One-dose Pfizer is not happening and here's why

I'm surprised even Dr. Sanjay Gupta has been low-key calling for a single-dose Pfizer vaccine because that's based on a dubious interpretation of the data.

Here's the one-dose vs two-dose story, written in Numbers Rule Your World style (link).

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The entire Pfizer 50-page briefing to the FDA contains just a single data graphic, and this chart has become the darling of medical reporters.

The chart paints a powerful picture of vaccine science. The lines trace the number of confirmed cases known to Pfizer as the trial progressed, starting with people getting their first shot on "Day 0". The red line tracks the placebo control group: participants who received fake shots were getting sick at a linear clip. The blue line showing the vaccine group initially hugged the red line but after the second week, the blue line started to flatten, and remained flat during the period of analysis (up till Day 100 or so).

The messenger RNA technology in the Pfizer vaccine sends our body a blueprint on how to make antibodies for the novel coronavirus, and this evidence shows it takes about two weeks after the first dose to take effect.

In fact, we learned from the vaccine trial not only that the Pfizer vaccine is super but also that only one dose produces all the protection you need. That blue line bends right as the third week starts; there was not much further benefit after the second dose was given at or after Day 21.

Therefore, instead of the two-dose treatment that Pfizer originally thought was necessary, we should roll out a one-dose treatment. Doing so doubles the number of people who will get protected.

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Now, let's start over. Go back to square one.

This chart paints a powerful picture of vaccine science. The lines trace the number of confirmed cases known to Pfizer as the trial progressed, starting with people getting their first shot on "Day 0". The red line tracks the placebo control group: participants who received fake shots were getting sick at a linear clip. The blue line showing the vaccine group initially hugged the red line but after the second week, a gap emerged between the two lines, and this gap continues to grow during the period of observation (up till Day 100 or so) as the blue line has almost completely flattened while the red line continues its linear upward trajectory.

Scientists obtain evidence of vaccine efficacy (VE) from the vaccine's share of confirmed cases (VSC). An effective vaccine should suppress the case rate - the baseline of which is measured by the placebo control group. The stronger the vaccine, the wider the gap between the control's case rate and the vaccine's case rate, the smaller the vaccine's share of confirmed cases. The following chart directly plots the VE and VSC as the trial progressed:

I also included the first chart so you can see that the new chart is a re-visualization of the data from the first chart.

The Pfizer vaccine requires two shots. Its benefit emerges over time. At the end of two weeks (Day 14), the case rate in the vaccine arm was 30 percent below that of the control arm (VE = 30%). The VE in the trial (brown line, right axis) breached 50% not long after the second shot was given on Day 21. This is an important moment because any vaccine must hit 50% VE to apply for emergency use authorization from the FDA.

What really impresses the medical community is the continual rise of VE as the vaccine's benefit shows no sign of abating during the next two months (from Day 30 to Day 90). As of the analysis time, the Pfizer vaccine appears to be 80% efficacious about two months after the second dose.

The evidence from the trial confirms Pfizer's two-dose treatment program. The first dose provides bare-minimum protection. The combination of two shots lifts the VE from marginally acceptable to stratospheric.

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It's a tale of two data graphics and two visual stories - arising from the same underlying data. Both the power of visual data story-telling and its danger are on display. The two stories lead to diametrically opposite recommendations, so only one of these stories can be correct.

The author of the first story has hidden an assumption about what the curve would look like beyond Day 21 if the second dose were scrapped - that the blue line in the first chart would just trace the same path as shown above. This assumption is equivalent to saying the second dose has no value because it asserts that the vaccine arm performs identically with or without the second dose.

In addition, this assumption stipulates that with just one dose, the vaccine efficacy would improve from about 30% after the second week to 80% by around week 75. This is possible but there aren't data to support it.

Alternatively, we make the assumption that should the second dose be scrapped, the vaccine efficacy would be frozen at the level reached on Day 21, and remain there for the rest of the analysis period. This leads to the following path (shown in dashed lines):

The gap between the vaccine and placebo curves is cut by half under this assumption. There are two reasons why this assumption may still be too optimistic. I'd assumed that the 50% efficacy seen in the trial will persist - which is not a given; in fact, if the trial returns a 50% VE, we are only comfortable saying the VE in general is over 30 percent. Besides, it's plausible that the vaccine's effect will wane over time.

For these and other reasons, neither Pfizer nor the FDA has accepted the one-dose argument.

The uncertainty goes away if a new clinical trial is designed to test the one-dose against the two-dose treatment. From a public health perspective, such a trial is desirable as it reduces the cost, the complexity and the speed of vaccination. The flip side is it also reduces revenues, and potentially the efficacy.

 

 

 

Comments

[James]

No. You are mathematically wrong. You need to start the efficacy on day 11 or so and compare to efficacy after day 21 (if wanting to compare to directly after dose 2) or day 31, etc. (if you wanted to compare efficacy 10 days after dose 2.)

Efficacy does not start on day 0 or 1 as you imply. Efficacy for those first 10 days or so appears to be zero, or close to it, for those first several days (10 or 11.) It takes time, so you need to subtract off the data that occurs before day 10 or 11 or whatever you choose. BUT, that needs to be clearly stated.

I'm unsure if you completely don't know what you are doing or are trying to mislead the audience. Either way, you are wrong.

[Kaiser]

James: Advise checking the data which is published.

[Harry Johnson]

Author is wrong.

[Kaiser]

HJ: I can't respond to that unless you tell us what you think is wrong.

[HJ]

If everyone was exposed to covid while getting their shot, efficacy would be zero using your flawed start at zero approach. None of the companies are reporting start at zero VE.

[Kaiser]

HJ: They are reporting it. The Pfizer chart would not start at Day 0 if it illustrated only cases starting at 7 days after 2nd dose. The Pfizer chart also does not lead to 95% efficacy unless you subtract the cases in the first 28 days. Every study since then have reported different case-counting windows, which usually includes Day 0.