Long ago, I warned that the failed vaccination attempt against Dengue, which led to many deaths in children in the Philippines, revealed a potentially massive long-term risk for SARS-COV-2 vaccination. And now, with Eric Topol arguing that we need a “variant independent vaccine”, I want to revisit this warning.
What I expect will take place as a consequence is that we’re going to see what evolutionary biologists call an adaptive radiation. History is filled with examples of animals that change very little for a long time, until they conquer a new ecological niche and suddenly evolve into all sorts of different directions as a consequence. With this virus, we have now created a situation where it’s going to branch of into numerous different directions.
This creates a huge problem, when it comes to creating a vaccine against these new strains. With the Dengue virus, we see that you can’t really develop a vaccine, because an immune response against one strain actually has the effect of enhancing the infection with another strain. With this virus, we haven’t reached that point yet, but genetic diversity is rapidly exploding, so we’re likely to see something similar eventually.
This was before the Omicron variant emerged, which is now recognized by many as a separate serotype, that forced the old serotype into (near) extinction. We now seem to be entering a new era however, in which different serotypes will circulate simultaneously. That’s a huge problem. And the Dengue virus illustrates why this is a huge problem.
A first Dengue infection tends to be mild. It is the second Dengue infection, by a different serotype, that tends to be severe. Such an infection uses antibodies from the first infection to its own advantage. After the second infection recedes, people tend to have protection that is variant-independent: The body now deploys antibodies that worked for the first, as well as for the second infection.
How is this possible? Mainly because of big antibodies that we call IgM. These antibodies can do their job, even when a part of a virus has mutated, because they bind on many different places at once. And through their size and by binding on many different places, they also tend to be much better at making the protein they bind to useless: They bend it out of shape and block its access to its receptor, so it can’t do its job.
With a second Dengue infection, we see an unusual antibody pattern that’s different from what you tend to learn in the classical biology textbooks: First the levels of the small IgG antibodies rise in blood. After this, the big IgM antibodies, which react with all serotypes, slowly rise in blood. And then as a result of those big antibodies, the patient gets better. And now with the body having developed a correct antibody response, a third infection becomes rare and typically mild when it does occur. The reason this happens, is because the IgG antibodies from the first infection make the second infection worse.
For coronaviruses, we observe something similar. The IgM and IgG antibodies from one coronavirus infection will also bind to another coronavirus. However, it’s only the IgM antibodies that also neutralize the other coronavirus. Unlike the IgM antibodies, the IgG antibodies just bind without neutralizing the other virus. They merely get in the way of IgM doing its job.
You might wonder: “If these IgG antibodies just make things worse for infections by different viruses that look kind of similar, why do we produce them anyway?” There are a number of reasons. To start with, they can stick to small regions where a foreign protein looks unlike anything your own body produces, regions too small for IgM to do something against.
Second, your immune system wants to keep track of the proteins your other cells are producing, to make sure they’re not producing viruses or other nasty stuff. For this reason, your cells generally have to display very small fragments of whatever protein they are producing in their MHC molecule. The IgG antibodies can bind to those small bits of protein, pointing out that the cell is up to no good. This is why IgG tends to emerge in blood after most of a virus was already removed by IgM: It points out the infected cells that also need to be destroyed, to make sure your body really gets rid of a virus altogether.
So why does this matter? Well, when your body first encounters a new respiratory virus like SARS2, it shows up in your nose or lungs, where it meets your mucous membranes. This is your first line of defense. You have B cells that produce two types of antibodies there: Mostly IgA and some IgM. IgM is also produced in blood however. And so when a virus enters your mucous membranes, IgM gets a head start over IgG. It can adjust (somatic hypermutation) to make an IgM antibody that fits well for whatever new virus infected you.
Unfortunately, all the vaccines against SARS2 were injected into people’s muscle, bypassing this first line of the immune system. As a result, IgM did not get its head start over IgG.
It’s also rare normally, for people to get reinfected by an identical virus. A reinfection by a different variant tends to help broaden the immune response and helps the IgM molecules learn to properly do their job. But with the vaccines against COVID, we injected people twice with an identical version of the Spike protein. That favors the IgG producing B cells, over the ones producing IgM.
Finally, there’s also the simple fact that the mRNA and DNA vaccines don’t produce circulating corona viral particles. Rather, they teach infected cells to produce the Spike protein on their surface. In the process these infected cells will also display small bits of the Spike protein inside their MHC molecule. You would expect there to also be big IgM antibodies that can clump different coronavirus proteins together, but when only exposed to Spike, that opportunity is unavailable.
All of these factors together seem to play a role in a problematic observation. What we see as a result is that once people get infected by the virus, vaccinated people show much greater amounts of IgG than IgM, when compared to unvaccinated people. The vaccinated were found in this study to produce 78 IgG antibodies for every IgM antibody. The unvaccinated were found to produce less than 3.
With every additional dose of the vaccine, the body expands its IgG antibody response, to include more parts of the Spike protein. This leaves less and less of a chance for IgM to learn to join the fight.
As a result, you end up with an immune response, that is inevitably very variant-specific. It will adjust over time through somatic hypermutation when exposed to other variants, but that will still be the same IgG antibodies your body will be deploying, now just against a different variant.
And this becomes a problem, once we start to have multiple very different versions of SARS2 circulating simultaneously. Because we know for SARS2, that the IgM antibodies remain useful against different variants, whereas the IgG antibodies become worse than useless: They keep binding, but can no longer stop the protein they bind to from doing its job, while prohibiting useful antibodies from doing their job.
Sometimes, these IgG antibodies can even directly help a viral strain, just as they do with Dengue. When they bind to the receptor binding domain, some can actually strengthen the connection between Spike and the ACE2 receptor. Some can pull open the Spike protein, by binding to the N-Terminal Domain. Yet others can pull the virus into your white blood cells.
So far, we haven’t seen an antibody dependent enhancement horror scenario yet. The first Omicron versions were intrinsically very mild compared to Delta, which they forced into extinction. The IgG antibodies adjusted to the first Delta variants and with later Omicron variants, the IgG antibodies once again adjusted to better fit those variants.
But with XBC in Australia and especially with the new Pirola BA.2.86 strain, we seem to be faced with a scenario where different versions of the virus will probably just keep circulating simultaneously, none strong enough to force the others into extinction.
Those different versions become different serotypes, like we have for Dengue. They will each carve out their own “turf”, not encroaching upon the others, while benefiting from the IgG antibodies produced by those other serotypes, just as we see for Dengue. You could compare this to men selling products on a farmer’s market. As long as they make sure they don’t sell the same products, they benefit from each other’s presence on the market.
Important to keep in mind is that the IgG antibody response isn’t just a liability once we start to have different serotypes. The IgG-dominant antibody response also actively facilitates the evolution of different serotypes. After all, unlike IgM it can’t neutralize different variants.
The Biden administration now wants to vaccinate everyone against SARS2 again this fall, other governments will probably do the same. Insofar as these vaccines will actually induce an antibody response that prohibits infection (this remains to be seen), they will just make the situation worse.
By preventing infections against the dominant XBB family, they would just make it easier for the newly emerging serotypes (XBC* and BA.2.86*) to establish their own permanent niche in our population.
Australia and New Zealand in particular would cause the world a big headache, if they now vaccinate their population again. They would give XBC* the opportunity to further improve itself, until it becomes ready to take on the rest of the world again. Australia’s high number of hospitalizations over the past few months suggests they’re already suffering the impact of simultaneous circulation of very divergent variants.
We have different serotypes for Dengue, as well as for Rhinovirus, but this is not the end of the world. There’s an important difference however. With Dengue, the body first has a mild immune response to the first infection and then during the second infection it figures out that it’s responding in the wrong manner, ultimately resulting in a variant-independent response that typically prevents any third infection.
With SARS2 it will be much harder for the body to figure out it’s responding in the wrong manner, because it has consistently been re-exposed to the virus many times, both to Spike from the vaccine and from infections.
Just as it’s easier to convince someone he’s doing something wrong if he has only done it once before in his life, than if he has been doing it in that same manner his entire life, it will now be very hard for the immune system to figure out that it’s responding in the wrong way to a novel serotype.
It’s worth keeping in mind that we don’t really know how many serotypes we will end up with. There are four big serotypes of Dengue circulating right now, with a fifth one argued to be coming into existence.
I think we currently face the simultaneous circulation of three serotypes (XBB*, XBC*, and BA.2.86*), but this could change overnight. We could wake up tomorrow and learn that another chronic infection has led to the birth of a fourth serotype in some part of the world. It will take at least a few more months, until we can tell what the impact of simultaneous circulation of these serotypes will be.
What you would expect is that most of the unvaccinated have by now developed a variant-independent antibody response, as well as variant independent trained innate immunity. They would typically have been infected once pre-Omicron and one or more times in the Omicron era.
This is not what you expect to see in the vaccinated however. They generally tried to avoid suffering infection before Omicron and received two or three doses of the exact same Spike protein, a response that was then also deployed against Omicron and gradually shifts over time to adjust to the latest subtly different Omicron variants.
Just as with the failed Dengue vaccination program in the Philippines, the shortcomings of that response tend to become apparent once you’re dealing with two or more very divergent versions of the same virus. You would expect the biggest problems to emerge in people who were vaccinated at least twice before their first COVID infection.