I’m glad to be able to feature Gary Cornell again here. Some of the earliest blog posts on supplysideliberal.com were guest posts by Gary Cornell. Here he is again with a post about how the work being done to develop vaccines for Covid-19 is not targeted at the subset of the population that most needs vaccines: older folks. Here is Gary:

The risk of both hospitalization and death from Covid 19 increase greatly with age. Approximately 80% of the deaths from Covid 19 are people over 65 (https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/older-adults.html). The unfortunate truth is that a vaccine that is proven highly effective for seniors is not likely for a very long time, unless we dramatically increase the number of seniors in current trials now.

Why? The gold standard to determine efficacy is a large, placebo-controlled, double-blind clinical trial. There are currently eight vaccines in large Phase 3 trials. But it is very unlikely, maybe even impossible, that any of these vaccine trials will give us definitive information about how effective these vaccines are for people over age 55 — well, unless they change how they are currently setup.

Why? To begin with, none of the four trials that have released their protocols are properly stratified. While they aren’t lumping seniors into the same group as the 18 to 55-year-olds, they should be using three groups i.e. one for each age decile: 55 to 64, 65 to 74, and 75 and older. To be sure, it’s possible to tease out information about how different strata of seniors react to the vaccine even if they are lumped together in one group. However, it likely would take more data because you have to tease out the information for each age decile from a larger group.

But the bigger problem is that even if these trials give us some information about efficacy for seniors, they are unlikely to tell us everything we need to know quickly enough unless we have a far larger number of participants over 55 than the current trials are enrolling. Why? Since Covid-19 can be so deadly in older people, they and the communities they live in have generally been taking better precautions than the general public against becoming infected with the virus SARS-CoV-2 that causes Covid-19. For example, the CDC reports (https://www.cdc.gov/mmwr/volumes/69/wr/mm6939e1.htm#T1_down) that, as of August, roughly speaking, the prevalence among people >75 years old is 1/15 that of people 18–55 years old. And, even if you lump all people over 55 into one group, it is roughly 1/3. And, of course, we are all hoping that prevalence among seniors has gone down significantly since August. But prevalence is what determines the time needed to have a statistically significant efficacy signal from a vaccine trial.

Here’s what information I have gotten from their published protocols for the percentages of seniors enrolled:

AstraZenica: “Randomization will be stratified by age (≥ 18 and < 65 years, and ≥ 65 years), with at least 25% of participants to be enrolled in the older age stratum.” They are also using a 2 to 1 active to placebo division

Johnson & Johnson: “The aim of having a minimum of approximately 25% of recruited participants ≥60 years of age has been adjusted to 30%”

Moderna: “At least 25% of enrolled participants, but not more than 40%, will be either ≥ 65 years of age or < 65 years of age and “at risk” at Screening”

Pfizer: “It is intended that a minimum of 40% of participants will be in the >55-year stratum”

I suppose we seniors should be thankful, originally it was much worse (https://www.nytimes.com/2020/06/19/health/vaccine-trials-elderly.html), and in at least one case, the published protocols made this clear, as people over 55 years old were only added via a late amendment.

Anyway, regardless of what they were planning on doing originally, none of these four trials are enrolling a far larger percentage of people over 55 than they are enrolling under 55. This means the time needed for getting enough cases for people over 55, and especially among people over 75, will be longer than the time needed to get an efficacy signal from 18- to 55-year-olds. And you need to get that signal for seniors as quickly as you get a safety and efficacy signal for younger people. Why? Because once we have a vaccine that has been shown to be safe and effective for people under 55, I believe it is unethical to continue any placebo-controlled Phase 3 trial in the elderly for a disease so deadly to them — all elderly participants would have to be offered the vaccine that worked among younger people. Since designers of these trials are hardly stupid, it seems to me that they are either betting that they will have enough cases in seniors to have an efficacy signal quickly or that enough seniors will agree to stay enrolled in the placebo arm.

A better solution is obvious, don’t bet: dramatically increase the number of participants over 55 in the current trials quickly, no matter what the expense and difficulty is in doing so. The more people we have over 55 in a trial, the more likely it is we will have an efficacy signal before ethical considerations force us to stop the arm of the trial being done on seniors.

What happens if we don’t do this? Then the only thing we will know quickly is what the vaccine candidate does to immune system markers on seniors,such as the antibody levels they induce. And, since the immune system of someone who is 75 tends to work differently than someone who is 55, let alone 25, even having immune system markers in seniors that match those of a 25 year old won’t mean enough to know anything definitive. But I want to make clear that of course, seniors can and should take an approved vaccine based on the results in 18–55 year olds even without their being an efficacy signal for them.

Then, interestingly enough, I expect the same things to happen whether or not we had an efficacy signal for seniors: it’s just that the consequences and information we gain from them is different. What I expect is that correctly stratified trials for people over 55 will quickly begin that compare the approved vaccine(s) to various tweaked formulations or dosing regimens. We did this in order to get a better flu vaccine for seniors for example. But not only will these trials take time, unless we have that efficacy signal for seniors from the original trials, these trials can give us only relative information, not absolute information. For example, a trial might show that half the dose doesn’t work very well while four times the dose is not only safe but it works twice as well. That sounds great, but we aren’t home free if we don’t know how well the original vaccine actually works on seniors of varying ages. Knowing that you have a vaccine tweak that works twice as well as the original vaccine actually doesn’t tell you anything about how well the improved vaccine will work without a baseline! For example, suppose the original vaccine was just 15% effective among people age 75 and older. Doubling the effectiveness with a tweaked formulation puts it at only 30%. Knowing that something is 2X, doesn’t tell you anything without information about X. And information on X is what we won’t have unless we spent the money and effort needed to get it from greatly enlarged trials of the original vaccine in seniors now. This puts us in a completely different position than the flu vaccine where we knew quite well how the original flu vaccine worked in seniors, so the “tweaked” version’s efficacy was easy to compute.

To summarize: given what I feel are the inescapable ethical issues in completing any placebo controlled study on seniors once you have a safe and effective vaccine based on trials in healthy 18–55 olds, we must enlarge the number of seniors in the trials quickly. Failing to do so means that we likely won’t know enough about how well the original vaccine worked in one or more age decile group of seniors. Your castle will be built on little if any foundation.

So, considering how deadly Covid 19 is among seniors, absent great therapeutics, would you, if you were over 55, really change the precautions you are taking such as not getting on a plane because you took a vaccine you have little absolute information about for your age group? I am and I wouldn’t! So, again, I am hoping (perhaps without hope) that we spend the money and take the effort to quickly expand the number of seniors in the current trials.

I want to end by explaining what will likely happen if we don’t change the current trials to include far more seniors. First off, you need to always keep in mind that absent that, we will likely be stuck in the twilight zone of having relative information but needing absolute information! Can biostatisticians do anything down the road to break the barrier between relative information and absolute information if we didn’t enroll enough seniors in the current trials? Of course. What they will do is what is called a paired retrospective study. This means they will look at seniors who chose to get the vaccine and compare them with a matched group of seniors that didn’t get the vaccine. Then, given enough cases and a good enough match between members of the two groups, we will finally have a way to get the absolute information we need. Only after that retrospective study is complete, would seniors know (roughly) how well the best of the vaccine tweaks works for them.

Still, a paired retrospective study would be both difficult and time consuming to perform. Why? The key to doing a paired retrospective study is to pair up the people so that there are no differences between them that can influence the incidence of the disease. And you need to know if seniors who declined to get an approved vaccine, or who didn’t have access to it, are different in some fundamental ways from those who did get the vaccine. I don’t know how to answer that, but I do know that the biostatisticians are going to have a difficult job designing a paired retrospective study.

So I personally would be shocked if we have any absolute information about the efficacy of a Covid-19 vaccine for seniors for a very long time to come unless we spend the money and effort to dramatically increase the number of seniors enrolled in the current trials now.