brianwang712

brianwang712's Comments

Has the effectiveness of fever screening declined?

It's worth noting here that coronaviruses are less vulnerable to selective pressure than most RNA viruses given that that they unusually encode proofreading activity, limiting genetic diversity. This article ( https://www.sciencemag.org/news/2020/03/mutations-can-reveal-how-coronavirus-moves-they-re-easy-overinterpret# ) claims that SARS-CoV-2 accumulates 1-2 mutations per month (its genome has 30,000 bases), which is...enormously inadequate to make even the smallest dent anytime this year in the monumental task that is modulating host immunity to modify onset of fever.

LessWrong Coronavirus Agenda

Hmm, well that book chapter claims measles and mumps vaccines are produced in chick embryo cell culture, which is different from propagation on chicken eggs. My quick Googling revealed that we don't have a licensed herpes vaccine, and that while there might be one or two smallpox vaccines that are produced in chicken eggs, many are done in cell culture.

You might be right about the broader (and more important) point about ease of facilities repurposing, however - I don't know enough to say, although the table in the book chapter makes me doubtful, given that pretty much all steps in the manufacturing process (production, isolation, purification, formulation) seem unique to each vaccine.

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

This is correct. We have lots of infrastructure and expertise for making new flu vaccines every year. It's not a good model for how long we should expect safety testing to take for a vaccine for a new virus. We don't have any licensed vaccines for any coronavirus, for example.

LessWrong Coronavirus Agenda

FWIW, eggs are actually specific to influenza vaccine manufacturing. Page 3 of this book chapter ( https://reader.elsevier.com/reader/sd/pii/B9780128021743000059?token=F492A74B3C4545B108379536769CF93D7F1DB89321DADE859256496F5D85CB6259372D34376809219BBBE2FFFDEF25FB ) has a really nice table showing the production process of a number of different vaccines - they are all very different from one another. This is why we need new vaccine platform technologies - i.e., tech that can be used to produce multiple different vaccines. mRNA vaccines would fall into this category and is a reason why Moderna's mRNA vaccine candidate for COVID-19 would be so exciting if it works.

How hard would it be to attack coronavirus with CRISPR?

It was only a matter of time before somebody tried this: https://www.biorxiv.org/content/10.1101/2020.03.13.991307v1.full.pdf

From the abstract: "Here we demonstrate a CRISPR-Cas13-based strategy, PAC-MAN (Prophylactic Antiviral CRISPR in huMAN cells), for viral inhibition that can effectively degrade SARS-CoV-2 sequences and live influenza A virus (IAV) genome in human lung epithelial cells. We designed and screened a group of CRISPR RNAs (crRNAs) targeting conserved viral regions and identified functional crRNAs for cleaving SARSCoV-2...The PAC-MAN approach is potentially a rapidly implementable pan-coronavirus strategy to deal with emerging pandemic strains. "

Why isn't increasing ventilation of public spaces part of the best practice response to the Coronovirus?

Here's a good op-ed on this topic: https://www.nytimes.com/2020/03/04/opinion/coronavirus-buildings.html

The author suggests that the lack of attention on building ventilation is due to uncertainty about how important close contact (i.e., close enough that a person's respiratory droplets could directly land on you) is for transmission, vs. more indirect airborne transmission.

(E.g., from CDC website: "Early reports suggest person-to-person transmission most commonly happens during close exposure to a person infected with COVID-19, primarily via respiratory droplets produced when the infected person coughs or sneezes. Droplets can land in the mouths, noses, or eyes of people who are nearby or possibly be inhaled into the lungs of those within close proximity. The contribution of small respirable particles, sometimes called aerosols or droplet nuclei, to close proximity transmission is currently uncertain. However, airborne transmission from person-to-person over long distances is unlikely.")

Open & Welcome Thread - February 2020

You might also be interested in the 1976 mass vaccination program in the US for swine flu, which was a case of perceived overreaction (given the anticipated pandemic never materialized) and also hurt the reputation of public health generally: https://www.discovermagazine.com/health/the-public-health-legacy-of-the-1976-swine-flu-outbreak

Or in "The Cutter Incident" in 1955, where a rush to get a polio vaccine out in advance of the next polio season resulted in some batches containing live polio virus, with several children receiving the vaccine actually getting polio instead: https://en.wikipedia.org/wiki/Cutter_Laboratories#The_Cutter_incident

There's definitely a history of incidents in public health of perceived overreaction followed by public backlash, which could potentially be playing into public health officials' heads nowadays. I don't know if becoming more conservative and less-quick-to-take-action is necessarily a wrong lesson, though – even if you think, just simply on the numbers, that taking preventative measures in each of these incidents was correct ex ante given the stakes involved, reputational risks are real and have to be taken into account. As much as "take action to prepare for low probability, high consequence scenarios when the expected cost < expected benefit" applies to personal preparation, it doesn't translate easily to governmental action, at least not when "expected cost" doesn't factor in "everyone will yell at you and trust you less in the future if the low probability scenario doesn't pan out, because people don't do probabilities well."

This does put us in a bit of a bind, since ideally you'd want to have public health authorities be able to take well-calibrated actions against <10%-likely scenarios. But they are, unfortunately, constrained by public perception to some extent.

Effectiveness of Fever-Screening Will Decline

Hmm, can you think of a plausible biological mechanism by which a virus could evolve to not cause fever, or to cause fever later than usual? My initial reaction is to be skeptical that fever screening would result in the effects you suggest, mainly because whether or not you get a fever is mostly a function of your innate immune system kicking in and not a function of the virus. Whether or not you get a fever is mostly out of the virus's control, so to speak. The virus could perhaps evolve methods of evading innate immunity, but other examples I've seen of viral adaptation to innate immunity seem like they involve complex mechanisms, which I would guess would not evolve on timescales as short as we're concerned with here (although here I'd welcome correction from someone with more experience in these matters).

But even if there were potential evolutionary solutions close at hand for a virus to evolve evasion to host innate immune responses, I'm not sure that fever screening would really accelerate the discovery of those solutions, given that the virus is already under such extreme selection pressure to evade host immunity. After all, the virus has to face host immune systems in literally every host, whereas fever screening only applies to a tiny fraction of them.

How hard would it be to attack coronavirus with CRISPR?

I downvoted this comment (as well as your comment below) for strongly pushing misinformation. As others have noted, the CRISPR/Cas9 system has evolved in bacteria precisely to target viral genomes — "CRISPR is not able to target viruses at all" is simply false. "...and also does not destroy the things it targets" is also false, in a sense; a well-targeted Cas9-induced double-stranded break in the DNA/RNA of a viral genome can certainly disable a crucial viral gene and reduce viral replication, even if you don't consider this "destruction" of the genome.

That's not to say that the CRISPR/Cas9 system is quite ready for antiviral therapy in vivo. One problem is that you could rapidly generate viral escape mutants. Not only do you create selection pressure for the virus to mutate such that your bespoke CRISPR/Cas9 system can't target it anymore, the Cas9 cutting itself guides this process along more rapidly, since double-stranded breaks are often accompanied by random insertions and deletions at the cut site (incorporated during attempted cellular repair of the break). This could potentially be addressed by targeting important, conserved regions of the viral genome and/or by multiplexed editing (i.e., targeting multiple sites simultaneously).

Perhaps a bigger challenge is delivery. Systemic delivery (i.e., throughout the body) is risky, since you can get off-target edits in cells that aren't even infected with virus, which could result in increased risk of cancer or other maladies. Targeted delivery to only a certain class of cells of interest is sometimes possible but difficult. There's also the perennial question of whether or not your looks-good-on-paper molecular mechanism of action translates to real clinical benefits, something that can only really be definitively answered in clinical trials. For example, you might see efficient viral genome cutting in vitro but see no clinical benefit in a patient, because maybe your Cas9 protein doesn't stick around long enough in cells, or maybe you can't get it into enough cells to matter, or it's detrimentally immunogenic, or a host of other hard-to-evaluate-in-advance reasons.

All that being said, this is a real direction of interest and many are looking into it — the OP is not "completely on the wrong track" and this idea is not "nowhere close to the sort of thing that would work". The fact that CRISPR/Cas9 is so programmable makes its potential use as an antiviral therapy exciting and at least worth exploring more, in my view. Here's a nice review if anyone would like to learn more (warning: paywalled): https://www.cell.com/trends/microbiology/fulltext/S0966-842X(17)30093-8

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