COVID mRNA vaccines can be quickly updated for new variants. So, where’s my Omicron booster?


Since Omicron was declared a variant of concern at the end of November, it quickly swept the globe, becoming the dominant COVID variant in many countries including Australia.

It’s the latest in a growing line of variants, and probably not going to be the last.

Yet every one of the hundreds of millions of approved mRNA vaccines administered around the globe were made to their original recipe, which was based on the COVID virus that first emerged in Wuhan.

One of the most promising aspects of the new mRNA COVID vaccines is their ability to be rapidly adjusted for maximum protection in the face of new variants.

So where’s my Omicron booster?

Remind me again: how do mRNA vaccines work?

Vaccines based upon mRNA contain a blueprint in the form of genetic material — called messenger RNA — that, when injected into our muscle, is “read” by our cells.

Using that RNA message as a guide, our cells construct replicas of the spike protein that the SARS-CoV-2 virus uses to infect us.

The freshly built spike proteins are pushed outside the cells, a bit like a flag, alerting the immune system.

In response, a type of white blood cell called B cells pump out antibodies — Y-shaped molecules that form an immune “memory” of the spike.

But as the SARS-CoV-2 virus mutated its genetic code and slightly remoulded its spike protein, it was better able to fly under our immune system’s radar.

The process of tailoring mRNA vaccines for new variants is “very straightforward”, says Archa Fox, an RNA biologist at the University of Western Australia.

“The beauty of the RNA [vaccine] platform is that you can very easily change the DNA template that you use to make the RNA.

“It’s the bread and butter of biochemists and molecular biologists, so very routine for [vaccine] companies.”

Large companies such as Pfizer and Moderna can feasibly make an Omicron-specific vaccine for testing within a week or so, says Colin Pouton, a pharmaceutical biologist at Monash University.

“And if an Omicron vaccine is going to be any good to you and I, it has to produce new antibodies against Omicron.”

So first, they test if the Omicron vaccine does that in mice.

“But if you do animal experiments [with an Omicron-specific booster shot], and look for protection against Omicron, an Omicron version of their vaccine actually doesn’t do any better than the original Wuhan vaccine,” Professor Pouton says.

So, what’s going on?

Slight spanner in the immune works

Giving a person (or mouse) multiple vaccines with ever-so-slight differences in their makeup can cause a phenomenon called “immunological imprinting”.

“When you give a vaccine, you prime the immune response to produce antibodies … then you boost it by giving a second dose or a third dose,” Professor Pouton says.

But if you’re then vaccinated against a slightly different variant, you might make fewer antibodies that specifically work on that new viral variant.

That’s because, when confronted with a similar vaccine, your immune system prefers to recruit existing antibody-producing B cells back into action, rather than develop new ones.

(This also happens with the seasonal flu vaccine, and is partly why it’s only partially effective. But you should still get it.)

And not all antibodies are created equal.

Our immune system, when presented with a spike protein, gets to work making antibodies that recognise and attach to many different parts of the spike.

Antibodies that help stop a virus from infecting cells are called neutralising antibodies.

We want these, and they work by blocking the very end of a virus’s spike protein, called the “receptor-binding domain”.

This is the bit that latches onto ACE2 receptors on our cells (hence “receptor binding”), and allows the virus to slip inside.

Another way to think of it is to imagine the spike protein is an arm, and the very end section is a hand that can grab hold of and twist open the ACE2 door handle.

If you get a really big, oversized clothes peg — this is a neutralising antibody — and clamp it onto the palm of the “hand” or between its fingers, you have a physical barrier between the hand and the door handle, and it won’t be able to open the door and infect the cell.

Pegs that prefer to dangle off the elbow or up near the shoulder won’t do much to stop the hand from working. These pegs are our non-neutralising antibodies.

And non-neutralising antibodies make up the lion’s share of COVID-vaccine-generated antibodies, says Dale Godfrey, an immunologist at the Peter Doherty Institute for Infection and Immunity.

“Only about 10-20 per cent of antibodies bind the receptor-binding domain compared to the rest of the spike protein when people are immunised with whole-spike vaccine.”

So, how do we get around this?

Scientists are looking for ways to beef up neutralising antibodies while avoiding immunological imprinting.

One way to do this is to make “slimmed down” versions of variant-specific vaccines.

Professors Pouton and Godfrey are involved in a trial of two such vaccines.

One is an mRNA vaccine, which contains instructions for our cells to make only the receptor-binding domain and not the rest of the spike, and the other comprises lab-made receptor-binding domain proteins.

“We’re trying to say [to the immune system], ‘here’s a new target which you haven’t seen before,'” Professor Pouton says.

“Don’t bother making all those antibodies to the rest of the spike protein — just to the new receptor-binding domain.”

The vaccines in the trial are based on the Beta variant, as that was the variant of concern when the project began.

The Beta variant shares some of Omicron’s mutations, Professor Godfrey says.

“As to whether this means the vaccine will provide superior protection against Omicron, we think and hope so, but don’t know yet.”

Pfizer and Moderna are continuing with clinical trials to see how their Omicron-specific whole-spike vaccines fare in people.

Moderna is also trialling a “bivalent” version that combines the original vaccine, as well as the new Omicron-specific spike mRNA.

We might not have to wait too long to find out how well they work.

A Pfizer spokesperson said they would share next-generation vaccine data “in the coming weeks”.

A Moderna spokesperson said the company expected to have first data on the bivalent vaccine this month “to inform selection of its candidate for the northern hemisphere [autumn] 2022 booster”.

Moderna is also in phase one trials of a receptor-binding-domain-specific Omicron booster, Professor Pouton says, but it’s very early days.

Eventually, he adds, the hope is COVID vaccines could become routine seasonal vaccines, like the yearly flu shot, and won’t need to run the clinical trial gauntlet each time.

“It’s still not certain whether we will need annual vaccines, but a lot of people would say we probably will — maybe not everyone, but certainly vulnerable people or ageing people.”

ABC News, 6 June 2022