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Scinv - Whilst the discussion here is interesting it’s nothing I haven’t heard before from a number of sources.
I hope you feel better for having got off your chest what you wanted to say.
But you spoilt it with your last comment. Perhaps a bit of humility and modesty would help you get along better in social situations.
Short version is Scinv is saying Interferon Beta is a better bet than Alpha. :)
Bearing in mind the injected form of IFN-A got an EUA today for hospitalised patients in India. An EUA for SNG looks a certainty upon trial completion. Very postive news.
Why - Better method of delivery and the better Interferon :)
You have no idea how much what I'm providing here for free costs
Wow scinv, 30 posts today so far must be £45 pounds you've racked up
Finally, if these autoantibodies ONLY appear in very late stage disease (so the patients did not have them before infection, even though we know these exist - what we don't know for 100% sure is if these particular patients in the study had them before covid) that could very well be a symptom of that stage of the disease rather than something that actually *drives* the disease, and therefore perhaps irrelevant from a therapeutic point of view.
Lol I meant to say "sometimes even in healthy individuals"
It is clear that there is a confusion here.
Autoantibodies against ifns exist in some people whether they had this virus or not. They exists in some conditions and never in otherwise healthy individuals. It is a type of autoimmune disorder. See examples below.
https://pubmed.ncbi.nlm.nih.gov/16784312/
https://pubmed.ncbi.nlm.nih.gov/27059145/
What they found with covid, is that about 10% of hospitalised patients with severe disease had autoantibodies against ifn alpha and omega while no one asymptomatic had them. Later, they found some against lamda as well but it seems not so much in ifnb (only very few). We see something similar even in people that never had covid, some have autoantibodies against ifns but again ifnb is one of the least common.
Going back to the covid patients, what this suggests is that if ifn a function hadn't been impaired, then they would not be as likely to have severe covid (since none of the asymptomatic had them). Whether these existed from before is still under investigation (it would have to be a study similar to vaccines where they follow them from before they get infected). Assuming that it is definitely the virus that causes this autoimmune condition, one could in fact argue that the virus does not induce against ifn b because it cares less about it. But given that immunity is probably the least straightforward part of human biology and that in other conditions there is also less preference for auto antibodies against ifnb, it is perhaps because it is simply not as easy to induce autoantibodies against ifnb.
But, IN ANY CASE, when in almost all cases when ifn a is inhibited the patient do worse, and they haven't found asymptomatic cases where autoantibodies against ifn a exist, then we can conclude that ifn a is beneficial when it is there. If can't make this argument for ifn a, then you can't make it for ifn b either based on this imformation.
If that is clear, then it should be clear why ifnb should have an advantage specifically in patients with autoantibodies against other ifns as well as why there is a higher chance it would best work there (because they are already missing at least one other and by the way, alpha and beta share the same receptor).
Thx for that Joey - the ‘Conclusion’ section addressed my questions. Good to know.
Equally important to consider and take on board any limitations.
(Not. If you can't keep up, thats your problem)
Sure sure Anthony. Just hang in there im gonna fetch it for you.
@Scinv "And just to add, in a large study back in october, when they checked the outcomes all cases with autoantibodies had more severe disease, it just that was only a subset of patients with severe disiease so it is not the only determining factor, but it is *definitely* one."
Please provide a link to this study. Also can you show me the break of what % autoantibody are for each IFN subtype. We have seen in the literature that IFN autoantibodies are expressed in COVID for the alpha variety. Happy to be proven otherwise but I prefer a scientific paper please.
So the advantage of ifn b is specific in cases with antibodies against ifn a or lamda, since even if they worked at higher concentrations, they still need a lot more drug to do anything useful.
Nothing is binary. I don't know the details of that trial. But as a general note (especially relevant in inhaled ifna formukations), there is always a comcentration effect. What happens at the molecular level is that there has to be sufficient antibody to inhibit sufficient % of ifn molecules so that in the end there is not enough unbound ifn to induce an adequate response. (It is also a matter of affinity to specific ab vs receptor which is also concentration dependent). That is why everyone is measuring how much antibody that actually neutralises the virus in the vaccine induced response. So it could be possible that enough ifn a could overcome antibodies against it. I don't know the answer to that question, no one does until they do the experiments. It could be that that level would be too high to be practical or not. And keep this also in mind as well, if patients with ifn a antibodies definitely do worse, then ifn a most likely is beneficial if not impaired.
Funnily enough after discussing IFN-a and benefits of it reducing viral replication, India have just given an EUA to Pegylated Interferon alpha-2b administered subcutaneously.
https://zyduscadila.com/public/pdf/pressrelease/Press_Release_Zydus_receives_Emergency_Approval_for_the_use_of_Pegylated_Interferon_alpha_2b_23_4_2021.pdf
Funnily enough IFN-a has jusr
Anthony, so?
Lol
And just to add, in a large study back in october, when they checked the outcomes all cases with autoantibodies had more severe disease, it just that was only a subset of patients with severe disiease so it is not the only determining factor, but it is *definitely* one.
For anyone interested you can download the PDF of the paper from here - https://jvi.asm.org/content/early/2021/04/16/JVI.00266-21
Here is viral load information
160 Next, we
161 examined the sensitivity of SARS-CoV-2 to pre- and post-infection treatment with IFN-a, IFN-y
162 and IFN-lambda. Consistent with recent reports (20, 23, 26, 27), replication of SARS-CoV-2 was
163 strongly inhibited by pre-treatment with IFN-a, whereas post-treatment had only a moderate
164 effect (Fig 5B). Interestingly, neither pre- nor post-treatment of cells with IFN-y reduced viral
165 replication whereas IFN-lambda inhibited virus replication but not to the same degree as IFN-a
Check figure 5B later on in the paper gives a good visual represenation of what these words mean.
Conclusions in regard to viral replication/load
* Type 1 interferons were better than Type 3 interferons.
* Pre-infected cells treated with type 1 interferon strongly inhibited SARS-CoV-2 replicating. Essentially non infected cells were protected by the administration of interferon and massively reduced further viral spread. Thats good news
* For cells already infected by SARS-CoV-2 there was only a moderate effect in reducing viral replication. So there was still a beneficial effect of using type 1 interferon however it clear once a cell has been infected by SARS-CoV-2 the effects are lessened.
These results are in line with many other papers showing the earlier inhaled interferon applied the more likely an affect it will have.
Still don't get it. It doesn't mean that necessarily only these people are nost likely to respond. It doesn't even guarantee all of them with autoantibodies will definitely respond very well. What it does is enriching for a population that *definitely* has a impairment exactly at the ifn ligand in particular. Then there are other susceptibility factors to severe disease due to the virus and there is a timing issue as well. All of them together will determine how many and to what extend will the patients improve. There was a high chance to recover within the timeframes they tested in the sng001 group in the phase 2, but the devil is in the details. The strength of this data is still driven by a subset of patients in the small trial, chance could easily make the difference between reaching statistical significance (which was marginal and only for some outcomes, release from hospital which is critical from a regulatory point of view wasn't). So the end results was a promising but far from conclusive mix.
We could break down all the known factors if you want, but do you really want to? There is a reason phase 3 trials and thatvis because very often, they don't replicate the phase 2 exactly.
At the end of the day, ot is all about maximising chances of success and that has been my point all along.
@Prion25. I normally ignore Scinv as he has agenda. I would like to say he is guilty of both being right and wrong. Yes there are autoantibodies to IFN. However, the literature suggests to IFN alpha that about 10% of patients express autoantibodies. There are about 13 types of IFN alpha subtypes. Only 1 IFN beta variety. SNG uses IFN beta currently.
Using Scinv findings that some patients will be resistant to ectopic Ifn beta and only 20percent will benefit that Have autoantibodies How do you explain the high singnal response of the P2 trials and other trials
Scinv - thx.
Joey - nope I haven't which I've stated.
The implications of the above is that you probably need to give it as early as possible. Before the virus, has taken hold of many cells in the tissue, therefore protecting as many cells as possibe before they get infected by the new virions produced in the lung .
This is on top of other vatiables like autoantibodies or other known or unknown susceptibilities to extreme reactions to the virus.
Yes. Their suggestion is that ifn would work optimally (and I'm being nice here) before the cells are actuslly infected. That's because the virus uses multiple approaches to block ifn pathway. But again, nothing is as straightforward as people (sometimes including scientists) like to suggest. That is why it is all about going for maximum confidence, no.matter what that may be.
Out of interest has anyone actually read the full paper or just the abstract?