[ Question ]

Does the 14-month vaccine safety test make sense for COVID-19?

by orthonormal 1 min read18th Mar 202028 comments

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I was first wondering why, if we keep hearing about teams rapidly generating vaccines for COVID-19, the common wisdom is that it will take 18 months to start vaccinating at a large scale.

Turns out that the scaling up takes a few months, but the real blocker is the Phase 1 trial, which requires monitoring patient health for 14 months after vaccination.

Doesn't it seem like the cost-benefit analysis changes a bit if we're in the midst of a pandemic? Wouldn't it be worth cutting it down to e.g. 3 months before at least vaccinating the highest-risk populations? Is anyone official even thinking about this?

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The article I summarize here goes over some of the specific bad vaccine reactions for SARS-1. I expect similar challenges for SARS-2.

Briefly:

In situations where someone took the vaccine, then gets infected by the contagion, they can have a bad reaction where the course of the disease is more severe than if they had not been vaccinated at all.*

Here's some of what we know about those bad reactions**

  • Th-2 type immune activation definitely happens
    • This is an allergy-like immune response
    • Th-2 reactions happen in severe cases of COVID-19 generally
  • There might also be a bad complement system related reaction
    • Complement system means protein complexes that kill cells by poking holes in membranes
  • Antibody Dependent Enhancement (ADE) might be possible, but is not likely
    • This is when imperfect antibodies are used as an anchor for the virus to infect white blood cells.
    • UPDATE: A related thing now strikes me as somewhat likely. It might be fusing with some white blood cells (at least T-cells) and ordering them to apoptose (activate cell-death). Article, h/t CellBioGuy.

* Going off of some other bits of research on this, these individuals probably have lower virus-titer, but higher severity and lethality. A damaging immune response, basically.

** Which vaccine types cause this bad reaction? For SARS-1, any whole-S-protein vaccines were more prone to this bad reaction. Some smaller S-protein fragments didn't have this issue, hopefully the same fix works for SARS-2. I heard of at least one case where an N-protein-only vaccine attempt also resulted in the Th-2 reaction, though. It's not totally clear how to avoid triggering it.


So maybe the speed-up you really want is to vaccinate, then deliberately expose to the live virus, and monitor what happens?

This is the type of test I'd rather we do on animal models than humans, to be frank. It seemed that you could test this phenomenon just fine with SARS-1 in animal models.

From what I can tell, it looks like the main danger is with a live vaccine, where the vaccine can give the disease to a large number of people (biggest actual disaster seems to have been the Cutter incident, which infected 40,000 people with polio).

I assume that the trial is also there to catch potential black swan issues.

IIRC the Covid-19 vaccines on trial are not live, so the case for doing the 14 month watch was not as strong as I expected. Certainly worth considering more carefully at least.

I don't think the timeline for Phase 1 trials looks anything like a 14 month delay before Phase 2 trials start.

  • [https://www.lesswrong.com/users/adele-lopez-1] already mentioned the live vs inactivated vaccine distinction.

  • Metaculus (admittedly not the best source of predictions) gives 45% that a vaccine is distributed starting in 2020. One user gives only 70%, taking into account the high urgency and high risk-tolerance of countries like China.

  • The American NIH says "If the clinical trial enrolls participants as planned, researchers hope to have initial data from the clinical trial within three months." This means either (a) they're being slightly misleading, or (b) that further trials will start immediately after that point.

There's a very tiny percentage chance that there's a completely unexpected long-term complication. Widespread distribution and vaccination with such a complication could be extinction-level.

I can't remember the term it's antibody specific amplification or something, but some promising vaccines will actually make you more susceptible.

I think we will likely get some acceleration out of heroic volunteers, if not in the US then elsewhere.

In 1957 they put together a flu vaccine in four months.


Of course, in 1969 we had flight-ready NERVA nuclear rocket engines. In 1962, Orion was ready for nuclear flight... progress doesn't always go in a straight line.

Least of all in biotech, where our incentives are so twisted that we use the most dangerous treatments first.

Moderna says they'll have their RNA vaccine in production by July, BTW. And there are safer treatments under study:

https://www.biorxiv.org/content/10.1101/2020.04.17.047480v1