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

Coronavirus: Plasma therapy has begun in 5 US patients. Will it work?

In New York and Houston, pints of straw-colored convalescent plasma have dripped into the veins of five U.S. coronavirus patients. Hundreds more there and across the nation are set to follow.

Whether the plasma, derived from the blood of people who recovered from COVID-19, will help them fight off the devastating disease caused by the new coronavirus that has killed more than 5,100 Americans is unknown. In less than three weeks, the effort to find out has gone from an idea to a worldwide program entirely self-organized by medical researchers.

Like so much about the desperate efforts to fight the COVID-19 pandemic, it’s seat-of-the-pants medicine. Doctors don’t know whether it will work but hope to find out in weeks, not the years it typically takes for studies to yield answers.
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https://eu.usatoday.com/story/news/...apy-5-us-patients-covid-19-donors/5090946002/
 
People are talking about recombining ACE2 with the FC region (antibody attachment site) to block the virus spikes and mark it for disposal.

https://f1000research.com/articles/9-72
The proposal is a biologic that blocks 2019-nCoV entry using a soluble version of the viral receptor, angiotensin-converting enzyme 2 (ACE2), fused to an immunoglobulin Fc domain (ACE2-Fc), providing a neutralizing antibody with maximal breath to avoid any viral escape, while also helping to recruit the immune system to build lasting immunity.
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https://www.biorxiv.org/content/10.1101/2020.02.01.929976v2.full.pdf
In this report, we generated a novel recombinant protein by connecting the extracellular domain of human ACE2 to the Fc region of the human immunoglobulin IgG1.
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Not sure what this is but it looks like its on sale for lab testing already!
https://www.sinobiological.com/recombinant-proteins/human-ace2-10108-h02h

Which looks interesting but having wrestled with trying to understand Antibody Dependant Enhancement of infection, I cant help wondering if it would carry any risks.

https://en.wikipedia.org/wiki/Antibody-dependent_enhancement
 
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Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2
https://www.cell.com/pb-assets/products/coronavirus/CELL_CELL-D-20-00739.pdf
Summary

We have previously provided the first genetic evidence that Angiotensin converting enzyme 2 (ACE2) is the critical receptor for SARS-CoV and that ACE2 protects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections.

ACE2 has now also been identified as a key receptor for SARS-CoV-2 infections and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19.

However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growth of SARS-CoV-2.

Here we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000-5 ,000.

An equivalent mouse rsACE2 had no effect.

We also show that SARS-CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2.

These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections.
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"BCG (TB) vaccine might protect against Covid19"

United Kingdom: The UK introduced universal BCG immunization in 1953. From then until July 2005, UK policy was to immunize all school children aged between 10 and 14 years of age, and all neonates born into high-risk groups. ... BCG was also given to protect people who had been exposed to tuberculosis.
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I didn't realise they'd stopped this in the UK.

But tuberculosis is bacterial, or doesn't that make any difference?
@Jonathan Edwards

eta:
https://www.reuters.com/article/us-...-help-fight-the-new-coronavirus-idUSKBN21K372
 
Sly Saint said:
But tuberculosis is bacterial, or doesn't that make any difference?
@Jonathan Edwards
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The tubercle bacterium has a particularly potent innate immune stimulant in it that became the central ingredient what was called Freund's adjuvant. It boosts reactivity to any vaccine given. Whether it would boost immunity to a clever virus or not is speculative but it might. The down side of the immune stimulant effect of TB is that it is probably part of the way the bacterium tricks the host into keeping it alive - by getting eaten by macrophages in which it then lives.

BCG is a benign variant of TB that can live locally in the host for a period of days and produce a local infection that is then controlled. I think the adjuvant effect would be fairly slow to take hold - over many days, which would be of little benefit in someone already very ill but might be relevant to people in the early mild phase seen in some Covid19 cases. BCG is instilled into the bladder to stimulate a local immune response that can help destroy bladder cancers.
 
Sly Saint said:
It would be relatively easy to check (providing peoples records are accurate) which frontline staff have had the BCG vaccination, they might have to double check with those who have come from other countries. But might the fact that someone was vaccinated sometime ago be sufficient or are they proposing to 're-vaccinate' as a treatment?
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Vaccination in the past I think would be irrelevant. The helpful action of BCG would be only at the time of giving.
 
I hesitate to ask but I wonder if any of the 2215 members of the forum think they have had Covid19? nd what was it like? The only people I know so far who have had it are people who visit hospitals regularly.

This post has been copied and responses moved to this thread in the members only area.
 
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It happened that I just came across this interesting review (already)

The neuroinvasive potential of SARS-cov-2 may play a role in the respiratory failure ...

abstract

Following the severe acute respiratory syndrome coronavirus (SARS‐CoV) and Middle East respiratory syndrome coronavirus (MERS‐CoV), another highly pathogenic coronavirus named SARS‐CoV‐2 (previously known as 2019‐nCoV) emerged in December 2019 in Wuhan, China, and rapidly spreads around the world. This virus shares highly homological sequence with SARS‐CoV, and causes acute, highly lethal pneumonia coronavirus disease 2019 (COVID‐19) with clinical symptoms similar to those reported for SARS‐CoV and MERS‐CoV. The most characteristic symptom of patients with COVID‐19 is respiratory distress, and most of the patients admitted to the intensive care could not breathe spontaneously.

Additionally, some patients with COVID‐19 also showed neurologic signs, such as headache, nausea, and vomiting. Increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases. The infection of SARS‐CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected.

Furthermore, some coronaviruses have been demonstrated able to spread via a synapse‐connected route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lung and lower respiratory airways. Considering the high similarity between SARS‐CoV and SARS‐CoV2, it remains to make clear whether the potential invasion of SARS‐CoV2 is partially responsible for the acute respiratory failure of patients with COVID‐19. Awareness of this may have a guiding significance for the prevention and treatment of the SARS‐CoV‐2‐induced respiratory failure.
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Maybe it sheds even some light on ME/CFS?
 
Amw66 said:
Interesting article - linking BCG vaccination to reduced prevalence of COVID19

https://www.irishtimes.com/news/hea...-changer-in-covid-19-fight-1.4220383?mode=amp
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There are many other uncontrolled factors, I wouldn't get too excited about this. It may even be a reporting bias, namely the non-BCG countries are reporting infection rates that are more accurate. There is a clear geographical bias between countries with current BCG vaccination policies and not: http://www.bcgatlas.org/ (on the map)

There is no reactivity between antibodies towards BCG and coronavirus.
 
News article in the San Jose Mercury news on one of the first community prevalence studies in the US run by Stanford University with antibody sampling of 2500 volunteers.

Coronavirus: New Stanford research reveals if you’ve been exposed
https://www.mercurynews.com/2020/04...nford-research-reveals-if-youve-been-exposed/
Long motorcades of volunteers converged at three Stanford University research sites this week, donating blood for a new test that identifies the prevalence of coronavirus in our community – and could help reveal the full scope of Santa Clara County’s epidemic.

The 2,500 test slots on Friday and Saturday filled up within hours, as news of the project — the first large scale study of its type in the U.S. — spread quickly through the county.

The test detects protective antibodies to the virus rather than the virus itself.

This gives scientists a snapshot of how many people in the county have already been infected, but weren’t seriously sick and didn’t realize it. And it tells residents whether they carry potentially protective antibodies – so may be immune to future infection.

“This is critical information,” said principal investigator Dr. Eran Bendavid, an infectious disease specialist and professor of medicine with Stanford Health Policy.

“We will show the country what to do and how to do it,” he said.
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This snippet in the news article about whether antibodies provide protection was concerning
It is not yet proven that these antibodies actually provide protection. Related coronaviruses offer a spotty record. Some, which cause the common cold, return again and again. The antibodies to Middle East respiratory syndrome lasted merely a year.
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Got something from ProMED mail that you all might find interesting.

Microneedle array delivered recombinant coronavirus vaccines
Date: Thu 2 Apr 2020

(Apologies for the length, but when about 20 years ago I asked for permission to re-post some of their mails they wanted the whole mail sending. Probably a good idea anyway, as means anyone looking at it can find sources and previous sources.)

============>>>

[5] Microneedle array delivered recombinant coronavirus vaccines
Date: Thu 2 Apr 2020
Source: The Lancet [edited]
<https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(20)30118-3/fulltext>


ref: Kim E, Erdos G, Huang S, et al. Microneedle array-delivered
recombinant coronavirus vaccines: immunogenicity and rapid
translational development. EBioMedicine. 2 Apr 2020. doi:
<https://doi.org/10.1016/j.ebiom.2020.102743>.
--------------------------------------------------------------------------------
Abstract
---------
Background
Coronaviruses pose a serious threat to global health as evidenced by
severe acute respiratory syndrome (SARS), Middle East respiratory
syndrome (MERS), and COVID-19. SARS coronavirus (SARS-CoV), MERS
coronavirus (MERS-CoV), and the novel coronavirus, previously dubbed
2019-nCoV, and now officially named SARS-CoV-2, are the causative
agents of the SARS, MERS, and COVID-19 disease outbreaks,
respectively. Safe vaccines that rapidly induce potent and
long-lasting virus-specific immune responses against these infectious
agents are urgently needed. The coronavirus spike (S) protein, a
characteristic structural component of the viral envelope, is
considered a key target for vaccines for the prevention of coronavirus
infection.

Methods
We 1st generated codon-optimized MERS-S1 subunit vaccines fused with a
foldon trimerization domain to mimic the native viral structure. In
variant constructs, we engineered immune stimulants (RS09 or
flagellin, as TLR4 or TLR5 agonists, respectively) into this trimeric
design. We comprehensively tested the pre-clinical immunogenicity of
MERS-CoV vaccines in mice when delivered subcutaneously by traditional
needle injection, or intracutaneously by dissolving microneedle arrays
(MNAs) by evaluating virus-specific IgG antibodies in the serum of
vaccinated mice by ELISA and using virus neutralization assays. Driven
by the urgent need for COVID-19 vaccines, we utilized this strategy to
rapidly develop MNA SARS-CoV-2 subunit vaccines and tested their
pre-clinical immunogenicity in vivo by exploiting our substantial
experience with MNA MERS-CoV vaccines.

Findings
Here we describe the development of MNA-delivered MERS-CoV vaccines
and their pre-clinical immunogenicity. Specifically, MNA-delivered
MERS-S1 subunit vaccines elicited strong and long-lasting
antigen-specific antibody responses. Building on our ongoing efforts
to develop MERS-CoV vaccines, promising immunogenicity of
MNA-delivered MERS-CoV vaccines, and our experience with MNA
fabrication and delivery, including clinical trials, we rapidly
designed and produced clinically translatable MNA SARS-CoV-2 subunit
vaccines within 4 weeks of the identification of the SARS-CoV-2 S1
sequence. Most importantly, these MNA-delivered SARS-CoV-2 S1 subunit
vaccines elicited potent antigen-specific antibody responses that were
evident beginning 2 weeks after immunization.

Interpretation
MNA delivery of coronaviruses-S1 subunit vaccines is a promising
immunization strategy against coronavirus infection. Progressive
scientific and technological efforts enable quicker responses to
emerging pandemics. Our ongoing efforts to develop MNA-MERS-S1 subunit
vaccines enabled us to rapidly design and produce MNA SARS-CoV-2
subunit vaccines capable of inducing potent virus-specific antibody
responses. Collectively, our results support the clinical development
of MNA-delivered recombinant protein subunit vaccines against SARS,
MERS, COVID-19, and other emerging infectious diseases.

--
communicated by:
ProMED-mail
<promed@promedmail.org>

[Microneedle arrays (MN) are minimally invasive devices that
painlessly bypass the skin's stratum corneum, which is the principal
barrier to topically applied drugs. MN (50-900 micrometre in height,
up to 2000 MN per square centimetre) have been extensively
investigated in recent years as a means to enhance transdermal drug
and vaccine delivery.
(<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627464/>)

As mentioned in the report above, the researchers used a new approach
to deliver the drug, called a microneedle array, to increase potency.
This array is a fingertip-sized patch of 400 tiny needles that
delivers the SARS-CoV-2 S protein pieces into the skin, where the
immune reaction is strongest. The patch is applied similarly to a
plaster, and then the needles, made entirely of sugar and the protein
pieces, dissolve into the skin. Furthermore, according to the vaccine
developers, the system is highly scalable. The protein pieces are
manufactured by a "cell factory" -- multiple layers of cultured cells
engineered to express the SARS-CoV-2 S protein -- that can be stacked
further to multiply yield. Purifying the protein can be conducted at
industrial scale. Mass-producing the microneedle array involves
spinning down the protein-sugar mixture into a mould using a
centrifuge. Once manufactured, the vaccine can sit at room temperature
until it is needed, eliminating the need for refrigeration during
transport or storage.
(<https://www.europeanpharmaceuticalr...eveloped-to-deliver-covid-19-vaccine-to-mice/>)

This sounds extremely promising. The use of MN-mediated vaccine
delivery for SARS-CoV-2 and other emerging pathogens will hold immense
potential for expanding access to vaccines, particularly to access
populations in developing countries. - Mod.UBA]

[See Also:
COVID-19 update (79): research update
http://promedmail.org/post/20200404.7182653
COVID-19 update (78): countries with high local transmission
http://promedmail.org/post/20200404.7182833
COVID-19 update (77): global, polio vacc on hold, new countries, WHO
http://promedmail.org/post/20200404.7182744
COVID-19 update (76): China (HU) animal, cat, owned, stray,
seropositive http://promedmail.org/post/20200403.7179946
COVID-19 update (75): China (Hong Kong) cat, OIE
http://promedmail.org/post/20200403.7179945
COVID-19 update (74): countries with high local transmission
http://promedmail.org/post/20200403.7178356
COVID-19 update (73): global, cruise ships, new countries, WHO
http://promedmail.org/post/20200403.7178355
COVID-19 update (72): countries with high local transmission
http://promedmail.org/post/20200402.7174839
COVID-19 update (71): global, Taiwan, new countries, WHO
http://promedmail.org/post/20200402.7174769
COVID-19 update (70): China (Hong Kong) cat, pets & stock
http://promedmail.org/post/20200402.7173286
COVID-19 update (60): global, cruise ships, lessons learned, WHO
http://promedmail.org/post/20200329.7156949
COVID-19 update (50): China (Hong Kong) dog, 2nd case PCR positive,
OIE http://promedmail.org/post/20200323.7129951
COVID-19 update (40): global, Europe epicenter, lockdown, phone
tracking, WHO http://promedmail.org/post/20200315.7092618
COVID-19 update (30): China (Hong Kong) dog, susp, serology pending
http://promedmail.org/post/20200306.7057595
COVID-19 update (20): China, global, Italy, Iran, Nigeria, imported
cases, WHO http://promedmail.org/post/20200228.7032761
COVID-19 update (10): China, global, Iran, WHO
http://promedmail.org/post/20200219.7005749
COVID-19 update (01): China, global, EVZD, reporting criteria, WHO
http://promedmail.org/post/20200213.6984084
Novel coronavirus (42): China, global, COVID-19, SARS-CoV-2, WHO
http://promedmail.org/post/20200211.6979942
Novel coronavirus (41): China, global, clinical pics, asymptomatic
trans., WHO http://promedmail.org/post/20200210.6976117
Novel coronavirus (40): animal reservoir, pangolin poss intermediate
host, RFI http://promedmail.org/post/20200210.6972104
Novel coronavirus (30): updates, China, Viet Nam, research
http://promedmail.org/post/20200202.6945658
Novel coronavirus (20): China, wildlife trade ban
http://promedmail.org/post/20200127.6922060
Novel coronavirus (10): China (HU, GD, BJ)
http://promedmail.org/post/20200119.6898567
Novel coronavirus (01): China (HU) WHO, phylogenetic tree
http://promedmail.org/post/20200112.6885385
Undiagnosed pneumonia - China (HU) (10): genome available, Hong Kong
surveill. http://promedmail.org/post/20200111.6883998
Undiagnosed pneumonia - China (01): (HU) wildlife sales, market
closed, RFI http://promedmail.org/post/20200102.6866757
2019
---
Undiagnosed pneumonia - China (HU): RFI
http://promedmail.org/post/20191230.6864153]
.................................................uba/tw/sh

------------------------------

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End of ProMED Digest, Vol 94, Issue 13
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