Covid Vaccine Dosing Trials ?

I asked if, given the data collected in Phase III trials, it might be wise to delay second doses of the Pfizer and Moderna Covid 19 vaccines until supplies are ample.

Since then the UK government has decided to give second doses three months after the first dose. The reason is explicitly to get first doses in more people quickly. This is highly controversial. I’m just going to name drop (actually link drop) to show I am not the only person outside of the UK who supports this.

Another approach to vaccinating more people with limited supplies of vaccine is to reduce the dose. This was proposed by the now former head of the US program formerly known as Warp Speed. Here the logic is based on a clinical trial — with a sample size of 42 — the Moderna Phase 1 trial . The trial includes an estimate of the amount of infection blocking antibodies in participants serum. The measure is the blocking antibody titer — how much the serum has to be diluted before it blocks only half of the virus from infecting cells. After the first dose and before the second, a dilution of 8:1 (the lowest) allowed more than half of the control infection (of cells in vitro). However, even with a dose of vaccine of 25 micrograms per kilogram (half of the dose of 100 micrograms per kg which people are getting) there was a high average titer by day 43 soon after the second dose.

The phase 1 results explain why 2 doses were used in the phasee III trial (and in Pfizer phase 1-2-3 all merged to speed things up trial). It also makes the rareness of infection in the phase III trials more than 10 days after the first dose a bit surprising. My guess is that the rapid induction of blocking antibodies after the second exposure is enough to block infection even if the second exposure is infection with Sars Cov2 and not a second vaccination. However note that I am not an immunologist (my dad is an immunologist and he said better half the dose twice than the full dose once back when I started talking about this — as usual he knew what he was talking about).

The 14 who got 25 compared to the 14 who got 100 strongly suggest giving 50 micrograms per kg twice is a better way to spread out the vaccine.

However, there is no way either will be done in the USA without a large clinical trial. Also there is no way that there will be a large clinical trial (who would pay for it for one thing). But the point of this post is to ask how such a trial could be ethical if it were financed (the cost is negligible compared to Federal Covid relief spending and roughly equal to the cost of a delay of effective herd immunity of about one hour). I’d say if people are given the chance to get a first dose sooner than they otherwise could (and the second dose as soon as they would be allowed to get the first if they weren’t in the trial) then it is ethical. The trial can’t be double blind (or at least people who get a second shot have to be told if their first was placebo so they should get a third shot which will be the second of actual vaccine).

Similarly people can be invited to get half a dose if the alternative is no dose (with option to get full dose when it would be granted even if they weren’t in the trial). I think this can be done. I think it should be done. I am sure this won’t be done.

update: There is evidence from Israel that one dose of the Pfizer vaccine is less effective than was suggested by the few person-days of evidence in the phase III trials. In Israel  “over 12,400 have people tested positive for coronavirus after receiving vaccine shots” Israeli health officials estimate that one shot is about 50% effective after 14 days . The control group is not matched, it’s not a randomized trial, but it is enough evidence that it’s hard to argue for clinical trials (as I did above).