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I'm starting to get pretty optimistic. There seem to be a bunch of antivirals with very different mechanisms of action - this one blocks entry of the virus to cells, Molnupiravir fucks up accurate replication of the virus (nucleoside analog), others are protease inhibitors, which are very effective against HIV.

There's a caveat, most treatments that look promising don't pan out, but there are a lot in the pipeline and it seems likely that some will. What I think will happen is a cocktail of antivirals, and together these will significantly reduce the mortality. We need that, because it looks like the virus will probably be circulating endemically. The other great thing about a cocktail (as opposed to a single antiviral) is that the virus developing resistance is both less likely and less of a problem if it does happen.

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A limiting factor for the effectiveness of anti-virals for Covid is time. Maximum viral load happens often happens before any symptoms are present, and the most severe diseases occurs weeks after infection as a result of the bodies inflammatory response instead of the virus itself. This means that by the time you know that a patient will have severe Covid-19, it is likely too late for any treatment that is based on interfering with the virus itself.

Having said that, we have a good demographic understanding of who tends to get severe Covid-19, and a large testing capacity, so a cheap anti-viral treatment with few side effects could still be effectively deployed.

I imagine the willingness to get tested would also be a lot higher if the result of a positive test was a reasonably quick antiviral treatment instead of weeks of quarantine.

Sure, there will always be sceptics, but for large parts of people, organisations and governments having less perverse incentives might improve things a lot.

I feel like I'm pointing out the obvious, but another, extremely effect and quick "treatment" is vaccination. And it works great without the constant need for testing. I have to imagine that anyone willing to undergo treatment at the very start of getting covid, would have also been willing to be vaccinated.

The vaccine-hesitant aren't going to go for treatment until the outlook is dire.

Additionally, in my experience, physicians aren't terribly concerned about infections in vaccinated individuals. When I was last tested, the physician essentially just assured me that vaccinations have been shown to drastically reduce the likelihood of complications, and not to really worry about it. Granted, I could have had a less rigorous physician, or it could that I'm totally healthy.

> The vaccine-hesitant aren't going to go for treatment until the outlook is dire.

Many of them seem quite willing to get ivermectin (whether it works or not is another issue). This is a tribal thing: one tribe has determined that the vaccine isn't something their tribe gets, but many of them seem willing to try other treatments that are acceptable to the tribe. (and yes, that's not rational, but humans are often irrational)

It's too bad we couldn't arrange it so that one vaccine could be the "Trump vaccine" that Republicans could get and another could be the "Fauci vaccine" for Democrats. Then people could express their political affiliations in their medical choices but still get vaccinated. There were a lot of Democratic politicians talking about not trusting rushed vaccines a year ago and if that could have focused on specific vaccines and kept going maybe we'd be in a better place today with regards to vaccinations.

There's also the perceived seriousness of a treatment. A nasal spray is harmless, a capsule is more substantial, an injection is serious business. You see the same thing with placebos, with saline injections being more "effective" than sugar tablets. And a vaccine is not just an injection, it's some kind of miracle thing that cures an infection you don't even have yet.

It's not surprising people are far more willing to try out sprays and tablets than injections, even if there wasn't any misinformation and tribal politics

I distinctly remember some very prominent people saying they wouldn't get the vaccine because it came from Trump. While some Republicans don't want to get it, it is mainly because they are told they have to get it. But there are quite a few Democrats who aren't getting it either.

I agree, but vaccines in this case have their definite drawbacks as seen in vaccine-heavy Israel in that their effectiveness wears off after a few months.

I have personally heard of a number of pretty bad breakthrough cases where a person has had a fever for almost a month, another was extremely sick and there are still people who are afraid of covid for this very reason(and they are vaccinated). Having an effective anti-viral solution will bring down the fear about these scenarios and get people back to work and bring normalcy to society again.

Lets be careful there. While vaccines do wear off, they are not wearing off nearly as fast as most people using that line are saying.

Also, Isreal is no longer vaccine heavy. They were an early leader, but many other countries exceed their vaccine rates these days.

Not anymore. Because it turns out mRNA vaccination efficacy drops off after 6-9 months, which is why they're rolling out booster shots in my country. I fear that soon "fully vaccinated" will mean one has had a series of 4 shots by that point. (And if you don't like that, we're taking away your job).

Well if you can't be trusted to not infect the people around you, yeah get the hell out. Its literally the only pragmatic way to deal with it.

> I feel like I'm pointing out the obvious, but another, extremely effect and quick "treatment" is vaccination.

Does every discussion of about post-exposure prophylaxis have to have comments about vaccination?

> And it works great without the constant need for testing.

A primary reason for testing has been to help stop the spread of the virus (test positive = isolate), not necessarily to let people with mild symptoms or no symptoms know that they're infected.

Vaccinated individuals can still spread the virus and some people are at higher risk even when vaccinated, so testing is still of value.

> I have to imagine that anyone willing to undergo treatment at the very start of getting covid, would have also been willing to be vaccinated.

That's quite an assumption. Without passing judgment about his decision not to get vaccinated and to throw the kitchen sink at COVID once he was infected, Joe Rogan is an example of a person who is willing to treat an infection but not get vaccinated. I doubt he's the only one.

> Additionally, in my experience, physicians aren't terribly concerned about infections in vaccinated individuals.

Vaccination certainly reduces the incidence of hospitalization and death, and the data to date suggests that vaccinated individuals are less likely to develop "long COVID" symptoms. But there's still a lot we don't know. Research indicates that individuals with breakthrough infections can have viral loads that are as high as unvaccinated individuals, and some percentage report courses of illness that are virtually identical to a typical course of illness in unvaccinated individuals (respiratory symptoms, extreme fatigue, etc.) so I think it's premature to make too many assumptions. Especially since in immunologically naive people, some with "mild" or even largely asymptomatic infections also report lasting issues too.

Edit: My understanding of the science here was at least slightly wrong. Please see the reply from LurkingPenguin and eventually my reply to them

I think results like vaccinated individuals “can” have viral loads as high as unvaccinated individuals are next to useless. I need to know how likely I am to have high viral loads and my understanding of the science there is that vaccines still do a decent job of lowering the odds. I know you aren’t really arguing against vaccination here, but it seems like it needed to be said and I think the “vaccinated individuals can have high viral loads” line is particularly bad

> Research indicates that individuals with breakthrough infections can have viral loads that are as high as unvaccinated individuals, and some percentage report courses of illness that are virtually identical to a typical course of illness in unvaccinated individuals

But that's totally expected (depending of course on how you define "some"). If the vaccine had 100% efficacy, it would be shocking. The fact that it doesn't is not a surprise.

I'm assuming the point you're trying to make is vaccines aren't as good as expected. If the point is just that there is still value in developing treatments even with vaccines, than yes i agree with you.

But you'd need to get tested for every minor sniffle, or if the claim about no symptoms being a time of maximum viral load, you'd have to constantly get tested even without symptoms.

Rapid antigen tests take take about 20 minutes.

That's a good point on the limitation, and to expand on your last point, an immediate demographic this could help is frontline healthcare workers and similar jobs who do get routine testing and are at higher risk in general.

Yup.

I'm a teacher and vaccinated. If I found out that I was exposed, and then tested positive... post-exposure prophylaxis sounds great.

Also there's my dad, who has an immune condition due to old age. He's vaccinated, but who knows how effective the vaccine was for him. The existence of PEP could make it possible for him to do more at a similar level of safety... vs. the current option of staying in a small bubble for the rest of his life despite being otherwise able-bodied and capable.

FYI, your dad would most likely already qualify to receive the antiviral antibody treatments that have been given emergency authorization by the FDA.

https://www.covid19treatmentguidelines.nih.gov/therapies/ant...

Oh sure-- if he got infected, we'd throw the kitchen sink at it-- remdesivir, monoclonals, etc. A "better remdesivir" which is supremely effective would improve the risk picture a lot.

Given that time is of the essence with antivirals, we need to give people lateral flow antigen tests they can take at home (very accurate if they come up positive) as well as some kind of pre-presciption (show the pharmacist your positive test result and get the antivirals or some such). Waiting for a doctors appointment will take too much time.

According to the founders of Ridgeback, Molnupiravir is being tested prophylacticly. They suggested that hopefully by sometime next year, if someone you’ve been in within close contact tests positive, you get on the cocktail of Molnupiravir + the upcoming Pfizer antiviral.

Molnupiravir is not a benign medication. There are serious concerns about mutagenic risks. Until more long-term safety studies are completed it certainly shouldn't be prescribed as a routine prophylactic for most patients who are at low risk anyway.

https://www.medicalnewstoday.com/articles/molnupiravir-vs-co...

If the antivirals are highly effective one could really slam the immune system to stop any damaging response without the virus again going out of control.

And I'm going to hazard a guess that the likelihood of not getting early testing correlates strongly with the likelihood of not getting vaccinated.

Mortality is going to be dramatically reduced once nearly everyone has T-cells+B-cells that recognize the virus. If everyone got vaccinated we'd be out of the pandemic phase and into the endemic phase with a virus that looked more like just a flu/cold.

Vaccines are a 10x or 20x improvement in death and hospitalization rates. That's just a fact. All these antivirals won't have that kind of impact and are closing the barn doors after the horse has escaped. Which is not to say we don't research both, but vaccination is the simple easy and effective answer. There's a considerable technological fetish with antivirals while boring vaccines are now treated with skepticism, which is backwards. Antivirals should be used after vaccines have failed in vulnerable populations, the major weapon against viruses is vaccines, and they work.

mRNA vaccines look extremely promising too. It’s entirely possible that some classes of cancer will be effectively eliminated in our lifetime because of it, along with HIV and/or Malaria. The latter would probably be the biggest reduction in human death and misery since the invention of the Polio vaccine

I've been saying for roughly a year now that if nothing else good can come from Covid, we at the very least are dumping a ton of time and resources and research into mRNA vaccines.

I know basically nothing about virology, but I remember hearing a podcast a million years ago talking about mRNA vaccines, and I remember after it was over thinking "if this is even half as cool as it sounds to a lay person, the implications of this are huge". It appears that it's substantially more than half as cool as it sounded, and the fact that we are even having discussions about being able to wipe out malaria is mind-boggling to me (in a good way).

We developed several working vaccines, and in record time. A triumph of scientific engineering.

I too am very hopeful for mRNA vaccines, although I don't know how much I should temper my expectations. The idea of curing certain cancers, not just preventing them, is wild.

I haven't even heard about the curing cancer part, that's awesome if it's true.

I think I'm going to temper my expectations to "faster and more vaccines increasingly exotic diseases" for now. I would absolutely love to be proven wrong though.

Chimeric antigen receptor (CAR) T-cell therapy is a way to get immune cells called T cells (a type of white blood cell) to fight cancer by changing them in the lab so they can find and destroy cancer cells. CAR T-cell therapy is also sometimes talked about as a type of cell-based gene therapy, because it involves altering the genes inside T cells to help them attack the cancer.

...

In CAR T-cell therapies, T cells are taken from the patient's blood and are changed in the lab by adding a gene for a man-made receptor (called a chimeric antigen receptor or CAR). This helps them better identify specific cancer cell antigens. The CAR T cells are then given back to the patient.

https://www.cancer.org/treatment/treatments-and-side-effects...

Right now this is done in a very personalized and labor intensive way. I think the thought is mRNA is potentially a gigafactory compared to artisanal methods.

Except we had to change the definition of “working vaccine” to fit these new therapies.

Traditionally a vaccine has to keep efficacy for a year. We haven’t got a year of data but the efficacy has dropped significantly

I call bullshit. Antibodies wane but the memory cell response is robust and holds up over what looks to be a pretty long period (studied intensively for 6 months but with no sign of decline). Here's a new paper that shows that in detail (paper itself is dense but Twitter thread is fairly accessible):

https://twitter.com/rishirajgoel/status/1448711946010710023

By basically all measures, these vaccines work better than the flu vaccine, which for some reason doesn't attract the same sort of criticism.

I don't know enough about vaccines to dispute what you're saying (though I feel like I have heard contrary data on this), but even if it's only fully effective for 8-9 months, isn't the fact that we had a vaccine that accomplished at least some of its goals safely designed and tested in record time a really cool thing?

Even if it's only effective for 6 months, that's still 6 months of slowing the spread, and conceivably we can extend the efficacy by administering booster shots.

It's efficacy as measured as "chances of getting sick" declines significantly, but it's still pretty effective.

But the protection against hospitalization and death is still very robust even after almost a year.

A really excellent survey on the prospects for mRNA technology from Derek Lowe: https://www.science.org/content/blog-post/what-mrna-good-and...

I wonder if the final stage will rather be direct production and injection of tailored antibodies instead of going around the corner by having ordinary cells express proteins that then trigger the immune system.

> direct production and injection of tailored antibodies instead of going around the corner by having ordinary cells express proteins that then trigger the immune system

Triggering the immune system does a lot more than produce a single wave of antibodies.

Does "going around the corner," mean vaccines?

It's almost like we're emerging into a world just like the world when antibiotics were invented, but for antivirals. We basically had just a small handful of treatments for viruses, now there's a huge pipeline all of a sudden. Maybe in the future, having effective antivirals for just about any virus will be the norm, not the exception.

> Molnupiravir [interferes with] accurate replication of the virus

At first glance this sound like a really bad idea, given that the #1 concern is future covid mutations.

It specifically causes non-viable mutations. Therefore, the concern isn't currently that it'll cause mutations in the virus and create new strains, but rather that we have to be very confident that it isn't resulting in mutagenicity in mammalian cells.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136050/

Thanks, I wasn't aware of that.

Molnupiravir seems pretty good. I think in the trials eight people died in the placebo group, zero with the drug.