Posts Tagged ‘Dr Michael Mina’
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)