“That’s some catch, that Catch-22,” he observed. “It’s the best there is,” Doc Daneeka agreed.” — a conversation in Joseph Heller’s novel “Catch-22”
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). Reporting to date has not made clear the unfortunate truth that a hidden “Catch-22” means that no vaccine that is proven highly effective for seniors is likely for a very long time. What is the Catch 22? It’s that the faster we have information on safety and efficacy for healthy 18-55 years olds, then as you will see below, the less likely it is that we will have that information for people over 55. But please note I am not saying that we won’t have a vaccine that seniors can use and that will very likely have benefit for them, what I am saying is: we won’t know quickly: how much benefit seniors will get from any approved vaccine.
The gold standard to determine efficacy is a large, placebo-controlled, double-blind clinical trial. There are currently eight vaccines (nine if you count the Russian one) 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. Why? To begin with none of the three 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 obviously, they should be using three groups i.e. one for each age decile of age: 55 to 64, 65 to 74, and 75 and older. Enrolling participants in a properly stratified trial is more difficult and perhaps takes a bit longer than enrolling volunteers in a nonstratified trial. To be sure, it’s possible to tease out information about different strata of seniors react to the vaccine even they are lumped together in one group, but it takes more data about individual cases because you have to tease out the information for each age decile from a larger group. So even if these trials give us some information about efficacy for seniors, they are unlikely to tell us everything we need to know quickly. The only thing we will know for sure 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.
So when will we have a completed, placebo controlled, properly stratified phase 3 trial on people over 55? As far as I can see, the answer is never. Why? Since Covid-19 can be so deadly in older people, they, their families, and their communities have generally been taking better precautions than the general public against becoming infected with the novel coronavirus. For example the CDC reports (https://www.cdc.gov/mmwr/volumes/69/wr/mm6939e1.htm#T1_down) as of August that roughly speaking the prevalence among people >75 years old is roughly 1/15 that of people 18-55 years old. And, even if you lump all people over 55 into one group it is 1/3. And of course we are all hoping that prevalence has gone down since August. And prevalence affects the time needed to have a statistically significant efficacy signal out of the current vaccine trials: the time needed for people over 55, and especially among people over 75, will be far longer than the time needed to get an efficacy signal from 18- to 55-year-olds.
But that takes me to my point: 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 — all participants should be offered the vaccine that worked among younger people. Thus the Catch-22: the faster we get a safe and effective vaccine based on trials on 18-55 year olds, the less likely it is we will have all the information we need on its efficacy for people older than 55.
Still, I do want to stress that a vaccine that is proven safe and effective on 18-55 year olds will have a benefit for people over 55, if you are in this group you will definitely want to take it when it becomes available. What I am saying is you just won’t know how effective it is on your age group absent a completed placebo controlled study.
What happens then? In an ideal world, correctly stratified trials for people over 55 will compare the approved vaccine(s) to various tweaked formulations or dosing regimens. But not only will these trials take time, they 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. For example, the optimal dose of the flu vaccine for people over 65 turns out to be four times the antigen dose of the regular vaccine and it is approximately 25% more effective than the original flu vaccine (https://www.nejm.org/doi/full/10.1056/NEJMoa1315727?query=featured_home) but that took time to determine.
That sounds great, but we aren’t home free. Since 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 vaccine is working! Suppose, say the original vaccine was just 10% effective among people age 75 and older. Doubling the effectiveness with a tweaked formulation puts it at only 20%. Knowing the something is 2X, doesn’t tell you anything without information about X, and that is what we won’t have. 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.
To summarize: given what seems to me to be the inescapable ethical issues in completing any placebo controlled study on seniors, if you very quickly have a safe and effective vaccine based on trials in healthy 18-55 as people are hoping, you won’t know enough about how well the original vaccine worked in one or more age decile group of seniors-you just don’t know that “X” for them. 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 of a vaccine you have little absolute information about for your age group? I am and I wouldn’t!
We are stuck in the twilight zone of having relative information but needing absolute information! Can biostatisticians do anything to break the barrier between relative information and absolute information? 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 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, will 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.