What happens when you vaccinate chickens against influenza?

Something a little different for today. Personally, I am just interested in understanding how the world works. Whether it earns me a buck or validates one ideology or another, is of little concern to me. Humans like to vaccinate themselves, in an effort to prevent the spread of disease. There is a lot I have written about this phenomenon by now, but today I want to look at what happens when we decide to vaccinate the animals that humans eat.

It’s worth pointing out again that our vaccines roughly fall into one of two categories: Live vaccines and inactivated vaccines. The prior are a little riskier and less predictable than the latter, when it comes to the risk of adverse effects. As a consequence live vaccines are increasingly replaced by inactivated vaccines.

This comes with a cost: Whereas live vaccines generally help improve immunity against unrelated pathogens, inactivated vaccines tend to reduce immunity against unrelated pathogens. This can be attributed mostly to training of the innate immune response, which happens when we are exposed to vaccines with live viruses.

Long ago, humans began their vaccination experiment with vaccines against smallpox. We found a related virus called cowpox and discovered that injecting people with this related virus also helped prepare the immune system against smallpox. This was what you might call low-hanging fruit. Smallpox normally kills 30% of people it infects and killed 500 million people during the last century of its existence.

But other viruses are more difficult to deal with. Consider influenza. You’re not going to eradicate influenza off the face of the Earth. It affects many different species, rapidly mutates, rapidly jumps from one species into another species and readily reinfects a given animal after a few years.

When you can’t eradicate a virus, you’ll have to learn to live with it, as hard as that may be for many people to accept. In such a situation, what matters is the behavior of the virus: Does it kill its host or not? The behavior of influenza is governed by a number of factors, including the lives of the animals susceptible to it.

Birds spread influenza around the world, from where it jumps into many different mammals species. In recent months, we’ve seen seal and other mammal species affected, by influenza viruses that jumped over from birds.

To understand why this is happening, it’s important to point out one thing: There are a lot of chickens today. Here you have a chart, of bird biomass:

Measured by weight, chickens are now 57% of all birds in the world. This affects how viruses like influenza behave. When migratory birds spread influenza, they have to be able to survive their long journeys around the world. An influenza virus that makes these birds very sick will struggle to spread itself.

On the other hand, when humans put huge numbers of genetically identical chickens in cages where they all inhale the same air, influenza viruses start behaving differently. Under these circumstances, the influenza virus has no real reason to keep its host alive. In fact, if some mutated version of influenza were to emerge in such a situation, that keeps its host alive by not multiplying as rapidly, it would be rapidly outcompeted by the other variants in the factory farm.

We thus see the emergence of highly pathogenic influenza strains in our factory farms. These variants of influenza have a trait that is only observed to emerge in laboratories and in factory farms, but never in the wild: A polybasic cleavage site. In the wild, influenza viruses in birds tend to be mild and have just a single basic amino acid in their cleavage site. In the factory farms, more basic amino acids emerge, increasing the virulence of the influenza viruses.

Farmers don’t like it when their birds die before earning them money, so we see widespread vaccination of chickens. These vaccines are typically inactivated vaccines, that work by producing a strong antibody response against particular spots on the Hemagglutinin protein.

As the corona virus vaccines so readily demonstrated once Omicron emerged, viruses evolve in response to such antibodies, to avoid them. In Omicron, you can observe the virus began to bind more strongly to the ACE2 receptor. This allowed it to escape a subset of antibodies that bind weakly to the Spike protein. This is called affinity escape.

Affinity escape is different from regular antibody escape. A protein can mutate, so that a particular antibody no longer “fits” the protein. That’s antibody escape. But affinity escape is more sinister: The antibody still “fits” the protein, but the protein now changed to bind more strongly to its receptor, so that the antibody doesn’t manage to bind the protein before it finds the receptor. This is how you breed viruses that spread rapidly from cell to cell.

In an effort to prevent factory farms from becoming breeding grounds for influenza viruses, we vaccinate chickens with inactivated vaccines, that raise concentrations of antibodies against the particular influenza strains that appear to be dominant. This works well, at least initially. But watch how Influenza responds to this attempt, to shut it out of its host:

We characterized 55 influenza A(H9N2) viruses isolated in Pakistan during 2014–2016 and found that the hemagglutinin gene is of the G1 lineage and that internal genes have differentiated into a variety of novel genotypes. Some isolates had up to 4-fold reduction in hemagglutination inhibition titers compared with older viruses. Viruses with hemagglutinin A180T/V substitutions conveyed this antigenic diversity and also caused up to 3,500-fold greater binding to avian-like and >20-fold greater binding to human-like sialic acid receptor analogs. This enhanced binding avidity led to reduced virus replication in primary and continuous cell culture. We confirmed that altered receptor-binding avidity of H9N2 viruses, including enhanced binding to human-like receptors, results in antigenic variation in avian influenza viruses. Consequently, current vaccine formulations might not induce adequate protective immunity in poultry, and emergence of isolates with marked avidity for human-like receptors increases the zoonotic risk.

What does this say, in simple English? Under pressure from vaccine-induced antibodies, the H9N2 influenza virus mutated in a manner that allows it to escape antibodies. A single mutation to the virus results in a need for four times as many antibodies, to neutralize the same amount of viral particles.

The reason this version of the virus does not emerge spontaneously, is because it is less efficient at replicating itself. Unfortunately however, it is intrinsically better capable at binding to receptors needed to enter cells. This is what you would expect of course, from a virus that is very competent at escaping antibodies: It displays the affinity escape phenomenon we know from the SARS2 pandemic.

The problem is that this affinity escape has consequences. The virus does not just get better at binding to the chicken’s receptor, it gets better at binding to various bird versions of this receptor, as well as the human version of this receptor. Through these inactivated vaccines, you are encouraging the birth of a virus that is intrinsically very competent at jumping from chickens into other bird species and even mammal species.

That’s what this study says, so it recommends “new vaccine formulations”. But think carefully for a moment. We’re seeing here the same basic problem we see with the SARS2 virus: We vaccinate an animal to protect it with antibodies. These antibodies don’t bind very strongly, so the virus can escape those antibodies by increasing the strength with which it binds to its receptor. As a result, we end up with a virus that is intrinsically more infectious and thereby develops the ability to jump into other species too.

In the absence of vaccination, this version of the influenza virus does not manage to spread in chickens, because it is intrinsically less capable of reproducing in cells. It’s only through vaccination, that we force the virus into this strategy of affinity escape, where it survives the antibodies by binding more strongly to its receptor, thereby offering it the chance to jump into other species too.

Another study found a similar result, for H5N1: A subset of antibodies against the receptor binding domain of the virus can be easily escaped through a mutation in position 90. This change however, also has the effect of making it much easier to infect humans:

Two important mutations for avian influenza H5N1 HA identified in this study involved aa 90 and aa 160. A mutation at aa position 90 in the H5N1 hemagglutinin (HA), outside the receptor binding domain (RBD), could simultaneously induce a conformational change in the RBD that allowed escape from neutralization as well as a change in receptor preference through long-range regulation. A mutation at aa position 160 in the RBD only induced a change in receptor preference. Other research has also demonstrated that aa position 160 is essential for the receptor specificity [3]. From the results of this study, we could conclude that mutations distant from the RBD can induce a conformational change in the RBD to allow escape from nAbs and change the receptor preference simultaneously. These mutations are deemed “key events”, particularly during interspecies transmission, and they ensure that the original invasion is successful, i.e., the mutation at aa 90 on QH H5N1 HA. They are the result of positive selection caused by antibodies. Some mutations in the RBD could only induce a change in receptor preference, and these are deemed “maintaining adaptations” to ensure that the variants circulate in the new species, i.e., the mutation at aa 160 on QH H5N1 HA. They are the result of adaptation caused by the receptor. After global change of the tip of HA by the aa 90 mutation, and then the local readjustment of RBD by the aa 160 mutation, avian influenza virus would be more suitable for a mammal-like binding pocket, and this would make infection of humans successful. The continuing appearance of these two types of mutations make the variants persist in the new host species.

So rather than remaining adapted for the chickens they infect, antibodies induced by vaccination encourage the highly lethal influenza viruses in chickens to jump the species barrier.

We can see the effects around the world today. Factory farms breed highly lethal influenza viruses, as in the farm conditions the virus has no incentive to keep its host alive. These viruses subsequently mutate to become abnormally infectious, due to antibodies induced by inactivated vaccines. These viruses thus jump into other bird species and eventually spread around the world. Thousands of seals and sea lions around the world are now dying from bird flu as a result.

This is not just extremely disruptive for our ecosystems and cruel towards these animals. It is setting our own species up for a bad situation too. It seems inevitable that at some point, the bird flu that has evolved to become so deadly in chickens, finds out how to spread rapidly within our own species.

Important to note is that something has changed since 2020. Whereas in the past, the biggest viral threat to our lungs was Influenza, today our adaptive immune response in our lungs has been reoriented, towards the new coronavirus. And as I have previously explained, through vaccination with inactive vaccines, we induce an immune response that comes at the cost of our protection against unrelated viruses. This has been documented for non-influenza respiratory infections after inactivated influenza vaccines. You have shifted the immunological landscape in the entire human population, it’s anyone’s guess what the consequences will be.

I’m not claiming to be a genius, endowed with a crystal ball that allows me to tell you exactly what is going to happen. But take a serious and open look at this:

The deadly H5N1 bird flu virus has spread more aggressively than ever before in wild birds and marine mammals since arriving in South America in 2022, raising the risk of it evolving into a bigger threat to humans, according to interviews with eight scientists.

Of more immediate concern is evidence the disease, once largely confined to bird species, appears to be spreading between mammals. This strain has already killed a handful of dolphins in Chile and Peru, some 50,000 seals and sea lions along the coasts, and at least half a million birds regionwide.

You now have these highly lethal forms of bird flu bred in human factory farms, spreading between mammals, disrupting entire ecosystems. And if a year from now we’re all locked up at home again, this time due to highly pathogenic influenza that finally jumped into our own species, it will seem obvious in hindsight.

This is another problem that is in theory entirely preventable. There is simply no reason for humans to produce so many chickens that these animals end up weighing more than all of the world’s wild birds put together. There is no biological need for humans to eat chickens and eggs.

Unfortunately, we’re faced with so many converging catastrophes, that nobody can really be seriously motivated to do anything about any single one of them. It’s also just a fool’s errand, to think you can predict what the next big disaster is going to be. We’re clearly still dealing with a SARS virus, that is rapidly evolving to escape the vaccine induced antibody response.

How that will unfold is anyone’s guess. As I have documented before, molecular evidence suggests this can go very wrong very suddenly, with just two amino acid mutations sufficient to escape most remaining antibodies. Governments and the public are happy to pretend we closed that chapter.

Simultaneously however, we have highly virulent bird flu spreading, that humans bred themselves. Again, the safe bet is to ignore it and expect that nothing special will happen. The general pattern in our society now is to ignore problems until they become so big that we’re forced to think about them.

But it seems to me, that the bird flu experiment could have taught us a lesson when it comes to trying to control rapidly mutating respiratory viruses with inactivated vaccines: It doesn’t work. It means kicking the can down the hall. And in the process, you make the long term outcome that much worse, breeding increasingly deadlier variants that spread into other species.

In a sane society, all this stuff would be shut down. You can’t put 26 billion inbred chickens in giant cages around the world, vaccinate them with bad vaccines and hope that everything will just work out. It means you breed superviruses that end up destabilizing everything.

But in our society, we can’t even get people to agree we need to stop changing our atmosphere. We can’t even get governments to agree on tackling problems, because the world’s major nuclear superpowers are now engaged in war in Ukraine.

It seems to me this is a ticking time bomb. You’ll be considered a fear-mongering doomsday prophet if you point it out. But it will seem obvious in hindsight once it goes off.