Hello. This is doctor Russell Kohl, chief medical officer with TMF with our ongoing COVID updates. Certainly, the biggest story in the last 24 hours, at least, has been the August 18 announcement by the CDC that they are intending to rollout booster shots of the mRNA vaccines over the course of the next month or so. Obviously, there is a whole lot of confusion around that, at the moment, and certainly a new number of studies that were released would make folks question, so, what has changed that suddenly we have made these changes? So, we wanted to make a special episode just to talk a little bit about that situation in and of itself. I think it is important to start with the fact that there has not been a Food and Drug Administration or the Advisory Committee on Immunization Practices review of the third booster shot for any populations other than those that are immune compromised. And so, while there was significant evidence about the effectiveness of and need for a booster shot for those immune compromised populations, as of yet, we really haven’t seen information that suggested that it was true for the whole population. However, there were four studies that were cited in the release. So, let’s dive into those a little bit and see what the evidence might tell us. So, they were four studies. One from the New York State Health Department. One from the Mayo Clinic. One from the CDC reporting system for nursing homes, and then from Israel’s Ministry of Health. Now, each of these are retrospective, cohort, reviews of data, largely around vaccinate rates and dates for individuals. Now, before we jump into the studies themselves, let’s think about the advantages and disadvantages of a retrospective study. Now, it is certainly much quicker, cheaper, and easier to do those retrospective chart reviews; however, there can be challenges associated with it. It’s important to remember the difference between correlation and causation, and retrospective studies have a significant problem in trying to prove causation. They also have a significant amount of recall bias. And can have really some challenges with confounding factors. There may be things that were simply not understood, or not taken into account as we did the review of the outcomes. So, certainly there are some advantages, but there are some certain cautions we want to take when we are looking at a retrospective study. When it comes to evidence-based medicine, I’m a big fan of the PP-ICONS’ model of looking at articles. And so what that stands for is problem. First off, we look at is this the problem that we are looking for? We look at the patient or population that is involved. We look at what intervention was tested, what’s the comparison group, what are the outcomes, what’s the number of subjects and is this a large enough study to be able to generalize the results, and then look at the statistics. Looking at actual risk reduction as opposed to relative risk reduction and those sorts of items. Just to make things a little more difficult for you, I’m going to take those a little out of order in our discussion though because I think that it makes it a little bit easier to approach some of the ones that have a little bit more of an issue. So, let’s start off with the patient or population. In each of the studies, the population were those who were vaccinated, and that remained stable throughout the period. Particularly, the Israeli study, there was a very broad population that was taken into account that makes it more generalized. The intervention in both [studies] was the messenger RNA vaccines, whether Pfizer or Moderna, that was administered on time. The comparison was actually a temporal comparison, so it looked at what was the outbreak rate of COVID-19 during a previous time period, versus a more recent time period, and attempted to draw conclusions from that. Finally, in my out-of-order approach, we’ll jump to number of subjects. Since these were very large studies, they were able to be accomplished by database systems. The number of subjects were generally in the tens of thousands, which gives us pretty good statistical significance for the findings that we would have. So, let’s go back and take a few of these items more in order, and see if it really is the data that we’re looking for to make the decisions that we need. The first P in the PP-ICON’s mode is problem. The question that was asked in each of these studies is whether a person tested positive. This presents a particularly challenging and interesting approach because the question becomes, do you care if you’re positive, as opposed to looking at sever illness or hospitalization of the populations. These studies were actually designed to look for any evidence of a COVID infection. I think that is an important factor when we get to discuss the statistics in just a moment. So since the problem was designed as a positive COVID test, the outcome, then, was simply looking at positive COVID tests, as opposed to hospitalizations, sever illness, those sorts of things. In each of the studies, there was a significant difference shown over time. In the New York study, comparing May versus July of 2021, they showed a decrease in the vaccine effectiveness for New York adults, from 91.7% in May, to 79.8% in July. The Mayo Clinic study looked from January to July of 2021, and that actually broke out separately the Moderna versus the Pfizer vaccine. What they found with regard to the Moderna vaccine was 86% effectiveness in January, but only 76% effectiveness in July. The Pfizer vaccine in their study showed 76% effectiveness in January, but dropped to only 42% effective in July. However, the effectiveness against hospitalization for both of the vaccines was completely unchanged during the course of the study. The study based upon on NHSN data actually looked at nursing homes and their outbreak of SARS-CoV-2, or COVID, between March and August of 2021. What they found at that time was two doses of the vaccine were 74.7% effective against infection amongst nursing home residents in March; however, by July, when the delta variant had become predominant, the effectiveness of those two doses of an mRNA vaccine had been decreased to 53.1% effective at avoiding infection. They do specifically comment that they have no information about whether these were symptomatic or asymptomatic infections based upon the data they received and also included a caveat that recognized that a large portion of this population, since it is a nursing home-based population, would actually fall under the proven concerns regarding immunocompromised patients and the need for a booster shot. So, it may not be as replicable to the entire population as the other studies are. So the final study is the Israeli study, which has a pretty interesting design. Using a nationwide electronic health record, they were able to look at the time from vaccination to the incidents of a breakthrough infection. They took the date from when you got your final vaccine, and moved forward until there was a positive COVID case, once again looking for only a positive laboratory result. Not necessarily a symptomatic or a hospitalized case. What their study demonstrated was that those who were immunized early had a greater rate of breakthroughs later in time than those who had been vaccinated more recently. So, this obviously creates some degree of a selection bias when you think about who are the folks who got the vaccine when it was initially approved versus those who got them more recently. Certainly, the focus on high risk populations at the very beginning would give them a higher likelihood of having an immunocompromised conditions or conditions that would certainly lead them to have problems down the road, as opposed to the later vaccinated, which were more often healthy and younger patients. So, this leaves us with a great question. This question is what does this evidence tell us, and what should we do as a result of it? In the simplest of terms, I would say the evidence is showing that the vaccine is not preventing infection as well now as it did in the past. However, there are a couple of large caveats to that. The first is that it is preventing hospitalization and sever illness exactly the same as it has throughout the entire outbreak. The second, is that we don’t know to what extent the increased breakthroughs are related to the vaccine itself and your immune response waning over time, versus the potential that the increased variants that have developed over time are less responsive to the vaccine itself. There are some ongoing studies in the British National Health System looking at quantitative antibody titers. Those are still ongoing studies at this time. I expect the next few weeks will be a particularly confusing time for folks as organized medicine and science attempts to look at these studies and come to what conclusions they need to regarding FDA approval, emergency use authorization, and even an ACIP recommendation regarding the vaccines. As health care quality improvement professionals, certainly we understand the importance of having patient-oriented evidence that matters, and really looking at how things affect the patient. Certainly that is going to be an ongoing discussion around the vaccines, and I do think it is also important to point out that this is a very different situation than the data we have supporting the two vaccines series. As it moves forward, we will continue to update you as more studies come out, and more information becomes available and as we’re able to wade through the additional data to try and make the best decisions that we can to support those folks in our community. In closing, I’ll leave you with just one last thought, and that is, throughout the entire pandemic, one of the things we have learned is that it is important to plan ahead. And so whether or not a third booster dose becomes ultimately scientifically proven to be an effective strategy or not, I think it is important for us to think about the planning process of what would it take for us to be able to launch a third dose of the vaccine, and how would we distribute that? How would we get it to the folks that most need those doses. Regardless of where the science ends up. And the confusing discussions that I am sure will occur in the next couple of weeks, there certainly is still value in the planning process of, “If we were going to do this, how would we go about doing it?” Once again, we’ll keep you up-to-date as more information comes in, and I completely encourage you to reach out to me with any questions or comments that you have. With that said, keep up the good fight, and keep making the world a better place.