COVID the Gift that Keeps on Giving

Nonsterilizing Immunity Drives the Evolution of Immune Escape Variants

I thought by now it would be time for an interim summary post, one of those look back and see if you agree with the writer about what we got right, (some but not enough) and what we fumbled repeatedly; but the SARS2-Cov19 virus never adheres to the human agenda and once again is both on the rise, and a moving target. There are enough new developments, and more than enough retrospectives out there, so let’s dive into some new information. Total new cases for the US as a whole have begun a small upswing due to the BA.2 echo wave, and so far are quite moderate, even though BA.2 is by far the most dominant variant. New Yorkers are once again being treated to the early COVID experience. Two new sub-variants off Omicron, BA.2.12 and BA.2.12.1 are responsible for the higher rate of new cases which is occurring in the central upstate and Finger Lakes region. In that area, these newer variants have very rapidly replaced BA.2 as the dominant virus, and have a clear rate of spread advantage over the parent strain. BA.2.12.1 is the the one to keep an eye on since it has a mutation in the receptor binding domain (RBD), that was previously seen in the Lambda variant, which became dominant in areas of South America. That mutation is felt to confer significant antibody escape potential and is not present in BA.2. There is no clear signal that we have a genuine, certified bad boy here, as was obvious immediately with Omicron. For one thing this sub-variant has been noted in other places around the country, like Houston, where it has not spread rapidly and replaced BA.2. It bares watching but not real concern, perhaps there are some unique local factors in upstate New York, like the water, or local politics that are having an influence.

We are all sick of the Alphabet Soup of COVID variants, and many very reasonable people have decided to tune out. Since you are still reading I’ll assume you are taking the proactive, “know your enemy” approach. Let’s look at why these variants keep appearing and will continue to do so. First, there was a fundamental misunderstanding of this virus’ ability to mutate; the virologists got it wrong in the beginning. Science is a set of principals for asking questions about the natural world and testing our assumptions to see if they are correct. Don’t let anyone ever tell you it is set of settled answers which must not be questioned. If you question from a solid background of well validated, multiple-tested and proven scientific knowledge, then there is every reason to think you might be correct, even if most of the experts believe differently. If you question because of a post on Facebook, Twitter, your friend the auto mechanic or a politician striving to define themselves from the pack, then you will almost certainly be wrong.

To answer the question of why COVID variants are appearing in great numbers we need to review some basic premises of viral evolution. Some of you have a sophisticated understanding of all this, but bare with me, there still might be some nuggets worth mining. We all know by now that COVID is mutating very quickly, approximately four times as fast as the H1N1 Influenza virus. According to Trevor Bedford, an expert on viral evolution at the Fred Hutchinson Institute who has had an impressive record of utilizing big data analysis for tracking the evolution of SARS2-Cov19; in 2021 it was mutating at about 12 amino acid changes/ year in the S1 region of the spike, which includes the RBD. https://www.fda.gov/media/157471/download You should think of variants as arising in two distinct ways. The random errors that occur at a predictable rate as the virus copies it’s RNA, these are like the genetic drift that occurs at a slower rate in the Flu virus all the time. These changes give rise to the sub-lineages of a variant: BA.2 evolving into the two new strains now seen in New York State for example. Then there is the more dramatic shift which occurs when two different variants of the virus infect the same person and exchange significant segments of genetic information in one fell swoop. There also is felt to be another mechanism for the sudden appearance of a highly divergent variant, and that is the accumulation of a lot of single mutations in a chronically infected person with a poor immune response. Either of these latter two mechanisms are analogous to the large shifts that occur in Flu virus every few years and can set the stage for pandemic spread. Unfortunately, COVID has been able to make these large jumps in evolutionary change far more rapidly than originally imagined.

The rate of mutational change in COVID began to pick up in late 2020, in particular the rate of mutational change in the S (spike) gene. That rate of change continued to increase into 2021. What was driving that acceleration in evolution was the human population developing first natural immunity, and then vaccine induced immunity. The problem for us is the irrefutable fact that we do not acquire long lasting sterilizing immunity from infection or vaccination with this corona virus. As more and more of the population developed partial immunity, which did not prevent infection, random mutations which either made the virus adhere to its receptor on human cells, or able to hide more efficiently from our immune response gave the emerging variant an advantage and were powerfully selected for.

Why would this pattern change going forward? My answer is the old adage often incorrectly ascribed to Einstein: “Doing the same thing over and over and expecting a different result is stupidity”. We are using an outmoded vaccine developed against a virus now somewhat remote from the ones confronting us today. These vaccines were extremely important in kick-starting our immunity so that far fewer of us died, but at this point they barely prevent infection, and as has been noted recently by several of the biggest vaccine cheerleaders— we cannot boost our way out of the pandemic. We are aiming at this point for COVID endemnicity, it’s not going away. But we have not reached an endemic balance with the virus yet, despite many aspects of life returning to a more normal state in the US. Endemic balance and living with COVID does not involve wave after wave of new variants every few months circling the globe and infecting tens of millions or more. This is true even if the CDC has stopped using cases as a metric, and indeed in my opinion, has very little accurate data on the actual current numbers of new cases. If you think that for some reason Omicron and the BA.2 were the last of their ilk, I hope you’re correct, but I’m probably not going to let you calculate my taxes.

If the virus is going to continue in the same vein, constantly evolving under the evolutionary pressure of non-sterilizing immunity, what can we do differently. Getting the last 20% of our population vaccinated is not going to make a difference, (except perhaps to them in terms of lessening the chance of a vacation on a respirator or a longer term vacation in the beyond). I think we need to look to science and the government. An effective sterilizing pan-corona virus vaccine should be the goal. There are already multiple candidates. The pharmaceutical industry did spectacular work developing the current vaccines; however, the brass ring was clearly displayed for them from the start, by the government. There is a palpable complacency now in the both Pharma and the Administration. The prevailing ethos is, “We will keep monitoring and if a variant shows up that looks sufficiently scary, then we will modify our RNA spike vaccine to address it”. This whack a mole mentality does not appear likely to improve the current situation of endless rounds of globe circling variants. We need the government to stop playing last year’s hymn: “Just get your vaccine and your booster” — or play it if they must for the sake of recalcitrant. But let’s get to the real business of pushing hard for the next generation of truly sterilizing pan-corona virus vaccines.