COVID Transmissions for 1-7-2021

One shot vaccination

Jan 07, 2021

Good morning and welcome to COVID Transmissions.

It has been 417 days since the first documented human case of COVID-19.

Today’s newsletter comes at a very difficult time, which was true of all the newsletters before it, but we in the US are at a new level of chaos after what happened yesterday. I try to refrain from generalized political commentary in this newsletter and I do not think I will be changing that policy. However, what happened yesterday was extremely troubling and it has affected me deeply. As ever I implore you all to stay safe, but today this has a slightly different edge to it.

As usual, bolded terms are linked to the running newsletter glossary.

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Now, let’s talk COVID.

FDA statement on single-dose vaccination

I’ve written here about single-dose vaccination, a schedule that was not tested but that some are advocating should be done even without testing. Last night, I blocked a physician—an Associate Professor at Stanford!—who was advocating for this to be done widely to the American public, because frankly, I cannot condone this type of ethical breach. You cannot use untested medical regimens on tens of millions of people. It’s wrong.

Thankfully, the FDA agrees, and issued a statement today on this topic, clarifying exactly why they do not agree with moving to an untested, single-dose approach:

https://www.fda.gov/news-events/press-announcements/fda-statement-following-authorized-dosing-schedules-covid-19-vaccines

My official personal position on this is that I would support a clinical trial of a single-dose regimen. I do not believe that such a trial would be successful, but I believe it would waste fewer doses of vaccine in its failure than would trying to do this experiment with every dose of the vaccine that we have.

I fear that immune responses to a single dose are weak, the efficacy of a single dose is weak, and using a single dose only offers ample opportunity for the virus to successfully mutate to escape immune reactions induced by the vaccine. The data collected in the clinical trials for these vaccines is, unfortunately, inconclusive on the topic of a single dose, but they do not inspire confidence for strong efficacy.

Several times, I have seen people suggest that the efficacy of 1 dose of the Pfizer or Moderna vaccines is around 80%. It was even in an op-ed in The Washington Post (https://www.washingtonpost.com/opinions/2021/01/03/its-time-consider-delaying-second-dose-coronavirus-vaccine). It happens to be completely untrue. I’d like to share with you an explanation of some of the data that we have on single-dose vaccination, to explain why I think a clinical trial is needed to answer the question of single-dose efficacy.

Each Phase 3 trial had only a brief window in which only 1 dose had been administered. In the Pfizer trial, this was a 21-day period, which is a sufficient period for immunity to be induced, but only just. The first 14 days of that period probably involve quite weak immunity, because the response is still developing. Pfizer reported three different relevant dosing-related VE numbers in their VRBAC briefing:

VE from 7 days after second dose: 95%
VE from after Dose 1 to end of study, including the period after dose 2: 82%
VE from after Dose 1 until administration of dose 2 (21 days): 52%

There is only one part of the study that models a single-dose infection, and it is that third piece of data. There is a VE of 52%, but that is not an accurate VE because the followup is very short and it includes about 7 days of peak immunity at best. This is not enough followup to make any conclusions.

However, the 82% number gives us an idea of how big the benefit of the second dose is, because it includes follow up after the second dose. It’s the two doses combined that get above 80%. Not one dose alone.

The same pattern is observed in the Moderna briefing data, but maddeningly they did not include the full inter-dose period so it's much harder to make any conclusions at all (all numbers from interim analysis because these numbers were not provided for the final analysis):

VE from 14 days after dose 2: 94.5%
VE from 14 days after dose 1, including followup after dose 2: 92%
VE after dose 1, including period after dose 2: 80.2%
VE from dose 1 until 14 days after dose 1: 50.2%

Again it's that last one that is the only number that gives us any insight into the efficacy of a single dose. Unfortunately, the time scale is too short for this to be a meaningful reflection of peak immunity. I wish they had covered the full interdose period.

Regardless, again here the 80% and 92% numbers cover a lot of follow-up time where patients had received two doses. The inclusion of that second-dose followup causes the VE to leap from around 50%, which is below preestablished thresholds for approvability, to well above those thresholds. But again, that 50% number represents a brief follow-up period covering a time during which patients’ immune responses to the first dose were still developing. I don’t think we can use it as definitive evidence of the efficacy of a single dose; a real experiment would be needed in a purpose-built clinical trial.

It is incredibly misleading for the authors of that op-ed to present this as single-dose efficacy. Perhaps they misread the findings presented. I can't really speculate. I would like to believe they misread them, though, because the idea that their ignorance of the trial design here could be willful leaves me troubled.

Returning to what we do know, the evidence collected does not rule out single-dose. The followup is too short to do that. 21 days is not enough time and 14 days is certainly not enough time. I bring this evidence to show that we do not have good evidence of efficacy for a one-dose regimen. That's the main point. I am not making a case that we have good evidence of poor efficacy, either. We have low-quality evidence of poor efficacy for the single-dose regimen. We have no high-quality evidence regarding this regimen at all.

Generating such evidence through a proper clinical trial designed to evaluate a single dose would be appropriate, but using a single-dose regimen without that clinical trial would be reckless and dangerous. While I don’t think the clinical trial would succeed, I do think that it is worth doing. The suggested regimen may work well, and the gains of being able to vaccinate more people would indeed be tremendous if it actually works. It’s worth the test. It’s not worth doing that test on millions of people without an ethically-designed and well-monitored clinical study. That’s where I am on this; I’m glad the FDA seems to have a similar position.

What am I doing to cope with the pandemic? This:

Cardio training

I’ve been working to go an extra mile, quite literally, on my long-run workouts. I’ve found that since I’m trying to minimize time out, I want to get more bang from the time that I do spend away from home. That means more distance.

One of the issues with adding distance is that the impact of the exercise is more cumulative. Usually, once you can run a few miles, adding one more to the routine isn’t too hard from an endurance perspective. However, it’s hard in terms of how a little bit of muscle fatigue or a bad cramp can really ruin the workout.

I think that since we’re in a new year, it’s possible that a lot of you are trying out new workout regimens to try to lose quarantine pounds or meet other fitness goals. I’m not exactly a fitness expert, but one thing I’m finding is that fitness is a 24/7 experience even though I only work out formally about 5 hours a week. I don’t mean nonstop dieting and calorie-counting—I find those don’t work well for me and are more trouble than they’re worth—but instead I mean planning my day around the workout that I’m going to do.

I choose meals on workout days that I think are going to sustain me through the workout. Slightly more carbs before the workout; slightly more protein after. I also keep a close eye on hydration the entire day, since I find that even mild dehydration and cramps are closely associated for me. If you’re getting into a new fitness routine, it’s important to test out the effects of the workout on you and tweak other parts of your life to help support the new routine. Doing this will help you feel better all the time, which will help you want to exercise, and will also help you feel good while exercising.

Reader Carl Fink had a comment yesterday, which included several questions:

Hi, John. I'd love to see some expert like, say, a virologist discuss immunity to the viral shell "carriers" of certain vaccines, e. g. the AZ and J&J vaccines for COVID-19. My particular train of thought: they use a viral capsid to carry genetic material into the host cell, which then manufactures viral proteins to sensitize the immune system. They also will generally contain an adjuvant, yes?
So ... the host presumably develops immunity to both the carrier virus and the intended target, and I can't see how the adjuvant can only intensify immunity to the target. Now the patient is immune to the carrier. By itself, immunity to a harmless adenovirus (or whatever type) is fine, but what if you need a booster shot? Wouldn't there be a reasonable chance that the immune system would destroy the pseudo-virions containing the viral genetic material before it entered the patient's cells? OTOH, I don't know a darn thing about the kinetics of the immune system ... if you wait a year for circulating antibodies to drop, would the immune system react too slowly (with memory cells having to proliferate) to prevent re-immunization?
Thanks.

I am not too proud to admit that this strains my expertise. Chimeric vector-based vaccines are something I’ve worked on, but the immune reactions to the vectors can be very specific to the virus used. Here’s how I answered:

Hi Carl!
This is a great question. There are definitely substantial immune reactions to the vectors used in chimeric vector vaccines. I don't think it's typical for such vaccines to contain an adjuvant--this will depend upon whether the vector itself solicits a meaningful inflammatory response. Sometimes the vector induces enough of an infection that it is, sort of, self-adjuvanting.
I've written a little bit about this in an earlier edition of the newsletter, actually in two issues:
https://covidtransmissions.substack.com/p/covid-transmissions-for-9-1-2020
https://covidtransmissions.substack.com/p/covid-transmissions-for-9-3-2020
When it comes to reactions against the vector, I have to confess that I don't feel fully equipped to answer you. I do know that several chimeric COVID-19 vaccine designs have had major problems with reactions to the vector befouling immunity. I think this may also be the reason that the half-dose priming with the AstraZeneca vaccine worked better; I think this generated less of a response to the vector, allowing the boost to be more effective. But, again, I feel like this goes a little bit out of my depth. However, I do know someone who is qualified and an expert on this. I'm going to check in with her and see if I can do an interview with her for a future issue, where we can try to address some of your questions more specifically. I'm not sure that there are straightforward answers to any of these.

You might have some questions or comments! Send them in. As several folks have figured out, you can also email me if you have a comment that you don’t want to share with the whole group.

Join the conversation, and what you say will impact what I talk about in the next issue.

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