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Great points BBN, well made. TL;DR: it’s a good investment and until further news ignore the nonsense? Some good research nuggets do pop up on here though. And I enjoy your long-form twitter missives as another source of thinking points. But i think you’re right that this is all just spinning the wheels until we have more substantial news to deal with. Time to go and do something else...
Good find, thanks for sharing.
I imagine at peak demand they’ll have night and weekend shifts to keep them running 24/7. This is pretty standard practice in manufacturing to maximise return on investment in the equipment and the real estate that houses it. Assuming running all the time, 24/7/365 at 80% capacity (some downtime for maintenance, loading raw materials, etc) = 12.6 million/year from one machine.
Same ballpark as your number. We’ve previously seen estimates touted on this BB of global LFA manufacturing capacity stated at either 200 million or 2 billion per annum (no sources given). This is certainly making the latter number seem much closer to the likely truth. Seems good news to me for the feasibility of scaling up production to meet the scenario of colossal demand.
Hi PL, I agree - very interested to see how it comes out. While the focus has been on the S&S in this doc, and how it stacks up against Al’s stated aspirations, I’m really intrigued by these figures for LOD; <100copies/ml desired, <1000copies/ml acceptable. If these figures are broadly in alignment with the S&S ranges, and Al’s confidence extends to meeting them, it could be a phenomenal test.
We’ve previously discussed LOD here. Ophidian’s tentative conclusion using the Zika test as an analogue was that the covid-19 test might be able to detect on the order of 10,000’s copies/ml and that this would probably be good enough to detect early cases. Further, the research papers suggest common Covid-19 viral loads range in the 10,000’s /ml upwards (with a few low-side outliers). If we can achieve an LOD in the 100’s copies/ml - 2 orders of magnitude better than this previous estimate - I would be more confident than ever. It would give much more leeway for sampling variability in viral load, and subjects with overall low viral loads.
Of course, these numbers might have no correspondence to the S&S ranges whatsoever, but they are the sort of numbers you’d expect to get from pre-clinical lab tests on spiked samples, which we should have for the initial prototypes already.
Also explicitly stated in the document: “Point of Care SARS-CoV-2 tests for other purposes are not part of this profile and might include: ... self-tests to be performed by a lay individual.” i.e. for the consumer market, the LFA might have to meet a different (as yet tbd) set of target performance criteria.
Nice bump - somehow missed this. Interesting further details:
- Acceptable limit of detection (LOD): “Fewer than 1000 SARS-CoV-2 copies/mL”
- Desirable LOD: “Fewer than 100 SARS-CoV-2 copies/mL“
- For estimation of clinical (diagnostic) sensitivity, “At least 150 positive clinical samples [required]. The samples should cover a clinically meaningful range of viral loads (i.e. should be from people with high, medium and low viral load) that represents the population the test is intended to be used in.”
I had been wondering if clinical sensitivity estimation would come to luck of the draw on viral load of the positive samples you get for test validation. Nice to see there are efforts to avoid this.
Also, in terms of nearly all the other target design specifications, it’s worth reading through for a warm fuzzy glow that the Avacta rapid antigen test falls consistently in the desirable category.
Hi Ophidian, thanks for taking the time to check it and reply. Indeed, not knowing the finer nuances of the terms in other settings, all I am going on is the clinical definitions, as described in Alistair’s video.
Perhaps a phrase in the explanation you cited that could muddy the waters for some is “actual ... results”. “Actual positives” (P, or TP+FN) is distinct from “positive results” (TP+FP). Hence, SENS = TP/P = TP/(TP+FN).
I think we’re on the same page in the end. But if this can cause differences in opinion among us scientists, even after watching Al’s excellent video, you can see why grappling with this causes problems for most of the general public!
Have a good week ahead.
Great video Timster, watched it already and confirms my points. What isn’t written on the slide of definitions in the first minute, but leads a lot of people to confusion if you don’t grasp it, is:
Ophidian, when you said “A HIGH specificity gives a Low number of False negatives and so hence - a HIGH NPV (Negative Predictive Value)”.
Did you mean to type sensitivity here?
My reasoning, apologies if it’s like teaching you to suck eggs, but might be useful for others... If you’ve actually got the virus, sensitivity is about whether the test detects it or not, and so determines the fraction of actual positives that are either detected as true positives or not detected, I.e. read as false negatives. Conversely, specificity controls rates of true negatives and false positives for the actual negatives.
Negative Predicitvie Value (NPV) is a function of false negatives, true negatives and prevalence, so specificity and sensitivity both have an impact on it, albeit sensitivity is more important.
NPV will always be between (1 minus prevalence) and 1 - otherwise you wouldn’t use the test, so a high number for NPV is to be expected for low prevalence, but you want the test to push it closer to 1.
Therefore I think NPV doesn’t tell you much for low prevalence settings, e.g. population screening. Most important to remember is: high sensitivity reduces false negatives, which will help to detect and keep more infected people isolated. High specificity reduces false positives, meaning fewer people have to isolate for nothing while awaiting PCR confirmation, and less strain on the test and trace system.
Has anyone ever played a little board game called Saboteurs? It’s great fun. You are semi-cooperative little gnomes playing cards to a map as you dig tunnels to try and find gold. The catch is, roles are distributed randomly at the start and one or more players might be “saboteurs” trying to mislead the group and send them down a wrong passageway to a lump of coal. I’ve played this a few times where throughout the game everyone is pointing fingers at each other making all sorts of accusations, and in the end it turns out we’re all on the same team. The very potential for the presence of traitors tends to lead to an excess of suspicion. Some life lessons there I feel.
That said, there are some very obvious green box applicants that pop up here intermittently when the shorting is in full swing. I don’t much care to partake in conflict with them or anyone else, and doing so even with good intentions only advances the anti-informative agenda.
PL, agreed - that was a good watch!
Specifically on the differences in test design we are alluding to, there was talk from these experts of how inconsistent saliva can be as a sample - between different people, between the same person from one moment to the next, and within a given sample, which is not homogenous. There are pH variations, salt/sugar concentration variations, viscosity variations, etc, all of which can affect the interaction with the test components, in particular the sample pad and conjugate pad.
I’m sure there are design considerations we are not even aware of, but the key usability question for me is whether any pre-treatment of the sample will be required to optimise the test (e.g. addition of a buffer solution), which is the sort of step you might give to a medical professional, but not so much an end consumer. Probably the best outcome will be if they can incorporate some chemistry magic into the sample pad +/- conjugate pad to process the sample into a more consistent liquid to bind the reagents and advance to the NC membrane, such as with whole blood LFAs where RBCs are captured on the pads. I guess this might be what Ophidian was speaking of the other day when suggesting the physical components might now be fixed, with the chemistry still in the optimisation phase.
Another usability issue would be with delivering appropriate sample volume - making sure enough but not too much saliva is added. Too little would slow the test down and reduce sensitivity, too much could flood the sample pad, overwhelm the absorbent paper at the end producing backflow, and reduce the ability of any clever chemistry in the pads to process the sample. This sort of thing you would have to trust to the end user, but no matter what you put on the instructions, there’s always going to be a small % of the population that assumes that “more is better” and drowns the device in a river of gob. Interesting to see what they engineer to avoid this!
Avacta have a wonderful way of posting helpful material to educate and clear up misconceptions in their investor community. This week in their blog on responding to disease outbreaks:
They point something out twice:
- “Avacta is currently working in collaboration with our partners at Cytiva and Adeptrix to develop Affimer-based diagnostics for the SARS-CoV-2 virus across all three diagnostic markets; POC, consumer and laboratory-based tests.”
- “Currently for COVID-19, we are working with Cytiva to develop POC and consumer LFA diagnostics, to detect the SARS-CoV-2 virus spike protein from saliva samples, which are less intrusive for patients than nasal and throat swabs.”
This tells us again that there will be two LFA tests (or at the very least, two LFA test releases) from the Cytiva collaboration - an initial POC test, and a later consumer one. From an investor’s point of view, I think this both makes good commercial sense, and will lead to greater news flow.
As Dr Al has told us before, a consumer test takes longer to get approved because it has to be fool-proof and pass more stringent approval processes. I suspect the consumer offering may ultimately be lower sensitivity/specificity (S/S) than the POC test, either because of compromises in design for ease of use, or - if the same design is used for both settings - because of increased user error by the general public as compared to health professionals. Either way - it makes sense to get a POC test out sooner (rather than working towards a later release of a “one-size-fits-all” test) - it will be quicker to get approved, could include more complex design features as it will be used by trained professionals, and may potentially be higher S/S due to these features and users.
We should embrace this. It will mean greater news flow! Even if they do go for a “one-size-fits-all” test design, the approvals for POC and consumer use will be staggered, and they will likely be taking many orders for a high S/S POC version well before the consumer version is released.
Just some thoughts for a Saturday morning... Does anyone else have an alternative take?
Agreed, Rich. Worth the repost! A couple highlights from the week for me, amongst the madness:
Cytiva’s Klaus (and two others - but Klaus is best) in 2012 detailing the steps in LFA development:
- They go to a lot of effort to make the complex look simple! Takes time.
- False positives can come about for other reasons than reagent selectivity, and test components must be rigorously developed to avoid this. “100% specificity” would be incredibly impressive, regardless of how good the Affimers are!
Avacta’s blog on responding to disease outbreaks:
- Great context for their testing efforts
Great post and information, monkshood, thank you.
More than ever I think it fits an interpretation that Adeptrix may have been targeting this research and drug development market as their focus all along. As stated in the latest RNS on the Adeptric collaboration (9th June):
“ Dr. Jeffrey C. Silva, Director of Product Development, Adeptrix Corporation commented:
"We are excited to apply Avacta's Affimer reagents to monitor COVID-19 infection because they are very well suited for large-scale manufacturing and have stable lot-to-lot performance due to it being a recombinant technology.
The BAMS assay for the spike protein serves as a useful diagnostic tool because this particular viral protein is displayed on the surface of the virus particle and directly involved in engaging host cells (via ACE2 receptor) during infection. For this reason, the same BAMS assay for the spike protein can also be used for drug development efforts to screen compounds that block interaction with host cells through the ACE2 receptor to prevent virus infection.
Future work will include testing Affimer reagents to other SARS-COV-2 antigens, such as nucleocapsid protein. Diagnostic assays to nucleocapsid protein may enhance sensitivity for detection of COVID-19 infection, since this is a highly abundant viral protein.
Expanding detection to other SARS-COV-2 antigens will enable configuration of a multiplexed BAMS assay to simultaneously monitor multiple viral proteins for added specificity in the case of future pandemics. The precision and accuracy of mass spectrometry detection using the BAMS assay platform will allow researchers to monitor molecular changes that may occur through natural evolution of the virus." ”
In other words (my interpretative paraphrase) - ‘now we have developed the perfect assay for drug development and virus research (which can also be used as a diagnostic assay), we can focus on making a more sensitive diagnostic assay.’
Personally I think we should be delighted that Affimers could potentially make a huge positive impact in sars-cov-2 research and drug development, as well as in diagnostics. But it does suggest a rethink of our economic models for this line of the business might be in order, not that it moves the dial much in current estimation. Who knows where it will go? Gold standard lab test with SARS-cov-2 nucleocapsid-BAMS in time?
What! I thought this was going to be an episode of ceLABrity bake off?!
Before Avacta, I would never have spent my lunch break watching that. Very informative though. Thanks.
I learned, among other things:
- The hardest part in the development process is often getting the conjugate pad right.
- False positives can come about for a number of reasons related to suboptimal interactions between the various test components, not just issues with reagent specificity.
The more you know...
Myles, it was worth the wait - thank you for putting this together and sharing it. I appreciate what you do to shine a light on worthy AIM stocks that otherwise don’t get enough detailed analytical coverage.
Hard not to conclude that Avacta is heavily undervalued at present. I hope the MM’s, II’s and PI’s alike all take note.
I think the northern connections can’t be underestimated, especially when you look at the long term strategic picture.
Avacta - based in Wetherby - have already teamed up with Medusa19 - the “Boohoo boys” - based in Manchester. Abingdon are based in York, and as others have pointed out have been building their manufacturing capacity and announcing they will make both antibody and antigen tests.
I expect there will be multiple manufacturers put in place to achieve the required scale-up for the covid-19 crisis, but long term they might want an LFA manufacturing partner of choice for the growing diagnostics division. Why not a local company?
Ophidian, very much appreciate the insights on the process and timeline.
To my eyes, the RNS has us still working on bullet point 4, but I’ve been wrong before when I assume I know too much... Interested to know how it could be interpreted otherwise?
Perhaps they saw a trading response to yesterday’s video and decided an official update was necessary?
I’m hoping that’s the case because if not, then I think this RNS says they might not have an optimised test quite ready at the end of June and they wanted to give us an update on progress as soon as possible before then. Then yesterday’s video may have been bolted on up front to educate us, manage our expectations and let us know why the optimisation step is so important, so we might have more patience with it.
Does anyone have any idea about how long this design optimisation process would typically take? One week (to the end of June) seems short. Personally I’d rather they take the time to make it as good as possible.
The video obviously worked on me. Delighted with the RNS but not “wetting myself” - yet.