Great find, pythagoras; it's a little technical bu

Great find, pythagoras; it's a little technical but everyone should check it out to understand the challenges facing humanity with finding a vaccine.

https://twitter.com/VirusesImmunity/status/12...5804142593

I forget the name of the company, but someone keeps bringing up that Dr. and company that was on Netflix's 'Pandemic' and their "array of antibodies"; this is exactly what they will face and why IMO they won't be finding any successful treatment. Quite the contrary, just dumping antibodies willy-nilly into patients could actually prove harmful , possibly even lethal.

Sobering thought.

Edit: I'll try to C&P the thread here for simplicity's sake.. the images and charts on Twitter are worth a look, though

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This is a cautionary tale of how anti-Spike antibody may make COVID disease worse. In this study, the authors show that anti-Spike IgG made SARS-CoV disease worse by switching macrophage from wound-healing to proinflammatory phenotype. A thread (1/n)

When rhesus macaques were immunized with SARS-Spike MVA vaccine, high titers of neutralizing Ab (NAb) generated correlated with severe diffuse alveolar damage NOT protection upon i.n. challenge with SARS-CoV, despite reducing viral load. Loss of disease tolerance by S-IgG. (2/n)

Next, rhesus macaques injected with low or high dose of anti-Spike-IgG (passive transfer) and challenged with SARS developed worse disease. Thus, S-IgG alone can lead to SARS disease exacerbation. (3/n)

Anti-Spike IgG fails to prevent viral entry. Instead, it binds to virus, facilitating uptake by macrophages expressing FcR. This leads to macrophage stimulation and their production of proinflammatory cytokines (IL-6, IL-8, MCP1) and loss of tissue-repair cytokine (TGFb). (4/n)

Finally, sera from early stage SARS-infected patients reveal that elevated anti-Spike IgG was observed in those that ended up dying from infection. (5/n)

If these results also apply to #COVID19, targeting Spike as vaccine antigen may have detrimental effects. Passive transfer of anti-Spike mAb alone also may have detrimental effects. A protective vaccine approach may need to include other viral antigens (nucleocapsid?). (6/n)

Relevant to this thread is that in #COVID19 patients, the level of serum IgG against Spike protein correlates with older age, disease severity and lymphopenia. (7/n)

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Replying to
@VirusesImmunity
I've been telling people of studies in mice with inactivated SARS or subunit vaccines administered by footpad injection - that actually increased lung immunopathologies when the mice were challenged with live virus. May not bode well for spike protein-based vaccines.

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and HOLY CRAP, here he is!

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Dr. Jacob Glanville
@CurlyJungleJake
·
Mar 29
Replying to
@VirusesImmunity
We are building our IgG1 antibodies with LALA effector function knockout mutations to avoid ADE. It preserves FcRn binding but otherwise all other Fc binding is lost. Do you see any problem with this? Thank you for your feedback.

Mike Clark
@mrc7cam
·
Mar 29
That would knockout all FcR binding to macrophages. For what purpose are you doing this, passive immunity? If so by what mechanism do you expect viral clearance? It would be worth looking at different subclasses eg IgG2 in case low affinity FcR and complement may be beneficial.

John Desjarlais
@JrdDesjarlais
·
Mar 30
Hi Mike, long time no see/talk. Jake's/Distributed Bio's approach is passive for sure, focusing on neutralization to prevent ongoing infection. Agreed though, you're potentially given up important vaccinal effects by removing FcR binding. Vir Bio seems to be trying both.

Mike Clark
@mrc7cam
·
Mar 30
Nice to hear from you John. I retired from active research 5 years ago, was enjoying the quiet life, but there suddenly seems to be a lot of interest in antibodies and immunology! It's tricky for sure, quite likely that the Ab will behave differently in different patient cohorts

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Yeah... there is going to be a long road to test safety and efficacy with them