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.
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.