Omicron OT?

[RonO]

https://www.science.org/content/article/omicron-cases-are-exploding-scientists-still-don-t-know-how-bad-wave-will-be

They don't know exactly what makes Omicron so infective, but other
articles that I have seen claim that it may be 3 times more infective
than Delta, which was more infective than the UK variant, that was more
infective than the original virus.

Omicron still uses ACE2 to infect the cells. Treatments include
monoclonal antibody treatment and most of these antibodies bind to the S
protein of the virus. The S protein binds to ACE2 and then the virus is
drawn into the host cell. Our current vaccines (except the killed virus
vaccines that has a lot of viral proteins in it) present the S protein
as the vaccine antigen. The fear is that mutations in the S protein
will make the S protein based vaccines less effective. So far all the
viral variants have used binding to the S protein, so all the S protein
variants need to allow the virus to bind to the ACE2 host protein.

This seems to mean that we can use the evolutionary tactic of reducing
vaccine effectiveness as a more effective treatment. We already have
the very expensive antibody treatments, but we could create antibodies
that would present the ACE2 sequence as it is presented on the cell
surface. These antibodies should always bind to the viral S protein
because all the viral S protein sequence variants need to bind to the
ACE2 sequence.

It would be using the natural selection for increased infectivity
involving ACE2 from beating the current treatments. It would just take
replacing the normal antibody binding region with ACE2 sequence so that
the sequence would be presented as it is on the cell surface. Such a
GMO antibody would replace the current antibody treatment. If we had
such an ACE2 representation then it should be good against any S protein
modification because it would be the S protein binding to the GMO
antibody and not the other way around.

I'm not a virologist nor an immunologist, but we already make the
antibodies in cell culture, so we could make engineered antibodies that
should be more effective and be able to adapt to any S protein changes
because it is the viral S protein that would be binding to the GMO
antibody sequence. We would be using the viral strategy of infecting
the cell to make a treatment that would not be subject to the virus
adapting to beating the current S protein vaccines.

Ron Okimoto

[Lawyer Daggett]

I hate this nonsense. It does not make sense to claim that Omicron developed
its changes to the spike protein through natural selection driven by immune evasion.
That is a process that exists but it isn't magic. Pay attention to the underlying
mathematics and natural history here and it obviously isn't what happened.
The selection here is not significantly being influenced by vaccine
based immunity as there are so many unvaccinated individuals world-wide.

There hasn't been enough time, there haven't been enough generations. And we
lack a history of intermediates despite significant levels of diagnostic surveillance
with excellent temporal and geographic resolution.

You're tossing about the worst sort of "just-so" stories. Stop it.

Further, while we could rapidly manufacture Omicron specific monoclonals, or Omicron
specific mRNA vaccines, each path requires many months of safety and efficacy
testing. Sure, we know the underlying science and what should work, but it remains
essential that we conduct controlled trials to verify safety.

There's always a chance that you develop antibodies to non-linear epitopes that
will cross react to self-antigens and cause serious problems, even if in a relatively
small subset of those being vaccinated. If a particular virus was exceptionally
deadly, the risk/benefit calculation might shift to bypass some testing but I don't
think we're there. I don't think we're even close if you factor in the sort of backlash
that the anti-vax movement would gain traction with if there were serious adverse
consequences.

If you want to inform yourself, the Moderna vaccine designed against the original
wild-type is called mRNA-1273. They have been doing clinical trials on the Beta
Variant of Concern (VOC) called mRNA-1273.211. They also have a Delta based
candidate called mRNA-1273.617.2. They've been looking at combinations. And
they've frankly been caught by the fact that they put a great deal of time and money
into their Beta variant but then the pandemic moved on and Delta was the thing.
And now Omicron is the thing.

Pfizer has been testing BNT162b2SA which is a Beta based variant mRNA vaccine
but again it's shooting at a moving target. Clinical trials take time. And it's gotten
more complex. For the first wave, we had a large naive population. Now, you've
got to look at boosting already vaccinated people because the sort of people that
are willing to volunteer for a clinical trial have already gotten vaccinated. We got
so lucky in the first wave because it was a record pace for recruiting volunteers for
large scale clinical trials. That's typically a very slow step, easily taking years.
Turns out that they've had some pretty good success recruiting people who took
part of the first wave of clinical trials to take part of VOC boosters but there's
significant attrition. Taking time for the blood draws wears on people.

It would be a challenge to match the pace of spread if it were merely a manufacturing
challenge but it is so much more than that.

[RonO]

There is no doubt that Omicron can infect previously infected
individuals, and can do so more effectively than previous variants. I
just stated the fears of all the S protein changes and efficacy of the
vaccines. They are less effective to prevent infection, but they still
attenuate infection in some way.

The proposal that I made was not about changing vaccine antigen
sequence. ACE2 is a host expressed protein that the virus uses as a
receptor for entry into the host cells. I just indicated that we could
improve the efficacy of antibody treatments and make the monoclonals
less likely to fail due to changes in their binding region to the S
protein, by putting the extracellular portion of ACE2 onto an antibody.
It would be a GMO construct and would be produced by the monoclonal
antibody cells. It would bind to the viral S protein, but because the S
protein would bind to it. Current monoclonal antibodies can become
ineffective if the S protein sequence that they bind to changes. For
viral mutations in the S protein that do not affect monoclonal antibody
binding we only worry about viral mutations in the S protein that make
binding to ACE2 better and infection more efficient. These mutations
would only bind to the ACE2 chimeric antibody more effectively. Such a
chimeric antibody would not be subject to the same issues as the
monoclonal antibodies currently in use because any S protein sequence
changes would still bind to the chimeric ACE2 GMO antibody if it can
still infect the host cells and mutations that make the S protein to
bind to ACE2 better would only make the chimeric antibody more effective.

This is not a vaccine, but a replacement for current monoclonal antibody
treatments that are currently the best that they can do. I was just
pointing out that using the extra cellular part of ACE2 that the virus
binds to in order to infect the cell we could create an effective
antibody that would not be subject to changes in the Viral S protein
that are issues with current treatments and viral infection efficiency.

Ron Okimoto

[Lawyer Daggett]

You are even more stupid than I thought. You want to administer antibodies
against ACE2? Beg forgiveness for that level of stupid. Return your PhD.
Resign your teaching position.

You want to eviscerate a fundamental physiological pathway? Impair the virus
by killing the patient. Cyanide would work too. ACE2 is an essential functional
enzyme in the renin angiotensin system. Learn some basic (high school) physiology.
Damn!

[*Hemidactylus*]

I thought he was saying to replace the binding regions of antibodies with
something mimicking ACE2 receptor so variants would preferentially lock
onto these Franken-CDRs via their spikes and not enter susceptible cells.
More an outside the box thought I suppose.

I had thought they were working on ACE2 gum to reduce viral particles in
the oral cavity somehow.

[*Hemidactylus*]

If Omicron spent a year on walkabout in a population of mice the human
immune evasion would be incidental but fortuitous, no? If it was emerging
in people cryptically because lack of sequencing could that involve
adaption to evade? Are populations in South Africa greatly antigen naive
after Delta, previous variants, or some level of vaccination?

> There hasn't been enough time, there haven't been enough generations.

Generation time is pretty short in viruses no? The mouse origin paper
points to the amount of change indicating selection within a mouse milieu
toward better fit toward murine ACE2 but from mid 2020 to Fall of 2021.
Kinda make you not want to cough until a pest control person has cleared
your house. But there are other potential mammalian ping-pong partners.

> And we
> lack a history of intermediates despite significant levels of diagnostic surveillance
> with excellent temporal and geographic resolution.
>

Everywhere? Omicron if evolved in people couldn’t have escaped sequence
attuned notice? If inside an immune compromised person who wasn’t having
samples sequenced….

>
> You're tossing about the worst sort of "just-so" stories. Stop it.
>
> Further, while we could rapidly manufacture Omicron specific monoclonals, or Omicron
> specific mRNA vaccines, each path requires many months of safety and efficacy
> testing. Sure, we know the underlying science and what should work, but it remains
> essential that we conduct controlled trials to verify safety.
>
> There's always a chance that you develop antibodies to non-linear epitopes that
> will cross react to self-antigens and cause serious problems, even if in a relatively
> small subset of those being vaccinated. If a particular virus was exceptionally
> deadly, the risk/benefit calculation might shift to bypass some testing but I don't
> think we're there. I don't think we're even close if you factor in the sort of backlash
> that the anti-vax movement would gain traction with if there were serious adverse
> consequences.
>

What would happen with monoclonals having ACE2 mimic spliced to replace
spike targeted CDRs? Sounds weird but that was Ron’s point.

>
> If you want to inform yourself, the Moderna vaccine designed against the original
> wild-type is called mRNA-1273. They have been doing clinical trials on the Beta
> Variant of Concern (VOC) called mRNA-1273.211. They also have a Delta based
> candidate called mRNA-1273.617.2. They've been looking at combinations. And
> they've frankly been caught by the fact that they put a great deal of time and money
> into their Beta variant but then the pandemic moved on and Delta was the thing.
> And now Omicron is the thing.
>

Until another spillback that looks different from anything else?

>
> Pfizer has been testing BNT162b2SA which is a Beta based variant mRNA vaccine
> but again it's shooting at a moving target. Clinical trials take time. And it's gotten
> more complex. For the first wave, we had a large naive population. Now, you've
> got to look at boosting already vaccinated people because the sort of people that
> are willing to volunteer for a clinical trial have already gotten vaccinated. We got
> so lucky in the first wave because it was a record pace for recruiting volunteers for
> large scale clinical trials. That's typically a very slow step, easily taking years.
> Turns out that they've had some pretty good success recruiting people who took
> part of the first wave of clinical trials to take part of VOC boosters but there's
> significant attrition. Taking time for the blood draws wears on people.
>
> It would be a challenge to match the pace of spread if it were merely a manufacturing
> challenge but it is so much more than that.
>

What about the Walter Reed approach using a multifaceted vaccine with
several different spikes to present a broader range of spike looks?

[Lawyer Daggett]

I see I misread that but it's almost worse. One of the major drawbacks of
monoclonal antibodies has always been their immunogenicity.
People wrote that off when they were mouse mAb and even when they
were chimeric "humanized" mAbs. We just need to make authentic human
forms they thought. But even with fully human mAbs there's still a danger
of breaking tolerance. In that case it would be like vaccinating against
the ACE2 receptor and those that do break tolerance would face what would
likely be a devastating autoimmune reaction.

The situation isn't improved when the therapy is intended to be given to
someone in the midst of a severe viral infection and the accompanying
heightened inflammatory state.

[Ernest Major]

I think I recall people proposing manufacturing ACE2 (genetically
engineered bacteria?) and spraying it into people's airways as a
prophylactic against COVID-10. (Turns out that Wikipedia has a link to
an in-vitro study - https://doi.org/10.1016/j.cell.2020.04.004 - but
they seem to be proposing it as a treatment rather than a prophylactic.
According to Google Scholar that paper has 1401 citations, so finding
the relevant responses is a daunting task.)

That product (rhACE2) is a proposed treatment for acute lung injury.

However, ACE2 is involved in the regulation of blood pressure (and is
"an essential regulator of heart function"). Engineer too much of the
ACE2 protein into a recombinant antibody and you risk adverse effects.
Engineer too little and you may not mimic the SARS-COV-2 binding site,
and still risk adverse effects. Also, Wikipedia tells me that the
half-life of rhACE2 in vivo is ten hours, so you'd need regular dosages.

It would be simpler to select monoclonal antibodies that bind tightly to
the spike receptor binding domain - we know how to manufacture
monoclonal antibodies - manufacturing a chimaeric protein, which seems
to be what you're proposing, is a tougher challenge. Examination of the
degree of conservation of the RBD would shed light on the robustness of
such antibodies as a treatment.

--
alias Ernest Major

[RonO]

No. I want to put the ACE2 sequence onto an antibody so that the S
protein will bind to it. How dense are you? Putting a sequence that
binds to an antigen onto an antibody is not producing antibodies against
ACE2.

There is a retroviral resistance where the retrovirus that integrates
into the genome is defective and can no longer replicate, but it still
produces envelope proteins like the S protein. The production of these
envelope proteins acts as competitive exclusion where they compete for
intact viral envelope proteins and inhibit virus binding to their
receptors and entering the cell. This proposal would put the ACE2
extracellular portion on the the antibody so that the viral S protein
would bind to it, and trigger the immune response instead of getting
into the cell.

>
> You want to eviscerate a fundamental physiological pathway? Impair the virus
> by killing the patient. Cyanide would work too. ACE2 is an essential functional
> enzyme in the renin angiotensin system. Learn some basic (high school) physiology.
> Damn!
>

You totally misunderstood. No one was proposing making antibodies
against ACE2.

Ron Okimoto

[RonO]

You only need the extra cellular part of the ACE2 protein. The
signalling part is not required.

The paper that you cited was trying competitive exclusion, but the
competitive exclusion that works is to have excess amounts of the viral
envelope proteins like the S protein that binds the receptors before the
virus can. That seems to work for retrovirus, and is found to be a
genetic resistance to retroviral infection. The retrovirus has inserted
into the genome, but that copy is defective and does not replicate, but
if it still produces high amounts of envelope protein there is
competitive exclusion for further viral infections.

>
> It would be simpler to select monoclonal antibodies that bind tightly to
> the spike receptor binding domain - we know how to manufacture
> monoclonal antibodies - manufacturing a chimaeric protein, which seems
> to be what you're proposing, is a tougher challenge. Examination of the
> degree of conservation of the RBD would shed light on the robustness of
> such antibodies as a treatment.
>

You could select for one, but this option would not be deterred from a
sequence substitution in the S protein binding domain that more
efficiently bound to the ACE2. As long as it still bound to the
extracellular portion of ACE2 the chimeric antibody would work. The
chimeric monoclonal would work for as long as the virus used ACE2 to
enter the cell. It should also work against other corona virus that use
ACE2 to enter the cell.

Ron Okimoto

[Ernest Major]

This has turned up

Researchers think that they've found a broad-spectrum anti-spike
antibody - effectively what Ron is asking for, less the baggage of more
of the ACE2 protein.

https://medicalxpress.com/news/2022-01-antibody-inhibits-broad-range-sarbecoviruses.html

If it works, and doesn't have adverse side-effects, it will be a weapon
in humanity's arsenal when the next sarbecovirus makes the jump.

--
alias Ernest Major