The biology of coronavirus COVID-19 - including research and treatments

[lunarainbows]

https://www.statnews.com/2020/04/16...uggests-patients-are-responding-to-treatment/

Early peek at data on Gilead coronavirus drug suggests patients are responding to treatment

Chicago hospital treating severe Covid-19 patients with Gilead Sciences’ antiviral medicine remdesivir in a closely watched clinical trial is seeing rapid recoveries in fever and respiratory symptoms, with nearly all patients discharged in less than a week, STAT has learned.

Remdesivir was one of the first medicines identified as having the potential to impact SARS-CoV-2, the novel coronavirus that causes Covid-19, in lab tests. The entire world has been waiting for results from Gilead’s clinical trials, and positive results would likely lead to fast approvals by the Food and Drug Administration and other regulatory agencies. If safe and effective, it could become the first approved treatment against the disease.

The University of Chicago Medicine recruited 125 people with Covid-19 into Gilead’s two Phase 3 clinical trials. Of those people, 113 had severe disease. All the patients have been treated with daily infusions of remdesivir.

“The best news is that most of our patients have already been discharged, which is great. We’ve only had two patients perish,” said Kathleen Mullane, the University of Chicago infectious disease specialist overseeing the remdesivir studies for the hospital.”

I’m a bit confused though as there wasn’t a placebo? I thought all Phase III trials had a placebo arm? Is it because they have to fast track the drug and it’s not really ethical to give patients placebo?

If the trial shows that people got a lot better, does that mean that this drug will be approved everywhere?

 

[Andy]

COVID-19 therapy, vaccine, epidemiology and policy development research boosted by twenty-one new projects
https://www.ukri.org/news/covid-19-research-boosted-by-new-projects/

 

[Jonathan Edwards]

I’m a bit confused though as there wasn’t a placebo? I thought all Phase III trials had a placebo arm? Is it because they have to fast track the drug and it’s not really ethical to give patients placebo?

If there is no placebo this particular trial can tell us nothing about efficacy. It may indicate a level of safety. I think the researchers have tried quite hard to emphasise that no conclusions can be drawn. I assume that a controlled study is being done on earlier cases as well that will give the real results.

 

[Snow Leopard]

Convalescent Plasma - clinical trial

https://www.nhsbt.nhs.uk/how-you-can-help/convalescent-plasma-clinical-trial/

Convalescent Plasma is likely to be effective, but there is no way they can make enough of it - unless they let a large proportion of the population become infected.

COVID-19 therapy, vaccine, epidemiology and policy development research boosted by twenty-one new projects
https://www.ukri.org/news/covid-19-research-boosted-by-new-projects/

The vaccine projects seem well behind schedule if they are expected to complete human trials in 12-18 months...

 

[Adrian]

I'm confused about what is happening with Vaccines. There is the Oxford group https://www.theguardian.com/society...ccine-trials-could-be-completed-by-mid-august who are claiming that they will have a vaccine tested by September. Yet others (including Lipkin) talked about it being hard to reduce the development time from 18 months. I did see some mention of the Oxford vaccine being a platform vaccine which makes it easier and also running the testing phases in parallel rather than sequentially (what ethics considerations here?). The paper quoted for the Oxford vaccine was https://www.ncbi.nlm.nih.gov/pubmed/24374965 but that is an influenza vaccine.

Then I listened to the latest TWiV recording (https://www.microbe.tv/twiv/) with Stanley Perlman who I believe is an expert in Corona viruses and he talks much more about the issues with creating vaccines and the potential pitfalls and dangers - including what was learned from SARS-1 and MERS. They don't discuss the timing for making a vaccine. But he does talk about potential vaccine damage and long term immunity issues.

The thing that I'm wondering about is whether they can really accelerate virus testing to a few months from the normal testing times. Does this mean a loss in certainty that the vaccine works, or works in the long term or does it compromise on potential safety problems?

 

[Adrian]

I thought one of the interesting things he talked about was whether the bad symptoms (putting people in ICU) were due to the virus or I think he was suggesting that they were due to the host response to the virus.

 

[Sasha]

The WHO now seem to be saying that they're worried that having been infected with coronavirus doesn't necessarily mean that you're immune but if so, how can a vaccine work?

 

[Snow Leopard]

I'm confused about what is happening with Vaccines. There is the Oxford group https://www.theguardian.com/society...ccine-trials-could-be-completed-by-mid-august who are claiming that they will have a vaccine tested by September. Yet others (including Lipkin) talked about it being hard to reduce the development time from 18 months.

I'm skeptical of all these timeframes unless they show a clear planned timeframe of all the procedures involved. Even 18 months requires significant overlapping of the various trial phases and extremely fast decision making by approval authorities.

But unapproved/incomplete evidence vaccines may be rolled out sooner - in developing countries or for at-risk health care workers, given that some authorities can decide not to wait for the evidence.

A am willing to bet however that we will be able to find a vaccine that will be at least as effective as our influenza vaccines and that given the observed spike protein mutation rates, those who seroconvert from an effective vaccine or the virus itself will have protection that lasts at least a few years. I don't suggest buying into the catastrophisation that somehow despite our immune systems working for similar infections, that it will somehow fail for SARS-2. (keep in mind, SARS-2 is not a sophisticated virus like HIV or EBV/CMV that have proteins dedicated to fucking with the immune system.)

 

[Snow Leopard]

Clotting issues are also likely due to ACE2 receptor related dysfunction:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107144/

 

[Mij]

Most of the available antibody tests can say only whether someone has antibodies, not how many they have or how powerful they are at fighting the virus. Many of the tests are also flawed and signal the presence of antibodies even when there are none.

 

[Sly Saint]

 

[Sly Saint]

Neurological Implications of COVID-19 Raise Concerns

 

[Mithriel]

Most of the available antibody tests can say only whether someone has antibodies, not how many they have or how powerful they are at fighting the virus. Many of the tests are also flawed and signal the presence of antibodies even when there are none.

I agree. Having a very low number of antibodies in the blood doesn't mean much, it is how fast the body can make new ones when there is a new infection.

Antibody tests are used successfully for things like hepatitis, but the kits are tested and quality controlled before they are licensed and that takes a lot of time.

 

[spinoza577]

https://www.medrxiv.org/content/10.1101/2020.03.30.20048058v1
Interleukin-6 in COVID-19: A Systematic Review and Meta-Analysis
Eric Anthony Coomes, View ORCID ProfileHourmazd Haghbayan
doi: https://doi.org/10.1101/2020.03.30.20048058

Purpose: Coronaviruses may activate dysregulated host immune responses. As exploratory studies have suggested that interleukin-6 (IL-6) levels are elevated in cases of complicated COVID-19 and that the anti-IL-6 biologic tocilizumab may be beneficial, we undertook a systematic review and meta-analysis to assess the evidence in this field.

Methods: We systematically searched MEDLINE and EMBASE for studies investigating the immunological response in COVID-19 or its treatment with tocilizumab; additional grey literature searches were undertaken. Meta-analysis was undertaken using random effects models.

Results: Eight published studies, three pre-prints, and five registered trials were eligible. Meta-analysis of mean IL-6 concentrations demonstrated 2.9-fold higher levels in patients with complicated COVID-19 compared with patients with non-complicated disease (six studies; n=1302; 95%CI, 1.17-7.19; I2=100%). A single non-randomized, single-arm study assessed tocilizumab in patients with severe COVID-19, demonstrating decreased oxygen requirements, resolution of radiographic abnormalities, and clinical improvement. No adverse events or deaths were observed.

Conclusions: In patients with COVID-19, IL-6 levels are significantly elevated and associated with adverse clinical outcomes. While inhibition of IL-6 with tocilizumab appears to be efficacious and safe in preliminary investigation, the results of several ongoing clinical trials should be awaited to better define the role of tocilizumab in COVID-19 prior to routine clinical application.

Further mechanism might be found here:

re: IL-6

the dose-response association between nitrogen dioxide exposure and serum interleukin-6 concentration
Perret et al 2017

abstract


conclusion


In so far the corona deaths might rather be not of respsiratory origin
maybe this could be an explanation for a pattern to be possibly seen in the future
as corona deaths are highest in Sao Paulo so far, in Brazil (if NO 2 is very high there, too)

effects of NO 2 exposure on daily mortality in sao paulo, brazil
Costa et al 2017

NO 2 is, if I remember rightly, physiologically produced to get rid of physiological NO, cf second article here.
This might be an avenue, I think.

Interaction of Nitrogen Monoxide With Hemoglobin and the Artefactual Production of S-nitroso-hemoglobin
Herold 2003, a review



Reaction of Hemoglobin With Nitric Oxide and Nitrogen Dioxide in Mice
Oda et al 1980

Doing a last try with this speculation.


Transport and Peripheral Bioactivities of Nitrogen Oxides Carried by Red Blood Cell Hemoglobin: Role in Oxygen Delivery
Sonveaux et al 2007

 

[Marco]

Coronavirus strains may determine the the optimal treatment :

Coronavirus’s ability to mutate has been vastly underestimated, and mutations affect deadliness of strains, Chinese study finds

In hospitals, Covid-19 has been treated as one disease and patients have received the same treatment regardless of the strain they have. Li and her colleagues suggested that defining mutations in a region might determine actions to fight the virus.

“Drug and vaccine development, while urgent, need to take the impact of these accumulating mutations … into account to avoid potential pitfalls,” they said.

https://www.scmp.com/news/china/sci...tions-affect-deadliness-strains-chinese-study

 

[lansbergen]

To verify the theory, Li and colleagues infected cells with strains carrying different mutations. The most aggressive strains could generate 270 times as much viral load as the weakest type. These strains also killed the cells the fastest.

Coronavirus strains may determine the the optimal treatment :

Coronavirus’s ability to mutate has been vastly underestimated, and mutations affect deadliness of strains, Chinese study finds



https://www.scmp.com/news/china/sci...tions-affect-deadliness-strains-chinese-study

 

[lansbergen]

To verify the theory, Li and colleagues infected cells with strains carrying different mutations. The most aggressive strains could generate 270 times as much viral load as the weakest type. These strains also killed the cells the fastest.

When it multiplies to fast the host will lose the battle.

 

[Snow Leopard]

When it multiplies to fast the host will lose the battle.

If it kills too fast, the virus will lose the battle because the host will die before the virus can spread.

 

[lansbergen]

If it kills too fast, the virus will lose the battle because the host will die before the virus can spread.

Not if it spreads before the host dies.

Virusses do not want to kill the host, they want to multiply.

Maybe the less virulent strains will get the upperhand.

 

[spinoza577]

If it kills too fast, the virus will lose the battle because the host will die before the virus can spread.

Not if it spreads before the host dies.

Virusses do not want to kill the host, they want to multiply.

Maybe the less virulent strains will get the upperhand.

And it even could be enough that the host stays at home in bed and not speaking to anybody else, for getting out of the traffic.

(May this is the reason that common colds do spread only to some percentage of the population?)