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Great Expectations

Vaccine roulette?

12th August 2020:

As the world struggles with the Covid-19 pandemic, changing the fundamentals of this infection is hugely dependent on vaccines. For example, preventing large numbers of people from being infected and spreading the virus even when they have no signs of disease as well as averting life-threatening illness and the longer-term disabilities. Covid-19 is increasingly turning out to be a multi-system disease. We can be encouraged that there are many different vaccine candidates being developed, a handful of which are now into clinical trials. Ideally, we want a vaccine that interrupts person to person spread of the virus (transmission) as well as preventing disease, but the current trials may not provide clear answers on this. Nonetheless, in the coming weeks and months, we’ll have at least two important kinds of results; data on whether vaccines protect against disease and on the induction of good immune responses (based on blood tests for antibodies and T-cells).

It has been an incredible experience to witness the unprecedented sharing of scientific ideas in the fight against this common enemy.  These international collaborations, exchanges of reagents and know-how among scientists have driven innovation at an accelerated pace. But we are fast approaching the time when decisions on the next steps are going to become complicated. If any of the vaccines show clear evidence of protection against Covid-19, then will this guarantee progression to large scale production and implementation and how will these decisions be made?

There are already major partnerships between vaccine research groups and manufacturers. Making enough vaccine to enable clinical trials on a few thousand people is relatively straight forward.  Scaling up production for widespread vaccine deployment requires billions of doses – a very different kettle of fish. For example, the UK government has secured early access to manufacturing capacity of 3 different candidate vaccines to the tune of 90 million doses through BioNTech/Pfizer (a mRNA vaccine) and Valneva (an inactivated whole virus vaccine). Astra Zeneca is committed to manufacturing 100 million doses of the Oxford University vaccine (based on the spike protein in an adenovirus vector). In the USA, a deal has been struck between the large pharmaceutical firms Glaxo Smith Kline (GSK) and Sanofi to produce 100 million doses of recombinant protein and mRNA vaccines with later scale up to 1 billion doses in 2021. These are mind-boggling numbers associated with astronomical costs and, of course, pharmaceutical companies are answerable to their shareholders.

European leaders have given assurances that if their laboratories are the first to develop a vaccine, it will be broadly licensed around the world to ensure global access with priority being given to vulnerable populations. In contrast, the USA and China are gripped by an escalating trade war of nationalistic imperatives in which Covid-19 vaccines could become a bargaining chip, a new global arms race to own the patent rights to effective vaccines. There has already been an ominous precedent in the recent controversial machinations over the rights of the drug Remesdevir in the US. Then, yesterday, out of the blue, Vladamir Putin announced that Russia will be implementing a vaccine that has apparently been tested in only hundreds of people with no evidence that it confers protection. Sputnik V seems a brazen example of political expediency2.

So, which vaccines will be chosen to go forward and on what basis? Most trials rely on testing candidate vaccines in young, healthy volunteers, yet the most susceptible people are the elderly, especially those with other health problems such as diabetes, pre-existing lung disease and obesity. We’ll need to know a lot more about the responses of people at different ages. Following natural infection with the Covid19 virus, the duration of protection appears to be short-lived. Vaccines may do better, but even so, repeated immunisations may be needed if immunity wanes. The need for ‘boosting’ raises complex questions as to whether it can be carried out with the original vaccine formulation or whether it will be possible to have a mix and match approach. 

Another dominant issue will be concerns about adverse reactions and the safety profiles of different vaccine formulations. Trust in immunisation is critical and recent polls in the UK and USA suggest that hesitancy over Covid-19 vaccines is prevalent.  Vaccines are our most powerful public health tool, but people must have confidence in them and the healthcare workers and scientists that administer them.  Yet the social factors that underpin personal choices and behaviour concerning immunisation are poorly understood. As Sir Jeremy Farrar cautions in a recent review: “Understanding people and society – through history, sociology, anthropology – is at least as important as understanding viruses and immunology”1

The problem of evaluating new vaccines and developing policies for their implementation is a well-trodden path.  But the urgency and scale of the Covid-19 pandemic challenges their adequacy and appropriateness. For example, governments usually rely strongly on a cost-effectiveness analysis to inform policies on vaccine deployment. This evaluates (using mathematical models) the economic gains of immunisation in relation to the costs of purchasing and distributing a vaccine.

As of August 11th. 2020, more than 20 million people have tested positive for Covid-19 with three quarters of a million deaths; the numbers are still growing at an alarming rate. But there is a jewel that shines undimmed: science can get us through these difficult times. Within weeks of the first case, the Covid-19 virus was identified, its sequence determined and made available to all scientists worldwide. We know how the virus spreads and that no place on earth is exempt. Although the economic and societal penalties are punitive, social distancing, wearing masks and washing hands drastically reduces person to person transmission of the virus. I am optimistic that vaccines and new treatments will become available in the months ahead. Successful science depends on global cooperation. The message could not be clearer.

  1. www.wellcome.ac.uk/global-monitor
  2. http://www.nytimes.com>world>Europe

Copyright Richard Moxon 11.08.20

As mentioned in the Home Page, I will be taking a break for a short while. Thank you all for your incredible interest and input over the past months. Thanks to you, the blog has surpassed my expectations – on one memorable day there were more than 600 hits in a single day.  I’ll be back in September, in the meantime I will also be hard at work on the final stages of my book Brain Fever that will be published next year.

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50 thoughts on “Blog

  1. 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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  2. 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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  3. 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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  4. 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

  5. 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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  6. 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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  7. 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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  8. 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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  9. 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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  10. 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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  11. 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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  12. 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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  13. 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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  14. 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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  15. 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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  16. 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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  17. 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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  18. 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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  19. 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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  20. 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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  21. 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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  22. 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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  23. 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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  24. 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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