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Comment by aphextron | Hacker News Reader

It's important to note that the AstraZeneca vaccine is adenovirus based [0], not mRNA based like the Pfizer and Moderna candidates. It was to be expected that this approach could cause more complications. mRNA vaccines have their own issues, but they do not involve live viruses being injected [1]. Instead they use lipid nanoparticles as a substrate to enter the body's cells [2].

[0] https://www.astrazeneca.com/media-centre/press-releases/2020...

[1] https://www.phgfoundation.org/briefing/rna-vaccines

[2] https://www.nature.com/articles/s41586-020-2639-4

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> rather than producing them outside the body and then injecting them

That's not what the Oxford/AZ vaccine does, is it? From what I understand, it's a viral vector vaccine engineered to deliver DNA that encodes the SARS-CoV-2 spike protein into human cells and induce them to express the protein, stimulating the immune response.

The plan was never to introduce spike protein "produced outside the body." The mechanism of action is getting the body to produce spike protein and learn to attack it as foreign. If the Oxford/AZ vaccine doesn't "take advantage of your own cells to produce the spike protein," I don't know what does.

https://labblog.uofmhealth.org/rounds/top-5-covid-19-vaccine...

Yes, that was made in comparison to conventional vaccines that either use inactivated viruses or viral proteins

Plenty of vaccines both today and historically used LAV or other natural strains of the virus when possible.

Yes, the ChAdOx is an adenovirus carrier (chimp? to minimize human pre-infection) while Moderna and BioNTech as the parent states involve injection of mRNA (not DNA although there are other vaccines that do that) lipid particles that human cells then generate spike protein to simulate viral infection.

There are still other attenuated virus and other vaccines under development, they just haven't reached Phase III. Novavax even does something similar to what you describe (spike proteins with adjuvant), but it's also not past Phase I/II.

It could still be an immune system misfire. A vaccine is trying to create an large immune system response enough that the real infection is thwarted.

With that, a misfire can happen with any vaccine attempt, because an immune response is what's required.

I think COVID is going to be make or break for mRNA, at least for infectious disease. It's either going to usher in an exciting new era of treatments, or we're going to see a lot of funding dry up and shops close. I for one obviously hope for the former, but given the prior actions/statements of some in Inovio, Moderna, et al, it gives me pause.

You cannot roll out such a vaccine on a large scale within a at least a year. Far too many unknowns compared to the virus itself.

So how does this one work? Live adeno’s?

>So how does this one work? Live adeno’s?

Yes. It uses a live (weakened) chimpanzee adenovirus to insert the spike protein.

https://www.drugs.com/history/azd1222.html

Do the adenos actually have to infect the cells to produce the spikes?

Yes, they don’t replicate virons that could be assembled the virus was modified to mainly replicate the spike proteins since your cells send samples of anything they replicate to the cell wall for your immune system to monitor and sample this is how the adaptive immune response is achieved.

Exactly, for strong long term response you want T-cell involvement.

> cells send samples of anything they replicate to the cell wall for your immune system to monitor

Wow nature is truly a marvel! How do they do that? Or where could I read more?

> Wow nature is truly a marvel! How do they do that? Or where could I read more?

Read about the HLA/MHC class I pathway. And also about JAK/STAT1, which is how cells decide if they are infected.

The chimpanzee adenovirus is used as a vector, with its payload replaced with instructions to manufacture SARS-CoV-2 spike protein.

Virus enters body, hopefully survives immune system long enough to insert instructions into your cells, your cells churn out tons of copies of coronavirus spike protein, your immune system sees the surfeit of spike protein and develops a response (antibodies and T* cells).

https://blogs.sciencemag.org/pipeline/archives/2020/04/23/a-...

This sounds pretty harmless. Any idea how they got a bad adverse event out of it?

Imagine a 4 billion year old codebase, written by dice throws and unit testing.

The immune system is a "complicated" thing to work with.

I'm going to print this out and frame it.

Yeah, I just wrote this down to remember for later. What a quote.

Repressed humour from the programmer son of a pathologist.

My favorite dad quip was 'Biology itself is proof against an intelligent designer.'

Biology is too "complicated" for our intelligence at least.

His point was more along the lines of it being poorly designed.

Evolution isn't going to nicely separate functionality into clean, single-purpose biochemical pathways.

It's going to overload something that it already has to support a new feature, leading to a rat's nest of intertwined effects.

The hard part in drug development isn't affecting your target: that's pretty easy to guarantee with modern tools. It's finding out that that target also governs 10 other, completely unrelated bodily functions.

> It's going to overload something that it already has to support a new feature,

Some companies in the valley just call that Wednesday.=)

Absolutely, which gives me a chuckle when people trivialize biology, but run screaming from a (gasp!) 20 year old legacy codebase.

And it has to work on 7 billion similar but slightly different operating systems

> unit testing.

Did you mean integration testing?

Absolutely not.

Evolution unit tests, then integrates in prod.

> Imagine a 4 billion year old codebase, written by dice throws and unit testing.

That's a great analogy, except it doesn't go quite far enough. The code for the toolchain that compiles the codebase (not to mention the unit testing framework) is just as old, and written the same way.

Note to self: while the code (including the toolchain code etc.) is in a monorepo, it is actually surprisingly modular. OTOH, much of the functionality was implemented by copy-and-paste of existing code elsewhere in the repo, and the copies then diverged with subsequent modification.

It sounds harmless because it omits the incredibly complex process of developing immunity.

Your body basically is trying to do a sort of brute force/random combination of immune cells on the retrieved virus spike proteins until it comes up with the right combination.

https://en.wikipedia.org/wiki/Somatic_hypermutation

This process can result in B cells that produce antibodies which stick to virus proteins but also stick to your own cells. The B cells are essentially permanent, that’s how you develop lasting immunity, that unfortunately also means you have lasting immunity on one of your own cell types — autoimmunity https://en.wikipedia.org/wiki/Autoimmune_disease

A 50000 people study is likely to see adverse events completely unrelated to the vaccine. Halting the trial is not a sign that they think it is related either, since it is protocol to rule things out before continuing.

Thought Emporium has a decent video where he modifies an Adenovirus to inject the lactase gene into the cells of his intestinal tract. https://www.youtube.com/watch?v=J3FcbFqSoQY

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