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Comment by zmmmmm | Hacker News Reader

It's fascinating to see how knowledge evolves over time. So far most of the emphasis has been on the spike protein and its cleavage mechanisms. Now we start to see that may even be a relatively minor factor compared to the nucleocapsid.

It is quite important to understand all these things if we are seeing new variants arise and need to assess how dangerous they are likely to be. Most especially since vaccines are based on the spike protein on the premise that it is essential to the infectiousness. But what if a variant can arise with a highly compromised spike protein yet compensate enough to still be highly infectious due to other factors?

The most interesting thing is to think about where the other empty spaces in our knowledge are that are yet to be filled in - what will we know this time next year that will have us saying "previously we thought ...."

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The nucleocapsid is inside the live virus - it's not accessible from the outside. So we don't currently know of a way to train the human immune system to bind to it to kill live virus particles. So while it's important to understand the role of the nucleocapsid in infectivity, it's not actionable for vaccine technology.

Conversely, there is currently no evidence that the spike can be "highly compromised" without reducing infectivity. The spike has to bind specifically to ACE2 in order to enter the cell. As long as that's true, vaccines can continue to target live virus using the ACE2 receptor binding domain in the spike protein.

I lived through the entire HIV cycle (from first announcements in the press to the current situation).

There weren't really any credible origin stories for HIV for years after the discovery of the virus and the syndrome it causes (AIDS). Eventually (more than a decade later), a reasonably good origin narrative evolved, but not until there were plenty of now-discredited origin theories: https://en.wikipedia.org/wiki/Discredited_HIV/AIDS_origins_t...

It's a pretty sobering thought that HIV took 40 years to get to 37 million people confirmed dead, and that COVID-19 took only two years to get to 5 million confirmed dead.

The official statistics start the clock in the 1980s when HIV became widespread enough to get noticed, but it probably infected humans quite a lot earlier.

(which I think that period is probably relevant in the comparison to COVID)

> It's a pretty sobering thought that HIV took 40 years to get to 37 million people confirmed dead, and that COVID-19 took only two years to get to 5 million confirmed dead.

The transmission mechanism for one of them is "being in the same room with the other person", and the transmission mechanism for the other is "having gay sex with the other person". [1] Almost everyone had pre-existing behavioral immunity.

If you can only infect a tiny portion of the population, you can only cause a tiny number of deaths.

[1] This is not the primary transmission mechanism in Africa, but it's pretty much the exclusive mechanism as far as the Western history of AIDS goes, with the runner-up being "receive a blood transfusion from the other person".

What about heterosexual sex?

Not relevant to Western transmission of AIDS. It is the primary transmission mechanism in Africa.

The difference is that Westerners generally form small, closed sexual networks, while Africans participate in a gigantic sexual network including most of the local sexually active population.

The term of art here is the fairly awkward "multiple simultaneous sexual partners", but that concept isn't quite enough - a typical Westerner with multiple simultaneous sexual partners might be a man with a wife and a mistress, but when neither of them is cheating on him, that's still just a tiny, closed three-person network. But in Africa, the typical case is that most people have multiple simultaneous sexual partners, so even with the low transmission rate from heterosexual intercourse, the paths still exist for the virus to flow from one person in the society to (almost) anyone else.

(I don't think mettamage deserved to be downvoted. I specified gay sex for a reason, but the followup question "why not heterosexual sex?" is pretty obvious. It has a lower transmission rate, but that's a minor issue compared to the behavioral difference.)

> typical Westerner with multiple simultaneous sexual partners

is a man with many casual dates / FWBs / one night stands, not a man with two long term partners.

How common do you think that is?

Note that one-night stands can never, by definition, be simultaneous with each other, though a succession of one-night stands can each be simultaneous with a long-term girlfriend.

FWIW, this is just one paper, but it argues that the important factor for HIV transmission in their rural Africa sample is having many lifetime sexual partners, and less so whether they're simultaneous (although that certainly makes it much easier to rack up the count): https://doi.org/10.1016/S0140-6736(11)60779-4

Simultaneity is theoretically valuable to the virus in another way.

If the average number of sexual partners in a community is 5, then a lot of links exist for the virus to flow through. But the links are of much "higher quality" if the partners are simultaneous, because in the serial case, a lot of paths through the graph are, when you look at them closer, made impossible by the chronology. If Marie sleeps with Jim, and then Jim sleeps with Agnes, and Agnes carries HIV, the virus can't flow from Agnes to Marie (along what appears to be a valid path in the sexual network) unless Jim goes back and sleeps with Marie again.

So it's not just about lifetime sexual partners, though it's certainly true that high average lifetime sexual partners contributes to spread.

They're using terrible, imprecise terms. Homosexual vs heterosexual sex is irrelevant here.

What matters is the orifice/method (and whether giving or receiving). The CDC has data here [1]. Anal sex has a much, much higher rate of transmission (especially receptive), regardless of the gender of the participants. Oral sex has almost no transmission, regardless of the gender of the participants.

Just as a counterpoint to the "gay AIDS" narrative, AIDS is extremely low in the lesbian community because I don't think there are even any high-risk sexual activities available.

It's kind of humorous to me that lesbians are above the straight community on the "STDs as a judgement of moral purity" scale. Somebody tell the TV pastors that they're going to have to rework it.

1. https://www.cdc.gov/hiv/risk/estimates/riskbehaviors.html

> Homosexual vs heterosexual sex is irrelevant here.

> What matters is the orifice/method (and whether giving or receiving).

No, this isn't what matters. Anal sex has a higher rate of transmission. Receptive sex (of any variety) has a higher rate of transmission. But that isn't what matters.

What matters is the sexual behavior of the community as a whole. The higher transmission rate of anal sex is not enough to explain why heterosexual sex was so insignificant as a vector for AIDS -- heterosexual sex is safer, but there's much, much more of it!

But the only way to participate in the gay sexual culture of the period, which is what caused the problem, was by having gay sex.

Why would you focus on the Western history over Africa's when the vast majority of AIDS deaths are in Africa?

Because the statistics ("HIV took 40 years to get to 37 million people confirmed dead") come from the West.

How so? Those numbers are worldwide deaths and most of them were in Africa

Hi, as a scientist who worked at UCSF during the HIV crises and saw the direct impact of HIV/AIDS, I can tell you that your understanding of HIV science aand transmission is very limited. It's not completely and totally incorrect, but it looks like you're trying to push a personal agenda on top of some shaky beliefs.

COVID appears very impactful but I also suspect if you integrate over biological time (IE 1+M years) the integral of retroviruses is probably larger than rhino/coronaviruses. I mean COVID killed a lot of people but then several years later, a large fraction of the world is at least partly immunized (by their own immune system). We can't say for sure but it may be that the total sum of COVID after 40 years will be smaller than HIV.

That's a good point and I had not taken that into account. Thank you for pointing that out.

I've been waiting to point it out until most of the people who ran around say "ohh, COVID, it's terrible, look how many people died". Nothing in public health seems that bad when viewed from the lens of biological history.

It's the 'we can't say for sure' bit that has my full attention, the problem is that these kind of relatively rare events seem extremely improbably until they happen and given that we haven't had a pandemic of this kind of virulent pathogen with the world as closely connected and as populated as we have today that it may be that circumstances have changed enough to invalidate our past experience.

Populations go up and up until they crash.

let's just say I've worked in science long enough to watch many exponential graphs turn to sigmoids over time and that makes perfect sense.

Personally I believe that were the flu or cold to arise anew todya, we'd have seen something very similar (a pandemic), but presumably, due to the lower rate of connectedness, local populations evolved (both in the DNA sense, and in the immune learning sense) responses that dull the scale (and even then, some bad flu years are Really Bad, although nobody really freaked out about it). The plague killed what, 1 in 10 people in Europe?

The other important thing to realize is that COVID was and isn't and won't ever be a truly existential risk, medically speaking, and the existential risks came more from economic collapse.

Agreed, that that is the most likely outcome. But that's not a guarantee. So here's to hoping that this will all blow over at some point.

Don't panic, nothing significant has changed. The previous coronavirus pandemic in 1889 spread quickly around the world even though it wasn't as closely connected.

https://sfamjournals.onlinelibrary.wiley.com/doi/full/10.111...

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252012/

Especially sobering when those 5 million dead preempted death by other causes! Meaning that people weren't surviving long enough to die by influenza or motorcycle accident.

Amazing work, and it would be gratifying to see Doudna bag another Nobel prize, to be awarded in a year when the celebrations aren't markedly subdued by rampant disease.

As important as the posted story demonstrates the N protein to be, it's probably not a good idea to direct a vaccine towards it without a much deeper understanding of the consequences. Derek Lowe's wonderful column in the same magazine touched that point earlier this year, in https://www.science.org/content/blog-post/antibody-dependent...

See the last paragraph under the subheading "ADE and Coronaviruses" for a very brief account of candidate vaccines (against the closely related SARS-CoV) which included the N protein tending to make the disease worse.

For those who have already read that story, but not recently, you may want to check back on it, because I see now that Derek has added an update and more references:

"There was trouble after immunization with a nucleoprotein-directed vaccine, but ADE could also be seen with some of the Spike-directed vaccine candidates as well - see reviews here, here, and here."

Not sure exactly what you, zmmmmm, mean by a "compromised" spike protein, but if it's something like one that is not well neutralized by antibodies raised against epitopes from the early generations of SARS-CoV-2, this post recently would be relevant https://news.ycombinator.com/item?id=29004006

Forthcoming vaccine Valneva will be based on inactivated virus. Nucleocapsid preserved.

Novavax has also applied for approval in Canada, UK, Australia and NZ, and possibly already received EUA in Indonesia.

https://news.ycombinator.com/item?id=29111197

https://ir.novavax.com/press-releases?category=2

https://www.forbes.com/sites/joshuacohen/2021/11/03/if-appro...

The Novavax vaccine is a recombinant protein vaccine and only contains the spike protein: https://mvec.mcri.edu.au/references/novavax-covid-19-vaccine...

...plus the 'Matrix-M1' adjuvant - saponin from tree bark.

And, if you wish, polysorbate 80 to assemble the spike proteins into nanoparticle "parcels". In fact, I think the Novavax particles should be radial bunches of spike proteins tied at their "tail" - see e.g. https://www.nytimes.com/interactive/2020/health/novavax-covi...

Adequately technical and well done is the description at https://www.sciencemediacentre.co.nz/2021/09/14/what-do-we-k...

Thanks for the correction and the great link.

Sinovac and Sinopharm, the Chinese vaccines that may or may not actually work, are also inactivated.

>So far most of the emphasis has been on the spike protein and its cleavage mechanisms.

This is something that bothers me about science, why has most of the emphasis been on the spike protein? Has that prevented many researchers from looking for other mechanisms that increase infectiousness? Maybe not in this case, but it seems really difficult to tell what science believes are facts and what are assumptions. I think that if you could identify all the assumptions in science and test them you would find rich material for groundbreaking research. One assumption that seems to be universal is that old science is correct, that it has "stood the test of time", except that often nobody tested it and a lot of it is turning out to be wrong. Those old folk had a tendency to make things up and no one at the time checked them on it because they were an authority unto themselves. I'd like to see any statements that are assumptions specifically highlighted in research papers. There is a little of this in security research papers but not in other research as far as I can tell. How might it be possible to tell how much of "what is true" is actually based on assumptions? Maybe a semantic mining of research papers using an AI could identify assumptions and list them as interesting areas for further testing and research? To start with any statement that doesn't have a citation is a candidate for being an assumption. Also statements like "it is well known" without a citation. Maybe a dependency of logic upon an unsupported statement could be used to find assumptions.

The known is practically nothing compared to the unknown. What we know is inconceivably less than a rounding error.

Appearing to know is essential for our social hierarchies. So... here we are.

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