Covid 19 Vaccination: One Dose or Two ?
I am going to write more on the topic of Covid 19 vaccines. I will argue that it would be better to give second (booster) shots only when vaccine supplies are plentiful. I think that so long as the vaccine is in short supply, people should be given one dose. I criticise the current policy of withholding vaccine to make sure that everyone who gets a first dose gets the scheduled booster either 3 weeks later (for the Pfizer vaccine) or 4 weeks later (for the Moderna vaccine). I argue that more lives will be saved with the one dose until supplies are plentiful strategy (even if many people don’t show up for the booster when supplies are plentiful). I think that the current policy will lead to tens of thousands of un-necessary deaths in the US alone with worse consequences for countries further back in line for vaccine supplies.
The post will have two sections. One will be an attempt to analyse the published data, which are mostly Kaplan and Meier plots with numbers read off by eyeballing. I will conclude that the best (poor) estimate of the reduction of infections from the first dose is more than 18 times the reduction due to the second dose. This calculation requires the key unproven assumption that the effect of one shot is weaker than but as durable as the effect of two shots.
This would mean that efficient deployment is one dose for as many as possible as soon as possible and second doses when giving them doesn’t interfere with this. I will go on to bore people with some p-values. I think that the null that it is as efficient to give second doses on schedule is rejected at at the 5% level (given published data). I note that benefits probably include the (unproven) prevention of transmission as well as benefits for the vaccinated people. I also note that giving two to some and zero to others is unfair especially given the difficulty of deciding who gets vaccinated first and the necessarily partly arbitrary decisions. The second section will come back to arguing about public policy and ethics as I just did.
OK so data. Basically all I know is here. I am going to write mostly about the Pfizer data, so I will start with Moderna.
Moderna
I do not think it is easy to see when the second dose was given, the Kaplan Meier plot of infection of vaccinated people is almost horizontal. The risk of diagnosed infection was very low also during the interval between doses. The second dose was given on day 28. The researchers assumed that vaccine elicit immunity over a 14 day period, so the full test began on day 42. I can’t guess how many vaccinated participants were diagnosed by day 28 or day 42. One problem with interpreting the Moderna study is that the control group’s hazard of infection increased over the study period. One should really look at the ratio of the hazards for the two populations. However, I can’t do that eyeballing the graph. I think it is clear that, for the first 28 days, the blue curve is less than half the grey curve — that is an estimate of the effectiveness of the vaccine would have to be more than 50% effective. This means that the reduction of infections due to the first shot would be greater than the reduction from the second shot even if the full vaccination schedule were 100% effective. Eyeballing, the first shot looks 80-90% effective.
The Pfizer study
Again it is hard to guess when the second dose was given. In this study it was given on day 21.
This graph contains more useful information. In particular it shows each infection of a vaccinated person (red circles). In the Pfizer study, they assumed that vaccines work over 7 days not 14 days. It is important to me to count infections after 14 days (Moderna) not 7 (Pfizer). The number is semi arbitrary. I see 5 cases after day 13 and before day 35. there were 9 cases after day 34. One advantage of the Moderna graph is that they have the population at risk, but Pfizer does report watching 4015 vaccinated person years or 208,780 person weeks. I assume everyone was followed for 5 weeks so there were 65,006 person weeks of vaccinated people in week 2 4 and 5 and 100,435 of vaccinated people in weeks 6 and on. So if the risk before and after the second vaccination (plus 14 days) were equal there should be a bit more than 3/8 of the post day 13 cases should have been before day 35 so 42/8 or 5.25. In fact there were 5 cases. The risk did not decline 14 days after the second vaccination.
One unfortunate participant was diagnosed on day 14 and one on day 35. Counting them as within 14 days of the first and the second vaccination I get 5 of 13 cases in the period sufficiently after the first vaccination but not sufficiently after the second. With this slightly different arbitrary window, I get the expected number of cases 3*13/8 = 4.875. Again not a statistically or medically significant decline.
With more radical eyeballing, I estimate (guess) that about 0.3% of the control group were diagnosed from day 14 through day 34 so about 60 people (one significant figure is all my eyes can maybe manage). So my guess is that the first shot was about 90% effective over this period. The full schedule was 95% effective over the full period, so I get a point estimate that the benefit of the first shot is 18 times the benefit of the second shot.
Importantly, the Pfizer trial is a unified phase 1-2-3 study. The protocol was written and approved before the vaccine had been injected in a person. The choice of 2 doses and an interval of 3 weeks was not based on data on Covid19 vaccine in humans.
OK policy. I think the best guess of an efficient strategy of vaccination is; “it is better to delay booster shots until additional supplies are plentiful”. I am sure this will not happen. The reason is that once a protocol is chosen, it is not changed. This is an important rule for experimental science, because it guarantees that the experimental interventions are exogenous to the entities being studied. The FDA also (very properly) requires a pre-approved protocol for data analysis. This eliminates the risk of data dredging. It rules out the sort of amateur eyeballing I did here.
The FDA also has a rule that they allow no changes unless they are proven to be improvements (and they accept no evidence except for randomized controlled trials). In general this limits approval of new pharmaceuticals and biologicals, but does not limit the practice of medicine. Doctors can and due prescribe pharmaceuticals off label for treatments other than the one which obtained FDA approval.
The vaccines are different, because all vaccine supplied to the USA belongs to the US Federal Government. The policy decision of how to deploy it is, in practice, governed by FDA rules for approval of pharmaceuticals. A proposal to change the schedule of booster shots to free up vaccine for more first vaccinations is like a new proposed drug — guilty until proven innocent.
I think this is a mistake.
It sure seems to me you are right.
“In the Pfizer study, they assumed that vaccines work over 7 days not 14 days.”
My eye (guess) indicates that they assumed wrong. There is a clearly changing slope well after 7 days. If the 7 days is part of their protocol, they would be forced to report one dose not as effective as two.
The Protocol: has no scheduled visits between 35 days and 175 days [1.3.2]? If that is right, all of the incidents are based on COVID-19 being suspected? If that is right, the protocol does not catch asymptomatic incidents?
This editorial from October:
https://www.bmj.com/content/371/bmj.m4058
asserts: “none of the vaccine trials are designed to detect a significant reduction in hospital admissions, admission to intensive care, or death.” I suspect he would share your concern that because of protocols the best use of the vaccine may not be well considered.
Even if one dose is (truly) not as effective at preventing incidents, does it still reduce severity?
Doesn’t really matter in the end
Gregory,
You must have posted on the wrong thread.
With luck we will be compiling data during the vaccination process that will tell us who and when got shots and infection. Tests right before 2nd dose would be a handy indicator. Then after healthcare workers and the most vulnerable, particularly long term care residents, have been made safe there will be data to support giving the younger, stronger, and less proximate people single doses. The application logistics are more challenging the further from the healthcare system that we get. Herds of unprotected people lining up for shots sounds like a Trump plan since the vaccine likely does not protect from day one.
Problem not being taken into consideration much is the mental health degradation due to familial separation for healthcare workers and the institutionalized. Donald Trump was an endogenous disorder.
In VA front line healthcare workers in some hospitals received vaccine yesterday. That should solve half of the problem for front line healthcare workers, the dread of their own wellness risk. Now they just need to face death taking their patients every day without the comfort of a hug from their loved ones.
It is unlikely that long term care residents will be able to receive visitors even after they get vaccinated, but at least those refrigerator trucks can be cleaned out and again be used for shipping seafood :<)
Oh, and front line health care workers can still die of exhaustion or amphetamine overdose.
“I think the the best guess of the efficient strategy of vaccination is that it is better to delay booster shots until the virus is plentiful.”
I assume you mean “until the *vaccine* is plentiful.” The virus is plentiful, indeed abundant.
I don’t see any evidence that vaccine manufacture will be rate-limiting in the US. Right now, what is rate-limiting in the US is the supply chain. Eventually, what will be rate-limiting in the US is vaccine refusal.
This proposal fills a much-needed gap.
Even in a perfect world then it would not be the choices that would be difficult, but rather the consequences :<0
What problem would be posed by later accelerating vaccination by skipping the second dose when compared to the alternative of beginning single dose vaccination and then later changing policy to delay vaccinations while people got a second dose? How long does one dose protect versus two doses? Who could possibly know given the rapid development and approval process? Whose credibility is at stake? How would procedural failure affect acceptance rates among those uncertain whether the vaccine is safe?
The more certain that one is then the less likely they can be held accountable.
How does my increased risk of contracting Covid-19 from waiting longer for vaccination staying at home except for senior hours grocery shopping once every week or two compare to the increased risks of front line health care workers or workers and patients in long term care facilities with even a marginal difference in efficacy between one and two doses of vaccination? In any case, that is still over-simplified. In a healthcare crisis not all individual deaths are the same in the long run. People are not just numbers when their social utility is critical or their ability to isolate is nonexistent.
In subsequent cohorts of vaccination candidates the logistics of delivery will likely overshadow the manufacture delay of vaccine, but if not then certainly the results of interim experience will determine whether the two dose prescription prevails. OTOH, there is still some chance that longer term efficacy and interval of second vaccination will prove important enough to maintain the present regime.
A couple weeks ago I called my best surviving friend to ask how things were going for his family particularly with respect to his decade younger wife, who like my own is still working. But my wife works from home and his wife is a nurse in a hospital in Tucson AZ. Well, his wife will still be isolated from her family for the foreseeable future. The conversation turned to the trial results indicating that Moderna had proved better efficacy for over 65 than Pfizer’s vaccine. But my friend informed me that the datasets from the trials were far too small to reach any such nuanced conclusions.
“…the datasets from the trials were far too small to reach any such nuanced conclusions.”
[OK, too be far conclusion jumping is one of the few sport that geeks are good at. So, conclusions are easy to reach. I should have wrote “the datasets from the trials were far too small to RELIABLY reach any such nuanced conclusions.”
[I understand the fallacy of the argument from authority in contrast to evidence, but under conditions of a novel virus pandemic vaccine on a warp-speed fast track, then I will bet on authority if it is well established with real world experience rather than merely academic rigor.]
https://www.thedenverchannel.com/news/national/coronavirus/dr-fauci-explains-why-coronavirus-vaccines-come-in-two-doses
Dr. Fauci explains why coronavirus vaccines come in two doses
By: Justin Boggs
Posted at 9:28 PM, Dec 04, 2020
and last updated 11:28 PM, Dec 04, 2020
Whenever you get vaccinated for the coronavirus, there is a good chance you will need to get two doses of the vaccine. Two types of vaccines are expected to begin being distributed this month and both require two doses 28 days apart.
Dr. Anthony Fauci said during a CNN town hall on Friday that the first vaccine is the “prime” vaccine dose, and the second one is a booster. The two vaccines, one from Pfizer and the other Moderna, are expected to receive an FDA emergency use authorization in the coming weeks.
Fauci said another vaccine, one produced by Johnson and Johnson, would only require one shot. But Fauci cautioned that the data from that vaccine candidate has not been reviewed. The Moderna and Pfizer vaccines are showing an efficacy of 95%, and both vaccines had a near 100% effectiveness against severe coronavirus cases.
While the first shot will offer some protection against the virus, Fauci says that the boost will give Americans “optimal” protection against the virus.
“What you have is you get some degree, not optimal, but some degree of immunity a couple of weeks after the first dose,” Fauci said. “That’s not optimal. After the second dose, you get optimal immunity anywhere from seven to 10 days after the second dose.”
As vaccine doses begin to make their way to health care workers and high risk patients, Fauci says it will be important for everyone, even those who are vaccinated, to still wear masks and conduct social distancing. Fauci says that those who are vaccinated could potentially carry the virus, even if they will not become symptomatic.
Fauci said that it will take a vast majority of Americans getting vaccinated before the US reaches herd immunity. When the US reaches herd immunity, that is when social distancing measures can be eased, Fauci says.
“Even if you’re vaccinated, you may be protected against getting sick, but you may not necessarily be protected against getting infections. So you may have some virus in your nasal pharynx. It wouldn’t bother you, and maybe it wouldn’t even infect anybody else, but it would be there. That’s the reason why you can’t abandon all public health measures.”
*
[So, why should there be an air of caution surrounding public policy designed to control a pandemic disease that is lethal only about 2% of the time?]
In summary, the two dose protocol is an artifact of the extreme risk exposure of the health care worker and long term care cohorts, decades of epidemiology experience, “warp-speed” FDA approval, endemic uncertainty, and hard realism.
It seems to me the two dose protocol also assumes there will be no shortage. I suspect health care workers could be better served if the number of patients was reduced more quickly.
Not 1 dose or 2.
One or more vaccines.
Should I get both the Pfizer and the Moderna?
Should I get another 5 different vaccines?
Arne,
“… I suspect health care workers could be better served if the number of patients was reduced more quickly…”
[Indubitably so. However, consider all that would have to happen to make that reduction in patients at all significant to the hospitalization rate. With limited vaccine and no way to inoculate the prime transmission candidates other than those already on the top of the priority list, healthcare workers and long term care residents, then protecting the most vulnerable and the most exposed is the next step. So, people over 75 and people that work indoors in groups (Walmart workers before Walmart shoppers) not of the same household would be next.
The biggest risk for most people is themselves. They are unwilling to isolate, social distance, and wear masks until vaccine has been widely applied. Too bad for them then since the protocols are likely to hang on for a while even after theoretical herd immunity critical mass. Some of the risky people will get vaccinated and some will not. The logistics of doing wide scale vaccinations during a winter rise in transmissions is not just difficult, it is bat-shit crazy.
The time line that we are on was understood at least a year ago. There was no realistic way to do things any faster. We are just lucky that we were able to toe that line.]
@Ron
“…The time line that we are on was understood at least a year ago…”
[Understood means penciled in and shepherded going forwards. It was not inked until FDA approved the first vaccine but that dependency was penciled from the start.]
@Dave,
The Pfizer and Moderna vaccines are both spike mRNA vaccines. From the standpoint of the immune response mechanism, they are identical, and the protection data bear that out. So it would make no more sense to get the Moderna *and* Pfizer vaccines than it would to get four shots of the Moderna or four shots of the Pfizer.
The AstraZenica and J&J Janssen vaccines are recombinant adenovirus vaccines (single dose) but also express the spike protein. And there are two vaccines under testing that are recombinant spike protein. So really it would make no sense at all to get vaccinated over and over to the same antigen. It would be a waste of perfectly good vaccine.
When I told my wife last January how this was all going to unfold then she did not even believe that there was going to be a global pandemic. She is only now really beginning to become afraid. Well the worst part is still ahead, but at least she believes me now. It did not hurt that Joe Biden said the same on TV after the electors had voted.
https://www.npr.org/sections/biden-transition-updates/2020/12/22/948929003/watch-live-biden-gives-remarks-ahead-of-the-holiday
The ‘Darkest Days’ Are Ahead Of Us, Biden Warns About COVID-19 Pandemic
December 22, 20201:30 PM ET
Updated at 9:52 a.m. ET Wednesday
President-elect Joe Biden warned Tuesday that the coronavirus pandemic will get worse before it gets better.
“Our darkest days in the battle against COVID are ahead of us, not behind us,” Biden told reporters during a year-end news conference in Wilmington, Del.
He said that Americans, when united, could overcome the crisis, and he called the first vaccines being administered a good thing. But he noted that distribution of the vaccines is one of the biggest operational challenges the country has ever faced….
*
[Merry Christmas and stay frosty.]
I told my wife last January that January 2021 was really going to suck.
Joel,
I am really hoping that Dave Barnes was just being facetious. After all, it is late in the day to be shouting from the sidelines that we only need to give a single dose to conserve vaccine. We cannot know, we have no power, and commitments are already made. This is a logistics and risk management nightmare, not a simple supply and demand problem. This thread presented the right answer to the wrong calculus. Reminded me of an Ian Mitroff workshop problem on how not to address mass immunization. The real issue is the logistics of administering vaccine, whether 250 million doses or 500 million doses, to reach the 75% herd threshold. It is not going to be done by crowding people together during the transmission peak in winter. I knew that a year ago because I am not a moron.
Seems to me you’re actually asking the question: should we vaccinate X number of people, or pretend to vaccinate twice as many.
Doesn’t seem overly useful to me.
The good news is that by spring when outdoor vaccination drives and abundant vaccines combined with (hopefully) few bad side effects experienced. then the number of people refusing vaccine will have declined substantially, mostly because almost everyone will by then know at least one of the over one million US residents that have died from Covid-19 complications.