On vaccine timing, from the comments

Current US excess all-cause mortality is running around 10K above trend line on a good week. For these purposes we need neither know nor care if this is do to Covid directly, fear of catching Covid, or the effects of lockdown policies (e.g. increased rates of suicide from business failure).

Suppose we vaccinated the entire population. We would have to have a fatality rate of 1/32,000 to match a single week of the excess deaths the CDC is reporting every week.

Phase III, according to Moderna, is going to last around 4 months. If we skipped phase III and just jumped to phase IV, we could look to avert around 170,000 deaths with perfect effectiveness. Let’s say that between it being a lousy vaccine and people giving up on social distancing early we only save half of those lives. That gives us around 85,000 lives saved.

This means that we are looking at a 1/4,000 as our rough fatality rate for vaccines to be safer than waiting.

To date, I know of no vaccine that passed phase II clinical trials that has ever had this sort of fatality rate. Further, the vaccine adverse event rate is typically an order of magnitude or more higher than the fatality rate so absent truly astonishingly high rates of clinically significant adverse events it is highly unlikely to hit something greater than 1/4000 but not see some evidence of it with just a few hundred patients under your belt in the early phase trials.

My pre-test probability that any vaccine fall into a mortality rate somewhere between 1/100 and 1/4000 absolute risk increase is pretty low. So low, that all the papers I have read name them specifically rather than tabulating (e.g. Merck V710) and even those tend not to have dramatic increases in mortality (e.g. V710 had increased rates of Staph infections, but no increase in mortality).

Maybe something will be different this time and that will happen. Maybe we will be stuck with an inferior vaccine (though my guess is if we declared all of the top candidates ready for phase IV we could get a wide variety of use). But from where my point of view as I understand things from the coroner, we would need some massively high pre-test priors to make a dent in the weekly excess mortality rates.

For places that have been able to limit the virus’s entry (e.g. the island nations), this is all moot. For places that had massive initial spikes (e.g. Italy), this may also be moot. But for the US which flatten the initial curve and has maintained a steady excess death rate, early adoption seems to have very good Bayesian odds

You could of course make a QALY argument about Covid fatalities against vaccine fatalities, but again you are trying to hit a pretty narrow window: dangerous enough to beat down 10,000 excess deaths a weak, not so dangerous that it would have obviously failed early studies.

Challenge studies may have their place (e.g. ruling out antibody dependent enhancement), but we need to be sure that the immune response works in real world conditions. And at this point I still have terrible data for what actually happens during the course of the infection.

Inaction has one of the highest price tags we have ever seen in modern medicine. I just do not see any evidence that my pre-test priors for a vaccine being that deadly should be remotely high enough to make the math on delay work out (particularly if we can avoid the most susceptible patient populations for VAEs). Certainly my priors for the ability of social action to stop infections is far worse (e.g. HIV, Lyme, Scabies) so I am increasingly convinced that long term it is either a vaccine or the hard road to herd immunity.

CatintheHat addds:

I agree with this rough analysis and the risk is even less because we, probably only have to vaccinate 25 % of the population to stop the epidemic completely which could be done relatively quickly.

For the opposite case, don’t forget this earlier in August post of Alex’s.

I would very gladly run further estimates of this kind.  To be clear, I am not endorsing any particular conclusion, rather I think several hundred smart people should be working on this full time.  My personal suspicion is that the decisive factor will be “the gains from possibly ending a global depression a few months earlier” vs. “the risk that with a lower quality vaccine we don’t end said depression more effectively than we otherwise might have.”  And I hardly see anyone considering that trade-off at all.

There is also a closely related but conceptually separate question of how many vaccines to approve on an earlier basis, and also for how many should we be in a position to do so.


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