Investing General Discussion

Interesting times we live in. Moderna might be a bigger scam than Theranos.

Araysar said:

Is the vaccine bullshit?

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Everything about Moderna seems to be

How far off are we from that challenge step for Moderna? Seems like a hell of a lot of premature optimism in the markets today.

Well, not strictly speaking. Theranos didn't start out as a lie they actually believed it was possible, and when the choice was to admit failure or lie they chose lie and to perpetuate that lie as long as they could. Moderna seems to be following the same script. They promised a vaccine "in a few months" when they've never delivered a single anything in their 10 year existence.

Hence the comparison I made. We have no idea at the moment whether they are or are not lying but we do know they haven't developed a single vaccine ever, and received almost $500 million in government funding because they claimed they could deliver in the shortest timeframe of every company that was asked.

Furry said:

Challenge is where they take someone or an animal that has apparently developed antibodies and intentionally infect them with the virus to see if those antibodies work to prevent illness. With the high asymptomatic rate of covid, this will be harder to prove than typical. It's typically about the last step, so a couple to a few months before the vaccine would be ready in this accelerated world. Most vaccines fail at this step, some even fail spectacularly (Greatly increase fatality rates).

With the way things are, I think the QC on doing that step will not be as high as typical, so it's anybodies guess who will be the first to get past it. A vaccine that does will probably be a big winner for a company, and with the number of things in development I'd guess someone out there probably has one that'd make it.

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Let me clear up some misinformation before this spreads anymore:

• Moderna, and all other frontrunners have completed animal challenge studies. A pre-print of their results in mice has been available for over a month, and I can guarantee you that they have completed NHP (monkey) challenge(s) as well. Normally, multiple challenge studies are completed before approval to enter Phase I clinical studies, but for this pandemic the challenge studies were being performed while IND was being reviewed. In Moderna's case, they almost certainly initiated Ph1 before challenge (or even PK) results were available, which I think was irresponsible, but I can also guarantee that they were providing animal PK and challenge readouts to the FDA as they became available.
• "Most vaccines" are not tested in a human challenge setting. There are too many ethical and technical issues, especially for diseases with high fatality. It's being hotly discussed as a way to accelerate vaccine development in this case, but most recent vaccines are not tested in human challenge.
• Some vaccine candidate (dengue, RSV) cause what's called antibody-dependent enhancement, where vaccine-generated antibodies can "prime" the immune system to overreact when exposed to the real pathogen. There's no evidence of this for any of the SARS-CoV-2 candidates yet.
• Most vaccines fail in Phase 2/3 clinical studies (not during challenge studies). There are many reasons for this: a more diverse population, randomization, placebo control, etc. It's hard to predict what will generate immunity! Sometimes they fail due to safety profile (adverse events outweigh the benefits), and sometimes it's lack of efficacy. I want to emphasize that vaccines are historically the most well-tested and safe drugs in existence, and the FDA sets an incredibly high bar because they are one of the few drugs intended to be mass delivered to a healthy population. So when I say a safety profile is unacceptable, that could mean headaches, fever, or soreness that go away within a day.
• Based on clinical results released so far by Moderna as well as Pfizer/BioNTech, I would guess they will both generate some protection in humans (sterile immunity would be extremely impressive, but as long as they can reduce or prevent lower respiratory infection, that would be huge). I'm basing this on their strong binding and neutralizing titers, which are thought to be involved in immunity (and animal challenge results support this).

This is the investing thread, and I've made it sound like these are slam-dunk successes, so what are the technical risks preventing me from putting my life savings on MRNA and BNTX?

• Lack of T-cell response. Pfizer/BioNTech haven't published them yet, and Moderna's results look mediocre (weak CD4+ / virtually no CD8+). Some T-cells help create antibodies (stronger / longer-lasting immune response), while some T-cells kill infected cells and actively clear virus from the system. These candidates don't look promising here
• Safety profile (see above). There are a LOT of adverse events. Yes, they are mostly mild, but once the old / obese / at-risk individuals start getting vaccinated, how will they handle these side effects?
• Anti-vector response. Both these platforms use mRNA complexed with a charged lipid + polymer to create nanoparticles. These particles can cause inflammation, toxicity, and undesired immune responses. In the short-term, it looks like the vector can act as an adjuvant, but if the body becomes "immune" to the particles then subsequent could cause problems or more likely not work.
• Durability of humoral response. Too early to tell, but we expect circulating antibodies to fade over time. Neutralizing Abs fade way faster than binding Abs, so I'm concerned about how long these vaccines will last. If there's also an anti-vector response, then boosting might not even be an option.
• Competition: There are a lot of other platforms and candidates out there with their own pros and cons. Until Phase 3 results, we won't know which approaches work best.

That being said, I've invested a few thousand dollars in both MRNA and BNTX (as well as others). I'm betting on multiple approvals or emergency use authorizations, which would be an inflection point for any of these companies.

For context, I am a scientist who works in this field so I have a pretty good understand of MRNA's tech. I also worked in the diagnostics industry in the mid-late 2000s when Theranos was considered a rising star, and there is absolutely no comparison between Moderna and Theranos. I remember hearing Elizabeth Holmes' claims and thinking: "that's insane, we aren't even close to achieving that level of multiplexing, let alone in a POC setting from a single drop of blood!". If she was even telling a shred of truth she would have put us out of business. This is a very different situation... Moderna has their faults, and their political connections + secrecy aren't doing them any favors, but their technology is legit, if flawed.

Edit: forgot to finish some sentences...

Sanrith Descartes said:

This is why threads like this are a godsend to investors. Information is key to returns. Thanks P Pescador

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Happy to help. 99% of this thread goes over my head, but I live and breathe the scientific side of biotech / pharma so hopefully it adds an interesting perspective.