Archive for the ‘vaccines’ Category
Is/was the Covid 19 pandemic overblown?
Jacinta: So clearly Covid-19 fatigue is becoming a worldwide phenomenon, and I’m not talking about long Covid. Mask-wearing here in Australia has reduced almost to pre-Pandemic levels, and I’m beginning to hear more claims that it was never really that much worse than the flu, and that the world has suffered more from lock-downs and other restrictions than from the virus itself. This is a bit shocking, so it’s time to evaluate these claims, for what they’re worth.
Canto: Well we haven’t been keeping tabs on this lately, but in the first year of the pandemic we regularly visited the Johns Hopkins and Worldometer sites to keep track of the global and nation-by-nation statistics on SARS CoV-2. Returning now, I find that Worldometer provides an overall death toll so far of a little over 6.7 million. The Johns Hopkins Coronavirus Resource Center has almost exactly the same figures…
Jacinta: And how does this compare to flu figures? Someone asked.
Canto: Actually, this is not a simple question. For a start, people may die with a particular illness or infection but not necessarily of it. And death certificates can often be ambiguous on this matter. This also allows ‘Covid skeptics’ – and there have long been plenty of them – to distort the figures any way they can. Death certificates are used by the UK’s Office for National Statistics:
The ONS uses data from death certificates to count deaths from Covid-19 and all other causes. This is distinct from public health measures, which include deaths within 28 days of a positive Covid-19 test. We use the term ‘due to Covid-19’ when referring only to deaths with an underlying cause of death of Covid-19. When taking into account all of the deaths that had Covid-19 mentioned anywhere on the death certificate, whether as an underlying cause or not, we use the term ‘involving Covid-19’. This is also the same for flu and pneumonia.
Jacinta: Yes, this is good policy, as it puts Covid-19 and flu etc on the same footing. But mightn’t it be the case that, due to the prevalence and greater public face of Covid-19 in these times, medical authorities would be more likely to attribute cause of death to Covid-19 than to anything else, just because the patient tested positive? I mean, why test for anything else when they’re sick and Covid-positive?
Canto: Hmmm, well why indeed – if they’re sick and have the symptoms of Covid, trying to reduce those symptoms would be the medico’s first duty. After all, Covid-19 is a far more deadly disease than flu.
Jacinta: But not everyone agrees, apparently.
Canto: Yeah, and not everyone agrees that the Earth is an oblate spheroid – so what? You asked about deaths from Covid v flu. Looking at the data from the UK is a good idea, because both the flu and pneumonia are more prevalent there than in Australia.
Jacinta: And yet interestingly the relaxed restrictions and reduced mask-wearing that occurred from mid-22 resulted in our worst – most deadly – flu season in five years. Influenza was considerably reduced in Australia in the winters of 2020 and 2021, obviously due to those restrictions.
Canto: Well we’ve asked, by someone sceptical of the fuss and perhaps the over-reaction to this pandemic, to look into it more deeply, though this is probably a task way beyond our powers. We’ve been given a reference to start us off, an essay by John Ioannidis, a professor of medicine, epidemiology and population health at Stanford – at least he was at the time of writing the essay, back in March 2020, only 2 months into the pandemic.
Jacinta: Yes I remember there was something of a furore around this essay, a lot of blowback as the Yanks say. I never read it, but we did do a lot of reading and listening vis-a-vis SARS-CoV2 in the first months of 2020.
Canto: That’s right – the Medcram coronavirus updates, delivered by Dr Roger Seheult and designed, as the name suggests, for medical students, were always our first port of call. I watched over a hundred of them on YouTube, and educated myself pretty well on the structure of the virus, its method of action within the body, from the lungs into the epithelial tissue and the bloodstream, the ensuing cytokine storm, and of course the method of transmission from person to person. It was quite an education.
Jacinta: When Ioannidis wrote his piece there were 68 recorded deaths from Covid-19 – according to his own figures.
Canto: yes, here’s a quote from the essay:
Some worry that the 68 deaths from Covid-19 in the U.S. as of March 16 will increase exponentially to 680, 6,800, 68,000, 680,000 … along with similar catastrophic patterns around the globe. Is that a realistic scenario, or bad science fiction? How can we tell at what point such a curve might stop?The most valuable piece of information for answering those questions would be to know the current prevalence of the infection in a random sample of a population and to repeat this exercise at regular time intervals to estimate the incidence of new infections. Sadly, that’s information we don’t have.
Jacinta: And Johns Hopkins puts the total number of US deaths from Covid-19 at 1,097, 660, as of January 10 2023 – far worse than Ioannidis’ most catastrophic scenario. And yet, Ioannidis has never backed down from the claim that the world is over-reacting. One has to wonder how many people would have to die before he changed his mind.
Canto: Maybe he wants to argue that many of these people didn’t ‘really’ die of Covid-19 – that they would’ve died anyway. Now that’s a hard thing to prove. We all die, after all.
Jacinta: And interestingly, the USA’s death toll is about 16% of the global toll, though the USA has only about 4% of the world’s population. Does this mean the USA’s response has been a big failure, or are they attributing more deaths to Covid-19?
Canto: The USA has suffered way more deaths from Covid-19 than any other country, and it jumped to the lead very early on. In that period there was huge criticism about how the Trump administration had gutted the CDC and the FDA, and of course Trump’s response to the outbreak was to mock mask-wearing and to compare it to the flu – ‘it’ll be gone in weeks’. That’s when his approval rating – already much lower than his disapproval rating – really tanked, and he started talking – in April – about the November election being rigged, but only if he lost!
Jacinta: Well some thugocracies like Russia and China can’t be trusted on their figures, but getting back to Ioannidis, in his March 2020 essay, he seemed to be concerned more about the under-estimation of figures rather than the opposite:
Given the limited testing to date, some deaths and probably the vast majority of infections due to SARS-CoV-2 are being missed. We don’t know if we are failing to capture infections by a factor of three or 300. Three months after the outbreak emerged, most countries, including the U.S., lack the ability to test a large number of people and no countries have reliable data on the prevalence of the virus in a representative random sample of the general population.
Canto: Yes, and the ability to test clearly improved in most developed countries over time, but Ioannidis still wasn’t satisfied. And how do you measure a country’s ‘ability to test’? Clearly you can’t force everyone to be tested – not even the Chinese Testosterone Party can do that – because they’ve allowed too many people to exist. Even a ‘no child policy’ would take too long to improve the situation, they need another Mao-style ‘great leap forward’ to do the job. But that only killed 70 million at most, a mere drop in the bucket…
Jacinta: Yeah well, back to the topic. Ioannidis talks about an ‘evidence fiasco’, but surely he’s being unrealistic – we could never expect to test everyone, and so of course plenty of unsymptomatic carriers, especially the young, would pass through the net and unsuspectingly pass on the virus. That’s why physical distancing and mask-wearing became a high priority as we learned how the virus was being transmitted.
Canto: Of course it must be remembered that Ioannidis wrote this essay (referenced below) at the very outset of the pandemic. Even so, his predictions were way off. He projected case fatality rates from the Diamond Princess outbreak onto the general (US) population:
Projecting the Diamond Princess mortality rate onto the age structure of the U.S. population, the death rate among people infected with Covid-19 would be 0.125%. But since this estimate is based on extremely thin data — there were just seven deaths among the 700 infected passengers and crew — the real death rate could stretch from five times lower (0.025%) to five times higher (0.625%).
Please note that Ioannidis’ projected worst-case scenario, adjusting for the higher age range of the Diamond Princess crew, was 0.625%. According to the latest figures from Johns Hopkins and the WHO, the USA’s current case fatality rate is about 1.1%, almost twice Ioannidis’ worst case projection. Of course, Ioannidis can’t be blamed for his under-estimation in the early stages of the pandemic, but it’s rather surprising that he hasn’t modified his views in line with ongoing evidence. So, unfortunately, he has become a beacon for contrarian views about the impact of and response to Covid-19. Even the highly-regarded Scientific American magazine defended Ioannidis in a brief November 2020 article that it later apologised for as an ‘opinion piece’ containing a series of factual errors.
Ioannidis doubled down on his claims of an over-reaction to the pandemic, appearing on various news networks throughout 2020 to express caution and to question the measures taken to prevent spread, but he was arguing against a growing consensus. The Washington Post put it this way in December 2020, after a terrible year in the USA:
… as the pandemic enters its deadliest phase, Ioannidis is losing the argument over how to combat covid-19. Among epidemiologists, consensus now exists that it was inaction, not overreaction, that helped create the worst public health crisis in a century. The uncontrolled spread of the virus has led to overrun ICUs in South Dakota and makeshift morgues in Texas. States and countries are locking down in a bid to preserve lives as vaccines start to roll out. Even Sweden, which resisted tough restrictions through the spring, is now reversing course to avert catastrophe.
So, of course we can’t compare what happened with restrictions, lockdowns and mandatory mask-wearing with what might have happened had we continued with business as usual and relied on herd immunity (that’s to say, the development of natural immunity without vaccines), but it’s surely worth listening to those who work in the field of virology and immunology. And within those circles there appears to be broad agreement. Here’s what the Mayo Clinic has to say:
There are some major problems with relying on community infection to create herd immunity to the virus that causes COVID-19:
- Reinfection. It’s estimated that getting COVID-19 results in a low risk of another infection with a similar variant for at least six months. However, even if you have antibodies, you could get COVID-19 again. Because reinfection can cause severe medical complications, it’s recommended that people who have already had COVID-19 get a COVID-19 vaccine.
- Health impact. Infection with the COVID-19 virus could lead to serious complications and millions of deaths, especially among older people and those who have existing health conditions. The health care system could quickly become overwhelmed.
Vaccines
Herd immunity also can be reached when enough people have been vaccinated against a disease and have developed protective antibodies against future infection. Unlike the natural infection method, vaccines create immunity without causing illness or resulting complications. Using the concept of herd immunity, vaccines have successfully controlled contagious diseases such as smallpox, polio, diphtheria, rubella and many others.
I should also add that the pandemic, for all the suffering caused, has led to a marked improvement in the time-frame for effective vaccine production, and of course a breakthrough in the form of mRNA vaccines, which has been something of a revolution in immunology.
I’ve not properly answered the question – are there more deaths from flu than from covid? A 2021 article from the British Medical Journal answers precisely that question, again quoting the ONS:
Data from the Office for National Statistics show that in England and Wales the number of deaths from influenza was 1598 in 2018 and 1223 in 2019. This is way below the annual deaths from covid-19, which at the current rate of around 800 deaths a week in England and Wales equates to more than 40 000 a year.
That’s a huge difference, despite all the caveats mentioned above and repeated in the BMJ article. But unfortunately people will believe what they want to believe.
References
A fiasco in the making? As the coronavirus pandemic takes hold, we are making decisions without reliable data
https://www.washingtonpost.com/dc-md-va/2020/12/16/john-ioannidis-coronavirus-lockdowns-fox-news/
https://www.bmj.com/content/375/bmj.n2514
Americans who turn to the White House for coronavirus news tend to think the media’s pandemic coverage is overblown
more on rapid antigen testing, and the vaccine race
So to continue with this issue of rapid at-home testing, there are/were many tests of a more simple and potentially cheaper type being manufactured, but they were all diagnostic tests (i.e tests that require expert interpretation as part of a diagnosis), and even if they’d been scaled up fairly rapidly they wouldn’t meet the kind of demand Dr Mina was envisaging. That’s to say, not doubling the tests available but multiplying those tests by a hundred or more, for nationwide availability in the US.
I want to get clear here, for myself, about the difference between an antigen test and a PCR test. An antigen test detects viral proteins. The paper strip test Dr Mina refers to contains antibodies that will bind to the antigens, or proteins, if those antigens are present in sufficient numbers. The presence of those antigens, or viral proteins, indicates that the virus is active – it is producing the antigens via the ribosomes of host cells. The PCR test detects viral RNA, whether or not the RNA is active. And so the antigen test reveals infectivity. The PCR test more often than not finds inactive viral fragments, since this RNA remains in the cell for some time after the period of infectivity, the upswing, which is relatively short.
Dr Mina has this to say about the sensitivity of the two test types. The PCR test will pick up virus from a few days to six weeks (or more) after infection, but the subject may be infective, that is, able to spread the virus, for the first two weeks (or less) after acquiring it. So its sensitivity to detecting an infective subject is not so great as its sensitivity to the virus itself (living and reproducing, or dead, or disabled). An antigen will be testing negative, both in the very early phase of infection, when the virus isn’t yet producing enough viral protein to show up on the test, and in the long phase when the virus, or parts of it, are still present but no longer replicating and infecting. So it is actually more sensitive to infectivity, which is exactly what’s required. And this essentially has to do with the frequency with which the antigen test can be used, because the PCR test has this lag time built into it.
It’s hard to believe that it’s this simple and straightforward, and that supposedly smart regulators aren’t jumping on this and getting these tests out there. Could I be missing something? I note that Dr Mina uses transmissible rather than infective, by the way.
So why aren’t such tests available? In the USA, it’s because it sounds a lot like a diagnostic, which requires approval or licensing from an organisation called CLIA – but that’s for them to work out. As to the situation here in Australia, which hasn’t had to deal with anything like the mess they’ve made for themselves in the USA, such a testing system would still help to detect spreaders, providing there was blanket use, and this would mean fewer lock-downs and less economic impact. As would be the case globally. An ABC article from late October features an interview with Prof. Deborah Williamson, director of clinical microbiology at Melbourne’s Doherty Institute, who recognises the value of rapid antigen testing, but feels that we need ‘to better understand their effectiveness as a screening tool in different epidemiological contexts’. This is understandably cautious, but then there isn’t the urgency in Australia that there so obviously is in the USA. But the USA has another major problem, which is almost incomprehensible considering the disaster that has unfolded there – and that is lack of compliance. Even if rapid antigen testing – cheap and in such supply that it could be utilised on a daily basis by the whole population – even if this was made available, there’s surely a major question as to whether most people would use the test any time they looked a bit peely-wally [under the weather], let alone when they were completely asymptomatic. So you could say that Americans are paying the price for their ‘rights without responsibility’ ideology – not shared by all Americans of course, but apparently shared by too many for them to escape from this, or any other pandemic, lightly.
Anyway, if we imagine a world, or a country, of largely compliant, responsible individuals, and widely available, cheap or free antigen testing, there would be no need for the quite onerous contact tracing mechanisms that we now have – signing in by phone or by hand at restaurants, pubs and the like – because those testing positive at home wouldn’t be attending those places until they tested negative again. Businesses could run, schools, airlines, etc. Economies could function almost as normal.
Of course now we have the vaccine, or almost. So far though it’s the Pfizer/BioNTech two-shot vaccine, which needs to be kept at way below zero (celsius) temperature, so, difficult to scale up and make available to those without proper facilities. No sign of that one coming to Australia for a while. I read an article yesterday, ‘The Amazing Vaccine Race’, in Cosmos mag. It outlines some of the contenders – the companies and the vaccine types. It points out that some companies are trying to play the long game, to try not for the first vaccine, or one of the first, but the best. The problem though, says, Nicolai Petrovsky, whose company Vaxine is based here in Adelaide, is that ‘the first runners end up getting all the resources’. And it may take quite a while to work out the best, and if the early runners turn out to be good enough, we may never find out which would’ve been the best. Vaxine is currently trialling a covid19 vaccine which combines the virus’s spike protein with an adjuvant (a treatment which enhances the immune response of the vaccine) based on a plant polysaccharide. And there are some 160 other contenders, according to the article. One in Sydney is combining the spike protein with bacillus Calmette-Guerin (BCG) which has been shown to reduce mortality from a range of viral respiratory infections. And there are others, just sticking with Australia, some with a degree of complexity that defeats me, for now. However, there are scant resources for local production here.
Although phase 3 trials of the current front-runners tested for safety among many thousands, it’s unlikely that scaling up to the millions will be without casualties, however minimal. And there’s the question of long-term immunity, which can’t really be tested for in this rushed situation. So it will be very interesting to see which of the current contenders wins out in the ultra-long run, or if something we’ve barely heard of yet finally proves the best option.
References
Rapid Coronavirus Testing – At HOME (COVID-19 Antigen Tests) with Dr. Michael Mina (video)
https://www.abc.net.au/news/health/2020-10-24/rapid-antigen-tests-for-coronavirus-screening/12808176
Dyani Lewis, ‘The Amazing Vaccine Race’, in Cosmos: the science of everything, issue 88, September-December 2020.
the rapid testing system that went begging
this is a screen shot taken from the video – the Ct values are inversely proportional to the viral load, and are plotted on a logarithmic scale (not drawn to scale though!). the x-axis is the infection time scale. viral particles can remain in the host for some time
For something completely different, I want to return to the matter of this pandemic, which in the past 24 hours has claimed more reported deaths in the USA since it began – a disaster of mismanagement, neglect, and of course the selfish civil disregard so typical of that country.
But of course that’s a generalisation, there are plenty of productive, socially concerned, often frustrated individuals trying to buck the trend, and Dr Michael Mina is one of them. He’s been advocating for a type of cheap, home-based, fast turnaround test for this virus (actually for the proteins that the virus produces via the host’s own ribosomes) which would vastly reduce spread, eliminate the need for contact tracing, and help the economy. Had this type of monoclonal antibody testing been scaled up at the outset, and made available worldwide, it’s likely that countless lives would have been saved. And it may well be generalised for other outbreaks.
So I’m writing this based on a video I watched, called ‘Rapid Coronavirus Testing – At HOME (COVID-19 Antigen Tests) with Dr. Michael Mina’. The video was produced in late July, and of course no progress has been made, and in the US the case numbers and the death numbers have jumped to the highest so far recorded, and rising.
So Dr Mina is a well-qualified immunologist whose impressive bio is detailed in the video. His ideas on this topic are published in a paper entitled ‘Test sensitivity is secondary to frequency and turnaround time for Covid-19 surveillance’, which has eight co-authors. The title captures the whole argument really, but I want to clarify to myself and others these issues of sensitivity and frequency. The video begins with a point-by-point comparison of the ‘paper antigen testing’ Dr Mina advocates, and RT-PCR (reverse transcriptase – polymerised chain reaction) tests, which are currently considered the gold standard. Firstly, the antigen tests are potentially much cheaper, once scaled up, and can be made for $1 to $2 per test. The PCR tests currently cost between $35 and $100 each. Secondly, the result of the antigen test can be known in 15 minutes, while the PCR test takes a minimum of 3 days, sometimes 7 days or longer. Third, the antigen test can be self-administered at home, while the PCR cannot. Fourth, the antigen test can be used daily, or three times a week, or with as much regularity as can be wished for or afforded, whereas this isn’t really viable for the expensive PCR test. Fifth, the simple antigen test can easily be mass-produced, but the lab processing involved in the PCR test would make this difficult. The sixth comparison favours PCR, which has a high sensitivity at over 90%, meaning that if there’s any virus present, it is over 90% likely to detect it, whereas the antigen test has a likelihood of around 55%. However, the antigen test will be able to pick up the majority of infectious cases, which is the key requirement. This will be explained later.
As Dr Mina points out, the rapid antigen test is a public health measure, unlike vaccines and therapeutics, which are medical interventions. The vital point he is making is that much investment is being put into the medical interventions, which, if successful, will bring solid returns on those investments. And so that is why so many private firms are competing for producing these ‘quick’ and hopefully effective, fixes, whereas there’s no return on investment for a public health measure such as a rapid, effective testing regime, even though this would be the best thing for keeping an economy running during a pandemic. It would require effective, good faith governance – something in short supply, particularly in the US.
So there’s a lack of financial incentive to scale up this rapid testing system, and according to Dr Mina, there’s also a regulatory problem. There’s no technical problem to scaling up, but as Mina says, there is a grey zone for this kind of testing which means it doesn’t quite fall under FDA’s guidelines, and there seems to be no governmental will (given that the USA currently has no federal government, and hasn’t really had one for four years) to provide a regulatory pathway for this kind of unique public health tool. FDA or other authorised approval is essential for mass-manufacture, and this isn’t forthcoming. As Mina says, this isn’t a diagnostic test, and isn’t meant to compete as a diagnostic test, it’s meant as a public health measure to prevent spread. So it’s a human and political problem, and this period in the USA is obviously bad for that sort of thing.
So the regulators appear obsessed with high-sensitivity testing, which tends to be expensive. If PCR testing could be done cheaply, at home, with rapid turnaround, that would be ideal, bit it isn’t going to happen, for a variety of reasons. This sensitivity issue needs to be looked at more closely, in the context of a rapidly multiplying virus, within a particular host. The rapid antigen tests may be a thousand times less sensitive than PCR, which sounds useless but not if you understand the virus and its action. It starts with a tiny number of parts per millilitre, and when it gets to a larger number, the PCR test will pick it up, and then when it gets much larger still, the androgen test will pick it up. But even then, the viral load will not be enough to effect transmission (and this will vary between individuals). And the whole aim is to prevent transmission, rather than the virus itself. The antigen test will tell you that you are transmitting (more later), and is effective in stopping or breaking that transmission chain. Testing frequency becomes more important than sensitivity. PCR tests conducted weeks apart could miss a whole infection cycle.
The FDA at the time had a news release entitled ‘FDA posts new template for at-home and over-the-counter diagnostic tests for use in non-lab settings, such as homes, offices and schools’, which sounds like just what the doctor ordered, but Mina points out that, though the regulators are showing willingness to relinquish testing power to members of the public to some degree, they’re clearly not willing to swap what is in essence a lab-based, PCR-type test, with all its super-sensitivity, for a rapid antigen test. So, no real possibility of rapid turnaround, and they require reporting of all positive and negative tests to the relevant lab or the Department of Health, rather than at-home monitoring. Among other things that means more work and more expenses for the monitoring company. Most results would obviously be negative, so a great deal of logistics to cover every negative result, which people probably wouldn’t comply in reporting anyway. So, not very viable. Dr Mina compared it to cheap instant coffee compared to those super-expensive Nespresso coffee machines that presumably the elites buy. The instant coffee version does the job without the bells and whistles, and he believes it’s the best intervention possible, short of a vaccine.
And that was in July, and the current death rate and case rate are breaking all records, but of course a vaccine is round the corner – maybe. So the moment has probably gone, but the lessons still need to be learned, by a more responsible administration. I will keep on this topic for the next couple of posts.
Reference
Rapid Coronavirus Testing – At HOME (COVID-19 Antigen Tests) with Dr. Michael Mina (video)
Covid-19: the USA and a bit of ranting
Jacinta: So I note that, unsurprisingly, there are some Americans protesting about physical distancing and lockdowns, while their nation has proved to us all that their overall handling of this pandemic has been the worst on Earth by a long way. I mean, apologies to all those who are working their arses off on the frontline, and to the innocent victims, and to the governors and other leaders trying their level best, but the sheer size of the US failure compared to just about any other country is a fantastic advert for American exceptionalism.
Canto: Well yes, the USA has failed massively in its handling of Covid-19, though of course the virus has been very patchy in its incidence around the nation, for reasons nobody can quite understand. But here’s an interesting metric in comparing the USA to Australia, and anyone can check this on the Worldometer figures. The USA’s population is approximately 13 times that of Australia, but as of today, April 21, the death toll from Covid-19 in the USA is approximately 600 times that in Australia. Compare also Taiwan, one of the world’s best performed country so far, which has a similar population to Australia. This very close neighbour of China has a death toll so far of 6, compared to the USA’s 42,518.
Jacinta: Yes, yes, so what does this say about the USA when you get so many otherwise intelligent people there still clinging to the bullshit claim that their country is the greatest on the planet? Adam Schiff said it in his otherwise excellent speech at the end of the impeachment process – and today, listening to a Sam Harris interview with Caitlin Flanagan (someone I’ve never heard of but who seemed otherwise perfectly rational), I heard her say exactly the same thing – or not exactly. She said that she really believed (almost as if she wished it were so) that America is the world’s greatest country. As if intensity of belief counted for anything. But I doubt that the USA is ahead of the rest of the world in any field worthy of measuring, apart from military might, and that’s surely a questionable value.
Canto: Hmmm, so why don’t you tell me what you really think? But isn’t this just a bit of harmless patriotism after all? We’re expected to love our country, as a value.
Jacinta: Well, I just don’t. I’ve just never had that feeling. Call me aberrant. Or contrary. I’ve often been described as a contrarian, but on this I agree with Venki Ramakrishnan, the Nobel Prize-winner, whose excellent book Gene Machine we’ve just read. He was inundated with congratulatory calls and honorary awards from India after winning the prize, even though he’d had nowt to do with the country since he was a teenager. It started to annoy him, because as he wrote, we don’t get to choose where we’re born. An obvious truth that seems to escape most people. But I’m also a contrarian in that I often find myself undermining my own responses. For example, I want to respond to patriots by calling myself a humanist, but then I think ‘I didn’t get to choose to be a human, why should I be jingoistic about humanity? Birds are pretty cool too.’ Isn’t that contrarian?
Canto: Hmmm. Ramakrishnan was tragically led astray by the transnational values of science haha. And birds can’t do science. I wonder about the blow to US credibility of this event though. They’ve completely failed in the readiness and collaboration Bill Gates wrote about in that New England Journal of Medicine article back in late February. I mean, they’re advancing with possible treatments no doubt, but testing is a shambles from what I’ve heard, and the federal government is non-existent under the boy-king. What little there is of it just gets in the way.
Jacinta: The irony of it is that the more their government fails, the more the libertarians and the knee-jerk anti-government loons will feel vindicated. And now I hear that our own Dear Leader thinks that we should have a more co-ordinated international response but maybe without the WHO. I mean, wtf? Seems to be trying to crawl up the boy-king’s capacious arse. Wrong side of history, mate.
Canto: So I’ve been avidly watching this series of Medcram videos on the pandemic. They’re informative on the science, on immunology and new types of vaccines and treatments, but they’re also a fascinating look back on the innocent-seeming days of six or seven weeks ago, when there were hardly any deaths outside of China. Watching them only adds to my sense of the unreality of it all, somehow. Anyway, microbiology’s a fun topic to learn about don’t you think?
Jacinta: Along with all the others. It’s certainly a lot more calming and inspiring than politics.
References
https://www.nejm.org/doi/full/10.1056/NEJMp2003762
Gene machine, by Venki Ramakrishnan
the science of Covid-19: vaccines and trials in the pipeline
Experts are still claiming 18 months at best for an effective vaccine, and with reports of re-infection, or resurgent virus activity in supposedly recovered subjects, it has become clear (or seems to have?) that we don’t know quite what we’re dealing with. Which of course poses problems for immunologists.
Still, the race is on. The WHO recently reported ‘more than 5 dozen vaccine candidates being pursued around the world’. The essential reason for the ‘delay’, however, is the three-phase human testing program that has become de rigueur for vaccine development. This video from YourekaScience, made five years ago, goes through the process, and note that it talks about a 6 to 10 year process, sometimes longer. The first phase focuses on safety (e.g. are there notable side-effects?), tolerability (does the vaccine cause pain, if so, what type, how long etc) and immune reaction (does the immune response look like being effective?). Phase 2 will involve larger numbers of volunteers to further test safety, and to determine proper dosage and timing of vaccines for strongest immune response. If all goes well, testing will move to phase 3, the largest trials, in which the drug will be compared with placebo and its ability to prevent infection can be more accurately measured – for example, whether it’s more effective in some sub-groups than others. Efficacy will determine approval, with possible recommendations, positive or negative, for different sub-groups. (I should add, after further reading, that stage 2 trials are often further divided into a and b phases).
So first-step safety tests on individuals have begun, in China, the USA and no doubt elsewhere. China’s vaccine is a version of a genetically engineered product developed against Ebola, while the USA’s different candidates are made from copies of a part of the SARS-CoV-2 genetic code.
Meanwhile, in Western Australia, volunteers are being recruited from the staff of a group of hospitals for an interesting experiment. They will be given the Bacillus Calmette–Guerin (BCG) injection, developed against tuberculosis. The jab is also known to boost immunity to other respiratory infections, and has a long history of safe clinical use. The trial has already been endorsed by the WHO. A similar trial, using healthcare workers, is planned for South Australia.
Australia also has a potential Covid-19 vaccine ready to go into first-phase testing in mid-May. It’s called NVX-CoV2373 (remember that name – or maybe not). Its developer, the biopharma company Novovax Inc, has partnered with Australia’s Nuclear Network, a clinical trials specialist, for the trials. The online mag Biowold reports:
The candidate, NVX-CoV2373, is going to have “a very similar safety profile” to Novavax’s phase III Nanoflu nanoparticle vaccine and, given preclinical findings, appears to be stable and productive, [Gregory Glenn, Novovax president of R&D said]. “The conformation is exactly what you need. And now we’re seeing that manifest after immunizing animals [in which we’re seeing] very, very high neutralizing antibody, which I think everyone would agree is highly likely to be protective,” he added.
Although we may be able, with the sort of effective collaboration this pandemic requires, to reduce the time-frame for a vaccine, reducing the current fatality rate is also a priority, hence the importance of the Australian (and other) trials. We are benefitting from the experience of a host of immunologists and biochemists whose experience has helped us to to look at solutions in this area. An article in The Lancet from a week ago is a good example. The authors suggest that anti-tumour necrosis factor (TNF) therapy is a therapy well worth trying:
Anti-tumour necrosis factor (TNF) antibodies have been used for more than 20 years in severe cases of autoimmune inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, or ankylosing spondylitis. There are ten (as reported on Sept 29, 2019) US Food and Drug Administration approved and four off-label indications for anti-TNF therapy,4 indicating that TNF is a valid target in many inflammatory diseases. TNF is present in blood and disease tissues of patients with COVID-195 and TNF is important in nearly all acute inflammatory reactions, acting as an amplifier of inflammation. We propose that anti-TNF therapy should be evaluated in patients with COVID-19 on hospital admission to prevent progression to needing intensive care support.
Whether the WHO or national government bodies or private companies take up this proposal is a question, but this is a time when investments of this sort should be made, and the results shared worldwide. This and other pandemics should provide the best opportunity for the kind of collaboration that transcends boundaries and individual reputations. We’ve done inspiring work on so many diseases that once thrived in our own ancestral communities – smallpox, leprosy, cholera, typhoid, scurvy, polio, tuberculosis, measles, whooping cough and many more. Our detailed knowledge of our immune system and how it can be primed and harnessed is distributed in researchers and their writings worldwide. All we need is the collective will and the appropriate collaborative approach to take advantage, for humanity’s sake, of all we’ve learned.
References
https://abcnews.go.com/Health/wireStory/search-covid-19-vaccine-heats-china-us-70147204
Vaccine Clinical Trials 101: How do we develop and test new vaccines? (video)
the science of Covid19: testing
So here in South Australia we have fairly drastic social distancing rules with pubs and restaurants and many businesses closed and so on, though in terms of case numbers we’re doing better than other states, and Australia in general is doing a lot better than other countries with comparable populations. Our crude case fatality rates (deaths per million) are smaller than any country ahead of us in number of cases in general – we’re currently ranked twentieth in case numbers. All of this is based on worldometer figures, which we can only hope are as reliable as they can be.
Our relative success has been attributed by some to our testing system. Worldometer has recently added a couple of new lines to their country-by-country statistics, ‘total tests’ and ‘tests per million’, which gives some idea of the testing rate, though little idea of the testing criteria, or the spread of testing throughout the country. According to these figures, the testing rate here is impressive compared to any other country of similar or larger population. Of course, there are just too many variables to make a direct connection between testing and fatality rates, but all experts agree that high rates of testing are beneficial. Worldometer also allows us to make some telling comparisons. For example, neighbours Sweden and Norway are recording a similar number of Covid-19 cases, 6400 and 5500 respectively, though Sweden has almost twice the population. That looks bad for Norway. But Sweden has had 373 fatalities compared to only 62 for Norway. That looks very bad for Sweden. And when we compare the testing, we find that, for half the population, Norway has carried out almost three times the number of tests that Sweden has. That’s almost 6 times the rate of testing. In fact Norway has the highest testing rate in Europe (apart from those with much smaller populations such as Iceland and Luxembourg). Other countries that appear to have greatly reduced fatality rates through comprehensive testing include Germany and South Korea. Clearly, large scale testing is working to keep fatalities down. It’s not unreasonable to attribute the escalating rate of infections in the US to the lack of a co-ordinated and comprehensive testing system, though the fatality rate there is relatively low. It’s clear that, with testing as well as with other responses, the states have failed to unite, largely due to a complete absence of federal governance.
The essential test for Covid-19 is polymerase chain reaction (PCR), and the detection process is well explained in the illustration above, and a little more fully on the JAMA (Journal of the American Medical Association) website. Or, at least, I assume so, as a non-scientific person. But in order to fully understand the process I need to capture it in my own words.
So SARS CoV-2 infects humans by binding to their ACE2 receptors by means of their spike proteins, one of four types of structural proteins pertaining to the virus. Studies have found that SARS CoV-2 has ‘a higher affinity to human ACE2 than the original SARS virus strain’, which presumably goes some way to explain its greater infectiousness. A PCR test is able to detect specific genetic material within the virus. A swab sample is taken from the throat or the nose or the lower respiratory tract or the stool, depending on test type. The JAMA website puts it this way:
After a sample is collected, RNA, which is part of the virus particle, is extracted and converted to complementary DNA for testing. The PCR test involves binding sequences on the DNA that only are found in the virus and repeatedly copying everything in between. This process is repeated many times, with doubling of the target region with each cycle. A fluorescent signal is created when amplification occurs, and once the signal reaches a threshold, the test result is considered positive. If no viral sequence is present, amplification will not occur, resulting in a negative result.
Australia’s Department of Health describes two types of test for the presence of SARS-CoV-2, nucleic acid/PCR tests (as above) and serology antibody tests, but the department sounds a warning:
The reliability of COVID-19 tests is uncertain due to the limited evidence base. Available evidence mainly comes from symptomatic patients, and their clinical role in detecting asymptomatic carriers is unclear.
This statement is dated March 27, and with the fast-moving situation, may no longer be relevant. And speaking of fast-moving situations, here in South Australia we’ve had our first recorded death from the virus, while I’ve been writing this. There’s also news overnight that a tiger from the Bronx zoo has tested positive. This has been confirmed by further testing. Other cats there are showing milder versions of the same symptoms but haven’t been tested. The tiger is described as being in a stable condition, and authorities are claiming that there’s no evidence of transmission from zoo or domestic animals to humans, but this kind of news may well lead to a public panic. And after all, absence of evidence doesn’t necessarily mean evidence of absence. There’s no doubt that the tiger’s infection raises a host of worrisome questions. Was the tiger infected by humans, as seems likely? If not, where did it get the virus from? And if the other cats are positive (they haven’t been tested due to problems with anaesthetics), then where will it end?
Antibody tests look not at infection but immunity. An effective test will show whether a person’s immune system has detected and neutralised the virus. Demand for these types of tests is extremely high, as immunity would mean that these people would be able to return to normal activity., with all the attendant economic benefits. Antibody detection would be of particular importance for current health workers. Such tests would show that the workers have already been infected by SARS-CoV-2 (perhaps without symptoms), and have developed immunity. Widespread use of the tests would also reveal the number of asymptomatic cases. Currently the number of people infected can only be an estimate based on current testing (the worldometer figures tell of confirmed cases, which can only be confirmed by testing). Children, for example, may be infected (and infectious) but asymptomatic, but the extent of this is pure guesswork. Getting real data would be useful in determining schools’ operations.
However, there are difficulties with antibody tests. According to The Lancet,
the technology behind antibody tests is fundamentally distinct and generally harder to get right. “If you have a sequence today, you have a PCR tomorrow”, says Linfa Wang, director of Duke-NUS Medical School’s programme in emerging infectious diseases, in Singapore. “Whether the sensitivity [of PCR] will be enough is another thing, but usually in the first round, it will give you data that you can use. Serology is different.”
One of the issues is knowing which protein, or antigen, on the virus to target. The spike protein is seen as the obvious target, as it’s the means of entering the host cell. Virologists in China have been using the spike protein (due to its specificity) and the nucleocapsid protein (due to its abundance). At least ten antibody test types have already been used throughout China. Specificity is important because, according to The Lancet, ‘the more unique [the protein] is, the lower the odds of cross-reactivity with other coronaviruses—false positives resulting from immunity to other coronaviruses’. These include those that cause the common cold, as well as SARS-CoV.
So that’s enough for now, I’ll continue to try and inform myself, having nothing better to do, and post some more results from that process next time. Keep well!
References
https://jamanetwork.com/journals/jama/fullarticle/2764238
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30788-1/fulltext
https://www.livescience.com/how-coronavirus-tests-work.html
the science of Covid-19: the virus, symptoms, spread, vaccine, incubation period, crude case fatalities
So I’m now embarking on a series devoted entirely to the virus that’s shutting so many of us in our homes, feeling slightly (or considerably) fearful, for our lives as well as our livelihoods, feeling both frustrated and fascinated, both mystified and enlightened about human behaviour, governmental responses and the like.
First, some people call this virus Covid-19, some call it SARS-CoV-2, and most just call it coronavirus. But most well-informed people know by now that coronaviruses are quite commonplace RNA viruses (numbering in the hundreds). They’re relatively large and get their name from the corona or crown of proteins that spike out from the virus membrane. The official name of this new coronavirus is SARS-CoV-2 (that’s severe acute respiratory syndrome), and Covid-19 is the name of the disease or condition that the virus causes.
This is the third coronavirus in the last 20 years to infect large numbers of humans. Coronaviruses are zoonotic – they spread from animals to humans, becoming more potentially lethal in the process. The others were SARS in 2002 and MERS (Middle East respiratory syndrome) in 2012. The immediate species origin of this new strain is still unclear. According to leading epidemiologist Dr Edison Liu, sequencing has shown that it arose from a bat coronavirus, but it probably passed through a series of vectors before passing to humans. It appears to be less lethal than SARS or MERS, but its spread has been far more rapid. In an interview on the Jackson Laboratory website (JAX), Liu explains that the Covid-19 epidemic occurred at the same time as an influenza epidemic, and while the symptoms are very similar, Covid-19 has about ten times the mortality rate. The essential symptoms are fever, shortness of breath and coughing. Acute symptoms appear to result from a mix of direct viral damage and intense immunologic response in some cases.
The virus is spread primarily by coughing and sneezing, and from the time of contact with it until the time of symptoms is approximately four to seven days. The virus passes from the body in about 14 days on average – hence the recommended minimum quarantine period.
Liu had this to say about a vaccine. Vaccine development generally takes 12 to 18 months, not only to prove its efficacy but to scale up production to the required level. Animal models are needed to test the efficacy of any antiviral treatment. Covid-19 enters our cells through the ACE-2 receptor (angiotensin-converting enzyme 2). Mice, which are often used as test animals, don’t take up Covid-19 through their ACE-2 receptor, but scientists at Iowa University have developed an animal model for infection, in which the human ACE-2 receptor has been engineered into the animal (a mouse). So the effectiveness of antiviral drugs can be tested on these animals, which can apparently be provided en masse, with the Jackson Lab as a premier provider.
The invaluable worldometer website has regularly updated stats on total cases (about 1.1 million as of today, April 4), total deaths, total recovered, death rates and much else, as well as a country-by-country breakdown. It also has well-sourced and referenced info on symptoms, incubation period and other useful stuff. The incubation period is defined as the time from exposure to the development of symptoms. Worldometer sets this period as 2 to 14 days, according to data from WHO, China’s National Health Commission and the USA’s Center for Disease Control. Note that this period is longer than that stated earlier, in information from Jackson Laboratory CEO Edison Liu. Similarly a Chinese online community for physicians and healthcare workers has reported an incubation period of ‘3 to 7 days, up to 14 days’. However, rare outliers have been reported, with incubation periods up to 27 days. The WHO has considered these might be due to second exposures – incidentally raising the issue of re-infection. However, most experts feel that re-infection is unlikely, and this appears to have been borne out as the global spread advances.
Over the past day I’ve listened to two Sam Harris podcasts on Covid-19, interviews with experts conducted in early March – already long ago, it seems. The second, which I listened to first, was with Dr Amesh Adalja, of the Johns Hopkins Center for Health Security. He made an educated guess of the death rate for Covid-19 at 0.6%, based on his analysis of South Korean figures. This is approximately six times the rate for seasonal flu (though it should be mentioned that the most recent seasonal flu has been the most fatal for children in many years), but somewhat lower than many of the predictions of other experts. He also seemed, at that point, less concerned about the need for social distancing and other mitigating measures than others, but it seems that the rapid spread of the virus and growing public concern has rendered obsolete his nonchalance in this area. Also, stop press, a New Scientist article posted yesterday (April 3) has this to say on the South Korean data:
Crude case fatality rates are so-called because they don’t take into account the fact that some of the people counted in the infected numbers have not recovered yet and may still go on to die. Early in March, for instance, South Korea had a crude case fatality rate of just 0.6 per cent. That has risen to 1.7 per cent.
As to the fatality rate of Covid-19 at present, this is difficult to assess, largely due to ‘severity bias’, which means that many milder infections may be going untested, with only the more severe cases capturing the attention of the health care system, or even the infected. New Scientist reports ‘a wide range of estimates, from as low as 1 in 1000 to as high as 1 in 30’. It seems clear from current figures that death rates vary wildly from region to region, and country to country, but the reasons for this are still very unclear. To give some examples of the variation, the current crude case fatality rate for the UK is around 9%, for Italy it’s nearly 12%, but for Germany it’s only 1%. Here in Australia, it’s considerably less even than that, and no doubt governments around the country will be keen to take the credit. But there seems to be more to this variation than government action/inaction. This question along with many others will be explored in future posts.
References
https://www.jax.org/coronavirus
https://www.worldometers.info/coronavirus/#countries
https://www.worldometers.info/coronavirus/coronavirus-incubation-period/
https://samharris.org/podcasts/191-early-thoughts-pandemic/
some more stuff we’ve learned about vaccines
Vaccinology, I would say that it’s not rocket science. It’s a lot harder than rocket science.
Alan Schmaljohn, virologist, 2014
Canto: So, reading The Vaccine Race, by Meredith Wadman – maybe we should just do book reviews? – I find myself getting excited, or confused, by a passage, and wanting to do more research, and then forgetting about it…
Jacinta: It’s probably pretty normal to forget 95% of what you read within a week or so of having read it. You just hope the things you retain are the principal things.
Canto: Yeah well, I was probably hoping the book would help me get my head around how vaccines work, as well as providing juicy and inspiring tales of heroism and malpractice in the history of vaccine development, and it has helped, but I think I’d need to read half a dozen such books and watch a dozen videos before it penetrated my thick skull…
Jacinta: Yes, for example, when I found myself reading, well into the book, about Leonard Hayflick’s human diploid cells, taken from the lungs of an aborted foetus, which were used to provide a sort of base for creating vaccines against all sorts of diseases, most notably rubella, I thought ‘obviously the author has explained human diploid cells, probably in great detail, before, but I can’t recall a whit’…
Canto: That’s what comes of reading too many books at once, and spreading your focus. You know it’s a myth that women can multi-task better than men, but the major finding of research is that multi-tasking is bad for everyone. Let’s resolve to read books one at a time, from start to finish.
Jacinta: Resolved. Anyway, diploid cells are just standard human cells, with 23 pairs of chromosomes. The only other human cells are haploid sperm and eggs, with 23 unpaired chromosomes. Hayflick’s cell line, gathered in the fifties, was ‘cleaner’ than the cells previously used from other animals, such as monkey kidney cells, which contained many viruses. I used the index.
Canto: So these cells were taken from the lungs of a foetus, and Hayflick was able to produce a cell line from them, that’s to say a line of almost endlessly reproducing cells, I’m not sure how that worked, but these cells, which had to be free of every virus or pathogen, would then be somehow injected with, say, the rubella virus, in some sort of reduced form, so as to produce antibodies in those who are vaccinated. The trick with vaccinology, it seems, is to produce a safe vaccine with no side effects, or minimal side effects, but with enough potency to produce a reaction, thus producing antibodies to the antigens in the vaccine. The vaccine must contain antigens, must have some potency, otherwise it’s useless. And every immune system is subtly different, so producing a one-size-fits-all vaccine is in many respects a monumental undertaking. I may have this completely wrong by the way.
Jacinta: Probably only partially wrong, let’s not be absolutists. What about this difference between killed vaccines and live vaccines. Can we talk about that?
Canto: Well first I want to understand how a ‘cell line’ is produced. How were Hayflick’s famous WI-38 (human diploid) cells produced in a constant stream from the lungs of a single legally aborted foetus in 1962?
Jacinta: Let me try to summarise Wadman’s description of the process from this online article. The tiny lungs were minced up and then placed in a container with a mix of enzymes that separated them into individual cells. These cells were separated again into small glass bottles, and a ‘nutrient broth’ was added, causing the cells to divide. thus began the most thoroughly described, studied and utilised human cell line to date, from which was created vaccines for rubella, rabies, adenovirus, measles, polio, chicken pox and shingles.
Canto: A nutrient both? You mean ‘at this point a miracle happens’?
Jacinta: Well, this was a well-established miracle, only previously it was done with non-human cells, and still is. Monkey and canine kidney cells, chicken embryo fibroblasts, hamster ovary cells… Of course using human cells was bound to be controversial.
Canto: So – obviously the cells in these tiny lungs would’ve gone on dividing had the foetus survived, so microbiologists had worked out a way, of making this happen – mitosis, isn’t it? – outside the host. How long have they been able to do this?
Jacinta: Well the first vaccine was created by Edward Jenner in the late eighteenth century, but they weren’t actually culturing cells then. Cell culture is a broad term meaning a process of growing cells – obviously by cell division – outside of their natural environment, usually in a lab. A cell line (e.g. Hayflick’s WI-38 cells) is ‘a population of cells descended from a single cell and containing the same genetic makeup’, to quote Wikipedia. Cell culture started with the maintenance of cell tissue independent of the host animal in the late nineteenth century, but techniques advanced rapidly in the 1940s and 50s to support virology and the manufacture of vaccines. A key event was the growing of poliovirus in monkey kidney cells in 1949, for which John Enders, Tom Weller and Fred Robbins won the Nobel Prize. Their methods were used by Jonas Salk and others to produce the first polio vaccine.
Canto: But the problem with using monkey kidney cells was that they potentially carried their own viruses, right? Which may or may not be harmful to humans, and how would they know? Without using human guinea pigs?
Jacinta: Human subjects, yes. And there’s also the question of the potency of the virus being used, presumably to stimulate the production of antibodies. Is it just a question of stimulating enough antibodies? And isn’t there an obvious danger of infecting subjects with the virus itself? Presumably a killed virus solves that problem, but is it really effective?
Canto: Yes, Wadman’s book has been fascinating on the politics of the vaccine race, but I’m still left much confused – probably due to stupidity or inattentiveness – as to how some vaccines work better than others, and how a cell line – I know it’s essentially about exponential growth – can produce enough material for millions of vaccine doses.
Jacinta: Yes it’s about exponential growth, and it was once thought that, given the right conditions, these cells could go on multiplying ad infinitum, to immortality so to speak, but it was Hayflick who showed this not to be true in a much-cited paper. Even so, the number of replications of individual cells assured a sufficient supply of cells for generations. And since then, much more has been discovered about cell ageing and its causes, what with telomeres and telomerase, but that’s another story. As to why vaccines developed from the WI-38 cells have been so much less problematic than others, it clearly has much to do with their being ‘clean’ human foetal cells, with no other lurgies lurking.
Canto: So let me get this clear. The WI-38 cells are provided to different labs that are wanting to create a vaccine for, say, measles. Or that have already created a vaccine, or at least have isolated the virus – but then of course viruses can’t be isolated, they need cells to survive in. So they get the WI-38 cells, and then they inject them with the virus – killed or attenuated – and then they start trialling it on rats or mice or something, trying out different strengths of the virus, without really having much idea whether the dose will translate to humans, so they must find some willing volunteers (or, in the early days, orphaned or intellectually disabled kids) to experiment on, making sure they err on the conservative side initially, then upping the dosage? I’m no doubt simplifying and speculating wildly here.
Jacinta: yes and I’m no wiser than you, but it’s a good thing we have people taking these risks, and working so hard in this field – with clearer ethical guidelines than before – because millions of lives have been saved by vaccines, and so much has been learned about our immune system in the process of developing them.
Wadman, Meredith. The Vaccine Race. Doubleday 2017.
https://www.historyofvaccines.org/content/articles/human-cell-strains-vaccine-development
http://www.nature.com/news/medical-research-cell-division-1.13273