Moderna's Financials

> Eventually, he figured he had had a name under his nose since 2008, when his lab’s staff started experimenting with modified mRNA and referring to it, for short, as “mod RNA.” Moderna.

https://qz.com/2001718/modernas-founder-says-mrna-can-treat-...

However, their key advantage over competitors is development speed.

Until COVID-19 though, that wasn't something we needed. If vaccines took an extra 2, or 4, or 10 years to develop, it was usually okay.

But all these things help you get to the expensive part more easily: testing safety and efficacy.

https://www.science.org/content/blog-post/big-problems

https://www.science.org/content/blog-post/ai-and-drug-discov...

https://www.science.org/content/blog-post/another-ai-generat...

https://www.bloomberg.com/news/articles/2021-02-05/out-of-gr...

A large part of the cost and complexity is the clinical trials, of which several stages of increasing complexity are required to get FDA approval. While it might seem inefficient, it's also the reason why vaccines work so well and have such small side effects - about half of Phase 3 candidates either fail the clinical trial or are rejected by the government for some other reason.

Each round of clinical trials requires significantly more money than the one before it, but it's also arguably easier to get investors on board in the later rounds as risk is lower. Smaller pharma companies often aim to get bought outright before their product is brought to market because it makes more sense for everyone involved.

Maybe someone will come up with an algorithm that lets us simulate clinical trials with sufficient precision, but that seems like a far-off sci fi fantasy to me.

US gov't (NIH) = $41.6B (not all is for biotech) Biggest pharma (PhRMA members) R&D = $83B VC biotech funding + follow-on rounds = $62B

So private funding is ~3.5x what the gov't spends today.

changing the world is very risky, might not be as much of an upside as you expect

For number 1), what you have to know is that the human immune system is a goofy non-linear Rube Goldberg machine. It's not something that an engineer would come up with. Some vaccines work by promoting an ongoing immune response to certain proteins. You can think of the antibodies as like "wanted" posters, and when a real virus with matching features is detected, it sets off your immune system. But if those proteins are passively introduced, they will decay in your bloodstream over time. Some proteins will hang around longer, others do not, perhaps because it just happens to be structurally similar to some protein that is metabolized by naturally present enzymes. There are also crazy feedback loops that can keep your immune system primed by synthesizing the antibodies from a sort of "memory". Look at the B-cells, they basically pick up any random proteins they think are junk, learn how to synthesize new proteins that stick to it, and then it wears all those proteins around like a hat. And when it's hat sticks to stuff, it tells some other cell to start making lots of party hats for all the other white blood cells to wear so they can sweep up the foreign substances. But these feedback loops are not always stable and can also fade with time. Some antibodies are more stable than others, and some just need a much lower blood concentration to be effective. It's really hard to predict, especially with new diseases.

The best vaccines work by having an actual live virus that lives and replicates inside your body, sometimes for decades. These are your "one-and-done" vaccines, and they're actually really hard to make! You basically have to engineer a virus that lives inside of you, forever, but doesn't hurt you. Instead, it just looks sufficiently similar to a different virus that could hurt you, and it keeps your immune system primed with antibodies to keep the virus in check if you are exposed to it.

Number 2) is the reason we have to get a new flu shot every year. The virus mutates very rapidly and different strains can mix-n-match easily. The Covid virus is already mutating into several variants of concern, and because people are not getting the vaccine which is effective for the strains that are out there now, this will likely become a reason why we have to get regular covid shots.

The upshot of all of this: we had an emergency and needed a vaccine fast. We've come up with two solutions so far: non-replicating adenovirus vaccines (such as AstraZenica, sputnik, etc), and the mRNA ones (Pfizer and Moderna). Both of these work by basically introducing a dead protein into your system, which teaches your immune system how to identify Covid and start attacking it before it can take hold and do damage. But as you can see, it's hard to say how long this can be effective before it needs to be renewed.

Anyone who doesn't like the idea of getting follow-up shots should get to work on making a one-and-done, live, replicating Adenovirus vaccine! But they had better hurry up because if situation 2) takes hold, you're going to need a new shot every year anyways.

Growth is a constant and we are not putting the genie back into the bottle. All of these are addressed in some capacity by embracing and enhancing globalism and multilateralism. Working together towards empathic, transnational societies is the only real sustainable way forward. Regression into isolationist fiefdoms with autocratic or monarchic leadership is simply unworkable and not going to happen. I am continually saddened when I see outright or implied support of this kind of thing on HN of all places. The "intellectual dark web" has really done a number.

I'm guessing you have seen reports of antibody levels falling, but that is not an indication of immunity.

So far I have seen no reports of natural immunity (as measured in confirmed reinfections) falling.