Epistemic status: Building a better gears-level understanding of why antivirals don’t work very well, explaining why portfolio construction for technology isn’t the same as investing in markets, then speculating on implications.
Note: Crossposted to Lesswrong
The public conversation around COVID-19 response, especially pre-vaccine, prominently featured the idea that there are treatments which we just need to find. The claim is that if we found good, broad-spectrum antivirals, we could treat COVID.
But there is no guarantee that the thing we’re looking for exists. We might be searching up and down the street, under the lamps and elsewhere, for keys that are figments of our collective hopes and imaginations. There are words that describe things that do not exist. Like unicorns. Or antigravity. Fortunately, antivirals definitely exist. They just aren’t what I assumed when I was looking into the issue. And investing in them seems like a less promising avenue than I assumed.
NOTE: I am not arguing against any investment in antivirals. I’m discussing the relative promise and synergies or anti-synergies of the approaches for fighting a pandemic.
Antibiotics versus Antivirals
Antibiotics, i.e. antibacterial drugs, are definitely a thing. Actually, around a dozen things. They prevent basic things that bacteria need to do, such as forming cell walls, using a specific protein synthesis pathway, or unwinding their DNA to replicate. Thankfully, some of the things bacteria need to do are unique to bacteria - their cell walls are different from animal cell walls, so interrupting formation of bacterial cell walls doesn’t kill human cells. Other things are the same. Protein synthesis and DNA unwinding are critical for human cells, but they happen inside of the cell, so we can use drugs that human cells keep out, but bacterial cells don’t. Those drugs are a bit more toxic, but if you need to kill off bacteria, sometimes it’s worth it.
Viruses are different. They use our cells to replicate, so they don’t do many things which human cells don’t. There just aren’t as many targets - and interfering with the ones that exist are more likely to hurt the human hosts.
We want to find a useful antiviral, but we have good reasons to think that safe ones might not exist.
To be clear, we know of drugs that are effective at fighting viruses. Idoxuridine was the first antiviral, in the 1960s, and it is effective in fighting herpes. And by fighting, we mean slowing replication. It doesn’t actually eliminate herpes - nor do the other newer antivirals used for herpes and related viruses. Humanity had great success in finding cures for HIV. And by cures, we mean semi-toxic combinations of drugs that when taken indefinitely, slow viral replication enough that the hosts can live indefinitely and, due to very low viral load, not spread the virus. The drugs take months to work, but they are effective enough.
Other, newer antivirals fight things like influenza. Maybe. But not well. So where are we pinning our hopes, and why are we pursuing antivirals(1)?
I want to be incredibly clear; looking for antivirals is worth the money spent.
We spend a few tens of billions of dollars per year looking for them, we learn more about viral biology and immunology, and we can treat HIV and herpes better. We might even find new treatments for other diseases. Value of Information here is really hard to compute, but it seems pretty high. At the very least, we have no fundamental reason to think we won’t find something that works.
But in constructing portfolios for investment, we aren’t just looking for positive returns, we are looking for a coherent plan, hopefully with synergies and risk mitigation. Unlike financial investments in the market, there are places where investing in one technology accelerates our returns in other places, or unnecessarily duplicates effort and wastes money, or actually makes success impossible.
If we’re in the stock market and banking stocks are highly correlated, splitting our money among them is typically a bit better than investing all of it in any one, because we’re diversifying, with little or no cost in terms of returns. If we want to eliminate malaria and spend half our money on bed-nets and half on gene-drive mosquitoes, we mitigate risks of either approach, but they aren’t complementary or even parallel. Instead, there is likely to be wasted effort. If we’re SpaceX and invest in reusable spacecraft and also batteries for ion drives, we’re probably wasting the money on batteries. They aren’t compatible with the approach we’ve picked. And if we’re building a PC and invest half our money on an awesome graphics card, and the other half on a huge SSD, we end up with no CPU, and we’ve wasted all of our money by failing to get everything we need.
The above examples are talking about very different strategies, in different domains, with different failure modes. Which one seems to describe investing in antivirals alongside other parts of pandemic response?
Applying Portfolio Theory to Antivirals
I’m not sure exactly how this applies, but the new 100-day plans for response seems to be either split-the-money, and hope one approach works, or pick-incompatible-approaches, waste lots of money. Why?
If effective vaccines are available in 100 days, and we can scale up manufacturing, the game is over, we win. Treatment of the cases that happen later is either useful as a mitigation measure to slightly reduce impact, or a backup plan in case we don’t manage to make vaccines.
Perhaps these are independent resources, and we can spend money and research effort on antivirals without reducing the investments in vaccines? That seems implausible. Budgets are limited, and vaccine manufacturing is expensive. An extra couple million dollars might only expand production of vaccines by 5%, but if antivirals and vaccines show up at the same time, per the 100 day goal, that’s probably a better investment than antivirals.
Conclusion
Please correct me if I’m wrong on any of this. Otherwise, I’m interested in figuring out what we should do differently in the future for pandemic preparedness on the basis of this partial/tentative analysis.
- An aside: The investment in antivirals isn’t confusing as an outcome. There are reasons that vested interests push for the approaches they can make money with, and reasons for both clinicians and regulators to push for better treatments, even if they are only marginal improvements or are unlikely to succeed. There is no guarantee that markets pursue socially optimal policies - quite the opposite. So this is an expected failure mode.
Hey David, thanks for the post, always healthy to hear ideas about what not to do. I have a much more positive view of the promise and importance of antivirals for future pandemics, broadly for the following reasons.
Biological diversity & over-updating from one disease
COVID-19 vaccines have been exceptionally successful, in fact surprisingly effective to the expert community. It appears that COVID-19 is a disease that is (1) sufficiently immunogenic to elicit strong and lasting immunity, (2) was readily adaptable to the new vaccine platforms, thanks to prior research with SARS-1, and (3) shows sufficiently low antigenic variation that vaccines remained effective so far (thanks to its for respiratory RNA viruses unusually low mutation rate).
These properties do not hold for all viruses. For example, for the HIV pandemic vaccine development has been very unsuccessful, and antiviral development highly successful.
One under-appreciated theme in biology is that living systems can show unexpected behavior, and observations from one example often do not generalise. The success of COVID vaccines implies that vaccines (if we can speed up clinical testing and manufacturing) can be a powerful pandemic defense. It does not, in my view, imply that they will be a sufficient defense against most or all possible threats.
Future promise of antivirals vs current performance
The absence of success stories to date is not evidence that a promising technology under development will not be successful - this is the nature of tech development. (E.g. mRNA vaccines didn't have such a success story until COVID, and we shouldn't have stopped developing mRNA vaccines in, say, 2015 because of the absence of successes.)
From a 'first-principles' look at the challenges of antivirals (as a biologist but without drug dev expertise), I am pretty excited about foundational research to accelerate their development.
a) Scale: the 'big win' would be sets of antibiotic-like therapeutics that wipe out a majority of viral pandemic risk; a close second 'platform therapeutics' to be made in response to new pathogens that can be deployed like vaccines
b) Tractability: several promising approaches are discussed in the literature - in brief (i) host-directed drugs that target human cell pathways that viruses need to replicate, (ii) virus-specific drugs (e.g. polymerases that are distinct from human polymerases, see HIV drugs) and (iii) drugs that tune the immune system in response to an infection (e.g. dexamethasone). No doubt it's much harder than antibiotics, but we have made much progress in bio and drug dev since the first antibiotic has been discovered in the 1920s too.
c) Neglectedness: infectious disease is - with the notable exception of HIV - not a problem in western countries. For this reason, antiviral research (like antibiotic research) has received much less attention and funding than other diseases (cancer, gene therapy, neurodegenerative diseases, ...). mRNA vaccines had the advantage that mRNA technology may also be used for cancer and other diseases, so I find it likely that antivirals are especially under-invested in the portfolio of medical countermeasures.
Portfolio theory and scientific innovation
In foundational (bio)tech development, I am pessimistic about our ability to 'pick the winners' at a high level. The history of biomedical research is full of examples of promising technologies that never succeeded, and others that were unexpectedly successful. A 'split-the-money' approach of diversification, in principle, will always be required at such success rate, though I grant that working out the relative % of investments is very hard.
Thanks so much for the excellent feedback. I've updated a bit, but I don't think we disagree as much as it seems at first glance, or I'm not understanding your position. In general, I think you're responding about antivirals in general, and I was talking about antivirals specifically as a response option for during a nascent pandemic. But I do see a few points of clear disagreement.
1) Biological diversity & over-updating from one disease
Antivirals work poorly everywhere. The "best" antivirals we have for flu, like tamiflu, don't have any significant clinical impact, according to all of the studies not run by the company making it. And yes, antivirals are relatively more important for diseases that don't have vaccines, but as I noted, HIV antiretrovirals are weak and only work slowly and in combinations, and "highly successful" seems like a weird claim given how long it took and how complex it is.
And I agree that vaccines aren't always practical for all diseases, at least yet. But that doesn't lead me to think that we might be successful with antivirals.
[Edit to add: "The success of COVID vaccines... does not, in my view, imply that they will be a sufficient defense against most or all possible threats."
No, but finding vaccines not working says nothing about the success of other approaches - nothing guarantees that anything works, so pessimism on one front doesn't justify optimism on another, even if it causes us to invest differently.]
2) Future promise of antivirals vs current performance
I think I agree with all of this, which is why I think antiviral work should continue to be funded. But none of this makes me think it's a valuable target for emergency response.
3) Portfolio theory and scientific innovation
Agreed on our inability to pick winners, and the difficulty of exactly choosing relative investment amounts - but again, I'm not talking about foundational research, where a diversity of approaches are really important, I'm talking about last-ditch emergency response. We need more and faster COMPARE-like trials for extant treatments, but new drugs seem like a dumb place to put money if we need results this year.