Risk Management and Two-Dose Vaccines

[rslade]

Now that vaccines have started to roll out, we have a new risk management lesson from them. Most of the vaccines that have been approved so far are two-dose vaccines. With the rush to get vaccines into people in the most expeditious manner, there is now a new controversy. Do you give as many people as possible one dose of the vaccine, or do you hold back doses so that there will be a guaranteed supply for those who need a second shot?

First, let’s look at the mechanics of what is going on with the two-dose vaccines. (There are some one dose vaccines coming, but they seem to be at least a month away from approval, so we’ve got some time to discuss this.) The first shot, in a two-dose series, is often referred to as a primer shot. It is delivering some material to the body to alert the immune system to something it should be paying attention to. Most often this is some kind of protein that is foreign to the human body. The Pfizer and Moderna vaccines are kind of interesting in that they contain messenger RNA (mRNA) that makes our bodies produce the protein spikes that are on the coronavirus. Having produced these proteins (without ever having encountered the actual virus), our bodies then produce antibodies that identify and attack these proteins. The idea is that, by the time we actually encounter some coronavirus, our bodies are primed and ready to attack the actual virus. (Given the trials that have gone on, and the data collected, the idea seems to be correct.)

With many two-dose vaccines, the second dose, sometimes known as a booster shot, as opposed to the initial primer shot, is often just more of the same. (Both the Pfizer and Moderna vaccines are of this type.) In past studies of vaccines, it seems to be that, in the case of many vaccines, a second shot of the same material does two things. The first is that it increases the protective effectiveness of the vaccine, by boosting the immune response that we produce. The second is that it increases the duration over time that the body is able to produce this response, thus conferring protection over a longer period. For example, after a single shot the body may produce an effective immune response for a period of four months. After a second shot, that might be increased to two years. (At this point we don’t have good data about duration in regard to the Pfizer and Moderna vaccines, since they haven’t existed for more than a few months, but we assume they will follow a similar pattern.)

The increase in duration is, of course, a benefit. But, in the midst of a pandemic, and particularly in the midst of huge second and third wave surges, it is the increase in effectiveness that sets up the possible controversy. Do you leave some people only partly protected, so that you can partly protect others?

Since this is risk management, we again have to note probabilities and uncertainties and the fact that none of this is quantum. Protection isn’t absolute, and it doesn’t turn on and off. In particular, protection doesn’t turn on instantly, and takes time to develop. And it also takes time to go away again.

In a two-dose vaccine regime, you receive an initial primer shot. That does not mean you can now safely go to bars and insurrection mobs without being at risk of getting CoVID-19. It will take some time for your body to develop any kind of immune response. After three weeks or so, you may have about 80% protection. Note that this isn’t 100% protection. You can still get infected if you encounter someone who is infectious. But you are less likely to become infected.

(Actually, even though it might sound low, 80% is pretty good for a vaccine. The flu vaccines that we get every year are only about 50% effective. That, and the effects of herd immunity when almost everyone gets the vaccine, means far fewer cases of the flu, and fewer deaths, and less time lost to sickness, and less impact on the economy, and so even a 50% effective vaccine is a very good thing.)

At this point, two things may be happening. Your body may (and probably is) still increasing it’s protection, even without any further intervention. Some of the Pfizer and Moderna data indicates that, over a longer period of time, even a single dose of the vaccine can confer protection over 90%. But you can, at this point, get the second, booster, dose of the vaccine. Following the booster dose, after some time (possibly a week, possibly six weeks), your protection level can rise to around 95%.

A couple more points to note. I said “at this point.” Vaccine studies in the past have clearly shown that, if you give the booster shot too early, it is basically a waste of vaccine. There is a minimum time, after the primer shot, before a booster shot gives any booster effect. This minimum time seems to be three weeks, in the case of Pfizer, and four weeks, in the case of Moderna.

Another factor to consider is that, while there is a definite minimum time period between shots in terms of maximum effect, the maximum time between shots is much more open ended. If the minimum time is three weeks, then there is no diminution of effect if you wait until four weeks to give the booster. In fact, many studies seem to indicate that, to a certain extent, the longer you wait for the second, booster, shot, the stronger the protection and the longer the duration of protection. (Again, the coronavirus vaccines simply haven’t been in existence long enough for us to have really good data on the timing, but studies or existing vaccines show that this is very likely.)

Yet another consideration goes back to those numbers. You will recall that I said 80% was pretty good protection. It is. 90% is better, and 95% is better still. But even 95% isn’t that much better than 80%, and 80% is a whole lot better than nothing.

So, back to the controversy. When we start giving vaccines, we can stick with the minimum time regime, and give everyone a second dose as soon as they hit the three week mark. That way we get more people up to 95% protection sooner.

Or, we can delay the second dose out to five weeks. The downside is that those people spend an extra two weeks at 80% protection before they get the booster dose. But, during those two weeks, we can start bringing even more people to 80% protection (rather than leaving them with nothing). Which means we start building herd immunity faster. And the early lot are not, after all, being left with no protection. They are probably at 80%, and may be building, themselves, towards 90%. And they are still well within the time period during which they are going to get the booster effect. They may even get a better booster effect for the delay.

The calculus involved here is complex. It involves the infectiousness of the virus, the effectiveness of the vaccine, the total numbers of cases, and a number of other considerations. However, in our situation, the answer seems to fall on the “delay” side of the equation.

[Steve-Wilme]

Rob,

It's a complex area.  It is hoped that the immunity conferred by the vaccines is long term, although there is some evidence that those infected early and recovered still have a good level of immunity 6-7 months later.  The evidence from SARS is that those infected the 60% that didn't die back in 2004 still have a level of immunity to the virus.  The key point is to get the logistics in place to enable the swift vaccination of the majority of the population to cut down the rate of community transmission, before the more infections strains become dominant.

[denbesten]

The FDA does have a statement:

...

We know that some of these discussions about changing the dosing schedule or dose are based on a belief that changing the dose or dosing schedule can help get more vaccine to the public faster. However, making such changes that are not supported by adequate scientific evidence may ultimately be counterproductive to public health.

We have committed time and time again to make decisions based on data and science. Until vaccine manufacturers have data and science supporting a change, we continue to strongly recommend that health care providers follow the FDA-authorized dosing schedule for each COVID-19 vaccine.

...

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So, the next step is to trial the theory that this vaccine behaves similarly to those in the mentioned trials.  The FDA statement is is not much different than the reasoning behind an I.T. policy stating "the implemented change must match the approved change".  

Inventory vs just-in-time for the second dose is definitely an interesting strategy question. Manufacturing and retail have been playing this game for many years.   In the idealized manufacturing scenario, a truckload of new widgets will arrive at the gate just as the prior truck's last widget is placed onto the assembly line.  Of course, this has risk given the realities of supplier outages and logistical delays (e.g. accidents).  As such, an inventory buffer is often built in (e.g. parts trucks arrive an hour before their scheduled unload time), with larger inventories being maintained when greater risk is perceived. 

By maintaining 50% vaccine inventory, the decision-maker is demonstrating a disturbing lack of faith that orders will be fulfilled on time, at the right place and in the quantity requested.  They key to reducing inventory below this threshold is to improve this faith in the manufacturing and supply chain.

[Steve-Wilme]

The experience in Israel should give pause, as the vaccine used is reported to be only 50% effective after first dose, based on the real world experience of the vaccination rollout.  It sounds like one to keep an eye on.