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‘Mixing and matching’

Is the UK confounding the experts?

4th January 2021:

For the second time within a month, the UK has been criticised by US scientists over their handling of vaccines against the Covid-19 virus. In early December, it was rebuke at the speed with which the Pfizer-BioNTech vaccine had been approved by the UK Medicines Regulatory Authority (MHRA) – although an unconvincing apology ensued the following day. On New Year’s Day, the New York Times1featured an article in which several US scientists were openly opposed to decisions made by the UK government’s advisory body, the Joint Committee on Vaccines and Immunisation (JCVI) to delay second (booster) doses, immunise more people and allow different vaccines to be used for the first and second (booster) dose.

It all comes at a time of crisis due to uncontrolled spread of the Covid-19 virus in the UK. This weekend saw the highest daily number of new cases since the beginning of the epidemic.  The recent surge in cases is a multifactorial phenomenon but – as I described a few days ago – a major factor is that a more contagious variant of the virus is circulating throughout the British Isles. At least in the short to medium term, immunisation is the only public health intervention that can substantially lessen the impact of this epidemic. Neither ‘testing and tracing’ or closing-down the country’s activities in the middle of winter – with all its detrimental consequences – have been able to stem the surge of new cases2. It’s therefore critical to deploy vaccines as efficiently as possible.

Graph showing daily cases in UK2

There are scientific reasons why it makes sense to adjust recommendations on key issues – such as booster doses, the mixing and matching of different vaccines – according to changed circumstances.  There are hardly valid grounds to support the allegation of US public health experts that: ‘………the British have abandoned science completely now and are just trying to guess their way out of a mess’.  Indeed, I would argue that the opposite is the case. The Joint Committee on Vaccines and Immunisation (JCVI) has used scientific analysis to resolve how best to implement the existing available vaccines to deliver the optimal outcome. Which brings us to a central question. How to judge what is best for the health of the nation? There is nothing new in this question, although Covid-19 has brought a compelling resonance to it. The answer is somewhat prosaic. The UK has a National Health Service and, given limited resources, a central mantra of its operation is based on cost-effectiveness. In stark terms, the economic evaluation of the costs and effects of different health interventions. It is measured in health outcomes; for example, what is the cost of preventing a death or a hospital admission from Covid-19 and, given a set of alternatives, which gives the best outcome for the money invested?  

Given this rationale, the JCVI is adhering to the principles of their parent advisory body, the National Institute of Clinical Excellence (NICE) that, over decades, has served our National Health Service well.   Recommendations on medical interventions are advisory, not executive, but we abandon them at our peril. This is not to deny that there are pros and cons to the two major JCVI recommendations: (1) delaying (not cancelling) the second or booster vaccine jabs; (2) allowing different vaccines to be used for the first and second (booster) dose.

There are counter arguments to delaying the second booster dose (close to a million persons have currently received the Pfizer-BioNTech vaccine). It is logistically complicated because this change must be communicated by the heath professional responsible for giving the immunisations.  It will be time-consuming and demanding of resources. Many of those who expected to be recalled have already made arrangements that must now be cancelled. Ethically, it can be argued that they have been denied a vaccine to which they are entitled (these were the terms under which they agreed to be immunised). Finally, protection afforded by two doses is better than just one. The debate is whether these arguments outweigh the JCVI recommendations to protect more people thereby potentially reducing hospital admissions, deaths and disabilities (including long Covid).  It is also likely (but not certain) that reduction of person to person spread of the virus will be decreased in proportion to the number of persons immunised. There is a biological rationale to giving a booster with a commercially different vaccine in the exceptional circumstance that further doses of the original vaccine are not available or there is no record of which vaccine was given as the primary immunisation. Both stimulate an immune response to the Covid-19 spike protein, but no trials have been performed to test the validity of reciprocity (‘mixing and matching’) of vaccines from different manufacturers.

I think the JCVI has made a correct and courageous decision. It’s the responsibility of scientists to use existing data (while recognising the shortcomings) to assess what we know and to recommend action that has the best public health outcome. There is not likely to be a one-size fits all directive (anyway, it is for governments to formulate policy), so discrepancies on global recommendations and policy may be divergent depending on temporal and geographical variables.

To summarise: immunising more people is undeniably cost-effective. Delaying (not cancelling) the booster has only a marginal downside. Giving a different vaccine to that used for the first dose, providing it is based on inducing a response to the ‘spike protein’, may be beneficial, but we do not know this. In what are expected to be exceptional circumstances, it is important that there is formal evaluation of outcome in all instances of ‘mixing and matching’ (including adverse events). Individual heath providers have discretion as to whether or not to they follow the JCVI’s recommendation.

If we have learned anything from this pandemic, it’s that the best science does not deliver certainties. Absolutes or statements that include words such as ‘never’ are anathema to the modus operandi of science. Debate, rigorous argument and diversity of scientific disciplines forge a pathway that progresses knowledge. Science increases our probability of making good decisions. In contrast, ‘ex cathedra’ statements from the US Chief Scientific Adviser and other US scientists are neither wise, nor helpful. It might be added that the US does not have a National Health Service.  Delivery of medical care is inequitable, biased to benefit those who are wealthy, rather than those in need.  

  1. https://www.nytimes.com/2021/01/01/health/coronavirus-vaccines-britain.html#click=https://t.co/93quRhYrlr
  2. www.https://coronavirus.data.gov.uk/ (04/01/2020)

Copyright Richard Moxon 03.01.2021

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59 thoughts on “Blog

  1. Hi Richard,
    I wondered if you might help me with a specific question & dilemma. I am very keen to receive the vaccine, and as a healthcare worker I am lucky enough to have access to it through my work. However, I am in my late 30’s and hope to try for a baby later this year. PHE advise “If you are planning to get pregnant in the next 3 mths, you should delay your vaccination”. I am aware that many leading scientists have said it is highly unlikely that the vaccine will have any impact on fertility (for both men & women), but I’d really appreciate your thoughts on this matter. Obviously we don’t yet have any longitudinal data on this possible side effect.
    Many thanks.

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  2. Thank you very much Richard for helping non-scientists like me to understand what this is all about. I am rather worried by suggestions that the South African variant may be able to evade the vaccine. Is it possible or even likely that, though the vaccine could not stop people being infected by this variant , it might stop them becoming seriously ill with it?
    Gillian Keene

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    1. To my knowledge, there is no evidence that any mutations of the virus, including those of the UK and South African variants – and there are bound to be others – either cause more serious disease or escape the currently approved vaccines. Indeed, the trend from past experience with viruses is that mutations that increase transmission are more likely to be accompanied by a decrease in virulence. But, evolution keeps us guessing and it’s good news that scientists are very much on the case. Vigilance is the watchword. If mutations do occur that lead to ‘vaccine escape’, adjustments to the vaccines can be made although let’s hope it won’t be necessary.

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  3. Richard, should we be alarmed about the mix and match of vaccines? I refer to this NYT article from yesterday:

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  4. Does the muscle cell secrete free spike protein into the circulation or is it expressed on the cell surface?
    If on the cell surface will it not be blocked by circulating antibody reducing the effect of a booster dose?
    Does the spike protein remain on the cell so that the cell will be attacked by the T-cell inducing a local myositis?

    Liked by 1 person

    1. Following immunisation the spike protein or a fragment of it, is processed and expressed on the surface of muscle cells (HLA class 1 presentation). This engages with immune cells that trigger immune response responses – B cells (antibody), T cells.
      Antibody will not block the original antigen presentation but could be relevant to interfering with subsequent boosting as antibody could ‘recognise’ the viral (adenovirus vector) in the case of the Oxford AstraZeneca vaccine, for example.

      The last part of your question is intriguing. I think that this would depend on the number of muscle cells that are presenting the antigen (low?) and the half life of presentation (brief?).

      I failed to answer your previous question, Chris, as I was behind on deadline for my book. The outcome of treatment with monoclonal or polyclonal antibodies can only be assessed critically through appropriate trials. I agree that I cannot recall recent attempts to deal with actively replicating virus with modern techniques of making antibody ‘cocktails’. The rationale is not, I believe, to have a quantitative equivalence of antibody and virus. Rather, by reducing viral load, the host’s immunity is better able to tip the balance in favour of recovery rather than progression. For example, antibiotics do not kill all the bacteria at an infected site, but by lowering the numbers, the host’s innate and perhaps acquired immunity is able to turn the tide.

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  5. Is there. a precedent for giving antibodies (passive immunity) being effective against a proliferating pathogen? I know this can work to prevent progression of rabies but not when the brain is involved; antibodies can neutralise tetanus toxin and diphtheria toxin; may help in Ebola but SARS-Cov-2 involves an actively replicating virus in lung parenchyma.
    Has anyone done the maths of the ratio of antibody binding sites (two per molecule) and the likely number of viruses?It seems implausible that there would be enough in a convalescent plasma infusion but possible for a monoclonal preparation,

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  6. Chris Winearls:
    Given the mode of transmission – via the airways direct to the surface cells of the respiratory epithelium, how would an antibody in the blood stream prevent this invasion? I can see how specific cytotoxic T-cells would contain the infection by destroying virally infected cells expressing antigen on their surfaces but not how antibody would work. The administration of antibody contained in convalescent plasma also seem an implausible treatment for active infection but a reasonable form of post exposure passive immunisation, albeit short-lived given the half life of IgG

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    1. After giving candidate Covid-19 vaccines, the antigens make their way to the draining lymph nodes close to the injection site. From there, immune cells (including B and T cells) are activated, some of which travel to other parts of the body, including the networks of lymphatic tissues in the linings of the nose and throat. These immune cells are therefore perfectly positioned to respond when infection with Covid-19 virus occurs. In addition, in many mucosal sites, such as the nose and throat, immune substances in the blood (including antibodies) can leak across small blood vessels that supply the linings of the airways and access the virus. Nonetheless, right now we do not know whether Covid-19 vaccines will protect through these and other mechanisms. That is why trials are urgently needed.

      Convalescent plasma is a form of treatment for Covid-19 that is currently being evaluated in clinical trials. The rationale is that infusions of immune substances, including antibodies, may limit the spread of viruses that are released from infected (dead or live) cells and reduce the severity of the infection. There are precedents for this. Infusions of this kind have been successful in treating or preventing rabies, hepatitis or varicella-zoster viruses. You are correct that they are a short-term fix, but the immune substances remain effective for many days and even several weeks before they wane.

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    1. Person to person spread of measles occurs very efficiently and more than 90% uptake of vaccine is needed to achieve and maintain herd immunity. Herd (or community) immunity occurs when the spread of disease from person to person is unlikely, because most people are not susceptible either through immunisation or exposure to natural infection. However, it doesn’t take much of a decrease in the proportion of people who are immune before there are enough susceptible individuals for outbreaks of measles to occur. Indeed, there will always be some children who cannot be vaccinated for medical reasons. In addition, some refuse immunisation because of mistrust, misinformation (often through social media) or for religious reasons.

      But, there’s more to the story. Recently, measles cases have surged across Europe and the US in the past two years. In Europe, 90,000 cases of measles were reported in the first 6 months of 2019. A major global survey conducted by the Wellcome Trust helps shed light on what’s going on. Researchers asked 140,000 people ages 15 and older in more than 140 countries about their views on religion, science, and health, including their attitudes toward vaccines. People in higher-income European countries were less confident in the benefits and safety of vaccines compared to poorer countries in Asia and Africa where high rates of deaths and disabilities from measles were common. The more distant is the memory of diseases like measles, polio, diphtheria and whooping cough, the more likely they are to shun vaccines. We can ill afford this hubris. Measles often results in complications that include pneumonia and encephalitis (inflammation of the brain) leading to permanent brain damage. Measles also damages the immune system’s memory (“immune amnesia”) for months or even years following infection, leaving survivors vulnerable to other potentially deadly diseases.

      To achieve measles eradication, the strategy must be global given that the disease is highly contagious and international travel results in frequent importation of infections. All the social, economic and political pieces of a complex jigsaw need to be in place. Unlike smallpox where spread occurs largely through those obviously ill and shedding virus from blisters and pustules, measles spreads very efficiently from the respiratory tract for several days before the tell-tale rash develops, making eradication a much harder challenge.

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  7. Could you summarise the evidence on susceptibilty to COVID -19 infection and prognosis in BAME subjects as compared to white British and white US subjects? Incidence and prognosis seem to be worse but is this an association explained by socio-economic and co-morbidity factors or is there a a biological/genetic explanation?

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  8. From Gus Maffry:
    With over 40,000 covid deaths recorded so far and climbing, why are UK authorities cutting back on contact restrictions for the public rather than maintaining or extending them?

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    1. The obvious response is that the main driver behind the UK government’s present policy on how to manage the Covid-19 epidemic in the UK is the economy. There comes a point when the balance between the benefits of ‘restrictions’ are outweighed by the downsides. But, drawing up the balance sheet, the risk assessment exercise, lacks a secure evidence base. So, engulfed in uncertainties, the UK government is gambling. Rates of new infections in the UK are decreasing but more slowly than anyone would like. Currently, each infected person on average passes on the virus to less than 1 person, so if this continues, the epidemic will eventually peter out. But, of course, the current change in policy may change the epidemiology. In particular, the measures to test, track and quarantine are not adequately established in the UK. To me, this is the most worrying aspect. The inadequacy of this essential public health infrastructure may prove the decisive factor in whether there is a terrible sting in the tail, especially as summer recedes and we face the increased risks of the coming winter season.

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  9. This blog encourages curiosity and discussion. I often receive personal emails withheld from the blog because of fears that the question will seem ignorant or even stupid. I assure you that there is no such thing as a stupid question, only a question that is not asked. These are often just the kind of questions that help me to understand what information people are seeking. Please post these queries; doubtless other people will be wondering the same things.

    Liked by 1 person

  10. From Tracey Evans Gilbert
    I recently read that funds are being secured for GAVI to ensure the vaccination of children against COVID 19. Why the least susceptible group? The studies suggest children are least to likely to transmit to others or become ill.

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    1. Response: I think this must refer to the Global Vaccine Summit held in Geneva on June 4. 2020. The major aim was to raise US$ 7.4 billion to protect an estimated 300 million children in lower income countries against common, vaccine preventable infections such as diphtheria, measles and polio. It is not to support immunisation of children against COVID-19. As you rightly point out, this would be targeting an age group that is least susceptible and not the major source of transmission of COVID-19. Rather as the WHO Director General, Dr. Tedros Adhanom stated:”Disruption to immunisation programmes because of the COVID-19 pandemic threatens to unwind decades of progress against vaccine preventable diseases ”.

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  11. Richard, ref my text a month ago sent on the “wrong” channel 🙂 on the paper in the Virology Journal Aug 2005 on the effect of chloroquine on the viral load of the SARS coronavirus (“Chloroquine is a potent inhibitor of SARS coronavirus infection and spread” by 2 teams of scientists from the US and Canada). Why wouldn’t the same treatment have similar effects on another coronavirus, the Covid-19 especially since in your last blog you indicate “SARS, a virus very closely related to Covid-19”?
    The plot thickens if I may say when we see how the Lancet discredited itself with the publication of a BS big data study against the hydroxychloroquine/azythromycine approach. Why did that happen I do not understand.
    It seems that when taken in due time (important apparently!) the treatment is followed by good clinical results, consistent with what could be expected from the article cited above. But then Oxford is not Marseilles I guess, or could it be that the procedure used here and there were not precisely the same? All very disturbing I find and a subject that seems to have somewhat escaped science long ago, but to where is a mystery.
    If taken in due time that treatment does indeed have an impact on Covid-19’s viral load, it is clearly not ideal and not a vaccine. However -and this is my third question/remark- if we accept that we do not deal with things in time of war the same way as we deal with them in time of peace, then evidence based medicine should be complemented by other approaches in times of pandemic when people are dying, so as to “bridge the gap” to when the vaccine is ready. Its really not like if we need to create yet another dichotomy here (there are already far too many these days!).
    Dan

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    1. The article in 2005 found that hydroxychloroquine prevented the spread of SARS-CoV in cell culture. It was not a paper about treatment of people. There is a world of difference.

      The Lancet paper on hydroxychloroquine treatment of Covid-19 was retracted when it was found that one of the co-authors was the founder of Surgisphere, the provider of a corporate health care analytical platform whose data sets were, on investigation, found to be unreliable. Surgisphere declined to cooperate citing data protection and confidentiality agreements. An embarassing and shocking incident.

      Although there have been published results of beneficial effects of hydroxychloroquine treatment of Covid-19 infections, the evidence has been disputed. Indeed, no investigation to date has been free of potential bias, including the Oxford study I cited. Decisions on whether or not to use hydroxychloroquine to treat Covid-19 (or even to prevent it) do depend on interpretation of the existing imperfect evidence base. In my opinion, the balance of this evidence does not support its use and hydroxychloroquine treatment has documented adverse effects, including serious effects on the heart (arrhythmias).

      It is certainly true that this pandemic has left insufficient time to carry out the kinds of investigations that would provide the compelling data that we would all like to have. Making decisions (risk assessment) on incomplete information is unfortunately an all too familiar experience of real life. Scientific evidence remains our most reliable guide to making decisions – whether in war or in peace. We abandon it at our peril. Unfortunately, the very essence of science is disagreement, debate, challenging ideas and seeking truth – although so often it is ‘through a glass darkly’.

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  12. Hydroxychloroquine: Can we conclude that HC is not an effective treatment for subjects with established Covid-19 infection; has not been shown to prevent disease in subjects definitely exposed to the virus; but need to be tested as a prophylactic agent in subjects likely to be exposed.? So by analogy with malaria it might be worth taking if the subject is obliged to be in an at risk environment where aerosols described above are circulating e.g. public transport?

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    1. Thank you for this. Just to make the current information on hydroxychloroquine clear, a recent randomised trial of this drug to treat Covid-19 infection carried out in Oxford enrolled 1542 patients who were treated with hydroxychloroquine and compared the outcome with 3132 patients randomised to usual care alone. There was no statistical difference in the primary endpoint of 28-day mortality (26% hydroxychloroquine vs. 24% comparison group) There was also no evidence of beneficial effects on hospital stay duration or other outcomes.

      As you rightly point out, this does not rule out a possible benefit of chloroquine in preventing infection in healthy people who might be exposed to the virus. However, I think to draw an analogy with chloroquine in preventing malaria and its utility for preventing Covid-19 is not a level playing field. Chloroquine is highly effective in treating malaria as well as preventing it.

      We now have very strong evidence that chloroquine is NOT effective in treating Covid-19 infection. The plausibility that it might prevent Covid-19 is therefore much less likely. It is not ruled out, but I suspect there will not be great enthusiasm to do a randomised trial to vindicate President Trump’s decision to self-medicate. I would urge everyone NOT to use chloroquine for warding off (prophylaxis) Covid-19 infection unless and until there is compelling evidence to the contrary.

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  13. Response to Jane Mitchel’s enquiry about the possibility of COVID emerging earlier than announced.

    This is an interesting observation. I am learning not to be surprised by anything when it comes to Covid-19! The evidence at present does not provide support for circulation of the pandemic virus strain in the UK as early as October 2019. However, absence of evidence is not the same as ruling out such a possibility. Indeed, there have been some completely unverified suggestions that the outbreak in Wuhan started earlier than has been stated. But this has not yet been confirmed by direct evidence.

    Many other viruses or possibly even bacteria may have been responsible for the very nasty infections you describe. Incidentally, it’s really important to understand that antibiotics do not fight off viruses of any kind. Giving antibiotics to fight virus infections merely increases the likelihood of resistance. Antibiotic resistance is one of the most important threats to public health (according to WHO it’s currently classified as a Global Emergency). Meantime, I’ll stay alert to the idea that evidence MAY emerge to indicate earlier presence of the virus in the UK than is currently thought to be the case.

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  14. A game theorist colleague, Peyton Young of Oxford University and London School of Economics comments: ‘Game theory Is indeed relevant and there are many interesting game theoretic aspects to the situation. For example, if A identifies friend B as a contact, she knows that B will be placed in quarantine. This is a hardship for B, so A may be reluctant to inform the authorities about her contacts in the first place.’

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  15. In a conversation with a colleague over Blog 5 (09.05.20 The Covid-19 infection ratio Ro), I was asked whether it was actually important to distinguish between the infection ratio Ro and the infection rate. My response is in a Box (See additional material in Archive). Given the lack of precision of broadcasters and politicians over the “R number”, it’s no surprise to me that many people are confused.

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    1. The game theory analogy is brilliant. I think people’s willingness to cooperate also hinges on trust in government. Both the US and the UK have done poorly with managing the pandemic and trust in government is low in both (far worse in the US) and lower than in the countries that have managed it well. Trust in government likely reduces the perceived risk of cooperating in the prisoner’s dilemma.
      Great blog!

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  16. Richard yes: a tsunami of sighs.
    As to more information ,do you know why the UK seems to be one of only two countries which does not,( cannot?), supply data on recovered cases?Not to do so tends to produce a distorted impression of the actual caseload.

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  17. Challenge Trials of Vaccine,

    Is a placebo group planned? How many subjects would need to be in the study to detect a protective effect given the reduced pathogenicity of Covid-19 in young healthy subjects? What would the end point be? Would it be symptom complex, pneumonia confirmed on imaging, duration of virus carriage?

    Pleased to read of formal trial of hydroxychloroquine. Donald Trump not eligible as he has self treated and would not have been able to understand the consent form.

    Chris Winearls

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    1. In response to Chris Winearls: the design of human challenge studies is indeed extremely challenging! First of all, to avoid potential confusion, it is important to make a very clear distinction between two quite different kinds of clinical trials of vaccines.

      In the first (going on right now in Oxford and elsewhere), human volunteers are being given the candidate Covid-19 vaccine to investigate safety, immune responses and protection. The design of the Oxford trial is to give half of the volunteers the candidate Covid19 vaccine and the other half a different vaccine (one that protects against meningitis) that would not be expected to confer any protection against Coronavirus. So, not a placebo). It’s a classic double blind, randomised trial, meaning the volunteers are assigned by a blind process to one group or the other so that neither the volunteers nor the investigators know who is getting which vaccine. This aims to mimimise biases that might affect the outcome of the trial. In Oxford, 10,000 volunteers are involved. The statisticians estimate that this will be sufficient to demonstrate protection, but I do not know the details of this calculation. After vaccination, they will be followed and closely monitored to assess any side effects, blood samples will be taken to assess immune responses and, most importantly, the volunteers will be tested to find out whether or not they come down with Covid-19 virus infection. This will allow comparison of 5000 volunteers who received the Covid-19 vaccine with those who received the meningitis vaccine. If all goes to plan, this will provide the crucial evidence on whether or not the vaccine is protective. The end point is the number of volunteers in each group that become infected with Covid-19 virus – with or without illness. Because the incidence of severe disease in healthy young adults is expected to be very low, the hope is that severe disease, including pneumonia, will not occur in any of the volunteers. I hope this addresses the issues raised.

      In the second kind of study, described in the current Blog, I discuss some issues concerning potential use of human challenge studies, including the ethical framework commented on astutely by Gus and Liz Maffry. For Covid-19, these studies involve the deliberate infection of volunteers with the virus, not natural exposure in everyday life. The design (including the possible inclusion of placebo, endpoints and other details) will involve a completely different investigational framework. No such studies have been done to date but many people are giving detailed thoughts as to how they might be carried out.

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  18. Regarding use of human subjects for vaccine testing, in making such a difficult ethical judgment, we’d suggest aiming between two extremes:

    –the recklessly dangerous, as when pioneer virologists injected hemselves with hugely dangerous pathogens, which led to some great breakthroughs, but were unacceptably risky.

    – the other extreme: take no risk and have slow or no progress.

    Where to draw the line?

    We’d explain to volunteers in exhaustive detail the best calculations of risk, including all unknowns—then, any willling volunteers would have to sign about a 100 releases from legal liability of testers..We therefore think deliberate infection is ethically acceptable in right circumstances, and recommend that committee proceed with this in mind.

    Will be interested to learn composition of said committee.

    Gus and Liz

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    1. Richard ,this is an invaluable aid to understanding.It,like its five precursors,is a model of cool profundity,penetration,concision, and pellucidity.

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    2. Richard, this is an invaluable aid to understanding,as have. been its precursors.They are a welcome model of profundity,penetration concision and pellucidity.

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  19. Richard, it looks that the rules or parameters for collecting/reporting data have not been agreed. Is the WHO the institution that should issue this directives? Can you explain how it works.
    Recently I have read and article by Dr Bill Frist in Times magazine April 27/May 4 and he suggested to create a single “National Response Portal, conveniently accessible on a single iPad dashboard.To efficiently and wisely make life-or-death decisions in emergency situations, doctors need at their fingertips complete real-time information about the virus-where it is, how to test for it immediately, the timely return of test results, which proven treatments will work, what intensive-care-unit beds are nearby, the whereabouts of ventilators, how much disease is in the neighborhood.
    This virus is evolving fast. To win, we must evolve faster and smarter.
    The portal, which would analyze public-health date, private-sector data, and mobility and traffic patterns, would also provide ongoing community monitoring that would speed the reopening of our schools and businesses as we relax social distancing- and again tighten it if COVID-19 begins to resurface. We’d know: Where is the enemy and where will it strike next?” (I hope I have copied the article correctly)
    It looks as a sensible proposal, better then the surveillance imposed to track the movements of citizens, especially when the Accuracy of Testing is not accurate, it could increase the tensions, racial attacks, recently in the UK against the Chinese and Far Eastern population.

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    1. My understanding of WHO’s role is that it is ADVISORY, not executive (or directive). It does and is expected to provide leadership in its advisory capacity. How well or badly it fulfils this role is a matter of judgement but there can be no doubt about its potential importance as a global organisation.

      On Bill Frist and his article in Time, the issues from a scientific point of view fall into two categories. 1. Pandemic preparedness, including adequate PPE, accurate testing and the utility of advanced and advancing technology; 2. The evolution of viruses, ‘smart’ behaviour (both microbial and human!). The latter should not to be confused with the dynamics of viral spread, because the ‘smart’ (adaptive) behaviour of microbes is a different issue! Both merit further discussion, so thanks for the stimulus do deal with these in future blogs! Neither are simple topics, both are important. Be patient; I am on the case! Thanks Bob.

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  20. Something to think about: According to various articles, it appears that many countries with female political or scientific leaders are more successful in managing the crisis. Some examples are Jacinda Adern in New Zealand, Angela Merkel in Germany, Mette Frederiksen in Denmark, Erna Solberg in Norway, Katrin Jacobsdottir in Iceland, Thai Ing-wen in Thailand, Shanna Marin of Finland and South Korea’s head of the centre for disease control, Jeong Eun-kyeong. It may be that women are more likely to be elected in “a political culture in which there’s relative support and trust in the government “ and/or it may be attributed to women’s calm & determination, clarity and willingness to trust the experts.

    See: https://www.msn.com>en-GB>News

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    1. Interesting too that Angela Merkel was the only national political leader to explain the R number correctly and communicate it clearly and concisely. She has a science background and it shows:
      coronoavirus-in-germany-angela merkel>

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    2. Marianne
      Yes, Yes agreed, I have been following the news on this and it is great to see that women are stepping in to put their citizens and lives first.

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  21. Richard: This is more an answer to my previous question than a question demanding an answer or comment..

    The 1957-58 Asian Flu was comparable in mortality to current covid pandemic,,at one point 4000 Americans dying a week. Why is 1957-58 largely forgotten, even among those who were there? The explanation may lie among following factors, in no order:

    –illness (and death) just accepted as tolerable. Larger family members then–both young,and old just died.

    –recent memories of polio, TB,, dyphtheria (more scary)d

    –no economic/mobility restriction (lockdown makes news)
    ,
    — there was lots of press on it back then but not wall-to-wall media coverage, plus internet. TV still new at time

    –slow, poor record-keeping
    ,
    — not so distant memories of WW2,,Korea,, constant, fear of nuclear war (very scary) and illness and death,including flu just accepted and lliveable (!). Families were larger..,..young and old just died. Today there is more non acceptance of evil/hardship

    –there was a vaccine developed in 1957, (40 million doses available in four motnhs) thanks to vaccinologist Maurice Hilleman, but too little too late to arrest the epidemic.or make dramatic difference

    –scientists then didn’t understand well how new strains of flu could lead to new pandemics,, except for the legendary Hilleman

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  22. Richard: No need for point by point answers. Just your general comments?

    Why is testing in the West often inadequate? After all, in S. Korea, Singapore and Wuhan they seem to have managed fast,,accurate testing..

    How much does the reliability of testing matter? Should we just go ahead with best we in West have, however imperfect? If uncertainty is universal for estimating R, why did Asian countries seem to have guessed right on their models? Was .U.S.. only country to have botched early testing?

    Is effective testing/tracing still possible in UK, France and U.S.? Or does it have to be social distancing/lockdown, or even herd immunity if epidemic becomes too widespread?

    Gus and Li z

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  23. Thanks for this Richard.
    I have a question: much has been made of the greater susceptibility BAME people with reasons of relative deprivation, smaller living accommodation, multi-generational family groups offered. Has any work been done on genetic differences? Presumably it would also be possible to look for genetic variants in those who become seriously ill compared with those who show mild symptoms.

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    1. Great question. I do not know of any studies that address the question of the proposed increased susceptibility of Black, Asian and ethnic minorities directly. Complete genome sequencing is now achieved with speed, accuracy and relatively low cost. I am sure that many scientific groups will be using genomics to identify genetic signatures that address your question as well as the more general issue of why some people get a devastating, perhaps fatal, illness from Covid-19 infection while others recover quickly or maybe didn’t even know they were infected.

      For sure, our genes will be a factor in disease severity, although how powerful they are as a determinant remains to be seen. The University of Edinburgh is leading a large study in the UK involving numerous intensive care units who have provided details and DNA samples from very sick patients.

      It is possible that single genes (Mendelian inheritance) with powerful effects on disease severity may be identified, but more likely the patterns will be polygenic, indicating the involvement of multiple genes, each making a small contribution to disease susceptibility. Recall from an earlier blog (Blog 3. Immunity and Disease Severity) my point about nature via nurture. Susceptibility will be more complex than genes alone. Nonetheless, there is a good chance that genomics will uncover associations that link DNA sequences (haplotypes) to disease severity. Around 300 out of our 20-25 thousand known genes account for a high percentage of common differences between complex human traits (height, eye colour etc.) and these DNA sequences may prove to be a useful starting point in the analysis of the genomes of patients enrolled in the Edinburgh study. Identifying common variations that may differ between those who had severe disease compared to those who recovered quickly and without severe complications would be a useful start.

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  24. Thank you Rich, very dense and informative. A few basic questions/remarks:
    B1: Any progress on the natural variation in the spike structure of covid19? If not, looking for a vaccine is like shooting in the dark I guess!
    B4: the SIR model. Clear. I had read about the difficulties of determining R0, the reproductive number which is the base of the model from I understand (in a totally susceptible population, how many people would one person go on to infect). It is fascinating to see that practically everyone got R0 and the ensuing predictions for the SIR model wrong. Some by excess, others by default. Some massively, others less. From experts and cheats alike I’m afraid (cheats or politicians if you prefer!). In my humble opinion, there is an element here that comes into play and that has nothing to do with science and even less with maths but rather with the fact that we’re all human beings, its cognitive biases. Be very interesting to see, amongst many other things, which ones are at play with which population in order to learn from mistakes and improve R0 predictions and model performance for the next pandemic. For as we all know with models, you put rubbish in you get rubbish out 😉
    B3: “We have no effective treatment to treat covid19 at present”. I am very perplexed by the opposing views in relation to the effects of using hydroxychloroquine. The molecule has been existing for 80 years if I am correct, has done wonders against malaria, it is not a covid vaccine (!), it is not a cure per se, it has not followed a scientific assessment for covid treatment. All that is factual. But there are a large number of accounts according to which it seems to work in reducing viral effects at the beginning of the infection and hence help prevent hyper inflammatory issues afterwards (and not only in Bouches du Rhone – CHU Marseilles). There are other accounts that say the contrary. Seems impossible to get to the truth of this. I guess we will have to wait the end of it all to get a clearer idea.
    B4: “WHO: don’t shoot the messenger”. To announce in April to the world that natural infection with covid may not necessarily induce immunity is either super bold or outright stupid. I do have respect for Maria VanKerkhove but I wonder what she was thinking then. Btw, I have much less respect for the (Chinese?!) institution she works for.
    xx
    D

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    1. Dan. Thanks.
      B1. Recent study from Glasgow, not yet published or peer reviewed but discussed by press (www.gla.ac.uk>news>headline_722109_en), says that there are no biologically relevant mutations in virus. I think that from the vaccine perspective, the likelihood of mutations in the spike protein is not high.
      B2. Ro is a tough one. See next blog!
      B.3. The only way to know is to do a randomised double blind trial of hydroxy-chloroquine. No easy answers to this one.
      B.4. Covid-19 induces an immune response, but whether this confers protection and if so for how long is unknown.

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  25. Richard ,
    following your blog with interest, it troubles me that this pandemic is starting to be hijacked by politicians, and the very important work done by scientific community world wide is being pushed to the background.
    It looks that all the good work done so far will be lost as it was after SARS and MERS.
    I hope we will learn a lesson and governments will invest in scientific research and global cooperation to create a safer tomorrow.

    SCIENTIFIC ADVICE MUST BE OPEN, SAYS FORMER ADVISOR

    As reported by The Independent today, top scientists are setting up a shadow version of the government’s Scientific Advisory Group for Emergencies (Sage), amid concerns about “dangerous” political interference in advice to the government.

    Sir David King, a former government chief scientific adviser, has assembled a group of independent experts to look at how the UK could work its way out of the coronavirus lockdown.

    He said the 12-strong committee had been created “in response to concerns over the lack of transparency” from Sage.

    ▪ Watch the independent Sage Committee’s first meet live on Twitter at twitter.com/Sir_David_King/status/1257249193074102273 at on YouTube at youtube.com/watch?v=cFLAwZeNfxE

    ▪ Watch 6-minute video on why Sir David King has set up an independent Sage Committee. Link: facebook.com/JonDanzigWrites/posts/1919220851543739

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    1. Thanks Bob. You are not the only one who feels that the science is gradually being high-jacked by political expediency. Their lack of humility is at times breath taking given how little we know about Covid-19 and how much complexity surrounds it. However, considering that it’s only been around 4-5 months, the scientists have made huge strides, the progress on vaccines (more than 90 projects globally) being just one example. But, we still don’t really know how good our testing is (both for the virus and for immune responses). So, humility is the order of the day. Be interesting to follow the 12 man committee ……

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  26. My comment is of a personal nature as I absorb your first blog post:

    Thank you, Richard, for sharing your knowledge, and for seeking and offering answers to the questions we all have. I look forward to following your blogs and your search for solutions to this plague. And thank you, Timothy, for developing this platform. And, Marianne, ni hablar – gracias por todo lo bueno que tu familia ha logrado crear.

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    1. Thank you Gregory. Tribute to Timothy duly noted; richly deserved. After years of Spanish lessons, I even understood the last part of your message! Un fuerte abrazo.

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  27. Liz Routier

    Q. If roughly 25 per cent of patients were infected by the virus(“I box “) and we can assume they aquired some immunity through antibodies , will this immunity last weeks ? months? Long enough to protect from a possible second wave of infections in the autumn when respiratory infections show up?
    In the 10 per cent Resistant (” R box”) is it possible that previous vaccines -such as BCG or Seasonal flu could be contributing factors or could there be others?

    A. There will be an immune response, but whether or not this mediates protection is uncertain and very much something that needs more research. This is a ‘new’ virus and we are learning as we go along. Previous experience with other Coronaviruses, such as SARS, make it clear that the immune response to natural infection may only protect for a short time, if at all. This may turn out to be too pessimistic, but time will show. To date, the blog has dealt with this whole issue very superficially. Of course, how to develop a vaccine that induces strong and lasting protective immunity (and safely) is of the highest importance. I have already mentioned the point that the vaccine may have to be much more successful that natural infection in inducing protection. The potential facilitating or adjunct role of other vaccines is an important and complicated one. But, as a general rule, protective immunity is very SPECIFIC for each infectious agent, so a major contribution from BCG or other vaccines is not to be expected.

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  28. Great Blog, would like to understand the details of what differentiates immunity from Resistance and how that would affect people with COVID. Does that mean some people won’t get it, or that it will be less severe?

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    1. Terrific question. I have used the term immunity in a restricted sense in the SIR box model: immunity that is PROTECTIVE. In other words, these people are resistant to infection. Its duration is a major unknown, hence my emphasis that the SIR boxes change with time. But I also oversimplified. Infection with Covid-19 may induce an immune response that may not protect at all, partially, or completely (at least for a time). Mathematical modelers like clarity and it has advantages. But of course, biology is not simple. Your point – and a reminder that I need to say more about immunity and its complexities.

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  29. Hi Richard,
    Interesting, thanks and things of which most people need to be informed.
    One comment i would make, though i am sure you will address it at length later is to suggest that the susceptible are subdivided into those mildly at risk and those for whom infection is likely to have serious consequences and how scientific analysis of the symptoms might differentiate between them.
    i look forward to hearing more,
    Neil

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    1. Agreed. The boxes represent the simplest model in quantitative, not QUALITATIVE, terms. There is of course a need to specify the extent, severity, duration and long-term outcome of those who are susceptible if and when they become infected. Similarly, the Resistant (R) box does not infer anything about the extent, mechanisms or duration of protection.

      At the present time, predicting what will happen when susceptible people are infected does not have the necessary scientific basis. This is a ‘new’ virus and there’s only been a few months to investigate its unique biology. But there will be progress. For example, analysis of the very early responses of the body to the virus may indicate ‘signatures’ that predict those who are likely to have severe or mild disease. There are several research laboratories that are doing these kinds of analyses, but it will take time.

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