a sufficiently large antibody response
  • Thus the vaccine needs to include other chemicals that will give a greater ‘push’ on the immune system to produce antibodies
  • This is not an unusual approach for vaccines: for example tetanus and diphtheria vaccines are based on giving harmful proteins (‘toxoids’) and not part of the infecting bacteria themselves
  • A vaccine like this could be very stable and cheap to produce but we have no idea if this one will work

5. Just give the antibodies so the body doesn’t need to make its own 

  • Another obvious question – if the challenge is to get the body to produce antibodies, why not give antibodies as a vaccine?
  • Indeed, newborn babies are protected against so many infections from the antibodies passed down from the mother
  • Antibodies injected into the body will not last very long – maybe months, maybe longer – but this approach could be useful to give short term protection
  • This might be useful in people who
    •  react badly to other vaccines
    •  have some problem with their immune system 
    •  may need special protection – I am guessing but for example a specialist doctor in an intensive care unit during a pandemic but for whom the normal vaccines did not work
  • This approach is very expensive, could be £/$’000’s per shot
  • Trials of this were announced just yesterday 

Conclusions

Yet more vaccines I am sure will create some confusion about which is best and ‘which should I have?’ What this post aims to show is that for this fundamental strategic approach to getting rid of the virus, we have so many different possibilities – that has to be good news!

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Covid-19 Vaccines

Pfizer study new data: easy to understate this success!

Pfizer released earlier today the full data from their trial which they had press released just 9 days ago. These updated results are very reassuring and in this brief post I will point out the extent of this achievement.

What’s new?

  • There are now data on double the number of cases compared to that which Pfizer presented last week
  • The results remain (or are indeed more) impressive with just a handful of cases in the active vaccine group compared with 162 in the placebo group
  • Of the 10 ‘severe’ cases both groups, only 1 was in the active vaccine group
  • Again very few side effects with 1 in 30 reporting significant fatigue and 1 in 50 headache after the second vaccine dose
  • Interestingly these side effects were greater in the younger participants

Pfizer commented on the success of the vaccine in older people

  • Without giving the numbers of cases they quote an overall reduction in the number of cases of 94% in those aged over 65
  • There was similar benefit in all ethnic groups studied – an important finding as the infection does appear to be more severe in many ethnic minority groups

Why am I so optimistic?

  • Yes, of course we don’t know how long the immunity will last for as well as about long term side effects
  • These data though are so remarkably similar to the Moderna data that they provide a very convincing case for the success of the novel RNA approach to vaccine production
  • In theory, because this vaccine does not contain any actual whole virus, it should be much safer than the standard approach to vaccine production
  • Albeit this is only a short extra time since their initial analysis but the USA is in the middle of a major wave of infection which is exactly when one would want a vaccine to work
  • Worldwide demand for vaccines will outstrip availability until may be the middle of next year but there are an amazing number of vaccine developers who are also proceeding down the mRNA route (see below)
List of RNA vaccines in development from WHO
  • This is so important as Covid-19 is unlikely to be the last Corona virus pandemic to hit us. Knowing we have a means of producing a vaccine in such a quick time takes away (I think) some of the overarching concern that we are sitting on a volcano that can erupt again

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Another vaccine success but is there a question we will not get answered?

Today Moderna announced almost identical positive results to those from the Pfizer trial reported last week.  Although there are differences in dosage, storage and manufacturing, the two vaccines themselves are very similar.  This is good news as the Moderna results provide an independent validation of the value of an RNA vaccine which gives support to Pfizer and other companies pursuing the same approach.  But there could be an issue in the way that results from these trials are being communicated and acted upon.

Anything more we learnt about RNA vaccines from the Moderna trial?

  • Reassuringly, as implied above the results from Moderna were almost identical to the Pfizer data
  • Moderna in their press release announced that even though there were a few cases of Covid-19 in the active vaccine group, all of the 11 with a severe disease had received the placebo vaccine 
  • Moderna also reported some mild side effects (nothing was mentioned in the Pfizer press release on this) but they were minor
  • Both vaccines require two doses
  • As widely reported, the Moderna vaccine is easier to store at conventional deep freezer temperatures and transport, making the logistics easier  leading to probably to a cheaper vaccination programme  

Of course, we have the same unknowns..

  • Will the vaccine be effective in the elderly (we don’t have enough numbers to know that)?
  • Will the vaccine be effective for longer than just the 1-2 months so far studied? We need to wait and see – but this might be the problem!

How long should the clinical trials run for?

  • The trials were all designed to follow up the participants for a full two years to see how long the protection lasts for
  • Not unreasonably, given the urgent national public and political interest, we are getting the preliminary results issued as press releases, as soon as there is evidence of a real effect
  • Scientifically reviewed publications will follow, but there is now the expectation that these vaccines will be approved and rapid introduction of their use will follow
  • But what happens to the thousands of people in the trials who had the placebo vaccine and will continue to be followed up?
    • On the one hand, if we do not continue to obtain data on the relative success of the active vaccine versus the placebo, we can’t know whether the advantage persists for the 2-year period
    • On the other hand, if vaccines are approved, then the participants in the trials who had the placebo vaccines will want to ‘convert’ to the active vaccine
  • A fascinating article in last week’s New Orleans Picayune Times* suggested that the latter indeed would happen

This is what he wrote:

*Thanks to RS for pointing this article out to me!

Does this matter?

  • At first sight the trials are likely to come to a premature end: what had been planned as 2-year trials could be stopped after 2 months
  • One could argue that this is ethical, and indeed it would be unethical in an active pandemic to allow participants in these trials to continue with the placebo vaccine unprotected once  something is now known to work
  • Does this mean though that we will not now have the reliable longer-term comparison data on success of the vaccine? 
  • It is not unusual in clinical trials to have a stopping rule, which would terminate a trial if a treatment is shown to work before the planned end date
  • Think about a cancer treatment trial which shows a survival benefit with a new treatment: it would be unethical not to allow the group of patients who had received the old treatment to switch to the new drug
  • So, what happens now?
  • It is likely that the trials will stop the true comparison stage earlier than planned, but there will be an unblinded follow up of everyone to see what the rate of new Covid-19 cases is over time 
  • This follow up provides information on how long the protection from the vaccine will last
  • But, if say 10% of those vaccinated get Covid-19  infection during  the next 2 years, what we won’t be able to do is say how much higher that rate would have been if they had not been vaccinated
  • If, over this time period, it does prove to be the case that there are new infections occurring in those who had had the Covid-19 vaccine, then we will need different research trials which for example –  in people who had had a course of a successful vaccine – could compare the following groups:
    • just continued follow up
    • with a booster of the same vaccine after say 6 months or a year 
    • or with a second, different vaccine after a shorter interval

Conclusion

From a scientific perspective an early end to a randomised trial, with some key questions unanswered, is not ideal, though there is a strong case for unblinding the trials once a vaccine is licensed and widely available.  Hopefully the long-term benefits of any of the vaccines under test will persist, but we will not know exactly what might have happened without the vaccine.

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Covid-19 Immunity transmission Vaccines

What percent of the population needs to be vaccinated to end the pandemic?

As I mentioned in my posts this week, a vaccine protects us in two ways: (i) direct benefit from our our vaccination and (ii) by herd immunity – the vaccine protecting enough of the population to put an end to the virus spreading between people. There is a need for any CoVid-19 vaccine programme to produce herd immunity as the vaccine may not work in everyone and its effects may not last. In this post I consider, given our current knowledge about the possible vaccines and the behaviour of the virus, just how easy it will be to induce herd immunity.

(A quick note to say that I have tried to make the answer to a complex question easy to follow, especially for people who are not experts in maths!  Feel free to go straight to the conclusions at the end!  You might find it easier to read this on an iPad or laptop rather than a mobile to take it all in – but do feedback whether it is too complicated).

A quick refresher on herd immunity!

  • During an epidemic we can divide the population into 3 groups
    • those who are infected (the red figures below)
    • those who are susceptible – ie have no immunity to the infection (the light blue figures below)
    • those who are  immune-ie are protected against infection and therefore cannot pass it on to others (the green figures below)
    • (Individuals can be immune either because of natural infection or because of vaccination)
  • In the picture below, when there has been no vaccination programme, the larger red figure can spread the infection to lots of the susceptible people 
https://www.technologynetworks.com/immunology/news/herd-immunity-is-a-dangerous-strategy-for-tackling-covid-19-339142
  • Now, following a vaccination programme, together with people who have become immune naturally, the situation is as in the picture below
  • The infected person has far fewer people that they can pass on the infection to. More importantly, the people who are still susceptible are less likely to come in contact with an infected person.  In this picture the large red figure can only infect one other person, whilst the light blue figures are surrounded by people who are immune
  • When transmission of infection effectively stops, we say that there is a state of  herd immunity.
  • As shown in the pictures, we don’t need for everyone to be immune to bring about herd immunity 
  • The proportion who need to be immune varies between viruses.  The more infectious a virus, the higher the proportion needs to be  

What are the key factors that will determine how many people need to be vaccinated to achieve herd immunity with Covid-19?

  • A paper in the Lancet* on November 4th showed that is possible to calculate the answer to this question
  • The calculations need to consider the following factors:
    • What is the rate of transmission? 
    • The short term efficacy of the vaccine
    • How long the vaccine protection will last
  • These are considered in turn below

*https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32318-7/fulltext

What is the rate of transmission?

  • This is the ‘R’ we’ve been hearing so much about
  • We all know that if ‘R’ is below 1.0, then the infection will die out (and theoretically no vaccination is needed)
  • We can only achieve an ‘R’ of that level with very strict social distancing and other mitigation strategies (eg face masks)
  • Without any mitigation strategies, the natural ‘R’ for Covid-19 is around 2.5-3.5 (each infected person, on average, infects between 2.5 and 3.5 other people)
  • In my calculations, I have considered 3 possible scenarios with a vaccination programme
    • We continue to adopt mitigation measures such as face masks and social distancing, accepting that the ‘R’ will fall to say 1.2, but won’t get below the magic 1.0
    • Once the vaccination programme starts, those who have been vaccinated then go back to normal life, ie the transmission rate is 2.5
    • As above, but a more pessimistic R of 3.5
  • This is what the calculations show:
  • To explain this graph, the blue bars show the percent of people who need to be vaccinated to achieve herd immunity for different values of R
  • If R is 1, as explained above, we don’t need a vaccination programme as the infection will disappear in time
  • If R remains as 1.2, then only around 16% of the population will need to be vaccinated to achieve herd immunity, but that means staying in some kind of lockdown until that has been achieved
  • If we go back to normal life and R is as high as 3.5 then we would need to vaccinate around 70% of the population to achieve herd immunity (shown approximately by the white arrows)

The short term efficacy of the vaccine

  • The calculations above assume the vaccine is 100% effective 
  • The Pfizer vaccine data suggested 90% efficacy – that might be optimistic and may not apply to all sub-groups, e.g. those who are elderly
  • Obviously the lower the efficacy, the lower the proportion who are vaccinated who are actually immune 
  • We also do not know what the efficacy of other vaccines might be, so I have assumed that the range will be from 60% to 100%
  • I have recalculated the figures from the graph above to allow for differences in the efficacy rate
  • This is what I found:
  • Let me help you to follow this graph*
  • The orange bars could represent Pfizer’s vaccine, with its reported 90% efficacy
  • The yellow bars could represent another company’s vaccine which may report 70% efficacy
  • Thus, if we remain in some kind of lockdown, ie with a ‘R’ of around 1.2, then to achieve herd immunity we would need to vaccinate 18.5% with the Pfizer vaccine and 22.8% with the new vaccine (red arrows)
  • If we resume normal activities and accept an ‘R’ of 3. 5, then we would need to vaccinate 79% with the Pfizer vaccine and 98% with the new vaccine (blue arrows)
  • Comment: it is highly unlikely that we could achieve anything like a 98% coverage 

*It’s a bit confusing as there are two percentages here. The figures above the coloured squares show the percentage efficacy of the vaccine. The numbers on the vertical axis of the graph show the percentage of people that need to be vaccinated

How long the vaccine protection will last?

  • This will also prove to be a challenge
  • We don’t know how long the immunity reported in the initial findings of the Pfizer trial, or with any of the vaccines, will last for
  • This is important as it will influence over how short a time the vaccination programme needs to be delivered. This will then impact on how long herd immunity will last for
  • If herd immunity begins to be lost, then booster immunization programmes will be needed
  • The Lancet paper did some fairly complex calculations and from their figures I have produced the following graph based on an assumption of
    • A vaccine which is 80% effective
    • An R value of 2.5
  • What this graph shows is that if a vaccine is 90% effective then herd immunity will last for around 17 months.  If it is 97.5% effective it will last for over 2 years.  If it is only 75% effective it will last just 10 months
  • Whenever that time point is reached then, as stated above, if the infection is still around a booster may be needed
  • None of these calculations have considered the fact that over time a new vaccine may be required to cope with a changing strain of the virus
  • However, the vaccine developers have shown they ae very nimble and should be able to adapt production of any new vaccine to cope 

Conclusions

  • Whether or not the vaccine is effective for any of us as individuals: for our continued protection and for society to return to normal, we need a vaccination programme to deliver herd immunity
  • The chances of herd immunity are obviously increased the more effective the vaccine. Vaccines with lower than the current reported success for the Pfizer vaccine can achieve herd immunity – but these would need very high take up rates of vaccination
  • Herd immunity will be easier to achieve if coupled with a continued stringency in adherence to mitigation actions such as mask wearing and social distancing – although this is something of a balancing act, as the aim of a successful vaccination programme is to return to normality  

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Covid-19 Vaccines

Pfizer vaccine success: better than we could have hoped for?

Early this morning USA time Pfizer, together with BioNtech, announced in a press briefing that their vaccine had successfully reduced the incidence of Covid-19 infection by 90%.  The results were announced in a press briefing though are yet to be published.  Does this mean that this (and hopefully other vaccines) are going to be the success we hoped for?

What was the study?

  • Like many other companies developing a vaccine, Pfizer started a major clinical trial of 43,538  participants, randomly divided into half that received the active vaccine and half that received a placebo
  • Participants from all ages from 12-85 were studied, the aim was that 45% would be over age 45
  • As far as I can tell none of the participants had a previous clinical history of Covid-19 infection and all were free of symptoms at the start
  • They had two doses of the vaccine, 21 days apart
  • The plan was that they would be followed up for up to 24 months to assess the risk of contracting Covid-19 and having side effects
  • The  researchers in the team who were collecting the follow up data did not know which group any participant was in, to avoid bias
  • Any of the participants who developed any symptoms suggestive of Covid-19 were then given a detailed assessment
  • Anyone who developed evidence of Covid-19 before 7 days had elapsed after the second dose were ignored
The detailed 146 page protocol for the study

What was the rationale for giving the results today?

  • Like any such trial, the researchers were only going to know if the vaccine was successful if the numbers of cases of infection were lower in the vaccine treated group compared to the placebo group
  • What had been agreed, based on statistical considerations, was that the first look at the results would take place after a total of 94 cases of Covid-19 had been documented across both groups of the participants combined.
  • A that stage, the code would be broken for those cases and an independent group would then be provided with the information as to how many of the cases had had the active vaccine and how many had the placebo.  
  • Prior to this analysis no-one in Pfizer would have had any idea how the numbers would turn out!

What did the result show?

  • Pfizer have not release the actual numbers but did say that the vaccine was “above 90%” effective
  • My simple maths would suggest that what this means is that probably 86 of the cases occurred in the placebo group and only 8 in the active vaccine group
  • There were no serious safety concerns reported by the independent data monitoring group
  • Thus, the headline result is of a substantial successful reduction in risk, which begins 28 days after the first vaccine dose

What is still to be found out?

  • It will take a bit longer to find out if there were any safety concerns that were not considered as ‘serious’
  • Normally a ‘serious’ side effect means one that requires admission to hospital
  • There are too few cases to know if the vaccine was successful in all age groups and in other sub-groups of the population, for example by ethnic background
  • We can only know the rate of infection up to the period of time the participants have been followed up.
  • We need to know how long the protection will last for, as immunity might wane over time
  • The virus may also change over time (mutate)
  • Thus as more information accumulates over the longer term follow up, these headline figures might change.
  • These preliminary findings will be being written up for a scientific journal and be scrutinised for their accuracy.  I have however read the detailed protocol for this study and I fully expect that the announcement in the press release will prove to be a robust conclusion of the results 

What happens now?

  • No vaccine can be administered in a public vaccination campaign without it being licensed by an appropriate national body
  • The Food and Drug administration in the USA will thus look at these results, probably as an emergency this week, and are likely to grant approval on the basis that the benefits considerably outweigh the risks
  • I trust that Pfizer and their partners will then, or simultaneously, ask the European Medicines Agency and (sadly since BREXIT) the UK’s MHRA to similarly grant a license
  • Once a license has been issued, public health  authorities are then free to begin mass vaccination of their target populations
  • There are only limited stocks of this vaccine worldwide.  I assume that most will be in the USA but UK and other countries will have some stocks I am sure

Was this result surprising?

  • No one could have predicted what the result would be
  • We knew that this and other vaccines in widespread trials did produce antibodies and that these antibodies could, in the laboratory, neutralise the virus
  • We did not know if this would translate into either:
    • A reduction in catching infection
    • A reduction in any infection being serious
  • Experts were hoping for say a reduction in infection rates of between 60-80%
  • Thus, these results are at the very optimistic end of the guesses

What about other vaccines in development?

  • The good news is that most other vaccines in development are attacking the same part of the Covid-19 virus: the ‘spikey bit’
  • The other vaccines have also shown that, like the Pfizer vaccine, they can produce antibodies that can neutralise the virus
  • There are differences in the way that these vaccines work and it is not certain that they will all be able to reproduce the results from the Pfizer vaccine 
  • But expect results from these vaccines to come out fairly rapidly as especially governments will want to be able to have access to sufficient quantities of any successful vaccine.

A quick comment on the anti-vacc lobby

  • I will be posting later this week what are the issues and challenges faced as a consequence of the anti-vaccination lobby
  • The Editor of the Lancet posted this weekend his concerns about fake news upending the success of the vaccine programme
  • Remember that there are 2 ways individuals are protected by a vaccine:
    • The vaccine that they receive
    • The herd immunity that is provided if enough other people are vaccinated 

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Categories
Vaccines

Is there a short cut to prove a vaccine is successful?

Everyone wants a vaccine to be available now.  The UK government announced last week a ‘world first’ in setting up a specialised centre in London to test possible new vaccines by exposing volunteers to the virus rather than waiting for the slower clinical trial.  How likely is it such an initiative would shorten the time to showing a vaccine is successful?  What are the practical and ethical issues involved?  

Background

September 30 09:53 EST
  • There are several clinical trials around the globe currently comparing the rate of infection contracted naturally between a group of volunteers given a new Covid-19 vaccine and a group given a ‘dummy’ vaccine
  • Definitive results of the success of these trials may be available before the end of the year, but that depends on how many people in the studies become infected naturally 
  • In my post of 13 August*, I referred to a letter from 15 Nobel laureates suggesting that waiting for these clinical trials to prove the benefits of any new vaccine would take too long.
  • The letter argued for a speedier process, and 30,000 volunteers had signed up, willing to be deliberately exposed to the virus. This is known as a challenge study.  

*https://wordpress.com/block-editor/post/makingsenseofcovid19withs.com/205

  •  The UK government have now committed to establishing a Unit to do just that. 

How will such a challenge study be undertaken?

  • Companies developing vaccines would come to the facility with their product and a study planned to test it.  
  • For each study, the volunteers would be vaccinated and then exposed to the virus.  They would be closely followed up over I guess 2 weeks to determine if they develop of Covid-19
  • According to the press release any affected volunteers would be treated with remdesivir: a drug shown to have a modest effect on reducing the severity of infection in patients admitted to hospital 
  • The version of the virus to which they are exposed has been developed by hVivo, a company experienced in producing strains of viruses for vaccine challenge studies in influenza
  • The strain they developed should be sufficiently similar to the current natural strains, but would produce a milder infection
  • The ‘dose’ of the virus the volunteers are exposed to would need to be determined.  This might involve a few studies, gradually increasing the dose 

Are there ethical issues?

  • Of course, and any company wishing to test their vaccine would need to obtain specific ethical approval
  • The regulators who grant ethical approval will want to review the background information from each vaccine manufacturer very carefully to ensure as far as possible that the risk to any volunteer would be minimal
  • It is obvious that Covid-19 is not flu and young healthy people have (albeit rarely) become seriously ill from Covid-19, which is not easily treatable   
  • There is also awareness that one volunteer who developed severe complication or died from the virus would be a PR disaster, which would affect both the challenge initiative as well as further development of the vaccine
  • There are likely to be very large payments to volunteers.  Volunteers to hVivo’s influenza trials are paid nearly £4000 (in part because they need to be compensated for their time).  We don’t know what the Covid-19 volunteers will be paid , but the recompense might not surprisingly be a consideration in the minds of those who volunteer.
  • It is not an epidemiological question but let me ask you the readers of this blog, what would be an appropriate payment? 

How will the results accelerate vaccine development?

  • This is the area on which I have the greater number of questions!
  • The challenge studies could be done on new vaccines which have yet to be tested in humans or on those vaccines that are already in large scale clinical trials.
  • If the former was the case then the testing could allow a more rapid progression of new vaccines into larger trials than say the 6 months that is the case for current vaccines.  
  • If the latter was the case then I am not sure what the challenge studies would add.
  • As far as side effects are concerned: the clinical trials already underway are studying very large numbers of volunteers, of all ages, and thus hopefully could be big enough to assess the risk of short and long term side effects – which the smaller sized challenge studies cannot do
  • As far as any vaccine being protective is concerned: many vaccine experts are anticipating that a ‘good result’ from a vaccine would be a protection of 60-80%.  Even if a challenge study shows a vaccine stops the occurrence of infection in 100% of the small number of  volunteers; we would still need to await the results of the larger trials
  • There is also the question whether the engineered virus used in the challenge studies is sufficiently similar to the natural virus currently infecting people to be a useful comparison  

Conclusion

Given the stage we are at now with the vaccines under development, I am not sure what advantage this initiative will bring.

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Categories
Vaccines

Who should be vaccinated?

A vaccine is now the only likely successful path for the elimination of the threat from Covid-19.  Clinical trials are well underway but results may not emerge until spring 2021.  The UK government* as well as the USA (ie Donald Trump) are considering employing vaccines without waiting for the full trial results.  Vaccine manufacture is proceeding ‘at pace’. What is not clear is whether the vaccine should be offered to those most at risk or the whole population.

*The UK government are considering supporting challenge trials- the issues surrounding these will be discussed in my next blog post

What are the issues?

Who should get the vaccine depends on the following issues:

  • Who is most at risk from the adverse health consequences of infection?
  • What are the risks from the vaccine?
  • How effective is the vaccine?
  • The role of vaccines in achieving herd immunity
  • Population acceptability

These are considered in turn:

Who is most at risk?

  • For annual influenza, most countries only vaccinate the elderly and others with pre-existing health disorders 
  • Covid-19 as is well known poses by far a greater risk to the elderly.  I illustrate this below with mortality data from the UK and USA
  • The chart also shows that the rates of being admitted to ICU and are still tiny for those under age 65
  • Population data on long term ill health, so called ‘long CoVid’, (eg the persistence of symptoms such as being breathless and fatigue) will take some time to accumulate but reports so far suggest that these are not uncommon consequences in the young 

What are the risks from the vaccine?

  • There are short term reactions in the young volunteers in the trials, but these are controlled easily by paracetamol (USA-acetaminophen)
  • At the moment we don’t know the risk of serious side effects such as the recent cases of neurological problems (see my previous blog posts)
  • Based on studies of mass use of flu vaccines, the increased risk of serious neurological problems is very small, say less than 1/million population 
  • As a worst case scenario though, let us suppose that with the Covid-19 vaccines there is an incidence of 1/10,000
  • The red line shows the rate of serious complications of the vaccine at 1/10000.  This could be a wild over-estimate but those who (like me) advocate for high take up of what will be a successful vaccine  need to be able to address the potential consequences of this strategy

How effective is the vaccine?

  • The jury is still out on how successful the vaccines in development will be in preventing infection over a sustained period
  • There is the real possibility, due to waning in the activity of the immune system as we age, that the vaccines will be more effective in those least at risk of a complication or dying from Covid-19
  • The FDA (the USA regulatory body) has a threshold of 50% reduction in infection although those developing vaccines are hoping their trials will yield a 60% reduction: which may or may not be large enough to give herd immunity (see below) 
  • Any reduction in the likelihood of individual protection could influence perceptions of the balance  between the risks and benefits 

Personal protection versus herd immunity 

  • The introduction of a new vaccine gives individuals two paths whereby they can be protected:
    • Individual protection from own vaccination
    • Community protection from others being vaccinated, leading to herd immunity.
  • As shown clearly in the picture below, once the vaccination levels get up to a sufficient size (more blue blobs) then there are fewer routes for an infected person to infect an unvaccinated individual 
https://www.brookings.edu/blog/usc-brookings-schaeffer-on-health-policy/2015/02/06/what-the-anti-vaxxers-are-getting-dangerously-wrong/
  • We cannot easily determine what that level of vaccination should be: it depends on the infectivity of the virus (eg R value) and also the current level of natural immunity (from people who had become immune from being infected) 
  • There is a range of suggestions as to what that proportion of the population needs to be, with estimates ranging from 60-80%

“If I’m vaccinated why should I worry about herd immunity?”

Individuals, even those who are willing to be vaccinated, cannot ignore the benefits from herd immunity – why?

  • There will always be a number of people who should not be vaccinated, because of problems with their immune system – either from diseases or from drugs that damp down the immune system.  This group would have to rely on herd immunity for their protection 
  • Some people may have a bad reaction to the first dose of vaccine and in a regime that requires a booster dose, would be left unimmunized 
  • The vaccine may not be sufficiently successful in some people, for example older people
  • Vaccine effectiveness may wane over time, again perhaps more so in older people
  • The damage done to our societies by the virus needs to be controlled and that will require herd immunity to be achieved as rapidly as possible

The anti-vax lobby

Perhaps because of, or in spite of, the issues raised in this post, the size of the lobby against vaccination is substantial and could seriously impact on our ability to achieve herd immunity.

  • Public opinion changes but between 1/3 to 1/2 of the population might refuse vaccination
  • There is a strong view amongst the ‘libertarian right wing’ especially in the USA against vaccination 

Why is there an opposition to vaccination?

  • We need to distinguish between individuals who are opposed to vaccines for themselves and the smaller but more vocal group who are opposed to vaccines for the population. 
  • Concern is that the increased publicity to the latter group will increase the size of the former.
  • There is an established body of research identifying the reasons for opposition to vaccination
  • In a recent large European study, the most prominent single reason for opposition to Covid-19 vaccines is concern about side effects 
https://link.springer.com/article/10.1007/s10198-020-01208-6
  • There are other reasons including the perception that:
    • The target disease is not a major risk to public health in general
    • The target disease is not a major risk to them in particular – important in Covid-19 in relation to younger people
    • The vaccine is not effective
    • Governments and/or vaccine companies have dubious motives

Conclusion 

  • There is a paradox:
    • Vaccinating the most vulnerable in the population may not be adequate to have the necessary impact on the rate of serious outcomes from this virus 
    • Yet it is going to be a challenge to achieve high levels of vaccine uptake amongst the least vulnerable
  • Any further publicised cases of serious side effects, however rare, could have a disproportionate negative influence on vaccine uptake

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Further reading:

  1. Once we have it, will we use it? A European survey on willingness to be vaccinated against COVID-19. Eur J Health Econ 21, 977–982 (2020). https://doi.org/10.1007/s10198-020-01208-6
  2. WHO Influenza Vaccine – Observed Rates of Vaccine Reactions Information Sheet (PDF)
  3. COVID-vaccine results are on the way — and scientists’ concerns are growing (news article): https://www.nature.com/articles/d41586-020-02706-6