My blog normally focuses on interpreting the science to get the key messages across. Sometimes there are other ways and a friend send me this link – we all need to be uplifted from this really challenging week with the depth and severity of this new wave and the anxieties that anti-vaxxers could scupper the essential achievement of herd immunity. Leonard Cohen would be smiling in his grave!
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As vaccine delivery is rolled out, the major worry globally is whether this action will protect against the new variants of the virus. Yesterday media worldwide reported on a third new variant, emerging from Brazil, similar genetically to those from South Africa and the UK. The most recent data suggest that current vaccines are probably still going to work but we are right to remain cautious. The aim of this post is to explain in simple terms how these variants could reduce the success of the virus.
Let’s start with the virus
Apologies for repeating what most of you will know, but it is the spikey bits on the surface of the virus that are most important in terms of its ability to cause infection
These spikes have at their tip a bit of the protein that allows the virus to attach itself to human cells. I call it the ‘key bit’ in that picture (the posh word is “receptor binding domain” or RBD), ie it is like a key that needs to find the right lock
Thus, when the virus has multiplied it can only attach to human cells, for example in the nose or throat, when it finds a lock it can fit
The posh word for that perfect lock is called a ‘receptor”
So how do the vaccines directed against the spike protein work?
In simple terms Covid-19 vaccines aim to stop the spike protein attaching to cells by preventing that ‘lock and key’ process
Vaccines work by producing antibodies (as I am sure you all know by now!) that stick to the spike protein of the virus, thereby stopping it attaching to the receptors
In the picture below, antibodies are shown as Y shaped chemicals that have locked onto the spikes, thus preventing the virus locking onto the surface of cells
How does this relate to the new variants?
The spike protein is a very complex shape indeed (see picture below!)
The antibodies produced by all the vaccines all recognise the main aspects of the shape of the spike protein
The virus mutates all the time and thus the exact shape of the spike protein will vary between different mutations*
Thus the spike protein that the vaccines are designed to produce may be different from the spike protein of a new variant of the virus that we are exposed to
Fortunately, most mutations do not sufficiently affect the shape of the spike protein to interfere with the success of the antibodies
The particular problem with the new variants (which was not the case with other mutations) is that these mutations do affect the shape of the key bit (RBD) of the spike protein
Thus, the concern is that antibodies produced against the spike protein in the vaccine will not lock onto the spike proteins on the new variants of virus, so the virus will be free to lock onto the human cells and cause a clinical infection
As mentioned above this is such an active, even frenzied, area of research, my comments may be out of date even as I publish this post (I will try and keep abreast!)
Some things do seem clear:
It seems that the antibodies produced by the vaccines may have reduced potency against the new variants, but will not be completely rendered ineffective so
Pfizer have however carried out new laboratory tests of their vaccine with the UK variant and found that the antibodies produced were successful in neutralising this variant – that is what we needed to know
The theoretical likelihood of new variants being a problem for the vaccines is also greater with the Brazilian and South African variants than with the UK one
The reason is a complex one: the UK variant does not have exactly the same mutations in the key part of its spike protein and so the antibodies from the existing vaccines should still be effective (ie supporting the results of the Pfizer study above)
What about immunity to natural infection?
I only covered this 2 days ago, before some of these new data appeared!
My take at present is that although the same concerns apply – “if I have been infected will I also be protected against the new variant?” – my guess is that natural immunity should be more resilient than vaccines to changes in the virus because:
Vaccines produce an immune response just to the (albeit very important) spike protein
Whereas natural infection (as I said in this week’s post) produce an immune response to many different parts of the virus
What is disturbing about the news yesterday of the spread of the new variant in Manaus, is that this region of Brazil had already been devastated by Covid-19 and it was hoped that the population had reached herd immunity
I don’t think this proves that natural immunity did not work in the 60% of the population that had been infected, but rather that with the new variant herd immunity is going to be that much harder to achieve
Take home message from all this – we ALL need to be vaccinated
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Since the beginning of the pandemic – for both the public and policy makers – one question has been “Can someone catch Covid-19 twice?”: specifically, everyone wants to know not just “is this a possibility” but “what is the likelihood that this could happen?”. Further, if immunity following an infection does wane over time, and given that we are now 12 months into the pandemic, is the rate of cases of a second infection increasing? These questions are brought into recent focus with the spread of the new variant, with concern that immunity acquired from earlier variants may not now be protective. In this post, I summarise what we know.
There are some challenges in proving that someone had caught the infection twice
Broadly speaking it is highly unlikely that someone would continue to be shedding virus (posh word for spreading active virus from nose and mouth), more than one month after the start of an infection
Thus clinically, when a person has been ill, recovered and is symptom free, a new infection after 28 days is broadly considered to be a second infection
This would require a new positive swab test to confirm
There are however several reports of people still being positive on swab tests up to 8 weeks after their first positive test
For that reason, ‘proof’ of a new infection requires detailed genetic analysis of the virus between the two positive swabs to show that they are different.
To complicate matters a little (!) it is not impossible for someone to have two separate strains causing their infection at the same time – but this is probably highly unusual
However common sense would suggest that a person who had an obvious infection, recovered well and then some months later developed a second diagnosed infection, had caught the infection twice
“I have had one infection, I want to know my risk of having a second infection”
There are two ways to approach this question:
The direct way; by providing information on the rate of second infection, over the chosen time period – which could be the next month, the next year or lifetime!
The indirect way; by measuring the level of immunity by antibody tests for example, on the understanding that such knowledge would be an accurate guide to the future risk of a getting ill with an infection
These are considered in turn below
What is the rate of second infections?
Perhaps surprisingly we do not know how common is a second infection in people who have had one infection
Thinking about this, the rate of second infection will be clearly related to how exposed a person is:
If following a first infection the person stays at home and meets no one else, then their risk of a second infection would be almost zero
Further although the rate of having an asymptomatic infection is the same across age groups, the risk of being ill increases with age. Thus, the rate of a second symptomatic infection will vary with the age and indeed other risk factors such as obesity and possibly ethnic background
Perhaps for this reason there has not, as far as I can tell, been a comprehensive epidemiological study where people who have recovered have been regularly tested with a swab test to measure the rate of getting a further infection
As mentioned above, to distinguish a new infection from a continuing old infection also requires sophisticated genetic analysis which is not widely available
What does appear to be happening is that when a second infection does occur, the clinicians feel they should report such cases in the scientific press
It is difficult to draw conclusions from what are at most a few handfuls of cases. Reports from the majority of individual patients, though not all, suggest the second infection is milder
An informal report attempting to identify all cases worldwide (subject to masses of errors) had found 1673 by December from the several millions who we know had been ill
A recent study from Oxford undertook an antibody test on 12000 health workers, of whom 1246 were positive for antibodies against Covid-19
They were then followed up for over 6 months with swab tests: finding 3 with a positive result (all of whom were well)
Conclusion: 12 months into the pandemic, second cases appear to be exceptionally rare
Do we know how long immunity last for?
As we don’t know how common a second infection is, then we could get some idea if we knew how long the level of immunity following an infection lasts for
One approach is to measure the levels of antibodies in the blood at different intervals after an infection
This has been done in several studies, but of course we only have data for the length of time that people have been followed up, which – given the global pandemic only started in spring 2020 – is not much more than 6 months
Thus far though antibody levels in general do persist for 6 months
The actual levels do decline over time, but this is normal after any infection
What is true for Covid-19 is that antibody levels are lower, and may indeed by undetectable, in people who have had very mild disease or were asymptomatic
Although that could mean that a mild dose of the disease does not confer immunity, it is also possible that a mild disease means that there was an efficient immune response to prevent a serious infection, that could come into play next time
However just because the levels of antibodies decline does not mean that there will not be an adequate immune response if faced with the virus again
The body’s immune system, following an infection with Covid-19, is primed to respond to a second infection in two ways:
Producing antibodies that neutralise the virus
Bringing some special cells, T cells, into operation that also can destroy the virus
These responses are stored in our immune memory to be brought out of ‘hibernation’ when there is a signal of a second attack
We still do not know how far the antibody memory and the T cell response would come into play if antibody levels were low or even undetectable
What about the new variant?
If the virus causing the new infection is sufficiently different from that causing the first infection then the pre-existing immune response theoretically may not provide protection
There has been one case reported last week of a person who contracted new variant Covid-19 (‘VOC – variant of concern’) months after recovering from a first Covid-19 infection, but one case does not prove any significant risk for all
At the moment in truth there is inadequate research on whether for most people antibodies from a first infection will protect against infection with the new variant
I am however reassured that thus far testing of the new vaccines suggest they should still protect against the new variant
Remember the current vaccines work by stimulating the body’s response to just one part of the virus – the spike protein
Natural infection with Covid-19 should produce antibodies to other parts of the virus, for example there is another protein called the N (nucleocapsid) protein.
Indeed, this has also been targeted for vaccine development
Thus the point being that pre-existing immunity from ‘old infection’ has a number of targets in any new variant that could still work
And Covid-19 is not the only coronavirus in history!
There are some reassuring data from longevity of immune responses from other coronaviruses
Coronaviruses that cause the common cold produce antibodies that last at least a year
Further when people are re-challenged with the same virus some get infected again but the symptoms are milder
People infected in the first SARS epidemic in 2003 still had a T cell immunity to that coronavirus this year, after 17 years – interestingly that was directed against the N protein
And (not a coronavirus) but in 2008, 90 years after the Spanish flu pandemic, some people still alive had neutralising antibodies to that virus!!
Conclusion
Yes of course it is reasonable to want to know about the risk of getting Covid-19 twice
Thus far second infections seem to be exceptionally rare
When they do occur, they tend to be mild
The immune response following natural infection is also sustained for at least 6 months and protection may last longer
We await further research, but at the moment no need to panic that the new variant poses a particular risk of a second infection
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My recent posts have focused on emerging data from the newly licensed vaccines. As these are now being rolled out, I am aware of many questions that people want answering about the vaccines both for themselves and their families. In this post I aim to address as many of these questions as I can from the data and expert opinions I have reviewed
Below is the list of questions covered – if you are interested in just specific questions click on the hypertext links
What does it mean that “a vaccine is 90% effective”?
The figure about the percent reduction comes from the clinical trials
The reduction is calculated by comparing the rates of infection between people who had the new vaccine and those who had the dummy vaccine
Thus, if the number of volunteers in each of those two groups in the trial were the same, the number in the real vaccine group who became infected would be one tenth of those in the dummy vaccine group
If infection rates are very high as they are at the moment, the absolute number of vaccinated people who get infected will be higher than when infection rates are lower, but the relative reduction should be the same
Will I get the same benefit as those in the clinical trials?
The short answer is we don’t know yet until more data has been gathered.
Obviously the results of the trials are the best estimate we currently have but the vaccines could possibly be less effective in the ‘real world’.
This may be because the people who volunteered for the trials may have been, for example, healthier and less likely to become infected for a variety of reasons
Experience from the results of many new drugs in general use is that, once they are licensed, their effectiveness is lower than they were in the trials
But this may not apply to the current vaccines and the very high success rates reported in the trials is, I anticipate, likely then to be repeated following their widespread use
Of course, the above assumes that no new mutation, like the new UK variant, will be less likely to respond to the current vaccines. At the moment there is no evidence to support that theoretical worry
Which of the available vaccines is the best?
The headline effectiveness rates were higher from the Pfizer and Moderna (RNA) vaccines than from the AstraZeneca (viral vector) vaccine: does that prove the former two are better?
It is not sound statistical practice to compare the results between vaccines that were not directly compared in the same study
There are several reasons for this caution – related to who participated in the different trials; for example the volunteers came from different countries and regions, may have:
had different background immunity
been exposed to different mutations of the virus that were around in each trial
The only sure way to compare between two vaccines is to do a ‘head to head’ trial. Such studies will not be done because they are expensive and not deemed necessary
Further, regulators and governments would argue that all these vaccines are sufficiently successful and we need as many doses of them available as we can get
I think though that given the very high success rate for both the RNA vaccines, it is unlikely that any new vaccine could have an even greater success rate – but it is not impossible that say the Astra Zeneca vaccine could have very similar success rates when tested in identical populations
How likely is it there will be a one-dose vaccine?
Firstly, for very sound biological reasons the body’s ability to develop a strong immune response to a vaccine is increased with more than one dose
As I wrote in previous posts on this blog, this is not true for all anti-viral vaccines but is for most
But all 3 of the recently licensed vaccines were only tested in clinical trials of a two-dose regime
Janssen have a vaccine, being marketed by Johnson and Johnson, which showed a strong immune response in the laboratory after one dose – but so did the other vaccines.
The Janssen trial in humans, unlike the trials of the other vaccines, is also comparing one versus two doses and we await the results of that study
This vaccine is very similar to the AstraZeneca vaccine so (sticking my neck out!) I would be surprised if one dose was sufficiently effective. The results are due at the end of January
Will having two doses from different vaccines be better than from the same vaccine?
Hypothetically this does make sense
If the body responds to the virus by producing antibodies that attack it in 2 different ways then this might be a very effective strategy. (Not an identical parallel but there are many infections that are best treated with combinations of different antibiotics)
Indeed this week there was an announcement of a tie-up between AstraZeneca and the Russian Sputnik vaccine, which is an interesting idea
There are particular reasons for trying this combination. Both these vaccines have DNA instructions to make just the spike protein bit of the Covid-19 virus
This DNA piece is then bolted on to another harmless virus (called a viral ‘vector’-literally carrier). This carrier virus is a human virus in the Sputnik and a monkey one in the AstraZeneca vaccines
Thus as the body might make antibodies to the vector in the first dose, as well as to the spike protein, then a second dose with the same vector might be ‘neutralised’ by these unwanted antibodies
Having a different vectors for each of the two doses makes that much less likely
I have had Covid-19 infection naturally, do I need to be vaccinated?
Short answer is ‘Yes’, for many reasons!
Firstly, we don’t know how long immunity from natural infection will last so you may not still be immune
Secondly, some people with mild infection or who have had no symptoms may have little natural immunity to start with
Finally there is no specific extra risk from a vaccine if you have some immunity, think of it as an extra booster!
Are the vaccines as effective in all older age groups?
Success may not be as good as we get older, as in general the body’s ability to produce antibodies does decline with age
In the trials, despite recruiting very large numbers of volunteers, there were too few people aged over 65 who became infected to provide a definitive answer
AstraZeneca provided no data on age group in their trial
The Pfizer trial did show an identical success in those above and below the age of 55 and the data supported a similar reduction in risk in those over 65, but there were too few over 75 for any useful conclusion
In the Moderna trial the effectiveness was lower in those over 65 (86%) than those under that age – but 86% is still very satisfactory
My view is that even these limited data are much more encouraging relative to what I might have expected – the effectiveness will not be as high I am sure in those over age 65 but might be ‘high enough’. We will get more data in planned future analyses from all these vaccines
Are the vaccines safe for women who are pregnant?
Again, short answer is we don’t know as women who were pregnant or were considering pregnancy were excluded from the clinical trials
Almost certainly as the vaccines are being rolled out in different countries especially amongst key workers in the health and care sectors, many of those will be pregnant at the time they are vaccinated, so some data on risks and benefits will emerge
However, pregnancy is associated with a decline in natural immunity (so the mother doesn’t ‘reject’ the baby)
A report from the USA identified 8000 pregnant women who were also infected with Covid-19. These women had a fivefold risk of being admitted to hospital and a twofold risk of needing ventilation compared to similar aged non-pregnant women
So, for some groups who have high risks of exposure (eg nurses) vaccination is now advised
Despite the absence of data from the use of vaccines, all experts are of the view that that the RNA vaccines (Pfizer and Moderna) – which do not contain live virus – should not be any risk to the mother
The AstraZeneca vaccine contains a live but harmless virus so again experts believe it should pose no harm
Are the vaccines safe for the foetus in women who are pregnant?
Expectant parents do worry about taking anything that might damage their growing foetus
There are limited data but most reviews I have read confirm that there could well be a small chance of serious defect in the foetus for a mother who contracts Covid-19 infection early on in pregnancy
Despite presumably the large number of such women worldwide who had Covid-19 in pregnancy, there only a very few reports of serious defects.
There maybe a small increased risk but how large this is is not known
Further even if the virus itself did not cause the defect, some of the treatments that might be needed if the mother was really ill with Covid-19 could also be harmful
We have no data yet on the risks from vaccines to the foetus and newborn infant
Most experts therefore believe that any risk from vaccines to the foetus is probably outweighed by the risks from the mother being infected
Are Covid-19 vaccines safe for the infants when given to mothers who are breastfeeding?
Again, there are no data on this
Given what we know about what is in the vaccines and how compounds are transmitted through breast milk, there is no reason to believe that any of the vaccines licensed for use pose a risk to the mother who is breastfeeding
Indeed, there is evidence that some of the antibody protection that the mother has from vaccination may be passed into the milk and may give some protection to the feeding infant
Generally speaking though, we shouldn’t rely on maternal immunisations to protect infants from any infectious disease
Can or should children be vaccinated?
As is well known, children are at very low risk of a serious complication from Covid-19*. Indeed, if Covid-19 only affected children then probably no one would have considered developing a vaccine
Children are however at no different risk of contracting the infection and passing on the virus to others
Indeed because of their greater social interaction, and the high proportion without symptoms, child-to-adult transmission is an important route for adult infection
The situation in terms of vaccinating children is complicated!
In the UK the Pfizer vaccine is only licensed for those over the age of 16 and the AstraZeneca over the age of 18
In the USA the Pfizer and Moderna vaccines are licensed for children over the age of 16
All companies have some data from their trials on younger children but not sufficient for regulators to make a decision about their use
Childhood response to vaccines does vary and will thus need specific studies to address the level of antibody and other immune response
For the moment no vaccines will be delivered to children
*Readers will remember possibly media reports of very rare complications of Covid-19 in early childhood now called “Multisystem Inflammatory Syndrome in Children (MIS-C)”. This is so rare that further discussion is outside the focus of this post
What about people who have underlying diseases, or are on drugs, that affect the immune system?
Doctors use the term ‘immunosuppressed’ to cover this very large group of people in the population
This has been the largest source of questions from readers who have contacted me and I understand their concerns
Becoming infected with Covid-19 in people who are immunosuppressed poses much more of a risk and hence up to now they have been advised to shield as being particularly vulnerable
Thus the availability of a successful vaccine for this group could allow a return to a much more normal life
There are though 2 separate questions in this situation:
Are vaccines safe?
For vaccines that do not contain a live virus eg Pfizer and Moderna, most experts do not see why there should be any risk for those who are immunosuppressed and hence should be safe
For vaccines that do contain a live virus, even a harmless one such as in the AstraZeneca vaccine, expert opinion is more divided. The problem being as with so many other issues, immunosuppressed people were excluded from the trials
Data from use of vaccines for other infections are also challenging to interpret but, for many of these diseases, live but otherwise harmless viral vaccines are not advised
Are vaccines effective?
This is also more challenging as immunosuppressed people may be less likely to produce a good enough immune response to give protection
Again, there are no data. But, as Fauci says, where there is no concern about risk, having the vaccine even if it may not be as effective as in a person with normal immunity is not a reason not to be vaccinated
I would make two other points if the above sounds disheartening
Immunosuppressed individuals will benefit from herd immunity so they may not need to be protected themselves (but this is another reason why those who don’t have such problems agree to be vaccinated!)
There will be other options including new vaccines that are antibody based such as the ‘second’ new AstraZeneca vaccine
Note to all the readers – I welcome comments especially on items that are unclear or are not addressed. I regret I am not able to answer individual emails. This blogpost is not a substitute for obtaining individual clinical advice
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Pfizer/BioNtech together with the US and European regulators have criticised the UK authorities for allowing up to 12 weeks between vaccine doses, news which was headlines in Australia today.
The UK now recommends a 3 month gap between doses of the Pfizer vaccine which coincided with the UK regulator also recommending a 3 month gap between doses for the AstraZeneca vaccine.
Public Health Argument
As is now well known worldwide, the UK is the epicentre of a major uncontrolled epidemic of new variant Covid-19. As mentioned in the UK Prime Minister’s press briefing this afternoon, the UK government, aware of constraints in the availability of vaccine and the logistics for widespread delivery, is focusing on maximising the number of people to get their first dose, and delaying the second dose for 3 months for both of these 2 vaccines.
Support for this comes from a re-analysis of the AstraZeneca trial, which showed a greater protection against infection the longer the interval between vaccine doses from 28 up to 84 days.
The UK’s argument for the dose delay for the Pfizer vaccine is that it is also likely that even with a 3 month interval between doses there should not be any reduction in the benefit achieved
Thus, given the urgent public health need, it is better to direct resources to give as many people as possible one dose in the hope they would get some level of protection
What this post adds to the debate?
In this post I review some of the laboratory data on the vaccines from last summer but also some very recent data from AstraZeneca that was published in December. I use this new information to address again:
What protection can there be from just one dose?
How long would such protection last if there was not a second dose?
I have looked at the data from the Pfizer/BioNtech, Oxford AstraZeneca and Moderna/NIAID* vaccines to address these questions
*US National Institute of Allergic and Infectious Diseases.
The pyramid approach to assessing the value of vaccines
Developing and testing vaccines is a costly and lengthy business
Following toxicity testing in animals and healthy human volunteers, a vaccine’s effectiveness is assessed by a series of research steps
First research question – the yellow slice: does the body make antibodies* and how much?
*There is another part of the immune system-‘T cells’ which is part of our response to vaccines, but is not discussed here
The next research question: the grey slice: having made these antibodies, do they do anything useful for fighting infection, such as stopping the virus multiplying? We use the term ‘neutralising’ – it has a military tone as in neutralising the enemy!
All the 3 vaccines showed they could produce ‘neutralising’ antibodies
The third major research question – the orange slice: do these antibodies actually stop the occurrence of clinical cases of infection?
To address this, phase 3’ studies of all 3 vaccines recruited large numbers of volunteers who entered randomised trials
It was the success of these ‘phase 3’ studies at the end of last year that has led to the starting of the worldwide vaccination programme
Phase 3 studies did not look at the protection after just one dose!
At the moment we really have no data from these phase 3 studies to answer the question: “will one dose provide sufficient protection against infection?”
The reason is a simple one which is that the phase 3 studies for all these 3 vaccines only looked at a vaccination regime that required 2 vaccine doses and, further, the trials only started counting the people who had developed an infection after the second dose.
The actual numbers in each trial that were published are shown below
The AstraZeneca trial, with their wider gap could have looked at the number of cases between doses but their protocol was only designed to test the efficacy of a two dose regime
Thus in the AstraZeneca data available to me, I cannot find any analysis of protection that may have occurred in the interval between the doses
Thus, none of the major trials that collected data can answer the question on how far any of the vaccines can prevent new cases with just one dose
This does not mean that one dose cannot prevent cases occurring we just do not know how large this reduction might be
Note to readers, you might just want to go to my conclusions at the end of this post-that’s fine: I use the detailed dissection of the antibody data below to justify these conclusions
Thus, the basis why those advising the UK government and others believe that there may be a reasonable level of protection after the first dose is likely to be based just on the laboratory antibody, and especially the neutralising antibody, data (the ‘yellow and grey slices’ of my pyramid). These data are discussed below.
Antibody levels after one and two doses of the AstraZeneca Vaccine
Last summer AstraZeneca recruited
100 people aged 18-55
120 people aged 56-69
200 people aged over 70
The volunteers in the two older age groups were then divided into two groups: half who received just one dose of the vaccine and half who received two doses.
In this study all those who received a second dose did this after a 28 day interval
Antibody levels were measured in everyone after 28, 42 and 56 days (4, 6 and 8 weeks)
This is what they found:
The amount of antibody response is shown on the vertical axis (on a log scale)
The first and important finding is that antibody levels rose rapidly by 28 days in people in all 3 age groups
In the two older groups, who only had one dose of vaccine, (the orange and purple dashed lines), the antibody levels broadly remained level over the next 28 days
In all age groups that had two doses of vaccine, the levels of antibody continued to rise to reach a peak after 42 days and levelled off after
As mentioned above antibodies themselves may not be protective and in a separate analysis the levels of neutralising antibodies were examined and this is what they found (same key for age group):
In this case again, there was a rise in neutralising antibodies after the first dose in all age groups.
In those who only had one dose of the vaccine (the dashed lines again) the levels did fall between 28 and 56 days
In those who had a second dose the levels rose to a peak by 42 days and then had dropped slowly by 56 days
To repeat, we do not know though from this type of research at what level of neutralising antibody is needed to protect against infection
Antibody protection after one dose of Pfizer and Moderna Vaccines
I just provide the brief summary of my findings from two articles in the prestigious new England Journal or Medicine
The Pfizer study focused on looking at the immune response after two doses of vaccine 21 days apart
In that study the maximal level of neutralising antibody levels were found 2 weeks after the second dose of the vaccine
In their study levels of neutralising antibodies were low after 21 days before the second dose was administered
This Moderna vaccine study examined the antibody response in volunteers who had two vaccine doses 28 days apart
The Moderna vaccine is the identical type (RNA) to the Pfizer vaccine
In this study neutralising antibodies were much higher after the second dose which the authors argue “support the need for a two-dose schedule”
Conclusions
No authority in the West is suggesting that any of the vaccines should be given as a single dose, the issue is what is the protection in the time between doses
All the 3 vaccines now licensed in Western countries will produce some protective neutralising antibodies after one dose
The level of neutralising antibodies though is greater after two doses, and without a second dose may wane
In my previous post on the AstraZeneca vaccine* I had shown that a gap of 12 weeks may be optimal to achieve maximal clinical benefit.
These new data do not contradict that observation as the second dose after a long gap of 12 weeks may tickle up the immune system more efficiently
What remains unknown is whether whilst waiting for a second dose for any of the vaccines there is sufficient protection from a single dose
Given that, I would happily accept an offer to have my first dose of any of the vaccines tomorrow, but I would consider myself unprotected until I had the second dose
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The UK now tops the global league table of both new cases and new deaths from Covid-19. An in-depth regional analysis from within the UK, in research made available yesterday, has shone a light on the impact of the new variant on the spread of the infection. These new data show why more stringent measures may be needed to control the pandemic with this new strain: which has now spread worldwide.
UK’s sad position
Global league tables need to be interpreted with caution and countries vary in how they capture and record new cases from Covid-19
The more testing there is and the more assiduous the follow up of contacts, the greater the number of cases identified
However, it seems very compelling that the UK in the past few days has recorded a higher rate of new cases of Covid-19 than any other country for which I can find data
The UK similarly leads the global ranking in the average number of deaths (per million) over the past few days
Again, the definition of what counts as a Covid-19 death varies and the recent holiday period means that national data records are subject to some delays
Recap about the new strain
Although first identified in November, it probably emerged first in September 2020 in the South East of England
There are a large number of genetic differences between this new strain and all previous strains
The major difference with this strain is that it changes the properties of the spike protein of the virus, allowing the virus to enter human cells more easily and multiply itself
It is thus more likely to be transmitted from one person to another
As a result of these properties it has become the dominant strain in much of England
It has now been identified in 32 other countries:
Imperial College Report
A research report was published yesterday from Imperial College analysing the data accrued from the detailed genetic testing of 50000 virus samples in England
With this data the research was able to chart the growth of the variant and how it has contributed to the recent surge of cases in the UK
How quickly has this variant become the dominant strain?
As reported widely in the press both in UK and overseas, the new variant is spreading very rapidly
The Imperial College report now estimated that across the whole of England the R number is:
1.45 for the new variant
0.92 for the old variant
The research also estimates that the doubling time (ie how long does it take for the number of cases to double) could be as short as 3.7 days
Further analyses showed there was no evidence that this new variant has a shorter incubation period. ie it is not more transmissible because people get ill quicker
There was an effect of age with proportionately more younger people testing positive with the new variant – although this was only part of the story – but the differences were modest
The key finding is the in-depth analysis by region
Below I reproduce the figures from the Imperial report for the 3 most affected regions
The different colours show the increasing proportion of cases in these 3 regions
Green dots are London
Brown dots are Eastern counties
Blue dots are South Eastern counties
*for the mathematically inclined the numbers on the vertical axis are expressed as logs!
The patterns of dots all show the exponential rise in this variant as a proportion of all cases in these regions
This was not the cases in all regions (up to now)
Indeed, during this 7-week period some regions of England showed substantial decreases
Before the new variant was identified, these differences between regions in their time trends were difficult to explain
The Government progressively introduced stricter lockdown rules which had been successful in some areas but not others
This now seems to be related to the emergence of the new strain
However, the proportion of cases due to the new variant is increasing in all in the different regions of England but the regional analysis has important policy implications
A tale of 2 regions:
I will illustrate the point by focusing on 2 very different parts of England
(1.) Humberside.
Humberside is in the Northeast of England
This is a graph plotting the number of cases in that region between weeks 44 and 50 of the year 2020
The thick line on the graph shows how the number of cases declined in the last couple of months from around 6000 per week to over 2000 now
Most cases had not been tested for whether they were new variant or not
In those that were tested, almost all cases (thin turquoise line-labelled ‘S+’) were the ‘old’ variant. There were no cases with the new variant (thin orange line-labelled ‘S-‘)
The two red vertical lines indicate the timing of changes in government policy to a more stringent lockdown
Lockdown restrictions have brought down the number of cases substantially in a very short time period in a region with no new variant viruses
(2.) Kent
Kent is in the Southeast of England
Here we see a very different picture
Cases (the thick line*) grew from just over 2500 to around 8000 per week
Because of the interest in this region, more cases were tested for the new variant
Most of the cases tested were due to the new variant (thin orange line) which parallels the trend in all cases
Very few of the new cases were due to the ‘old variant’ (thin turquoise line)
New cases grew substantially despite the increasing lockdown restrictions, which had no effect on the incidence of new variant Covid-19
*This line varies in colour to show how the orange is taking over from the turquoise
Conclusion
The first conclusion is that this new variant has the capacity to spread very quickly and become the dominant strain
Its emergence in so many other countries has to be a cause for concern
Most telling is that lockdown measures that had controlled the spread of the ‘old variant’ seem to be inadequate to control the spread of the new variant
The assumption has to be that only with more stringent measures than have been currently employed will bring the rates down
Just to emphasise again, there is still no reason to believe that the new vaccines will not protect against this new variant
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Plus does this shed light on the AstraZeneca vaccine dose mystery?
Today Astra Zeneca had their vaccine approved for use by the UK regulator, with the suggestion that their vaccine would be more successful if the second dose was given after a longer interval.
By contrast, in an unexpected intervention before Christmas, Tony Blair argued for the priority of giving more people a single dose of the available vaccines: a suggestion that received support from some scientists but was dismissed by others.
What do we know about whether one or two doses and, if the latter, what should be the interval?
The AstraZeneca dose mystery
The overall success rate for the AstraZeneca vaccine was 70% – lower than the 90+% achieved with the other two licensed vaccines (Pfizer and Moderna)
Readers will though probably recall the unexplained finding in the group of around 25% of participants from the trial who – unplanned – received only half the expected amount of vaccine in their first dose
That group had a 90% reduction in the number of cases of infection
In the remaining group – 75% of the participants – the reduction was only around 60%.
This difference did not make sense to many experts
Newly reported data might now give an explanation, which I discuss later in this post
Science behind 2 doses for any vaccine
The aim of any viral vaccine is to give the body’s immune system a memory so it will respond with antibodies when faced with the ‘real’ virus
One measure of how the body will respond to the real virus is to measure the antibody response following a dose of a vaccine
In animals and in humans the size of the response is increased by the number of doses of vaccine: more than 3 doses probably though has no further benefit
There is however a minimum period between doses to allow the body’s response to develop fully, too short a gap and maximum effect is not achieved
Mathematically for influenza at least, it has been shown that if a sufficient response can be achieved after one dose, then despite a two–dose regime being more effective, the one-dose approach may achieve a greater benefit in terms of herd immunity
What is the recommendation for other viral vaccines in adults?
In the table below, I list the current recommendation about number of doses and the intervals for some common vaccines in adults
Interesting to note that for some vaccines there is still a debate as to how many doses are needed
The recommendations focus on the minimum gap and this is relevant: too short an interval and full protection is not achieved, but within reasonable limits a longer delay than the minimum is not a problem
Is there any evidence in Covid-19 vaccines that one dose is sufficient?
The Pfizer and AstraZeneca trials only collected new cases that were diagnosed one week after the second dose
The only trial with data on the effectiveness from a single dose is from Moderna
In their trial a small number of only around 2000 participants just had a single injection (half were given active vaccine, half placebo)
Moderna were able then to compare the infection rates between these groups
In that ‘mini’ trial a single dose of vaccine was 80 to 90% effective, but the numbers were too small for this to be more than a rough estimate
We need more data, but Johnson and Johnson have a vaccine very similar to the AstraZeneca vaccine and have completed recruitment to a trial of just a single dose
Their results will be emerging at the end of January
What are the current recommendations for the licensed vaccines?
The current recommendations for the interval between doses as of 30th December are listed below
The FDA has chosen the intervals between doses based on those that were actually used in the two trials – Pfizer and Moderna – at 3 and 4 weeks respectively and have suggested that these are the gaps that should be used.
That makes sense as both vaccines had over 90% success with those intervals so there is no reason to suggest a longer interval.
The shorter the interval (above that minimum), the quicker immunity is achieved
MHRA reported today on the AstraZeneca data and although they approved a minimum interval of 4 weeks they suggested a 12-week interval
MHRA looked at the data from those who received the full amount of vaccine at each dose
The results of clinical trials conducted by AZ that produced these data come from studies in different populations, including the UK, Brazil and South Africa.
For a variety of logistic reasons, the gap between doses varied considerably in the trial volunteers
The interval ranged from 4 – 10 weeks and was higher (typically 7-9 weeks) in the UK volunteers compared to the Brazilian participants (typically 4-8 weeks)
MHRA looked at the impact of the delay on the effectiveness of the vaccine, these data are not yet publicly available, but concluded that the longer delay the more effective the vaccine
Indeed, reports suggest that in those with a 12 week interval, the AstraZeneca vaccine provides an 80% success
Further it is suggested that the previously reported greater effectiveness in those who had the lower amount of vaccine first time round might be explained by their longer time interval (typically 11-13 weeks)
How do I put this all together!
OK it’s all a bit confusing but this is my take:
If a single dose was effective enough then given the logistics and costs of distributing vaccines, then there might be an arguable case for just using a single dose which would double the number of people vaccinated
The data supporting such a strategy come only from the very small number in the Moderna trial and we need to wait and see if they are supported by the results of the Johnson and Johnson trial
In general, most vaccines require two doses but we should perhaps keep an open mind on this
The AstraZeneca results however argue not only for two doses but that there is a necessary longer minimum interval
There will be arguments, I am sure, about MHRA’s interpretation of the AstraZeneca results and their conclusion about 80% effectiveness
It is however plausible that it was the longer gap between doses that explained the greater benefit in those who only had half the vaccine in their first dose
Both individuals and society are keen to achieve maximum protection as rapidly as possible so a 3- month gap for the AstraZeneca vaccine might seem to be a disadvantage compared with the other vaccines
However, given the substantially lower cost and the easier logistics, the AstraZeneca vaccine can have a major part to play in the worldwide battle against Covid-19. Interestingly since I first posted this the UK government have announced a 12 week gap for the Pfizer vaccine, even for those who have had their first dose!
Of course, on current data, protection is only assured after the second dose
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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!
Mutation – a change in one of the genes of the virus as it multiplies
Variant – as a consequence of one or more mutations, a different version of the virus appears with slightly different genes from the initial version
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
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
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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An effective drug that could treat a person once infected with Covid-19 and prevent the potential serious consequences would clearly dramatically reduce the impact of the pandemic. Indeed, if there was a very effective and very safe drug, we wouldn’t need to worry about a new vaccine! It is also reasonable to ask that as new vaccines have been developed within 12 months from start to finish, can we be similarly optimistic about new treatments?
Do we actually need a new drug?
As the Christmas panto season happens (or not this year!), what does the story of Aladdin tell us about prospects of new drugs for Covid-19?
At the beginning of the pandemic there was an important question to be asked about treating Covid-19: “Can any drugs already licensed for treating other viral infection or indeed other diseases, be successful against Covid-19?”
In technical terms – can we repurpose existing drugs rather than the much longer and risker process of developing new drugs?
In this post, I review where we are up to in repurposing and point out the challenges in starting to develop completely new drugs.
What do we want an antiviral drug to do for Covid-19?
There are two ways any antiviral drug might work- by preventing
the virus multiplying once it enters a human cell
the damage after the virus has multiplied resulting in part as a consequence of the body’s defence mechanisms
As the second of these is common to a whole range of infections (and indeed immune diseases like rheumatoid arthritis), repurposing a range of existing drugs was worthwhile trying in Covid-19
The best example of this was the trial of the steroid dexamethasone, which has significantly cut the death rate of seriously ill Covid-19 patients
The rest of this post will focus on specific antiviral drugs to stop the virus multiplying.
These could then be given to people in the community at the first signs of infection
How likely is it that there are such existing drugs that could do this for Covid-19?
What examples are there of drugs that stop other viruses multiplying?
The best example is in HIV/AIDS. Indeed, the so called anti-retroviral treatments are the mainstay of AIDS management (there is no vaccine for this infection) and have dramatically improved the outcome
Actually, there are around 24 drugs that stop the HIV virus multiplying
There need to be so many as patients get resistant to individual drugs and combinations of different agents work better than single drugs
You may remember during the Swine Flu H1N1 epidemic there was much enthusiasm for the antiviral drugs Tamiflu and Relenza that we’re widely prescribed in primary care
In truth the infection turned out to be not as serious as was feared
The only difference was a modest reduction in the number of days people felt ill for and indeed recent analyses have suggested they weren’t that effective
This all suggests that antiviral drugs make sense as a concept but there was no evidence that drugs which worked for one virus would necessarily work for other viruses
What about using existing antiviral drugs for Covid-19?
Lots of have been tried!
There are a vast number of trials investigating a whole range of existing antiviral drugs for Covid-19
I searched the available databases yesterday and found this!
The only drug thus far with any positive data is remdesivir
There was initial enthusiasm for this drug as a specific antiviral agent for Covid-19 19
It had been developed for use against other corona viruses eg SARS
Some data suggested it could make a modest difference to how long people had symptoms
The USA was very enthusiastic and, looking after their own interests, went out shopping!
Although there have been many trials, the most recent data suggest the benefit from remdesivir is minor and it is not a candidate for widespread use
How easy will it be to develop a new drug from scratch?
It is simplest to divide up the process into stages:
The early laboratory work for identifying a possible drug
There is a considerable drop out at each stage (one estimate is that only 0.5-1% of all drugs tested in animals end up being marketed for human use)
The full process takes on average 10-15 years
What it costs is obviously variable, but a reasonable average for recently licensed drugs is between $1-2bn
Developing drugs is a risky business!
What are the risks?
There are clinical and commercial risks. I have put these in a reasonably sensible order, but for example evidence of harm can emerge at any stage, which would at that point stop the drug being developed further or sold
Drug doesn’t work
Drug works but proves to be harmful
Early investors lose confidence and development stops
Drug works but gets overtaken by better/cheaper drugs
Technical problems in production etc
Disease stops being a problem so sales plummet
Who takes the risk?
Conventionally this has been the big pharmaceutical companies
However much more common these days is for ‘big pharma’ to enter into the process some way down the line and pay a reasonable premium for a license to develop a drug further
After university researchers have shown there may be a promising future for something they have discovered
When a small biotech company, perhaps set up by a university specifically to further develop their discovery, has shown benefit in animal testing
To get to the stage, individual researchers, universities and small companies may seek external speculative investors or use their own funds (including researchers remortgaging their own homes!)
Should this not be different for a global pandemic like Covid-19?
It has been easy getting billions for vaccine development
By contrast, governments and other organisations have only funded $millions (not billions) into research for new drug treatments
There has to be some shared risk/reward for companies to make the size of investment that is needed
Is there any possibility of speeding up/making the development process cheaper and quicker ?
Again, the short answer is that the pace of change in drug development is staggering
Use of artificial intelligence (* see my post on protein structures) has meant that the very lengthy development stages can be reduced in time and screen thousands of potential drugs very quickly so that clinical development can focus on the most likely
The clinical testing period which has up to now been say 5-10 years can also be reduced as has been demonstrated by the speed at which vaccines have been brought to market
There is one major difference between vaccines and other drugs in that the mechanism of vaccines – to enhance the body’s production of its own antibodies – is generally known to be successful and safe
For drugs designed for new treatment, this is more speculative
It would have been great to have reached the end of this difficult year with exciting news of a successful new antiviral drug to match the success of vaccines
Of course, if the vaccines are successful and provide long term protection, then new treatments may not be needed
However, we should be reassured that such development is happening (albeit more slowly) but also could make us better able to cope with the next viral pandemic
And finally!
This will be my last post this year. Thanks for all the positive comments and the interest across so may countries. Hopefully our governments will be better able or willing to ‘follow the science’ in 2021!
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Earlier this evening the UK Health Secretary Matt Hancock announced that a new genetic variant of the Covid-19 virus could be responsible for the large upswing of cases in the South East of the UK. What does this mean and should we be worried?
(Later this evening, following the first posting of this blog, there has been more information released about this variant and hence this post has been updated)
What do we know about this new mutation in the Covid-19 virus?
Readers of his blog may remember I covered the background to Covid-19 mutations in October.
The UK has been taking an international lead (as far as I can tell) in monitoring for the appearance of different strains of the virus, by a detailed analysis of their genetic code via The CoVid-19 Genomics UK Consortium (COG-UK)
COG-UK followed up the minister’s announcement with some more detail
Is it unusual for new strains to appear?
Not at all, the development of new strains of a virus is a natural process especially during an epidemic as protracted as this
2. Is it usual for such changes to take over and become the predominant strain in an area?
Yes, this is not unusual.
One theory is that the virus mutates as it multiplies in our bodies and one of the changes could make it easier for the virus to multiply
If this was the case, then this new mutation is the one that is more likely to be transmitted and could rapidly become the predominant strain
3. Could the emergence of a new strain be the explanation of the increasing number of cases?
This does seem to be a reasonable hypothesis based on what I said above.
The new strain of the virus might be present in such large numbers of new cases because it is better able to transmit infection.
I might therefore expect ‘R’ to be higher with this new strain
4. Does this mean the new strain will be more dangerous?
Not at all.
There are plenty of examples from coronaviruses in other species where a new strain can cause less severe disease, although there are examples where it can be more serious.
Most expert virologists believe that there is no connection between how good a virus is at spreading to how severe the infection is.
So, the individual risk of severe infection is not altered but the numbers who become ill could rise
5. Will this affect the success of vaccines?
Again, expert opinion is on balance probably not
As readers will know, vaccines are directed against the spike protein of the virus.
There are over 4000 mutations previously described in the spike protein
The variant announced late this evening does contains several mutations including one in the spike protein
This particular strain (N501Y) though also affects a critical part of the spike protein- the part that allows it to lock onto human cells
Other previously defined mutations in the spike protein are not thought to affect vaccines’ success.
Thus, despite the fact that this new variant contains such a mutation, antibodies produced in response to the vaccines hopefully should still neutralise the virus.
For the moment therefore it is reasonable to assume that the current vaccines will still work but this will be under test
6. Could this increase the chances of someone getting a second infection?
The reassuring thing about Covid-19 is that since the pandemic started, and there have been very large numbers of mutations reported, the numbers of people who have had a second, new infection with a different strain remain small.
But we cannot know for sure that the previous infections will confer immunity against this new strain or indeed any future mutation.
We know for example that with seasonal flu there is limited overlap in immunity between annual strains
7. Is there any good news from this?
The good news is that we have the surveillance in place with this highly sophisticated genetic analysis that has allowed this strain to be detected.
Using this information scientists might get data-driven answers to the questions above as opposed to opinions!
Conclusions
Genuinely I am not personally worried unless there is evidence that vaccine success may be influenced
My answers to (2) and (3) above do offer an explanation to why we are seeing such an increase in the UK (and might also be the case in other countries of course)
The case for continuing to be vigilant and practice Covid-19 safe behaviours is reinforced
The quicker we can get roll out of a population-wide vaccination programme to stop transmission, the less the opportunity for the virus to be around to mutate
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